CN114478528A

CN114478528A - Aroyl-substituted tricyclic compound, preparation method and application thereof

Info

Publication number: CN114478528A
Application number: CN202111256015.0A
Authority: CN
Inventors: 周福生; 蒋涛; 刘颖涛; 林崇懒; 彭灵; 张磊涛; 刘柱博; 蔡礼健; 徐晓明; 兰炯
Original assignee: Genfleet Therapeutics Shanghai Inc; Zhejiang Genfleet Therapeutics Co Ltd
Current assignee: Genfleet Therapeutics Shanghai Inc; Zhejiang Genfleet Therapeutics Co Ltd
Priority date: 2020-10-28
Filing date: 2021-10-27
Publication date: 2022-05-13

Abstract

The invention discloses an aromatic formyl substituted tricyclic compound with an inhibiting effect on BTK or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, which is shown as a formula I, wherein the definitions of all groups in the formula are detailed in the specification. In addition, the invention also discloses a pharmaceutical composition containing the compound and application thereof in preparing medicines for diseases or symptoms related to BTK and/or abnormal B cell activation.

Description

Aroyl substituted tricyclic compound and its preparation method and use

Technical Field

The invention belongs to the field of medicines, and particularly relates to an aroyl-substituted tricyclic compound, and a preparation method and application thereof.

Background

Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of non-receptor tyrosine kinases, a key kinase in the B cell antigen receptor (BCR) signaling pathway. The signals emitted by the BCR control a series of effector responses, including activation, proliferation and differentiation of mature antibody-producing cells. Aberrant BCR-mediated signal transduction can lead to misregulated B cell activation and/or the formation of pathogenic autoantibodies, resulting in a variety of human diseases, including cancer, autoimmune diseases, and heteroimmune diseases. Ibrutinib (Ibrutinib, trade name immvacica) has enjoyed great success as the first BTK inhibitor to enter the market. However, as with many other anticancer drugs, some patients exhibit drug resistance to the drug. The C481S mutation of BTK kinase is found to be the main reason for drug resistance, ibrutinib is pharmacodynamically effective through irreversible covalent binding with the C481 tryptophan residue of BTK kinase, and the C481S mutation changes tryptophan into serine so as to lose the ability to covalently bind to ibrutinib. In view of the above, there remains a need in the art to develop more potent inhibitors against BTK.

Disclosure of Invention

The invention provides an aroyl substituted tricyclic compound which is used as a BTK inhibitor and has the advantages of high activity, good selectivity, low toxic and side effects and the like.

A first aspect of the invention is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

in the formula (I), the compound is shown in the specification,

G₃、G₄、G₅and G₆Is selected from the group consisting of:

(1)G₃is N; g₄Is CH; g₅Is CR₁；G₆Is N or CR₂；

(2)G₃Is C; g₄Is NH or CH₂；G₅Is CR₁、NR₃Or CR₄R₅；G₆Is N, CR₂Or C (═ O);

in the above-mentioned respective groups, the first and second groups,

R₁、R₃each independently selected from: H. c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-20Cycloalkyl, 3-to 20-membered heterocyclyl, -C_1-4Alkyl-cyano, -C_1-4Alkyl-hydroxy, -C_1-4Alkyl-amino, -C_1-4Alkyl-carboxy, -C_1-4alkyl-C_3-20Cycloalkyl, -C_1-4Alkyl-3 to 20 membered heteroA cyclic group; the 3-to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C is_1-6Alkyl radical, said C_2-6Alkenyl radical, said C_2-6Alkynyl, said C_3-20Cycloalkyl, said 3-to 20-membered heterocyclyl, said hydroxy, said cyano, said carboxy each independently being unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1;

R₂each independently selected from: H. cyano, halogen, nitro, carboxyl, hydroxy, C _1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-20Cycloalkyl, 3-to 20-membered heterocyclyl, -C_1-4Alkyl-cyano, -C_1-4Alkyl-hydroxy, -C_1-4Alkyl-amino, -C_1-4Alkyl-carboxy, -C_1-4alkyl-C_3-20Cycloalkyl, -C_1-4Alkyl-3 to 20 membered heterocyclyl; the 3-to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C is_1-6Alkyl radical, said C_2-6Alkenyl radical, said C_2-6Alkynyl, said C_3-20Cycloalkyl, said 3-to 20-membered heterocyclyl, said hydroxy, said cyano, said carboxy each independently being unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1;

R₄、R₅each independently selected from: H. c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-20Cycloalkyl, 3-to 20-membered heterocyclyl, -C_1-4Alkyl-cyano, -C_1-4Alkyl-hydroxy, -C_1-4Alkyl-amino, -C_1-4Alkyl-carboxy, -C_1-4alkyl-C_3-20Cycloalkyl, -C_1-4Alkyl-3 to 20 membered heterocyclyl; or R₄And R₅Together with the carbon atom to which they are attached form C_3-20Cycloalkyl or 3 to 20 membered heterocyclyl; the 3-to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C is_1-6Alkyl radical, said C_2-6Alkenyl radical, said C_2-6Alkynyl, said C_3-20Cycloalkyl, said 3-to 20-membered heterocyclyl, said hydroxy, said cyano, said Each carboxyl group is independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1;

a is CR₆Or N; wherein R is₆Is H, halogen, -C_1-6Alkyl, -halo C_1-6Alkyl, deuterated C_1-6Alkyl or-C_3-6A cycloalkyl group;

b is CR₇Or N; wherein R is₇Is H, halogen, -C_1-6Alkyl, -halo C_1-6Alkyl, deuterated C_1-6Alkyl or-C_3-6A cycloalkyl group;

G₁is C_6-14Aryl, 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl; wherein the 5-or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 8-to 10-membered bicyclic heteroaryl has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring atoms; and said C is_6-14Aryl, said 5 or 6 membered monocyclic heteroaryl or said 8 to 10 membered bicyclic heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2;

G₂is C_6-14Aryl, 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl; wherein the 5-or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 8-to 10-membered bicyclic heteroaryl has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring atoms; and said C is_6-14Aryl, said 5 or 6 membered monocyclic heteroaryl or said 8 to 10 membered bicyclic heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2;

L is a bond, CR⁸R⁹、O、NH、NHC(O)、C_1-2alkyl-NHC (O) or NHC (O) -C_1-2An alkyl group; wherein R is⁸、R⁹Each independently of the others being H, halogen, hydroxy, cyano, -C_1-6Alkyl, -halo C_1-6Alkyl, -deuterated C_1-6Alkyl, -C_1-6Alkoxy, -halo C_1-6Alkoxy, -deuterated C_1-6Alkoxy, -C_3-6Monocyclic cycloalkyl, -C_1-4Alkyl-hydroxy, -C_1-4An alkyl-cyano group,-C_1-4alkyl-C_1-6Alkoxy, -C_1-4Alkyl-halo C_1-6Alkyl, -C_1-4Alkyl-halo C_1-6Alkoxy, -C_1-4alkyl-C_3-6Monocyclic cycloalkyl, -C_1-4alkyl-NR^aR^b、-C_1-4alkyl-C (O) NR^aR^b、-C_1-4alkyl-SO₂C_1-3Alkyl, -C_1-4Alkyl-carboxy;

each of the groups of group S1 or S2 independently comprises: deuterium, halogen, cyano, hydroxy, carboxy, nitro, -C_1-6Alkyl, -halo C_1-6Alkyl, -deuterated C_1-6Alkyl, -C_1-6Alkoxy, -halo C_1-6Alkoxy, -deuterated C_1-6Alkoxy, -C_3-6Monocyclic cycloalkyl, -halo C_3-6Monocyclic cycloalkyl, -O-C_3-6Monocyclic cycloalkyl, 3-to 6-membered monocyclic heterocyclyl, -C_1-4Alkyl-hydroxy, -C_1-4Alkyl-cyano, -C_1-4alkyl-C_1-6Alkoxy, -C_1-4Alkyl-halo C_1-6Alkyl, -C_1-4Alkyl-halo C_1-6Alkoxy, -C_1-4alkyl-C_3-6Monocyclic cycloalkyl, -C_1-4Alkyl-3 to 6 membered monocyclic heterocyclyl, -C_1-4alkyl-NR^aR^b、-C_1-4alkyl-C (O) NR^aR^b、-C_1-4alkyl-SO₂C_1-3Alkyl, -C_1-4Alkyl-carboxy, -C (O) C_1-6Alkyl, -C (O) OC _1-6Alkyl, -C (O) C_3-6Monocyclic cycloalkyl, -C (O) NR^aR^b、-C(O)-C_1-4alkyl-NR^aR^b、-NHC(O)R^c、-NHC(O)OR^c、-NR^aR^b、-SO₂C_1-3An alkyl group; the 3-to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

in each of the above groups, R^a、R^bEach independently is H, C_1-6Alkyl, deuterated C_1-6Alkyl radical, C_3-6Monocyclic cycloalkyl, -C_1-4alkyl-C_1-6Alkoxy radical,3-to 6-membered monocyclic heterocyclyl, -C_1-4Alkyl-3 to 6 membered monocyclic heterocyclyl, C (O) C_1-6An alkyl group; wherein the 3-to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and said 3-to 6-membered monocyclic heterocyclyl is optionally substituted with 1 or 2 groups selected from: c_1-6An alkyl group; or

In each of the above groups, R^a、R^bTogether with the nitrogen atom to which they are attached form a 3-to 6-membered nitrogen-containing heterocyclic group; wherein the 3-to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms; and said 3-to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from: c_1-6An alkyl group;

in each of the above groups, R^cIs hydrogen, C_1-6Alkyl or halo C_1-6An alkyl group.

In one embodiment, the compound has the structure of formula (II):

in the formula, G₄₁Is NH or CH₂(ii) a When in use

When it is a double bond, G ₆₁Is N or CR₂；G₅₁Is CR₁(ii) a When in use

When it is a single bond, G₆₁Is C (═ O); g₅₁Is NR₃Or CR₄R₅；R₁、R₂、R₃、R₄、R₅、A、B、L、G₁、G₂The definitions are the same as those of each group in the formula (I).

In one embodiment, the compound has the structure of formula (III):

in the formula, A, B, L, G₁、G₂、R₁Definition ofThe same as the definition of each group in the formula (I).

In one embodiment, the compound has a structure represented by formula (IIa):

in the formula, G₆₁Is N or CR₂；R₁、R₂、A、B、L、G₁、G₂The definitions are the same as those of the radicals in the formula (II).

In one embodiment, the compound has the structure of formula (IIb):

in the formula, G₄₁Is NH or CH₂；G₅₁Is NR₃Or CR₄R₅；R₃、R₄、R₅、A、B、L、G₁、G₂The definitions are the same as those of the radicals in the formula (II).

In one embodiment, the compound has a structure represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), or formula (II-5):

in the formulae, R₁、R₂、R₃、R₄、R₅、L、G₁、G₂The definitions are the same as those of the radicals in the formula (II).

In one embodiment, the compound of formula (II-1) is a compound having a structure represented by formula (II-1A) or formula (II-1B):

in the formulae, R₁、R₂、L、G₁、G₂The definitions are the same as those of the radicals in the formula (II).

In one embodiment, the compound of formula (II-2) is a compound having a structure represented by formula (II-2A) or formula (II-2B):

in the formulae, R₁、L、G₁、G₂The definitions are the same as those of the radicals in the formula (II).

In one embodiment, the compound of formula (II-3) is a compound having a structure represented by formula (II-3A) or formula (II-3B):

In the formulae, R₃、L、G₁、G₂The definitions are the same as those of the radicals in the formula (II).

In one embodiment, the compound of formula (II-5) is a compound having a structure represented by formula (II-5A) or formula (II-5B):

In one embodiment, G in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₁And G₂Are all unsubstituted.

In one embodiment, in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5), G₁Is unsubstituted, G₂Substituted with 1, 2, 3 or 4 groups independently selected from group S2.

In one embodiment, G in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₁Substituted with 1, 2, 3 or 4 groups independently selected from group S2; g₂Is unsubstituted.

In one embodiment, G in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₁And G₂Each independently substituted with 1, 2, 3 or 4 groups independently selected from group S2.

In one embodiment, G in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₁Is phenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, thiazolyl or pyrazolyl; said phenyl, said pyridyl, said pyrimidinyl, said furanyl, said pyrrolyl, said thiazolyl or said pyrazolyl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2.

In one embodiment, G in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₁Is phenyl or pyridyl; said phenyl or said pyridyl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2.

In one embodiment, G in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₁Is phenyl or pyridyl; said phenyl or said pyridyl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2; wherein the groups of group S2 include: fluorine, chlorine, -C_1-3Alkyl, -halo C_1-3Alkyl, -C _3-6A monocyclic cycloalkyl group.

In one embodiment, G in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₂Is phenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, thiazolyl or pyrazolyl; said phenyl, said pyridyl, said pyrimidinyl, said furanyl, said pyrrolyl, said thiazolyl or said pyrazolyl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2.

In one embodiment, formula (I), formula (II), formula (III)(III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5), G₂Is phenyl or pyridyl; said phenyl or said pyridyl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2.

In one embodiment, G in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₂Is phenyl or pyridyl; said phenyl or said pyridyl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2; wherein the groups of group S2 include: fluorine, chlorine, -C _1-3Alkyl, -halo C_1-3Alkyl, -C_3-6A monocyclic cycloalkyl group.

In one embodiment, G in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₁Is phenyl, and said phenyl is substituted with fluoro or chloro; g₂Is phenyl or pyridyl, and said phenyl or said pyridyl is unsubstituted or substituted by fluoro, chloro, methyl, trifluoromethyl or cyclopropyl.

In one embodiment, G in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₁Is phenyl and said phenyl is substituted with fluoro or chloro; g₂Is phenyl and said phenyl is unsubstituted or substituted by fluorine, chlorine, methyl, trifluoromethyl or cyclopropyl.

In one embodiment, G in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₁Is phenyl and said phenyl is substituted with fluoro or chloro; g₂Is a pyridyl group and the pyridyl group is unsubstituted or substituted by fluorine, chlorine, methyl, trifluoromethyl or cyclopropyl.

In one embodiment, G in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5) ₁Selected from the group consisting of:

in the formulae, R₁₁Each independently is cyano, hydroxy, halogen, C_1-6Alkyl, halo C_1-6Alkyl, deuterated C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, deuterated C_1-6An alkoxy group. In the formula (I), the compound is shown in the specification,

meaning that the group is linked to the rest of the compound by the single bond.

An unspecified position indicates that the moiety may be attached to the rest of the compound through any ring atom on the group.

In one embodiment, G in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₂Selected from the group consisting of:

In one embodiment, R in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₁、R₃Each independently selected from: H. c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl radical 、C_3-20Cycloalkyl, 3-to 20-membered heterocyclyl, -CH₂-cyano, -CH₂-hydroxy, -CH₂-amino, -CH₂-carboxy, -CH₂-C_3-20Cycloalkyl, -CH₂-a 3 to 20 membered heterocyclyl; the 3-to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C is_1-6Alkyl radical, said C_2-6Alkenyl radical, said C_2-6Alkynyl, said C_3-20Cycloalkyl, said 3-to 20-membered heterocyclyl, said hydroxy, said cyano, said carboxy are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1.

In one embodiment, R in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₁、R₃Each independently selected from: H. c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, 3-to 20-membered heterocyclyl; the 3-to 20-membered heterocyclyl is selected from the group consisting of: 3-to 8-membered monocyclic heterocyclic group, 5-to 20-membered spiro heterocyclic group, 5-to 20-membered fused heterocyclic group, 5-to 20-membered bridged heterocyclic group; said C is_1-6Alkyl radical, said C_2-6Alkenyl radical, said C_2-6Alkynyl, said C_3-6Cycloalkyl, said 3 to 20 membered heterocyclyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1.

In one embodiment, R in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5) ₁、R₃Each independently selected from: H. c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-20Cycloalkyl, 3-to 20-membered heterocyclyl; said C is_1-6The alkyl group is selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; said C is_3-20The cycloalkyl group is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the 3-to 20-membered heterocyclyl is selected from the group consisting of: oxetanyl, azetidinyl, tetrahydropyrrole, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, morpholinyl, 6-to 14-memberedFused heterocyclic groups, 6 to 14 membered spiroheterocyclic groups; said C is_1-6Alkyl radical, said C_2-6Alkenyl radical, said C_2-6Alkynyl, said C_3-20Cycloalkyl, said 3 to 20 membered heterocyclyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1.

In one embodiment, in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), each R is₁Each independently selected from: c_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 20-membered heterocyclyl; the 3-to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C is_1-6Alkyl radical, said C_3-6Cycloalkyl, said 3 to 20 membered heterocyclyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1; the groups of group S1 include: deuterium, halogen, cyano, hydroxy, -C _1-6Alkyl, -halo C_1-6Alkyl, -deuterated C_1-6Alkyl, -C_1-6Alkoxy, -halo C_1-6Alkoxy, -deuterated C_1-6Alkoxy, -C_3-6Monocyclic cycloalkyl, 3-to 6-membered monocyclic heterocyclyl, -C_1-4Alkyl-hydroxy, -C_1-4Alkyl-cyano, -C (O) C_1-6Alkyl, -C (O) OC_1-6Alkyl, -C (O) -C_1-4alkyl-NR^aR^b、-NHC(O)OR^c、-NR^aR^b、-SO₂C_1-3An alkyl group; the 3-to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

in each of the above groups, R^a、R^bEach independently is H, C_1-6Alkyl or deuterated C_1-6An alkyl group; or R^a、R^bTogether with the nitrogen atom to which they are attached form a 3-to 6-membered nitrogen-containing heterocyclic group; wherein the 3-to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms;

in each of the above groups, R^cIs C_1-6Alkyl or halo C_1-6An alkyl group.

In one embodiment, formula (I), formula (II)In the formula (III), the formula (IIa), the formula (IIb), the formula (II-1) and the formula (II-2), each R₁Each independently selected from: methyl, ethyl, isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, pyranyl, tetrahydropyranyl, morpholinyl, tetrahydropyrrolyl, azetidinyl, tetrahydrofuranyl, 3-azabicyclo [3.1.0]Cyclohexyl, 2-azaspiro [3.5 ]]Nonane, 2-oxaspiro [3.5 ] ]Nonane, 2-oxaspiro [4.5 ]]Decane, 2-azaspiro [4.5 ]]Decane; r₁Is unsubstituted or substituted with 1 or 2 groups independently selected from group S1; the groups of group S1 include: methyl, trifluoromethyl, methoxy, trifluoromethoxy, -SO₂CH₃、-C(O)CH₃、-C(O)OCH₃、-C(O)-CH₂-morpholine, NH₂OH, morpholinyl, tetrahydropyrrolyl, -CH₂-hydroxy, cyano, CH₂-cyano, dimethylamino.

In one embodiment, in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), each R is₁Each independently selected from:

in one embodiment, in formula (I), formula (II), formula (IIa), formula (IIb), formula (II-3), formula (II-5), each R₃Each independently selected from: c_1-6Alkyl radical, C_3-6Cycloalkyl, 3-to 20-membered heterocyclyl; the 3-to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C is_1-6Alkyl radical, said C_3-6Cycloalkyl, said 3 to 20 membered heterocyclyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1; the groups of group S1 include: deuterium, halogen, cyano, hydroxy, -C_1-6Alkyl, -halo C_1-6Alkyl, -deuterated C_1-6Alkyl, -C (O) OC_1-6An alkyl group.

In one embodiment, formula (I), formula (II), formula (IIa), formula (IIb), formula (II-3) ) In the formula (II-5), each R₃Each independently selected from: piperidinyl, tetrahydropyranyl, methyl, ethyl, n-propyl, isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-azabicyclo [3.1.0]Cyclohexyl, 2-azaspiro [3.5 ]]Nonane, 2-oxaspiro [3.5 ]]Nonane, 2-oxaspiro [4.5 ]]Decane, 2-azaspiro [4.5 ]]Decane; r₃Is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1; the groups of group S1 include: methyl, cyano, -C (O) OCH₃。

In one embodiment, in formula (I), formula (II), formula (IIa), formula (IIb), formula (II-3), formula (II-5), each R₃Each independently selected from:

in one embodiment, in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), each R is₁、R₃Each independently selected from:

R₁₁selected from the group consisting of: deuterium, halogen, cyano, hydroxy, -C_1-6Alkyl, -halo C_1-6Alkyl, -deuterated C_1-6Alkyl, -C_1-6Alkoxy, -halo C_1-6Alkoxy, -deuterated C_1-6Alkoxy, -C_3-6Monocyclic cycloalkyl, 3-to 6-membered monocyclic heterocyclyl, -C_1-4Alkyl-hydroxy, -C_1-4Alkyl-cyano, -C (O) C_1-6Alkyl, -C (O) OC_1-6Alkyl, -C (O) -C_1-4alkyl-NR^aR^b、-NHC(O)OR^c、-NR^aR^b、-SO₂C_1-3An alkyl group; the 3-to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

in each of the above groups, R^cIs C_1-6Alkyl or halo C_1-6An alkyl group.

In one embodiment, R₁₁Selected from the group consisting of: methyl, trifluoromethyl, methoxy, trifluoromethoxy, -SO₂CH₃、-C(O)CH₃、-C(O)OCH₃、-C(O)-CH₂-morpholine, NH₂Hydroxy, morpholinyl, tetrahydropyrrolyl, -CH₂-hydroxy, cyano, CH₂-cyano, dimethylamino.

In one embodiment, R in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₄、R₅Each independently selected from: H. c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-20Cycloalkyl, 3-to 20-membered heterocyclyl, -CH₂-cyano, -CH₂-hydroxy, -CH₂-amino, -CH₂-carboxy, -CH₂-C_3-20Cycloalkyl, -CH₂-a 3 to 20 membered heterocyclyl; or R₄And R₅Together with the carbon atom to which they are attached form C_3-20Cycloalkyl or 3 to 20 membered heterocyclyl; the 3-to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C is _1-6Alkyl radical, said C_2-6Alkenyl, said C_2-6Alkynyl, said C_3-20Cycloalkyl, said 3-to 20-membered heterocyclyl, said hydroxy, said cyano, said carboxy are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1.

In one embodiment, formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3)In the formula (II-4) or the formula (II-5), R₄、R₅Each independently selected from: c_1-6An alkyl group; or R₄And R₅Together with the carbon atom to which they are attached form C_3-20Cycloalkyl or 3 to 20 membered heterocyclyl; the 3-to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C is_1-6Alkyl radical, said C_3-20Cycloalkyl, said 3 to 20 membered heterocyclyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1.

In one embodiment, R in formula (I), formula (II), formula (IIa), formula (IIb), formula (II-4)₄、R₅Each independently selected from: c_1-6An alkyl group; or R₄And R₅Together with the carbon atom to which they are attached form a 3-to 6-membered heterocyclic group; the 3-to 6-membered heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms.

In one embodiment, R in formula (I), formula (II), formula (IIa), formula (IIb), formula (II-4) ₄、R₅Each independently is methyl.

In one embodiment, R in formula (I), formula (II), formula (IIa), formula (IIb), formula (II-4)₄And R₅Together with the carbon atom to which they are attached form a 6-membered heterocyclic group; the 6-membered heterocyclic group has 1 heteroatom selected from N, O as a ring atom. Preferably, the 6-membered heterocyclic group is

In one embodiment, R in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5)₂Each independently is cyano.

In one embodiment, L is a bond.

In one embodiment, in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5), L is CR⁸R⁹(ii) a Wherein R is⁸、R⁹Each independently is H, -C_1-6Alkyl, -halo C_1-6Alkyl, -deuterated C_1-6Alkyl, -C_1-6Alkoxy, -halo C_1-6Alkoxy, -deuterated C_1-6Alkoxy, -C_1-4Alkyl-hydroxy, -C_1-4Alkyl-cyano, -C_1-4alkyl-C_1-6Alkoxy, -C_1-4Alkyl-halo C_1-6Alkyl, -C_1-4Alkyl-halo C_1-6An alkoxy group.

In one embodiment, in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5), L is CH ₂。

In one embodiment, in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5), L is O.

In one embodiment, in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5), L is NH.

In one embodiment, in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4), or formula (II-5), L is NHC (O).

In one embodiment, in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5), L is CH₂NHC(O)。

In one embodiment, in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5), L is NHC (O) CH₂。

In one embodiment, in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5), A is CH; b is CH.

In one embodiment, in each group, C_3-20Cycloalkyl is each independently C_3-10Cycloalkyl (preferably, is C)_3-8Cycloalkyl or C_3-6Cycloalkyl groups).

In one embodiment, the 3-to 20-membered heterocyclic group in each group is each independently a 3-to 8-membered monocyclic heterocyclic group (preferably a 3-to 6-membered monocyclic heterocyclic group), a 5-to 20-membered fused heterocyclic group (preferably a 6-to 14-membered fused heterocyclic group), a 5-to 20-membered spiroheterocyclic group (preferably a 6-to 14-membered spiroheterocyclic group), or a 5-to 20-membered bridged heterocyclic group (preferably a 6-to 14-membered bridged heterocyclic group).

In one embodiment, the groups of group S1 include: -SO₂C_1-3Alkyl, -C (O) C_1-6Alkyl, -C_1-6Alkyl, -C (O) -C_1-4alkyl-NR^aR^b、-C(O)OC_1-6Alkyl, -NHC (O) OR^c、-NR^aR^bHydroxy, 3-to 6-membered monocyclic heterocyclyl, -NHC (O) R^c、-C_1-4Alkyl-hydroxy, -C_1-6Alkoxy, -halo C_1-6Alkyl, cyano; wherein the 3-to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and said 3-to 6-membered monocyclic heterocyclyl is optionally substituted with 1 or 2 groups selected from: c_1-6An alkyl group; or R^a、R^bTogether with the nitrogen atom to which they are attached form a 3-to 6-membered nitrogen-containing heterocyclic group; wherein the 3-to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms; and said 3-to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from: c_1-6An alkyl group; r ^cIs hydrogen, C_1-6Alkyl or halo C_1-6An alkyl group.

In one embodiment, the groups of group S1 include: -SO₂CH₃、-C(O)CH₃、-CH₃、-C(O)CH₂NR^aR^b、-C(O)O(CH₃)₃、-NHC(O)O(CH₃)₃、-NH₂Hydroxy, 3-to 6-membered monocyclic heterocyclyl, -NHC (O) CH₃、-CH₂-hydroxy, -OCH₃、-CF₃A cyano group; wherein the 3-to 6-membered monocyclic heterocyclyl is morpholinyl or tetrahydropyrrolyl; and said 3-to 6-membered monocyclic heterocyclyl is optionally substituted with 1 or 2 groups selected from: c_1-6An alkyl group; or R^a、R^bTogether with the nitrogen atom to which they are attached form a 3-to 6-membered nitrogen containingA heterocyclic group; wherein the 3-to 6-membered nitrogen-containing heterocyclic group is morpholinyl; and said 3-to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from: c_1-6An alkyl group; r^cIs hydrogen, C_1-6Alkyl or halo C_1-6An alkyl group.

In one embodiment, the groups of group S2 include: fluorine, chlorine, -C_1-3Alkyl, -halo C_1-3Alkyl, -C_3-6A monocyclic cycloalkyl group.

In one embodiment, the groups of group S2 include: fluorine, chlorine, methyl, trifluoromethyl, cyclopropyl.

In one embodiment, each formula₁、R₂、R₃、R₄、R₅、A、B、G₁、L、G₂、G₃、G₄、G₅、G₆、G₄₁、G₅₁、G₆₁Each independently is the corresponding group in each particular compound in the examples.

In one embodiment, in formula (I), formula (II), formula (III), formula (IIa), formula (IIb), formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5),

Is composed of

In one embodiment, the compound of formula (I) is selected from the compounds prepared in the examples herein. For example selected from compounds Z1 to Z65 and their individual stereoisomers.

In one embodiment, the compound of formula (I) is selected from the group consisting of:

in a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable carrier.

As used herein, the term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium representative of a vehicle capable of delivering an effective amount of an active agent of the present invention, without interfering with the biological activity of the active agent and without toxic side effects to the host or subject, including water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. These include suspending agents, viscosity enhancers, skin penetration enhancers, and the like. Their preparation is known to those skilled in the cosmetic or topical pharmaceutical field.

In an embodiment of the invention, the pharmaceutical composition may be administered in any of the following ways: oral, aerosol inhalation, rectal, nasal, buccal, topical, parenteral, e.g. subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or via an external reservoir. Among them, oral, intraperitoneal or intravenous administration is preferable. When administered orally, the compounds of the present invention may be formulated in any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions or suspensions. Carriers for tablets typically include lactose and corn starch, and additionally, lubricating agents such as magnesium stearate may be added. Diluents used in capsule formulations generally include lactose and dried corn starch. Aqueous suspension formulations are generally prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, sweetening, flavoring or coloring agents may be added to the above oral dosage forms. When applied topically, particularly for treating affected surfaces or organs that are easily accessible by topical application, such as the eye, skin or lower intestinal tract, the compounds of the invention can be formulated in different topical formulations depending on the affected surface or organ, and when applied topically to the eye, the compounds of the invention can be formulated as a micronized suspension or solution in sterile saline at a pH that is isotonic, with or without the addition of a preservative such as benzylalkenoxide. For ophthalmic use, the compounds may also be formulated in the form of ointments such as vaseline. When applied topically to the skin, the compounds of the present invention may be formulated in a suitable ointment, lotion, or cream formulation, in which the active ingredient is suspended or dissolved in one or more carriers. Carriers that may be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The compounds of the present invention may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oleaginous suspensions or solutions. Carriers and solvents that may be used include water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oil may also be used as a solvent or suspending medium, such as a monoglyceride or diglyceride.

In another aspect, the present invention provides a compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition of the second aspect, for use in the preparation of a medicament for the prevention and/or treatment of a disease or condition; the disease or disorder is associated with BTK and/or with aberrant B-cell activation.

In one embodiment, the disease or condition is selected from the group consisting of: xenogenic immune diseases, autoimmune diseases, inflammatory diseases, cancer.

In one embodiment, the xenoimmune disease, autoimmune disease, inflammatory disease may be selected from the group consisting of: rheumatic diseases, glomerulonephritis, Goodpasture's syndrome, atherosclerosis, autoimmune blood disorders, autoimmune gastritis, autoimmune inflammatory bowel disease, irritable bowel syndrome, allograft rejection, chronic thyroiditis, graves ' disease, sjogren's disease, scleroderma, diabetes, hepatitis, pancreatitis, primary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, dermatomyositis, contact dermatitis, eczema, vasculitis, chronic renal insufficiency, Stevens-Johnson syndrome, inflammatory pain, idiopathic diarrhea, cachexia, sarcoidosis, Guillain-Barre syndrome, uveitis, conjunctivitis, otitis media, periodontal disease, parkinson's disease, alzheimer's disease, septic shock, interstitial fibrosis of the lung, asthma, bronchitis, rhinitis, sinusitis, Pneumoconiosis, pulmonary insufficiency syndrome, emphysema, pulmonary fibrosis, chronic inflammatory lung disease and other inflammatory or obstructive diseases on the airways.

In one embodiment, the cancer is leukemia or lymphoma.

In one embodiment, the cancer may be selected from the group consisting of: small Lymphocytic Lymphoma (SLL), Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), acute promyelocytic leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, fahrenheit macroglobulinemia, follicular lymphoma, multiple myeloma, Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), non-hodgkin's lymphoma.

In another aspect, the present invention provides the use of a compound according to the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect, as described above, for the preparation of a BTK inhibitor.

In another aspect, the present invention provides a method for treating cancer, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or any combination thereof, or a pharmaceutical composition of the second aspect.

Herein, the term "subject" refers to an animal, in particular a mammal. Preferably a human.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. In embodiments of the invention, where a patient is treated according to the invention, the amount of a given drug will depend on factors such as the particular dosing regimen, the type of disease or disorder and its severity, the uniqueness (e.g., body weight) of the subject or host in need of treatment, however, the dosage administered may be routinely determined by methods known in the art depending on the particular circumstances, including, for example, the particular drug that has been employed, the route of administration, the disorder being treated, and the subject or host being treated. In general, for dosages used for adult human therapy, dosages administered will typically range from 0.02 to 5000 mg/day, for example from about 1 to 1500 mg/day. The desired dose may conveniently be presented as a single dose, or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example two, three, four or more divided doses per day. It will be appreciated by those skilled in the art that, notwithstanding the dosage ranges set forth above, the specific effective amounts may be adjusted as appropriate to the circumstances of the patient and in conjunction with the diagnosis by the physician.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and that has the pharmacological activity of the parent compound. Such salts include: acid addition salts with inorganic acids such as nitric acid, carbonic acid, etc., or with organic acids; such organic acids as gluconic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present on the parent compound is replaced by a metal ion, e.g., an alkali metal ion or an alkaline earth metal ion; or a complex compound with an organic base such as ethanolamine, etc. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.

As used herein, the terms "solvate" and "solvate" are used interchangeably and refer to a substance formed by combining a compound of the present invention with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include acetic acid and the like. Solvates include stoichiometric and non-stoichiometric solvates. Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

Herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist as stereoisomers and thus encompass all possible stereoisomeric forms including, but not limited to, cis, trans, tautomers, enantiomers, diastereomers, atropisomers, and the like, and the compounds of the present invention may also exist as any combination or any mixture of the foregoing stereoisomers, e.g., meso, racemic, an equivalent mixture of atropisomers, and the like. For example a single enantiomer, a single diastereomer or a mixture thereof, or a single atropisomer or a mixture thereof. When the compound of the present invention contains an olefinic double bond, it includes cis-isomers and trans-isomers, and any combination thereof, unless otherwise specified. Atropisomers of the present invention are axial or planar chiral stereoisomers based on restricted rotation within the molecule. And as the drug, a stereoisomer having an excellent activity is preferable. The compound of the formula (I) has optical isomers derived from asymmetric carbon and the like, and when necessary, a single isomer can be obtained by resolution by a method known in the art, for example, crystallization or chiral chromatography.

As used herein, the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group. The term "C_1-20Alkyl "refers to a straight or branched chain alkyl group having 1 to 20 carbon atoms. Is preferably C_1-10An alkyl group. More preferably C_1-6Alkyl (i.e., straight or branched chain alkyl groups having 1,2, 3, 4, 5, or 6 carbon atoms). More preferably C_1-4An alkyl group. More preferably C_1-3An alkyl group. Specific examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the various branched chain isomers thereof and the like.

As used herein, the term "alkoxy" refers to a group having the structure-O-alkyl, wherein alkyl is as defined above. The term "C_1-10Alkoxy "refers to an alkoxy group having 1 to 10 carbon atoms. Is preferably C_1-6An alkoxy group. More preferably C _1-4An alkoxy group. More preferably C_1-3An alkoxy group. Specific examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy, and the like.

As used herein, the term "alkenyl" refers to an alkyl group as defined above having one or more carbon-carbon double bonds at any position in the chain, the term "C_2-8Alkenyl group "Refers to an alkenyl group having 2 to 8 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon double bond. Preferably C_2-6Alkenyl groups (i.e., alkenyl groups having 2 to 6 carbon atoms and 1 to 2 carbon-carbon double bonds). More preferably C_2-4Alkenyl groups (i.e., alkenyl groups having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds). Specific examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, pentenyl, hexenyl, butadienyl, and the like.

As used herein, the term "alkynyl" refers to an alkyl group as defined above having one or more carbon-carbon triple bonds at any position in the chain, the term "C_2-8Alkynyl "refers to alkynyl groups having 2 to 8 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon triple bond. Preferably C_2-6Alkynyl (i.e., alkynyl groups having 2 to 6 carbon atoms and 1 to 2 carbon-carbon triple bonds). More preferably C _2-4Alkynyl (i.e., alkynyl groups having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds). Specific examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.

Herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

Herein, the term "halo" refers to fluoro, chloro, bromo, or iodo.

As used herein, the term "haloalkyl" refers to an alkyl group wherein one or more (e.g., 1,2, 3, 4, or 5) hydrogen atoms are replaced with a halogen, wherein alkyl is as defined above. The term "halo C_1-10Alkyl "refers to haloalkyl groups having 1 to 10 carbon atoms. Preferably a halogen atom_1-6An alkyl group. More preferably a halogenated C_1-4An alkyl group. More preferably a halogenated C_1-3An alkyl group. Specific examples of haloalkyl groups include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.

As used herein, the term "haloalkoxy" refers to an alkoxy group wherein one or more (e.g., 1,2, 3, 4, or 5) hydrogen atoms are replaced by halogen, wherein the alkoxy group is as defined above. The term "halo C _1-10Alkoxy "refers to a haloalkoxy group having 1 to 10 carbon atoms. Preferably a halogen atom_1-6An alkoxy group. More preferably a halogenated C_1-4An alkoxy group. More preferably a halogenated C_1-3An alkoxy group. Specific examples of haloalkoxy include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.

As used herein, the term "deuterated" refers to a group in which one or more hydrogen atoms are replaced with deuterium atoms.

As used herein, the term "deuterated alkyl" refers to an alkyl group having one or more (e.g., 1,2, 3, 4, or 5) hydrogen atoms replaced with a deuterium atom, wherein the alkyl group is as defined above. The term "deuterated C_1-10Alkyl "refers to deuterated alkyl having from 1 to 10 carbon atoms. Preferably deuterated C_1-6An alkyl group. More preferably deuterated C_1-4An alkyl group. More preferably deuterated C_1-3An alkyl group. Specific examples of deuterated alkyl include, but are not limited to, mono-deuterated methyl, di-deuterated methyl, tri-deuterated methyl, mono-deuterated ethyl, 1, 2-di-deuterated ethyl, tri-deuterated ethyl, and the like.

As used herein, the term "deuterated alkoxy" refers to an alkoxy group having one or more (e.g., 1,2, 3, 4, or 5) hydrogen atoms replaced with a deuterium atom, wherein the alkoxy group is as defined above. The term "deuterated C _1-10Alkoxy "refers to a deuterated alkoxy having from 1 to 10 carbon atoms. Preferably deuterated C_1-6An alkoxy group. More preferably deuterated C_1-4An alkoxy group. More preferably deuterated C_1-3An alkoxy group. Specific examples of deuterated alkoxy include, but are not limited to, trideuteromethoxy, trideuteroethoxy, monoduteromethoxy, monoduteroethoxy, dideuteromethoxy, dideuteroethoxy, and the like.

As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably to refer to a saturated monocyclic or polycyclic cyclic hydrocarbon group, including, for example, monocyclic cycloalkyl, spirocycloalkyl, fused ring alkyl, and bridged ring alkyl. The cycloalkyl groups described herein may be optionally substituted at ring carbon atoms with 1, 2 or 3 oxo groups to form a cyclic ketone structure. The term "3 to 20 membered cycloalkyl" or "C_3-20Cycloalkyl "refers to cycloalkyl groups having 3 to 20 ring carbon atoms, including monocyclic cycloalkylsAlkyl, spirocycloalkyl, fused ring alkyl and bridged ring alkyl. Preferably C_3-12Monocyclic cycloalkyl, C_5-20Spiro cycloalkyl, C_5-20Condensed ring alkyl or C_5-20A bridged cycloalkyl group. More preferably C_3-8A monocyclic cycloalkyl group.

The term "C_3-8Monocyclic cycloalkyl "and" 3 to 8 membered monocyclic cycloalkyl "refer to saturated monocyclic cyclic hydrocarbon groups having 3 to 8 ring carbon atoms. Preferably C_3-6Monocyclic cycloalkyl (i.e. 3-to 6-membered monocyclic cycloalkyl) or C _4-6Monocyclic cycloalkyl (i.e., 4 to 6 membered monocyclic cycloalkyl). More preferably C₃、C₄、C₅Or C₆A monocyclic cycloalkyl group. Specific examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

As used herein, the terms "spirocycloalkyl" and "spirocycloalkyl ring" refer to polycyclic cyclic hydrocarbon groups formed from two or more monocyclic rings which share a common carbon atom (referred to as a spiro atom). Spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, di-spirocycloalkyl groups and multi-spirocycloalkyl groups according to the number of spiro atoms shared between rings. The term "5 to 20 membered spirocycloalkyl" or "C_5-20Spirocycloalkyl "refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic ring that shares a spiro atom is a 3 to 8 membered monocyclic cycloalkyl ring. Preferably 6 to 14 (i.e.C)_6-14) Spirocycloalkyl. More preferably 6 to 14 membered mono spirocycloalkyl. More preferably 7 to 11 (i.e., C)_7-11) Spirocycloalkyl. More preferably 7 to 11 membered mono spirocycloalkyl. Most preferred is a 7-membered (4-membered monocyclic cycloalkyl ring/4-membered monocyclic cycloalkyl ring), 8-membered (4-membered monocyclic cycloalkyl ring/5-membered monocyclic cycloalkyl ring), 9-membered (4-membered monocyclic cycloalkyl ring/6-membered monocyclic cycloalkyl ring, 5-membered monocyclic cycloalkyl ring/5-membered monocyclic cycloalkyl ring), 10-membered (5-membered monocyclic cycloalkyl ring/6-membered monocyclic cycloalkyl ring) or 11-membered (6-membered monocyclic cycloalkyl ring/6-membered monocyclic cycloalkyl ring) monocyclic spirocycloalkyl. Specific examples of spirocycloalkyl groups include, but are not limited to:

These spirocycloalkyl groups may be attached to the rest of the molecule through any one of the ring atoms.

As used herein, the terms "fused cyclic alkyl" and "fused cycloalkyl ring" refer to polycyclic cyclic hydrocarbon groups formed by two or more monocyclic rings sharing an adjacent pair of carbon atoms. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls depending on the number of rings formed. The term "5-to 20-membered fused ring alkyl" or "C_5-20Fused-ring alkyl "refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic rings that share adjacent pairs of carbon atoms are 3 to 8 membered monocyclic cycloalkyl rings. Preferably 6 to 14 (i.e.C)_6-14) A fused ring alkyl group. More preferably 6 to 14-membered di-fused cycloalkyl. More preferably 7 to 10 (i.e., C)_7-10) A fused ring alkyl group. More preferably 7 to 10-membered di-fused cycloalkyl. Most preferred is an 8-membered (5-membered monocyclic cycloalkyl ring fused with a 5-membered monocyclic cycloalkyl ring), 9-membered (5-membered monocyclic cycloalkyl ring fused with a 6-membered monocyclic cycloalkyl ring), or 10-membered (6-membered monocyclic cycloalkyl ring fused with a 6-membered monocyclic cycloalkyl ring) double fused-ring alkyl group. Specific examples of fused ring alkyl groups include, but are not limited to:

these fused ring alkyl groups may be attached to the rest of the molecule through any one of the ring atoms.

As used herein, the terms "bridged cycloalkyl" and "bridged cycloalkyl ring" refer to polycyclic cyclic hydrocarbon groups formed between two or more monocyclic rings by the sharing of two carbon atoms which are not directly connected. They can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups depending on the number of rings formed. The terms "5 to 20 membered bridged cycloalkyl" and "C _5-20Bridged cycloalkyl "refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein any two rings share two carbon atoms not directly attached. Preferably 6 to 14 (i.e.C)_6-14) A bridged cycloalkyl group. More preferably 7 to 10 (i.e., C)_7-10) A bridged cycloalkyl group. Specific examples of bridged cycloalkyl groups include, but are not limited to:

these bridged cycloalkyl groups may be attached to the rest of the molecule through any one of the ring atoms.

As used herein, the term "halocycloalkyl" refers to a cycloalkyl group in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are replaced by halogen, wherein the cycloalkyl group is as defined above.

As used herein, the term "halo C_3-8Monocyclic cycloalkyl "refers to halogenated monocyclic cycloalkyl groups having 3 to 8 ring carbon atoms. Preferably a halogen atom_3-6A monocyclic cycloalkyl group. More preferably a halogenated C₃Halogen substituted C₄Halogen substituted C₅Or halo C₆A monocyclic cycloalkyl group. Specific examples include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.

As used herein, the terms "heterocyclyl" and "heterocyclyl ring" are used interchangeably to refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, including, for example, monocyclic heterocyclyl, spiro heterocyclyl, fused heterocyclyl, and bridged heterocyclyl groups. Ring carbon atoms of the heterocyclic groups described in the present invention may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure. The term "3-to 20-membered heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon radical having 3 to 20 ring atoms, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (═ O) _m'(wherein m' is an integer of 0 to 2) but does not include a cyclic moiety of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Wherein when the ring atom is a nitrogen atom, it may be substituted or unsubstituted (i.e. N or NR, R being hydrogen or other substituents as already defined herein). The 3-to 20-membered heterocyclic group described in the present invention includes monocyclic heterocyclic groups (e.g., 3-to 8-membered monocyclic heterocyclic groups), spiro heterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups.

Herein, the terms "3 to 8 membered monocyclic heterocyclyl" and "3 to 8 membered monocyclic heterocyclyl ring" refer to a ring having 3 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen or S (═ O)_m'(wherein m' is an integer of 0 to 2) a saturated or partially unsaturated monocyclic cyclic hydrocarbon group of a heteroatom. Preferably having 3 to 6 ring atoms, which3-to 6-membered monocyclic heterocyclic group in which 1 or 2 ring atoms are hetero atoms. More preferred are 4-to 6-membered monocyclic heterocyclic groups having 4 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. More preferred is a 5-or 6-membered monocyclic heterocyclic group having 5 or 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e. N or NR, R is hydrogen or other substituents as already defined herein). When the heteroatom is a sulfur atom, the sulfur atom may be optionally oxidized (i.e., S (═ O) _m', m' is an integer of 0 to 2). The monocyclic heterocyclic group may have ring carbon atoms optionally substituted with 1,2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure. Specific examples of monocyclic heterocyclic groups include, but are not limited to, aziridine, ethylene oxide, azetidine, azetidin-2-one, oxetane, oxetan-2-one, oxazolidine, pyrrolidin-2-one, pyrrolidine-2, 5-dione, 1, 3-dioxolane, dihydrofuran-2 (3H) -one, dihydrofuran-2, 5-dione, piperidin-2-one, piperidine-2, 6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1, 3-dioxolan-2-one, oxazolidin-2-one, imidazolidin-2-one, piperidine, piperazine, piperazin-2-one, piperazine-2-one, and the like, Morpholine, morpholine-3-one, morpholine-2-one, thiomorpholin-3-one 1, 1-dioxide, thiomorpholine-1, 1-dioxide, tetrahydropyran, 1, 2-dihydroazetidine, 1, 2-dihydrooxetane, 2, 5-dihydro-1H-pyrrole, 2, 5-dihydrofuran, 2, 3-dihydro-1H-pyrrole, 3, 4-dihydro-2H-pyran, 1,2,3, 4-tetrahydropyridine, 3, 6-dihydro-2H-pyran, 1,2,3, 6-tetrahydropyridine, 1, 3-oxazine, hexahydropyrimidine, 1, 4-dioxane, hydrogen peroxide, tetrahydropyrimidin-2 (1H) -one, 1, 4-dioxan-2-one, 5, 6-dihydro-2H-pyran-2-one, 5, 6-dihydropyrimidin-4 (3H) -one, 3, 4-dihydropyridin-2 (1H) -one, 5, 6-dihydropyrimidin-4 (1H) -one, pyrimidin-4 (3H) -one, pyrimidin-4 (1H) -one, 4, 5-dihydro-1H-imidazole, 2, 3-dihydrooxazole, 1, 3-dioxole, 2, 3-dihydrothiophene, pyridine, and pyridine, 2, 5-dihydrothiophene, 3, 4-dihydro-2H-1, 4-oxazine, 3, 4-dihydro-2H-1, 4-thiazine 1, 1-dioxide, 1,2,3, 4-tetrahydropyrazine, 1, 3-dihydro-2H-pyrrol-2-one, 1, 5-bis hydrogen-2H-pyrrol-2-one, 1H-pyrrol-2, 5-dione, furan-2 (3H) -one, furan-2 (5H) -one, 1, 3-dioxol-2-one, oxazol-2 (3H) -one, 1, 3-dihydro-2H-imidazol-2-one, furan-2, 5-dione, 3, 6-dihydropyridin-2 (1H) -one, pyridine-2, 6- (1H, 3H) -dione, 5, 6-dihydro-2H-pyran-2-one, 3, 4-dihydro-2H-1, 3-oxazine, 3, 6-dihydro-2H-1, 3-oxazine, 1,2,3, 4-tetrahydropyrimidine, and the like.

Herein, the term "3-to 6-membered nitrogen-containing heterocyclic group" means having 3 to 6 ring atoms, of which 1 ring atom is a nitrogen atom and the other 1 or 2 ring atoms are selected from nitrogen, oxygen or S (═ O)_m'(wherein m' is an integer of 0 to 2) a saturated or partially unsaturated monocyclic cyclic hydrocarbon group of a heteroatom. Specific examples include, but are not limited to, azapropynyl, azetidinyl, azapentylnyl (i.e., tetrahydropyrrole), azahexylnyl (i.e., piperidine), morpholinyl, piperazinyl, oxazolidine.

Herein, the term "3 to 8-membered monocyclic heterocycloalkyl" refers to a saturated monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. Preferably 3 to 6 membered monocyclic heterocycloalkyl, i.e. a saturated monocyclic cyclic hydrocarbon group having 3 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. Specific examples of heterocycloalkyl include, but are not limited to, aziridinyl, oxiranyl, azetidinyl, oxetanyl, oxazolidinyl, 1, 3-dioxolanyl, dioxanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl-1, 1-dioxido, tetrahydropyranyl, 1, 4-oxazepanyl, 1, 3-oxazinyl, hexahydropyrimidyl, 1, 4-dioxanyl.

The 2 ring atoms attached to the monocyclic heterocyclyl ring, including C-C, N-C, can each be optionally fused to a cycloalkyl, heterocyclyl, aryl or heteroaryl group as defined herein, such as a monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, monocyclic aryl ring, 5-or 6-membered monocyclic heteroaryl ring, to form a fused polycyclic ring. The 2 ring atoms attached to the monocyclic heterocyclic group which forms a fused ring with other rings are preferably C-C.

As used herein, the terms "spiroheterocyclyl" and "spiroheterocyclyl ring" refer to polycyclic heterocyclic groups formed by two or more saturated or partially unsaturated monocyclic rings which share a single carbon atom, referred to as the spiro atom, wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, or S (═ O)_m'(wherein m' is an integer from 0 to 2) and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e. N or NR, R is hydrogen or other substituents as already defined herein). One or more double bonds may be present in each single ring, but none of the rings has a completely conjugated pi-electron system. Spiro heterocyclic groups are classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group, or a multi-spiro heterocyclic group according to the number of spiro atoms shared between rings. The term "5 to 20 membered spiroheterocyclyl" refers to spiroheterocyclyl groups having 5 to 20 ring atoms, wherein one monocyclic ring of the monocyclic rings sharing a spiro atom is a 3 to 8 membered monocyclic heterocyclyl ring, and the other monocyclic ring is a 3 to 8 membered monocyclic heterocyclyl ring or a 3 to 8 membered monocyclic cycloalkyl ring. Preferred are 6-to 14-membered spiroheterocyclic groups having 6 to 14 ring atoms, of which 1 or 2 ring atoms are heteroatoms. More preferred are 7-to 11-membered spiroheterocyclic groups having 7 to 11 ring atoms, of which 1 or 2 ring atoms are heteroatoms. Most preferred is 7-membered (4-membered monocyclic heterocyclyl ring/4-membered monocyclic heterocyclyl ring, 4-membered monocyclic heterocyclyl ring/4-membered monocyclic cycloalkyl or 4-membered monocyclic cycloalkyl ring/4-membered monocyclic heterocyclyl ring), 8-membered (4-membered monocyclic heterocyclyl ring/5-membered monocyclic heterocyclyl ring, 4-membered monocyclic cycloalkyl ring/5-membered monocyclic heterocyclyl ring or 4-membered monocyclic heterocyclyl ring/5-membered monocyclic cycloalkyl ring), 9-membered (4-membered monocyclic heterocyclyl ring/6-membered monocyclic heterocyclyl ring, 4-membered monocyclic cycloalkyl ring/6-membered monocyclic heterocyclyl ring, 4-membered monocyclic heterocyclyl ring/6-membered monocyclic cycloalkyl ring, 5-membered monocyclic heterocyclyl ring/5-membered monocyclic heterocyclyl ring, 5-membered monocyclic cycloalkyl ring/5-membered monocyclic heterocyclyl ring), 10-membered (5-membered monocyclic heterocyclyl ring/6-membered monocyclic heterocyclyl ring etc.) or 11-membered (6-membered monocyclic heterocyclyl ring/6-membered monocyclic heterocyclyl ring etc.) mono-spiroheterocyclyl ring . Specific examples of spiroheterocyclyl groups include, but are not limited to:

These spiroheterocyclic groups may be attached to the rest of the molecule through any suitable ring atom.

As used herein, the terms "fused heterocyclyl" and "fused heterocyclyl ring" refer to polycyclic heterocyclic groups formed by two or more saturated or partially unsaturated monocyclic rings sharing an adjacent pair of ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms is selected from nitrogen, oxygen, or S (═ O)_m'(wherein m' is an integer from 0 to 2) and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e. N or NR, R is hydrogen or other substituents as already defined herein). One or more double bonds may be present in each single ring, but none of the rings has a completely conjugated pi-electron system. The shared adjacent ring atom pair may be C-C or N-C. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings. The term "5-to 20-membered fused heterocyclyl" refers to fused heterocyclyl groups having 5 to 20 ring atoms in which the monocyclic ring sharing an adjacent pair of ring atoms is a 3-to 8-membered monocyclic heterocyclyl ring. Preferred are 6-to 14-membered fused heterocyclic groups having 6 to 14 ring atoms, of which 1 or 2 ring atoms are heteroatoms. More preferred are 6-to 10-membered fused heterocyclic groups having 6 to 10 ring atoms, of which 1 or 2 ring atoms are heteroatoms. More preferred are 8-to 10-membered fused heterocyclic groups having 8 to 10 ring atoms, wherein 1 or 2 ring atoms are heteroatoms. Most preferred are 8-membered (5-membered monocyclic heterocyclyl ring fused with 5-membered monocyclic heterocyclyl ring), 9-membered (5-membered monocyclic heterocyclyl ring fused with 6-membered monocyclic heterocyclyl ring), or 10-membered (6-membered monocyclic heterocyclyl ring fused with 6-membered monocyclic heterocyclyl ring) bicyclic fused heterocyclyl. Specific examples of fused heterocyclic groups include, but are not limited to:

These fused heterocyclic groups may be attached to the rest of the molecule through any suitable ring atom.

As used herein, the terms "bridged heterocyclyl" and "bridged heterocyclyl ring" refer to two or more than twoPolycyclic heterocyclic groups formed by a saturated or partially unsaturated monocyclic ring sharing two ring atoms which are not directly linked, wherein one or more (e.g. 1, 2 or 3) ring atoms is selected from nitrogen, oxygen or S (═ O)_m'(wherein m' is an integer from 0 to 2) and the remaining ring atoms are carbon. They can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups depending on the number of rings formed. The term "5-to 20-membered bridged heterocyclyl" refers to a saturated or partially unsaturated polycyclic heterocyclic group having 5 to 20 ring atoms in which any two rings share two ring atoms which are not directly connected, and which may contain one or more double bonds in each single ring, but none of the rings has a completely conjugated pi-electron system. Preferably a 6 to 14 membered bridged heterocyclyl group. More preferably a 7 to 10 membered bridged heterocyclyl group. Specific examples of bridged heterocyclic groups include, but are not limited to:

these bridged heterocyclic groups may be attached to the rest of the molecule through any suitable ring atom.

In the present invention, each of the above heterocyclic groups may be optionally substituted, and when substituted, the substituent is preferably one or more of the substituent groups described in the present application.

As used herein, the terms "aryl", "aryl ring" and "aromatic ring" are used interchangeably and refer to an all-carbon monocyclic, all-carbon non-fused polycyclic (rings linked to rings by covalent bonds, non-fused) or all-carbon fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group in which at least one of the rings is aromatic, i.e., has a conjugated pi-electron system. The term "C_6-14Aryl "refers to an aryl group having 6 to 14 ring atoms. Preferably C_6-10And (4) an aryl group. In the invention C_6-14The aryl group includes monocyclic aryl groups, non-fused polycyclic aryl groups, and aromatic fused polycyclic groups, wherein examples of the monocyclic aryl groups include phenyl groups, and examples of the non-fused polycyclic aryl groups include biphenyl groups and the like.

In the present invention, when C_6-14When aryl is an aromatic fused polycyclic ring, the aromatic fused polycyclic ring may be a monoaryl ring with one aromatic fused polycyclic ringOr a polycyclic group formed by fusion of a plurality of monoaryl rings, non-limiting examples of which include naphthyl, anthryl and the like.

In some embodiments of the invention, when C_6-14When the aryl group is an aromatic fused polycyclic group, the aromatic fused polycyclic group can also be a polycyclic group formed by fusing a single aryl ring (e.g., phenyl) to one or more non-aromatic rings, wherein the ring attached to the parent structure is aromatic or non-aromatic. The non-aromatic ring includes, but is not limited to, a 3-to 6-membered monocyclic heterocyclyl ring (preferably a 5-or 6-membered monocyclic heterocyclyl ring, the ring carbon atom of which may be substituted with 1 to 2 oxo groups to form a cyclic lactam or a cyclic lactone structure), a 3-to 6-membered monocyclic cycloalkyl ring (preferably a 5-or 6-membered monocyclic cycloalkyl ring, the ring carbon atom of which may be substituted with 1 or 2 oxo groups to form a cyclic ketone structure). Polycyclic groups fused to the above-mentioned monoaryl ring and one or more non-aromatic rings may be linked to other groups or the parent structure through a nitrogen atom or a carbon atom, and the ring linked to the parent structure may be a monoaryl ring or a non-aromatic ring.

In the present invention, each of the above-mentioned types of aryl groups may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the substituent groups described in the present application.

The terms "heteroaryl", "heteroaryl ring" and "heteroaromatic ring" are used interchangeably herein to refer to a monocyclic or fused polycyclic (i.e., sharing adjacent pairs of ring atoms, which may be C-C or N-C) group in which the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized) groups in which the ring atoms are substituted with at least one heteroatom independently selected from nitrogen, oxygen or sulfur. The heteroaryl groups have 6, 10 or 14 pi electrons in common and at least one ring in the group is aromatic. The term "5-to 14-membered heteroaryl" refers to a heteroaryl group having 5 to 14 ring atoms, wherein 1, 2, 3 or 4 ring atoms are selected from nitrogen, oxygen or S (═ O)_m'(wherein m' is an integer from 0 to 2) heteroaryl of a heteroatom. Preference is given to 5-to 10-membered heteroaryl having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms. The 5-to 14-membered heteroaryl group in the present invention may be a monocyclic heteroaryl group, a fused bicyclic heteroaryl group or a fused tricyclic heteroaryl group。

Herein, the term "5-or 6-membered monocyclic heteroaryl" refers to a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen or S (═ O) _m'(wherein m' is an integer from 0 to 2) a monocyclic heteroaryl group of heteroatoms. Specific examples of monocyclic heteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like.

Herein, the term "8 to 10 membered bicyclic heteroaryl" refers to a heteroaryl group having 8 to 10 ring atoms, wherein 1,2,3, 4 or 5 ring atoms are selected from nitrogen, oxygen or S (═ O)_m'(wherein m' is an integer of 0 to 2) a fused bicyclic heteroaryl group of a heteroatom. The fused bicyclic heteroaryl may be a bicyclic group (preferably a 9-or 10-membered bicyclic heteroaryl ring) formed by fusing a monocyclic heteroaryl ring (preferably a 5-or 6-membered monocyclic heteroaryl ring) to a monocyclic heteroaryl ring (e.g., phenyl), or a bicyclic group formed by fusing a monocyclic heteroaryl ring (preferably a 5-or 6-membered monocyclic heteroaryl ring) to a monocyclic heteroaryl ring (preferably a 5-or 6-membered monocyclic heteroaryl ring).

Any of the 2 ring atoms attached to the monocyclic heteroaryl ring described above, including C-C, N-C, N-N, may be fused to a cycloalkyl, heterocyclyl, aryl or heteroaryl group as defined herein, such as a monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, monocyclic aryl ring, 5-or 6-membered monocyclic heteroaryl ring, to form a fused polycyclic ring. The 2 ring atoms attached to the monocyclic heteroaryl ring that form fused rings with other rings are preferably C-C, including, without limitation, the following forms:

Through the above-mentioned groups

The labeled ring atom is attached to the rest of the molecule.

Non-limiting examples of 8-to 10-membered bicyclic heteroaryls include: benzo [ d ] isoxazole, 1H-indole, isoindole, 1H-benzo [ d ] imidazole, benzo [ d ] isothiazole, 1H-benzo [ d ] [1,2,3] triazole, benzo [ d ] oxazole, benzo [ d ] thiazole, indazole, benzofuran, benzo [ b ] thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido [3,2-d ] pyrimidine, pyrido [2,3-d ] pyrimidine, pyrido [3,4-d ] pyrimidine, pyrido [4,3-d ] pyrimidine, 1, 8-naphthyridine, 1, 7-naphthyridine, 1, 6-naphthyridine, 1, 5-naphthyridine, pyrazolo [1,5-a ] pyrimidine, imidazo [1,2-b ] pyridazine, and the like.

Specific examples of bicyclic heteroaryls include, but are not limited to:

these groups may be attached to the rest of the molecule via any suitable ring atom. The ring attached to the parent structure may be a monocyclic heteroaryl ring or a benzene ring.

In some embodiments of the invention, the fused bicyclic heteroaryl or fused tricyclic heteroaryl may be a monocyclic heteroaryl ring (preferably a 5 or 6 membered monocyclic heteroaryl ring) fused to one or more non-aromatic rings to form a polycyclic group, wherein the ring attached to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring. The non-aromatic ring includes, but is not limited to, a 3-to 6-membered monocyclic heterocyclyl ring (preferably a 5-or 6-membered monocyclic heterocyclyl ring, the ring carbon atom of which may be substituted with 1 to 2 oxo groups to form a cyclic lactam or a cyclic lactone structure), a 3-to 6-membered monocyclic cycloalkyl ring (preferably a 5-or 6-membered monocyclic cycloalkyl ring, the ring carbon atom of which may be substituted with 1 or 2 oxo groups to form a cyclic ketone structure), and the like. The polycyclic group formed by the fusion of the monocyclic heteroaryl ring and one or more non-aromatic rings may be linked to other groups or to the parent structure through a nitrogen or carbon atom, and the ring linked to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring.

In the present invention, each of the above heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the substituent groups described in the present application.

Herein, the term "hydroxy" refers to-OH.

As used herein, the term "hydroxymethyl" refers to-CH₂OH, "hydroxyethyl" means-CH₂CH₂OH or-CH (OH) CH₃。

As used herein, the term "cyanomethyl" refers to-CH₂CN, "cyanoethyl" means-CH₂CH₂CN or-CHCHCH₃。

As used herein, the term "amino" refers to-NH₂。

Herein, the term "cyano" refers to — CN.

As used herein, the term "nitro" refers to-NO₂。

As used herein, the term "benzyl" refers to-CH₂-benzene.

Herein, the term "oxo" refers to ═ O.

As used herein, the term "carboxy" refers to-C (O) OH.

As used herein, the term "carboxylate" refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl).

As used herein, the term "acetyl" refers to the group-COCH₃。

As used herein, the term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, and may include variations of deuterium and hydrogen, so long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., ═ O), it means that two hydrogen atoms are substituted. Oxo substitution does not occur on aromatic groups. The term "optionally substituted" or "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemical realizability.

When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

In any embodiment, any or all of the hydrogens present in the compound, or in particular groups or moieties within the compound, may be replaced with deuterium or tritium. One to the maximum number of hydrogens present in the compound may be replaced by deuterium. One to the maximum number of hydrogens present in any group in the compound of formula (la) or the specific compound may be deuterated. For example, when a group is described as ethyl, the ethyl group may be C₂H₅Or C wherein x (1 to 5) hydrogens are replaced with deuterium₂H₅E.g. C₂D_xH_5-x. When a group is described as deuterated ethyl, the deuterated ethyl can be C with x (1 to 5) hydrogens replaced with deuterium₂H₅E.g. C₂D_xH_5-x。

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art. Preferred embodiments include, but are not limited to, examples of the present invention. For example, the compound of formula II-2 can be prepared by the following synthetic route. The compound 1 is used as a raw material, and the compound shown in the formula II-2 is prepared through reduction, cyclization, protecting group removal, condensation and oxidation reactions.

Detailed Description

Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.

The preparative HPLC method used in the following examples may be either a preparative HPLC base method or a preparative HPLC acid method. The preparative HPLC alkaline method can employ the following conditions: column: waters XBridge C18,190 × 250mm,5 μm; the mobile phase A is 0.1 percent of ammonium bicarbonate aqueous solution; b, preparing grade acetonitrile; the flow rate is 15 ml/min; 20% -100% of B; column temperature, room temperature. The preparative HPLC acid method may employ the following conditions: column: waters XBridge C18,190 × 250mm,5 um; the mobile phase A is 0.1 percent of formic acid or trifluoroacetic acid aqueous solution; b, preparing grade acetonitrile; the flow rate is 15 ml/min; 20% -100% of B; column temperature, room temperature. If the isomeric compound is detected by analytical HPLC, the following conditions are used: column XBridge C18,3.5 μm4.6 x 150mm, mobile phase a purified water (0.05% TFA); preparative grade acetonitrile (0.05% TFA), gradient 5% -95% B, run time 15min, flow rate 1ml/min, column temperature: at 40 ℃.

EXAMPLE 1 preparation of Compound Z1

The method comprises the following steps: 5-Nitro-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ]]Pyridin-4-amine (3.18g,10.0mmol) was suspended in 60mL of ethanol and 20mL of water, and iron powder (2.80g,80.0mmol) and ammonium chloride (4.28g,80.0mmol) were added in that order, and the reaction was stirred at 90 ℃ for 2 hours. The reaction solution was filtered through celite, the filter cake was washed with ethanol, the filtrate was spin-dried, and 60mL of water and 60mL of ethyl acetate were added for extraction 2 times. The combined organic layers were washed with 30mL of saturated brine, dried and concentrated to give 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] -peptide]Pyridine-4, 5-diamine (1.9g, 66% yield) as a brown solid. ES-API [ M + H ]]⁺＝289.1。

Step two: to a 50mL lock tube were added in sequence: 1- (phenylsulfonyl) -1H-pyrrole [2,3-b]Pyridine-4, 5-diamine (300mg,1.04mmol), 15mL methanol, 4-formylpiperidine-1-carboxylic acid tert-butyl ester (243mg,1.14mmol), 10% Pd/C (50mg), reacted at 120 deg.CStirred for 6 hours. Filtering the reaction solution with diatomite, washing the filter cake with methanol, and concentrating the filtrate to obtain 4- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (480mg, yield 96%) as a yellow solid. ES-API [ M + H ]]⁺＝482.2。

Step three: 4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ] ]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (480mg,1.0mmol) was dissolved in 12mL methanol, 2mL tetrahydrofuran and 2mL water, sodium hydroxide (280mg,7.0mmol) was added and the reaction stirred in a sealed tube at 90 ℃ for 18 h. To the reaction solution, 30mL of water and 4mL of a saturated ammonium chloride solution were added, and the mixture was extracted with 100mL of ethyl acetate. The organic phase was washed with 30mL of a saturated sodium bicarbonate solution and 30mL of a saturated brine in this order, dried and concentrated to give 4- (3, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (340mg, yield 100%) as a yellow solid. ES-API [ M + H ]]⁺＝342.3。

Step four: 4- (3, 6-dihydroimidazole [4,5-d ]]Pyrrole [2,3-b ]]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (170mg,0.50mmol) and 2-chloro-4-phenoxybenzaldehyde (116mg,0.50mmol) were dissolved in methanol (10mL), the reaction cooled to 0 deg.C, potassium hydroxide (196mg,3.50mmol) was added, and the reaction stirred at room temperature for 18 h. The reaction mixture was poured into 50mL of water, adjusted to pH 8 with 1.0M dilute hydrochloric acid, and extracted with 100mL of ethyl acetate. The organic phase was washed with 30mL of saturated brine, dried and concentrated to give 4- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d]Pyrrole [2,3-b ]]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (280mg, crude) as a yellow solid. ES-API [ M + H ] ]⁺＝574.2。

Step five: 4- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d]Pyrrole [2,3-b ]]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (280mg, crude) was dissolved in 10mL tetrahydrofuran, cooled to 0 deg.C, dess-martin oxidant (212mg,0.50mmol) was added and the reaction stirred at room temperature for 2 hours. 6mL of a saturated sodium thiosulfate solution and 20mL of a saturated sodium bicarbonate solution were added to the reaction solution, followed by extraction with 50mL of ethyl acetate. The organic phase is washed with 15mL of saturated brine, dried and concentrated, and the crude product is purified using a thin layer prep. plate (dichloromethane/methanol 10:1) to give 4- (8- (2-chloro-1)-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d]Pyrrole [2,3-b ]]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (55mg, 19% yield over two steps) as a yellow solid. ES-API [ M + H ]]⁺＝572.2。

Step six: 4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (50mg,0.09mmol) was dissolved in 3mL dichloromethane, cooled to 0 deg.C, 1mL trifluoroacetic acid was added and the reaction stirred at room temperature for 1 hour. The reaction mixture was concentrated, 15mL of saturated sodium bicarbonate solution was added, and the mixture was extracted 2 times with 20mL of ethyl acetate. The organic phase is washed with 10mL of saturated brine, dried and concentrated, and the crude product is purified by preparative HPLC to give (2-chloro-4-phenoxyphenyl) (2- (piperidin-4-yl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-8-yl) methanone (Z1, 27mg, 60% yield) as a white solid.¹H NMR(500MHz,DMSO-d₆)δ12.00(s,1H),8.67(s,1H),8.41(s,1H),7.79(s,1H),7.65(d,J＝8.5Hz,1H),7.49(t,J＝8.0Hz,2H),7.27(t,J＝7.5Hz,1H),7.23-7.17(m,3H),7.05(dd,J＝8.5,2.5Hz,1H),3.44(d,J＝11.0Hz,1H),3.27(d,J＝12.5Hz,2H),2.86(t,J＝12.0Hz,2H),2.13(d,J＝11.0Hz,2H),1.98-1.87(m,2H).ES-API:[M+H]⁺＝472.1。

EXAMPLE 2 preparation of Compound Z2

The method comprises the following steps: 4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (40mg,0.085mmol) was dissolved in 5mL dichloromethane, cooled to 0 deg.C, added to a solution of methanesulfonyl chloride (14mg,0.13mmol) in 0.5mL dichloromethane, and the reaction stirred at room temperature for 1 hour. The reaction mixture was washed with 3mL of water and 5mL of saturated brine in this order with 20mL of dichloromethane, dried and concentrated, and the crude product was purified by preparative HPLC to give (2-chloro-4-phenoxyphenyl) (2- (1- (methylsulfonyl) piperidin-4-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z2, 16mg, yield 34%) as a white solid.¹H NMR(500MHz,DMSO-d₆)δ12.79(s,1H),12.04(s,1H),8.68(s,1H),7.79(s,1H),7.65(d,J＝8.5Hz,1H),7.49(t,J＝8.0Hz,2H),7.27(t,J＝7.5Hz,1H),7.23-7.19(m,3H),7.05(dd,J＝8.5,2.5Hz,1H),3.70(d,J＝12.0Hz,2H),3.38-3.30(m,1H),2.97-2.82(m,5H),2.19(d,J＝11.0Hz,2H),1.96-1.86(m,2H).ES-API:[M+H]⁺＝550.0。

EXAMPLE 3 preparation of Compound Z3

The method comprises the following steps: 4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (40mg,0.085mmol) was dissolved in 5mL dichloromethane, cooled to 0 deg.C, added a solution of acetyl chloride (11mg,0.13mmol) in 0.5mL dichloromethane, and the reaction stirred at room temperature for 1 hour. The reaction mixture was washed with 20mL of dichloromethane, 4mL of water and 5mL of saturated brine in this order, dried, concentrated, and the crude product was purified by preparative HPLC to give 1- (4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b]Pyridin-2-yl) piperidin-1-yl) ethan-1-one (Z3,15mg, 34% yield) as a white solid.¹H NMR(500MHz,DMSO-d₆)δ12.79(s,1H),12.01(s,1H),8.66(s,1H),7.79(d,J＝3.0Hz,1H),7.65(d,J＝8.5Hz,1H),7.54-7.44(m,2H),7.27(t,J＝7.4Hz,1H),7.23-7.18(m,3H),7.05(dd,J＝8.5,2.5Hz,1H),4.46(d,J＝12.5Hz,1H),3.95(d,J＝14.0Hz,1H),3.47(t,J＝11.5Hz,1H),3.19(t,J＝11.5Hz,1H),2.73(t,J＝11.3Hz,1H),2.12-2.00(m,5H),1.90-1.79(m,1H),1.75-1.63(m,1H).ES-API:[M+H]⁺＝514.1。

EXAMPLE 4 preparation of Compound Z4

The method comprises the following steps: 4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (50mg,0.11mmol) was dissolved in 6mL acetonitrile, and sodium triacetoxyborohydride (93mg,0.44mmol), and 37% aqueous formaldehyde (36mg,0.44mmol) were added sequentially under ice bath,the reaction was stirred at room temperature for 2 hours. 2mL of concentrated aqueous ammonia was added to the reaction mixture, the reaction was stirred at room temperature for 1 hour, and 6mL of a saturated sodium bicarbonate solution was added and extracted with 30mL of ethyl acetate. The organic phase is washed with 6mL of saturated brine, dried and concentrated, and the crude product is purified by preparative HPLC to give (2-chloro-4-phenoxyphenyl) (2- (1-methylpiperidin-4-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z4, 24mg, 47% yield) as a white solid.¹H NMR(500MHz,DMSO-d₆)δ12.77(s,1H),11.92(s,1H),8.66(s,1H),7.78(s,1H),7.65(d,J＝8.5Hz,1H),7.53-7.42(m,2H),7.27(t,J＝7.5Hz,1H),7.23-7.16(m,3H),7.05(dd,J＝8.5,2.5Hz,1H),3.22-3.12(m,1H),2.91(d,J＝11.5Hz,2H),2.24(s,3H),2.09-1.98(m,5H),1.94-1.84(m,2H).ES-API:[M+H]⁺＝486.0。

EXAMPLE 5 preparation of Compound Z5

The method comprises the following steps: 4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (47mg,0.10mmol) and 2-morpholineacetic acid (29mg,0.20mmol) were dissolved in 10mL of dichloromethane, cooled to 0 deg.C and triethylamine (101mg,1.0mmol) and 1-propylphosphoric anhydride (127mg,0.20mmol) were added in that order and the reaction stirred at 0 deg.C for 30 minutes. The reaction mixture was washed with 6mL of water and 10mL of saturated brine, and then dried and concentrated, and the crude product was purified by preparative HPLC to give 1- (4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-2-yl) piperidin-1-yl) -2-morpholinoethan-1-one (Z5, 24mg, 40% yield) as a white solid.¹H NMR(500MHz,DMSO-d₆)δ12.79(s,1H),11.99(s,1H),8.66(s,1H),7.79(s,1H),7.65(d,J＝8.5Hz,1H),7.53-7.44(m,2H),7.27(t,J＝7.5Hz,1H),7.23-7.17(m,3H),7.06(dd,J＝8.5,2.5Hz,1H),4.44(d,J＝13.0Hz,1H),4.19(d,J＝13.5Hz,1H),3.66-3.54(m,4H),3.54-3.43(m,1H),3.30-3.24(m,1H),3.21-3.03(m,2H),2.77(t,J＝11.0Hz,1H),2.43(s,4H),2.08(t,J＝9.5Hz,2H),1.92-1.82(m,1H),1.76-1.62(m,1H).ES-API:[M+H]⁺＝599.2。

EXAMPLE 6 preparation of Compound Z6

The method comprises the following steps: adding 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] into the sealed tube]Pyridine-4, 5-diamine (150mg,0.5207mmol), tetrahydro-2H-pyran-4-carbaldehyde (65mg,0.5698mmol) and palladium on carbon (20mg, 10%), and finally anhydrous methanol (10.0mL) was added. The mixture was stirred at 120 ℃ for 6 hours under a sealed tube condition. Cooling the reaction system to room temperature, adding diatomite for filtration, and performing rotary drying on the solvent under reduced pressure to obtain a crude product of 6- (benzenesulfonyl) -2- (tetrahydro-2H-pyran-4-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (200mg, crude), pale yellow solid. ES-API [ M + H ]]⁺＝383.2。

Step two: in a sealed tube, 6- (benzenesulfonyl) -2- (tetrahydro-2H-pyran-4-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (200mg, crude) was dissolved in 10mL methanol, 10mL tetrahydrofuran and 2mL water, and finally sodium hydroxide (180mg,4.448mmol) was added and the reaction stirred at 90 ℃ for 15 h. After completion of the reaction, the reaction mixture was cooled to room temperature, 20mL of water and 5mL of a saturated ammonium chloride solution were added thereto, the pH was adjusted to about 8, and the mixture was extracted with 160mL of ethyl acetate. The organic phase was washed with 40mL of a saturated sodium bicarbonate solution and 60mL of a saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate and concentrated to give 2- (tetrahydro-2H-pyran-4-yl) -3, 6-dihydroimidazo [4,5-d ]Pyrrolo [2,3-b ] s]Pyridine (150mg, crude), off-white solid. ES-API [ M + H ]]⁺＝243.1

Step three: 2- (tetrahydro-2H-pyran-4-yl) -3, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (150mg, crude) and 2-chloro-4-phenoxybenzaldehyde (286mg,1.233mmol) were dissolved in methanol (12.0mL), the reaction was cooled to 0 deg.C, and potassium hydroxide (250mg,4.455mmol) was added. The reaction was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was poured into 30mL of a saturated aqueous ammonium chloride solution, the pH was adjusted to 8, and 120mL of ethyl acetate was extracted. The organic phase was washed with 63mL of saturated brine, dried and concentrated to give crude (2-chloro-4-phenoxyphenyl) (2- (tetrahydro-2H-pyran-4-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) Methanol (352mg, crude), light yellow solid. ES-API [ M + H ]]⁺＝475.1。

Step four: (2-chloro-4-phenoxyphenyl) (2- (tetrahydro-2H-pyran-4-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (352mg, crude) was dissolved in 20mL of anhydrous tetrahydrofuran, cooled to 0-5 ℃ in an ice water bath, and then dessimutan oxidant (350mg,0.8252mmol) was added to the solution, and the reaction was stirred at room temperature for 3 hours. The reaction solution was quenched by adding 30mL of saturated sodium thiosulfate solution and extracted 2 times with 50mL of ethyl acetate. Washing the organic phase with 60mL of saturated saline solution, drying the organic phase with anhydrous sodium sulfate, performing rotary drying under reduced pressure to obtain a crude product, and performing high performance liquid phase preparation to obtain the (2-chloro-4-phenoxyphenyl) (2- (tetrahydro-2H-pyran-4-yl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-8-yl) methanone (Z6, 15mg, 5% over 4 steps), light yellow solid, ES-API: [ M + H ]]⁺＝473.2。¹H NMR(500MHz,DMSO-d₆)δ12.79(s,1H),11.96(s,1H),8.67(s,1H),7.78(s,1H),7.65(d,J＝8.4Hz,1H),7.54-7.45(m,2H),7.27(t,J＝7.4Hz,1H),7.24-7.17(m,3H),7.06(dd,J＝8.4,2.4Hz,1H),3.99(d,J＝11.4Hz,2H),3.47(dd,J＝11.6,9.4Hz,3H),1.99(d,J＝12.8Hz,2H),1.91(td,J＝11.7,3.5Hz,2H)。

EXAMPLE 7 preparation of Compound Z7

The method comprises the following steps: adding 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] into the sealed tube]Pyridine-4, 5-diamine (150mg,0.5207mmol), 3-formylpiperidine-1-carboxylic acid tert-butyl ester (122mg,0.5724mmol) and palladium on charcoal (50mg, 10%), and finally anhydrous methanol (10.0mL) was added. The mixture was stirred at 120 ℃ for 6 hours under a sealed tube condition. Cooling the reaction system to room temperature, adding diatomite for filtration, and performing rotary drying on the solvent under reduced pressure to obtain a crude product of 3- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (260mg, crude) as a yellow solid. ES-API [ M + H ]]⁺＝482.2。

Step two: 3- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4,5-d ] is placed in a sealed tube]Pyrrolo [2,3-b]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester(260mg, crude) was dissolved in 10mL of methanol, 10mL of tetrahydrofuran and 2mL of water, and finally sodium hydroxide (191mg,4.781mmol) was added, and the reaction was stirred at 90 ℃ for 15 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 20mL of water and 5mL of a saturated ammonium chloride solution were added thereto, the pH was adjusted to about 8, and the mixture was extracted with 160mL of ethyl acetate. The organic phase was washed with 40mL of a saturated sodium bicarbonate solution and 60mL of a saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate and concentrated to give 3- (3, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (200mg, crude) as an off-white solid. ES-API [ M + H ]]⁺＝342.0

Step three: 3- (3, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (200mg, crude) and 2-chloro-4-phenoxybenzaldehyde (273mg,1.176mmol) were dissolved in methanol (10.0mL), the reaction cooled to 0 deg.C and potassium hydroxide (250mg,4.455mmol) added. The reaction was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was poured into 30mL of a saturated aqueous ammonium chloride solution, the pH was adjusted to 8, and 120mL of ethyl acetate was extracted. The organic phase was washed with 63mL of saturated brine, dried and concentrated to give crude 3- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) tert-butyl 1-carboxylic acid piperidine (408mg, crude) as a pale yellow solid. ES-API [ M + H ]]⁺＝574.2。

Step four: 3- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridine-2-yl) tert-butyl 1-carboxylic acid piperidine (408mg, crude) was dissolved in 20mL of anhydrous tetrahydrofuran, cooled to 0-5 ℃ in an ice-water bath, and then dessimutan oxidant (408mg,0.9623mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction solution was quenched by adding 30mL of saturated sodium thiosulfate solution and extracted 2 times with 60mL of ethyl acetate. Washing the organic phase with 70mL of saturated saline solution, drying the organic phase with anhydrous sodium sulfate, performing rotary drying under reduced pressure to obtain a crude product, and performing high performance liquid phase preparation to obtain the 3- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d ]Pyrrolo [2,3-b ] s]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (500mg, crude) as a pale yellow solid, ES-API: [ M + H ]]⁺＝572.2。

Step five: 3- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Azole compoundsAnd [2,3-b ]]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (500mg, crude) was dissolved in dichloromethane (12.0mL), and trifluoroacetic acid (4.0mL) was added thereto to conduct a reaction at room temperature for 3 hours. After the reaction is finished, the crude product obtained by decompressing and spin-drying the solvent is purified by high performance liquid chromatography to obtain (2-chloro-4-phenoxyphenyl) (2- (piperidine-3-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone 2,2, 2-trifluoroacetate (Z7, 40mg,5 steps total yield), as a pale white solid. ES-API [ M + H ]]⁺＝472.1。

EXAMPLE 8 preparation of Compounds Z8 and Z9

The method comprises the following steps: 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] is reacted with]Pyridine-4, 5-diamine (0.2g, 0.69mmol), 3-formylpyrrolidine-1-carboxylic acid tert-butyl ester (166mg,0.83mmol), 10% Pd/C (40mg) and methanol (6ml) were charged into a 20ml sealed tube, heated to 120 ℃ and reacted for 6 hours. Cooling to room temperature, filtering, concentrating, purifying with silica gel column to obtain 3- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (300mg, yield 92%). ES-API [ M + H ] ]⁺＝468.1。

Step two: reacting 3- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (300mg,0.64mmol) and sodium hydroxide (128mg,3.2mmol) were added to a mixed solvent of methanol/tetrahydrofuran/water (6ml/6ml/3ml), heated to 90 ℃ and reacted for 18 hours. Cooling to room temperature, adding saturated ammonium chloride aqueous solution to neutrality, extracting with ethyl acetate, washing with saturated saline solution, drying, filtering, and concentrating to obtain crude product 3- (3, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (220 mg). ES-API [ M + H ]]⁺＝328.1。

Step three: mixing the crude product 3- (3, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (220mg), 2-chloro-4-phenoxybenzaldehyde (188mg,0.81mmol) and potassium hydroxide (263mg,4.69mmol) were added to 6ml of methanol, and stirred at room temperature for 18 hours. After the reaction is finished, the reaction is carried outQuenching with ammonium chloride, extracting with ethyl acetate, concentrating, and purifying with silica gel column (0-7% methanol/dichloromethane) to obtain 3- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) tert-butylpyrrolidine-1-carboxylate (240mg, purity 59%). ES-API [ M + H ] ]⁺＝560.2。

Step four: reacting 3- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) tert-butylpyrrolidine-1-carboxylate (240mg, crude) was added to tetrahydrofuran (6ml), cooled to 0 ℃ and then DMP (363mg,0.86mmol) was added. After stirring at room temperature for 2 hours, the reaction was completed. Adding 10mL sodium thiosulfate aqueous solution for quenching, washing with saturated sodium bicarbonate aqueous solution and saturated brine in sequence, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by HPLC (column: Waters XB-C18150 mm × 19mm,5 um; column temperature: 25 deg.C flow rate: 15 mL/min; mobile phase A: 0.1% ammonium bicarbonate aqueous solution, B: ACN solution) to obtain 3- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (Z8, 76mg, yield 31%). ES-API [ M + H ]]⁺＝558.2。

Step five: 3- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (70mg,0.12mmol) was added to trifluoroacetic acid (0.5 mL)/dichloromethane (1 mL). After stirring at room temperature for 1 hour, the reaction was completed. The reaction solution was concentrated and purified by preparative HPLC (column: Waters XB-C18150 mm × 19mm,5 um; column temperature: 25 ℃ flow rate: 15 mL/min; mobile phase A: 0.1% aqueous ammonium bicarbonate solution, B: ACN solution) to give (2-chloro-4-phenoxyphenyl) (2- (pyrrolidin-3-yl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z9, 35mg, yield 63%). ES-API [ M + H ]]⁺＝458.0。¹H NMR(400MHz,DMSO-d₆)δ8.64(s,1H),7.77(s,1H),7.64-7.61(m,1H),7.50-7.47(m,2H),7.28-7.20(m,4H),7.07-7.05(m,1H),3.77-3.73(m,1H),3.23-3.21(m,1H),3.05-3.02(m,2H),2.91-2.88(m,1H),2.16-2.07(m,2H)。

EXAMPLE 9 preparation of Compound Z10

The method comprises the following steps: 1- (phenylsulfonyl) -1H-pyrrolo [2,3-b]Pyridine-4, 5-diamine (150mg,0.52mmol) and tert-butyl 3-formylazetidine-1-carboxylate (192mg,1.04mmol) were dissolved in methanol (5mL), palladium on carbon (15mg, 0.1% mmol) was added and the reaction stirred at 120 ℃ for 16 h. Adding diatomite, filtering, washing with 60mL ethyl acetate for 2 times, drying and concentrating to obtain crude product of 3- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) azetidine-1-carboxylic acid tert-butyl ester (241mg, crude), yellow solid. ES-API [ M + H ]]⁺＝454.1。

Step two: 3- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) azetidine-1-carboxylic acid tert-butyl ester (241mg,0.52mmol) was dissolved in 10mL methanol, 5mL tetrahydrofuran and 2mL water, sodium hydroxide (146mg,3.64mmol) was added and the reaction stirred at 90 ℃ for 12 h. To the reaction solution were added 15mL of water and 4mL of a saturated ammonium chloride solution, and the mixture was extracted with 100mL of ethyl acetate. The organic phase was washed with 20mL of a saturated sodium bicarbonate solution and 20mL of a saturated brine in this order, dried and concentrated to give 3- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b ]Pyridin-2-yl) azetidine-1-carboxylic acid tert-butyl ester (105mg, 64% yield) as an off-white solid. ES-API [ M + H ]]⁺＝314.1。

Step three: 3- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) azetidine-1-carboxylic acid tert-butyl ester (105mg,0.33mmol) and 2-chloro-4-phenoxybenzaldehyde (153mg,0.66mmol) were dissolved in methanol (8mL), the reaction cooled to 0 deg.C and potassium hydroxide (129mg,2.31mmol) added. The reaction was stirred at room temperature for 15 hours. The reaction mixture was poured into 60mL of water, adjusted to pH 8 with 1.0M dilute hydrochloric acid, and extracted with 80mL of ethyl acetate. The organic phase is washed with 25mL of saturated brine, dried and concentrated, and the crude product is purified using thin layer prep. plates (dichloromethane/7M ammonia methanol ═ 100:7.5) to give 3- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) tert-butyl 1-carboxylic acid azetidine (70mg, 39% yield) as a pale yellow solid. ES-API [ M + H ]]⁺＝546.1。

Step (ii) ofFourthly, the method comprises the following steps: 3- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) tert-butyl 1-carboxylic acid azetidine (70mg,0.13mmol) was dissolved in 6mL tetrahydrofuran, dess-martin oxidant (96mg,0.26mmol) was added and the reaction stirred at room temperature for 4 hours. 5mL of a saturated sodium thiosulfate solution and 20mL of a saturated sodium bicarbonate solution were added to the reaction solution, followed by extraction with 60mL of ethyl acetate. The organic phase is washed with 15mL of saturated brine, dried and concentrated, and the crude product is purified by column chromatography (dichloromethane/methanol 100:10) to give 3- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b]Pyridin-2-yl) azetidine-1-carboxylic acid tert-butyl ester (27mg, yield 38%) as a pale yellow solid. ES-API [ M + H ]]⁺＝544.0。

Step five: 3- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) azetidine-1-carboxylic acid tert-butyl ester (27mg,0.05mmol) was dissolved in 3mL dichloromethane, trifluoroacetic acid (2mL) was added, the reaction was stirred at room temperature for 1 hour and concentrated to give (2- (azetidin-3-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) (2-chloro-4-phenoxyphenyl) methanone (34mg, crude) as a pale yellow solid. ES-API [ M + H ]]⁺＝444.0。

Step six: (2- (azetidin-3-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) (2-chloro-4-phenoxyphenyl) methanone (34mg,0.07mmol) was dissolved in 3mL acetonitrile, aqueous formaldehyde (2mL) and sodium borohydride acetate (30mg,0.14mmol) were added, the reaction was stirred at room temperature for 1 hour, 60mL ethyl acetate was added and extracted, the organic phase was washed with 20mL saturated brine, dried and concentrated, and purified by preparative HPLC to give (2-chloro-4-phenoxyphenyl) (2- (1-methylazetidin-3-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z10, 8mg, yield: 25%) white solid. ES-API [ M + H ] ]⁺＝458.0。¹H NMR(500MHz,DMSO-d₆)δ12.82(s,1H),12.02(s,1H),8.70(s,1H),8.21(s,1H),7.79(s,1H),7.64(d,J＝8.4Hz,1H),7.49(t,J＝8.0Hz,2H),7.27(t,J＝7.4Hz,1H),7.21-7.20(m,3H),7.05(dd,J＝8.4,2.3Hz,1H),4.21-4.09(m,1H),3.74(t,J＝7.5Hz,3H),2.36(s,3H)。

EXAMPLE 10 preparation of Compound Z11

The method comprises the following steps: adding 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] into the sealed tube]Pyridine-4, 5-diamine (300mg,1.0416mmol), tert-butyl 2-formylpyrrolidine-1-carboxylate (249mg,1.250mmol) and palladium on charcoal (30mg, 10%) and finally anhydrous methanol (20.0mL) was added. The mixture was stirred at 120 ℃ for 6 hours under a sealed tube condition. Cooling the reaction system to room temperature, adding diatomite for filtration, and performing rotary drying on the solvent under reduced pressure to obtain a crude product of 2- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (250mg, yield 51%) as a yellow solid. ES-API [ M + H ]]⁺＝468.1。

Step two: in a sealed tube, 2- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ] is added]Pyrrolo [2,3-b]Pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (250mg,0.5353mmol) was dissolved in 12mL methanol, 2mL tetrahydrofuran and 2mL water, and finally sodium hydroxide (150mg,3.747mmol) was added and the reaction stirred at 90 ℃ for 18 h. After completion of the reaction, the reaction mixture was cooled to room temperature, 20mL of water and 5mL of a saturated ammonium chloride solution were added thereto, the pH was adjusted to about 8, and the mixture was extracted with 160mL of ethyl acetate. The organic phase was washed with 40mL of a saturated sodium bicarbonate solution and 60mL of a saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate and concentrated to give 2- (1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (160mg, 91% yield) as an off-white solid. ES-API [ M + H ]]⁺＝328.1

Step three: 2- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (160mg,0.4891mmol) and 2-chloro-4-phenoxybenzaldehyde (227mg,0.9783mmol) were dissolved in methanol (10.0mL), the reaction cooled to 0 deg.C and potassium hydroxide (191mg,3.423mmol) added. The reaction was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was poured into 33mL of a saturated aqueous ammonium chloride solution, the pH was adjusted to 8, and 110mL of ethyl acetate was extracted. The organic phase was washed with 60mL of saturated brine, dried and concentrated to give crude tert-butyl 2- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazoleAnd [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) pyrrolidine-1-carboxylic acid ester (400mg, crude), a light yellow solid. ES-API [ M + H ]]⁺＝560.2。

Step four: tert-butyl 2- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine-2-yl) pyrrolidine-1-carboxylic acid ester (400mg, crude) is dissolved in 30mL of anhydrous tetrahydrofuran, cooled to 0-5 ℃ in an ice water bath, and then dessimidine oxidant (300mg,0.7075mmol) is added, and the reaction is stirred at room temperature for 3 hours. The reaction solution was quenched by adding 30mL of saturated sodium thiosulfate solution and extracted 2 times with 60mL of ethyl acetate. Washing the organic phase with 70mL of saturated saline solution, drying the organic phase with anhydrous sodium sulfate, performing rotary drying under reduced pressure to obtain a crude product, and performing high performance liquid phase preparation to obtain the 2- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d ]Pyrrolo [2,3-b]Pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (Z11, 31mg, 11% over 2 steps), light yellow solid, ES-API: [ M + H ]]⁺＝558.1。

EXAMPLE 11 preparation of Compound Z12

The method comprises the following steps: tert-butyl 2- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine-2-yl) pyrrolidine-1-carboxylic acid ester (400mg, crude) is dissolved in 30mL of anhydrous tetrahydrofuran, cooled to 0-5 ℃ in an ice water bath, and then dessimidine oxidant (300mg,0.7075mmol) is added, and the reaction is stirred at room temperature for 3 hours. The reaction solution was quenched by adding 30mL of saturated sodium thiosulfate solution and extracted 2 times with 60mL of ethyl acetate. Washing the organic phase with 70mL of saturated saline solution, drying the organic phase with anhydrous sodium sulfate, and then carrying out rotary drying under reduced pressure to obtain a crude product of 2- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (300mg, crude) as a pale yellow solid, ES-API: [ M + H ]]⁺＝558.1。

Step two: 2- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (300mg, crude) was dissolved in dichloromethane (12mL),after adding trifluoroacetic acid (3.0mL), the mixture was stirred at room temperature for 2 hours. Purifying the crude product obtained after the solvent is decompressed and dried by spinning by high performance liquid chromatography to obtain (2-chloro-4-phenoxyphenyl) (2- (pyrrolidine-2-yl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z12, 8.56mg,3 steps Total yield 3.5%), a pale white solid, ES-API: [ M + H ]]⁺＝458.0。

EXAMPLE 12 preparation of Compound Z13

The method comprises the following steps: 1- (phenylsulfonyl) -1H-pyrrolo [2,3-b]Pyridine-4, 5-diamine (150mg,0.52mmol) and tetrahydro-2H-pyran-2-carbaldehyde (119mg,1.04mmol) were dissolved in methanol (5mL), palladium on carbon (15mg, 0.1% mmol) was added, and the reaction was stirred at 120 ℃ for 16 hours. Filtering with diatomaceous earth, washing with 60mL ethyl acetate for 2 times, drying, and concentrating to obtain 6- (benzenesulfonyl) -2- (tetrahydro-2H-pyran-2-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (211mg, crude), yellow solid. ES-API [ M + H ]]⁺＝383.0。

Step two: 6- (benzenesulfonyl) -2- (tetrahydro-2H-pyran-2-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (211mg,0.55mmol) was dissolved in 10mL methanol, 5mL tetrahydrofuran and 2mL water, sodium hydroxide (154mg,3.85mmol) was added, and the reaction was stirred at 90 ℃ for 12 hours. To the reaction solution were added 15mL of water and 4mL of a saturated ammonium chloride solution, and the mixture was extracted with 100mL of ethyl acetate. The organic phase was washed with 20mL of saturated sodium bicarbonate solution and 20mL of saturated brine in this order, dried and concentrated to give 2- (tetrahydro-2H-pyran-2-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b ]Pyridine (90mg, yield 68%) as an off-white solid. ES-API [ M + H ]]⁺＝243.0。

Step three: 2- (tetrahydro-2H-pyran-2-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (90mg,0.37mmol) and 2-chloro-4-phenoxybenzaldehyde (172mg,0.74mmol) were dissolved in methanol (8mL), the reaction was cooled to 0 deg.C and potassium hydroxide (145mg,2.59mmol) was added. The reaction was stirred at room temperature for 15 hours. The reaction mixture was poured into 60mL of water, adjusted to pH 8 with 1.0M dilute hydrochloric acid, and extracted with 80mL of ethyl acetate. 25mL of organic phaseWashed with saturated brine, dried and concentrated, and the crude product purified using thin layer prep. plates (dichloromethane/7M methanolic ammonia ═ 100:5) to give (2-chloro-4-phenoxyphenyl) (2- (tetrahydro-2H-pyran-2-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (62mg, yield 35%) as a pale yellow solid. ES-API [ M + H ]]⁺＝475.0。

Step four: (2-chloro-4-phenoxyphenyl) (2- (tetrahydro-2H-pyran-2-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (62mg,0.13mmol) was dissolved in 6mL tetrahydrofuran, dess-Martin oxidant (96mg,0.26mmol) was added and the reaction stirred at room temperature for 4 hours. 5mL of a saturated sodium thiosulfate solution and 20mL of a saturated sodium bicarbonate solution were added to the reaction solution, followed by extraction with 60mL of ethyl acetate. The organic phase is washed with 15mL of saturated brine, dried and concentrated, and the crude product is purified by preparative HPLC to give (2-chloro-4-phenoxyphenyl) (2- (tetrahydro-2H-pyran-2-yl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z13, 20mg, 33% yield) as a pale yellow solid. ES-API [ M + H ]]⁺＝473.0。¹H NMR(500MHz,DMSO-d₆)δ12.89(s,1H),11.40(s,1H),8.72(s,1H),7.85(s,1H),7.66(d,J＝8.4Hz,1H),7.49(t,J＝7.9Hz,2H),7.27(t,J＝7.4Hz,1H),7.23-7.15(m,3H),7.06(dd,J＝8.4,2.3Hz,1H),4.87(d,J＝10.8Hz,1H),4.09(d,J＝11.6Hz,1H),3.68(t,J＝10.6Hz,1H),2.09(d,J＝12.9Hz,1H),1.93(s,1H),1.90-1.78(m,1H),1.76-1.53(m,3H).

EXAMPLE 13 preparation of Compound Z14

The method comprises the following steps: 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridine-4, 5-diamine (200mg,0.694mmol), tert-butyl 2-formylmorpholine-4-carboxylate (179mg,0.833mmol), 5% Pd/C (20mg) and methanol (6mL) were charged into a 20mL vial, and the mixture was heated to 120 ℃ for 6 hours. LCMS check reaction complete. The reaction was cooled to room temperature, filtered, concentrated and the crude product was purified on silica gel flash column to give the product tert-butyl 2- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) morpholine-4-carboxylate (210mg, 50% yield). ES-API [ M + H ] + ═ 484.1.

Step two: tert-butyl 2- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) morpholine-4-carboxylate (210mg,0.435mmol) and sodium hydroxide (122mg,3.045mmol) were added to a mixed solvent of methanol/tetrahydrofuran/water (12mL/2mL/2mL), heated to 90 ℃ and stirred overnight. LCMS check reaction complete. The reaction mixture was cooled to room temperature, and saturated aqueous ammonium chloride solution was added thereto to make the mixture neutral, followed by extraction with ethyl acetate, washing with saturated brine, drying, filtration and concentration to give crude tert-butyl 2- (1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) morpholine-4-carboxylate (122mg, yield 82%). ES-API [ M + H ] + ═ 344.2.

Step three: the above crude tert-butyl 2- (1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) morpholine-4-carboxylate (122mg,0.356mmol), 2-chloro-4-phenoxybenzaldehyde (83mg,0.356mmol) and potassium hydroxide (140mg,2.492mmol) were added to 5mL of methanol and stirred at room temperature overnight. LCMS check reaction complete. Adding water into the reaction solution to quench and react, then adding 1N diluted hydrochloric acid to adjust the pH of the reaction solution to 4-5, extracting with ethyl acetate, concentrating, and purifying a crude product by a rapid silica gel column (0-7% methanol/dichloromethane) to obtain a product, namely tert-butyl 2- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) 4-carboxylic morpholine (125mg, yield 61%). ES-API: [ M + H ] + ═ 576.1.

Step four: adding tert-butyl 2- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) 4-carboxylic acid morpholine (125mg,0.217mmol) to tetrahydrofuran (15mL), cooling to 0 ℃, then adding dess-martin oxidant (138mg,0.326mmol), stirring at room temperature for 2 hours, LCMS detecting that the reaction is complete, adding 10mL sodium thiosulfate aqueous solution to quench the reaction, extracting ethyl acetate three times, washing the combined organic phases successively with saturated sodium bicarbonate aqueous solution and saturated saline, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude 2- (8- (2-chloro-4-phenoxybenzoyl) -1, tert-butyl 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) morpholine-4-carboxylate (124 mg). ES-API [ M + H ] + ═ 574.1.

Step five: trifluoroacetic acid (2mL) was added to 2- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) morpholine-4-carboxylic acid tert-butyl ester (124mg) in dichloromethane (4 mL). Stirred at room temperature for 1 hour. LCMS check reaction complete. Concentrating the reaction solution, and purifying by preparative HPLC to obtain (2-chloro-4-phenoxyphenyl) (2- (morpholine-2-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z14, 22.01mg, yield 22%). ES-API [ M + H ]]⁺＝474.1。¹H NMR(500MHz,DMSO-d₆)δ11.57(bs,2H),8.73(s,1H),7.85(s,1H),7.66(d,J＝9.0Hz,1H),7.51-7.48(m,2H),7.28-7.25(m,1H),7.22-7.20(m,3H),7.06(dd,J1＝3.0Hz,J2＝8.5Hz,1H),4.90(d,J＝7.0Hz,1H),3.95-3.92(m,1H),3.73-3.68(m,1H),3.22(dd,J1＝3.0Hz,J2＝12.5Hz,1H),3.00-2.96(m,1H),2.82-2.80(m,2H).

EXAMPLE 14 preparation of Compound Z15

The method comprises the following steps: to dry N.N-dimethylformamide (10.0mL) was added sodium hydride (300mg,7.5mmol) and then 4, 4-dimethoxybutan-2-ol (500mg,3.7288mmol) at room temperature, followed by stirring for 20 minutes and dropwise addition of 1- (chloromethyl) -4-methoxybenzene (705mg,4.518mmol) and reaction at room temperature for 24 hours. After the reaction, water (7.0mL) was added to quench the reaction, ethyl acetate was extracted 2 times (2 x 80mL), the organic phase was washed with saturated brine 1 time (60mL), dried over anhydrous sodium sulfate, filtered and rotary-dried under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain 1- ((((4, 4-dimethoxybut-2-yl) oxy) methyl-4-methoxybenzene (860mg, yield 90%).

Step two: 1- ((((4, 4-dimethoxybut-2-yl) oxy) methyl-4-methoxybenzene (860mg,3.385mmol) was dissolved in a mixed solution of acetic acid/water (5/1,30mL), stirred at room temperature for 48 hours after completion of the reaction, the solvent was dried by evaporation under reduced pressure to give 3- ((4-methoxybenzyl) oxy) butyraldehyde (240mg, yield 765%).

Step three: adding 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] into the sealed tube]Pyridine-4, 5-diamine (300mg,1.0416mmol), 3- ((4-methoxybenzyl)Yl) oxy) butyraldehyde (240mg,1.145mmol) and palladium on carbon (50mg, 10%), followed by addition of anhydrous methanol (20.0 mL). The mixture was stirred at 120 ℃ for 6 hours under a sealed tube condition. Cooling the reaction system to room temperature, adding diatomite for filtration, and performing rotary drying on the solvent under reduced pressure to obtain a crude product of 2- (2- ((4-methoxybenzyl) oxy) propyl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (210mg, yield 42%) as a brown solid. ES-API [ M + H ]]⁺＝477.1。

Step four: 2- (2- ((4-methoxybenzyl) oxy) propyl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ] in a sealed tube]Pyrrolo [2,3-b]Pyridine (200mg,0.4202mmol) was dissolved in 12mL methanol, 2mL tetrahydrofuran and 2mL water, and finally sodium hydroxide (117.6mg,2.9411mmol) was added and the reaction stirred at 90 ℃ for 18 h. After completion of the reaction, the reaction mixture was cooled to room temperature, 20mL of water and 5mL of a saturated ammonium chloride solution were added thereto, the pH was adjusted to about 8, and the mixture was extracted with 160mL of ethyl acetate. The organic phase was washed with 40mL of a saturated sodium bicarbonate solution and 60mL of a saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate and concentrated to give 2- (2- (((4-methoxybenzyl) oxy) propyl) -1, 6-dihydroimidazo [4,5-d ]Pyrrolo [2,3-b ] s]Pyridine (110mg, yield 74%) as an off-white solid. ES-API [ M + H ]]⁺＝337.1

Step five: 2- (2- (((4-methoxybenzyl) oxy) propyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (100mg,0.2976mmol) and 2-chloro-4-phenoxybenzaldehyde (200mg,0.8620mmol) were dissolved in methanol (20.0mL), the reaction was cooled to 0 deg.C and potassium hydroxide (120mg,2.083mmol) was added. The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into 33mL of a saturated aqueous ammonium chloride solution, the pH was adjusted to 8, and 110mL of ethyl acetate was extracted. The organic phase was washed with 60mL of saturated brine, dried and concentrated to give crude (2-chloro-4-phenoxyphenyl) (2- (2- (((4-methoxybenzyl) oxy) propyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridine-8-methanol) (240mg, crude) as a pale yellow solid. ES-API [ M + H ]]⁺＝569.2。

Step six: (2-chloro-4-phenoxyphenyl) (2- (2- (((4-methoxybenzyl) oxy) propyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridine-8-methanol) (240mg, crude) was dissolved in 30mL of dichloromethane and 2, 3-dichloro-5, 6-dicyan added at room temperature1, 4-benzoquinone (440mg,1.938mmol), the reaction was stirred at room temperature for 2 hours. The reaction solution was quenched by addition of 30mL of saturated sodium bicarbonate solution and extracted 2 times with 50mL of ethyl acetate. The organic phase was washed with 60mL of saturated brine, dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by preparative HPLC to give (2-chloro-4-phenoxyphenyl) (2- (2-hydroxypropyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-8-yl) methanone (Z15, 4.5mg, 4.5% yield), light yellow solid, ES-API: [ M + H ]]⁺＝447.1。

EXAMPLE 15 preparation of Compound Z16

The method comprises the following steps: 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] is reacted with]Pyridine-4, 5-diamine (0.3g, 1.04mmol), 2-methyl-2-morpholinopropanal (196mg,1.25mmol), 10% Pd/C (100mg), and methanol (10mL) were added to a 20mL sealed tube, heated to 120 ℃ and reacted for 6 hours. Cooled to room temperature, filtered and concentrated. The solid after concentration was dissolved in tetrahydrofuran (10mL), to which I was added₂(317mg,1.25mmol) the reaction was carried out at 65 ℃ for 16 hours. After the reaction was complete, the saturated sodium sulfite was quenched, extracted with ethyl acetate, concentrated and purified on column silica gel (0-7% methanol/dichloromethane) to give the crude 4- (2- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ] product]Pyrrolo [2,3-b]Pyridin-2-yl) propan-2-yl) morpholine (220mg, 50% purity). ES-API [ M + H ]]⁺＝426.1。

Step two: reacting 4- (2- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) propan-2-yl) morpholine (200mg) and sodium hydroxide (94mg,2.35mmol) were added to a mixed solvent of methanol/tetrahydrofuran/water (1mL/2mL/0.6mL), heated to 90 ℃ and reacted for 16 hours. Cooling to room temperature, adding saturated aqueous ammonium chloride solution to neutrality, concentrating to obtain crude product, and purifying by preparative HPLC (column: Waters XB-C18150 mm mm,5 um; column temperature: 25 deg.C flow rate: 15 mL/min; mobile phase A: 0.1% aqueous ammonium bicarbonate solution, B: ACN solution)) to obtain 4- (2- (1, 6-dihydroimidazo [4, 5-d) ] solution ]Pyrrolo [2,3-b ] s]Pyridin-2-yl) propan-2-yl) morpholine (20mg, 14% over two). ES-API [ M + H ]]⁺＝286.1。

Step three: reacting 4- (2- (1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) propan-2-yl) morpholine (20mg,0.07mmol), 2-chloro-4-phenoxybenzaldehyde (33mg,0.14mmol) and potassium hydroxide (27mg,0.49mmol) were added to 2mL of methanol, stirred at room temperature for 18 hours and at 50 ℃ for 6 hours. Quenching with saturated ammonium chloride, adding DCM/iPrOH (4: 1), extracting, drying, and concentrating to obtain (2-chloro-4-phenoxyphenyl) (2- (2-morpholinopropan-2-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (36mg, 33% purity). ES-API [ M + H ]]⁺＝518.1。

Step four: reacting (2-chloro-4-phenoxyphenyl) (2- (2-morpholinopropan-2-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (36mg, crude) was added to dioxane (3ml) and water (0.04ml), cooled to 0 ℃ and then DDQ (31mg,0.14mmol) was added. After stirring at room temperature for 2 hours, the reaction was completed. Adding 10mL sodium thiosulfate aqueous solution for quenching, washing with saturated sodium bicarbonate aqueous solution and saturated brine in sequence, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by HPLC (column: Waters XB-C18150 mm × 19mm,5 um; column temperature: 25 deg.C flow rate: 15 mL/min; mobile phase A: 0.1% ammonium bicarbonate aqueous solution, B: ACN solution) to obtain (2-chloro-4-phenoxyphenyl) (2- (2-morpholinopropan-2-yl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z16, 5mg, yield 14%). ES-API [ M + H ]]⁺＝516.1。¹H NMR(400MHz,DMSO-d₆)δ8.64(s,1H),7.77(s,1H),7.64-7.61(m,1H),7.50-7.47(m,2H),7.28-7.20(m,4H),7.07-7.05(m,1H),3.77-3.73(m,1H),3.23-3.21(m,1H),3.05-3.02(m,2H),2.91-2.88(m,1H),2.16-2.07(m,2H)。

EXAMPLE 16 preparation of Compound Z17

The method comprises the following steps: a borane-tetrahydrofuran solution (1M,15mL,15mmol) was added dropwise to 2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) acetic acid (1.7g,7.41mmol) in tetrahydrofuran (15mL) under ice-bath conditions. Warmed to room temperature and stirred for 3 hours, and thenThe reaction solution was quenched with methanol (10mL) and concentrated under reduced pressure to give the crude product as a clear oily compound, tert-butyl 3- (2-hydroxyethyl) pyrrolidine-1-carboxylate (1.5 g). ES-API [ M + Na ]]⁺＝238.1。

Step two: Des-Martin reagent (4.72g,11.15mmol) was slowly added to a solution of crude tert-butyl 3- (2-hydroxyethyl) pyrrolidine-1-carboxylate (800mg,3.72mmol) above in dichloromethane (50mL) and the mixture was stirred at room temperature for 3 h. The reaction was quenched with 30mL of saturated aqueous sodium thiosulfate, extracted three times with 30mL of dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified with a flash silica gel column (0-30% ethyl acetate/petroleum ether) to give 3- (2-oxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (250mg) as a colorless oily liquid with 100% purity in 32% yield. ES-API [ M + Na ]]⁺＝236.1

Step three: 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] is reacted with ]Pyridine-4, 5-diamine (250mg,0.87mmol), 3- (2-oxyethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (200mg,0.94mmol), 10% Pd/C (100mg) in methanol (2ml) mixed solution was reacted at 120 ℃ for 45 minutes by microwave. Cooling to room temperature, filtering, concentrating, purifying with flash silica gel column (0-10% methanol/dichloromethane) to obtain 3- (((6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d) product]Pyrrolo [2,3-b ] s]Pyridin-2-yl) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester (200mg) with 100% purity in 48% yield. ES-API [ M + H ]]⁺＝482.1。

Step four: reacting 3- (((6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester (150mg,0.31mmol) and sodium hydroxide (62mg,1.56mmol) were added to a mixed solvent of methanol/water (2ml/0.5ml), and microwave reaction was carried out at 90 ℃ for 1 hour. The reaction solution is concentrated to obtain crude product 3- (((1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl]Methyl) methyl group]Pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg). ES-API [ M + H ]]⁺＝342.3。

Step five: to the crude 3- (((1, 6-dihydroimidazo [4, 5-d) product]Pyrrolo [2,3-b]Pyridin-2-yl]Methyl) methyl group]To a solution of tert-butyl pyrrolidine-1-carboxylate (200mg,0.59mmol) in methanol (10mL) were added 2-chloro-4-phenoxybenzaldehyde (400mg,1.72mmol) and potassium hydroxide (230mg,4.10mmol), and the mixture was stirred at room temperature overnight. Inverse direction After completion, the pH was adjusted to 7 with 1M hydrochloric acid solution, extracted three times with 20mL ethyl acetate, the organic phases were combined, dried, concentrated and purified on a flash silica gel column (0-20% methanol/dichloromethane) to give tert-butyl 3- (((8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d) as a yellow solid]Pyrrolo [2,3-b ] s]Pyridin-2-yl) methyl) pyrrolidine-1-carboxylic acid ester (130mg) was obtained in 100% purity and 38% yield. ES-API [ M + H ]]⁺＝574.2。

Step six: to tert-butyl 3- (((8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) methyl) pyrrolidine-1-carboxylic acid ester (120mg,0.21mmol) was added to a mixed solution of 1, 4-dioxane/water (2ml/0.2ml) with 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (95mg,0.42mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction is finished, adding 2mL of sodium thiosulfate aqueous solution for quenching, adding 20mL of ethyl acetate, washing with 20mL of saturated sodium bicarbonate aqueous solution and 20mL of saturated saline solution in turn, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product of tert-butyl 3- (((8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) methyl) pyrrolidine-1-carboxylic acid salt (200 mg). ES-API [ M + H ] ]⁺＝572.2。

Step seven: to the crude tert-butyl 3- (((8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d) is added under ice-bath conditions]Pyrrolo [2,3-b]Pyridin-2-yl) methyl) pyrrolidine-1-carboxylic acid salt (200mg) in dichloromethane (4mL) was added trifluoroacetic acid (1mL) slowly and stirred at room temperature for 1 hour. After the reaction was complete, concentrated under reduced pressure and purified by preparative HPLC for base to give (2-chloro-4-phenoxyphenyl) (2- (pyrrol-3-ylmethyl) -1, 6-dihydroimidazo [4, 5-d) as an off-white solid]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z17, 58mg, purity 92%, yield 35%).¹H NMR(500MHz,DMSO-d₆)δ8.66(s,1H),7.80-7.76(m,1H),7.65(d,J＝8.5Hz,1H),7.51-7.46(m,2H),7.27(t,J＝7.5Hz,1H),7.23-7.18(m,3H),7.06(dd,J＝8.5,2.5Hz,1H),3.74-2.97(m,6H),2.82-2.67(m,1H),2.08-1.92(s,1H),1.74-1.57(m,1H).ES-API:[M+H]⁺＝472.0。

EXAMPLE 17 preparation of Compound Z18

The method comprises the following steps: 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] is reacted with]Pyridine-4, 5-diamine (0.25g, 0.87mmol), (1R,5S,6R) -6-formyl-3-azabicyclo [3.1.0]Hexane-3-carboxylic acid tert-butyl ester (220mg,1.04mmol), 10% Pd/C (50mg) and methanol (8ml) were charged into a 20ml stopcock, and the reaction was heated to 120 ℃ for 6 hours. Cooling to room temperature, filtering, concentrating, and purifying with silica gel column (0-80% ethyl acetate/petroleum ether) to obtain tert-butyl (1R,5S,6R) -6- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) -3-azabicyclo [3.1.0]Hexane-3-carboxylate (120mg, yield 28%). ES-API [ M + H ] ]⁺＝480.1。

Step two: tert-butyl (1R,5S,6R) -6- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) -3-azabicyclo [3.1.0]Hexane-3-carboxylate (120mg,0.25mmol) and sodium hydroxide (30mg,0.75mmol) were added to a mixed solvent of methanol/tetrahydrofuran/water (1mL/3mL/0.5mL), and the mixture was heated to 90 ℃ to react for 16 hours. Cooling to room temperature, adding saturated ammonium chloride aqueous solution to neutrality, extracting with ethyl acetate, washing with saturated saline solution, drying, and concentrating to obtain crude tert-butyl (1R,5S,6R) -6- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) -3-azabicyclo [3.1.0]Hexane-3-carboxylate (85 mg). ES-API [ M + H ]]⁺＝340.1。

Step three: mixing the crude product of tert-butyl (1R,5S,6R) -6- (1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) -3-azabicyclo [3.1.0]Hexane-3-carboxylic acid ester (85mg,0.25mmol), 2-chloro-4-phenoxybenzaldehyde (116mg,0.5mmol) and potassium hydroxide (98mg,1.75mmol) were added to 6ml of methanol, and stirred at room temperature for 18 hours. Quenching with saturated ammonium chloride, adding ethyl acetate for extraction, drying, and concentrating to obtain crude tert-butyl (1R,5S,6R) -6- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b]Pyridin-2-yl) -3-azabicyclo [3.1.0]Hexane-3-carboxylic acid ester (143 mg). ES-API [ M + H ]]⁺＝572.2。

Step four: tert-butyl (1R,5S,6R) -6- (8- (((2-chloro-4-phenoxy) phenylPhenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) -3-azabicyclo [3.1.0]Hexane-3-carboxylate (143mg, crude) was added to dioxane (3ml) and water (0.2ml), cooled to 0 ℃ and then DDQ (113mg,0.50mmol) was added. After stirring at room temperature for 2 hours, the reaction was completed. Quenching with saturated aqueous sodium bicarbonate solution, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, and purifying with silica gel column (0-10% methanol/dichloromethane) to obtain tert-butyl (1R,5S,6R) -6- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) -3-azabicyclo [3.1.0]Hexane-3-carboxylic acid ester (80mg, 56% yield in three steps). ES-API [ M + H ]]⁺＝570.1。

Step five: tert-butyl (1R,5S,6R) -6- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) -3-azabicyclo [3.1.0]Hexane-3-carboxylate (80mg,0.14mmol) was added to trifluoroacetic acid (1 mL)/dichloromethane (1 mL). Stir at room temperature for 30 minutes and concentrate the reaction to dryness to give an oil. The oily substance was dissolved in acetonitrile (3mL), followed by addition of aqueous formaldehyde (30%, 0.2mL) and sodium cyanoborohydride (18mg,0.29mmol) to the mixture, concentration of the reaction mixture, and preparative HPLC purification (column: Waters XB-C18150 mm × 19mm,5 μm; column temperature: 25 ℃ flow rate: 15 mL/min; mobile phase A: 0.1% aqueous ammonium bicarbonate solution, B: ACN solution)) to give (2-chloro-4-phenoxyphenyl) (2- ((1R,5S,6R) -3-methyl-3-azabicyclo [3.1.0 ] as a 2-chloro-4-phenoxyphenyl group ]Hex-6-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b ] s]Pyridin-8-yl) methanone (Z18, 35mg, yield 63%). ES-API [ M + H ]]⁺＝458.0。¹H NMR(400MHz,DMSO-d₆)δ8.64(s,1H),7.77(s,1H),7.64-7.61(m,1H),7.50-7.47(m,2H),7.28-7.20(m,4H),7.07-7.05(m,1H),3.77-3.73(m,1H),3.23-3.21(m,1H),3.05-3.02(m,2H),2.91-2.88(m,1H),2.16-2.07(m,2H)。

EXAMPLE 18 preparation of Compounds Z19, Z20, Z21

The first step is as follows: 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridine-4, 5-diamine (200mg,0.694mmol), (tert-butyl 2-oxyethyl) carbamate (133mg,0.833mmol), 5% Pd/C (20mg) and methanol (6mL) were charged into a 20mL vial, and the mixture was heated to 120 ℃ for 6 hours. LCMS check reaction complete. The reaction was cooled to room temperature, filtered, concentrated and the crude product was purified on silica gel flash column to give tert-butyl ((6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) methyl) carbamate (157mg, 42% yield). ES-API [ M + H ] + ═ 428.0.

Step two: tert-butyl ((6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) methyl) carbamate (157mg,0.368mmol) and sodium hydroxide (103mg,2.574mmol) were added to a mixed solvent of methanol/tetrahydrofuran/water (5mL/1mL/1mL), and the mixture was heated to 90 ℃ and stirred overnight. LCMS check reaction complete. The reaction mixture was cooled to room temperature, and saturated aqueous ammonium chloride solution was added thereto to make the reaction mixture neutral, followed by extraction with ethyl acetate, washing with saturated brine, drying, filtration and concentration to give crude tert-butyl carbamate ((1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) methyl) (77mg, yield 73%). ES-API [ M + H ] + ═ 288.1.

Step three: ((1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) methyl) (77mg,0.268mmol), 2-chloro-4-phenoxybenzaldehyde (62mg,0.268mmol), and potassium hydroxide (105mg,1.876mmol) were added to 5mL of methanol, and stirred at room temperature overnight. Reaction was checked by LCMS and about 20% product was formed. Adding water into the reaction solution to quench and react, then adding 1N diluted hydrochloric acid to adjust the pH of the reaction solution to 4-5, extracting with ethyl acetate, concentrating, and purifying a crude product through a quick silica gel column to obtain a product, namely tert-butyl (((8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) methyl carbamate (84mg, yield 60%). ES-API: [ M + H ] + ═ 520.2.

Step four: tert-butyl (((8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) methylcarbamate (84mg,0.162mmol) was added to tetrahydrofuran (10mL), cooled to 0 deg.C, then dess-martin oxidant (103mg,0.243mmol) was added, stirred at room temperature for 2 hours and LCMS checked that the reaction was complete. Adding 10mL of sodium thiosulfate aqueous solution to quench the reaction, and adding acetic acid BThe ester was extracted three times, and the combined organic phases were washed successively with a saturated aqueous sodium bicarbonate solution and a saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude tert-butyl ((8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-2-yl) methyl) carbamate (58 mg). Purification of 18mg of the crude product by preparative HPLC afforded tert-butyl ((8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d) as a white solid]Pyrrolo [2,3-b]Pyridin-2-yl) methyl) carbamate (Z19, 1.40 mg). ES-API [ M + H ]]⁺＝518.2。

Step five: trifluoroacetic acid (1mL) was added to a solution of crude tert-butyl ((8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) methyl) carbamate (40mg,0.077mmol) in dichloromethane (2 mL). Stirred at room temperature for 2 hours. LCMS check reaction complete. The reaction mixture was concentrated and purified by preparative HPLC to give (2- (aminomethyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-8-yl) (2-chloro-4-phenoxyphenyl) methanone (Z20, 9.2mg, yield 29%). ES-API [ M + H ] + -. 418.1.

Step six: (2- (aminomethyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-8-yl) (2-chloro-4-phenoxyphenyl) methanone (6mg,0.014mmol), acetic acid (0.86mg,0.014mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4mg,0.021mmol), N-diisopropylethylamine (3mg,0.021mmol) and 4-dimethylaminopyridine (0.86mg,0.007mmol) were dissolved in dichloromethane (2 mL). The reaction solution was stirred for 2 hours at room temperature. LCMS check reaction complete. The reaction was concentrated and purified by preparative HPLC to give N- ((8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) methyl) acetamide (Z21, 2.4mg, yield 38%). ES-API [ M + H ] + -. 460.0.

EXAMPLE 19 preparation of Compound Z22

The method comprises the following steps: 1- (phenylsulfonyl) -1H-pyrrolo [2,3-b]Pyridine-4, 5-diamine (500mg,1.74mmol) and 3-ethoxy-3-iminoEthyl propionate hydrochloride (679mg,3.48mmol) was dissolved in ethanol (20mL) and the reaction stirred at 95 ℃ overnight. Washing with 50mL of water, washing with 60mL of ethyl acetate for 2 times, drying, concentrating, and purifying by column chromatography (petroleum ether: ethyl acetate 20:1) to obtain 2- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b ] s]Pyridin-2-yl) acetic acid ethyl ester (937mg, yield: 70%) yellow solid. ES-API [ M + H ]]⁺＝385.0。

Step two: 2- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (937mg,2.44mmol) was dissolved in a mixture of tetrahydrofuran (20ml), methanol (4ml) and water (4ml), lithium hydroxide (491mg,20.44mmol) was added thereto, the reaction was carried out at room temperature for 3 hours, 1.0M diluted hydrochloric acid was added thereto to adjust pH to 6, and the mixture was concentrated and dried to obtain crude 2- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ] product]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid (1.1g, crude), white solid. ES-API [ M + H ]]⁺＝357.0。

Step three: 2- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid (1.1g,3mmol) was dissolved in DMF (20mL), methylamine hydrochloride (1g,15mmol) and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (5.7g,15mmol) were added, the reaction was allowed to react overnight at room temperature, 30mL of water was added to the reaction solution, and extraction was carried out with 50mL of ethyl acetate. The organic phase was washed three times with 20mL of saturated saline, dried, and purified by column chromatography to give N-methyl-2- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4,5-d ] ]Pyrrolo [2,3-b]Pyridin-2-yl) acetamide (450mg, 41% yield) as an off-white solid. ES-API [ M + H ]]⁺＝370.0。

Step four: n-methyl-2- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) acetamide (450mg,1.2mmol) was dissolved in 20mL methanol, 10mL tetrahydrofuran and 4mL water, sodium hydroxide (336mg,8.4mmol) was added and the reaction stirred at 90 ℃ for 12 h. To the reaction mixture were added 20mL of water and 5mL of a saturated ammonium chloride solution, and the mixture was extracted with 100mL of ethyl acetate. The organic phase was washed with 50mL of saturated sodium bicarbonate solution and 50mL of saturated brine in this order, dried and concentrated to give 2-methyl-1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (92mg, 45% yield) as an off-white solid. ES-API [ M + H ]]⁺＝173.0。

Step five: 2-methyl-1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (92mg,0.54mmol) was dissolved in methanol (8mL), the reaction was cooled to 0 deg.C, and potassium hydroxide (212mg,3.78mmol) was added. The reaction was stirred at room temperature overnight. The reaction was adjusted to pH 8 with 1.0M dilute hydrochloric acid. The organic phase was dried and concentrated and the crude product was purified using thin layer prep. plates (dichloromethane/7M methanolic ammonia ═ 100:8) to give (2-chloro-4-phenoxyphenyl) (2-methyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (32mg, yield 15%) as a pale yellow solid. ES-API [ M + H ] ]⁺＝405.0。

Step six: (2-chloro-4-phenoxyphenyl) (2-methyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b ] s]Pyridin-8-yl) methanol (32 mg,0.08mmol) was dissolved in 6mL tetrahydrofuran, dess-martin oxidant (72mg,0.16mmol) was added and the reaction stirred at room temperature for 4 hours. 5mL of a saturated sodium thiosulfate solution and 20mL of a saturated sodium bicarbonate solution were added to the reaction solution, followed by extraction with 60mL of ethyl acetate. The organic phase is washed with 15mL of saturated brine, dried and concentrated, and the crude product is purified by preparative HPLC to give (2-chloro-4-phenoxyphenyl) (2-methyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z22, 3.3mg, 10% yield) as a pale yellow solid. ES-API [ M + H ]]⁺＝403.0。

EXAMPLE 20 preparation of Compound Z23

Step one, 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridine-4, 5-diamine (558mg,1.938mmol), tert-butyl 3-formylmorpholine-4-carboxylate (500mg,2.326mmol), 5% Pd/C (40mg) and methanol (12mL) were added to a 20mL vial, heated to 120 ℃ and reacted for 6 hours. LCMS check reaction complete. The reaction was cooled to room temperature, filtered, concentrated and the crude product was purified on silica gel flash column to give the product tert-butyl 3- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) morpholine-4-carboxylate (148mg, 16% yield). ES-API [ M + H ] + ═ 484.1.

Step two tert-butyl 3- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) morpholine-4-carboxylate (148mg,0.306mmol) and sodium hydroxide (86mg,2.145mmol) were added to a mixed solvent of methanol/tetrahydrofuran/water (5mL/1mL/1mL), heated to 90 ℃ and stirred overnight. LCMS check reaction complete. The reaction solution was cooled to room temperature, and saturated aqueous ammonium chloride solution was added to the reaction solution to neutralize the reaction solution, followed by extraction with ethyl acetate, washing with saturated brine, drying, filtration and concentration to give crude tert-butyl 3- (1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) morpholine-4-carboxylate (105 mg). ES-API [ M + H ] + ═ 344.2.

Step three tert-butyl 3- (1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) morpholine-4-carboxylate (105mg,0.306mmol), 2-chloro-4-phenoxybenzaldehyde (71mg,0.306mmol) and potassium hydroxide (120mg,2.142mmol) were added to 10mL of methanol and stirred at room temperature overnight. Reaction was monitored by LCMS and very little product was formed, mostly starting material. The reaction solution was heated to 50 ℃ and reacted for 8 hours, and still little product was produced. Adding water into the reaction solution to quench and react, then adding 1N diluted hydrochloric acid to adjust the pH of the reaction solution to 4-5, extracting with ethyl acetate, concentrating, and purifying a crude product by preparative HPLC to obtain 3- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) tert-butyl 4-carboxylic morpholine (1.39mg, yield < 1%). ES-API: [ M + H ] + ═ 576.1.

Step four, adding morpholine-3- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) tert-butyl 4-carboxylate (1.39mg,0.0024mmol) to tetrahydrofuran (1mL), cooling to 0 ℃, then adding dess-martin oxidant (1.5mg,0.0036mmol), stirring at room temperature for 2 hours, LCMS detecting that the reaction is complete, adding 5mL sodium thiosulfate aqueous solution to quench the reaction, extracting with ethyl acetate for three times, washing the combined organic phases with saturated sodium bicarbonate aqueous solution and saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating to obtain crude product 3- (8- (2-chloro-4-phenoxybenzoyl) -1, tert-butyl 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) morpholine-4-carboxylate (1.37mg, yield 99%). ES-API: [ M + H ] + ═ 574.2.

Step five trifluoroacetic acid (0.5mL) was added to a solution of tert-butyl 3- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) morpholine-4-carboxylate (1.37mg,0.0024mmol) in dichloromethane (0.5 mL). Stirred at room temperature for 1 hour. LCMS check reaction complete. The reaction mixture was concentrated and purified by preparative HPLC to give (2-chloro-4-phenoxyphenyl) (2- (morpholin-3-yl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-8-yl) methanone (Z23, 0.55mg, yield 48%). ES-API [ M + H ] + ═ 474.1.

EXAMPLE 21 preparation of Compound Z24

The method comprises the following steps: 3- ((benzyloxy) methyl) cyclobutane-1-carboxylic acid (2g,9mmol) is dissolved in anhydrous tetrahydrofuran (20mL), borane tetrahydrofuran (9mL,18mmol,2M) is added dropwise in an ice-water bath under the protection of nitrogen, the reaction is stirred for 2 hours at room temperature, methanol (2mL) is added dropwise to quench the reaction, and after concentration, column chromatography purification is carried out to obtain (3- ((benzyloxy) methyl) cyclobutyl) methanol (0.9g, 48.5%) as colorless oil. ES-API [ M + H ]]⁺＝207.0。

Step two: (3- ((benzyloxy) methyl) cyclobutyl) methanol (0.9g,4.4mmol) was dissolved in 20mL of dichloromethane, dess-martin oxidant (4.0g, 8.8mmol) was added and the reaction stirred at 45 ℃ for 1 h. 5mL of a saturated sodium thiosulfate solution and 20mL of a saturated sodium bicarbonate solution were added to the reaction solution, followed by extraction with 60mL of dichloromethane. The organic phase was washed with 15mL of saturated brine, dried and concentrated, and the crude product was purified by preparative HPLC to give 3- ((benzyloxy) methyl) cyclobutane-1-carbaldehyde (303mg, yield 34%) as a pale yellow solid. ES-API [ M + H ]]⁺＝205.0。

Step three: 1- (phenylsulfonyl) -1H-pyrrolo [2,3-b]Pyridine-4, 5-diamine (150mg,0.52mmol) and 3- ((benzyloxy) methyl) cyclobutane-1-carbaldehyde (212mg,1.04mmol) were dissolved in methanol (5mL), palladium on charcoal (15mg) was added, and the reaction was stirred at 120 ℃ for 6 hours. Filtering with diatomite, washing with 50mL ethyl acetate for 2 times, drying and concentrating to obtain 2- (3- ((benzyloxy) methyl) cyclobutyl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ]Pyrrolo [2,3-b]Pyridine (252mg, crude), yellow solid. ES-API [ M + H ]]⁺＝473.0。

Step four: 2- (3- ((benzyloxy) methyl) cyclobutyl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (252mg,0.53mmol) was dissolved in hydrochloric acid (5ml, 37%), the reaction was stirred at 70 ℃ for 2 hours, concentrated and dried in vacuo to give crude (3- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclobutyl) methanol (242mg, crude) as a yellow solid. ES-API [ M + H ]]⁺＝383.0。

Step five: (3- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclobutyl) methanol (242mg,0.63mmol) was dissolved in 10mL methanol, 5mL tetrahydrofuran and 2mL water, sodium hydroxide (177mg,4.4mmol) was added and the reaction stirred at 90 ℃ for 12 h. To the reaction solution were added 15mL of water and 4mL of a saturated ammonium chloride solution, and the mixture was extracted with 50mL of ethyl acetate. The organic phase was washed with 20mL of a saturated sodium bicarbonate solution and 20mL of a saturated brine in this order, dried and concentrated to give (3- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclobutyl) methanol (59mg, 39% yield) as an off-white solid. ES-API [ M + H ]]⁺＝243.0。

Step six: (3- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b ]Pyridin-2-yl) cyclobutyl) methanol (59mg,0.24mmol) and 2-chloro-4-phenoxybenzaldehyde (111mg,0.48mmol) were dissolved in methanol (5mL), the reaction was cooled to 0 deg.C, and potassium hydroxide (94mg,1.68mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was poured into 60mL of water, adjusted to pH 8 with 1.0M dilute hydrochloric acid, and extracted with 80mL of ethyl acetate. The organic phase is washed with 25mL of saturated brine, dried and concentrated, and the crude product is purified using thin layer prep. plates (dichloromethane/7M methanolic ammonia ═ 100:5) to give (2-chloro-4-phenoxyphenyl) (2- (3- (hydroxymethyl) cyclobutyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (32mg, 28% yield) as a pale yellow solid. ES-API [ M + H ]]⁺＝475.0。

Step seven: (2-chloro-4-phenoxyphenyl) (2- (3- (hydroxymethyl) cyclobutyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (27mg,0.06mmol) was dissolved in 6mL of tetrahydrofuran 1mL of water, 2, 3-dichloro-5, 6-dicyan p-benzoquinone (96mg,0.12mmol) was added, and the reaction was stirred at room temperature for 1 hour. 20mL of saturated sodium bicarbonate solution was added to the reaction mixture, followed by 50mL of ethyl acetateAnd (5) extracting with ethyl acetate. The organic phase is washed with 15mL of saturated brine, dried and concentrated, and the crude product is purified by preparative HPLC to give (2-chloro-4-phenoxyphenyl) (2- (3- (hydroxymethyl) cyclobutyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z24, 1.1mg, 4% yield) as a pale yellow solid. ES-API [ M + H ]]⁺＝473.0。

EXAMPLE 22 preparation of Compounds Z25, Z25-1, Z25-2, Z25-3, Z25-4

The method comprises the following steps: a solution of dimethyl 2-allylmalonate (15g,87mmol) in tetrahydrofuran (60mL) was added dropwise to a solution of lithium aluminum hydride in tetrahydrofuran (1M,180mL) under ice-bath conditions, and the mixture was heated to 50 ℃ and stirred overnight. The reaction mixture was cooled to 0 ℃ and quenched with 6.83mL of water, 6.83mL of 15% sodium hydroxide solution, and 20mL of water in that order, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-allylpropane-1, 3-diol (10g) as a colorless liquid. ES-API [ M + H ]]⁺＝117.1。

Step two: add sodium bicarbonate (5.42g,65mmol) and iodine (16.39g,65mmol) to a solution of 2-allylpropane-1, 3-diol (5g,43mmol) in EtOAc/water (80mL/20 mL). The mixture was stirred at room temperature overnight, then quenched with 30mL of sodium thiosulfate solution and extracted three times with 30mL of ethyl acetate. The organic phases were combined, dried, concentrated and purified by flash column on silica gel (0-50% ethyl acetate/petroleum ether) to give (4g) 5- (iodomethyl) tetrahydrofuran-3-yl) methanol as a colourless liquid, 100% pure, 38% yield. ES-API [ M + H ]]⁺＝242.9。

Step three: the mixture (5- (iodomethyl) tetrahydrofuran-3-yl) methanol (3.6g,14.88mmol), potassium acetate (2.92g,29.76mmol), 18-crown-6 (393mg,1.49mmol) in N, N-dimethylformamide (6mL) was stirred in a microwave at 120 ℃ for 1 hour. The reaction mixture was poured into 50mL of ethyl acetate, washed three times with 30mL of saturated brine, dried and concentrated, and purified with flash silica gel column (0-60% ethyl acetate/petroleum ether) to give methyl (4- (hydroxymethyl) tetrahydrofuran-2-yl) acetate (1.2g) as a colorless liquid with a purity of 100% and a yield of 46%. ES-API [ M + H ] ]⁺＝175.1。

Step four: Des-Martin reagent (3.65g,8.61mmol) was slowly added to a solution of methyl (4- (hydroxymethyl) tetrahydrofuran-2-yl) acetate (500mg,2.87mmol) in dichloromethane (30mL) and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with 30mL of saturated aqueous sodium thiosulfate solution, extracted three times with 30mL of dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude methyl (4-formyltetrahydrofuran-2-yl) acetate (450 mg). ES-API [ M + Na ]]⁺＝173.0.

Step five: 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] is reacted with]Pyridine-4, 5-diamine (350mg,1.21mmol), (4-formyltetrahydrofuran-2-yl) acetic acid methyl ester (460mg,2.67mmol), 10% Pd/C (100mg) in methanol (2ml) was mixed and reacted at 120 ℃ for 1 hour. Cooling to room temperature, filtering, concentrating, purifying with flash silica gel column (0-100% ethyl acetate/petroleum ether) to obtain the product (4- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) tetrahydrofuran-2-yl) acetic acid methyl ester (200mg) with 100% purity in 37% yield. ES-API [ M + H ]]⁺＝441.0。

Step six: mixing (4- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) tetrahydrofuran-2-yl) acetic acid methyl ester (200mg,0.45mmol) and sodium hydroxide (91mg,2.27mmol) were added to a mixed solvent of methanol/water (2ml/0.5ml), and microwave reaction was carried out at 90 ℃ for 1 hour. Concentrating the reaction solution to obtain crude product (4- (1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-2-yl) tetrahydrofuran-2-yl) methanol (120 mg). ES-API [ M + H ]]⁺＝259.1。

Step seven: to the crude product (4- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) tetrahydrofuran-2-yl) methanol (120mg,0.46mmol) was added to a solution of 2-chloro-4-phenoxybenzaldehyde (324mg,1.39mmol) and potassium hydroxide (182mg,3.25mmol) in methanol (10mL) and stirred at room temperature overnight. After the reaction was complete, pH was adjusted to 7 with 1M hydrochloric acid solution, ethyl acetate 20mL was added and extracted three times, the organic phases were combined, dried, concentrated and purified on flash silica gel column (0-20% methanol/dichloromethane) to give (2-chloro-4-phenoxyphenyl) (2- (5- (hydroxymethyl) tetrahydrofuran-3-yl) -1, 6-dihydroimidazo [4, 5-d) as a yellow solid]Pyrrolo [2,3-b]Pyridin-8-ylmethanol (100mg)Purity 100% and yield 44%. ES-API [ M + H ]]⁺＝491.1。

Step eight: to (2-chloro-4-phenoxyphenyl) (2- (5- (hydroxymethyl) tetrahydrofuran-3-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]2, 3-dichloro-5, 6-dicyan-p-benzoquinone (92mg,0.41mmol) was added to a mixed solution of pyridin-8-ylmethanol (100mg,0.20mmol) and 1, 4-dioxane/water (2ml/0.2ml), and the mixture was stirred at room temperature for 2 hours. After the reaction is completed, 2mL of sodium thiosulfate aqueous solution is added for quenching, 20mL of ethyl acetate is added, 20mL of saturated sodium bicarbonate aqueous solution and 20mL of saturated common salt water are sequentially used for washing, anhydrous sodium sulfate is dried, filtered, concentrated, and a crude product is purified by a preparative HPLC alkaline method to obtain (2-chloro-4-phenoxyphenyl) (2- (5- (hydroxymethyl) tetrahydrofuran-3-yl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-8-yl) methanone (Z25, 42 mg).¹H NMR(500MHz,DMSO-d₆)δ12.81(s,1H),12.11(s,1H),8.70-8.64(m,1H),7.80(d,J＝3.0Hz,1H),7.65(d,J＝8.5Hz,1H),7.53-7.46(m,2H),7.27(t,J＝7.5Hz,1H),7.24-7.17(m,3H),7.08-7.02(m,1H),4.75(s,1H),4.26-4.20(m,1H),4.20-4.10(m,1H),4.10-3.96(m,2H),3.95-3.86(m,1H),3.56-3.45(m,1H),2.45-2.33(m,1H),2.22-2.10(m,1H).ES-API:[M+H]⁺＝489.0。

Step nine: z25(42mg,0.08mmol) was resolved by chiral preparative resolution (separation column: IA250mm × 4.6mm × 5um, mobile phase: n-hexane: isopropanol: 50, flow rate: 1mL/min, column temperature: 30 ℃) to give the following product: one isomer, whose structure is arbitrarily designated Z25-3(13.9mg, Peak 2, Retention time 8.61min, yield 33%), white solid, ES-API: [ M + H ]]⁺489.0; the other isomer, whose structure is arbitrarily designated Z25-4(5mg, Peak 3, Retention time 11.60min, yield 12%), white solid, ES-API: [ M + H ]]⁺489.0; and a mixture of the other two isomers, arbitrarily designated as a mixture of Z25-1 and Z25-2 (22mg, peak 1, retention time 6.85min, yield 52%), white solid. The mixture was further resolved by chiral preparative resolution (separation column: IG 250mm 4.6mm 5um, mobile phase: n-hexane: ethanol: diethylamine ═ 50:50:2, flow rate: 1mL/min, column temperature: 30 ℃) to give two isomers. One of the isomers, whose structure is arbitrarily designated Z25-1(6.7mg, Peak 1, Retention time 14.46min, yield 16%), whiteColored solid, ES-API: [ M + H ]]⁺489.0; and another isomer, whose structure is arbitrarily designated Z25-2(12.7mg, Peak 2, Retention time 18.76min, yield 30%), white solid, ES-API: [ M + H ] ]⁺＝489.0。

EXAMPLE 23 preparation of Compound Z26

The method comprises the following steps: 4-chloro-1H-pyrrole [2,3-b]Pyridine-5-carboxylic acid (196mg,1.0mmol) was suspended in 10mL of dichloromethane, oxalyl chloride (254mg,2.0mmol) and one drop of N, N-dimethylformamide were added under ice bath, and the reaction was stirred at room temperature for 4 hours. The reaction mixture was poured into 40mL of water, and extracted with 60mL of ethyl acetate. Concentrating the reaction solution to obtain 4-chloro-1H-pyrrole [2,3-b]Pyridine-5-carbonyl chloride (215mg, yield 100%) as a pink solid. ES-API [ M + H ]]⁺211.1 (methyl ester).

Step two: benzyl 4- (2- (tert-Butoxycarbonyl) hydrazinopiperidine-1-carboxylate (349mg,1.0mmol) dissolved in 10mL tetrahydrofuran was added N, N-diisopropylethylamine (516mg,4.0mmol), the reaction cooled to 0 deg.C and 4-chloro-1H-pyrrole [2,3-b ] slowly added]A suspension of pyridine-5-carbonyl chloride (343mg,1.14mmol) in 5mL of tetrahydrofuran was stirred for 30 minutes while cooling on ice. The reaction mixture was added with 25mL of water and extracted with 60mL of ethyl acetate. The organic phase was washed with 25mL of a saturated sodium bicarbonate solution and 25mL of a saturated sodium chloride solution in this order, dried and concentrated, and the crude product was purified with a flash silica gel column (methanol/dichloromethane: 0-4%) to give 4- (2- (tert-butoxycarbonyl) -1- (4-chloro-1H-pyrrolo [2,3-b ] -pyrrole]Pyridine-5-carbonyl) hydrazinylpiperidine-1-carboxylic acid benzyl ester (330mg, 63% yield) as a white solid. ES-API [ M + H ] ]⁺＝528.1。

Step three: 4- (2- (tert-Butoxycarbonyl) -1- (4-chloro-1H-pyrrolo [2, 3-b)]Benzyl pyridine-5-carbonyl) hydrazinopiperidine-1-carboxylate (290mg,0.55mmol) and 2-chloro-4-phenoxybenzaldehyde (383mg,1.65mmol) were dissolved in methanol (12mL), the reaction cooled to 0 deg.C and potassium hydroxide (216mg,3.85mmol) added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was adjusted to pH 8 with 1.0M dilute hydrochloric acid, 70mL of ethyl acetate was added, and the mixture was washed with 30mL of saturated brine, dried and concentrated to give a crude productPurification on thin-layer preparative plates (dichloromethane/methanol ═ 15:1) afforded 4- (2- (tert-butoxycarbonyl) -1- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrole [2,3-b]Pyridine-5-carbonyl) hydrazino) piperidine-1-carboxylic acid ester (95mg, 22% yield) as a light brown solid. ES-API [ M + Na ]]⁺＝782.0。

Step four: 4- (2- (tert-Butoxycarbonyl) -1- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrole [2,3-b]Pyridine-5-carbonyl) hydrazino) piperidine-1-carboxylic acid ester (75mg,0.10mmol) was dissolved in 10mL tetrahydrofuran, cooled to 0 deg.C, dess-martin oxidant (64mg,0.15mmol) was added and the reaction stirred at room temperature for 4 hours. 4mL of a saturated sodium thiosulfate solution and 10mL of a saturated sodium bicarbonate solution were added to the reaction solution, followed by extraction with 50mL of ethyl acetate. The organic phase was washed with 15mL of a saturated sodium bicarbonate solution and 15mL of a saturated sodium chloride solution in this order, dried and concentrated to give 4- (2- (tert-butoxycarbonyl) -1- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrolo [2,3-b ] -c ]Pyridine-5-carbonyl) hydrazino) piperidine-1-carboxylic acid ester (75mg, yield 100%) as a yellow solid. ES-API [ M + Na ]]⁺＝780.0。

Step five: 4- (2- (tert-Butoxycarbonyl) -1- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrole [2,3-b]Pyridine-5-carbonyl) hydrazino) piperidine-1-carboxylic acid ester (70mg,0.09mmol) was dissolved in 4.0M methanolic hydrogen chloride (5mL) and the reaction was stirred at room temperature for 16 h. Concentrating the reaction solution to obtain 4- (8- (2-chloro-4-phenoxybenzoyl) -3-oxo-3, 6-dihydropyrazolo [3,4-d]Pyrrole [2,3-b ]]Pyridin-2 (1H) -yl) piperidine-1-carboxylic acid ester (70mg, crude). ES-API [ M + H ]]⁺＝622.2。

Step six: 4- (8- (2-chloro-4-phenoxybenzoyl) -3-oxo-3, 6-dihydropyrazolo [3,4-d]Pyrrole [2,3-b ]]Pyridin-2 (1H) -yl) piperidine-1-carboxylic acid ester (70mg, crude) was dissolved in 3mL ethanol, 6.0M hydrochloric acid solution (3mL) was added at room temperature, and the reaction was stirred at 95 ℃ for 3 hours. The reaction was concentrated, 3mL of water was added, washed with 3mL of ethyl acetate, the aqueous layer was concentrated, 7.0M methanolic ammonia (5mL) was added, the mixture was concentrated again, and the crude product was purified by preparative HPLC to give 8- (2-chloro-4-phenoxybenzoyl) -2- (piperidin-4-yl) -1, 6-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Pyridin-3 (2H) -one (Z26, 30mg, 66% yield in two steps) was a yellow solid. ¹H NMR(500MHz,DMSO-d₆)δ8.36(s,1H),7.58-7.42(m,4H),7.25(t,J＝7.5Hz,1H),7.21-7.15(m,3H),7.01(dd,J＝8.5,2.5Hz,1H),4.45-4.37(m,1H),3.27(d,J＝12.0,2H),2.84(t,J＝12.0Hz,2H),2.19-2.09(m,2H),1.82(d,J＝10.5Hz,2H).ES-API:[M+H]⁺＝448.1。

EXAMPLE 24 preparation of Compound Z27

The method comprises the following steps: 3-Methoxybutan-1-ol (200mg,1.9mmol) was dissolved in 20mL of dichloromethane, and dess-martin oxidant (1.7g, 3.8mmol) was added to stir the reaction at room temperature for 30 minutes. 5mL of a saturated sodium thiosulfate solution and 20mL of a saturated sodium bicarbonate solution were added to the reaction solution, followed by extraction with 50mL of dichloromethane. The organic phase was washed with 15mL of saturated brine, dried and concentrated, and the crude product was purified by preparative column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give 3-methoxybutyraldehyde (156mg, yield 79%) as a pale yellow solid. ES-API [ M + H ]]⁺＝103.0。

Step two: 1- (phenylsulfonyl) -1H-pyrrolo [2,3-b]Pyridine-4, 5-diamine (150mg,0.52mmol) and 3-methoxybutyraldehyde (106mg,1.04mmol) were dissolved in methanol (5mL), palladium on carbon (15mg) was added, and the reaction was stirred at 120 ℃ for 6 hours. Filtering with diatomaceous earth, washing with 50mL ethyl acetate for 2 times, drying, and concentrating to obtain 2- (2-methoxypropyl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (202mg, crude), yellow solid. ES-API [ M + H ]]⁺＝371.0。

Step three: 2- (2-methoxypropyl) -6- (phenylsulfonyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (202mg,0.55mmol) was dissolved in 10mL methanol, 5mL tetrahydrofuran and 2mL water, sodium hydroxide (154mg,3.85mmol) was added, and the reaction was stirred at 90 ℃ overnight. To the reaction solution were added 15mL of water and 4mL of a saturated ammonium chloride solution, and the mixture was extracted with 50mL of ethyl acetate. The organic phase was washed with 20mL of a saturated sodium bicarbonate solution and 20mL of a saturated brine in this order, dried and concentrated to give 2- (2-methoxypropyl) -1, 6-dihydroimidazo [4,5-d ]Pyrrolo [2,3-b]Pyridine (91mg, 72% yield) as an off-white solid. ES-API [ M + H ]]⁺＝231.0。

Step four: 2- (2-methoxypropyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (91mg,0.39mmol) and 2-chloro-4-phenoxybenzaldehyde (181mg,0.78mmol) were dissolved in methanol (5mL), the reaction was cooled to 0 deg.C, and potassium hydroxide (153mg,2.73mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was poured into 60mL of water, adjusted to pH 8 with 1.0M dilute hydrochloric acid, and extracted with 80mL of ethyl acetate. The organic phase is washed with 25mL of saturated brine, dried and concentrated, and the crude product is purified using thin layer prep. plates (dichloromethane/7M methanolic ammonia ═ 100:5) to give (2-chloro-4-phenoxyphenyl) (2- (2-methoxypropyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (35mg, 19% yield) as a pale yellow solid. ES-API [ M + H ]]⁺＝463.0。

Step five: (2-chloro-4-phenoxyphenyl) (2- (2-methoxypropyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (35mg,0.07mmol) was dissolved in 6mL of tetrahydrofuran and 1mL of water, 2, 3-dichloro-5, 6-dicyan p-benzoquinone (39mg,0.14mmol) was added, and the reaction was stirred at room temperature for 30 minutes. 20mL of a saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with 50mL of ethyl acetate. The organic phase is washed with 15mL of saturated brine, dried and concentrated, and the crude product is purified by preparative HPLC to give (2-chloro-4-phenoxyphenyl) (2- (2-methoxypropyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-8-yl) methanone (Z27, 1.5mg, 5% yield) as a pale yellow solid. ES-API [ M + H ]]⁺＝461.0。

EXAMPLE 25 preparation of Compound Z28

The method comprises the following steps: 2-bromo-5-tosyl-5H-pyrrolo [2,3-b ]]Pyrazine (860mg,2.44mmol) was dissolved in 20mL of 1, 4-dioxane, tert-butyl carbamate (857mg,7.32mmol), cuprous iodide (23mg,0.122mmol), N, N' -dimethylethylenediamine (13mg,0.146mmol) and potassium carbonate (1.68g,12.2mmol) were added in that order, and the reaction was stirred at 100 ℃ for 6 hours. Filtering the reaction solution with diatomite, washing the filter cake with ethyl acetate, spin-drying the filtrate, and performing column chromatography to obtain (5-tosyl-5H-pyrrolo [2 ], [ solution of ] A2,3-b]Pyrazin-2-yl) carbamic acid tert-butyl ester (800mg, 84% yield) as a white solid. ES-API [ M + H ]]⁺＝389.0。

Step two: to a 25mL round bottom flask were added in sequence: (5-tosyl-5H-pyrrolo [2, 3-b)]Pyrazin-2-yl) carbamic acid tert-butyl ester (800mg,2.06mmol), 10mL dichloromethane, 2mL trifluoroacetic acid, the reaction stirred at room temperature for 2 hours. Concentrating the reaction solution, adding saturated solution of sodium carbonate, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, spin-drying, and performing column chromatography to obtain 5-tosyl-5H-pyrrolo [2,3-b ]]Pyrazin-2-amine (428mg, 73% yield) as a yellow solid. ES-API [ M + H ] ]⁺＝289.1。

Step three: 5-tosyl-5H-pyrrolo [2,3-b ]]Pyrazine-2-amine (428mg,1.48mmol) was dissolved in 4mL ethanol, tert-butyl 4- (2-bromoacetyl) piperidine-1-carboxylate (545mg,1.78mmol) was added, and the mixture was stirred for 5 hours at 100 ℃ by microwave reaction. Concentrating the reaction solution, and purifying by column chromatography to obtain 4- (3-tolyl-3H-imidazo [1, 2-a)]Pyrrolo [2,3-e]Pyrazin-7-yl) piperidine-1-carboxylic acid tert-butyl ester (180mg, yield 100%) as a colorless liquid. ES-API [ M + H ]]⁺＝496.1。

Step four: 4- (3-tolyl-3H-imidazo [1,2-a ]]Pyrrolo [2,3-e]Pyrazin-7-yl) piperidine-1-carboxylic acid tert-butyl ester (180mg,0.36mmol) was dissolved in 3mL1, 4-dioxane, 0.5mL water, sodium hydroxide (44mg,1.09mmol) was added and the reaction stirred at 50 ℃ in an oil bath for 3 hours. 5mL of water and 2mL of a saturated ammonium chloride solution were added to the reaction solution, followed by extraction with 100mL of ethyl acetate. The organic phase was washed with 10mL of saturated sodium bicarbonate solution and 10mL of saturated brine in this order, dried and concentrated to give the crude 4- (3H-imidazo [1,2-a ] product]Pyrrolo [2,3-e]Pyrazin-7-yl) piperidine-1-carboxylic acid tert-butyl ester, yellow liquid. ES-API [ M + H ]]⁺＝342.0。

Step five: crude product of 4- (3-tolyl-3H-imidazo [1, 2-a)]Pyrrolo [2,3-e]Pyrazin-7-yl) piperidine-1-carboxylic acid tert-butyl ester and 2-chloro-4-phenoxybenzaldehyde (168mg,0.72mmol) were dissolved in anhydrous methanol (5mL), the reaction solution was cooled to 0 ℃, potassium hydroxide (141mg,2.52mmol) was added, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was poured into 50mL of water, adjusted to pH 8 with 1.0M dilute hydrochloric acid, and extracted with 80mL of ethyl acetate. For organic phase 30 Washing with mL of saturated brine, drying over anhydrous sodium sulfate, concentrating, and performing column chromatography (ethyl acetate/petroleum ether ═ 0-100%) to give 4- (1- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -3H-imidazo [1,2-a ] methyl)]Pyrrolo [2,3-e]Pyrazin-7-yl) piperidine-1-carboxylic acid tert-butyl ester (110mg,0.19mmol), yellow solid. ES-API [ M + H ]]⁺＝574.2。

Step six: reacting 4- (1- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -3H-imidazo [1, 2-a)]Pyrrolo [2,3-e]Pyrazin-7-yl) piperidine-1-carboxylic acid tert-butyl ester (110mg,0.19mmol) was dissolved in 10mL tetrahydrofuran, cooled to 0 deg.C, dess-martin oxidant (162mg,0.38mmol) was added and the reaction stirred at room temperature for 2 hours. 6mL of a saturated sodium thiosulfate solution and 20mL of a saturated sodium bicarbonate solution were added to the reaction solution, followed by extraction with 50mL of ethyl acetate. The organic phase is washed with 15mL of saturated brine, dried and concentrated, and the crude product is purified by column chromatography (ethyl acetate/petroleum ether ═ 0-100%) to give 4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (73mg, 67% yield) as a yellow liquid. ES-API [ M + H ]]⁺＝572.2。

Step seven: 4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ] ]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (73mg,0.13mmol) was dissolved in 3mL dichloromethane, cooled to 0 deg.C, 1mL trifluoroacetic acid was added and the reaction stirred at room temperature for 1 hour. The reaction mixture was concentrated, 15mL of saturated sodium bicarbonate solution was added, and the mixture was extracted 2 times with 20mL of ethyl acetate. The organic phase is washed with 10mL of saturated brine, dried and concentrated, and the crude product is purified by preparative HPLC acid method to give 4- (1- (2-chloro-4-phenoxybenzoyl) -3H-imidazo [1,2-a ]]Pyrrolo [2,3-e]Pyrazin-7-yl) piperidine-1-carboxylate (Z28, 11.6mg, 19% yield) as a white solid. ES-API [ M + H ]]⁺＝472.1。¹H NMR(400MHz,DMSO-d₆)δ8.84(s,1H),8.69(s,1H),8.39(s,1H),7.65(s,1H),7.59(d,J＝8.4Hz,1H),7.52-7.44(m,2H),7.30-7.23(m,1H),7.21-7.14(m,3H),7.04(dd,J＝8.4,2.4Hz,1H),3.41-3.29(m,2H),3.24-3.11(m,1H),3.10-2.96(m,2H),2.26-2.16(m,2H),2.03-1.82(m,2H).

EXAMPLE 26 preparation of Compound Z29

The method comprises the following steps: 4-chloro-1- (triisopropylsilyl) -1H-pyrrolo [2,3-b]Pyridine-5-carbaldehyde (1.72g,5.1mmol) was dissolved in 20mL of THF, cooled to 0 deg.C, and 1N isopropyl magnesium chloride in tetrahydrofuran (10.2mL,10.2mmol) was added dropwise, after which the reaction was stirred at room temperature for 1 hour. Dropwise adding saturated ammonium chloride solution at 0 ℃ to the reaction solution for quenching, washing with ethyl acetate, drying with anhydrous sodium sulfate, spin-drying, and performing column chromatography (ethyl acetate/petroleum ether is 0-20%) to obtain 1- (4-chloro-1- (triisopropylsilyl) -1H-pyrrolo [2,3-b ]]Pyridin-5-yl) -2-methylpropan-1-ol (1.9g, 98% yield) as a yellow liquid. ES-API [ M + H ] ]⁺＝381.3。

Step two: 1- (4-chloro-1- (triisopropylsilyl) -1H-pyrrolo [2, 3-b)]Pyridin-5-yl) -2-methylpropan-1-ol (1.9g, 5.1mmol) was dissolved in 10mL tetrahydrofuran, cooled to 0 deg.C, dess-Martin oxidant (3.2g, 7.5mmol) was added and the reaction stirred at room temperature for 2 hours. 10mL of a saturated sodium thiosulfate solution and 20mL of a saturated sodium bicarbonate solution were added to the reaction solution, followed by extraction with 100mL of ethyl acetate. The organic phase is washed with 20mL of saturated brine, dried and concentrated, and the crude product is purified by column chromatography (ethyl acetate/petroleum ether ═ 0-10%) to yield 1- (4-chloro-1- (triisopropylsilyl) -1H-pyrrolo [2,3-b ] pyrrole]Pyridin-5-yl) -2-methylpropan-1-one (1.6g, 84% yield) as a pale yellow liquid. ES-API [ M + H ]]⁺＝379.3。

Step three: to a 25mL round bottom flask were added in sequence: 1- (4-chloro-1- (triisopropylsilyl) -1H-pyrrolo [2, 3-b)]Pyridin-5-yl) -2-methylpropan-1-one (1.1g,2.9mmol), 10mL tetrahydrofuran and 5.8mL tetrabutylammonium fluoride 1M tetrahydrofuran solution, the reaction was stirred at room temperature for 1 hour. Adding 20mL of water into the reaction solution, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, spin-drying, and performing column chromatography to obtain 1- (4-chloro-1H-pyrrolo [2,3-b ] pyrrole ]Pyridin-5-yl) -2-methylpropan-1-one (630mg, 96% yield) as a pale yellow liquid. ES-API [ M + H ]]⁺＝223.1。

Step four: 1- (4-chloro-1H-pyridine)Pyrrolo [2,3-b]Pyridin-5-yl) -2-methylpropan-1-one (630mg,2.83mmol) was dissolved in 10mL of anhydrous DMF, 60% NaH (170mg,4.25mmol) was added at 0 deg.C, stirred at this temperature for 15min, and PhSO was added dropwise to the reaction system₂Cl (1g, 5.66 mmol). Stirred at room temperature for 2 hours. Adding saturated ammonium chloride solution, quenching, extracting with ethyl acetate, drying with anhydrous sodium sulfate, concentrating the reaction solution, and purifying by column chromatography (ethyl acetate/petroleum ether is 0-30%) to obtain 1- (4-chloro-1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-5-yl) -2-methylpropan-1-one (150mg, yield 15%) as a colorless liquid. ES-API [ M + H ]]⁺＝363.1。

Step five: 1- (4-chloro-1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-5-yl) -2-methylpropan-1-one (75mg,0.21mmol) was dissolved in 5mL anhydrous DMF and NaN was added₃(16mg,0.25mmol), stirring at 60 ℃ for 1 hour, adding 3mL of saturated aqueous sodium bicarbonate solution to the reaction system, extracting with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, and purifying by column chromatography (ethyl acetate/petroleum ether: 0-30%) to obtain 2, 2-dimethyl-6- (benzenesulfonyl) -1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d) ]Pyridin-3 (2H) -one (60mg, 83% yield) as a yellow liquid. ES-API [ M + H ]]⁺＝342.1。

Step six: 2, 2-dimethyl-6- (phenylsulfonyl) -1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d]Pyridin-3 (2H) -one (60mg,0.176mmol) was dissolved in 3mL methanol, 1mL tetrahydrofuran and 0.5mL water, sodium hydroxide (39mg,0.88mmol) was added and the reaction stirred for 2 hours at 60 ℃ in an oil bath. Concentrating the reaction solution to obtain a crude product 2, 2-dimethyl-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d]Pyridin-3 (2H) -one, brown liquid. ES-API [ M + H ]]⁺＝202.1。

Step seven: mixing the crude product of 2, 2-dimethyl-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d]Pyridin-3 (2H) -one and 2-chloro-4-phenoxybenzaldehyde (190mg,0.82mmol) were dissolved in anhydrous methanol (5mL), the reaction was cooled to 0 deg.C, potassium hydroxide (46mg,0.82mmol) was added, and the reaction was stirred at 50 deg.C for 2 hours. The reaction mixture was poured into 10mL of water, adjusted to pH 8 with 1.0M dilute hydrochloric acid, and extracted with 80mL of ethyl acetate. The organic phase was washed with 30mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (ethyl acetate/petroleum ether: 0-100%) to obtain 8- ((2-Chloro-4-phenoxyphenyl) (hydroxy) methyl) -2, 2-dimethyl-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d]Pyridin-3 (2H) -one (22mg, 31% yield) as a yellow solid. ES-API [ M + H ] ]⁺＝434.1。

Step eight: mixing 8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -2, 2-dimethyl-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d]Pyridin-3 (2H) -one (22mg,0.05mmol) was dissolved in 10mL tetrahydrofuran, cooled to 0 deg.C, dess-martin oxidant (42mg,0.10mmol) was added and the reaction stirred at room temperature for 1 hour. 3mL of a saturated sodium thiosulfate solution and 10mL of a saturated sodium bicarbonate solution were added to the reaction solution, followed by extraction with 50mL of ethyl acetate. The organic phase is washed with 10mL of saturated brine, dried and concentrated, and the crude product is purified by preparative HPLC to give 8- (2-chloro-4-phenoxybenzoyl) -2, 2-dimethyl-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d]Pyridin-3 (2H) -one (Z29, 1.3mg, 6% yield) as a white solid. ES-API [ M + H ]]⁺＝432.1。¹H NMR(400MHz,DMSO-d₆)δ12.79(s,1H),8.33(s,1H),8.04(s,1H),7.70(s,1H),7.63(d,J＝8.4Hz,1H),7.55-7.43(m,2H),7.31-7.24(m,1H),7.23-7.15(m,3H),7.03(dd,J＝8.4,2.4Hz,1H),1.33(s,6H).

EXAMPLE 27 preparation of Compounds Z30, Z30-1, Z30-2

The method comprises the following steps: 1- (phenylsulfonyl) -1H-pyrrolo [2,3-b]Pyridine-4, 5-diamine (300mg,1.04mmol) and 3-methoxybutyraldehyde (420mg,2.08mmol) were dissolved in methanol (10mL), palladium on carbon (30mg) was added, and the reaction was stirred at 120 ℃ overnight. Filtering with diatomaceous earth, washing with 50mL ethyl acetate for 2 times, concentrating, and purifying with column chromatography (petroleum ether: ethyl acetate 10:1) to obtain 2- (1- ((tert-butyldimethylsilyl) oxy) propan-2-yl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ]Pyrrolo [2,3-b]Pyridine (232mg, yield: 47%) as a yellow solid. ES-API [ M + H ]]⁺＝471.0。

Step two: 2- (1- ((tert-butyldimethylsilyl) oxy) propan-2-yl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (232mg,0.49mmol) in waterTo 10mL of methanol, 5mL of tetrahydrofuran and 2mL of water was added sodium hydroxide (137mg,3.43mmol), and the reaction was stirred at 90 ℃ overnight. To the reaction solution were added 15mL of water and 4mL of a saturated ammonium chloride solution, and the mixture was extracted with 50mL of ethyl acetate. The organic phase was washed with 20mL of a saturated sodium bicarbonate solution and 20mL of a saturated brine in this order, dried and concentrated to give 2- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) propan-1-ol (89mg, 84% yield) as an off-white solid. ES-API [ M + H ]]⁺＝217.0。

Step three: 2- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) propan-1-ol (89mg,0.41mmol) and 2-chloro-4-phenoxybenzaldehyde (190mg,0.82mmol) were dissolved in methanol (5mL), the reaction cooled to 0 deg.C and potassium hydroxide (161mg,2.87mmol) added. The reaction was stirred at room temperature overnight. The reaction mixture was poured into 60mL of water, adjusted to pH 8 with 1.0M dilute hydrochloric acid, and extracted with 80mL of ethyl acetate. The organic phase is washed with 25mL of saturated brine, dried and concentrated, and the crude product is purified using thin layer prep. plates (dichloromethane/7M ammonia methanol ═ 100:5) to give 2- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d ]Pyrrolo [2,3-b]Pyridin-2-yl) propan-1-ol (60mg, 33% yield) as a pale yellow solid. ES-API [ M + H ]]⁺＝449.1。

Step four: 2- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) propan-1-ol (60mg,0.14mmol) was dissolved in 6mL of tetrahydrofuran and 1mL of water, 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (64mg,0.28mmol) was added, and the reaction was stirred at room temperature for 30 minutes. 20mL of a saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with 50mL of ethyl acetate. The organic phase is washed with 15mL of saturated brine, dried and concentrated, and the crude product is purified by preparative HPLC to give (2-chloro-4-phenoxyphenyl) (2- (1-hydroxypropan-2-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z30, 20mg, 32% yield) as a pale yellow solid. ES-API [ M + H ]]⁺＝447.1。¹H NMR(400MHz,DMSO-d₆)δ12.81(s,1H),11.79(s,1H),8.67(s,1H),7.80(d,J＝3.1Hz,1H),7.65(d,J＝8.4Hz,1H),7.53-7.43(m,2H),7.27(t,J＝7.4Hz,1H),7.21(dd,J＝6.8,1.6Hz,3H),7.06(dd,J＝8.4,2.4Hz,1H),5.15(t,J＝5.1Hz,1H),3.82-3.65(m,2H),3.44(dt,J＝13.2,6.7Hz,1H),1.36(d,J＝7.0Hz,3H).

Step five: z30(18mg) was resolved manually (mobile phase: n-hexane: ethanol 60: 40; column: IE250 mm: 4.6mm 5 um; flow rate: 1.0 ml/min; column temperature: 40.3 ℃) to give the two isomers. An isomer, the structure of which is arbitrarily designated as (R) - (2-chloro-4-phenoxyphenyl) (2- (1-hydroxypropan-2-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z30-1, peak 1, retention time: 11.590min, 7mg, purity: 100%, ee value: 100%), ES-API [ M + H ] ]⁺447.0; and another isomer, the structure of which is arbitrarily designated (S) - (2-chloro-4-phenoxyphenyl) (2- (1-hydroxypropan-2-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z30-2, peak 2, retention time: 13.293min, 7mg, purity: 100%, ee value: 100%), ES-API [ M + H ]]⁺＝447.1。

EXAMPLE 28 preparation of Compound Z31

The method comprises the following steps: 2- (tetrahydro-2H-pyran-4-yl) hydrazine-1-carboxylic acid tert-butyl ester (572mg,2.65mmol) dissolved in 25mL tetrahydrofuran was added N, N-diisopropylethylamine (1.05g, 8.16mmol), the reaction cooled to 0 deg.C and 4-chloro-1H-pyrrole [2,3-b ] slowly added in portions]Pyridine-5-carbonyl chloride (438mg,2.04mmol), and the reaction was stirred for 30 minutes under ice bath. The reaction mixture was added with 50mL of water, and extracted with 100mL of ethyl acetate. The organic phase was washed with 30mL of saturated sodium bicarbonate solution and 30mL of saturated brine in this order, dried and concentrated, and the crude product was purified with flash silica gel column (methanol/dichloromethane: 0-4%) to give 2- (4-chloro-1H-pyrrolo [2,3-b ] -pyrrole]Pyridine-5-carbonyl) -2- (tetrahydro-2H-pyran-4-yl) hydrazine-1-carboxylic acid tert-butyl ester (550mg, 68% yield) as a white solid. ES-API [ M + H ]]⁺＝395.2。

Step two: 2- (4-chloro-1H-pyrrole [2, 3-b)]Pyridine-5-carbonyl) -2- (tetrahydro-2H-pyran-4-yl) hydrazine-1-carboxylic acid tert-butyl ester (250mg,0.63mmol) and 2-chloro-4-phenoxybenzaldehyde (588mg,2.52mmol) were dissolved in methanol (10mL), the reaction cooled to 0 deg.C and potassium hydroxide (247mg,4.41mmol) added. The reaction was stirred at room temperature for 18 hours. For reaction solution 1.0M dilute hydrochloric acid to pH 8, 80mL ethyl acetate was added, washed with 30mL saturated brine, dried and concentrated, and the crude product was purified using a thin layer prep plate (dichloromethane/methanol 15:1) to give 2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrole [2,3-b ] -pyrrole]Pyridine-5-carbonyl) -2- (tetrahydro-2H-pyran-4-yl) hydrazine-1-carboxylic acid tert-butyl ester (130mg, yield 33%) as a white solid. ES-API [ M + H ]]⁺＝627.1。

Step three: 2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrole [2,3-b]Pyridine-5-carbonyl) -2- (tetrahydro-2H-pyran-4-yl) hydrazine-1-carboxylic acid tert-butyl ester (118mg,0.19mmol) was dissolved in 8mL tetrahydrofuran, cooled to 0 deg.C, dess-martin oxidant (145mg,0.34mmol) was added and the reaction stirred at room temperature for 16H. 5mL of a saturated sodium thiosulfate solution and 10mL of a saturated sodium bicarbonate solution were added to the reaction solution, followed by extraction with 60mL of ethyl acetate. The organic phase was washed with 15mL of a saturated sodium bicarbonate solution and 15mL of a saturated sodium chloride solution in this order, dried and concentrated to give 2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrole [2,3-b ]]Pyridine-5-carbonyl) -2- (tetrahydro-2H-pyran-4-yl) hydrazine-1-carboxylic acid tert-butyl ester (118mg, crude) as a yellow solid. ES-API [ M + H ]]⁺＝625.2。

Step four: 2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrole [2,3-b ]Pyridine-5-carbonyl) -2- (tetrahydro-2H-pyran-4-yl) hydrazine-1-carboxylic acid tert-butyl ester (118mg, crude) was dissolved in 4.0M methanolic hydrogen chloride (8mL) and the reaction was stirred at room temperature for 6H. Concentrating the reaction solution, basifying with 7.0M methanolic ammonia solution, concentrating again, and purifying the crude product by preparative HPLC to obtain 8- (2-chloro-4-phenoxybenzoyl) -2- (tetrahydro-2H-pyran-4-yl) -1, 6-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b ] s]Pyridin-3 (2H) -one (Z31, 45mg, 49% yield over two steps) was obtained as a pale yellow solid.¹H NMR(400MHz,DMSO-d₆)δ13.01(s,1H),10.43(s,1H),8.60(s,1H),7.84(s,1H),7.62(d,J＝8.4Hz,1H),7.54-7.44(m,2H),7.27(t,J＝7.6Hz,1H),7.23-7.15(m,3H),7.04(dd,J＝8.4,2.4Hz,1H),4.53-4.40(m,1H),3.99(dd,J＝11.2,4.0Hz,2H),3.45(t,J＝11.2Hz,2H),2.30-2.17(m,2H),1.78(dd,J＝11.2,2.0Hz,2H).ES-API:[M+H]⁺＝489.1。

EXAMPLE 29 preparation of Compound Z32

The method comprises the following steps: 2-Isopropylhydrazine-1-carboxylic acid tert-butyl ester (461mg,2.65mmol) dissolved in 25mL tetrahydrofuran was added N, N-diisopropylethylamine (1.05g, 8.16mmol), the reaction cooled to 0 deg.C and 4-chloro-1H-pyrrole [2,3-b ] slowly added in portions]Pyridine-5-carbonyl chloride (438mg,2.04mmol), and the reaction was stirred for 30 minutes under ice bath. The reaction mixture was added with 50mL of water, and extracted with 100mL of ethyl acetate. The organic phase was washed with 30mL of saturated sodium bicarbonate solution and 30mL of saturated brine in this order, dried and concentrated, and the crude product was purified with flash silica gel column (methanol/dichloromethane: 0-4%) to give 2- (4-chloro-1H-pyrrolo [2,3-b ] -pyrrole]Pyridine-5-carbonyl) -2-isopropylhydrazine-1-carboxylic acid tert-butyl ester (530mg, yield 74%) as a white solid. ES-API [ M + H ] ]⁺＝353.2。

Step two: 2- (4-chloro-1H-pyrrole [2, 3-b)]Pyridine-5-carbonyl) -2-isopropylhydrazine-1-carboxylic acid tert-butyl ester (210mg,0.60mmol) and 2-chloro-4-phenoxybenzaldehyde (560mg,2.40mmol) were dissolved in methanol (10mL), the reaction was cooled to 0 deg.C, and potassium hydroxide (235mg,4.20mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was adjusted to pH 8 with 1.0M dilute hydrochloric acid, 80mL ethyl acetate was added, and the mixture was washed with 30mL saturated brine, dried and concentrated, and the crude product was purified using a thin-layer preparative plate (dichloromethane/methanol 15:1) to give 2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrole [2,3-b ] -pyrrole]Pyridine-5-carbonyl) -2-isopropylhydrazine-1-carboxylic acid tert-butyl ester (110mg, yield 31%) as a white solid. ES-API [ M + H ]]⁺＝585.1。

Step three: 2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrole [2,3-b]Pyridine-5-carbonyl) -2-isopropylhydrazine-1-carboxylic acid tert-butyl ester (110mg,0.19mmol) was dissolved in 8mL tetrahydrofuran, cooled to 0 deg.C, and dess-martin oxidizer (145mg,0.34mmol) was added and the reaction stirred at room temperature for 4 hours. 5mL of a saturated sodium thiosulfate solution and 10mL of a saturated sodium bicarbonate solution were added to the reaction solution, followed by extraction with 60mL of ethyl acetate. The organic phase was washed with 15mL of a saturated sodium bicarbonate solution and 15mL of a saturated sodium chloride solution in this order, dried and concentrated to give 2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrole [2,3-b ] ]Pyridine-5-carbonylYl) -2-isopropylhydrazine-1-carboxylic acid tert-butyl ester (125mg, crude) as a yellow solid. ES-API [ M + H ]]⁺＝583.2。

Step four: 2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrole [2,3-b]Pyridine-5-carbonyl) -2-isopropylhydrazine-1-carboxylic acid tert-butyl ester (125mg, crude) was dissolved in 4.0M methanolic hydrogen chloride (8mL), and the reaction was stirred at room temperature for 6 hours. Concentrating the reaction solution, alkalizing with 7.0M ammonia methanol solution, concentrating again, purifying the crude product with preparative HPLC to obtain 8- (2-chloro-4-phenoxybenzoyl) -2-isopropyl-1, 6-dihydropyrazole [3,4-d ]]Pyrrolo [2,3-b]Pyridin-3 (2H) -one (Z32, 55mg, 65% over two steps yield) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ12.74(s,1H),10.34(s,1H),8.58(s,1H),7.83(s,1H),7.62(d,J＝8.4Hz,1H),7.52-7.46(m,2H),7.27(t,J＝7.2Hz,1H),7.23-7.18(m,3H),7.04(dd,J＝8.4,2.4Hz,1H),4.66-4.51(m,1H),1.41(d,J＝6.8Hz,6H).ES-API:[M+H]⁺＝447.1。

EXAMPLE 30 preparation of Compound Z33

The method comprises the following steps: to a solution of ethyl 4,4, 4-trifluoro-3-hydroxybutyrate (2.5g,13.43mmol) in N, N-dimethylformamide (50mL) were added tert-butyldimethylchlorosilane (2.43g,16.12mmol) and imidazole (2.29g,33.58mmol), the mixture was stirred at room temperature overnight, and the reaction solution was 100mL of ethyl acetate, washed three times with 50mL of 1M dilute hydrochloric acid, three times with 50mL of saturated brine, and concentrated under reduced pressure to give the compound ethyl 3- ((tert-butyldimethylsilyl) oxy) -4,4, 4-trifluorobutyrate (4g) as a colorless oily product. ES-API [ M + H ]]⁺＝301.0。

Step two: diisobutylaluminum hydride (1.7M,1.96mL,3.33mmol) was added dropwise to ethyl 3- ((tert-butyldimethylsilyl) oxy) -4,4, 4-trifluorobutyrate (1g,3.33mmol) in dichloromethane (10mL) at-60 ℃ and stirred for 1 hour. The reaction was quenched with 10mL of methanol, pH adjusted to 5 with 1M dilute hydrochloric acid, extracted with ethyl acetate and concentrated to give crude colorless liquid 3- ((tert-butyldimethylsilyl) oxy) -4,4, 4-trifluorobutanal (800 mg). ES-API [ M + H ] ]⁺＝257.1

Step three: 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] is reacted with]Pyridine-4, 5-diamine (200mg,0.69mmol), 3- ((tert-butyldimethylsilyl) oxy) -4,4, 4-trifluorobutanal (600mg,2.34mmol), 10% Pd/C (50mg) in methanol (2ml) were mixed and reacted at 120 ℃ for 1 hour by microwave. Cooling to room temperature, filtering, concentrating, and purifying with flash silica gel column (0-100% ethyl acetate/petroleum ether) to obtain 2- (2- ((tert-butyldimethylsilyl) oxy) -3,3, 3-trifluoropropyl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d%]Pyrrolo [2,3-b]Pyridine (220mg), purity 100%, yield 60%. ES-API [ M + H ]]⁺＝525.1。

Step four: 2- (2- ((tert-butyldimethylsilyl) oxy) -3,3, 3-trifluoropropyl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridine (220mg,0.42mmol) and sodium hydroxide (84mg,2.10mmol) were added to a mixed solvent of methanol/water (2ml/0.4ml), and microwave reaction was carried out at 90 ℃ for 1 hour. Concentrating the reaction solution to obtain a crude product of 3- (1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) -1,1, 1-trifluoropropan-2-ol (200 mg). ES-API [ M + H ]]⁺＝271.1。

Step five: to the crude 3- (1, 6-dihydroimidazo [4,5-d ] product]Pyrrolo [2,3-b]Pyridin-2-yl) -1,1, 1-trifluoropropan-2-ol (200mg,0.74mmol) in methanol (10mL) was added 2-chloro-4-phenoxybenzaldehyde (516mg,2.22mmol) and potassium hydroxide (291mg,5.18mmol) and stirred at room temperature overnight. After the reaction was completed, pH was adjusted to 7 with 1M hydrochloric acid solution, 20mL ethyl acetate was added and extracted three times, the organic phases were combined, dried, concentrated, and purified by flash silica gel column (0-20% methanol/dichloromethane) to obtain 3- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d) as a white solid ]Pyrrolo [2,3-b]Pyridin-2-yl) -1,1, 1-trifluoropropan-2-ol (120mg), purity 95%, yield 32%. ES-API [ M + H ]]⁺＝503.0。

Step six: to 3- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) -1,1, 1-trifluoropropan-2-ol (120mg,0.24mmol) in a mixed solution of 1, 4-dioxane/water (4ml/0.4ml) was added with 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (81mg,0.36mmol), and the mixture was stirred at room temperature for 1 hourThen (c) is performed. After the reaction was completed, 2mL of an aqueous sodium thiosulfate solution was added to quench, 20mL of ethyl acetate was added, and the mixture was washed with 20mL of a saturated aqueous sodium bicarbonate solution and 20mL of a saturated common salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative HPLC alkaline method to give (2-chloro-4-phenoxyphenyl) (2- (3,3, 3-trifluoro-2-hydroxypropyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z33, 39mg, 100% purity, 32% yield) as an off-white solid.¹H NMR(400MHz,DMSO-d₆)δ12.84(s,1H),12.18(s,1H),8.69(s,1H),7.82(s,1H),7.66(d,J＝8.5Hz,1H),7.50(t,J＝8.0Hz,2H),7.34-7.17(m,4H),7.06(dd,J＝8.5,2.0Hz,1H),6.56(d,J＝7.0Hz,1H),4.70(s,1H),3.42-3.29(m,2H).ES-API:[M+H]⁺＝501.0。

EXAMPLE 31 preparation of Compound Z34

Step one, 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] is added]Pyridine-4, 5-diamine (0.5g, 1.73mmol), 3- ((tert-butyldimethylsilyl) oxy) -2-methylbutyraldehyde (0.525g, 2.43mmol), 10% Pd/C (100mg) and methanol (8ml) were charged into a 20ml sealed tube, heated to 120 ℃ and reacted for 6 hours. Cooling to room temperature, filtering, concentrating, and purifying on silica gel column to obtain the product 2- (3- ((tert-butyldimethylsilyl) oxy) butan-2-yl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ]Pyrrolo [2,3-b]Pyridine (170mg, yield 16%). ES-API [ M + H ]]⁺＝485.2。

Step two, 2- (3- ((tert-butyldimethylsilyl) oxy) butan-2-yl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridine (170mg,0.35mmol) and sodium hydroxide (98mg,2.45mmol) were added to a mixed solvent of methanol/water (5ml/1ml), heated to 90 ℃ and reacted for 18 hours. Cooling to room temperature, adding saturated ammonium chloride aqueous solution to neutrality, extracting with ethyl acetate, washing with saturated saline, drying, filtering, and concentrating to obtain crude product of 2- (3- ((tert-butyldimethylsilyl) oxy) but-2-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (75mg, yield 62%). ES-API [ M + H ]]⁺＝345.2。

Step three, the crude product of 2- (3- ((tert-butyldimethylsilyl) oxy) butyl-2-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (75mg, crude) was added to 2M methanol hydrochloride solution and stirred at room temperature for 1 hour. After the reaction is finished, adding ethyl acetate, washing with saturated sodium bicarbonate water solution and saturated brine in sequence, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product of 3- (1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) butan-2-ol (50mg, crude). ES-API [ M + H ] ]⁺＝231.1。

Step four, the crude product 3- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b ] s]Pyridin-2-yl) butan-2-ol (50mg,0.215mmol), 2-chloro-4-phenoxybenzaldehyde (100mg,0.43mmol) and potassium hydroxide (60mg,1.07mmol) were added to 5ml of methanol and stirred at room temperature for 5 hours. After the reaction is finished, quenching saturated ammonium chloride, adding ethyl acetate for extraction, concentrating, preparing a thin-layer chromatography plate for purification to obtain the 3- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) butan-2-ol (50mg, yield 50%). ES-API [ M + H ]]⁺＝463.1。

Step five, 3- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) butan-2-ol (50mg,0.108mmol) was added to a mixed solution of 1, 4-dioxane/water (2ml/0.3ml), followed by addition of DDQ (49mg,0.216mmol) in portions, and stirred at room temperature for 30 minutes, whereupon the reaction was completed. Adding 2ml sodium thiosulfate aqueous solution for quenching, washing with saturated sodium bicarbonate aqueous solution and saturated brine in sequence, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by preparative HPLC to obtain (2-chloro-4-phenoxyphenyl) (2- (3-hydroxybut-2-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z34, 18mg, yield 36%). ES-API [ M + H ] ]⁺＝461.1。¹H NMR(400MHz,DMSO-d₆)δ8.66(d,J＝3.3Hz,1H),7.80(s,1H),7.64(d,J＝8.4Hz,1H),7.49(t,J＝7.8Hz,2H),7.36-7.15(m,4H),7.05(dd,J＝8.4,2.4Hz,1H),6.05(s,2H),4.10-4.02(m,1H),3.94(d,J＝6.6Hz,1H),3.24-3.21(m,1H),1.37(t,J＝6.4Hz,3H),1.14-0.99(m,3H).

EXAMPLE 32 preparation of Compound Z35

Step one, a suspension of sodium hydride (976mg,24.4mmol) in tetrahydrofuran (50mL) was cooled to 0 ℃. To which 4-nitro-1H-pyrrolo [2,3-b ] is added portionwise]Pyridine (2g, 12.2mmol), stirred for 5 min. To this was added p-methylbenzenesulfonyl chloride (3.5g, 18.4 mmol). The reaction was carried out at 0 ℃ for 30 minutes. The reaction was poured into cold saturated sodium bicarbonate solution. Extracting with ethyl acetate, washing with saturated brine, drying, filtering, and concentrating. The crude product was washed with ethyl acetate/petroleum ether (1: 3, 30mL) to give 4-nitro-1-tolyl-1H-pyrrolo [2,3-b ]]Pyridine (3.5g, yield 90%). ES-API [ M + H ]]⁺＝318.1。

Step two, 4-nitro-1-tolyl-1H-pyrrolo [2, 3-b)]Pyridine (3.1g, 9.75mmol) and iron powder (2.7g, 48.7mmol) were added to acetic acid (15mL), heated to 75 deg.C, and reacted for 30 minutes. Cooling to room temperature, and sucking away the iron powder by using a magnet. Filtration and the filter cake washed with water and ethyl acetate. Collecting filter cakes, and drying to obtain crude product of 1-tosyl-1H-pyrrolo [2, 3-b)]Pyridin-4-amine (2.8g), yellow solid. ES-API [ M + H ]]⁺＝288.1。

Step three, the crude product 1-tosyl-1H-pyrrolo [2, 3-b)]Pyridin-4-amine (2.6g) and NIS (2.4g, 10.83mmol) were added to N, N-dimethylformamide (20mL) and stirred at 40 ℃ for 2 h. After the reaction was completed, the reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried, concentrated and purified on silica gel (0-50% ethyl acetate/petroleum ether) to give the product 5-iodo-1-tolyl-1H-pyrrolo [2,3-b ] ]Pyridin-4-amine (2.4g, 64% purity). ES-API [ M + H ]]⁺＝414.0。

Step four, 5-iodo-1-tolyl-1H-pyrrolo [2,3-b ]]Pyridin-4-amine (1.2g, 2.9mmol), 4-ethynylpiperidine-1-carboxylic acid tert-butyl ester (913mg,4.4mmol), Pd (PPh)₃)₄(204mg,0.29mmol), CuI (110mg,0.58mmol) and triethylamine (2mL) were added to N, N-dimethylformamide (20 mL). The reaction solution was purged with nitrogen for 1 minute. Sealing the tube at 150 deg.CThe reaction was carried out for 40 minutes under the conditions. Quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried, concentrated and purified on silica gel (0-45% ethyl acetate/petroleum ether) to give 4- (((4-amino-1-tolyl-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) piperidine-1-carboxylic acid tert-butyl ester (1g, yield 68%). ES-API [ M + H ]]⁺＝495.2。

Step five, 4- (((4-amino-1-tolyl-1H-pyrrolo [2, 3-b))]Pyridin-5-yl) ethynyl) piperidine-1-carboxylic acid tert-butyl ester (1g, 2.02mmol) and NaAuCl₄(109mg,0.3mmol) was added to ethanol (10 ml). Stirred in a 70 degree oil bath for 24 hours under nitrogen. Concentrating the reaction solution, and purifying with silica gel column (0-45% ethyl acetate/petroleum ether) to obtain 4- (6-tosyl-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d)]Pyridin-2-yl) tert-butyl-1-carboxylic acid tert-butyl ester (450mg, purity 79%). ES-API [ M + H ] ]⁺＝495.3。

Step six, under the zero degree, the crude product of the 4- (6-tosyl-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d)]Pyridin-2-yl) tert-butyl-1-carboxylate (450mg) was added to NIS (245mg,1.09mmol) in N, N-dimethylformamide (6 mL). The reaction was stirred at zero degrees for 1 hour. After the reaction was completed, the reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried, concentrated and purified on silica gel (0-50% ethyl acetate/petroleum ether) to give the product 4- (3-iodo-6-tosyl-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d)]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (340mg, yield 60%). ES-API [ M + H ]]⁺＝621.1。

Step seven, the suspension of sodium hydride (44mg,1.09mmol) in N, N-dimethylformamide (5mL) was cooled to 0 ℃. To this was added 4- (3-iodo-6-tosyl-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d]Pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (340mg,0.55mmol), stirred for 5 min. Chloromethyl trimethylsilylethyl ether (182mg,1.09mmol) was added thereto. The reaction was carried out at 0 ℃ for 30 minutes. The reaction solution was poured into a cold saturated sodium bicarbonate solution. Extracting with ethyl acetate, washing with saturated brine, drying, filtering, and concentrating. The crude product was purified on silica gel (0-30% ethyl acetate/petroleum ether) to give tert-butyl 4- (3-iodo-6-tosyl-1- ((2- (trimethylsilyl) methyl ester Yl) ethoxy) methyl) -1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d]Pyridin-2-yl) piperidine-1-carboxylic acid (360mg, yield 87%). ES-API [ M + H ]]⁺＝751.0。

Step eight tert-butyl 4- (3-iodo-6-tosyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d]Pyridin-2-yl) piperidine-1-carboxylic acid (340mg,0.45mmol), Zn (CN)₂(106mg,0.90mmol) and Pd (PPh)₃)₄(52mg,0.045mmol) was added to N, N-dimethylformamide (5 mL). The reaction solution was purged with nitrogen for 1 minute. The system was sealed and reacted for 1.5 hours under 115 ℃ microwave conditions. Quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried, concentrated and purified on column silica gel (0-30% ethyl acetate/petroleum ether) to give tert-butyl 4- (3-cyano-6-tosyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d)]Pyridin-2-yl) piperidine-1-carboxylic acid (270mg, 92% yield) as a white solid. ES-API [ M + H ]]⁺＝650.2。

To tert-butyl 4- (3-cyano-6-tosyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d]Pyridin-2-yl) piperidine-1-carboxylic acid (270mg,0.42mmol) in dioxane (3mL) was added dropwise a solution of 1mol/L potassium tert-butoxide in tetrahydrofuran (2.7mL, 2.7 mmol). The reaction was stirred in a 60 degree oil bath for 30 minutes. The reaction solution was poured into a cold saturated sodium bicarbonate solution. Extracting with ethyl acetate, washing with saturated brine, drying, and concentrating to obtain 4- (3-cyano-1- (((2- (trimethylsilyl) ethoxy) methyl) -1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d) ]Pyridin-2-yl) tert-butylpiperidine-1-carboxylate (200mg, 96%) as a yellow solid. ES-API [ M + H ]]⁺＝496.3。

Step ten reaction to 4- (3-cyano-1- (((2- (trimethylsilyl) ethoxy) methyl) -1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d)]Pyridin-2-yl) tert-butylpiperidine-1-carboxylate (160mg,0.32mmol) was added to a 1mol/L solution of potassium tert-butoxide in tetrahydrofuran (5mL, 5 mmol). The reaction was stirred in an 80 degree oil bath for 2 hours. The reaction solution was poured into a cold saturated sodium bicarbonate solution. Extracting with ethyl acetate, washing with saturated brine, drying, and concentrating to obtain 4-(3-cyano-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d)]Pyridin-2-yl) tert-butyl-1-carboxylic acid tert-butyl ester (80mg, crude) as a yellow solid. ES-API [ M + H ]]⁺＝366.1。

Step eleven, the crude product 4- (3-cyano-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d)]Pyridin-2-yl) tert-butyl-1-carboxylic acid tert-butyl ester (80mg), 2-chloro-4-phenoxybenzaldehyde (153mg,0.66mmol) and potassium hydroxide (86mg,1.54mmol) were added to 6ml of methanol and the reaction stirred in a 70 ℃ oil bath for 3 hours. After the reaction is finished, saturated ammonium chloride is quenched, ethyl acetate is added for extraction, concentration is carried out, and the product tert-butyl 4- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -3-cyano-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d) is obtained after silica gel purification (0-60% ethyl acetate/petroleum ether) through a column ]Pyridin-2-yl) piperidine-1-carboxylic acid (70mg, crude). ES-API [ M + H ]]⁺＝598.2。

Step twelve, tert-butyl 4- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -3-cyano-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d)]Pyridin-2-yl) piperidine-1-carboxylic acid (70mg, crude) was added to tetrahydrofuran (5ml) and water (0.5 ml). Cool to 0 deg.C, then add DDQ (53mg,0.23 mmol). After stirring at room temperature for 1 hour, the reaction was completed. Quenched with saturated aqueous sodium bicarbonate. Extracting with ethyl acetate, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain tert-butyl 4- (8- (2-chloro-4-phenoxybenzoyl) -3-cyano-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d]Pyridin-2-yl) piperidine-1-carboxylic acid salt (60mg, crude). ES-API [ M + H ]]⁺＝596.2。

Step thirteen, namely, the tert-butyl 4- (8- (2-chloro-4-phenoxybenzoyl) -3-cyano-1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d)]Pyridin-2-yl) piperidine-1-carboxylate (60mg) was added to trifluoroacetic acid (0.5 mL)/dichloromethane (2 mL). After stirring at room temperature for 1 hour, the reaction was completed. Concentrating the reaction solution, and purifying by HPLC formic acid method to obtain 8- (2-chloro-4-phenoxybenzoyl) -2- (piperidine-4-yl) -1, 6-dihydrodipyrrolo [2,3-b:2 ', 3' -d]Pyridine-3-carbonitrile formate (Z35, 20mg, 30% yield in two steps). ¹H NMR(400MHz,DMSO-d₆)δ11.4(brs,1H),8.66(s,1H),7.90(s,1H),7.65-7.64(m,1H),7.50-7.48(m,2H),7.29-7.20(m,4H),7.07-7.05(m,1H),3.55-3.53(m,1H),3.30-3.27(m,2H),2.84-2.82(m,2H),2.07-2.01(m,4H)。ES-API:[M+H]⁺＝496.1。

Example 33 preparation of Compounds Z36, Z36-1, Z36-2

The method comprises the following steps: 4-Oxocyclohexane-1-carbonitrile (950mg,7.72mmol) and tert-butyl hydrazinecarboxylate (1.02g, 7.72mmol) were dissolved in 1, 2-dichloroethane (40mL) and acetic acid (926mg,15.44mmol) and sodium triacetoxyborohydride (3.27g, 15.44mmol) were added. The reaction was stirred at room temperature for 18 hours, 10% potassium carbonate (80mL) was added, and the mixture was extracted with 100mL ethyl acetate. The organic phase was washed with 50mL of saturated brine, dried and concentrated, and the crude product was purified with flash silica gel column (ethyl acetate/petroleum ether: 0-40%) to give tert-butyl 2- (4-cyanocyclohexyl) hydrazine-1-carboxylate (1.5g, yield 81%) as a colorless liquid. ES-API [ M + Na ]]⁺＝262.1。

Step two: 2- (4-Cyanocyclohexyl) hydrazine-1-carboxylic acid tert-butyl ester (633mg,2.65mmol) dissolved in 25mL tetrahydrofuran N, N-diisopropylethylamine (1.05g, 8.16mmol) was added, the reaction cooled to 0 deg.C and 4-chloro-1H-pyrrole [2,3-b ] was slowly added in portions]Pyridine-5-carbonyl chloride (438mg,2.04mmol), and the reaction was stirred for 30 minutes under ice bath. The reaction mixture was added with 50mL of water, and extracted with 100mL of ethyl acetate. The organic phase was washed with 30mL of saturated sodium bicarbonate solution and 30mL of saturated brine in this order, dried and concentrated, and the crude product was purified with flash silica gel column (methanol/dichloromethane: 0-4%) to give 2- (4-chloro-1H-pyrrolo [2,3-b ] -pyrrole ]Pyridine-5-carbonyl) -2- (4-cyanocyclohexyl) hydrazine-1-carboxylic acid tert-butyl ester (450mg, yield 53%) as a white solid. ES-API [ M + H ]]⁺＝418.1。

Step three: 2- (4-chloro-1H-pyrrole [2, 3-b)]Pyridine-5-carbonyl) -2- (4-cyanocyclohexyl) hydrazine-1-carboxylic acid tert-butyl ester (250mg,0.60mmol) and 2-chloro-4-phenoxybenzaldehyde (557mg,2.40mmol) were dissolved in methanol (10mL), the reaction cooled to 0 deg.C and potassium hydroxide (235mg,4.20mmol) added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was adjusted to pH 8 with 1.0M dilute hydrochloric acid, 80mL of ethyl acetate was added, the mixture was washed with 30mL of saturated brine, and the crude product was prepared by thin layer chromatography after drying and concentrationThe prepared plate (dichloromethane/methanol ═ 15:1) was purified to give 2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrolo [2,3-b ]]Pyridine-5-carbonyl) -2- (4-cyanocyclohexyl) hydrazine-1-carboxylic acid tert-butyl ester (115mg, yield 30%) as a white solid. ES-API [ M + H ]]⁺＝650.1。

Step four: 2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrole [2,3-b]Pyridine-5-carbonyl) -2- (4-cyanocyclohexyl) hydrazine-1-carboxylic acid tert-butyl ester (100mg,0.15mmol) was dissolved in 10mL tetrahydrofuran, cooled to 0 deg.C, dess-martin oxidant (130mg,0.30mmol) was added, and the reaction was stirred at room temperature for 5 hours. 6mL of a saturated sodium thiosulfate solution and 10mL of a saturated sodium bicarbonate solution were added to the reaction solution, followed by extraction with 60mL of ethyl acetate. The organic phase is washed successively with 15mL of saturated sodium bicarbonate solution and 15mL of saturated brine, dried and concentrated and the crude product is purified using a thin layer preparative plate (dichloromethane/methanol 15:1) to give 2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrole [2,3-b ]Pyridine-5-carbonyl) -2- (4-cyanocyclohexyl) hydrazine-1-carboxylic acid tert-butyl ester (90mg, yield 90%) as a white solid. ES-API [ M + H ]]⁺＝648.1。

Step five: 2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrole [2,3-b]Pyridine-5-carbonyl) -2- (4-cyanocyclohexyl) hydrazine-1-carboxylate tert-butyl ester (90mg,0.14mmol) was dissolved in 3mL of methanol and 4.0M methanolic hydrogen chloride (3mL) was added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was added with 30mL of ethyl acetate, washed with 15mL of saturated sodium bicarbonate solution 2 times and 15mL of saturated brine in this order, dried and concentrated, and the crude product was purified by preparative HPLC to give 4- (8- (2-chloro-4-phenoxybenzoyl) -3-oxo-3, 6-dihydropyrazolo [3,4-d ]]Pyrrolo [2,3-b]Pyridin-2 (1H) -yl) cyclohexane-1-carbonitrile (Z36, 45mg, 63% yield) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ13.01(s,1H),10.40(s,1H),8.60-8.58(m,1H),7.83(s,1H),7.64-7.59(m,1H),7.49(t,J＝7.6Hz,2H),7.28(d,J＝7.2Hz,1H),7.25-7.14(m,3H),7.06-7.02(m,1H),4.32-4.19(m,1H),3.20(s,0.6H),2.78(t,J＝11.6Hz,0.4H),2.28-2.13(m,2H),2.03(d,J＝13.6Hz,2H),1.90(d,J＝11.6Hz,2H),1.81-1.63(m,2H).ES-API:[M+H]⁺＝512.1。

Step six: z36(42mg,0.08mmol) was resolved by chiral prep (split column)IC 250mm 4.6mm 5um, mobile phase n-hexane, ethanol 70:30, flow rate 1ml/min, column temperature: two isomers were obtained at 30 ℃. An isomer, the structure of which is arbitrarily designated as cis-4- (8- (2-chloro-4-phenoxybenzoyl) -3-oxo-3, 6-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Pyridin-2 (1H) -yl) cyclohexane-1-carbonitrile (Z36-1, 19mg, peak 1, retention time 16.754min, yield 45%) as a white solid; ¹H NMR(400MHz,DMSO-d₆)δ13.03(s,1H),10.47(s,1H),8.60(s,1H),7.85(d,J＝3.2Hz,1H),7.63(d,J＝8.4Hz,1H),7.49(t,J＝7.6Hz,2H),7.27(t,J＝7.2Hz,1H),7.24-7.13(m,3H),7.05(dd,J＝8.4,2.4Hz,1H),4.25(tt,J＝12.0Hz,3.2Hz,1H),3.21(s,1H),2.22(dd,J＝225.2,12.0Hz,2H),2.03(d,J＝13.6Hz,2H),1.90(d,J＝11.2Hz,2H),1.76(tt,J＝13.8Hz,4.0Hz,2H).ES-API:[M+H]⁺512.1; and another isomer, the structure of which is arbitrarily designated trans-4- (8- (2-chloro-4-phenoxybenzoyl) -3-oxo-3, 6-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Pyridin-2 (1H) -yl) cyclohexane-1-carbonitrile (Z36-2, 12mg, peak 2, retention time 21.289min, yield 28%) as a light yellow solid;¹H NMR(400MHz,DMSO-d₆)δ13.03(s,1H),10.35(s,1H),8.59(s,1H),7.84(d,J＝2.4Hz,1H),7.62(d,J＝8.8Hz,1H),7.50(t,J＝8.4,2H),7.27(t,J＝7.2Hz,1H),7.24-7.17(m,3H),7.05(dd,J＝8.4,2.4Hz,1H),4.27(tt,J＝12.0,4.0Hz,1H),2.78(tt,J＝12.4,3.6Hz,1H),2.17(d,J＝11.2Hz,2H),2.04(dd,J＝24.4,12.4Hz,2H),1.90(d,J＝9.6Hz,2H),1.71(qd,J＝12.8,3.2Hz,2H).ES-API:[M+H]⁺＝512.1。

EXAMPLE 34 preparation of Compounds Z37, Z38

The method comprises the following steps: 2-butanone (2.0g,15.13mmol) and tert-butyl carbazate (2.18g,30.27mmol) were dissolved in methanol (40mL) and the reaction was stirred at room temperature for 17 h. And (4) detecting the disappearance of the raw materials and the generation of imine by using thin-layer chromatography. The reaction was concentrated to a white solid, which was redissolved with acetic acid (20mL) and water (20mL), and sodium cyanoborohydride (1.43g, 22.70mmol) was added at room temperature. The reaction was stirred at room temperature for an additional 2 hours. Adding water into the reaction solution(50mL), the mixture was extracted with ethyl acetate (200 mL). The organic phase was washed 3 times with saturated aqueous sodium bicarbonate (50mL), once with saturated brine (50mL), dried and concentrated, and the crude product was purified on a flash silica gel column (ethyl acetate/petroleum ether: 0-40%) to give tert-butyl 2- (sec-butyl) hydrazine-1-carboxylate (2g, yield 70%) as a colorless transparent liquid.¹H NMR(400MHz,DMSO-d₆)δ8.17(s,1H),4.31(s,1H),2.74(dd,J＝11.6,6.0Hz,1H),1.45-1.40(m,1H),1.39(s,9H),1.15(dt,J＝13.6,7.2Hz,1H),0.88(d,J＝6.0Hz,3H),0.83(t,J＝7.2Hz,3H).

Step two: 4-chloro-1H-pyrrolo [2,3-b ] pyridine-5-carboxylic acid (500mg,2.54mmol) was dissolved in dichloromethane (15mL), the reaction was cooled to 0 deg.C, and oxalyl chloride (968mg,7.63mmol) and 2 drops of N, N-dimethylformamide were added. The reaction was stirred at room temperature for 17 hours. The reaction mixture was dried and concentrated to give 4-chloro-1H-pyrrolo [2,3-b ] pyridine-5-carbonyl chloride (546mg, yield 100%) as a white solid.

Step three: tert-butyl 2- (sec-butyl) hydrazine-1-carboxylate (956mg,5.08mmol) and N, N-diisopropylethylamine (985mg,7.60mmol) were dissolved in tetrahydrofuran (15mL), the reaction was cooled to 0 ℃ and 4-chloro-1H-pyrrolo [2,3-b ] -was added]Pyridine-5-carbonyl chloride (546mg,2.54 mmol). The reaction was stirred at room temperature for one hour. The reaction mixture was poured into water (30mL) and extracted three times with ethyl acetate (30 mL). The organic phase was washed once with saturated brine (50mL), dried and concentrated, and the crude product was purified on flash silica gel column (ethyl acetate/petroleum ether: 0-35%) to give 2- (sec-butyl) -2- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazine-1-carboxylic acid tert-butyl ester (430mg, yield 46%) as a white solid. ES-API [ M + H ]]⁺367.1 and 369.0.

Step four: 2- (sec-butyl) -2- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazine-1-carboxylic acid tert-butyl ester (300mg,0.818mmol) and 2-chloro-4-phenoxybenzaldehyde (760mg,3.27mmol) were dissolved in methanol (15mL), the reaction was cooled to 0 ℃ and potassium hydroxide (320mg,5.72mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction solution was adjusted to pH 8 with diluted hydrochloric acid (1.0M), and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (15mL), dried and concentrated, and the crude product was purified on flash silica gel (ethyl acetate/petroleum ether: 0-60%) to give 2- (sec-butyl) -2- (4-chloro-4-) -3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazine-1-carboxylic acid tert-butyl ester (170mg, yield 35%) as a pale yellow solid. ES-API [ M + H ]]⁺599.2 and 601.2.

Step five: 2- (sec-butyl) -2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazine-1-carboxylic acid tert-butyl ester (170mg,0.284mmol) was dissolved in tetrahydrofuran (5mL), the reaction was cooled to 0 deg.C, and dess-Martin oxidant (180mg,0.425mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was added with a saturated sodium thiosulfate solution (5mL) and a saturated sodium bicarbonate solution (10mL), and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium bicarbonate solution (15mL), saturated brine (15mL), dried and concentrated to give 2- (sec-butyl) -2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazine-1-carboxylic acid tert-butyl ester (150mg, yield 88%) as a white solid. ES-API [ M + H ]]⁺597.1 and 599.2.

Step six: 2- (sec-butyl) -2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazine-1-carboxylic acid tert-butyl ester (150mg,0.251mmol) was dissolved in hydrogen chloride and 4M methanol solution (5mL), and the reaction mixture was reacted at room temperature for 4 hours. The reaction was concentrated in vacuo to give a white solid. The resulting solid was redissolved in methanol (3mL) and adjusted to pH 9 with ammonia (7M in methanol) and concentrated in vacuo. The crude product was purified by preparative HPLC alkaline method and resolved by preparative chiral HPLC (column: IE 20 x 250mm, 10 um; mobile phase: n-hexane: ethanol: 70: 30; flow rate: 15 ml/min; column temperature: room temperature) to give two isomers. An isomer having a structure arbitrarily designated as (R) -2- (sec-butyl) -8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydropyrazolo [3,4-d ]Pyrrolo [2,3-b ] s]Pyridin-3 (2H) -one (Z37, 18mg, yield 16%, retention time: 17.123 min; Peak 1) as a white solid;¹H NMR(400MHz,DMSO-d₆)δ12.99(s,1H),10.29(s,1H),8.59(s,1H),7.83(s,1H),7.63(d,J＝8.4Hz,1H),7.49(dd,J＝8.4,7.6Hz,2H),7.27(t,J＝7.6Hz,1H),7.25-7.13(m,3H),7.04(dd,J＝8.4,2.4Hz,1H),4.45-4.35(m,1H),2.02-1.93(m,1H),1.79-1.68(m,1H),1.40(d,J＝6.8Hz,3H),0.83(t,J＝7.2Hz,3H).ES-API:[M+H]⁺461.1; and another isomer, the structure of which is arbitrarily designated as (S) -2- (sec-butyl) -8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Pyridin-3 (2H) -one (Z38, 18mg, yield 16%, retention time 17.626 min; Peak 2) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ12.99(s,1H),10.29(s,1H),8.58(s,1H),7.83(s,1H),7.63(d,J＝8.4Hz,1H),7.49(dd,J＝8.4,7.6Hz,2H),7.27(t,J＝7.6Hz,1H),7.24-7.18(m,3H),7.04(dd,J＝8.4,2.4Hz,1H),4.45-4.35(m,1H),2.01-1.92(m,1H),1.79-1.68(m,1H),1.40(d,J＝6.8Hz,3H),0.83(t,J＝7.2Hz,3H).ES-API:[M+H]⁺461.1. The isomers were detected by analytical chiral HPLC (column: IE 10 × 250mm, 5 um; mobile phase: n-hexane: ethanol ═ 70: 30; flow rate: 1 ml/min; column temperature ═ 30 ℃).

EXAMPLE 35 preparation of Compound Z39

The method comprises the following steps: 1- (tert-butyl) 4-ethyl-3-oxopiperidine-1, 4-dicarboxylate (5g,18.4mmol) was added to a mixture of sodium borohydride (1.39g,36.9mmol) in methanol (100mL) at-60 ℃. The mixture was stirred at this temperature for 3 hours, quenched with 30mL of saturated ammonium chloride solution, extracted three times with 50mL of dichloromethane, the organic phases were combined and concentrated to give 1- (tert-butyl) 4-ethyl 3-hydroxypiperidine-1, 4-dicarboxylate (5g) as a colorless liquid, crude product. ES-API [ M + Na ]]⁺＝296.2。

Step two: to a solution of 1- (tert-butyl) 4-ethyl 3-hydroxypiperidine-1, 4-dicarboxylate (2.5g,9.15mmol) in N, N-dimethylformamide (50mL) were added tert-butyldimethylchlorosilane (1.65g,10.98mmol) and imidazole (1.25g,18.30mmol), the mixture was stirred at room temperature overnight, and the reaction solution was 100mL ethyl acetate, washed three times with 50mL 1M dilute hydrochloric acid, three times with 50mL saturated brine, concentrated and purified with a flash silica gel column (0-15% ethyl acetate/petroleum ether) to give 1- (tert-butyl) 4-ethyl 3- ((tert-butyldimethylsilyl) oxy) piperidine-1, 4-dicarboxylate (1g) as a colorless oil in 100% purity in 28% yield. ES-API [ M + Na ] ]⁺＝410.0。

Step three: diisobutylaluminum hydride (1.7M,1.36mL,2.32mmol) was added dropwise to 1- (tert-butyl) 4-ethyl 3- ((tert-butyldimethylsilyl) oxy) piperidine-1, 4-dicarboxylate (900mg,2.32mmol) in dichloromethane (10mL) at-60 ℃ and stirred for 2 hours. The reaction was quenched with 10mL of methanol, adjusted to pH 5 with 1M dilute hydrochloric acid, extracted with 20mL of dichloromethane, and concentrated to give a crude colorless liquid of tert-butyl 3- (((tert-butyldimethylsilyl) oxy) -4-formylpiperidine-1-carboxylate (900mg)]⁺＝366.2

Step four: 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] is reacted with]Pyridine-4, 5-diamine (300mg,0.87mmol), 3- (((tert-butyldimethylsilyl) oxy) -4-formylpiperidine-1-carboxylic acid tert-butyl ester (900mg,3.12mmol), 10% Pd/C (100mg) in methanol (10ml) mixture microwave reacted at 120 ℃ for 1 hour, cooled to room temperature, filtered, concentrated, and purified by flash column on silica gel (0-100% ethyl acetate/petroleum ether) to give the product tert-butyl 3- ((tert-butyldimethylsilyl) oxy) -4- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) piperidine-1-carboxylic acid (120mg) in 84% purity in 27% yield. ES-API [ M + H ]]⁺＝612.3。

Step five: tert-butyl 3- ((tert-butyldimethylsilyl) oxy) -4- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-2-yl) piperidine-1-carboxylic acid (120mg,0.20mmol) and sodium hydroxide (55mg,1.37mmol) were added to a mixed solvent of methanol/water (2ml/0.4ml), and reacted with a microwave at 90 ℃ for 2 hours. Concentrating the reaction solution to obtain crude product of 3- ((tert-butyldimethylsilyl) oxy) tert-butyl-4- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) piperidine-1-carboxylic acid (120 mg). ES-API [ M + H ]]⁺＝472.3。

Step six: to the crude 3- ((tert-butyldimethylsilyl) oxy) tert-butyl-4- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) piperidine-1-carboxylic acid (120mg,0.26mmol) in methanol (10mL) was added 2-chloro-4-phenoxybenzaldehyde (178mg,0.76mmol) and potassium hydroxide (100mg,1.78mmol) and stirred at room temperature overnight. After the reaction was completed, the pH was adjusted to 7 with 1M hydrochloric acid solution, 20mL of ethyl acetate was added and extracted three times, and the organic phase was separatedCombined, dried, concentrated and purified on a flash silica gel column (0-20% methanol/dichloromethane) to give t-butyl 3- ((t-butyldimethylsilyl) oxy) -4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d ] as a white solid]Pyrrolo [2,3-b]Pyridin-2-yl) piperidine-1-carboxylic acid (60mg) in 100% purity and 33% yield. ES-API [ M + H ] ]⁺＝704.3。

Step seven: to tert-butyl 3- ((tert-butyldimethylsilyl) oxy) -4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) piperidine-1-carboxylic acid (60mg,0.085mmol) in a mixed solution of 1, 4-dioxane/water (1ml/0.1ml) was added with 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (39mg,0.17mmol), and the mixture was stirred at room temperature for 1 hour. After the reaction, 1mL of aqueous sodium thiosulfate solution was added for quenching, 10mL of ethyl acetate was added, and the mixture was washed with 10mL of saturated aqueous sodium bicarbonate solution and 10mL of saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude tert-butyl 3- ((tert-butyldimethylsilyl) oxy) -4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d-]Pyrrolo [2,3-b]Pyridin-2-yl) piperidine-1-carboxylic acid (60 mg). ES-API [ M + H ]]⁺＝702.2。

Step eight: trifluoroacetic acid (0.2mL) was added dropwise to tert-butyl 3- ((tert-butyldimethylsilyl) oxy) -4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) piperidine-1-carboxylic acid (60mg,0.085mmol) in dichloromethane (1mL) was stirred at room temperature for 2 hours. Concentrating to obtain crude product (2-chloro-4-phenoxyphenyl) (2- (3-hydroxypiperidin-4-yl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-8-yl) methanone trifluoroacetate (42 mg). ES-API [ M + H ]]⁺＝488.3。

Step nine: 1 drop of aqueous formaldehyde (37%) was added to the crude product (2-chloro-4-phenoxyphenyl) (2- (3-hydroxypiperidin-4-yl) -1, 6-dihydroimidazo [4, 5-d) under ice-bath conditions]Pyrrolo [2,3-b]Pyridin-8-yl) methanone trifluoroacetate (42mg,0.085mmol) was stirred in a turbid solution of acetonitrile (1mL) for 15 minutes. Sodium cyanoborohydride (10mg,0.17mmol) was then added and stirring continued for 15 min. The reaction solution is treated with 3mL ammonia water, stirred for half an hour, concentrated and purified by preparative HPLC (trifluoroacetic acid) to obtainOff-white solid (2-chloro-4-phenoxyphenyl) (2- (3-hydroxy-1-methylpiperidin-4-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone trifluoroacetate (1:1) (Z39, 7mg, purity 100%, yield 16%). ES-API [ M + H ]]⁺＝502.1。

EXAMPLE 36 preparation of Compound Z40

The method comprises the following steps: 4-chloro-1H-pyrrolo [2,3-b ] pyridine-5-carboxylic acid (500mg,2.54mmol) was dissolved in dichloromethane (10mL), the reaction was cooled to 0 deg.C, and oxalyl chloride (968mg,7.63mmol) and 2 drops of N, N-dimethylformamide were added. The reaction was stirred at room temperature for 17 hours. The reaction mixture was dried and concentrated to give 4-chloro-1H-pyrrolo [2,3-b ] pyridine-5-carbonyl chloride (546mg, yield 100%) as a white solid.

Step two: tert-butyl 2- (tert-butyl) hydrazine-1-carboxylate (956mg,5.08mmol) and N, N-diisopropylethylamine (985mg,7.62mmol) were dissolved in tetrahydrofuran (15mL), the reaction was cooled to 0 deg.C, and 4-chloro-1H-pyrrolo [2,3-b ] -was added]Pyridine-5-carbonyl chloride (546mg,2.54 mmol). The reaction was stirred at room temperature for one hour. The reaction solution was poured into 30mL of water, and extracted three times with 30mL of ethyl acetate. The organic phase was washed once with saturated brine (50mL), dried and concentrated, and the crude product was purified on flash silica gel column (ethyl acetate/petroleum ether: 0-60%) to give 2- (tert-butyl) -2- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazine-1-carboxylic acid tert-butyl ester (150mg, yield 16%) as a white solid. ES-API [ M + H ]]⁺367.1 and 369.0.

Step three: 2- (tert-butyl) -2- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazine-1-carboxylic acid tert-butyl ester (70mg,0.191mmol) and 2-chloro-4-phenoxybenzaldehyde (178mg,0.763mmol) were dissolved in methanol (2mL), the reaction was cooled to 0 deg.C, and potassium hydroxide (75mg,1.34mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction solution was adjusted to pH 8 with dilute hydrochloric acid (1.0M), and extracted with ethyl acetate (30 mL). The organic phase is washed with saturated brine (15mL), dried and concentrated, and the crude product is purified by preparative thin layer chromatography (silica, ethyl acetate/petroleum ether 4/3 v/v) To obtain 2- (tert-butyl) -2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazine-1-carboxylic acid tert-butyl ester (70mg, yield 61%) as a pale yellow solid. ES-API [ M + H ]]⁺599.1 and 601.0.

Step four: 2- (tert-butyl) -2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazine-1-carboxylic acid tert-butyl ester (60mg,0.10mmol) was dissolved in tetrahydrofuran (3mL), the reaction was cooled to 0 deg.C, and dess-martin oxidant (64mg,0.15mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was added with a saturated sodium thiosulfate solution (5mL) and a saturated sodium bicarbonate solution (10mL), and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium bicarbonate solution (15mL), saturated brine (15mL), dried and concentrated to give 2- (tert-butyl) -2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazine-1-carboxylic acid tert-butyl ester (55mg, yield 90%) as a white solid. ES-API [ M + H ]]⁺597.2 and 599.2.

Step five: 2- (tert-butyl) -2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazine-1-carboxylic acid tert-butyl ester (55mg,0.092mmol) was dissolved in hydrogen chloride and 4M methanol solution (2mL), and the reaction mixture was reacted at room temperature for 4 hours. The reaction was concentrated in vacuo to give a white solid. The resulting solid was redissolved in methanol (3mL) and adjusted to pH 9 with ammonia, 7M methanol solution and concentrated in vacuo. The crude product was purified by preparative HPLC (ammonium bicarbonate) to give 2- (tert-butyl) -8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydropyrazolo [3,4-d ]Pyrrolo [2,3-b ] s]Pyridin-3 (2H) -one (Z40, 23mg, 50% yield) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ13.03(s,1H),9.66(s,1H),8.56(s,1H),7.86(d,J＝3.2Hz,1H),7.61(d,J＝8.4Hz,1H),7.53-7.44(m,2H),7.27(t,J＝7.6Hz,1H),7.24-7.13(m,3H),7.05(dd,J＝8.4,2.4Hz,1H),1.63(s,9H).ES-API:[M+H]⁺＝461.1。

EXAMPLE 37 preparation of Compound Z41

The method comprises the following steps: 2-oxaspiro [3.5 ]]Nonan-7-one (500mg,3.57mmol) and tert-butyl hydrazinecarboxylate (566mg,4.28mmol) were dissolved in methanol (15mL) and the reaction was stirred at room temperature for 16 h. Concentrating the reaction solution to obtain 2- (2-oxaspiro [3.5 ]]Nonan-7-ylidene) hydrazine-1-carboxylic acid tert-butyl ester (1.05g, crude) as a white solid. ES-API [ M + Na ]]⁺＝277.1。

Step two: 2- (2-oxaspiro [3.5 ]]Nonan-7-ylidene) hydrazine-1-carboxylic acid tert-butyl ester (950mg, crude) was dissolved in tetrahydrofuran (25mL) under nitrogen, the reaction was cooled to 0 deg.C, and 2.0M borane in tetrahydrofuran (3.18mL, 6.36mmol) was added dropwise. After the addition was complete, the reaction was stirred at room temperature for 3 hours. The reaction solution was slowly dropped with 10mL of methanol, stirred at room temperature for 1 hour, concentrated, and then the crude product was purified with a flash silica gel column (methanol/dichloromethane: 0-4%) to obtain 2- (2-oxaspiro [3.5 ]]Nonan-7-yl) hydrazine-1-carboxylic acid tert-butyl ester (630mg, 69% yield over two steps) as a white solid.¹H NMR(400MHz,CDCl₃)δ6.22(s,1H),4.40(s,2H),4.34(s,2H),2.83(t,J＝10.8Hz,1H),2.13(d,J＝13.2Hz,2H),1.80(dd,J＝13.2,3.2Hz,2H),1.54-1.40(m,11H),1.17-1.06(m,2H).ES-API:[M+H]⁺＝527.2。

Step three: 2- (2-oxaspiro [3.5 ]]Non-7-yl) hydrazine-1-carboxylic acid tert-butyl ester (627mg,2.45mmol) dissolved in 25mL tetrahydrofuran was added N, N-diisopropylethylamine (1.05g, 8.16mmol), the reaction cooled to 0 deg.C and 4-chloro-1H-pyrrole [2,3-b ] slowly added in portions ]Pyridine-5-carbonyl chloride (438mg,2.04mmol), and the reaction was stirred for 15 minutes under ice bath. The reaction mixture was added with 50mL of water, and extracted with 100mL of ethyl acetate. The organic phase was washed with 30mL of saturated sodium bicarbonate solution and 30mL of saturated brine in this order, dried and concentrated, and the crude product was purified with flash silica gel column (methanol/dichloromethane: 0-4%) to give 2- (4-chloro-1H-pyrrolo [2,3-b ] -pyrrole]Pyridine-5-carbonyl) -2- (2-oxaspiro [3.5 ]]Nonan-7-yl) hydrazine-1-carboxylic acid tert-butyl ester (470mg, yield 53%), white solid. ES-API [ M + H ]]⁺＝435.3。

Step four: 2- (4-chloro-1H-pyrrole [2, 3-b)]Pyridine-5-carbonyl) -2- (2-oxaspiro [3.5 ]]Tert-butyl nonan-7-yl) hydrazine-1-carboxylate (250mg,0.58mmol) and 2-chloro-4-phenoxybenzaldehyde (534mg,2.30mmol) were dissolved in methanol (12mL), the reaction cooled to 0 deg.C and potassium hydroxide (227mg,4.06mmol) added. Reaction in the chamberStirred at room temperature for 18 hours. The reaction mixture was adjusted to pH 8 with 1.0M dilute hydrochloric acid, 80mL ethyl acetate was added, and the mixture was washed with 30mL saturated brine, dried and concentrated, and the crude product was purified using a thin-layer preparative plate (dichloromethane/methanol 15:1) to give 2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrole [2,3-b ] -pyrrole]Pyridine-5-carbonyl) -2- (2-oxaspiro [3.5 ]]Nonan-7-yl) hydrazine-1-carboxylic acid tert-butyl ester (120mg, yield 31%) as a white solid. ES-API [ M + H ] ]⁺＝667.2。

Step five: 2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) -2- (2-oxaspiro [3.5 ]]Nonan-7-yl) hydrazine-1-carboxylic acid tert-butyl ester (107mg,0.15mmol) was dissolved in 8mL tetrahydrofuran, cooled to 0 deg.C, dess-martin oxidant (136mg,0.32mmol) was added and the reaction stirred at room temperature for 5 hours. 5mL of a saturated sodium thiosulfate solution and 5mL of a saturated sodium bicarbonate solution were added to the reaction solution, followed by extraction with 50mL of ethyl acetate. The organic phase is washed successively with 10mL of saturated sodium bicarbonate solution and 10mL of saturated brine, dried and concentrated and the crude product is purified using a thin-layer preparative plate (dichloromethane/methanol 15:1) to give 2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrole [2,3-b]Pyridine-5-carbonyl) -2- (2-oxaspiro [3.5 ]]Nonan-7-yl) hydrazine-1-carboxylic acid tert-butyl ester (103mg, yield 96%) as a white solid. ES-API [ M + H ]]⁺＝665.2。

Step six: 2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrole [2,3-b]Pyridine-5-carbonyl) -2- (2-oxaspiro [3.5 ]]Nono-7-yl) hydrazine-1-carboxylic acid tert-butyl ester (85mg,0.13mmol) was dissolved in 4.0M methanolic hydrogen chloride (4mL) and the reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated to obtain 8- (2-chloro-4-phenoxybenzoyl) -2- (4- (chloromethyl) -4- (hydroxymethyl) cyclohexyl) -1, 6-dihydropyrazolo [3,4-d ]Pyrrole [2,3-b ] s]Pyridin-3 (2H) -one (70mg, crude), white solid. ES-API [ M + H ]]⁺＝565.2。

Step seven: 8- (2-chloro-4-phenoxybenzoyl) -2- (4- (chloromethyl) -4- (hydroxymethyl) cyclohexyl) -1, 6-dihydropyrazolo [3,4-d]Pyrrole [2,3-b ]]Pyridin-3 (2H) -one (70mg, crude) was dissolved in ethanol (5mL) and potassium hydroxide (109mg,1.95mmol) was added. The reaction was stirred at 85 ℃ for 16 h. The reaction mixture was cooled to room temperature, and a saturated ammonium chloride solution (2mL) and water (2mL) were added to the mixture, followed by extraction with 30mL of ethyl acetate. Is provided withThe organic phase is dried and concentrated and the crude product is purified by preparative HPLC to give 8- (2-chloro-4-phenoxybenzoyl) -2- (2-oxaspiro [3.5 ]]Nonan-7-yl) -1, 6-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Pyridin-3 (2H) -one (Z41, 40mg, 59% yield in two steps) was obtained as a pale yellow solid.¹H NMR(400MHz,DMSO-d₆)δ12.97(s,1H),10.36(s,1H),8.57(s,1H),7.82(s,1H),7.61(d,J＝8.0Hz,1H),7.49(t,J＝8.0Hz,2H),7.34-7.15(m,4H),7.04(dd,J＝8.0Hz,1.6Hz,1H),4.42(s,2H),4.25(s,2H),4.17(t,J＝10.8Hz,1H),2.19(d,J＝12.0Hz,2H),2.03-1.89(m,2H),1.79(d,J＝10.8Hz,2H),1.57(t,J＝12.0Hz,2H).ES-API:[M+H]⁺＝529.1。

EXAMPLE 38 preparation of Compounds Z42, Z43-1, Z43-2

The method comprises the following steps: 3-Oxocyclopentane-1-carbonitrile (800mg,7.33mmol) and tert-butyl carbazate (970mg,7.33mmol) were dissolved in methanol (25mL), and the reaction was stirred at room temperature for 17 hours. And (4) detecting the disappearance of the raw materials and the generation of imine by using thin-layer chromatography. The reaction was concentrated to a white solid, which was redissolved with acetic acid (10mL) and water (10mL), and sodium cyanoborohydride (1.38g, 21.99mmol) was added at room temperature. The reaction was stirred at room temperature for an additional 2 hours. The reaction mixture was added to water (30mL) and extracted with ethyl acetate (100 mL). The organic phase was washed 3 times with saturated aqueous sodium bicarbonate (30mL), once with saturated brine (50mL), dried and concentrated, and the crude product was purified on a flash silica gel column (ethyl acetate/petroleum ether: 0-30%) to give tert-butyl 2- (3-cyanocyclopentyl) hydrazine-1-carboxylate (1.5g, yield 90%) as a colorless transparent liquid. ES-API [ M + -C ] ₄H₈+H]⁺＝170.2

Step two: 4-chloro-1H-pyrrolo [2,3-b ] pyridine-5-carboxylic acid (300mg,1.53mmol) was dissolved in dichloromethane (15mL), the reaction was cooled to 0 deg.C, and oxalyl chloride (580mg,4.58mmol) and 2 drops of N, N-dimethylformamide were added. The reaction was stirred at room temperature for 17 hours. The reaction solution was dried and concentrated to give 4-chloro-1H-pyrrolo [2,3-b ] pyridine-5-carbonyl chloride (328mg, yield 100%) as a white solid.

Step three: 2-(3-Cyanocyclopentyl) hydrazine-1-carboxylic acid tert-butyl ester (369mg,1.64mmol) and N, N-diisopropylethylamine (577mg,4.46mmol) were dissolved in tetrahydrofuran (10mL), the reaction was cooled to 0 deg.C, and 4-chloro-1H-pyrrolo [2,3-b ] was added]Pyridine-5-carbonyl chloride (320mg,1.49 mmol). The reaction was stirred at room temperature for one hour. The reaction mixture was poured into water (30mL) and extracted three times with ethyl acetate (30 mL). The organic phase was washed once with saturated brine (50mL), dried and concentrated, and the crude product was purified on flash silica gel column (ethyl acetate/petroleum ether: 0-70%) to give 2- (4-chloro-1H-pyrrolo [2,3-b ]]Pyridine-5-carbonyl) -2- (3-cyanocyclopentyl) hydrazine-1-carboxylic acid tert-butyl ester (370mg, yield 62%) as a white solid. ES-API [ M + H ]]⁺404.2 and 406.0.

Step four: 2- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) -2- (3-cyanocyclopentyl) hydrazine-1-carboxylic acid tert-butyl ester (370mg,0.92mmol) and 2-chloro-4-phenoxybenzaldehyde (853mg,3.66mmol) were dissolved in methanol (15mL), the reaction was cooled to 0 deg.C, and potassium hydroxide (360mg,6.41mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction solution was adjusted to pH 8 with diluted hydrochloric acid (1.0M), and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (15mL), dried and concentrated, and the crude product was purified on flash silica gel column (ethyl acetate/petroleum ether: 0-60%) to give 2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrolo [2,3-b ] ]Pyridine-5-carbonyl) -2- (3-cyanocyclopentyl) hydrazine-1-carboxylic acid tert-butyl ester (120mg, yield 21%) as a pale yellow solid. ES-API [ M + H ]]⁺636.1 and 638.2.

Step five: 2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) -2- (3-cyanocyclopentyl) hydrazine-1-carboxylic acid tert-butyl ester (120mg,0.189mmol) was dissolved in tetrahydrofuran (5mL), the reaction was cooled to 0 deg.C, and dess-martin oxidant (160mg,0.377mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was added with a saturated sodium thiosulfate solution (5mL) and a saturated sodium bicarbonate solution (10mL), and extracted with ethyl acetate (30 mL). The organic phase was washed with a saturated sodium bicarbonate solution (15mL) and a saturated brine (15mL), dried and concentrated to give 2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrolo [2,3-b ]]Pyridine-5-carbonyl) -2- (3-cyanocyclopentyl) hydrazine-1-carboxylic acid tert-butyl ester (105mg, yield 88%),a white solid. ES-API [ M + H ]]⁺634.2 and 636.2.

Step six: 2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) -2- (3-cyanocyclopentyl) hydrazine-1-carboxylic acid tert-butyl ester (105mg,0.165mmol) was dissolved in hydrogen chloride, 4M methanol solution (5mL), and the reaction mixture was reacted at room temperature for 4 hours. The reaction was concentrated in vacuo to give a white solid. The resulting solid was redissolved with 1, 4-dioxane (5mL) and hydrogen chloride, 4M dioxane solution (2 drops) was added. The reaction solution was further stirred at 100 ℃ for 2 hours. The reaction was concentrated in vacuo and the crude product was prepared by preparative HPLC base method to give the following product: 3- (8- (2-chloro-4-phenoxybenzoyl) -3-oxo-3, 6-dihydropyrazolo [3,4-d ]Pyrrolo [2,3-b]Pyridin-2 (1H) -yl) cyclopentane-1-cyano (Z42,12mg, yield 15%, peak 1, retention time: 6.25min later, the reaction time is less than or equal to 6.25min later),¹H NMR(400MHz,DMSO-d₆)δ13.04(s,1H),10.50(s,1H),8.59(s,1H),7.85(s,1H),7.62(d,J＝8.4Hz,1H),7.51-7.45(m,2H),7.31-7.16(m,4H),7.07-7.04(m,1H),4.89-4.77(m,1H),3.18-3.05(m,1H),2.45-2.39(m,2H),2.26-2.10(m,3H),2.02-1.93(m,1H).ES-API:[M+H]⁺498.1; and two isomers, wherein one isomer is arbitrarily designated as trans-3- (8- (2-chloro-4-phenoxybenzoyl) -3-oxo-3, 6-dihydropyrazolo [3, 4-d)]Pyrrolo [2,3-b]Pyridin-2 (1H) -yl) cyclopentane-1-carboxylic acid methyl group (Z43-1,13mg, yield 15%, peak 2, retention time: 7.88min later, the reaction time is less than or equal to the total time of reaction),¹H NMR(400MHz,DMSO-d₆)δ13.04(s,1H),10.50(s,1H),8.58(s,1H),7.84(s,1H),7.62(d,J＝8.4Hz,1H),7.51-7.45(m,2H),7.30-7.25(m,1H),7.23-7.18(m,3H),7.04(dd,J＝8.4,2.4Hz,1H),4.92-4.83(m,1H),3.64(s,3H),3.25-3.15(m,1H),2.35-2.25(m,1H),2.22-2.03(m,4H),1.85-1.75(m,1H).ES-API:[M+H]⁺431.2; another isomer, optionally designated by the structure cis-3- (8- (2-chloro-4-phenoxybenzoyl) -3-oxo-3, 6-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Pyridin-2 (1H) -yl) cyclopentane-1-carboxylic acid methyl group (Z43-2,13mg, yield 15%, peak 3, retention time: 8.35min later, the reaction time is less than or equal to 8.35min),¹H NMR(400MHz,DMSO-d₆)δ13.02(s,1H),10.41(s,1H),8.59(s,1H),7.84(s,1H),7.62(d,J＝8.4Hz,1H),7.53-7.46(m,2H),7.30-7.25(m,1H),7.24-7.18(m,3H),7.05(dd,J＝8.4,2.4Hz,1H),4.90-4.78(m,1H),3.65(s,3H),3.02-2.90(m,1H),2.35-2.25(m,1H),2.27-2.18(m,1H),2.16-2.08(t,J＝10.2Hz,1H),2.06-1.88(m,3H).ES-API:[M+H]⁺431.2. All were light yellow solids.

EXAMPLE 39 preparation of Compounds Z44, Z44-1, Z44-2

The method comprises the following steps: a solution of n-butyllithium in tetrahydrofuran (2.5M,6.79mL,16.97mmol) was slowly added dropwise to methoxymethyltriphenylphosphonium chloride (5.82g,16.97mmol) in tetrahydrofuran (40mL) at-60 ℃ under nitrogen. The reaction solution was stirred at this temperature for 30 minutes. Then, a solution of 4-oxocyclohexane-1-carbonitrile (1.9g,15.43mmol) in tetrahydrofuran (10mL) was added dropwise to the solution, warmed to room temperature, and stirred for 2 hours. Quenching with 50mL of saturated ammonium chloride solution, extracting with 50mL of ethyl acetate for three times, combining the organic phases, drying, concentrating, and purifying with flash silica gel column (0-10% ethyl acetate/petroleum ether) to obtain 4- (methoxymethylene) cyclohexane-1-carbonitrile (1g) as a colorless oily compound with a purity of 100% and a yield of 43%. ES-API [ M + H ] ]⁺＝152.1。

Step two: to 4- (methoxymethylene) cyclohexane-1-carbonitrile (500mg,3.31mmol) in tetrahydrofuran (2mL) was added dropwise a 6M hydrochloric acid solution (1 mL). The reaction solution was stirred at 90 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude 4-formylcyclohexane-1-carbonitrile (500 mg). ES-API [ M + H ]]⁺＝138.1。

Step three: 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] is reacted with]Pyridine-4, 5-diamine (250mg,1.04mmol), 4-formylcyclohexane-1-carbonitrile (500mg), 10% Pd/C (100mg) in methanol (10ml) were mixed and reacted at 120 ℃ for 30 minutes by microwave. Cooling to room temperature, filtering, concentrating, purifying with flash silica gel column (0-10% methanol/dichloromethane) to obtain 4- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1-carbonitrile (300mg) had a purity of 100% and a yield of 71%. ES-API [ M + H ]]⁺＝406.1。

Step four: reacting 4- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) ringsHexane-1-carbonitrile (300mg,0.75mmol) and sodium hydroxide (147mg,3.75mmol) were added to a mixed solvent of methanol/water (2ml/0.4ml), and microwave reaction was carried out at 90 ℃ for 2.5 hours. Concentrating the reaction solution to obtain crude product 4- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1-carbonitrile (200 mg). ES-API [ M + H ]]⁺＝266.1。

Step five: to the crude 4- (1, 6-dihydroimidazo [4,5-d ] product ]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1-carbonitrile (200mg,75mmol) in methanol (10mL) was added 2-chloro-4-phenoxybenzaldehyde (510mg,2.19mmol) and potassium hydroxide (300mg,5.35mmol), and the mixture was stirred at room temperature overnight. After the reaction was completed, pH was adjusted to 7 with 1M hydrochloric acid solution, 20mL ethyl acetate was added and extracted three times, the organic phases were combined, dried, concentrated, and purified by flash silica gel column (0-20% methanol/dichloromethane) to obtain 4- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d) as a yellow solid]Pyrrolo [2,3-b ] s]Pyridin-2-yl) cyclohexane-1-carbonitrile (200mg) had a purity of 90% and a yield of 57%. ES-API [ M + H ]]⁺＝498.1。

Step six: to 4- (8- (((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1-carbonitrile (200mg,0.40mmol) was added to a mixed solution of 1, 4-dioxane/water (10ml/1ml) with 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (182mg,0.80mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, 2mL of an aqueous sodium thiosulfate solution was added to quench, 20mL of ethyl acetate was added, and the mixture was washed with 20mL of a saturated aqueous sodium bicarbonate solution and 20mL of a saturated common salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative HPLC alkaline method to give 4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d ] s ]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1-carbonitrile (Z44,60mg, purity 100%, yield 30%) as an off-white solid. ES-API [ M + H ]]⁺＝496.1。

Step seven: chiral preparative resolution (Z44,60mg,0.12mmol) on a separation column (IC 250mm 4.6mm 5um, mobile phase: n-hexane: isopropanol: 70:30, flow rate: 1mL/min, column temperature: 30 ℃) gives two isomers. Wherein one of the isomeric structures is arbitrarily designated as cis-4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1Nitrile (Z44-1,31mg, peak 1, retention time 9.71min, yield: 52%, de% ═ 100%), white solid. ES-API [ M + H ]]⁺＝496.1。¹H NMR(400MHz,DMSO-d₆) δ 12.81(s,1H),11.98(s,1H),8.68(s,1H),7.79(s,1H),7.66(s,1H),7.49(s,2H),7.33-7.17(m,4H),7.06(s,1H),3.25-3.19(m,1H),2.15-2.00(m,5H),1.95-1.84(m,2H),1.79-1.68(m, 2H). The other isomer structure is arbitrarily designated trans-4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1-carbonitrile (Z44-2,25mg, peak 2, retention time 11.21min, yield: 41%, de% ═ 100%) as a white solid. ES-API [ M + H ]]⁺＝496.1。¹H NMR(400MHz,DMSO-d₆)δ12.79(s,1H),11.95(s,1H),8.65(s,1H),7.79(s,1H),7.65(d,J＝8.0Hz,1H),7.50(t,J＝7.6Hz,2H),7.31-7.25(m,1H),7.25-7.17(m,3H),7.09-7.03(m,1H),3.30-3.22(m,1H),2.88-2.79(m,1H),2.24-2.08(m,4H),1.82-1.63(m,4H)。

EXAMPLE 40 preparation of Compounds Z45-1, Z45-2

The method comprises the following steps: reacting 8-oxo-2-azaspiro [4.5 ] ]Tert-butyl deca-2-carboxylate (0.5g, 1.97mmol), t-butyl hydrazinoformate (274mg,2.07mmol), acetic acid (0.5mL) and methanol (5mL) were charged in a 20mL eggplant-shaped bottle and reacted at room temperature for 1 hour. Sodium cyanoborohydride (372mg,5.91mml) was added, and stirring was continued at room temperature for 1 hour to complete the reaction. Adding 100ml ethyl acetate, washing with saturated sodium bicarbonate and brine in turn, drying with anhydrous sodium sulfate, filtering, concentrating, purifying with silica gel column to obtain the product 8- (2- (tert-butyloxycarbonyl) hydrazino) -2-azaspiro [ 4.5%]Tert-butyl deca-2-carboxylate (650mg, yield 89%). ES-API [ M + H ]]⁺＝258.1，314.2，392.2。

Step two: reacting 8- (2- (tert-butyloxycarbonyl) hydrazino) -2-azaspiro [4.5]Tert-butyl deca-2-carboxylate (650mg,1.76mmol) and diisopropylethylamine (903mg,7.0mmol) were added to dry tetrahydrofuran (20ml), cooled to 0 ℃ and 4-chloro-1H-pyrrolo [2,3-b ] was added slowly in portions]Pyridine-5-carbonyl chloride (300mg,1.4 mmol). Stirring was continued for 1 hourAfter the reaction is finished, extracting by ethyl acetate, washing by saturated saline solution, drying, filtering, concentrating, and purifying by silica gel column to obtain the product 8- (2- (tert-butyloxycarbonyl) -1- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazino) -2-azaspiro [4.5]Tert-butyl decane-2-carboxylate (500mg, yield 66%). ES-API [ M + H ] ]⁺＝436.1。

Step three: reacting 8- (2- (tert-butyloxycarbonyl) -1- (4-chloro-1H-pyrrolo [2,3-b ]]Pyridine-5-carbonyl) hydrazino) -2-azaspiro [4.5]Tert-butyl decane-2-carboxylate (250mg,0.457mmol), 2-chloro-4-phenoxybenzaldehyde (318mg,1.37mmol) and potassium hydroxide (179mg,3.2mmol) were added to a 5mL methanol solution, and the mixture was stirred at room temperature for 16 hours. After the reaction is finished, adding saturated ammonium chloride solution for quenching, extracting by ethyl acetate, washing by water and saturated saline water in sequence, drying by anhydrous sodium sulfate, filtering, concentrating, preparing a thin-layer chromatography plate for purification, and obtaining 8- (2- (tert-butyloxycarbonyl) -1- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridine-5-carbonylhydrazino) -2-azaspiro [4.5]Tert-butyl decane-2-carboxylate (100mg, yield 28%). ES-API [ M + H ]]⁺＝762.2。

Step four: reacting 8- (2- (tert-butyloxycarbonyl) -1- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrolo [2,3-b ]]Pyridine-5-carbonylhydrazino) -2-azaspiro [4.5]Tert-butyl decane-2-carboxylate (100mg,0.128mmol) was added to 5ml of tetrahydrofuran, cooled to 0 ℃ and dess-martin oxidant (108mg,0.256ml) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction is finished, quenching the sodium thiosulfate solution, adding ethyl acetate for extraction, washing the ethyl thiosulfate solution with water and saturated saline solution in sequence, drying the anhydrous sodium sulfate, filtering, concentrating, preparing a thin-layer chromatography plate for purification, and obtaining 8- (2- (tert-butyloxycarbonyl) -1- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrolo [2, 3-b) ]Pyridine-5-carbonyl) hydrazino) -2-azaspiro [4.5]Tert-butyl decane-2-carboxylate (72mg, yield 73%). ES-API [ M + H ]]⁺＝622.2，678.1。

Step five: reacting 8- (2- (tert-butyloxycarbonyl) -1- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrolo [2,3-b ]]Pyridine-5-carbonyl) hydrazino) -2-azaspiro [4.5]Tert-butyl decane-2-carboxylate (72mg,0.092mmol) was added to a 4M methanol hydrochloride solution (5ml), and the mixture was stirred at room temperature for 15 hours while closing the tube, whereupon the reaction was completedAfter that, the process is finished. Concentrating to obtain 8- (2-chloro-4-phenoxybenzoyl) -2- (2-azaspiro [ 4.5%]Dec-8-yl) -1, 2-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Pyridin-3 (6H) -one hydrochloride (75mg, crude). ES-API [ M + H ]]⁺＝542.2。

Step six: reacting 8- (2-chloro-4-phenoxybenzoyl) -2- (2-azaspiro [4.5 ]]Dec-8-yl) -1, 2-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Pyridin-3 (6H) one hydrochloride (75mg, crude), aqueous formaldehyde (33mg) were added to acetonitrile (5ml), stirred at room temperature for 1 hour, added sodium cyanoborohydride (43mg,0.69mmol), stirred for 30 minutes, and the reaction was complete. Concentrating to obtain 8- (2-chloro-4-phenoxybenzoyl) -2- (2-methyl-2-azaspiro [ 4.5%]Dec-8-yl) -1, 2-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Pyridin-3 (6H) -one (30mg, crude). ES-API [ M + H ]]⁺＝556.2。

Step seven: 8- (2-chloro-4-phenoxybenzoyl) -2- (2-methyl-2-azaspiro [4.5 ] ]Dec-8-yl) -1, 2-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Purification of pyridin-3 (6H) -one (30mg, crude) by reverse phase preparative HPLC resolution (separation column: IE250mm × 4.6mm × 5 um; mobile phase: n-hexane: ethanol: 80: 20; flow rate: 1 mL/min; column temperature 30 ℃) gave two isomers. An isomer, the structure of which is arbitrarily designated 8- (2-chloro-4-phenoxybenzoyl) -2- ((5s,8s) -2-methyl-2-azaspiro [4.5 ]]Decan-8-yl) -1, 6-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Pyridin-3 (2H) -one (Z45-1,9mg, 12% yield, peak 1, retention time 21.72min, 99% purity); ES-API [ M + H ]]⁺＝556.2。¹H NMR(400MHz,DMSO-d₆) δ 8.56(s,1H),7.82(s,1H),7.61(d, J ═ 8.5Hz,1H),7.52-7.47(m,2H),7.29-7.25(m,1H),7.23-7.18(m,3H),7.04(dd, J ═ 8.5,2.4Hz,1H),2.55(s,4H),2.34(s,3H),2.00(t, J ═ 12.0Hz,3H),1.76(d, J ═ 11.6Hz,4H),1.58(t, J ═ 6.9Hz,2H),1.45(t, J ═ 12.5Hz, 2H); another isomer, optionally designated by the structure 8- (2-chloro-4-phenoxybenzoyl) -2- ((5r,8r) -2-methyl-2-azaspiro [4.5]Decan-8-yl) -1, 6-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Pyridin-3 (2H) -one (Z45-2,10mg, 13% yield, peak 2, retention time 28.46min, 100% purity); ES-API [ M + H ]]⁺＝556.2。¹H NMR(400MHz,DMSO-d₆)δ8.57(s,1H),7.82(s,1H),7.61(d,J＝8.4Hz,1H),7.54-7.46(m,2H),7.29-7.25(m,1H),7.24-7.14(m,3H),7.04(dd,J＝8.4,2.4Hz,1H),2.69-2.59(m,2H),2.55-2.45(m,1H),2.38(s,2H),2.31(d,J＝12.6Hz,3H),2.13-1.95(m,3H),1.79-1.68(m,5H),1.48(dd,J＝14.2,10.7Hz,2H).

EXAMPLE 41 preparation of Compounds Z46, Z46-1, Z46-2

The method comprises the following steps: 4- ((tert-butyldimethylsilyl) oxy) cyclohexanone (500mg,2.19mmol), tert-butyl hydrazinoformate (318mg,2.41mmol), acetic acid (0.5mL) and methanol (5mL) were put in a 20mL eggplant-shaped bottle and reacted at room temperature for 1 hour. Sodium cyanoborohydride (414mg,6.57mml) was added, and stirring was continued at room temperature for 1 hour to complete the reaction. Ethyl acetate (100 ml) was added, and the mixture was washed with saturated sodium hydrogencarbonate and brine in this order, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column silica gel to give tert-butyl 2- (4- (((tert-butyldimethylsilyl) oxy) cyclohexyl) hydrazinecarboxylate (600mg, yield 79%). Example-API: [ M + H ]. sup.]⁺＝345.3。

Step two: tert-butyl 2- (4- (((tert-butyldimethylsilyl) oxy) cyclohexyl) hydrazinecarboxylate (600mg,1.74mmol) and diisopropylethylamine (1.12g, 8.72mmol) were added to dry tetrahydrofuran (20ml), cooled to 0 ℃ and 4-chloro-1H-pyrrolo [2,3-b ] added slowly in portions]Pyridine-5-carbonyl chloride (300mg,1.4 mmol). Stirring for 1 hr, extracting with ethyl acetate, washing with saturated brine, drying, filtering, concentrating, and purifying with silica gel column to obtain 2- (4- (((tert-butyldimethylsilyl) oxy) cyclohexyl) -2- (4-chloro-1H-pyrrolo [2,3-b ] product ]Pyridine-5-carbonyl) hydrazinecarboxylic acid tert-butyl ester (570mg, yield 73%). ES-API [ M + H ]]⁺＝523.2。

Step three: 2- (4- (((tert-butyldimethylsilyl) oxy) cyclohexyl) -2- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazinecarboxylic acid tert-butyl ester (300mg,0.57mmol), 2-chloro-4-phenoxybenzaldehyde (396mg,1.71mmol) and potassium hydroxide (223mg,3.99mmol) were added to 8mL of a methanol solution and stirred at room temperature for 16 hours. After the reaction is finished, adding saturated ammonium chloride solution for quenching, and extracting by ethyl acetateWashing with water and saturated sodium chloride water in sequence, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying with thin layer chromatography plate to obtain 2- (4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrole [2,3-b]Pyridine-5-carbonyl) hydrazinecarboxylic acid tert-butyl ester (170mg, yield 39%). ES-API [ M + H ]]⁺＝755.2。

Step four: reacting 2- (4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -2- (4-chloro-3- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1H-pyrrole [2,3-b ]]Pyridine-5-carbonyl) hydrazinecarboxylic acid tert-butyl ester (170mg,0.225mmol) was added to 5ml of tetrahydrofuran, cooled to 0 ℃ and dess-martin oxidant (191mg,0.450ml) was added and stirred at room temperature for 1 hour. After the reaction is finished, quenching the solution with sodium thiosulfate, adding ethyl acetate for extraction, washing the solution with water and saturated brine in sequence, drying the solution with anhydrous sodium sulfate, filtering the solution, concentrating the solution, preparing a thin-layer chromatography plate and purifying the product to obtain 2- (4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrolo [2,3-b ] ]Pyridine-5-carbonyl) hydrazinecarboxylic acid tert-butyl ester (190mg, crude). ES-API [ M + H ]]⁺＝753.2。

Step five: 2- (4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -2- (4-chloro-3- (2-chloro-4-phenoxybenzoyl) -1H-pyrrolo [2, 3-b)]Pyridine-5-carbonyl) hydrazinecarboxylic acid tert-butyl ester (190mg, crude product) was added to 4M hydrochloric acid methanol solution (5ml), and the reaction was completed by stirring at room temperature for 15 hours with a sealed tube. Concentrating to obtain 8- (2-chloro-4-phenoxybenzoyl) -2- (4-hydroxycyclohexyl) -1, 2-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Pyridin-3 (6H) -one (Z46, 150mg, crude). ES-API [ M + H ]]⁺＝503.1。

Step six: 8- (2-chloro-4-phenoxybenzoyl) -2- (4-hydroxycyclohexyl) -1, 2-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Pyridin-3 (6H) -one (190mg, crude) was prepared as two isomers by reverse phase HPLC alkaline method. An isomer, the structure of which is arbitrarily designated as cis-8- (2-chloro-4-phenoxybenzoyl) -2- (4-hydroxycyclohexyl) -1, 2-dihydropyrazolo [3,4-d]Pyrrolo [2,3-b]Pyridin-3 (6H) -one (Z46-1,23mg, 18% yield, peak 1, retention time 21.72min, 100% purity); ES-API [ M + H ]]⁺＝556.2；¹H NMR(400MHz,DMSO-d₆) δ 13.00(s,1H),10.33(s,1H),8.58(s,1H),7.83(s,1H),7.62(d, J ═ 8.4Hz,1H),7.50(t, J ═ 7.8Hz,2H),7.27(t, J ═ 7.3Hz,1H),7.20(d, J ═ 7.2Hz,3H),7.04(dd, J ═ 8.5,2.4Hz,1H),4.66(d, J ═ 4.4Hz,1H),4.19(s,1H),3.50(s,1H),2.04-1.94(m,4H),1.83(d, J ═ 12.2Hz,2H),1.32(q, J ═ 15.3,13.7, 2H); another isomer, the structure of which is arbitrarily designated trans-8- (2-chloro-4-phenoxybenzoyl) -2- (4-hydroxycyclohexyl) -1, 2-dihydropyrazolo [3,4-d ]Pyrrolo [2,3-b ] s]Pyridin-3 (6H) -one (Z46-2,30mg, yield 23%, peak 2, retention time 28.46min, purity 100%); ES-API [ M + H ]]⁺＝503.1；¹H NMR(400MHz,DMSO-d₆)δ12.98(s,1H),10.15(s,1H),8.59(s,1H),7.83(s,1H),7.63(d,J＝8.5Hz,1H),7.53-7.47(m,2H),7.29-7.25(m,1H),7.24-7.17(m,3H),7.05(dd,J＝8.4,2.4Hz,1H),4.52(d,J＝3.0Hz,1H),4.29-4.20(m,1H),3.88(s,1H),2.34-2.23(m,2H),1.81(d,J＝13.0Hz,2H),1.60(d,J＝11.8Hz,4H).

EXAMPLE 42 preparation of Compounds Z47, Z47-1, Z47-2

The method comprises the following steps: methoxymethyltriphenylphosphonium chloride (4.5g,13.1mmol) was dissolved in anhydrous tetrahydrofuran (50mL), bis (trimethylsilyl) aminolithium (13mL,13.1mmol,1M) was added dropwise under an ice-water bath under nitrogen protection, a solution of 4- ((tert-butyldimethylsilyl) oxy) cyclohex-1-one (2g,8.78mmol) in anhydrous tetrahydrofuran (10mL) was slowly added dropwise, the reaction was stirred at room temperature for 2 hours, a saturated ammonium chloride solution (100mL) was added, extraction was performed with ethyl acetate (100mL), the organic phase was dried over anhydrous sodium sulfate, concentration was performed, and purification was performed by column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give tert-butyl ((4- (methoxymethylene) cyclohexyl) oxy) dimethylsilane (2.1g, yield: 93%) as a colorless oil. ES-API [ M + H ]]⁺＝257.1。

Step two: tert-butyl ((4- (methoxymethylene) cyclohexyl) oxy) dimethylsilane (2.1g,8.17mmol) was dissolved in a mixture of tetrahydrofuran (20mL) and water (4mL), concentrated hydrochloric acid (12mL,12M) was added, and the reaction was stirred at 95 ℃ for 1 hour. The reaction was concentrated and the crude product was dried in vacuo to give 4-hydroxycyclohexane-1-carbaldehyde (3.1g, crude product) as a pale yellow oil.

Step three: 1- (phenylsulfonyl) -1H-pyrrolo [2,3-b]Pyridine-4, 5-diamine (600mg,2.08mmol) and 4-hydroxycyclohexane-1-carbaldehyde (532mg,4.16mmol) were dissolved in methanol (8mL), palladium on carbon (60mg) was added, and the reaction was stirred at 120 ℃ for 6 hours. Filtering with diatomaceous earth, washing with ethyl acetate (50mL) for 2 times, drying over anhydrous sodium sulfate, and concentrating to obtain 4- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexan-1-ol (900mg, crude), yellow solid. ES-API [ M + H ]]⁺＝397.1。

Step four: 4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexan-1-ol (900mg,2.27mmol) was dissolved in methanol (10mL), tetrahydrofuran (5mL) and water (2mL), sodium hydroxide (636mg,15.89mmol) was added, and the reaction was stirred at 90 ℃ for 12 hours. To the reaction mixture were added water (15mL) and a saturated ammonium chloride solution (4mL), followed by extraction with ethyl acetate (50 mL). The organic phase was washed with a saturated sodium bicarbonate solution (20mL), a saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (methanol: dichloromethane ═ 20%) to give 4- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexan-1-ol (561mg, yield: 95%) as an off-white solid. ES-API [ M + H ] ]⁺＝257.1。

Step five: 4- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b ] s]Pyridin-2-yl) cyclohex-1-ol (561mg,2.19mmol) and 2-chloro-4-phenoxybenzaldehyde (1.02g, 4.38mmol) were dissolved in methanol (20mL), the reaction cooled to 0 deg.C and potassium hydroxide (858mg,15.33mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was poured into water (60mL), adjusted to pH 8 with 1.0M dilute hydrochloric acid, and extracted with ethyl acetate (80 mL). The organic phase was washed with saturated brine (25mL), dried over anhydrous sodium sulfate and concentrated, and the crude product was purified using thin layer prep. plate (dichloromethane/7M ammonia methanol ═ 100:5) to give 4- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexan-1-ol (612mg, yield: 57%) as a pale yellow solid. ES-API [ M + H ]]⁺＝489.1。

Step six: 4- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexan-1-ol (612mg,1.25mmol) was dissolved in tetrahydrofuran (20mL) and water (2mL), 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (568mg,2.5mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction mixture was added with saturated sodium bicarbonate solution (20mL), and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (15mL), dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by preparative HPLC (column: Welch Xtimate, 21.2X 150mm, 5 um; mobile phase A:5mmol/L NH) ₄HCO₃Aqueous solution, mobile phase B: ACN; flow rate: 15 ml/min; chromatographic conditions are as follows: 15ml-35-85-13 min; column temperature: room temperature) to obtain (2-chloro-4-phenoxyphenyl) (2- (4-hydroxycyclohexyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z47,130mg, yield: 21%) as a pale yellow solid. ES-API [ M + H ]]⁺＝487.1。

Step seven: compound Z47(130mg) prepared above was resolved by chiral preparative resolution (separation column IC,250mm 4.6mm 5um, mobile phase: n-hexane: ethanol: diethanolamine: 70: 30: 0.2, flow rate: 1ml/min, column temperature: 30 ℃) to give two isomers. One of the isomeric structures is optionally designated as (2-chloro-4-phenoxyphenyl) (2- ((trans-4-hydroxycyclohexyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z47-1,42mg, Peak 1, Retention time 6.569min, 32.3%) as a white solid. ES-API [ M + H ]]⁺487.1; the other isomeric structure is optionally designated (2-chloro-4-phenoxyphenyl) (2- ((cis-4-hydroxycyclohexyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z47-2,84mg, Peak 2, Retention time 7.476min, 64.6%) as a white solid. ES-API [ M + H ]]⁺＝487.1。

EXAMPLE 43 preparation of Compounds Z48, Z48-1, Z48-2

The method comprises the following steps: under the protection of nitrogen and ice bath conditions, a tetrahydrofuran solution of lithium bis (trimethylsilyl) amide (1M,9.84mL,9.84mmol) is slowly added Methoxymethyltriphenylphosphonium chloride (3.37g,9.84mmol) in tetrahydrofuran (40mL) was added dropwise. The reaction solution was stirred at this temperature for 30 minutes. Then, a solution of 1-methyl-4-oxocyclohexane-1-carbonitrile (900mg,6.56mmol) in tetrahydrofuran (10mL) was added dropwise to the above solution, warmed to room temperature, and stirred for 2 hours. Quenching with saturated ammonium chloride solution (50mL), extracting three times with ethyl acetate (50mLX3), combining the organic phases, drying over anhydrous sodium sulfate, concentrating and purifying with flash silica gel column (ethyl acetate/petroleum ether ═ 0-10%) to give 4- (methoxymethylene) -1-methylcyclohexane-1-carbonitrile as a colorless oil (900mg, purity 100%, yield 83%). ES-API [ M + H ]]⁺＝166.1。

Step two: to 4- (methoxymethylene) -1-methylcyclohexane-1-carbonitrile (500mg,3.03mmol) in tetrahydrofuran (10mL) and water (2mL) was added dropwise concentrated hydrochloric acid solution (4 mL). The reaction solution was stirred at 90 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give 4-formyl-1-methylcyclohexane-1-carbonitrile (500mg, crude product). ES-API [ M + H ]]⁺＝152.1。

Step three: 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] is reacted with]Pyridine-4, 5-diamine (300mg,1.04mmol), 4-formyl-1-methylcyclohexane-1-carbonitrile (450mg,2.98mmol), and 10% Pd/C (100mg) in methanol (10ml) were mixed and reacted at 120 ℃ for 30 minutes by microwave. Cooling to room temperature, filtering, concentrating, purifying with flash silica gel column (0-10% methanol/dichloromethane) to obtain 1-methyl-4- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d% ]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1-carbonitrile (400mg, yield: 91%). ES-API [ M + H ]]⁺＝420.1。

Step four: 1-methyl-4- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1-carbonitrile (440mg,1.04mmol) and sodium hydroxide (210mg,5.24mmol) were added to a mixed solvent of methanol/water (10mL/2mL), and microwave reaction was performed at 90 ℃ for 2.5 hours. Concentrating the reaction solution to obtain 4- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) -1-methylcyclohexane-1-carbonitrile (290mg, crude). ES-API [ M + H ]]⁺＝280.1。

Step five: to the above 4- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) -1-methylcyclohexane-1-carbonitrile (290mg,1.04mmol) in methanol (10mL) was added 2-chloro-4-phenoxylBenzaldehyde (726mg,3.12mmol) and potassium hydroxide (408mg,7.28mmol), and the mixture was stirred at room temperature overnight. After the reaction was completed, pH was adjusted to 7 with 1M hydrochloric acid solution, ethyl acetate (20mLX3) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by flash silica gel column (methanol/dichloromethane ═ 0-20%) to give 4- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d) as a yellow solid]Pyrrolo [2,3-b]Pyridin-2-yl) -1-methylcyclohexane-1-carbonitrile (200mg, purity 90%, yield 37%). ES-API [ M + H ] ]⁺＝512.2。

Step six: to 4- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) -1-methylcyclohexane-1-carbonitrile (200mg,0.39mmol) was added to a mixed solution of 1, 4-dioxane and water (10mL/1mL), and 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (177mg,0.78mmol) was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched by addition of aqueous sodium thiosulfate (2mL), ethyl acetate (20mL) was added, and the mixture was washed with saturated aqueous sodium bicarbonate (20mL), saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative HPLC alkaline method to give 4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) -1-methylcyclohexane-1-carbonitrile (Z48,45mg, purity 100%, yield 22%) as a white solid. ES-API [ M + H ]]⁺＝510.1。

Step seven: compound Z48(45mg,0.09mmol) prepared above was resolved by chiral preparative resolution (separation column: AB250mm × 4.6mm × 5um, mobile phase: n-hexane: isopropanol: 50, flow rate: 1mL/min, column temperature: 30 ℃) to give two isomers. Wherein one of the isomeric structures is arbitrarily designated as cis-4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d ]Pyrrolo [2,3-b]Pyridin-2-yl) -1-methylcyclohexane-1-carbonitrile (Z48-1, 4mg, peak 1, retention time 8.67min, yield 9%, de% ═ 100%) as a white solid. ES-API [ M + H ]]⁺＝510.2。¹H NMR(400MHz,DMSO-d₆) δ 12.79(s,1H),11.92(s,1H),8.67(s,1H),7.79(s,1H),7.65(d, J ═ 8.4Hz,1H),7.55-7.46(m,2H),7.27(t, J ═ 7.2Hz,1H),7.24-7.19(m,3H),7.05(dd, J ═ 8.4,2.4Hz,1H),3.51-3.42(m,1H),2.11-1.83(m,8H),1.39(s,3H). another isomer structure optionally meansIs trans-4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) -1-methylcyclohexane-1-carbonitrile (Z48-2, 29mg, peak 2, retention time 13.29min, yield 64%, de% ═ 100%) as a white solid. ES-API [ M + H ]]⁺＝510.2。¹H NMR(400MHz,DMSO-d₆)δ12.88(s,1H),12.09(s,1H),8.75(s,1H),7.87(d,J＝2.4Hz,1H),7.73(d,J＝8.4Hz,1H),7.57(t,J＝8.0Hz,2H),7.35(t,J＝7.6Hz,1H),7.32-7.25(m,3H),7.13(dd,J＝8.4,2.4Hz,1H),3.34-3.26(m,1H),2.23(d,J＝11.2Hz,2H),2.14(d,J＝13.2Hz,2H),2.01-1.89(m,2H),1.64-1.55(m,2H),1.48(s,3H).

EXAMPLE 44 preparation of Compound Z49

The method comprises the following steps: dissolving (methoxymethyl) triphenyl phosphine chloride (3.74g, 10.95mmol) in tetrahydrofuran (20mL), slowly adding bis (trimethylsilyl) amino lithium (11mL, 10.95mmol, 1M tetrahydrofuran solution) under the condition of nitrogen protection in an ice-water bath, keeping the ice-water bath stirring for 30 minutes, slowly adding 2- (4-oxocyclohexyl) acetonitrile (1g, 7.3mmol) in tetrahydrofuran (5mL), slowly raising the temperature to room temperature for reaction for 2 hours, the reaction was quenched with aqueous ammonium chloride (10mL), ethyl acetate (50mL) was added, and the mixture was washed with water (30mL x2) and saturated brine (30mL x1) in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by a silica gel column (petroleum ether/ethyl acetate ═ 10/1) to give 2- (4- (methoxymethylene) cyclohexyl) acetonitrile (1.0g, yield: 83%). ES-API [ M + H ] ]⁺＝166.1。

Step two: 2- (4- (methoxymethylene) cyclohexyl) acetonitrile (0.5g,3.03mmol) was dissolved in tetrahydrofuran (8mL) and water (1.5mL), 2M diluted hydrochloric acid (0.5mL) was added, the tube was sealed, and the mixture was added at 100 ℃ for reaction for 2 hours. Concentration gave 2- (4-formylcyclohexyl) acetonitrile (400mg, crude). ES-API [ M + H ]]⁺＝152.1。

Step three: to a solution containing 1- (phenylsulfonyl) -1H-pyrrole [2,3-b]Pyridine-4, 5-diamine (300mg,1.04mmol), 2- (4-formylcyclohexyl) acetonitrile (157mg,1.04mmol) and 10%Anhydrous methanol (8mL) was added to a microwave tube containing a mixture of palladium on carbon (150mg), and the mixture was heated by microwave at 120 ℃ for 2 hours. Methanol (20mL) was added, filtered, concentrated and purified using thin-layer prep plate (petroleum ether/ethyl acetate-40/60) to give the product 2- (4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexaneacetonitrile (180mg, yield: 41%). ES-API [ M + H ]]⁺＝420.1。

Step four: 2- (4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexaneacetonitrile (160mg,0.381mmol) was dissolved in a mixed solvent of methanol (5mL) and water (1mL), and sodium hydroxide (107mg,2.673mmol) was added and reacted at 95 ℃ for 1 hour by microwave heating. After the reaction is finished, concentrating to obtain the product 2- (4- (1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-2-yl) cyclohexyl) acetonitrile (100mg, crude). ES-API [ M + H ]]⁺＝280.1。

Step five: 2- (4- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexyl) acetonitrile (100mg, crude) and 2-chloro-4-phenoxybenzaldehyde (249mg,1.075mmol) were dissolved in methanol (10mL), and potassium hydroxide (100mg,1.79mmol) was added to react at 30 ℃ for 6 hours. The reaction was quenched by adding saturated aqueous ammonium chloride (2mL), ethyl acetate (30mL) was added, and the mixture was washed with water (10mLX2) and saturated brine (10mLX1) in this order, dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin layer chromatography (dichloromethane/methanol ═ 10/1) to give 2- (4- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d ] imidazole]Pyrrole [2,3-b ]]Pyridin-2-yl) -cyclohexyl) acetonitrile (80mg, 2-step yield: 41%). ES-API [ M + H ]]⁺＝512.1。

Step six: reacting 2- (4- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) -cyclohexyl) acetonitrile (80mg,0.165mmol) was dissolved in a mixed solvent of 1, 4-dioxane (5mL) and water (1mL), and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (71mg,0.313mmol) was slowly added thereto to react at room temperature for 1 hour. After completion of the reaction, the reaction was quenched with aqueous sodium thiosulfate (10mL), ethyl acetate (30mL) was added, and the mixture was washed with saturated aqueous sodium bicarbonate (20mLX2) and saturated brine (20mLX1) in this order, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC alkaline method to give 2 - (4- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) cyclohexyl) acetonitrile (Z49, 40mg, yield: 47%). ES-API [ M + H ]]⁺＝510.1。¹H NMR(400MHz,DMSO-d₆)δ12.79(s,1H),11.86(s,1H),8.60(s,1H),7.77(s,1H),7.64(d,J＝8.4Hz,1H),7.52-7.46(m,2H),7.26(t,J＝7.5Hz,1H),7.23-7.18(m,3H),7.04(dd,J＝8.4,2.4Hz,1H),3.16-3.12(m,1H),2.33(d,J＝11.0Hz,2H),2.06(d,J＝13.0Hz,2H),1.96(d,J＝12.3Hz,2H),1.70(q,J＝12.7Hz,2H),1.16-1.12(m,1H)，1.31(q,J＝12.2Hz,2H).

EXAMPLE 45 preparation of Compounds Z51, Z51-1, Z51-2

The method comprises the following steps: 4-chloro-1H-pyrrole [2,3-b]Pyridine-5-carboxylic acid methyl ester (1.5g,7.14mmol) was dissolved in dimethylformamide (30mL), 60% sodium hydride (428mg,10.71mmol) was added at 0 deg.C, reaction was carried out at 0 deg.C for 30 minutes, benzenesulfonyl chloride (1.88g,10.71mmol) was added dropwise, and the reaction was stirred at room temperature for 2 hours. Water (50mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed successively with saturated sodium bicarbonate (40mL), saturated brine (40mL), dried over anhydrous sodium sulfate, concentrated and the crude product was purified on a flash silica gel column (dichloromethane) to give 4-chloro-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] -2]Pyridine-5-carboxylic acid methyl ester (2.40g, yield: 96%) as a white solid. ES-API [ M + H ]]⁺＝351.1。

Step two: to a 100mL round bottom flask was added 4-chloro-1- (benzenesulfonyl) -1H-pyrrole [2,3-b]Pyridine-5-carboxylic acid methyl ester (1.7g,4.86mmol), zinc cyanide (569mg,4.86mmol), tetrakis (triphenylphosphine) palladium (566mg,0.49mmol), N-dimethylformamide (20mL) were replaced with nitrogen three times, and the reaction was stirred at 120 ℃ for 18 hours under nitrogen protection. Water (60mL) was added to the reaction mixture, which was extracted with ethyl acetate (100 mL). The organic phase was washed successively with water (30mL), saturated brine (30 mL. times.2), dried over anhydrous sodium sulfate, concentrated and the crude product was purified with flash silica gel column (dichloromethane/petroleum ether: 40-100%) to give 4-cyano-1- (benzenesulfonyl) -1H-pyrrole [2,3-b ] ]Pyridine-5-carboxylic acidMethyl ester (1.05g, yield: 63%) as a white solid. ES-API [ M + H ]]⁺＝342.1。

Step three: 4-cyano-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ]]Pyridine-5-carboxylic acid methyl ester (500mg,1.47mmol) was suspended in methanol (40mL), 10% Pd/C (400mg) and concentrated hydrochloric acid (2mL) were added, and the reaction was stirred under hydrogen at room temperature for 16 hours. An additional 10% Pd/C (400mg) was added and the reaction was stirred under hydrogen at room temperature for an additional 24 hours. Filtering the reaction solution with diatomite, washing with methanol, and concentrating the filtrate to obtain 4- (aminomethyl) -1- (benzenesulfonyl) -1H-pyrrole [2,3-b]Pyridine-5-carboxylic acid methyl ester hydrochloride (530mg, yield: 95%) as a white solid. ES-API [ M + H ]]⁺346.1 (free base).

Step four: 4- (aminomethyl) -1- (phenylsulfonyl) -1H-pyrrole [2,3-b]Pyridine-5-carboxylic acid methyl ester hydrochloride (530mg,1.39mmol) was suspended in 1, 2-dichloroethane (30mL), and 4-oxocyclohexane-1-carbonitrile (256mg,2.08mmol), acetic acid (0.5mL) and sodium triacetoxyborohydride (589mg,2.78mmol) were added in this order, followed by stirring at room temperature for 4 hours. Dichloromethane (50mL) was added to the reaction mixture, and the mixture was washed with saturated sodium bicarbonate (40 mL. times.2) and saturated brine (40mL), dried over anhydrous sodium sulfate and concentrated, and the crude product was purified with flash silica gel column (methanol/dichloromethane: 0-3%) to give 4- (3-oxo-6- (benzenesulfonyl) -3, 6-dihydrodipyrrole [2,3-b:3',4' -d ] ]Pyridin-2 (1H) -yl) cyclohexane-1-carbonitrile (485mg, yield: 83%) as a white solid. ES-API [ M + H ]]⁺＝421.1

Step five: 4- (3-oxo-6- (phenylsulfonyl) -3, 6-dihydrodipyrrole [2,3-b:3',4' -d]Pyridin-2 (1H) -yl) cyclohexane-1-carbonitrile (435mg,1.04mmol) was dissolved in methanol (10mL), tetrahydrofuran (5mL) and water (2mL), and sodium hydroxide (124mg,3.12mmol) was added to stir the reaction at room temperature for 4 hours. The reaction solution was adjusted to pH 8 with 1.0M dilute hydrochloric acid and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (10mL), dried over anhydrous sodium sulfate, concentrated and the crude product was purified on flash silica gel column (methanol/dichloromethane: 0-5%) to give 4- (3-oxo-3, 6-dihydrodipyrrole [2,3-b:3',4' -d)]Pyridin-2 (1H) -yl) cyclohexane-1-carbonitrile (200mg, yield: 70%) as a white solid. ES-API [ M + H ]]⁺＝281.2。

Step six: 4- (3-oxo-3, 6-dihydrodipyrrole [2,3-b:3',4'-d]pyridin-2 (1H) -yl) cyclohexane-1-carbonitrile (200mg,0.71mmol) and 2-chloro-4-phenoxybenzaldehyde (494mg,2.13mmol) were dissolved in methanol (15mL), the reaction was cooled to 0 deg.C, and potassium hydroxide (278mg,4.97mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction solution was adjusted to pH 8 with 1.0M dilute hydrochloric acid and extracted with ethyl acetate (80 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated and the crude product was purified using thin layer prep. plate (dichloromethane/7M ammonia methanol ═ 15:1) to give 4- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -3-oxo-3, 6-dihydrodipyrrole [2,3-b:3',4' -d ]Pyridin-2 (1H) -yl) cyclohexane-1-carbonitrile (200mg, yield: 54%) as a white solid. ES-API [ M + H ]]⁺＝513.1。

Step seven: 4- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -3-oxo-3, 6-dihydrodipyrrole [2,3-b:3',4' -d)]Pyridin-2 (1H) -yl) cyclohexane-1-carbonitrile (200mg,0.39mmol) was dissolved in 1, 4-dioxane (10mL) and water (1mL), 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (177mg,0.78mmol) was added, and the reaction was stirred at room temperature for 4 hours. The reaction mixture was added with a saturated sodium thiosulfate solution (10mL) and a saturated sodium bicarbonate solution (10mL), and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated sodium bicarbonate solution (15mL), saturated brine (15mL), dried and concentrated, and the crude product was purified by preparative HPLC alkaline method to give 4- (8- (2-chloro-4-phenoxybenzoyl) -3-oxo-3, 6-dihydrodipyrrole [2,3-b:3',4' -d]Pyridin-2 (1H) -yl) cyclohexane-1-carbonitrile (Z51,105mg, yield: 52%) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ9.96(s,1H,br),8.69–8.64(m,1H),8.09–8.02(m,1H),7.58-7.55(m,1H),7.49(t,J＝7.6Hz,2H),7.34-7.13(m,4H),7.04(d,J＝8.4Hz,1H),5.02-4.89(m,2H),4.23-4.04(m,1H),3.25-3.17(s,0.5H),2.85-2.76(m,0.5H),2.20-1.98(m,2H),1.98-1.58(m,6H).ES-API:[M+H]⁺＝511.1。

Step eight: chiral resolution of compound Z51(100mg,0.20mmol) (column: IB, 10 μm,30 × 250mm, mobile phase: n-hexane: ethanol 60:30, flow rate: 25ml/min, column temperature: room temperature) gave cis-4- (8- (2-chloro-4-phenoxybenzoyl) -3-oxo-3, 6-dihydrodipyrrole [2,3-b:3',4' -d ] ]Pyridin-2 (1H) -yl) cyclohexane-1-carbonitrile (Z51-1,20mg, Peak 1, Retention time 7.848min, yield: 20%) as a pale solid.¹H NMR(400MHz,DMSO-d₆)δ13.15(s,1H),8.70(s,1H),8.09(s,1H),7.59(d,J＝8.4Hz,1H),7.53-7.45(m,2H),7.26(t,J＝7.2Hz,1H),7.25-7.15(m,3H),7.05(dd,J＝8.4,2.4Hz,1H),4.98(s,2H),4.84-4.81(m,1H),4.19-4.06(m,1H),3.25-3.17(m,1H),2.02(d,J＝10.0Hz,2H),1.92-1.73(m,6H).ES-API:[M+H]⁺511.1; and trans-4- (8- (2-chloro-4-phenoxybenzoyl) -3-oxo-3, 6-dihydrodipyrrole [2,3-b:3', 4' -d]Pyridin-2 (1H) -yl) cyclohexane-1-carbonitrile (Z51-2,20mg, Peak 2, Retention time 11.796min, yield: 20%) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ13.16(s,1H),8.69(s,1H),8.07(s,1H),7.59(d,J＝8.4Hz,1H),7.49(t,J＝8.0Hz,2H),7.27(t,J＝7.6Hz,1H),7.25-7.15(m,3H),7.04(dd,J＝8.4,2.0Hz,1H),4.92(s,2H),4.17-4.06(m,1H),2.81(t,J＝10.4Hz,1H),2.14(d,J＝5.2Hz,2H),1.91-1.64(m,6H).ES-API:[M+H]⁺＝511.1。

EXAMPLE 46 preparation of Compound Z52

The method comprises the following steps: to 50 parts of methylene chloride (50mL) was added triethylamine (6.07g,60.0mmol) and urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (9.1g,24.0mmol) in this order, and the mixture was stirred at room temperature for 30 minutes, followed by addition of N, O-dimethylhydroxylamine hydrochloride (2.93g,30.0mmol) and stirring at room temperature for 2 hours. The reaction mixture was concentrated, and water (30mL) and ethyl acetate (30mLX3) were added to conduct extraction. The organic layers were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography (ethyl acetate/petroleum ether ═ 0-50%) to give N-methoxy-N-methyltetrahydro-2H-pyran-3-carboxamide (2.6g, yield: 75%) as a colorless liquid. ES-API [ M + H ]]⁺＝174.1。

Step two: 4-chloro-1- (triisopropylsilyl) -1H-pyrrolo [2,3-b ]Pyridine (2.32g,7.5mmoL) and N, N, N ', N' -tetramethylethylenediamine (1.4g,12mmoL) were dissolved in anhydrous tetrahydrofuran (10mL) and a solution of sec-butyllithium (4.8mL, 12mmoL, 2.5M) in tetrahydrofuran was slowly added dropwise at-60 deg.C, and stirred at this temperature for 30 minutes. ThenA solution of N-methoxy-N-methyltetrahydro-2H-pyran-3-carboxamide (2.6g,15mmol) in tetrahydrofuran was added dropwise. The reaction solution was gradually warmed up to room temperature and reacted overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, extracted with 30mL of ethyl acetate (30mLX3), dried over anhydrous sodium sulfate, the filtrate was concentrated, and purified by flash column chromatography (ethyl acetate/petroleum ether ═ 0-25%) to give (4-chloro-1- (triisopropylsilyl) -1H-pyrrolo [2,3-b ] -pyrrolo [2]Pyridin-5-yl) (tetrahydro-2H-pyran-3-yl) methanone (1.32g, yield: 42%) as a yellow liquid. ES-API [ M + H ]]⁺＝421.3。

Step three: (4-chloro-1- (triisopropylsilyl) -1H-pyrrolo [2, 3-b)]Pyridin-5-yl) (tetrahydro-2H-pyran-3-yl) methanone (1.32g,3.14mmoL) was dissolved in tetrahydrofuran (10mL), tetrabutylammonium fluoride/tetrahydrofuran solution (4.7mL, 4.7mmoL, 1.0M) was slowly added dropwise at 0 deg.C and stirred at room temperature for 0.5H. Water (20mL) was added to the reaction mixture, which was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography (ethyl acetate/petroleum ether ═ 0-60%) to give (4-chloro-1H-pyrrolo [2, 3-b) ]Pyridin-5-yl) (tetrahydro-2H-pyran-3-yl) methanone (110mg, yield: 13%) as a pale yellow solid. ES-API [ M + H ]]⁺＝265.1。

Step four: (4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) (tetrahydro-2H-pyran-3-yl) methanone (110mg,0.415mmol) was dissolved in dry N, N-dimethylformamide (5mL), cooled to 0 deg.C, sodium hydride (25mg,0.62mmol, 60% dispersed in mineral oil) was added, the reaction stirred at 0 deg.C for 0.5H, and p-toluenesulfonyl chloride (146mg,0.83mmol, 0.1mL) was added dropwise. Adding saturated ammonium chloride aqueous solution into the reaction solution to quench the reaction, extracting with ethyl acetate (30mLX3), drying with anhydrous sodium sulfate, concentrating the filtrate, and purifying by flash column chromatography (ethyl acetate/petroleum ether is 0-20%) to obtain (4-chloro-1- (p-toluenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-5-yl) (tetrahydro-2H-pyran-3-yl) methylketone (156mg, yield: 90%) as a yellow solid. ES-API [ M + H ]]⁺＝419.1。

Step five: (4-chloro-1- (tosyl) -1H-pyrrolo [2, 3-b)]Pyridin-5-yl) (tetrahydro-2H-pyran-3-yl) methylketone (156mg,0.37mmol) was dissolved in dry N, N-dimethylformamide (5mL) and cooled to room temperatureSodium azide (48mg,0.74mmol) was added at 0 ℃ and the reaction stirred at 60 ℃ for 1 hour. The reaction solution was cooled to room temperature, and then, saturated aqueous sodium bicarbonate was added to quench the reaction, followed by extraction with ethyl acetate (10mLX 3). The organic phase was washed with saturated brine (10mL), dried over anhydrous sodium sulfate, the filtrate was concentrated and purified by flash column chromatography (ethyl acetate/petroleum ether ═ 0-80%) to give 6-p-toluenesulfonyl-1, 5',6,6' -tetrahydro-2 'H,3H,4' H-spiro [ dipyrrole [2,3-b:2',3' -d ] ]Pyridine-2, 3' -pyrans]-3-one (44mg, yield 30%) as a yellow liquid. ES-API [ M + H ]]⁺＝398.1。

Step six: 6-p-toluenesulfonyl-1, 5',6,6' -tetrahydro-2 'H,3H,4' H-spiro [ dipyrrole [2,3-b:2',3' -d ]]Pyridine-2, 3' -pyrans]-3-ketone (44mg,0.105mmol) was dissolved in methanol (12mL), tetrahydrofuran (2mL) and water (2mL), sodium hydroxide (21mg,0.525mmol) was added, and the reaction was stirred in a sealed tube at 60 ℃ for 2 hours. Concentrating the reaction solution to obtain 1,5',6',6' -tetrahydro-2 ' H,3H,4' H-spiro [ dipyrrolo [2,3-b:2',3' -d ]]Pyridine-2, 3' -pyrans]-3-ketone (70mg, crude), yellow oily liquid. ES-API [ M + H ]]⁺＝244.1。

Step seven: 1,5',6',6' -tetrahydro-2 ' H,3H,4' H-spiro [ dipyrrolo [2,3-b:2',3' -d ]]Pyridine-2, 3' -pyrans]-3-one (70mg, crude) and 2-chloro-4-phenoxybenzaldehyde (49mg,0.21mmol) were dissolved in methanol (5mL), cooled to 0 deg.C, potassium hydroxide (41mg,0.735mmol) was added, and the reaction was stirred at 30 deg.C for 6 hours. The reaction mixture was poured into water (10mL), adjusted to pH 8 with 1.0M dilute hydrochloric acid, and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (10mL), dried over anhydrous sodium sulfate, concentrated and purified by flash column chromatography (methanol/dichloromethane ═ 0-10%) to give 8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1,5',6,6' -tetrahydro-2 'H,3H,4' H-spiro [ dipyrrolo [2,3-b:2',3' -d ] ]Pyridine-2, 3' -pyrans]-3-ketone (25mg, yield: 50%) as a colorless liquid. ES-API [ M + H ]]⁺＝476.1。

Step eight: 8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1,5',6,6' -tetrahydro-2 'H,3H,4' H-spiro [ dipyrrolo [2,3-b:2',3' -d)]Pyridine-2, 3' -pyrans]-3-one (25mg,0.053mmol) was dissolved in tetrahydrofuran (5mL), cooled to 0 deg.C, dess-Martin oxidant (44mg,0.105mmol) was added and the reaction stirred at room temperature for 30 min. Adding saturated sulfo into the reaction liquidSodium sulfate solution (6mL) and saturated sodium bicarbonate solution (10mL) were extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (10mL), dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by preparative HPLC alkaline method to give 8- (2-chloro-4-phenoxybenzoyl) -1,5',6,6' -tetrahydro-2 'H,3H,4' H-spiro [ dipyrrolo [2,3-b:2',3' -d ]]Pyridine-2, 3' -pyrans]-3-one (Z52,3.61mg, yield 14%) as a white solid. ES-API [ M + H ]]⁺＝474.1。

EXAMPLE 47 preparation of Compound Z54

The method comprises the following steps: methoxymethyltriphenylphosphonium chloride (3.4g,9.15mmol) was dissolved in anhydrous tetrahydrofuran (50mL), bis (trimethylsilyl) aminolithium (9.2mL,9.15mmol,1M) was added dropwise in an ice-water bath under protection of nitrogen, a solution of 6- (((tert-butyldiphenylsilyl) oxy) methyl) dihydro-2H-pyran-3 (4H) -one (1.5g,6.1mmol) in anhydrous tetrahydrofuran (10mL) was slowly added dropwise, the reaction was stirred at room temperature for 2 hours, a saturated ammonium chloride solution (100mL) was added, extraction was performed with ethyl acetate (100mL), the organic phase was dried over anhydrous sodium sulfate, concentration was performed, and purification was performed by column chromatography (petroleum ether: ethyl acetate ═ 20:1) to obtain tert-butyl ((5- (methoxymethylene) tetrahydro-2H-pyran-2-yl) methoxy) diphenylsilane (1.6 g), yield 44%) as colorless oil. ES-API [ M + H ] ]⁺＝397.1。

Step two: tert-butyl ((5- (methoxymethylene) tetrahydro-2H-pyran-2-yl) methoxy) diphenylsilane (1.6g,4mmol) was dissolved in a mixture of tetrahydrofuran (20mL) and water (4mL), concentrated hydrochloric acid (12mL, 12M) was added, and the reaction was stirred at 95 ℃ for 1 hour. The reaction was concentrated and the crude product was dried in vacuo to give 6- (hydroxymethyl) tetrahydro-2H-pyran-3-carbaldehyde (2.1g, crude) as a pale yellow oil. [ M + H ]]⁺＝383.2。

Step three: 1- (phenylsulfonyl) -1H-pyrrolo [2,3-b]Pyridine-4, 5-diamine (200mg,0.71mmol) and 6- (hydroxymethyl) tetrahydro-2H-pyran-3-carbaldehyde (542mg,1.42mmol) were dissolved in methanol (8mL), palladium on carbon (50mg) was added, and the reaction was stirred at 120 ℃ for 6 hours. Diatomite filter cakeFiltering, washing with ethyl acetate (50mLX2) for 2 times, drying over anhydrous sodium sulfate, concentrating, and purifying the crude product by column chromatography (petroleum ether: ethyl acetate 40:1) to obtain (5- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) tetrahydro-2H-pyran-2-yl) methanol (140mg, yield: 49%) as a yellow solid. ES-API [ M + H ]]⁺＝413.1。

Step four: (5- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) tetrahydro-2H-pyran-2-yl) methanol (140mg,0.34mmol) was dissolved in methanol (10mL), tetrahydrofuran (5mL) and water (2mL), sodium hydroxide (95mg,2.38mmol) was added, and the reaction was stirred at 90 ℃ for 12 hours. To the reaction mixture were added water (15mL) and a saturated ammonium chloride solution (4mL), followed by extraction with ethyl acetate (50 mL). The organic phase was washed with a saturated sodium bicarbonate solution (20mL), a saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (methanol: dichloromethane ═ 20%) to give (5- (1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-2-yl) tetrahydro-2H-pyran-2-yl) methanol (30mg, yield: 32%) as an off-white solid. ES-API [ M + H ]]⁺＝273.1。

Step five: (5- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) tetrahydro-2H-pyran-2-yl) methanol (30mg, 0.11mmol) and 2-chloro-4-phenoxybenzaldehyde (51mg,0.22mmol) were dissolved in methanol (5mL), the reaction cooled to 0 deg.C and potassium hydroxide (43mg,0.77mmol) added. The reaction was stirred at room temperature overnight. The reaction mixture was poured into water (100mL), adjusted to pH 8 with 1.0M dilute hydrochloric acid, and extracted with ethyl acetate (50 mL). The organic phase was washed with brine (20mL), dried over anhydrous sulfuric acid, concentrated and the crude product was purified using thin layer prep. plate (dichloromethane/7M methanolic ammonia ═ 100:5) to give (2-chloro-4-phenoxyphenyl) (2- (6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (10mg, yield: 18%) as a pale yellow solid. ES-API [ M + H ]]⁺＝505.1。

Step six: (2-chloro-4-phenoxyphenyl) (2- (6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (10mg,0.02mmol) was dissolved in tetrahydrofuran (20mL) and water (2mL) and 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (9mg,0.0 mmol) was added 4mmol), the reaction was stirred at room temperature for 1 hour. The reaction mixture was added with saturated sodium bicarbonate solution (10mL), and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (15mL), dried over anhydrous sodium sulfate, concentrated and the crude product was purified by preparative HPLC (column: Welch Xtimate, 21.2X 150mm, 5 um; mobile phase A:5mmol/L NH)₄HCO₃Aqueous solution, mobile phase B: ACN; flow rate: 15 ml/min; chromatographic conditions are as follows: 15ml-35-85-13 min; column temperature: room temperature) to obtain (2-chloro-4-phenoxyphenyl) (2- (6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z54,0.98mg, yield: 9.7%) as a pale yellow solid. ES-API [ M + H ]]⁺＝503.1。

EXAMPLE 48 preparation of Compounds Z59-1, Z59-2, Z59-2-1, Z59-2

The method comprises the following steps: to a solution of 3-hydroxycyclopentane-1-carboxylic acid (500mg,3.844mmol) in dry N, N-dimethylformamide (20.0mL) were added N, O-dimethylhydroxylamine hydrochloride (484.0mg,4.988mmol), N, N-diisopropylethylamine (3.0mL,17.22mmol) and urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (1.75g,4.602mmol) in this order under ice-water bath conditions, and reacted at 35 ℃ for 4 hours. After the reaction, water (7.0mL) was added to quench the reaction, ethyl acetate (80mLX2) was extracted, the organic phase was washed with saturated brine (60mLX3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol: 100:0 to 90:10(v/v)) to give 3-hydroxy-N-methoxy-N-methylcyclopentane-1-carboxamide (1.6g, crude product).

Step two: lithium aluminum hydride (6.8mL,1M,6.8mmol) was added to a dry tetrahydrofuran (17.0mL) solution of 3-hydroxy-N-methoxy-N-methylcyclopentane-1-carboxamide (1.60g, crude) in an ice-water bath and stirred for 0.5 h in an ice-water bath. After the completion of the reaction, the solvent was spin-dried under reduced pressure to give 3-hydroxycyclopentane-1-carbaldehyde (402mg, 2-step total yield: 91%).

Step three: adding 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] into the sealed tube]Pyridine-4, 5-diamine (500mg,1.736mmol), 3-hydroxycyclopentane-1-carbaldehyde (300mg,2.631mmol) and palladium on charcoal (100mg, 10%), and finally anhydrous methanol (30.0mL) was added. The mixture was stirred at 120 ℃ for 8 hours in a sealed tube. Cooling the reaction system to room temperature, adding diatomite for filtration, and performing rotary drying on the solvent under reduced pressure to obtain the 3- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) cyclopentan-1-ol (700mg, crude), a brown solid. ES-API [ M + H ]]⁺＝383.2。

Step four: in a sealed tube, 3- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4,5-d ] is added]Pyrrolo [2,3-b]Pyridin-2-yl) cyclopentan-1-ol (700mg, crude) was dissolved in methanol (15mL), tetrahydrofuran (4mL) and water (2.5mL), and sodium hydroxide (500mg,12.5mmol) was added to stir the reaction at 90 ℃ for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and water (40mL) and a saturated ammonium chloride solution (10mL) were added to adjust the pH to about 8, followed by extraction with ethyl acetate (200 mL). The organic phase was washed with saturated sodium bicarbonate solution (80mL), saturated brine (80mL), dried over anhydrous sodium sulfate, and concentrated to give 3- (3, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-2-yl) cyclopentan-1-ol (801mg, crude), an off-white solid. ES-API [ M + H ]]⁺＝243.1。

Step five: 3- (3, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclopentan-1-ol (801mg, crude) and 2-chloro-4-phenoxybenzaldehyde (800mg,3.448mmol) were dissolved in methanol (20.0mL), the reaction was cooled to 0 deg.C, and potassium hydroxide (700mg,12.5mmol) was added. The reaction was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into saturated aqueous ammonium chloride (50mL), the pH was adjusted to 8, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (60mL), dried over anhydrous sodium sulfate and concentrated to give 3- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclopentan-1-ol (200mg, 3-step total yield: 24%) as a pale yellow solid. ES-API [ M + H ]]⁺＝475.1。

Step six: 3- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) cyclopentan-1-ol (200mg,0.4218mmol) was dissolved in tetrahydrofuran (20mL) and 2, 3-dichloro-5, 6-dicyano-1, 4-benzene was added at room temperatureQuinone (200mg,0.8437mmol), and the reaction stirred at room temperature for 2 hours. The reaction was quenched by addition of saturated sodium bicarbonate solution (30mL) and extracted with ethyl acetate (50mLX 2). The organic phase was washed with saturated brine (60mL), dried over anhydrous sodium sulfate and then dried under reduced pressure, and the crude product was purified by HPLC (ammonium bicarbonate method) to give two isomers. One of the isomeric structures is optionally designated (2-chloro-4-phenoxyphenyl) (2- (cis-3-hydroxycyclopentyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-8-yl) methanone (Z59-1,21.5mg, retention time: 7.548min, yield 10.8%), light yellow solid, ES-API: [ M + H ]]⁺473.2. The other isomer structure is arbitrarily designated as (2-chloro-4-phenoxyphenyl) (2- (trans-3-hydroxycyclopentyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z59-2,28.8mg, retention time: 7.656min, yield: 14.3%), light yellow solid, ES-API: [ M + H ]]⁺＝473.2。

Step seven: the chiral preparative resolution of Z59-2(204.6mg,0.4323mmol) obtained above was continued (separation column IC150mm X4.6 mm X5 um, mobile phase: n-hexane: ethanol: diethylamine 60:40:1, flow rate: 1ml/min, column temperature: 30 ℃) to give two isomers. Wherein one of the isomeric structures is optionally designated as (2-chloro-4-phenoxyphenyl) (2- ((1S,3S) -3-hydroxycyclopentyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z59-2-1, 25.0mg, Peak 1, retention time 5.544min, yield: 12.2%) as a pale white solid. ES-API [ M + H ]]⁺＝473.3。¹H NMR(500MHz,DMSO-d₆) δ 12.82(s,1H),12.14(s,1H),8.65(s,1H),7.81(s,1H),7.63(d, J ═ 8.5Hz,1H),7.49(t, J ═ 7.5Hz,2H),7.35-7.16(m,4H),7.05(dd, J ═ 8.5,2.0Hz,1H),5.71-5.17(m,1H),4.34(s,1H),3.74-3.62(m,1H),2.31-2.15(m,2H),2.10-1.91(m,2H),1.84-1.76(m, 2H). The other isomer structure is arbitrarily designated as (2-chloro-4-phenoxyphenyl) (2- ((1R,3R) -3-hydroxycyclopentyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-8-yl) methanone (Z59-2-2,26.0mg, Peak 2, retention time 6.290min, yield: 12.7%) as a pale white solid. ES-API [ M + H ]]⁺＝473.3。¹H NMR(500MHz,DMSO-d₆)δ12.82(s,1H),12.14(s,1H),8.65(s,1H),7.81(d,J＝2.5Hz,1H),7.63(d,J＝8.5Hz,1H),7.49(dd,J＝8.5,7.5Hz,2H),7.27(t,J＝7.5Hz,1H),7.23-7.17(m,3H),7.05(dd,J＝8.5,2.5Hz,1H),5.75-5.19(m,1H),4.33(s,1H),3.67(dd,J＝14.5,7.4Hz,1H),2.32-2.15(m,2H),2.07-1.89(m,2H),1.83-1.77(m,2H)。

EXAMPLE 49 preparation of Compounds Z60-1, Z60-2, Z60-2-1, Z60-2

The method comprises the following steps: to a solution of 3-hydroxycyclopentane-1-carboxylic acid (500mg,3.844mmol) in dry N.N-dimethylformamide (20.0mL) were added N, O-dimethylhydroxylamine hydrochloride (484.0mg,4.988mmol), N, N-diisopropylethylamine (3.0mL, 17.22mmol) and urea N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluorophosphate (1.75g,4.602mmol) in this order under ice-water bath conditions, and reacted at 35 ℃ for 4 hours. After the reaction was completed, water (7.0mL) was added to quench the reaction, ethyl acetate (80mLX2) was extracted, the reaction solution was washed with saturated brine (60mLX3), the organic phase was dried over anhydrous sodium sulfate, filtered and dried under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol H ═ 100:0 to 90:10(v/v)) to give 3-hydroxy-N-methoxy-N-methylcyclopentane-1-carboxamide (499mg, yield: 75%). ES-API [ M + H ]]⁺＝174.3。

Step two: methyl iodide (8.20g, 57.8mmol) and silver oxide (13.40g, 57.8mmol) were added in this order to a solution of 3-hydroxy-N-methoxy-N-methylcyclopentane-1-carboxamide (1001mg,5.78mmol) in acetonitrile (30.0mL) at room temperature, and the reaction was carried out at room temperature for 24 hours. After the reaction, celite was added to the reaction system, and the filtrate was spin-dried under reduced pressure to give N, 3-dimethoxy-N-methylcyclopentane-1-carboxamide (880mg, yield: 81%). ES-API [ M + H ] ]⁺＝188.2。

Step three: lithium aluminum hydride (9.5mL,1M,9.5mmol) was added to a solution of 3-hydroxy-N-methoxy-N-methylcyclopentane-1-carboxamide (880mg,4.70mmol) in dry tetrahydrofuran (30.0mL) in an ice-water bath and stirred for 0.5 h in an ice-water bath. After the completion of the reaction, the solvent was spin-dried under reduced pressure to give 3-methoxycyclopentane-1-carbaldehyde (350mg, yield: 58%).

Step four: adding 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] into the sealed tube]The pyridine-4 is a compound of general formula,5-diamine (600mg,2.082mmol), 3-methoxycyclopentane-1-carbaldehyde (350mg,2.732mmol) and palladium on charcoal (200mg, 10%), and finally anhydrous methanol (20.0mL) was added. The mixture was stirred at 120 ℃ for 6 hours in a sealed tube. Cooling the reaction system to room temperature, adding diatomite for filtration, and performing rotary drying on the solvent under reduced pressure to obtain 2- (3-methoxy cyclopentyl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (203mg, yield: 24%) as a brown solid. ES-API [ M + H ]]⁺＝397.1。

Step five: 2- (3-methoxycyclopentyl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ] is placed in a sealed tube]Pyrrolo [2,3-b]Pyridine (203mg, crude) was dissolved in methanol (24mL), tetrahydrofuran (6mL) and water (4mL), sodium hydroxide (144mg,3.587mmol) was added, and the reaction was stirred at 90 ℃ for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and water (40mL) and a saturated ammonium chloride solution (10mL) were added to adjust the pH to about 8, followed by extraction with ethyl acetate (200 mL). The organic phase was washed with saturated sodium bicarbonate solution (80mL), saturated brine (80mL), dried over anhydrous sodium sulfate and concentrated to give 2- (3-methoxycyclopentyl) -3, 6-dihydroimidazo [4,5-d ]Pyrrolo [2,3-b]Pyridine (218.0mg, crude), off-white solid. ES-API [ M + H ]]⁺＝257.2。

Step six: 2- (3-methoxycyclopentyl) -3, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (218.0mg, crude) and 2-chloro-4-phenoxybenzaldehyde (832mg,3.587mmol) were dissolved in methanol (30.0mL), the reaction was cooled to 0 deg.C, and potassium hydroxide (700mg,12.5mmol) was added. The reaction was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was poured into saturated aqueous ammonium chloride (60mL), the pH was adjusted to 8, and the mixture was extracted with ethyl acetate (230 mL). The organic phase was washed with saturated brine (80mL), dried over anhydrous sodium sulfate and concentrated to give (2-chloro-4-phenoxyphenyl) (2- (3-methoxycyclopentyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (202mg, crude) as a pale yellow solid. ES-API [ M + H ]]⁺＝489.3。

Step seven: (2-chloro-4-phenoxyphenyl) (2- (3-methoxycyclopentyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (202mg, crude) was dissolved in tetrahydrofuran (20mL) and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (200mg,0.8437mmol) was added at room temperatureThe reaction was stirred at room temperature for 2 hours. The reaction was quenched by addition of saturated sodium bicarbonate solution (30mL) and extracted with ethyl acetate (50mLX 2). The organic phase was washed with saturated brine (60mL), dried over anhydrous sodium sulfate and then dried under reduced pressure, and the crude product was purified by HPLC (ammonium bicarbonate method) to give two isomers. Wherein one isomer structure is arbitrarily designated as (2-chloro-4-phenoxyphenyl) (2- (cis-3-methoxycyclopentyl) -1, 6-dihydroimidazo [4,5-d ]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z60-1,7.0mg, retention time: 5.544min, yield: 2.8%), light yellow solid, ES-API: [ M + H ]]⁺＝487.1。¹H NMR(500MHz,DMSO-d₆) δ 12.78(s,1H),11.95(s,1H),8.64(s,1H),7.78(s,1H),7.65(d, J ═ 8.5Hz,1H),7.49(t, J ═ 7.5Hz,2H),7.27(t, J ═ 7.5Hz,1H),7.21(dd, J ═ 5.0,2.5Hz,3H),7.06(dd, J ═ 8.5,2.5Hz,1H),4.05-3.95(m,1H), 3.87-3.77 (m,1H),3.24(s,3H),2.23-2.14(m,2H), 2.13-2.08 (m,1H),2.06-1.99(m,1H),1.98-1.89(m,1H), 1.68(m,1H), 1.6-2- (1H), 2-dihydro-phenyl-1H) (any of the isomers of the phenyl-1H, 1-dihydro-1H isomers (1H) -1H, 1-phenyl-4-phenyl-1-hydroxy-imidazole (any of the structures, 5-d]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z60-2,5.0mg, retention time 6.299min, yield: 2.0%) as a pale yellow solid, ES-API: [ M + H ]]⁺＝487.1。

Step eight: z60-2(200mg,0.4095mmol) was further resolved by chiral preparative resolution (separation column IC150mm x 4.6mm x 5um, mobile phase: n-hexane: ethanol: diethylamine: 70:30:1, flow rate: 1ml/min, column temperature: 30 ℃) to give the two isomers. One of the isomeric structures is optionally designated as (2-chloro-4-phenoxyphenyl) (2- ((1S,3S) -3-methoxycyclopentyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z60-2-1,37.0mg, Peak 1, retention time 17.49min, yield 18.5%) as a tan solid. ES-API [ M + H ] ]⁺487.1. The other isomer structure is arbitrarily designated as (2-chloro-4-phenoxyphenyl) (2- ((1R,3R) -3-methoxycyclopentyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z60-2-2,43.0mg, Peak 2, retention time 18.70min, yield 21.5%) as a tan solid. ES-API [ M + H ]]⁺＝487.1。¹H NMR(500MHz,DMSO-d₆)δ12.80(s,1H),11.82(s,1H),8.64(s,1H),7.80(s,1H),7.66(d,J＝8.5Hz,1H),7.54-7.46(m,2H),7.27(t,J＝7.5Hz,1H),7.24-7.17(m,3H),7.06(dd,J＝8.5,2.5Hz,1H),4.04-3.98(m,1H),3.71-3.61(m,1H),3.38(s,3H),2.40-2.32(m,1H),2.23-2.15(m,1H),2.05-1.89(m,3H),1.83-1.74(m,1H).

EXAMPLE 50 preparation of Compound Z61

The method comprises the following steps: 1- (Isocyanato-sulfonyl) -4-toluene (8.44g,43.22mmol) and methyl 3-oxocyclohexane-1-carboxylate (4.5g,28.81mmol) were dissolved in tetrahydrofuran (25mL) and cooled to 0 ℃. To the above mixed liquid was added a solid of potassium tert-butoxide (6.47g,57.63mmol) at 0 ℃ under a nitrogen atmosphere. After the addition was complete, the reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (30mL) and extracted with ethyl acetate (30mL X3). The organic phase was washed with saturated brine (30mLX3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified with flash silica gel column (ethyl acetate/petroleum ether: 5-20%) to give methyl 3-cyanocyclohexane-1-carboxylate (2000mg,11.96mmol, yield: 41.5%) as a colorless transparent oily liquid. ES-API [ M + H ]]⁺＝168.3

Step two: to a mixed liquid of methyl 3-cyanocyclohexane-1-carboxylate (2000mg,11.96mmol), tetrahydrofuran (10mL), methanol (10mL) and water (10mL) was added sodium hydroxide (960mg,23.92mmol), and after the addition was completed, the reaction was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 6 with dilute hydrochloric acid (1M) and extracted with ethyl acetate (100mL X3). The organic phase was washed with saturated brine (50mLX3), dried over anhydrous sodium sulfate, and concentrated to give 3-cyanocyclohexane-1-carboxylic acid (1.6g,10.45mmol, yield: 87%) as a colorless transparent liquid. ES-API [ M + H ] ]⁺＝154.1。

Step three: 3-cyanocyclohexane-1-carboxylic acid (1.6g,10.45mmol) was dissolved in tetrahydrofuran (20mL) and cooled to 0 ℃. To the above solution was slowly added dropwise a tetrahydrofuran complex of borane (1M,20.89mmol,20.89 mL). After the addition was complete, the reaction was stirred at 0 ℃ for a further 1 hour. The reaction solution was quenched with dilute hydrochloric acid (0.5M) until no bubbles were formed, and then with ethyl acetate(30mLX3) extracting. The organic phase was washed with saturated brine (50mLX3), dried over anhydrous sodium sulfate, and concentrated to give 3- (hydroxymethyl) cyclohexane-1-carbonitrile (1.3g,9.34mmol, yield: 89%) as a colorless transparent liquid. ES-API [ M + H ]]⁺＝140.2。

Step four: 3- (hydroxymethyl) cyclohexane-1-carbonitrile (600mg,4.31mmol) was dissolved in dichloromethane (30mL) and cooled to 0 ℃. To the above solution was added desmartin periodinane (2.74g,6.47 mmol). After the addition was complete, the reaction was stirred at room temperature for an additional 2 hours. The reaction was quenched with saturated sodium sulfite solution (10mL) and extracted with dichloromethane (20mLX 3). The organic phase was washed with saturated sodium hydrogencarbonate (20mLX2) and saturated brine (20mLX2), dried over anhydrous sodium sulfate, and concentrated to give 3-formylcyclohexane-1-carbonitrile (500mg,3.64mmol, yield: 85%) as a colorless transparent liquid. ES-API [ M + H ]]⁺＝138.2。

Step five: adding 1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] into thick-walled pressure-resistant bottle ]Pyridine-4, 5-diamine (800mg,2.77mmol), 3-formylcyclohexane-1-carbonitrile (500mg,3.64mmol), wet palladium on carbon (5 wt%, 0.277mmol,295mg), and methanol (10 mL). The mixture was heated to 120 ℃ and stirred for 3 hours. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated, and purified with flash silica gel column (methanol/dichloromethane: 2-5%) to give 3- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1-carbonitrile (250mg,0.62mmol, yield: 22%) as a brown solid. ES-API [ M + H ]]⁺＝406.1。

Step six: reacting 3- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1-carbonitrile (250mg,0.62mmol) was dissolved in methanol (6mL), tetrahydrofuran (3mL) and water (1 mL). Then sodium hydroxide (173mg,4.32mmol) was added and the reaction stirred at 90 ℃ for 16 h. The reaction solution was adjusted to pH 8 with 1.0M dilute hydrochloric acid, and a saturated sodium bicarbonate solution (10mL) was added thereto, followed by extraction with ethyl acetate (10 mL). The organic phase was washed successively with a saturated sodium hydrogencarbonate solution (20mL), a saturated brine (20mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified with flash column silica (methanol/dichloromethane: 2-10%) to give 3- (1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1-carbonitrile (140mg,0.565mmol, yield: 86%) as a yellow solid. ES-API: [M+H]⁺＝266.2。

Step seven: reacting 3- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1-carbonitrile (140mg,0.565mmol) and 2-chloro-4-phenoxybenzaldehyde (385mg,1.70mmol) were dissolved in methanol (8mL), cooled to 0 deg.C, and potassium hydroxide (222mg,3.96mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction solution was adjusted to pH 8 with 1.0M diluted hydrochloric acid and extracted with ethyl acetate (20mLX 3). The organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified on a flash column (methanol/dichloromethane: 5-10%) to give 3- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1-carbonitrile (80mg,0.16mmol, yield: 28%) as a white solid. ES-API [ M + H ]]⁺＝498.1。

Step eight: 3- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexane-1-carbonitrile (80mg,0.16mmol) was dissolved in tetrahydrofuran (2mL) and water (0.2 mL). 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (73mg,0.321mmol) was added thereto at room temperature, and the reaction was stirred at room temperature for 2 hours. The reaction solution was added with a saturated sodium thiosulfate solution (5mL) and a saturated sodium bicarbonate solution (5mL), and extracted with ethyl acetate (15mLX 3). The organic phase was washed with saturated sodium bicarbonate solution (15mL), saturated brine (15mL), dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by preparative HPLC alkaline method to give 3- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-2-yl) cyclohexane-1-carbonitrile (Z61,18mg,0.036mmol, yield: 23%) as a white solid. ES-API [ M + H ]]⁺＝496.1。

EXAMPLE 51 preparation of Compound Z62

The method comprises the following steps: methyl 3-hydroxycyclohexane-1-carboxylate (1.0g,6.32mmol) and imidazole (1.29g,18.96mmol) were dissolved in N, N-dimethylformamide (15 mL). To the above solution was added tert-butyldimethylsilyl chloride (1.43g,9.48mmol) at room temperature and stirred for 17 hours. Adding water to the reaction solutionThe reaction was quenched (100mL) and extracted with ethyl acetate (30mL X3). The organic phase was washed with saturated brine (50mLX3), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified with flash silica gel column (ethyl acetate/petroleum ether: 0-2%) to give methyl 3- ((tert-butyldimethylsilyl) oxy) cyclohexane-1-carboxylate (1.5g,5.51mmol, yield: 87%) as a colorless transparent oily liquid. ES-API [ M + H ]]⁺＝273.3。

Step two: methyl 3- ((tert-butyldimethylsilyl) oxy) cyclohexane-1-carboxylate (1.0g,3.67mmol) was dissolved in tetrahydrofuran (20mL) and cooled to-78 ℃. Diisobutyl aluminum hydride (1.04g,7.34mmol, 26% in toluene) was slowly added to the above reaction solution under a nitrogen atmosphere. After the addition was complete, the reaction was stirred for an additional 2 hours at-78 ℃. The reaction solution was quenched with a saturated aqueous solution (20mL) of potassium sodium tartrate and extracted with ethyl acetate (30mLX 3). The organic phase was washed with saturated brine (50mLX3), dried over anhydrous sodium sulfate, and concentrated to give (3- ((tert-butyldimethylsilyl) oxy) cyclohexyl) methanol (700mg,2.89mmol, yield: 78%) as a colorless transparent liquid. ES-API [ M + H ] ]⁺＝245.3。

Step three: (3- ((tert-butyldimethylsilyl) oxy) cyclohexyl) methanol (700mg,2.89mmol) was dissolved in dichloromethane (20mL) and cooled to 0 ℃. To the above solution was added desmartin periodinane (1.82g,4.3 mmol). After the addition was complete, the reaction was stirred at room temperature for 2 hours. The reaction was quenched with saturated sodium sulfite solution (10mL) and extracted with dichloromethane (20mLX 3). The organic phase was washed with saturated sodium hydrogencarbonate (20mLX2) and saturated brine (20mLX2), dried over anhydrous sodium sulfate, and concentrated to give 3- ((tert-butyldimethylsilyl) oxy) cyclohexane-1-carbaldehyde (500mg,2.06mmol, yield: 72%) as a colorless transparent liquid. ES-API [ M + H ]]⁺＝243.1

Step four: adding 1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] into thick-walled pressure-resistant bottle]Pyridine-4, 5-diamine (476mg,1.65mmol), 3- ((tert-butyldimethylsilyl) oxy) cyclohexane-1-carbaldehyde (500mg,2.06mmol), wet palladium on carbon (10 wt%, 0.206mmol,212mg), and methanol (10 mL). The mixture was heated to 120 ℃ and stirred for 3 hours. Cooling the reaction solution to room temperature, filtering, concentrating the filtrate, and using quick silica gelColumn (methanol/dichloromethane: 5-35%) purification gave 2- (3- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d ]Pyrrolo [2,3-b ] s]Pyridine (200mg,0.392mmol, yield: 20%) as a brown solid. ES-API [ M + H ]]⁺＝511.3。

Step five: reacting 2- (3- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -6- (benzenesulfonyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (200mg,0.392mmol) was dissolved in methanol (6mL), tetrahydrofuran (3mL) and water (1 mL). Sodium hydroxide (110mg,2.74mmol) was added and the reaction stirred at 90 ℃ for 16 h. The reaction solution was adjusted to pH 8 with 1.0M dilute hydrochloric acid, and a saturated sodium bicarbonate solution (10mL) was added and extracted with ethyl acetate (10 mL). The organic phase was washed successively with saturated sodium bicarbonate solution (20mL), saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified with flash silica gel column (methanol/dichloromethane: 2-20%) to give 3- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohex-1-ol (100mg,0.371mmol, yield: 95%) as a yellow solid. ES-API [ M + H ]]⁺＝257.2。

Step six: reacting 3- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohex-1-ol (130mg,0.507mmol) and 2-chloro-4-phenoxybenzaldehyde (357mg,1.52mmol) were dissolved in methanol (8mL) and cooled to 0 deg.C, followed by addition of potassium hydroxide (199mg,3.55mmol) and stirring at room temperature for 16 h. The reaction solution was adjusted to pH 8 with 1.0M diluted hydrochloric acid and extracted with ethyl acetate (20mLX 3). The organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated and the crude product was purified with flash silica gel column (methanol/dichloromethane: 5-10%) to give 3- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexan-1-ol (80mg,0.164mmol, yield: 32%) as a white solid. ES-API [ M + H ]]⁺＝489.1。

Step seven: 3- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexan-1-ol (130mg,0.266mmol) was dissolved in tetrahydrofuran (3mL) and water (0.3 mL). 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (181mg,0.798mmol) was added thereto at room temperature, and the reaction was stirred at room temperature for 2 hours. Adding saturated sulfo into the reaction liquidSodium sulfate solution (5mL) and saturated sodium bicarbonate solution (5mL) were extracted with ethyl acetate (15mLX 3). The organic phase was washed with saturated sodium bicarbonate solution (15mL), saturated brine (15mL), dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by preparative HPLC alkaline method to give 3- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexan-1-ol (Z62,40mg,0.082mmol, yield: 31%) as a white solid. ES-API [ M + H ]]⁺＝487.1。

EXAMPLE 52 preparation of Compound Z64

The method comprises the following steps: 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] is reacted with]Pyridine-4, 5-diamine (180mg,0.63mmol), 7-formyl-2-azaspiro [3.5 ] spiro]A mixture of tert-butyl nonane-2-carboxylate (160mg,0.63mmol) and 10% Pd/C (60mg) in methanol (2mL) was reacted at 120 ℃ for 30 minutes by microwave. Cooling to room temperature, filtering, concentrating, and purifying the crude product with flash silica gel column (0-10% methanol/dichloromethane) to obtain 7- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4,5-d ] ]Pyrrole [2,3-b ] s]Pyridin-2-yl) -2-azaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (180mg, purity 100%, yield: 54%). ES-API [ M + H ]]⁺＝522.3。

Step two: reacting 7- (6- (benzenesulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) -2-azaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (200mg,0.38mmol) and sodium hydroxide (77mg,1.92mmol) were added to a mixed solvent of methanol/water (2mL/0.4mL), and microwave reaction was carried out at 100 ℃ for 2.5 hours. Concentrating the reaction solution to obtain 7- (1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) -2-azaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (146mg, crude). ES-API [ M + H ]]⁺＝382.3。

Step three: to the above 7- (1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) -2-azaspiro [3.5]To a solution of tert-butyl nonane-2-carboxylate (146mg,0.38mmol) in methanol (10mL) were added 2-chloro-4-phenoxybenzaldehyde (267mg,1.15mmol) and potassium hydroxide (298mg,2.66mmol), and the mixture was stirred at room temperature overnight. After the reaction is finished, 1M hydrochloric acid solution is usedAdjusting pH to 7, extracting with ethyl acetate (20mLX3) twice, combining the organic phases, drying over anhydrous sodium sulfate, concentrating, and purifying with silica gel flash column (0-20% methanol/dichloromethane) to give 7- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4, 5-d) as a solid ]Pyrrole [2,3-b ] s]Pyridin-2-yl) -2-azaspiro [3.5]Nonane-2-carboxylic acid tert-butyl ester (100mg, purity 50%, yield 21%). Yellow solid ES-API [ M + H ]]⁺＝614.3。

Step four: to 7- (8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -1, 6-dihydroimidazo [4,5-d]Pyrrole [2,3-b ]]Pyridin-2-yl) -2-azaspiro [3.5]2, 3-dichloro-5, 6-dicyan-p-benzoquinone (74mg,0.32mmol) was added to a mixed solution of tert-butyl nonane-2-carboxylate (100mg,0.16mmol) and 1, 4-dioxane/water (2mL/0.2mL), and the mixture was stirred at room temperature for 2 hours. After the reaction, aqueous sodium thiosulfate (2mL) was added to quench, ethyl acetate (20mL) was added, and the mixture was washed with aqueous saturated sodium bicarbonate (20mL) and brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 7- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) -2-azaspiro [3.5]Tert-butyl nonane-2-carboxylate (100mg) as a white solid. ES-API [ M + H ]]⁺＝612.3.

Step five: 7- (8- (2-chloro-4-phenoxybenzoyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrole [2,3-b ]]Pyridin-2-yl) -2-azaspiro [3.5]Tert-butyl nonane-2-carboxylate (115mg,0.19mmol) was dissolved in dichloromethane (2mL), and trifluoroacetic acid (0.8mL) was added and stirred at room temperature for 2 hours. After the reaction is finished, the mixture is decompressed and concentrated to obtain (2- (2-azaspiro [ 3.5) ]Non-7-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrole [2,3-b ] s]Pyridin-8-yl) (2-chloro-4-phenoxyphenyl) methanone trifluoroacetate (118mg, crude). ES-API [ M + H ]]⁺＝512.2。

Step six: 37% aqueous formaldehyde solution (3 drops) was added dropwise to (2- (2-azaspiro [3.5 ] azaspiro [ sic ]) under ice-bath conditions]Non-7-yl) -1, 6-dihydroimidazole [4,5-d]Pyrrole [2,3-b ]]Pyridin-8-yl) (2-chloro-4-phenoxyphenyl) methanone trifluoroacetate (118mg,0.19mmol) in acetonitrile (3mL) was stirred for 15 minutes. Sodium cyanoborohydride (25mg,0.40mmol) was added to the reaction solution, and stirred for 15 minutes. The reaction mixture was extracted with saturated ammonium chloride solution (5mLX3), dichloromethane (5mL X3), and the organic phase was anhydrousDrying over sodium sulfate, concentrating, and purifying by preparative HPLC (trifluoroacetic acid method) to give (2-chloro-4-phenoxyphenyl) (2- (2-methyl-2-azaspiro [3.5 ]]Non-7-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrole [2,3-b ]]Pyridin-8-yl) methanone trifluoroacetate (Z64, 12mg, purity 100%, yield 10%). ES-API [ M + H ]]⁺＝526.2。¹H NMR(400MHz,DMSO-d₆)δ12.94(s,1H),12.24(s,1H),10.19(s,1H),8.69(s,1H),7.86(s,1H),7.65(d,J＝8.4Hz,1H),7.50(t,J＝8.0Hz,2H),7.32-7.25(m,1H),7.24-7.16(m,3H),7.08-7.02(m,1H),4.17-3.58(m,4H),3.31-3.20(m,1H),2.87(d,J＝4.8Hz,3H),2.21-1.95(m,4H),1.81-1.55(m,4H).

EXAMPLE 53 preparation of Compound Z66-1

The method comprises the following steps: 4- (aminomethyl) -1- (phenylsulfonyl) -1H-pyrrole [2,3-b]Pyridine-5-carboxylic acid methyl ester hydrochloride (305mg,0.80mmol) was suspended in 1, 2-dichloroethane (25mL), and 4-hydroxycyclohexan-1-one (137mg,1.20mmol), acetic acid (144mg,2.40mmol) and sodium triacetoxyborohydride (339mg,1.60mmol) were added in this order, and the reaction was stirred at room temperature for 4 hours. Dichloromethane (50mL) was added to the reaction mixture, and the mixture was washed with saturated sodium bicarbonate (20 mL. times.2) and saturated brine (20mL) in this order, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified with a flash silica gel column (methanol/dichloromethane: 0-5%) to give 2- (cis-4-hydroxycyclohexyl) -6- (benzenesulfonyl) -1, 6-dihydrodipyrrole [2,3-b:3',4' -d ] ]Pyridin-3 (2H) -one (145mg, yield: 44%), white solid,¹H NMR(400MHz,DMSO-d₆)δ8.64(s,1H),8.16-8.07(m,3H),7.71(t,J＝7.6Hz,1H),7.61(t,J＝7.6Hz,2H),7.01(d,J＝4.0Hz,1H),4.70(s,2H),4.44(d,J＝2.8Hz,1H),4.02(tt,J＝12.0,3.6Hz,1H),3.88-3.82(m,1H),1.94-1.85(m,2H),1.68-1.77(m,2H),1.61-1.40(m,4H).ES-API:[M+H]⁺412.1; 2- (trans-4-hydroxycyclohexyl) -6- (phenylsulfonyl) -1, 6-dihydrodipyrrole [2,3-b:3',4' -d]Pyridin-3 (2H) -one (140mg, yield: 42%), white solid,¹H NMR(400MHz,DMSO-d₆)δ8.64(s,1H),8.16-8.07(m,3H),7.71(t,J＝7.6Hz,1H),7.61(t,J＝7.6Hz,2H),6.97(d,J＝4.0Hz,1H),4.83-4.49(m,3H),3.96(tt,J＝11.6,3.6Hz,1H),3.46-3.33(m,1H),1.90(d,J＝10.6Hz,2H),1.76-1.52(m,4H),1.41-1.20(m,2H).ES-API:[M+H]⁺＝412.1。

step two: 2- (cis-4-hydroxycyclohexyl) -6- (benzenesulfonyl) -1, 6-dihydrodipyrrole [2,3-b:3',4' -d]Pyridin-3 (2H) -one (130mg,0.32mmol) was dissolved in methanol (10mL), tetrahydrofuran (4mL) and water (2mL), sodium hydroxide (64mg,1.60mmol) was added, and the reaction was stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 8 with 1.0M dilute hydrochloric acid, the reaction solution was concentrated, and the crude product was purified with flash silica gel column (methanol/dichloromethane: 0-15%) to give 2- (cis-4-hydroxycyclohexyl) -1, 6-dihydrodipyrrole [2,3-b:3',4' -d]Pyridin-3 (2H) -one (80mg, yield: 93%) as a white solid. ES-API [ M + H ]]⁺＝272.2。

Step three: 2- (cis-4-hydroxycyclohexyl) -1, 6-dihydrodipyrrole [2,3-b:3',4' -d]Pyridin-3 (2H) -one (70mg,0.26mmol) and 2-chloro-4-phenoxybenzaldehyde (241mg,1.04mmol) were dissolved in methanol (7mL), the reaction cooled to 0 deg.C and potassium hydroxide (102mg,1.82mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction solution was adjusted to pH 8 with 1.0M dilute hydrochloric acid, the reaction solution was concentrated, and the crude product was purified with flash silica gel column (methanol/dichloromethane: 0-13%) to give 8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -2- (cis-4-hydroxycyclohexyl) -1, 6-dihydrodipyrrole [2,3-b:3',4' -d- ]Pyridin-3 (2H) -one (110mg, 84% yield) as a white solid. ES-API [ M + H ]]⁺＝504.5。

Step four: 8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -2- (cis-4-hydroxycyclohexyl) -1, 6-dihydrodipyrrole [2,3-b:3',4' -d]Pyridin-3 (2H) -one (100mg,0.20mmol) was dissolved in 1, 4-dioxane (5mL) and water (0.5mL), 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (91mg,0.40mmol) was added, and the reaction was stirred at room temperature for 4 hours. The reaction mixture was added with a saturated sodium thiosulfate solution (6mL) and a saturated sodium bicarbonate solution (6mL), and extracted with ethyl acetate (60 mL). The organic phase was washed with saturated sodium bicarbonate solution (20mL), saturated brine (20mL), dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by preparative HPLC alkaline method to give 8- (2-chloro-4-phenoxybenzoyl) -2- (cis-4-hydroxycyclohexyl) -1, 6-dihydrodipyrrole [2,3-b:3',4' -d ]]Pyridin-3 (2H) -one (Z66-1,82mgYield: 82%) of white solid.¹H NMR(400MHz,DMSO-d₆)δ13.06(s,1H),8.68(s,1H),8.07(s,1H),7.60(d,J＝8.4Hz,1H),7.54-7.45(m,2H),7.29-7.24(m,1H),7.24-7.17(m,3H),7.04(dd,J＝8.4,2.4Hz,1H),4.95(s,2H),4.53(d,J＝3.2Hz,1H),4.09(tt,J＝11.6,2.8Hz,1H),3.88(d,J＝2.0Hz,1H),2.08-1.96(m,2H),1.80(d,J＝12.0Hz,2H),1.65-1.48(m,4H).ES-API:[M+H]⁺＝502.1。

EXAMPLE 54 preparation of Compound Z66-2

The method comprises the following steps: 2- (trans-4-hydroxycyclohexyl) -6- (phenylsulfonyl) -1, 6-dihydrodipyrrole [2,3-b:3',4' -d ]]Pyridin-3 (2H) -one (140mg,0.34mmol) was dissolved in methanol (10mL), tetrahydrofuran (4mL) and water (2mL), sodium hydroxide (68mg,1.70mmol) was added, and the reaction was stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 8 with 1.0M dilute hydrochloric acid, the reaction solution was concentrated, and the crude product was purified with flash silica gel column (methanol/dichloromethane: 0-12%) to give 2- (trans-4-hydroxycyclohexyl) -1, 6-dihydrodipyrrole [2,3-b:3',4' -d ]Pyridin-3 (2H) -one (70mg, yield: 76%) as a white solid. ES-API [ M + H ]]⁺＝272.2。

Step two: 2- (trans-4-hydroxycyclohexyl) -1, 6-dihydrodipyrrole [2,3-b:3',4' -d]Pyridin-3 (2H) -one (70mg,0.26mmol) and 2-chloro-4-phenoxybenzaldehyde (241mg,1.04mmol) were dissolved in methanol (7mL), the reaction was cooled to 0 deg.C and potassium hydroxide (102mg,1.82mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction solution was adjusted to pH 8 with 1.0M dilute hydrochloric acid, the reaction solution was concentrated, and the crude product was purified with flash silica gel column (methanol/dichloromethane: 0-15%) to give 8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -2- (trans-4-hydroxycyclohexyl) -1, 6-dihydrodipyrrole [2,3-b:3',4' -d-]Pyridin-3 (2H) -one (102mg, yield: 78%) as a white solid. ES-API [ M + H ]]⁺＝504.4。

Step three: 8- ((2-chloro-4-phenoxyphenyl) (hydroxy) methyl) -2- (trans-4-hydroxycyclohexyl) -1, 6-dihydrodipyrrole [2,3-b:3',4' -d]Pyridin-3 (2H) -one (102mg,0.20mmol) was dissolved in 1, 4-dioxane (5mL) and water (0.5mL) and 2,3-Dichloro-5, 6-dicyanobenzoquinone (91mg,0.40mmol) was reacted for 4 hours under stirring at room temperature. The reaction mixture was added with a saturated sodium thiosulfate solution (6mL) and a saturated sodium bicarbonate solution (6mL), and extracted with ethyl acetate (60 mL). The organic phase was washed with saturated sodium bicarbonate solution (20mL), saturated brine (20mL), dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by preparative HPLC alkaline method to give 8- (2-chloro-4-phenoxybenzoyl) -2- (trans-4-hydroxycyclohexyl) -1, 6-dihydrodipyrrole [2,3-b:3',4' -d ] ]Pyridin-3 (2H) -one (Z66-2,84mg, yield: 82%) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ8.65(s,1H),8.03(s,1H),7.57(d,J＝8.4Hz,1H),7.53-7.45(m,2H),7.30-7.24(m,1H),7.23-7.16(m,3H),7.03(dd,J＝8.4,2.4Hz,1H),4.89(s,2H),4.02(tt,J＝12.0,4.0Hz,1H),3.50(tt,J＝9.6,4.0Hz,1H),1.94(d,J＝10.4Hz,2H),1.84-1.64(m,4H),1.40-1.27(m,2H).ES-API:[M+H]⁺＝502.1。

EXAMPLE 55 preparation of Compound Z67-1

The method comprises the following steps: methyl cis-4- ((tert-butoxycarbonyl) amino) cyclohexane-1-carboxylate (1.0g,3.87mmol) was dissolved in tetrahydrofuran (10mL) and cooled to-78 ℃. Diisobutyl aluminum hydride (5.18mL,7.77mmol,1.5M in toluene) was slowly added to the above reaction under a nitrogen atmosphere. After the addition was complete, the reaction was continued with stirring at-78 ℃ for 2 hours. The reaction was quenched with a saturated aqueous solution of potassium sodium tartrate (20mL) and extracted with ethyl acetate (30mLX 3). The organic phase was washed with saturated brine (50mLX3), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (cis-4- (hydroxymethyl) cyclohexyl) carbamate (700mg,3.05mmol, yield: 79%) as a colorless transparent liquid. ES-API [ M-C4H8+ H]⁺＝174.1。

Step two: tert-butyl (cis-4- (hydroxymethyl) cyclohexyl) carbamate (700mg,3.05mmol) was dissolved in dichloromethane (15mL), pyridinium chlorochromate (1.32g,6.11mmol) was added at room temperature, and the reaction was stirred at room temperature for 2 hours. Filtering the reaction solution, and concentrating the filtrate to obtain (cis-4-formylcyclohexyl) carbamateTert-butyl ester (500mg,2.20mmol, yield: 72%) as a pale yellow solid. ES-API [ M-C4H8+ H ]⁺＝172.1

Step three: adding 1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] into thick-walled pressure-resistant bottle]Pyridine-4, 5-diamine (300mg,1.04mmol), (cis-4-formylcyclohexyl) carbamic acid tert-butyl ester (592mg,2.60mmol), wet palladium on carbon (10 wt%, 0.101mmol,111mg) and methanol (10 mL). The mixture was heated to 120 ℃ and stirred for 3 hours. The reaction solution is cooled to room temperature, filtered, the filtrate is concentrated, and the crude product is purified by a flash silica gel column (ethyl acetate/petroleum ether: 0-100%) to obtain (cis-4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexyl) carbamic acid tert-butyl ester (300mg,0.605mmol, yield: 58%) as a brown solid. ES-API [ M + H ]]⁺＝496.3。

Step four: (cis-4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexyl) carbamic acid tert-butyl ester (300mg,0.605mmol) was dissolved in methanol (2mL) and a solution of hydrogen chloride in methanol (4M,2mL) and stirred at room temperature for 2 hours. The reaction solution is concentrated to obtain cis-4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohex-1-amine hydrochloride (261mg,0.625mmol, yield: 100%) as a white solid. ES-API [ M + H ]]⁺＝396.2。

Step five: cis-4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b ] s]Pyridin-2-yl) cyclohex-1-amine hydrochloride (261mg,0.625mmol), formaldehyde (260mg,3.03mmol, 35% aq.), a mixed solution of sodium cyanoborohydride (114mg,1.82mmol) and acetonitrile (5mL) was stirred at room temperature for 2 hours. The reaction solution was quenched by addition of saturated aqueous ammonium chloride (5mL) and extracted with ethyl acetate (15mLX 3). The organic phase was washed successively with saturated brine (15mL), dried over anhydrous sodium sulfate and concentrated, and the crude product was purified with flash silica gel column (methanol/dichloromethane: 3-18%) to give cis-N, N-dimethyl-4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohex-1-amine (120mg,0.283mmol, yield: 47%) as a pale yellow solid. ES-API [ M + H ]]⁺＝424.1。

Step six: reacting cis-N, N-dimethyl-4- (6- (phenylsulfonyl)1, 6-dihydroimidazo [4,5-d ] yl]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohex-1-amine (120mg,0.283mmol) was dissolved in methanol (2mL), tetrahydrofuran (0.8mL) and water (0.4 mL). Sodium hydroxide (80mg,1.98mmol) was added and the reaction stirred at 90 ℃ for 16 h. The reaction solution was adjusted to pH 8 with 1.0M dilute hydrochloric acid, and a saturated sodium bicarbonate solution (10mL) was added and extracted with ethyl acetate (10 mL). The organic phase was washed with a saturated sodium bicarbonate solution (20mL), a saturated brine (20mL), dried over anhydrous sodium sulfate and concentrated to give cis-4- (1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b]Pyridin-2-yl) -N, N-dimethylcyclohex-1-amine (200mg, crude) as a yellow solid was used in the next reaction without purification. ES-API [ M + H ]]⁺＝284.2。

Step seven: reacting cis-4- (1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) -N, N-dimethylcyclohex-1-amine (200mg, crude) and 2-chloro-4-phenoxybenzaldehyde (99mg,0.423mmol) were dissolved in methanol (2mL) and cooled to 0 deg.C, and potassium hydroxide (55mg,0.988mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction solution was adjusted to pH 8 with 1.0M diluted hydrochloric acid and extracted with ethyl acetate (20mLX 3). The organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified with a flash column of silica gel (methanol/dichloromethane: 5-20%) to give (2-chloro-4-phenoxyphenyl) (2- (cis-4- (dimethylamino) cyclohexyl) -1, 6-dihydroimidazo [4, 5-d%]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (35mg,0.068mmol, 2-step yield: 24%) as a white solid. ES-API [ M + H ]]⁺＝516.3。

Step eight: (2-chloro-4-phenoxyphenyl) (2- (cis-4- (dimethylamino) cyclohexyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (35mg,0.068mmol) was dissolved in tetrahydrofuran (1mL) and water (0.1 mL). 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (181mg,0.798mmol) was added thereto at room temperature, and the reaction was stirred at room temperature for 2 hours. The reaction solution was added with a saturated sodium thiosulfate solution (5mL) and a saturated sodium bicarbonate solution (5mL), and extracted with ethyl acetate (10mLX 3). The organic phase was washed with saturated sodium bicarbonate solution (15mL), saturated brine (15mL), dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by preparative HPLC alkaline method to give (2-chloro-4-phenoxyphenyl) (2- (cis-4- (dimethylamino) cyclohexyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z67-1,18mg,0.035mmol, yield: 52%) as a white solid. ES-API [ M + H ]]⁺＝514.2。

EXAMPLE 56 preparation of Compound Z67-2

The method comprises the following steps: methyl trans-4- ((tert-butoxycarbonyl) amino) cyclohexane-1-carboxylate (1.0g,3.87mmol) was dissolved in tetrahydrofuran (15mL) and cooled to 0 ℃. Lithium aluminum hydride (3.89mL,3.89mmol,1.0M solution in tetrahydrofuran) was slowly added to the reaction under a nitrogen atmosphere. After the addition was complete, the reaction was stirred for two more hours at 0 ℃. The reaction was quenched with a saturated aqueous solution of potassium sodium tartrate (20mL) and extracted with ethyl acetate (30mLX 3). The organic phase was washed with saturated brine (50mLX3), and dried and concentrated over anhydrous sodium sulfate to give tert-butyl (trans s-4- (hydroxymethyl) cyclohexyl) carbamate (700mg,3.05mmol, yield: 79%) as a colorless transparent liquid. ES-API [ M-C4H8+ H]⁺＝174.1。

Step two: tert-butyl (trans-4- (hydroxymethyl) cyclohexyl) carbamate (700mg,3.05mmol) was dissolved in dichloromethane (15mL), pyridinium chlorochromate (1.32g,6.11mmol) was added at room temperature, and the reaction was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give tert-butyl (trans-4-formylcyclohexyl) carbamate (500mg,2.20mmol, yield: 72%) as a pale yellow solid. ES-API [ M-C4H8+ H ]⁺＝172.1。

Step three: adding 1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] into thick-walled pressure-resistant bottle]Pyridine-4, 5-diamine (568mg,1.8mmol), (trans-4-formylcyclohexyl) carbamic acid tert-butyl ester (400mg,1.39mmol), wet palladium on carbon (10 wt%, 0.139mmol,148mg) and methanol (10 mL). The mixture was heated to 120 ℃ and stirred for 3 hours. The reaction solution was cooled to room temperature and filtered, the filtrate was concentrated, and the crude product was purified with flash silica gel column (ethyl acetate/petroleum ether: 0-100%) to give (trans-4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexyl) carbamic acid tert-butyl ester (400mg,0.807mmol, yield: 58%) as a brown solid.ES-API:[M+H]⁺＝496.3。

Step four: (trans-4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohexyl) carbamic acid tert-butyl ester (400mg,0.807mmol) was dissolved in methanol (2mL) and hydrogen chloride in methanol (4M,2mL) and stirred at room temperature for 2 hours. The reaction solution is concentrated to obtain trans-4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohex-1-amine hydrochloride (349mg,0.807mmol, yield: 100%) was a white solid. ES-API [ M + H ]]⁺＝396.2。

Step five: trans-4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohex-1-amine hydrochloride (348mg,0.807mmol), formaldehyde (346mg,4.03mmol, 35% aqueous solution), a mixed solution of sodium cyanoborohydride (152mg,2.42mmol) and acetonitrile (10mL) was stirred at room temperature for 2 hours. The reaction solution was quenched by addition of saturated aqueous ammonium chloride (5mL) and extracted with ethyl acetate (15mLX 3). The organic phase was washed successively with saturated brine (15mL), dried over anhydrous sodium sulfate and concentrated, and the crude product was purified with flash silica gel column (methanol/dichloromethane: 3-18%) to give trans-N, N-dimethyl-4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohex-1-amine (120mg,0.283mmol, yield: 35%) as a pale yellow solid. ES-API [ M + H ]]⁺＝424.1。

Step six: trans-N, N-dimethyl-4- (6- (phenylsulfonyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) cyclohex-1-amine (120mg,0.283mmol) was dissolved in methanol (2mL), tetrahydrofuran (0.8mL) and water (0.4 mL). Sodium hydroxide (80mg,1.98mmol) was added and the reaction stirred at 90 ℃ for 16 h. The reaction solution was adjusted to pH 8 with 1.0M dilute hydrochloric acid, and a saturated sodium bicarbonate solution (10mL) was added and extracted with ethyl acetate (10 mL). The organic phase was washed with a saturated sodium bicarbonate solution (20mL), a saturated brine (20mL), dried over anhydrous sodium sulfate and concentrated to give trans-4- (1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b]Pyridin-2-yl) -N, N-dimethylcyclohex-1-amine (200mg, crude) as a yellow solid was used in the next reaction without purification. ES-API [ M + H ]]⁺＝284.2。

Step seven: will be trans-4- (1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) -N, N-dimethylcyclohex-1-amine (200mg, crude) and 2-chloro-4-phenoxybenzaldehyde (99mg,0.423mmol) were dissolved in methanol (2mL) and cooled to 0 deg.C, and potassium hydroxide (55mg,0.988mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction solution was adjusted to pH 8 with 1.0M diluted hydrochloric acid and extracted with ethyl acetate (20mLX 3). The organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate and concentrated, and the crude product was purified with flash silica gel column (methanol/dichloromethane: 5-20%) to give (2-chloro-4-phenoxyphenyl) (2- (trans-4- (dimethylamino) cyclohexyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (35mg,0.068mmol, 2-step yield: 24%) as a white solid. ES-API [ M + H ]]⁺＝516.3。

Step eight: (2-chloro-4-phenoxyphenyl) (2- (trans-4- (dimethylamino) cyclohexyl) -1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-8-yl) methanol (35mg,0.068mmol) was dissolved in tetrahydrofuran (1mL) and water (0.1 mL). 2, 3-dichloro-5, 6-dicyan-p-benzoquinone (181mg,0.798mmol) was added thereto at room temperature, and the reaction was stirred at room temperature for 2 hours. The reaction solution was added with a saturated sodium thiosulfate solution (5mL) and a saturated sodium bicarbonate solution (5mL), and extracted with ethyl acetate (10mLX 3). The organic phase was washed with saturated sodium bicarbonate solution (15mL), saturated brine (15mL), dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by preparative HPLC alkaline method to give (2-chloro-4-phenoxyphenyl) (2- (trans-4- (dimethylamino) cyclohexyl) -1, 6-dihydroimidazo [4, 5-d) ]Pyrrolo [2,3-b]Pyridin-8-yl) methanone (Z67-2,8mg,0.016mmol, yield: 23%) as a white solid. ES-API [ M + H ]]⁺＝514.2。¹H NMR(500MHz,DMSO-d₆)δ12.78(s,1H),11.87(s,1H),8.64(s,1H),7.78(s,1H),7.65(d,J＝8.5Hz,1H),7.49(t,J＝8.0Hz,2H),7.27(t,J＝8.0Hz,1H),7.25-7.17(m,3H),7.05(dd,J＝8.0,2.5Hz,1H),3.14(t,J＝12.0Hz,1H),2.35-2.31(m,1H),2.25(s,6H),2.15(d,J＝11.5Hz,2H),1.98-1.95(m,2H),1.72-1.77(m,2H),1.36-1.33(m,2H).

The following compounds were prepared according to the synthetic methods of the above examples.

Test example 1: BTK and BTK C481S enzymological experiments

1000 XCompound 3-fold gradient stock solution in DMSO, reaction buffer (50mM HEPES, pH7.5, 0.0015% Briji-35,2mM DTT,10mM MgCl)₂) Dilute 100-fold to 10X compound stock, transfer 10X compound stock to 384-well plate. Enzymatic reactions were established using the BTK Kinase Enzyme System (Promega Catalog # V2941) or the BTK (C481S) Kinase Enzyme System (Promega Catalog # VA 7033). First, 2 Xenzyme solution containing 10nM BTK or 10nM BTK C481S was prepared in reaction buffer and added to the plate and incubated with compound for 10 min. Then, 2.5 Xsubstrate solution containing ATP (125. mu.M), Poly (Glu4, TyR) was prepared in reaction buffer and added to the plate₁) (0.05. mu.g/. mu.L) and reacted at 20 ℃ for 90 minutes. Finally, kinase activity was detected according to the experimental procedure provided by the ADP-GloTM kinase Assay kit (Promega, # V9101), and luminescence values were read out at the end. DMSO was used as the maximum signal value and no enzyme was added as the minimum signal value. The inhibition (%) of the compound was calculated as (maximum signal value-compound signal value)/(maximum signal value-minimum signal value) × 100%, and the IC50 value was calculated by fitting the compound gradient dilution concentration and the corresponding enzyme activity inhibition using XLFit four-parameter method. From the results, it is clear that the compound of the present invention has a superior inhibitory activity against BTK Wild Type (WT) and BTK C481S mutation with an IC50 of less than 10 μm; or less than 1000nM (e.g., 0.1nM to 1000nM), or less than 100nM (e.g., 0.1nM to 100 nM). The results of some of the compounds are shown in Table 1 below.

TABLE 1

Test example 2: p-BTK cell assay

The first day: taking logarithmic growth phaseHEK293 cells (ADDEXBIO, T0011001), enzyme EDTA digested cells were counted and 2E6 cells were plated in 10cm dishes and cultured overnight. The next day: a mixture containing 6ug of the BTK-WT/BTK-C481S plasmid and 18. mu.L of the FuGENE HD transfection reagent was prepared using 1000. mu.L of Opti-MEM, and after standing at room temperature for 10 minutes, the mixture was slowly added to a petri dish using a pipette gun and incubated overnight. And on the third day: the dishes were removed and the cells were digested with EDTA to collect the counts and seeded with 1E4 cells in 96 well cell culture plates for overnight culture. 1000 Xgradient of compound 3.16 concentrations in DMSO stock, room temperature. The fourth day: the prepared 1000X compound stock solution was removed and diluted 200-fold to 5X compound stock solution using medium, 5X compound stock solution was added to each cell culture well at a final concentration of 1X and a DMSO content of 0.1%. DMSO was used as experimental control. After two hours of incubation with compound addition, the residual medium was removed. Add 100. mu.L of cell lysis buffer per well, let stand on ice for 30 min, and sonicate on ice for 5 min. After diluting the cell lysate proportionally, 80. mu.L of the mixture was transferred to ELISA plates, and 80. mu.L of cell lysis buffer was added to blank wells. After incubation for 2 hours at 37 ℃ in an incubator, the plates were removed to complete antibody incubation and color development termination according to PathScan P-Btk (Y223) Sandwich ELISA Kit (Cell signaling #23843CA), and OD was read. The compound inhibition (%) was calculated as (OD) _Control-OD_{Compound (I)})/(OD_Control-OD_{Blank space}) X 100%, IC50 values were calculated using Prism 8 four parameter method to fit compound gradient dilution concentrations and corresponding cell proliferation inhibition rates. From the results, it is clear that the compounds of the present invention have better inhibitory activity against BTK Wild Type (WT) HEK293 cells and BTK C481S mutant HEK293 cells with IC50 less than 10 μm; or less than 5000nM, or less than 1000 nM. The results of some of the compounds are shown in Table 2 below.

TABLE 2

Numbering	p-BTK(WT)IC₅₀(nM)	p-BTK(C481S)IC₅₀(nM)
			Z47-1	50.82	114.12
Z51	189.16	237.88
			Z59-2-2	26.03	35.27

Test example 3: inhibition of proliferation of TMD-8 and OCI-LY10

TMD-8 cells were cultured in 10% FBS + 1% PS1640 medium, human diffuse large B lymphoma (Minggui Bo., MZ-0832). On the first day, cells from log phase growth were counted and seeded with 600 TMD-8 or 2000 OCI-LY10 cells in 384 well cell culture plates overnight. The following day, 400X compound 3-fold gradient stocks were made in DMSO, diluted 40-fold to 10X compound stocks in media, and 10X compound stocks were added to each cell culture well at a final concentration of 1X and a DMSO content of 0.25%. DMSO was used as experimental control and medium as blank control. Incubation was continued for three days after compound addition. On the fifth day, 25. mu.L of ADP-Glo was added to each well, and chemiluminescence values (RLU values) were read after incubation for 10 minutes with mixing. The cell proliferation inhibition (%) was calculated as (RLU) _Control-RLU_{Compound (I)})/(RLU_Control-RLU_{Blank space}) X 100%, IC50 values were calculated using XLFit four parameter method to fit compound gradient dilution concentrations and corresponding cell proliferation inhibition rates. From the results, it was found that the compound of the present invention is useful for TMD-8 cells have good inhibitory activity, with IC50 less than 10 μm; or less than 5000 nM; or less than 1000nM (e.g., 0.1nM to 1000 nM); even below 500nM (e.g., 0.1nM to 500 nM). The results for some of the compounds are shown in table 3 below.

TABLE 3

Numbering	TMD-8IC₅₀(nM)	Numbering	TMD-8IC₅₀(nM)	Numbering	TMD-8IC₅₀(nM)
						Z1	567.96	Z44-1	811.66	Z54	540.41
Z21	950.84	Z47-1	314.12	Z67-2	760.51
						Z24	285.42	Z64	787.0	Z59-1	748.74
Z25	339.51	Z52	382.6	Z59-2	174.92
						Z25-3	305.61	Z66-1	925.55	Z59-2-1	211.16
Z25-4	353.72	Z66-2	669.85	Z59-2-2	78.71
						Z30	519.95	Z62	640.68	Z60-2	288.96
Z30-1	376.71	Z47	427.77	Z60-2-1	307.20
						Z30-2	856.23	Z47-2	519.86	Z60-2-2	918.10

While specific embodiments of the invention have been described in detail, it will be appreciated by those skilled in the art that various modifications and alternatives to those details could be developed in light of the overall teachings of the disclosure, and that such modifications are intended to be included within the scope of the disclosure. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

in the formula (I), the compound is shown in the specification,

G₃、G₄、G₅and G₆Is selected from the group consisting of:

(1)G₃is N; g₄Is CH; g₅Is CR₁；G₆Is N or CR₂；

in the above-mentioned respective groups, the first and second groups,

R₁、R₃are independently selected fromFrom: H. c_1-6Alkyl radical, C _2-6Alkenyl radical, C_2-6Alkynyl, C_3-20Cycloalkyl, 3-to 20-membered heterocyclyl, -C_1-4Alkyl-cyano, -C_1-4Alkyl-hydroxy, -C_1-4Alkyl-amino, -C_1-4Alkyl-carboxy, -C_1-4alkyl-C_3-20Cycloalkyl, -C_1-4Alkyl-3 to 20 membered heterocyclyl; the 3-to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C is_1-6Alkyl radical, said C_2-6Alkenyl radical, said C_2-6Alkynyl, said C_3-20Cycloalkyl, said 3-to 20-membered heterocyclyl, said hydroxy, said cyano, said carboxy each independently being unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1;

R₂each independently selected from: H. cyano, halogen, nitro, carboxyl, hydroxy, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-20Cycloalkyl, 3-to 20-membered heterocyclyl, -C_1-4Alkyl-cyano, -C_1-4Alkyl-hydroxy, -C_1-4Alkyl-amino, -C_1-4Alkyl-carboxy, -C_1-4alkyl-C_3-20Cycloalkyl, -C_1-4Alkyl-3 to 20 membered heterocyclyl; the 3-to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C is_1-6Alkyl radical, said C_2-6Alkenyl radical, said C_2-6Alkynyl, said C_3-20Cycloalkyl, said 3-to 20-membered heterocyclyl, said hydroxy, said cyano, said carboxy each independently being unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1;

R₄、R₅Each independently selected from: H. c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-20Cycloalkyl, 3-to 20-membered heterocyclyl, -C_1-4Alkyl-cyano, -C_1-4Alkyl-hydroxy, -C_1-4Alkyl-amino, -C_1-4Alkyl-carboxy, -C_1-4alkyl-C_3-20Cycloalkyl, -C_1-4Alkyl-3 to 20 membered heterocyclyl; or R₄And R₅With carbon attached to themAtoms together forming C_3-20Cycloalkyl or 3 to 20 membered heterocyclyl; the 3-to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C is_1-6Alkyl radical, said C_2-6Alkenyl radical, said C_2-6Alkynyl, said C_3-20Cycloalkyl, said 3-to 20-membered heterocyclyl, said hydroxy, said cyano, said carboxy each independently being unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1;

G₁is C_6-14Aryl, 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl; wherein the 5-or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; the 8-to 10-membered bicyclic heteroaryl has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as ring atoms; and said C is _6-14Aryl, said 5 or 6 membered monocyclic heteroaryl or said 8 to 10 membered bicyclic heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2;

l is a bond, CR⁸R⁹、O、NH、NHC(O)、C_1-2alkyl-NHC (O) or NHC (O) -C_1-2An alkyl group; wherein R is⁸、R⁹Each independently of the others being H, halogen, hydroxy, cyano, -C_1-6Alkyl, -halo C_1-6Alkyl, -deuterated C_1-6Alkyl, -C_1-6Alkoxy, -halo C_1-6Alkoxy, -deuterated C_1-6Alkoxy, -C_3-6Monocyclic cycloalkyl, -C_1-4Alkyl-hydroxy, -C_1-4Alkyl-cyano, -C_1-4alkyl-C_1-6Alkoxy, -C_1-4Alkyl-halo C_1-6Alkyl, -C_1-4Alkyl-halo C_1-6Alkoxy, -C_1-4alkyl-C_3-6Monocyclic cycloalkyl, -C_1-4alkyl-NR^aR^b、-C_1-4alkyl-C (O) NR^aR^b、-C_1-4alkyl-SO₂C_1-3Alkyl, -C_1-4Alkyl-carboxy;

each of the groups of group S1 or S2 independently comprises: deuterium, halogen, cyano, hydroxy, carboxy, nitro, -C _1-6Alkyl, -halo C_1-6Alkyl, -deuterated C_1-6Alkyl, -C_1-6Alkoxy, -halo C_1-6Alkoxy, -deuterated C_1-6Alkoxy, -C_3-6Monocyclic cycloalkyl, -halo C_3-6Monocyclic cycloalkyl, -O-C_3-6Monocyclic cycloalkyl, 3-to 6-membered monocyclic heterocyclyl, -C_1-4Alkyl-hydroxy, -C_1-4Alkyl-cyano, -C_1-4alkyl-C_1-6Alkoxy, -C_1-4Alkyl-halo C_1-6Alkyl, -C_1-4Alkyl-halo C_1-6Alkoxy, -C_1-4alkyl-C_3-6Monocyclic cycloalkyl, -C_1-4Alkyl-3 to 6 membered monocyclic heterocyclyl, -C_1-4alkyl-NR^aR^b、-C_1-4alkyl-C (O) NR^aR^b、-C_1-4alkyl-SO₂C_1-3Alkyl, -C_1-4Alkyl-carboxy, -C (O) C_1-6Alkyl, -C (O) OC_1-6Alkyl, -C (O) C_3-6Monocyclic cycloalkyl, -C (O) NR^aR^b、-C(O)-C_1-4alkyl-NR^aR^b、-NHC(O)R^c、-NHC(O)OR^c、-NR^aR^b、-SO₂C_1-3An alkyl group; the above-mentionedThe 3-to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;

in each of the above groups, R^a、R^bEach independently is H, C_1-6Alkyl, deuterated C_1-6Alkyl radical, C_3-6Monocyclic cycloalkyl, -C_1-4alkyl-C_1-6Alkoxy, 3-to 6-membered monocyclic heterocyclyl, -C_1-4Alkyl-3 to 6 membered monocyclic heterocyclyl, C (O) C_1-6An alkyl group; wherein the 3-to 6-membered monocyclic heterocyclic group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; and said 3-to 6-membered monocyclic heterocyclyl is optionally substituted with 1 or 2 groups selected from: c_1-6An alkyl group; or

In each of the above groups, R ^a、R^bTogether with the nitrogen atom to which they are attached form a 3-to 6-membered nitrogen-containing heterocyclic group; wherein the 3-to 6-membered nitrogen-containing heterocyclic group has 1 nitrogen atom and optionally 1 or 2 heteroatoms selected from N, O and S as ring atoms; and said 3-to 6-membered nitrogen-containing heterocyclic group is optionally substituted with 1 or 2 groups selected from: c_1-6An alkyl group;

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof,

the compound has a structure represented by formula (II):

in the formula, G₄₁Is NH or CH₂(ii) a When in use

When it is a double bond, G₆₁Is N or CR₂；G₅₁Is CR₁(ii) a When in use

When it is a single bond, G₆₁Is C (═ O); g₅₁Is NR₃Or CR₄R₅；R₁、R₂、R₃、R₄、R₅、A、B、L、G₁、G₂The definitions are the same as those of each group in claim 1;

or

The compound has a structure represented by formula (III):

in the formula, A, B, L, G₁、G₂、R₁The definitions are as defined in claim 1 for each group.

3. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof,

the compound has a structure represented by formula (IIa):

in the formula, G₆₁Is N or CR₂；R₁、R₂、A、B、L、G₁、G₂The definitions are the same as those of each group in claim 2;

Or

The compound has a structure represented by formula (IIb):

in the formula, G₄₁Is NH or CH₂；G₅₁Is NR₃Or CR₄R₅；R₃、R₄、R₅、A、B、L、G₁、G₂The definitions are as defined in claim 2 for each group.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound has a structure according to formula (II-1), formula (II-2), formula (II-3), formula (II-4), or formula (II-5):

in the formulae, R₁、R₂、R₃、R₄、R₅、L、G₁、G₂The definitions are as defined in claim 2 for each group.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,

G₁is phenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, thiazolyl or pyrazolyl; said phenyl, said pyridyl, said pyrimidinyl, said furanyl, said pyrrolyl, said thiazolyl or said pyrazolyl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2; and/or

G₂Is phenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, thiazolyl or pyrazolyl; said phenyl, said pyridyl, said pyrimidinyl, said furanyl, said pyrrolyl, said thiazolyl or said pyrazolyl is unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S2; and/or

A is CH; b is CH; and/or

R₁、R₃Each independently selected from: H. c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-20Cycloalkyl, 3-to 20-membered heterocyclyl, -CH₂-cyano, -CH₂-hydroxy, -CH₂-amino, -CH₂-carboxy, -CH₂-C_3-20Cycloalkyl, -CH₂-a 3 to 20 membered heterocyclyl; the 3-to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C is_1-6Alkyl radical, said C_2-6Alkenyl radical, said C_2-6Alkynyl, said C_3-20Cycloalkyl, said 3-to 20-membered heterocyclyl, said hydroxy, said cyano, said carboxy are each independently unsubstituted or substituted with 1,2. 3 or 4 substituents independently selected from group S1; and/or

R₄、R₅Each independently selected from: H. c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-20Cycloalkyl, 3-to 20-membered heterocyclyl, -CH₂-cyano, -CH₂-hydroxy, -CH₂-amino, -CH₂-carboxy, -CH₂-C_3-20Cycloalkyl, -CH₂-a 3 to 20 membered heterocyclyl; or R₄And R₅Together with the carbon atom to which they are attached form C_3-20Cycloalkyl or 3 to 20 membered heterocyclyl; the 3-to 20-membered heterocyclyl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms; said C is_1-6Alkyl radical, said C_2-6Alkenyl radical, said C_2-6Alkynyl, said C_3-20Cycloalkyl, said 3-to 20-membered heterocyclyl, said hydroxy, said cyano, said carboxy are each independently unsubstituted or substituted with 1, 2, 3 or 4 groups independently selected from group S1.

6. A pharmaceutical composition comprising a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable carrier.

7. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition according to claim 6, in the manufacture of a medicament for the prophylaxis and/or treatment of a disease or condition; the disease or disorder is associated with BTK and/or with aberrant B-cell activation.

8. The use of claim 7, wherein the disease or condition is selected from the group consisting of: xenogenic immune diseases, autoimmune diseases, inflammatory diseases, cancer.

9. The use according to claim 8, wherein,

the xenogenic immune disease, autoimmune disease, inflammatory disease may be selected from the group consisting of: rheumatic diseases, glomerulonephritis, Goodpasture's syndrome, atherosclerosis, autoimmune blood disorders, autoimmune gastritis, autoimmune inflammatory bowel disease, irritable bowel syndrome, allograft rejection, chronic thyroiditis, graves ' disease, sjogren's disease, scleroderma, diabetes, hepatitis, pancreatitis, primary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, dermatomyositis, contact dermatitis, eczema, vasculitis, chronic renal insufficiency, Stevens-Johnson syndrome, inflammatory pain, idiopathic diarrhea, cachexia, sarcoidosis, Guillain-Barre syndrome, uveitis, conjunctivitis, otitis media, periodontal disease, parkinson's disease, alzheimer's disease, septic shock, interstitial fibrosis of the lung, asthma, bronchitis, rhinitis, sinusitis, Pneumoconiosis, pulmonary insufficiency syndrome, emphysema, pulmonary fibrosis, chronic inflammatory lung disease and other inflammatory or obstructive diseases on the airways; and/or

The cancer is leukemia or lymphoma; and/or

The cancer may be selected from the group consisting of: small Lymphocytic Lymphoma (SLL), Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), acute promyelocytic leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, fahrenheit macroglobulinemia, follicular lymphoma, multiple myeloma, Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), non-hodgkin's lymphoma.

10. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition according to claim 6, for the preparation of a BTK inhibitor.