CN116348453A

CN116348453A - Heteroaromatic carboxamide compounds and uses thereof

Info

Publication number: CN116348453A
Application number: CN202280007132.XA
Authority: CN
Inventors: 黄颖; 陈平; 李红海; 马晓初
Original assignee: Yehui Pharmaceutical Technology Shanghai Co ltd
Current assignee: Yehui Pharmaceutical Technology Shanghai Co ltd
Priority date: 2021-04-25
Filing date: 2022-04-22
Publication date: 2023-06-27
Also published as: WO2022228302A1

Abstract

The present disclosure relates to compounds of formula I, wherein the variables are as defined in the specification; pharmaceutical compositions containing them, processes for preparing them and their use.

Description

Heteroaromatic carboxamide compounds and uses thereof

Cross reference to related applications

The present application claims priority from international application PCT/CN2021/089684 filed on 25 th 4 th 2021; the contents of which are incorporated herein by reference in their entirety.

Technical Field

The present disclosure provides heteroaromatic carboxamide compounds that inhibit the bruton's tyrosine kinase BTK. The disclosure also provides methods of preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of using these compounds in the treatment of BTK-related diseases or disorders.

Background

Bruton's Tyrosine Kinase (BTK), a non-receptor tyrosine kinase belonging to the Tec family of kinases, is widely expressed in hematopoietic cells other than T cells. BTK plays a key role in signaling through B cell antigen receptor (BCR) and fcγreceptor (fcγr) in B cells and bone marrow cells, respectively, and is involved in all aspects of B cell development including proliferation, maturation, differentiation, apoptosis and cell migration. Abnormal BTK expression and/or activity has been demonstrated in different cancers and autoimmune diseases.

Significant progress has been made in developing BTK inhibitors as therapeutics targeting hematologic malignancies and chronic inflammatory diseases. In fact, the first generation BTK inhibitor ibrutinib (PCI-32765, imbruvica) has been successfully treated for B-cell malignancies and is approved for Chronic Lymphocytic Leukemia (CLL), recurrent or refractory Mantle Cell Lymphoma (MCL) and

macroglobulinemia (WM). However, treatment disruption occurs in up to 30% of ibrutinib patients, which leads to poor clinical results. Although second generation BTK inhibitors that provide greater BTK selectivity, such as acartinib (acalabrutinib), zebutinib (zanubutinib), and tiratrutinib (tirambutinib), can limit off-target toxicity, they allIs an irreversible BTK inhibitor. The compound reacts covalently and irreversibly with cysteine-481 in the ATP binding site of BTK, and thus does not overcome the common mechanism of ibrutinib resistance that occurs in 30% of patients after treatment lasting more than 12 months. Notably, reversible BTK inhibitors include vicat brutinib (vecabotinib), ARQ-531, and LOXO-305, which do not rely on cysteine-481 interaction with BTK, inhibit BTK activity in the presence of the C481S mutation, and clinical evidence begins to appear to show that they can overcome resistance to irreversible BTK inhibitors. In addition, there is currently no approved BTK targeted therapy for chronic autoimmune indications. The slow progression in autoimmune/inflammatory diseases may be due at least in part to the stringent safety requirements of these indications, such as RA and SLE requirements. Accordingly, efforts have been made to find reversible BTK inhibitors with better efficacy and lower toxicity.

Summary of The Invention

The above compounds and the active compounds disclosed herein (including compounds of formula I and specific compounds) or stereoisomers, racemates, geometric isomers, tautomers, hydrates or solvates thereof or pharmaceutically acceptable salts thereof are collectively referred to as "compounds of the present invention" or "compounds of the present disclosure".

The present disclosure provides compounds of formula I:

or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof, wherein:

X ₁ 、X ₂ and X ₃ Each independently is CR' or N; r' is selected from H, C _1-6 Alkyl, halo, and oxo;

R ₁ selected from H, deuterium, 3-10 membered heterocyclyl, 5-12 membered heteroaryl, C _3-10 Cycloalkyl, C _3-10 cycloalkyl-O-, C _3-10 Cycloalkenyl, 3-10 membered heterocyclyl-O-, C _6-10 Aryl, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, -C _1-6 alkyl-O-C _1-6 Alkyl, -NH ₂ 、-NH(C _1-6 Alkyl) and N (C _1-6 Alkyl group ₂ Wherein each alkyl or alkoxy group is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halo, -OH, -CN, -NH ₂ 、-NH(C _1-6 Alkyl) and-NH (C) _1-6 Alkyl group ₂ The method comprises the steps of carrying out a first treatment on the surface of the And wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted with one or more substituents selected from the group consisting of: -OH, -SH, -NH ₂ Oxo, halo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -C _1-6 alkyl-O-C _1-6 Alkyl, -NH (C) _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ 、C _1-6 alkyl-S-, -C _1-6 alkyl-OH, C _3-6 Cycloalkyl, C _3-6 Halogenated cycloalkyl, -C (O) C _1-6 Alkyl, -S (O) _n C _1-6 Alkyl, -C (O) OH, -C (O) OC _1-6 Alkyl, -C (O) NH ₂ 、-C(O)NH(C _1-6 Alkyl), -C (O) N (C) _1-6 Alkyl group ₂ 、-NHC(O)C _1-6 Alkyl and optionally oxo-substituted 3-6 membered heterocyclyl;

ar is-C _6-10 aryl-Y-R ₂ Or-5-6 membered heteroaryl-Y-R ₂ Wherein each aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of: halo, C _1-6 Alkoxy and C _1-6 An alkyl group;

y is selected from O, S, - (CH) ₂ ) _m -NH-C(O)-、-(CH ₂ ) _m -NH-S(O) _n -、-(CH ₂ ) _m -N(C _1-6 Alkyl) -C (O) - (CH) ₂ ) _m -N(C _1-6 Alkyl) -S (O) _n -、-(CH ₂ ) _m -C(O)-NH-、-(CH ₂ ) _m -S(O) _n -NH-、-(CH ₂ ) _m -C(O)-N(C _1-6 Alkyl) -and- (CH ₂ ) _m -S(O) _n -N(C _1-6 Alkyl) -;

R ₂ is C _6-10 Aryl or 5-10 membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of: c (C) _1-6 Alkoxy, deuterated C _1-6 Alkoxy, halo, C _1-6 Haloalkyl, -OH, -SH, -CN, -NH ₂ 、-NH(C _1-6 Alkyl), -NH (C) _1-6 Alkyl group ₂ 、C _1-6 alkyl-S-, -C _1-6 alkyl-O-C _1-6 Alkyl, -C (O) C _1-6 Alkyl, -C (O) OH, -C (O) OC _1-6 Alkyl, -C (O) NH ₂ 、-C(O)NH(C _1-6 Alkyl), -C (O) N (C) _1-6 Alkyl group ₂ and-NHC (O) C _1-6 An alkyl group;

m is 0 or 1; and is also provided with

n is 1 or 2.

The above compounds or stereoisomers, racemates, geometric isomers, tautomers, hydrates or solvates thereof, or pharmaceutically acceptable salts thereof, as well as active compounds disclosed in the context of the present invention and covered by the scope of the above compounds, are collectively referred to as "compounds of the present invention".

The present disclosure also provides compounds of the invention for use as a medicament.

The present disclosure also provides compounds of the invention for use in the treatment or prevention of BTK-related diseases or disorders.

The present disclosure also provides pharmaceutical compositions comprising a compound of the present invention and optionally a pharmaceutically acceptable carrier.

The present disclosure also provides a kit for treating or preventing a BTK-related disease or disorder comprising a pharmaceutical composition of the invention and instructions for use.

The present disclosure also provides the use of a compound of the invention for the treatment or prevention of a BTK-related disease or disorder.

The present disclosure also provides the use of a compound of the present invention in the manufacture of a medicament for the treatment or prevention of a BTK-related disease or disorder.

The present disclosure also provides methods of inhibiting BTK activity in vivo or in vitro comprising contacting an effective amount of a compound of the present invention with BTK.

The present disclosure also provides methods of treating or preventing a BTK-related disease or disorder, comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

The present disclosure also provides combinations comprising a compound of the present invention and at least one additional therapeutic agent.

The present disclosure also provides methods of preparing the compounds of the present invention, as well as intermediates useful in preparing the compounds of the present invention.

Detailed Description

Embodiments of the present disclosure

Embodiment 1. A compound of formula I:

R ₁ selected from H, deuterium, 3-10 membered heterocyclyl, 5-12 membered heteroaryl, C _3-10 Cycloalkyl, C _3-10 cycloalkyl-O-, C _3-10 Cycloalkenyl, 3-10 membered heterocyclyl-O-, C _6-10 Aryl, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, -C _1-6 alkyl-O-C _1-6 Alkyl, -NH ₂ 、-NH(C _1-6 Alkyl) and N (C _1-6 Alkyl group ₂ Wherein each alkyl or alkoxy group is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halo, -OH, -CN, -NH ₂ 、-NH(C _1-6 Alkyl) and-NH (C) _1-6 Alkyl group ₂ The method comprises the steps of carrying out a first treatment on the surface of the And wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted with one or more substituents selected from the group consisting of: -OH, -SH, -NH ₂ Oxo, halo, -CN, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -C _1-6 alkyl-O-C _1-6 Alkyl, -NH (C) _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ 、C _1-6 alkyl-S-, -C _1-6 alkyl-OH, C _3-6 Cycloalkyl, C _3-6 Halogenated cycloalkyl, -C (O) C _1-6 Alkyl, -S (O) _n C _1-6 Alkyl, -C (O) OH, -C (O) OC _1-6 Alkyl, -C (O) NH ₂ 、-C(O)NH(C _1-6 Alkyl), -C (O) N (C) _1-6 Alkyl group ₂ 、-NHC(O)C _1-6 Alkyl and 3-6 membered heterocyclyl, optionally substituted with oxo;

m is 0 or 1; and is also provided with

n is 1 or 2.

Embodiment 2. The compound of embodiment 1 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein X ₁ And X ₃ Each independently is CR' or N; r' is selected from H, C _1-6 Alkyl, halo, and oxo.

Embodiment 3 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein X ₂ Is CH.

Embodiment 4 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein Y is selected from O, S, - (CH) ₂ ) _m -NH-C (O) -or- (CH) ₂ ) _m -C(O)-NH-。

Embodiment 5 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein R ₂ Is C _6-10 Aryl or 5-6 membered heteroaryl, optionally substituted with 1, 2 or 3 groups selected from C _1-6 Alkoxy, deuterated C _1-6 Alkoxy, halo, C _1-6 Haloalkyl, -OH, -CN and-NH ₂ Is substituted by a substituent of (a).

Embodiment 6. The compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein:

X ₁ and X ₃ Each independently is CR' or N; r' is selected from H, C _1-6 Alkyl, halo, and oxo;

X ₂ is CH;

R ₁ selected from the group consisting ofH. 3-8 membered heterocyclyl, 5-12 membered heteroaryl, C _3-8 Cycloalkyl, C _3-8 cycloalkyl-O-, 3-8 membered heterocyclyl-O-, C _6-10 Aryl, C _1-6 Alkyl, C _1-6 Alkoxy, -NH ₂ 、-NH(C _1-6 Alkyl) and N (C _1-6 Alkyl group ₂ Wherein each alkyl or alkoxy group is optionally substituted with one or more substituents selected from the group consisting of: halo, -OH, -CN and-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the And wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted with one or more substituents selected from the group consisting of: -OH, -NH ₂ Oxo, halo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -NH (C) _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ 、C _1-6 alkyl-S-, -C _1-6 alkyl-OH, C _3-6 Cycloalkyl and C _3-6 Halogenated cycloalkyl;

ar is-C _6-10 aryl-Y-R ₂ Or-5-6 membered heteroaryl-Y-R ₂ Wherein each aryl or heteroaryl is optionally substituted with one or more substituents selected from halo, C _1-6 Alkoxy and C _1-6 Substituent substitution of alkyl;

y is selected from O, S, - (CH) ₂ ) _m -NH-C (O) -and- (CH) ₂ ) _m -C(O)-NH-；

R ₂ Is C _6-10 Aryl or 5-6 membered heteroaryl, optionally substituted with 1, 2 or 3 groups selected from C _1-6 Alkoxy, deuterated C _1-6 Alkoxy, halo, C _1-6 Haloalkyl, -OH, -CN and-NH ₂ Is substituted by a substituent of (a);

m is 0 or 1.

Embodiment 7 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein X ₁ Is CR' or N; r' is H or halo.

Embodiment 8 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solution thereofA pharmaceutical or pharmaceutically acceptable salt, wherein X ₃ Selected from CH, C (=o) and N.

Embodiment 9. The compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein:

X ₁ is CR' or N; r' is H or halo;

X ₂ is CH;

X ₃ selected from CH, C (=o) or N;

R ₁ selected from H, 3-8 membered heterocyclyl, 5-12 membered heteroaryl, C _3-8 Cycloalkyl, C _3-8 cycloalkyl-O-, 3-8 membered heterocyclyl-O-, C _6-10 Aryl, C _1-6 Alkyl, C _1-6 Alkoxy, -NH ₂ 、-NH(C _1-6 Alkyl) and N (C _1-6 Alkyl group ₂ Wherein each alkyl or alkoxy group is optionally substituted with one or more substituents selected from the group consisting of: halo, -OH, -CN and-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the And wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted with one or more substituents selected from the group consisting of: -OH, -NH ₂ Oxo, halo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -NH (C) _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ 、C _1-6 alkyl-S-and-C _1-6 alkyl-OH;

ar is-C _6-10 aryl-Y-R ₂ Or-5-6 membered heteroaryl-Y-R ₂ Wherein each aryl or heteroaryl is optionally substituted with one or more halo;

R ₂ Is C _6-10 Aryl or 5-6 membered heteroaryl, optionally substituted with 1, 2 or 3 groups selected from C _1-6 Alkoxy, deuterated C _1-6 Alkoxy, halo, C _1-6 Haloalkyl, -OH, -CN and-NH ₂ Is substituted by a substituent of (a); and is also provided with

m is 0 or 1.

Embodiment 10 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein

R ₁ Selected from H, 3-8 membered heterocyclyl, 5-12 membered heteroaryl, C _3-8 Cycloalkyl, C _3-8 cycloalkyl-O-, 3-8 membered heterocyclyl-O-, C _6-10 Aryl, C _1-6 Alkyl, C _1-6 Alkoxy and N (C) _1-6 Alkyl group ₂ Wherein each alkyl or alkoxy is optionally substituted with one or more substituents selected from halo, -OH and-CN; and wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted with one or more substituents selected from the group consisting of: -OH, -NH ₂ Oxo, halo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy and-C _1-6 alkyl-OH;

Preferably, R ₁ Selected from H, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C _3-8 Cycloalkyl, C _3-8 cycloalkyl-O-, 3-8 membered heterocyclyl-O-, C _6-10 Aryl, C _1-6 Alkyl, C _1-6 Alkoxy and N (C) _1-6 Alkyl group ₂ Wherein each alkyl or alkoxy group is optionally substituted with one or more substituents selected from halo; and wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted with one or more substituents selected from the group consisting of: -OH, oxo, halo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy and-C _1-6 alkyl-OH.

Embodiment 11 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein Ar is-C _6-10 aryl-Y-R ₂ Wherein the aryl is optionally substituted with one or more halo groups.

Embodiment 12 the compound of any one of the preceding embodiments or a stereoisomer thereofA isomer, racemate, geometric isomer, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof, wherein Ar is-5-6 membered heteroaryl-Y-R ₂ Wherein the heteroaryl is optionally substituted with one or more halo groups.

Embodiment 13 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein R ₂ Is C _6-10 Aryl or 5-6 membered heteroaryl, optionally substituted with 1, 2 or 3 groups selected from C _1-6 Alkoxy, deuterated C _1-6 Alkoxy, halo, C _1-6 Haloalkyl and-OH.

Embodiment 14 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein R ₂ Is a 5-6 membered heteroaryl group, optionally substituted with 1, 2 or 3 groups selected from C _1-6 Alkoxy, deuterated C _1-6 Alkoxy, halo, C _1-6 Haloalkyl and-OH.

Embodiment 15 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein R ₂ Is phenyl, optionally substituted with 1, 2 or 3 groups selected from C _1-6 Alkoxy, deuterated C _1-6 Alkoxy, halo, C _1-6 Haloalkyl and-OH.

Embodiment 16 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein R ₂ Is phenyl or 6-membered heteroaryl optionally substituted with 1 or 2 substituents selected from the group consisting of: c (C) _1-6 Alkoxy, deuterated C _1-6 Alkoxy, halo, C _1-6 Haloalkyl and-OH.

Embodiment 17 the compound of any one of the preceding embodiments or a stereoisomer, racemate thereofA isomer, geometric isomer, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof, wherein R ₂ Is phenyl optionally substituted with 1 or 2 substituents selected from the group consisting of: c (C) _1-6 Alkoxy, deuterated C _1-6 Alkoxy, halo, C _1-6 Haloalkyl and-OH.

Embodiment 18 the compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein R ₂ Is phenyl optionally substituted with 1 or 2 substituents selected from the group consisting of: c (C) _1-6 Alkoxy and halo.

Embodiment 19 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of O, -CH ₂ -NH-C(O)-、-CH ₂ -C (O) -NH-and-C (O) -NH-.

Embodiment 20 a compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein Y is O.

Embodiment 21 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein Y is-CH ₂ -NH-C(O)-。

Embodiment 22 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein X ₃ Is N.

Embodiment 23. The compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein:

X ₁ is CR' or N; r' is H or halo;

X ₂ is CH;

X ₃ is N;

R ₁ selected from 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C _3-8 Cycloalkyl, C _3-8 cycloalkyl-O-, C _6-10 Aryl and N (C) _1-6 Alkyl group ₂ Wherein alkyl is optionally substituted with one or more halo, -OH and-CN; and wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted with one or more substituents selected from the group consisting of: -OH, halo, CN, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 An alkoxy group;

ar is-C _6-10 aryl-Y-R ₂ Wherein each of said C _6-10 Aryl is optionally substituted with one halo;

y is-CH ₂ -NH-C (O) -; and is also provided with

R ₂ Is C _6-10 Aryl groups, which are selected from C by 1, 2 or 3 _1-6 Alkoxy, deuterated C _1-6 Substituents for alkoxy and halo groups.

Embodiment 24 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein X ₁ Is CH.

Embodiment 25 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein X ₃ Is N.

Embodiment 26A compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl-Y-R ₂ Wherein the phenyl group is optionally substituted with one halo group.

Embodiment 27 a compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein:

Ar is

Wherein R is ₃ Is H or halo.

Embodiment 28 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein Ar is

Wherein R is ₃ Is H or halo.

Embodiment 29 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein Ar is phenyl-Y-R ₂ 。

Embodiment 30 the compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein R ₂ Is 2-methoxy-phenyl or 2-methoxy-5-fluoro-phenyl.

Embodiment 31 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein R ₁ Selected from 4-6 membered heterocyclyl, 5-10 membered heteroaryl, C _5-6 Cycloalkyl, C _3-6 cycloalkyl-O-and phenyl, each of which is optionally substituted with one or more groups selected from-OH, halo, CN, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 The substituent of the alkoxy group is substituted.

Embodiment 32 the compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein R ₁ Selected from 5-to 10-membered heteroaryl groups, optionally substituted with one or more groups selected from-OH, halo, CN, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 The substituent of the alkoxy group is substituted.

Embodiment 33 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein R ₁ Is N (C) optionally substituted by one or more halo groups _1-6 Alkyl group ₂ The method comprises the steps of carrying out a first treatment on the surface of the Preferably, R ₁ Is substituted by one or more halo groups (C _1-6 Alkyl group ₂ The method comprises the steps of carrying out a first treatment on the surface of the More preferably, R ₁ Is that

Embodiment 34 the compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein R ₁ Selected from 5-6 membered heteroaryl groups optionally substituted with one or more groups selected from-OH, halo, CN, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 The substituent of the alkoxy group is substituted.

Embodiment 35 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein R ₁ Selected from 5 membered heteroaryl groups optionally substituted with one or more groups selected from-OH, halo, CN, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 The substituent of the alkoxy group is substituted.

Embodiment 36 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein R ₁ Selected from 6 membered heteroaryl groups optionally substituted with one or more groups selected from-OH, halo, CN, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 The substituent of the alkoxy group is substituted.

Embodiment 37 the compounds of any one of the preceding embodiments or stereoisomers, racemates, geometric isomers, tautomers thereofA construct, hydrate or solvate or pharmaceutically acceptable salt thereof, wherein R ₁ Is pyridinyl, optionally substituted with one or more groups selected from-OH, halo, CN, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 The substituent of the alkoxy group is substituted.

Embodiment 38 a compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein halo is F or Cl, preferably F.

Embodiment 39 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein C _1-6 Haloalkyl is CF ₃ 。

Embodiment 40 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein R ₁ Is pyridinyl, optionally substituted with one or two substituents selected from-OH, methyl, F, OMe and CF ₃ Is substituted by a substituent of (a).

Embodiment 41 the compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, wherein R ₁ Is pyridin-4-yl which is C-substituted in the 2-position _1-6 Alkyl is optionally further substituted in the 3-position by a member selected from the group consisting of-OH, halo, CN, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 The substituent of the alkoxy group is substituted.

Embodiment 42 a compound of any one of the preceding embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein:

R ₁ selected from:

further preferably, R ₁ Selected from:

and H. Embodiment 43. A compound of embodiment 1 selected from:

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or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof.

Embodiment 44 the compound of any one of embodiments 1-43 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate, or pharmaceutically acceptable salt thereof, for use as a medicament.

Embodiment 45 the compound of any one of embodiments 1-43, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a BTK-related disease or disorder;

preferably, the disease or disorder is selected from the group consisting of tumors, autoimmune diseases, infectious diseases, inflammatory diseases and neurological disorders, preferably hematological malignancies, more preferably B-cell malignancies, even more preferably leukemias, lymphomas, hodgkin's disease and myelomas;

More preferably, the disease or disorder is selected from Acute Lymphoblastic Leukemia (ALL), acute Myeloid Leukemia (AML), acute Promyelocytic Leukemia (APL), chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic Neutrophilic Leukemia (CNL), acute Undifferentiated Leukemia (AUL), anaplastic Large Cell Lymphoma (ALCL), juvenile lymphoblastic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T cell ALL, AML with myelodysplasia (AML/TMDS), mixed Lineage Leukemia (MLL), myelodysplastic syndrome (mds), myeloproliferative diseases (MPD) (e.g., polycythemia Vera (PV), idiopathic thrombocytopenia (ET) and idiopathic primary myelofibrosis (IMF/IPF/PMF)), diffuse Large B Cell Lymphoma (DLBCL) (e.g., activated B cell lymphoma (ABC-bcl), mantle cell lymphoma, peripheral lymphoblastoma, lymphoblastic lymphoma, peripheral lymphomatosis (ependympathies), lymphoblastoma, lymphomas (lymphomas, lymphomas of the peripheral region (schlemes) Hairy cell leukemia, chronic myelogenous leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasmacytoma, and Multiple Myeloma (MM); rheumatoid arthritis, osteoarthritis, gouty arthritis and spondylitis; asthma, chronic bronchitis, allergic rhinitis, adult Respiratory Distress Syndrome (ARDS), silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, emphysema, pneumonia, bronchiectasis, pulmonary oxygen poisoning and chronic pneumonic diseases; systemic Lupus Erythematosus (SLE), autoimmune thyroiditis, multiple sclerosis, chronic Obstructive Pulmonary Disease (COPD), myasthenia gravis, psoriasis, inflammatory Bowel Disease (IBD) and idiopathic thrombocytopenic purpura; graft Versus Host Disease (GVHD) and allograft rejection.

Embodiment 46. A pharmaceutical composition comprising a compound of any one of embodiments 1-43, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

Embodiment 47 the use of a compound of any one of embodiments 1-43, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a BTK-related disease or disorder;

preferably, the disease or disorder is selected from the group consisting of tumors, autoimmune diseases, infectious diseases, inflammatory diseases and neurological disorders, preferably hematological malignancies, more preferably B-cell malignancies, even more preferably leukemia, lymphoma, hodgkin's disease and myeloma;

Embodiment 48. A method of inhibiting BTK in vivo or in vitro comprising contacting an effective amount of a compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt thereof, with BTK.

Embodiment 49 a method of treating or preventing a BTK-related disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-43, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate, or a pharmaceutically acceptable salt thereof;

Embodiment 50. A combination comprising a compound of any one of embodiments 1-43, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably an anti-neoplastic agent, such as a radiation therapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, or a targeted therapeutic agent.

Embodiment 51 a compound selected from:

wherein P is ₁ Is an amino-protecting group, preferably P-methoxybenzyl, and P ₂ Is a hydroxy-protecting group, preferably methoxymethyl.

Embodiment 52 a compound selected from:

wherein the PMB is p-methoxybenzyl and MOM is methoxymethyl.

Definition of the definition

The following words, phrases and symbols used in this disclosure have the meanings described below, unless the context clearly indicates otherwise.

As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

The short dash ("-") that is not between two letters or symbols represents a point of attachment for a substituent. For example, C _3-8 cycloalkyl-O-is attached to the rest of the molecule through oxygen.

The term "alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon radical having 1 to 18 carbon atoms (C _1-18 ) Preferably 1 to 10, carbon atoms (C _1-10 ) Preferably 1 to 6 carbon atoms (C _1-6 ) And more preferably 1 to 4 carbon atoms (C _1-4 ) Or 1 to 3 carbon atoms (C) _1-3 ). For example, "C _1-6 Alkyl "means the alkyl group having 1 to 6 (1, 2, 3, 4, 5 or 6) carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

The term "alkenyl" as used herein refers to a straight or branched chain unsaturated hydrocarbon radical containing one or more, for example 1, 2 or 3, carbon-carbon double bonds (c=c) and having 2 to 10 carbon atoms (C _2-10 ) Preferably 2 to 6 carbon atoms (C _2-6 ) More preferably 2 to 4 carbon atoms (C _2-4 ). For example, "C _2-6 Alkenyl "means the alkenyl group having 2 to 6 (2, 3, 4, 5 or 6) carbon atoms, which preferably has 1 or 2 carbon-carbon double bonds; "C _2-4 Alkenyl "means the alkenyl group having 2 to 4 carbon atoms, which preferably has 1 carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl. The point of attachment of the alkenyl group may or may not be on a double bond.

The term "alkynyl" as used herein "refers to a straight or branched chain unsaturated hydrocarbon radical containing one or more, for example 1, 2 or 3, carbon-carbon triple bonds (C≡C) and having from 2 to 10 carbon atoms (C _2-10 ) Preferably 2 to 6 carbon atoms (C _2-6 ) More preferably 2 to 4 carbon atoms (C _2-4 ). For example, "C _2-6 Alkynyl "means the alkynyl group having 2 to 6 (2, 3, 4, 5 or 6) carbon atoms, which preferably has 1 or 2 carbon-carbon triple bonds; "C _2-4 Alkynyl "means the alkynyl group having 2 to 4 carbon atoms, which preferably has 1 carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The point of attachment of the alkynyl group may or may not be on a triple bond.

The term "halogen" or "halo" as used herein refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine, most preferably fluorine.

The term "haloalkyl" or halogen-substituted alkyl is used interchangeably herein to refer to an alkyl group as defined herein wherein one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same or different from each other. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein two or more, for example 2, 3, 4 or 5, hydrogen atoms are replaced by halogen atoms wherein the halogen atoms are identical to each other. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein two or more hydrogen atoms, for example 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are different from each other. Examples of haloalkyl groups include, but are not limited to, -CF ₃ 、-CHF ₂ 、-CH ₂ F、-CH ₂ CF ₃ 、-CF ₂ CF ₃ 、-CF ₂ CH ₃ Etc. Preferably haloalkyl is C _1-6 Trifluoroalkyl, more preferably-CF ₃ 。

The term "alkoxy" as used herein refers to the group-O-alkyl, wherein alkyl is as defined above. Examples of alkoxy groups include, but are not limited to, C _1-6 Alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy and hexoxy groups, including isomers thereof. Preferably the alkoxy group is methoxy.

The term "haloalkoxy" or halogen-substituted alkoxy, as used interchangeably herein, refers to an alkoxy group as defined herein wherein one or more, for example 1, 2, 3, 4 or 5, hydrogen atoms are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same or different from each other. Examples of haloalkoxy groups include, but are not limited to, trifluoroalkoxy groups, preferably C _1-6 Trifluoroalkoxy groups, more preferably

The term "cycloalkyl" as used herein means a compound having 3 to 10 ring carbon atoms (C _3-10 ) For example 3 to 8 ring carbon atoms (C _3-8 ) 3 to 7 ring carbon atoms (C) _3-7 ) Of 3 to 6 ring carbon atoms (C) _3-6 ) Or 5 to 6 ring carbon atoms (C) _5-6 ) May have one or more rings, for example 1 or 2 rings. "cycloalkyl" may include fused, bridged or spiro rings. For example, the cycloalkyl is a monocyclic cycloalkyl, preferably monocyclic C _3-8 Cycloalkyl, preferably monocyclic C _3-6 Cycloalkyl, more preferably monocyclic C _5-6 Cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl. For example, the cycloalkyl is a bicyclic cycloalkyl, preferably bicyclic C ₅ -C ₁₀ Cycloalkyl groups. Examples of bicyclic cycloalkyl groups include, but are not limited to, bicyclo [4.1.0]Heptyl, bicyclo [3.1.1]Heptyl, bicyclo [2.2.1]Heptyl, bicyclo [2.2.2]Octyl, bicyclo [3.2.2]Nonyl, spiro [3.3 ]]Heptyl, spiro [2.2 ]]Amyl, spiro [2.3 ]]Hexyl, spiro [2.4 ]]Heptyl, spiro [2.5 ]]Octyl and spiro [4.5 ]]And (3) a decyl group. Preferably, the cycloalkyl is a monocyclic C _3-6 Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "cycloalkenyl" as used herein means a compound having at least one carbon-carbonNon-aromatic unsaturated cyclic hydrocarbon groups of double bonds having 3 to 10 ring carbon atoms (C _3-10 ) Such as 3 to 8 ring carbon atoms (C _3-8 ) 3 to 7 ring carbon atoms (C) _3-7 ) Of 3 to 6 ring carbon atoms (C) _3-6 ) Or 5 to 6 ring carbon atoms (C) _5-6 ) It may have one or more rings, for example 1 or 2 rings. For example, the cycloalkenyl is a monocyclic cycloalkenyl. Examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl.

The term "heterocyclyl" as used herein refers to a saturated or partially unsaturated ring having 3 to 10 ring atoms (3 to 10 members), such as 3 to 8 ring atoms (3 to 8 members), 5 to 7 ring atoms (5 to 7 members), 3 to 6 ring atoms (3 to 6 members), 4 to 6 ring atoms (4 to 6 members) or 5 to 6 ring atoms (5 to 6 members), wherein one or more, such as 1, 2 or 3, preferably 1 or 2 ring atoms are heteroatoms independently selected from N, O and S, the remaining ring atoms are carbon, and having one or more, such as 1, 2 or 3, preferably 1 or 2 rings, wherein the N or S heteroatoms are optionally oxidized to various oxidation states. The point of attachment of the heterocyclic group may be on the N heteroatom or the carbon atom. The ring of the heterocyclic group also includes a condensed ring, a bridged ring, or a spiro ring. The ring of the heterocyclyl may be saturated or contain one or more, for example one or two double bonds (i.e. partially unsaturated), but not fully conjugated, and not heteroaryl as defined herein. For example, "3-8 membered heterocyclyl" refers to a heterocyclyl having 3-8 ring atoms and containing 1, 2 or 3, preferably 1 or 2 ring heteroatoms independently selected from N, O and S, preferably a saturated monocyclic 3-8 membered heterocyclyl. For example, "4-6 membered heterocyclyl" refers to a heterocyclyl having 4-6 ring atoms and containing 1 or 2 ring heteroatoms independently selected from N, O and S, preferably a saturated monocyclic 4-6 membered heterocyclyl, such as a saturated monocyclic 4, 5 or 6 membered heterocyclyl. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, thiiranyl, oxetanyl, azetidinyl (e.g., azetidin-1-yl, azetidin-2-yl, azetidin-3-yl), thietanyl, pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), oxopyrrolidinyl (e.g., 2-oxopyrrolidin-1-yl), tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl, tetrahydrofuran-3-yl), dioxolanyl, imidazolidinyl, morpholinyl (e.g., morpholin-1-yl), morpholin-2-yl, morpholin-3-yl), thiomorpholinyl, piperidin (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl), dihydropyranyl, tetrahydropyran (e.g., tetrahydropyran-2-yl, tetrahydropyran-3-yl), hexahydropyranyl, hexahydropyran-3-yl, and hexahydrothiopyranyl. Preferably, the heterocyclyl is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholino or tetrahydropyranyl, such as azetidin-1-yl, pyrrolidin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, piperidin-1-yl, piperazin-1-yl or morpholino.

The term "aryl" as used herein means a compound having 6 to 14 carbon atoms (C) consisting of one ring or multiple condensed rings _6-14 ) Preferably 6 to 10 carbon atoms (C _6-10 ) Wherein at least one ring is an aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, phenanthryl, indenyl, indanyl, azulenyl, preferably phenyl and naphthyl, more preferably phenyl.

The term "heteroaryl" as used herein refers to a monocyclic, bicyclic or tricyclic ring system having 5-12 ring atoms (5-12 members), such as 5-10 ring atoms (5-10 members), 8-12 ring atoms (8-12 members), 5-8 ring atoms (5-8 members), 5-7 ring atoms (5-7 members), 5-6 ring atoms (5-6 members), 5 ring atoms (5 members) or 6 ring atoms (6 members), wherein at least one ring is a 5 or 6 membered aromatic ring, wherein one or more, for example 1,2 or 3, preferably 1 or 2, ring atoms are heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon, and wherein the N or S heteroatoms are optionally oxidized to various oxidation states. For example, heteroaryl groups are:

-a 5-6 membered monocyclic heteroaryl, i.e. a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms (5 or 6 membered), wherein one or more, for example 1,2 or 3, preferably 1 or 2, ring atoms are ring heteroatoms independently selected from N, O and S (preferably N), and the remaining ring atoms are carbon; preferably a monocyclic aromatic hydrocarbon group having 6 ring atoms (6-membered), wherein 1,2 or 3, preferably 1 or 2 ring atoms are heteroatoms independently selected from N, O and S, preferably N;

Or (b)

-8-12 membered bicyclic heteroaryl, i.e. a bicyclic aromatic hydrocarbon group having 8, 9, 10, 11 or 12 ring atoms (8, 9, 10, 11 or 12 membered), wherein one or more, e.g. 1, 2, 3 or 4, preferably 1, 2 or 3, ring atoms are ring heteroatoms independently selected from N, O and S (preferably N), and the remaining ring atoms are carbon, wherein at least one ring is aromatic.

Examples of heteroaryl groups include, but are not limited to, pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl), pyridinyl N-oxides, pyrazinyl (e.g., pyrazin-2-yl, pyrazin-3-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl), pyridazinyl (e.g., pyridazin-3-yl, pyridazin-4-yl), pyrazolyl (e.g., pyrazol-1-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl), imidazolyl (e.g., imidazol-1-yl, imidazol-5-yl, imidazol-3-yl, imidazol-4-yl, imidazol-5-yl), oxazolyl, isoxazolyl (e.g., isoxazol-4-yl), oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl, triazinyl, thienyl, furanyl, pyranyl, pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl), benzodioxolyl, benzoxazolyl, benzisoxazolyl, benzothienyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, imidazopyrrolyl, triazolopyridinyl, indazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, tetrazolopyridinyl, tetrahydropyrazolopyridinyl, benzofuranyl, benzimidazolinyl, or indolyl. Preferably, the heteroaryl group is pyrazolyl, pyridinyl, pyridazinyl or pyrazinyl, more preferably pyrazol-1-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridazin-4-yl, pyrazin-2-yl or pyrazin-3-yl.

The term "oxo" as used herein refers to the group = O.

When the structures herein contain "(R)" and/or "(S)", it means that the chiral center of the compound labeled by "(R)" or "(S)" is a single configuration of either the R-configuration or the S-configuration. For example, a compound of the disclosure has an enantiomeric purity of at least 60% ee (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% ee (enantiomeric excess), or any value between those enumerated values), or a diastereomeric purity of at least 60% de (diastereomeric excess) (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% de, or any value between those enumerated values).

When the structure of a compound herein is labeled as an "isomer," it is meant that the compound is an individual stereoisomer, but the absolute or relative configuration of the compound is arbitrarily designated or unspecified.

When the structure of a compound herein is labeled "cis or trans," it means that the compound is a single stereoisomer, but the configuration of the compound is arbitrarily designated as cis or trans.

When the structure of a compound herein is labeled "cis" or "trans", it is meant that the compound is the individual stereoisomer, and the relative configuration of the compound is either cis or trans as shown, but the configuration is not defined.

When the structure of the compounds herein contains a compound formed by a wavy line

When referring to a bond, it refers to a mixture of isomers of the compounds in any proportion.

When the bond of the radical carries a wavy line

When wavy, the wavy line indicates the point of attachment of this group to the rest of the molecule.

The term "optional" or "optionally" as used herein means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted with one or more … …" includes "unsubstituted" and "substituted with 1, 2, 3, or more" as defined herein. It will be appreciated by those skilled in the art that for any group containing one or more substituents, the group does not include any sterically impractical, chemically incorrect, synthetically infeasible, and/or inherently unstable substitution or substitution pattern.

The term "substituted" or "substituted with … …" as used herein means that one or more hydrogen atoms on a given atom or group is replaced with one or more substituents independently selected from the indicated group of substituents, provided that the normal valence of the given atom is not exceeded. The term "substituted with one or more … …" means that one or more (e.g., 1, 2, 3 or 4, preferably 1 or 2) hydrogens on a given atom or group are replaced with one or more (e.g., 1, 2, 3 or 4, preferably 1 or 2) substituents independently selected from the indicated group of substituents, provided that the normal valence of that given atom is not exceeded. When the substituent is oxo (i.e., =o), then two hydrogen atoms on a single atom are replaced. Such combinations are permissible only if combinations of substituents and/or variables result in chemically correct and stable compounds. Chemically correct and stable compounds means that the compounds are sufficiently stable (robust) to be able to be separated from the reaction mixture.

It will be appreciated by those skilled in the art that some of the compounds disclosed herein may contain one or more chiral centers or rings, thus, there are two or more stereoisomers. Racemic mixtures of these isomers, single isomers and one enantiomerically enriched mixture, as well as diastereomeric and particular diastereomeric partially enriched mixtures when there are two chiral centers are all within the scope of the disclosure. Those of skill in the art will also appreciate that the present disclosure includes all individual stereoisomers (e.g., enantiomers, diastereomers, or cis-or trans-isomers), racemic mixtures, or partially resolved mixtures of compounds disclosed herein, and, where appropriate, individual tautomeric forms thereof.

The racemates or other mixtures of isomers may be used as such or may be resolved into their individual isomers. The resolution can be carried out to obtain a stereochemically pure compound or a mixture enriched in one or more isomers. Methods for separating isomers are well known (see, e.g., allinger n.l. and Eliel e.l. "Topics in Stereochemistry", volume 6, wiley Interscience, 1971).

The term "pharmaceutically acceptable salt" includes, but is not limited to: acid addition salts formed with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, and the like, of the compounds disclosed herein; and acid addition salts of the compounds disclosed herein with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, mesylate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate and compounds of the formula HOOC- (CH) ₂ ) _n -COOH (wherein n is 0-4) and the like. "pharmaceutically acceptable salts" also include base addition salts of the compounds of the invention having an acidic group with pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium.

Furthermore, if the compounds described herein are obtained in the form of an acid addition salt, the free base form thereof may be obtained by basifying a solution of the acid addition salt. Conversely, if the product is in the form of the free base, its acid addition salts, particularly the pharmaceutically acceptable acid addition salts, can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. One skilled in the art can determine, without undue experimentation, various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable acid or base addition salts.

The term "solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate.

The term "deuterated" group refers to a group in which one or more, for example 1, 2 or 3, hydrogen atoms are replaced by its isotope deuterium (D).

The term "protecting group" refers to a substituent typically used to block or protect a particular functional group when the other functional groups on the compound react. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in a compound. Suitable amino protecting groups include p-methoxybenzyl (PMB), benzyl (Bn), trityl (Trt), acetyl, trifluoroacetyl, phthalimido, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent that blocks or protects the hydroxyl group of a hydroxyl functional group. Suitable hydroxy protecting groups include methoxymethyl, benzyl, benzyloxymethyl, methyl, triarylmethyl, acetyl, trialkylsilyl, dialkylphenylsilyl, benzoyl and tetrahydropyranyl. For a general description of protecting groups and their use, see t.w.greene and p.g.m.wuts, "Protective Groups in Organic Synthesis", 5 th edition, wiley, new York,2014.

As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combining of more than one active agent, and includes both fixed and non-fixed combinations of active agents, e.g., a kit or pharmaceutical composition. The term "fixed combination" refers to the simultaneous administration of active agents, e.g., the presently disclosed and additional active agents, in a single entity or dosage form to an individual. The term "non-fixed combination" refers to the simultaneous, concurrent or sequential administration of active agents, e.g., the presently disclosed and additional active agents, as separate entities, to a patient in need thereof without specific time constraints, wherein such administration provides an effective level of the compound in the patient.

The term "treating" or "treatment" of a disease refers to administering one or more pharmaceutical substances, especially a compound of the invention or a pharmaceutically acceptable salt thereof, to an individual suffering from, or having symptoms of, the disease or disorder, for the purpose of curing, healing, alleviating, modifying, treating, ameliorating, improving, or affecting the disease or disorder, the symptoms of the disease or disorder. In some embodiments, the disease is a BTK-related disease or disorder, such as a disease or disorder responsive to inhibition of BTK, preferably cancer.

The term "preventing" a disease refers to administering one or more pharmaceutical substances, in particular a compound of the invention as defined herein or a pharmaceutically acceptable salt thereof, to an individual having a constitution susceptible to or at risk of suffering from said disease or disorder, in order to prevent or slow down the occurrence of said disease or disorder in said individual. In some embodiments, the disease is a BTK-related disease or disorder, such as a disease or disorder responsive to inhibition of BTK, preferably cancer.

The term "effective amount" as used herein refers to an amount of a compound of the invention described herein, or a pharmaceutically acceptable salt thereof, effective to "treat" or "prevent" a BTK-related disease or disorder, such as a disease or disorder responsive to inhibition of BTK, in an individual as defined above. An effective amount may cause any visible or detectable change in the individual as defined above in "treatment" or "prevention". For example, in the case of cancer, an effective amount can reduce the number of cancer or tumor cells; reducing the size of the tumor; inhibiting or preventing infiltration of tumor cells into peripheral organs, including, for example, the spread of tumors into soft tissues and bones; inhibit or prevent metastasis of tumors; inhibit or prevent tumor growth; to some extent, alleviate one or more symptoms associated with cancer; reducing morbidity and mortality; improving the quality of life; or a combination of the above effects. An effective amount may be an amount sufficient to reduce symptoms of a BTK-related disease or disorder. The term "effective amount" may also refer to an amount of a compound of the invention described herein, or a pharmaceutically acceptable salt thereof, effective to inhibit BTK activity in an individual.

The term "inhibition" means a decrease in the baseline activity of a biological activity or process. "BTK inhibition" refers to a decrease in BTK activity as a direct or indirect response to the presence of a compound of the invention or a pharmaceutically acceptable salt thereof relative to BTK activity in the absence of the compound of the invention or a pharmaceutically acceptable salt thereof. The decrease in activity may be due to direct interaction of the compound of the invention or a pharmaceutically acceptable salt thereof with BTK or due to interaction of the compound of the invention or a pharmaceutically acceptable salt thereof with one or more other factors which in turn affect BTK activity. For example, the presence of a compound of the invention described herein, or a pharmaceutically acceptable salt thereof, can reduce BTK activity by directly binding BTK, by directly or indirectly causing another factor to reduce BTK activity, or by directly or indirectly reducing the amount of BTK present in a cell or organism.

The term "individual" as used herein refers to both mammalian and non-mammalian animals. Mammal means any member of the mammalian class including, but not limited to, human; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs; etc. In some embodiments, the individual is a human. The term "individual" does not denote a particular age or sex. In some embodiments, the individual is a human. In some embodiments of any of the methods or uses described herein, the subject is not treated with a BTK inhibitor. In other embodiments of any of the methods or uses described herein, the subject is not treated with a BTK inhibitor.

The term "pharmaceutically acceptable" means that the substances defined hereinafter are useful in the preparation of pharmaceutical compositions which are generally safe, nontoxic, without undesirable properties in biological or other respects, particularly for human medicine.

The term "about" is used herein to mean approximately, within, roughly, or around. When the term "about" is used in connection with a range of values, it modifies that range by extending the boundaries above or below the numerical values set forth. Generally, the term "about" is used herein to modify a 20% change in a value above or below that value.

The term "tumor" refers herein to a cellular disorder characterized by uncontrolled or deregulated cell proliferation, reduced cell differentiation, the ability to inappropriately invade surrounding tissues, and/or the ability to establish new growth at other sites. The term "tumor" includes, but is not limited to, hematological malignancies and solid tumors, preferably B-cell malignancies. The term "tumor" includes, but is not limited to, leukemia, lymphoma (non-hodgkin's lymphoma), hodgkin's disease (also known as hodgkin's lymphoma), and myeloma. Non-limiting examples of tumors are Acute Lymphoblastic Leukemia (ALL), acute Myeloid Leukemia (AML), acute Promyelocytic Leukemia (APL), chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic Neutrophilic Leukemia (CNL), acute Undifferentiated Leukemia (AUL), anaplastic large cell lymphoma (ALL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T cell ALL, AML with myelodysplasia (AML/TMDS), mixed Lineage Leukemia (MLL), myelodysplastic syndrome (MDSs), myeloproliferative disease (MPD) (e.g., polycythemia Vera (PV), idiopathic thrombocytopenia (ET) and idiopathic primary myelofibrosis), diffuse large B-cell lymphomas (DLBCL) (e.g., activated B-cell like DLBCL (ABC-DLBCL)), follicular lymphomas, mantle cell lymphomas, marginal zone lymphomas (e.g., junction peripheral zone B-cell lymphomas, splenic marginal zone lymphomas), burkitt's lymphoma, waldenstem macroglobulinemia (lymphoplasmacytomer lymphomas (LPL)), primary central nervous system lymphomas, small lymphocytic lymphomas, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myelogenous leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasmacytoma, and Multiple Myeloma (MM). The term "tumor" includes cancers of the skin, tissue, organs, bones, cartilage, blood and blood vessels. The term "tumor" also includes primary tumors, metastatic tumors, recurrent tumors, and refractory tumors.

The term "autoimmune disease" refers herein to a disease or disorder caused by damage to an individual's own tissues or organs resulting from the body's immune response to an autoantigen. Examples of autoimmune diseases include, but are not limited to, chronic Obstructive Pulmonary Disease (COPD), allergic rhinitis, systemic lupus erythematosus, myasthenia gravis, multiple Sclerosis (MS), rheumatoid Arthritis (RA), psoriasis, inflammatory Bowel Disease (IBD), asthma, idiopathic thrombocytopenic purpura, and myeloproliferative diseases such as myelofibrosis, polycythemia vera/post-essential thrombocythemia myelofibrosis (post-PV/post-ET myelofibrosis).

The term "inflammatory disease" or "inflammatory disorder" refers to a pathological condition that causes inflammation, particularly inflammation due to chemotaxis of neutrophils. Non-limiting examples of inflammatory diseases include chronic inflammation, autoimmune diabetes, rheumatoid Arthritis (RA), spondylitis, gouty arthritis and other joint disorders, multiple Sclerosis (MS), asthma, systemic lupus erythematosus, adult respiratory distress syndrome, behcet's disease, psoriasis, chronic pneumonic disease, allograft rejection, crohn's disease, ulcerative colitis, inflammatory Bowel Disease (IBD).

All numerical ranges herein should be understood to disclose each and every value within the range, as well as each and every subset of values within the range, whether or not they are otherwise specifically disclosed. For example, when referring to any numerical range, it should be considered to refer to each numerical value in the numerical range, e.g., each integer in the numerical range. The present disclosure includes all values falling within these ranges, all smaller ranges, and the upper or lower limit of the range.

Technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

Pharmaceutical composition and administration

The compounds of the present invention (e.g., any of the compounds in the examples herein) may be formulated into pharmaceutical compositions, alone or in combination with one or more additional active agents. The pharmaceutical composition comprises (a) an effective amount of a compound of the present invention; (b) Pharmaceutically acceptable excipients (e.g., one or more pharmaceutically acceptable carriers); and optionally (c) at least one additional active agent.

Pharmaceutically acceptable excipients refer to excipients that are compatible with the active ingredient of the composition (and, in some embodiments, stabilize the active ingredient) and are not deleterious to the subject being treated. Suitable pharmaceutically acceptable excipients are disclosed in standard references in the art (e.g., remington's Pharmaceutical Sciences, remington: the Science and Practice of Pharmacy) and include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents and other known additives to provide a good appearance of the drug (i.e., the compound of the present invention or pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

The compounds of the present invention may be administered in a variety of known ways, such as orally, parenterally, inhaled or implanted. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intravertebral, intralesional and intracranial injection or infusion.

The compounds of the present invention may be administered in any convenient formulation, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions may contain conventional ingredients in pharmaceutical formulations, such as diluents, carriers, pH modifying agents, sweeteners, fillers and additional active agents.

In one example, an effective amount of a pharmaceutical compound of the present invention administered parenterally per dose will be in the range of about 0.01 to 100mg/kg patient body weight/day, or about 0.1 to 20mg/kg patient body weight/day, with typical initial ranges of the compound used being 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, contain from about 0.1 to about 1000mg of a compound of the invention.

Indications and methods of treatment

The present disclosure relates to methods of treating or preventing BTK-related diseases or disorders comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

In one embodiment, the compounds of the invention are useful for treating or preventing BTK-related diseases or disorders.

Preferably, the BTK-related disease or disorder as used herein is selected from the group consisting of a tumor, an autoimmune disease, an infectious disease, an inflammatory disease and a neurological disorder.

The tumor is a hematological malignancy or a solid tumor. More preferably the tumour is a B cell malignancy.

Non-limiting examples of BTK related diseases or disorders include:

1.tumors (BTK-related tumors) hematological malignancies, solid tumors, preferably B-cell malignancies

1.1The malignant tumor of bloodFor example, hematological malignancy, which is a BTK-related tumor, is selected from leukemia, lymphoma (non-hodgkin lymphoma), hodgkin's disease (also known as hodgkin's lymphoma), and myeloma, such as Acute Lymphoblastic Leukemia (ALL), acute Myeloid Leukemia (AML), acute Promyelocytic Leukemia (APL), chronic Lymphoblastic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic Neutrophilic Leukemia (CNL), acute Undifferentiated Leukemia (AUL), anaplastic Large Cell Lymphoma (ALCL), lymphoblastic leukemia (PML), juvenile myelomonocytic leukemia (jl), adult T cell ALL, AML with myelodysplasia (AML/TMDS), myeloid leukemia (MLL), myelodysplastic syndrome (mds), myeloproliferative disease (MPD) (e.g., polycythemia Vera (PV), idiopathic thrombocytopenia (ET) and idiopathic primary bone Myelofibrosis (IMF/IPF/PMF)), diffuse large B-cell lymphoma (DLBCL) (e.g., activated B-cell-like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., junction outer border zone B-cell lymphoma, spleen border zone lymphoma), burkitt's lymphoma, waldenstrom's macroglobulinemia (lymphoplasmacytomer lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myelogenous leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasma cell lymphoma, and Multiple Myeloma (MM).

Tumors as used herein also include transformations in hematological malignancies. Non-limiting examples of transformations in hematological malignancies include Richter transformation, prolymphocyte transformation (e.g., prolymphocyte transformation of CLL), transformed non-hodgkin's lymphoma, and blastoid lymphoma (blastoid lymphoma) (e.g., blast variant mantle cell lymphoma).

1.2Solid tumors(e.g., a solid tumor that is a BTK-related tumor). Examples of solid tumors include, for example, bone cancer, bone metastasis, breast cancer, gastroesophageal cancer, pancreatic cancer, ovarian cancer, cervical cancer, prostate cancer, lung cancer, colon cancer, uterine cancer, hepatocellular cancer, head and neck cancer, gastric cancer, esophageal cancer, bladder cancer, colorectal cancer, renal cancer, skin cancer, brain tumor, thyroid cancer, and glioma. See, for example, methods described in Campbell et al, journal of ClinicalMedicine,2018,7 (4): 62 and Zucha et al, journal of Clinical Medicine,2018,7 (4): 62, each of which is incorporated herein by reference in its entirety.

1.3B cell malignancyIncluding B-cell non-Hodgkin's lymphoma, hodgkin's lymphoma or B-cell leukemia. Examples of B-cell malignancies also include hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL) (e.g., activated B-cell like DLBCL (ABC-DLBCL)), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (e.g., junction outer border zone B-cell lymphoma, spleen border zone lymphoma), burkitt's lymphoma, waldenstrom's macroglobulinemia (lymphoplasmacy)Cytolymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia, acute Lymphocytic Leukemia (ALL), B-cell prolymphocytic leukemia, precursor B-lymphoblastic leukemia, or hairy cell leukemia.

2.Other BTK-related diseases (including inflammatory and autoimmune diseases):

2.1. arthritic diseases such as rheumatoid arthritis, osteoarthritis, gouty arthritis, spondylitis;

2.2. infectious diseases, sepsis, septic shock, endotoxic shock, gram negative sepsis, gram positive sepsis and toxic shock syndrome;

2.3. Multiple organ injury syndrome secondary to sepsis, trauma, or hemorrhage; ophthalmic diseases such as allergic conjunctivitis, vernal conjunctivitis, uveitis, and thyroid-related eye diseases; eosinophilic granuloma;

2.4. pulmonary or respiratory diseases such as asthma, chronic bronchitis, allergic rhinitis, adult Respiratory Distress Syndrome (ARDS), chronic pneumonia (e.g. chronic obstructive pulmonary disease), silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, emphysema, pneumonia, bronchiectasis, pulmonary oxygen toxicity and chronic pneumonitis;

2.5. reperfusion injury of the myocardium, brain or limbs;

2.6. fibrosis, such as cystic fibrosis; keloid formation or scar tissue formation; atherosclerosis;

2.7. autoimmune diseases including, but not limited to, systemic Lupus Erythematosus (SLE), autoimmune thyroiditis, multiple sclerosis, chronic Obstructive Pulmonary Disease (COPD), allergic rhinitis, lupus erythematosus, myasthenia gravis, rheumatoid Arthritis (RA), psoriasis, inflammatory Bowel Disease (IBD), asthma, idiopathic thrombocytopenic purpura, and myeloproliferative diseases such as myelofibrosis, polycythemia vera/post-essential thrombocythemia myelofibrosis (PV/ET post myelofibrosis);

2.8. Some forms of diabetes and Raynaud's syndrome;

2.9. graft rejection diseases such as Graft Versus Host Disease (GVHD) and allograft rejection;

2.10. chronic glomerulonephritis; inflammatory bowel disease, such as inflammatory bowel disease (CIBD), crohn's disease, ulcerative colitis, and necrotizing enterocolitis;

2.11. inflammatory skin diseases such as contact dermatitis, atopic dermatitis, psoriasis or urticaria; fever and myalgia caused by infection;

2.12. inflammatory diseases of the central or peripheral nervous system, such as meningitis, encephalitis, and brain or spinal cord injury caused by minor trauma;

2.13. sjogren syndrome;

2.14. diseases involving leukocyte exudation;

2.15. alcoholic hepatitis;

2.16. bacterial pneumonia; antigen-antibody complex mediated diseases; hypovolemic shock; type I diabetes; acute and delayed hypersensitivity reactions; a disease state caused by leukocytes;

2.17. cachexia and metastasis; thermal damage; granulocyte transfusion-associated syndrome; and cytokine-induced toxicity;

2.18. behcet's disease.

3.Diseases resistant to other BTK related therapies:

Diseases that are resistant to other BTK-related treatments include tumors that have BTK inhibitor resistance mutations (e.g., that result in increased resistance to the first BTK inhibitor, e.g., substitution at amino acid position 481, e.g., C481S, C481T, C481R, C481G, and/or one or more BTK inhibitor resistance mutations).

The compounds of the invention are useful for treating or preventing diseases that are resistant to other BTK-related therapies, either by co-administration or as a follow-up or additional (e.g., follow-up) therapy to existing drug therapies (e.g., the other BTK kinase inhibitors; e.g., the first and/or second BTK kinase inhibitors). In some embodiments, the first or second BTK kinase inhibitor may be selected from ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, acartinib, zebutinib, spebrutinib, poseltinib, ewobutinib (evobrinib), M7583, tiratinib, CG'806, ARQ 531, BIIB068, vicat brutinib, AS871, CB 1763, CB988, GDC-0853, RN486, dasatinib, GNE-504, GNE-309, BCB-311, BTK Max, CT-1530, CGI-1746, CGI-560, LFM Al3, TP-0158, dtrmwxhs-12, CNX-774, and LOU064. In some embodiments, the first or second BTK kinase inhibitor is a covalent inhibitor. Exemplary covalent inhibitors of BTK kinase include, but are not limited to, ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, acartinib, zebutinib, spebrutinib, poseltinib, el Wo Buti, M7583, and tiratinib. In some embodiments, the first or second BTK kinase inhibitor is a non-covalent inhibitor. Exemplary non-covalent inhibitors of BTK kinase include, but are not limited to CG'806, ARQ 531, BIIB068, vicat brutinib, AS871, CB 1763, CB988, GDC-0853, RN486, and dasatinib.

Pharmaceutical combination

The compounds of the invention may be used in combination with additional active agents for the treatment of BTK related diseases or disorders. The additional active agent may be administered separately from the compounds of the present invention or may be included in the pharmaceutical compositions according to the present invention together with the compounds of the present invention, e.g. as a fixed combination. In some embodiments, the additional active agents are those known or found to be effective in treating a BTK-related disease or disorder, such as another BTK inhibitor, or a compound that antagonizes an additional target associated with the particular disease. The combination may be used to increase the efficacy of the compounds of the invention, reduce one or more side effects, or reduce the required dose.

In some embodiments, the compounds of the present invention are administered in combination with an antineoplastic agent. Antitumor agents include, but are not limited to: radiotherapeutic agents, chemotherapeutic agents, immunotherapeutic agents, targeted therapeutic agents.

General synthetic method

Preparation of 1H-pyrazolo [4,3-c ] having the general Structure shown in A-1 and A-2]Pyridine-General application of 7-carboxamide analogues By synthesis (scheme 1)

Based on the synthesis of analogous compounds in the literature (WO 2017042100), A-1-1 is synthesized from the commercially available starting material 2,4, 6-trichloropyridine, followed by bromination and subsequent deprotection to give intermediate A-1-2. Treatment of A-1-2 with hydrazine gives the corresponding cyclized compound A-1-3, which, after separation from its regioisomer A-1-4b, is converted into the key intermediate compound A-1-4a. The target compound with the general structure of A-1 is obtained by carrying out selective and continuous bell wood reaction on two chlorine groups on a key intermediate A-1-4a 4, 6-dichloro-1H-pyrazolo [4,3-c ] pyridine-7-formamide and then carrying out a plurality of steps of functional group conversion. Alternatively, compound A-1-1 can be converted to intermediate A-2-2 after carboxylation, amide formation and deprotection. After ring closure and protection, A-2-2 is then converted to the key intermediate A-2-4a. After treatment of A-2-4a with the corresponding amine and subsequent Suzuki reaction, a 4-nitrogen analog having the general structure shown in A-2 can be obtained

Scheme 1

Wherein Ra is R attached to the ring through C ₁ And Rb is R linked to the ring through N or O ₁ ；P ₁ Or P ₂ Is a protecting group; r is R ₁ And Ar is as defined herein for formula I.

Preparation of 1H-pyrazolo [4,3-c ] having the general structures of the formulae B-1 and B-2]General application of pyridine-7-carboxamide analogues By synthesis (scheme 2)

Scheme 2

Wherein Ra is R attached to the ring through C ₁ And Rb is R linked to the ring through N or O ₁ ；P ₁ Or P ₂ Is a protecting group; r is R ₁ And Ar is as described hereinAnd formula I.

Intermediate B-1-1 can be obtained from commercially available 4-bromo-2, 6-difluorobenzonitrile according to the two-step process disclosed in WO2010059658 (but modified) as described in pathway 1. The protected formylation gives compound B-1-2, which is then converted to compound B-1-3a after separation from its regioisomer B-1-3B. B-1-3a and its deprotected form B-1-3c as key intermediates can be used as starting points for target compounds represented by B-1 or B-2, respectively, prepared in a multi-step sequence.

Alternatively, path 2 is also used in some cases. According to the improved process disclosed in US20180127370 and WO2004065367, commercially available methyl 5-bromo-2-hydroxy-4-methylbenzoate is converted to methyl 5-bromo-2-methoxy-4-methyl-3-nitrobenzoate, which is subsequently converted after the reduction step to the compound methyl 3-amino-5-bromo-2-methoxy-4-methylbenzoate. Subsequent ring closure reactions result in key intermediate B-1-6, which is converted to key intermediate B-1-9 after many bond and functional group conversion steps. The key intermediate B-1-9 is used to prepare the target compound represented by B-1.

The various embodiments described herein, as well as features of the various embodiments, should be understood to be combinable with each other in any manner, and each such combination is intended to be included within the scope of the present disclosure, as if the combination were specifically and individually set forth herein, unless the context clearly indicates otherwise.

The entire contents of all patents, patent applications, publications, and other documents cited or referred to herein are incorporated by reference to the extent allowed by law. The discussion of these references is intended only to summarize the assertions made therein. No admission is made that any of the patents, patent applications, publications or documents, or any portion thereof, is relevant material or prior art. Any claims directed to the accuracy and pertinence of such patents, patent applications, publications, and other documents are specifically reserved for the claims as related materials or prior art.

Examples

The following examples are intended to illustrate the invention only and should not be construed as limiting the invention in any way.

Unless otherwise indicated, temperatures are in degrees celsius and pressures are at or near atmospheric pressure. All MS (mass spectrometry) data are represented by Agilent 6120B; shimadzu LCMS 2010. ¹ The H-NMR spectrum was obtained using a nuclear magnetic resonance apparatus, operating at Bruker AVANCE NEO MHz. In expressing the multiplicity of peaks, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartet), br (broad), dd (doublet), dt (doublet). The coupling constants are given in hertz (Hz).

All reagents and starting materials used in the present invention, except for the intermediates prepared below, are commercially available or prepared according to the prior art.

All compounds except the reagent were named as Chemdraw. If the name and the structural formula of a compound are given simultaneously for the compound, in the case where the two are not identical, the structure of the compound is subject to unless the context indicates that the structure of the compound is incorrect and the name is correct.

In any of the formulae herein, if a free valence is present on any atom, the free valence is actually a hydrogen atom that is not specifically depicted for simplicity.

Unless otherwise indicated, if the isomers are separated from the same chromatographic separation conditions in the following examples, the isomers are named in the same order in which they were eluted.

The following abbreviations are used in the examples below:

list of abbreviations

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Synthesis of key intermediate A-1-4a

Synthesis of 2,4, 6-trichloro-3- (1, 3-dioxan-2-yl) pyridine (A-1-1)

Step 1LDA (27.4 mL,54.8 mmol) was added to a stirred suspension of 2,4, 6-trichloropyridine (9.1 g,49.8 mmol) in THF (100 mL) at-65℃and the resulting mixture was taken up in N ₂ Stirring was continued for 1 hour, after which piperidine-1-carbaldehyde (5.6 mL,49.8 mmol) was added at this temperature. The mixture was stirred at-65℃for 3 hours. The reaction mixture is then treated with saturated NH ₄ Cl was quenched, extracted with EtOAc (60 mL. Times.3), and the combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=2% in PE) to give 2,4, 6-trichloropyridine-3-carbaldehyde (4.1 g, yield: 39.1%) as a white solid. LC/MS (ESI) M/z 211 (M+H) ⁺ ， ¹ H-NMR(400MHz,DMSO)δ10.27(s,1H),8.09(s,1H)。

Step 2To a stirred suspension of 2,4, 6-trichloropyridine-3-carbaldehyde (4.1 g,19.5 mmol) and propane-1, 3-diol (2.1 mL,29.2 mmol) in toluene (40 mL) at 120deg.C was added p-TSA (0.7 g,3.9 mmol) and the resulting mixture was taken up in N ₂ Stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 ml×3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (etoac=0 to 10% in PE) to give 2,4, 6-trichloro-3- (1, 3-dioxan-2-yl) pyridine(A-1-1)(4.2 g, yield: 80.3%) as a white solid. LC/MS (ESI) M/z 268 (M+H) ⁺ 。

5-bromo-2, 4, 6-trichloro-smokeSynthesis of alkali aldehyde (A-1-2)

Step 1To 2,4, 6-trichloro-3- (1, 3-dioxan-2-yl) pyridine at-65 DEG C(A-1-1)To a stirred suspension of (4.2 g,15.6 mmol) and TMEDA (5.5 mL,54.7 mmol) in THF (40 mL) was added N-BuLi (31.4 mL,78.5 mmol) and the resulting mixture was taken up in N ₂ Stirred for 1 hour, followed by the addition of 1, 2-dibromotetrafluoroethane (4.1 mL,31.3 mmol). The mixture was stirred at the same temperature for 3 hours. After warming to room temperature, the reaction mixture was saturated with NH ₄ Cl was quenched and extracted with EtOAc (50 mL. Times.3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product, which was purified by flash chromatography on silica gel (etoac=0-10% in PE) to give 3-bromo-2, 4, 6-trichloro-5- (1, 3-dioxan-2-yl) pyridine (4 g, yield: 73.6%) as a white solid. LC/MS (ESI) M/z 348/350 (M+H) ⁺ 。

Step 2:to a stirred suspension of 3-bromo-2, 4, 6-trichloro-5- (1, 3-dioxan-2-yl) pyridine (4.0 g,11.5 mmol) in THF (10 mL) was added 3N HCl (20 mL,60 mmol) and the mixture was stirred overnight at 80 ℃. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (50 ml×3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave a crude product which was purified by silica gel column chromatography (etoac=0 to 10% in PE) to give 5-bromo-2, 4, 6-trichloronicotinaldehyde(A-1-2)(2.4 g, yield: 72%) as a white solid. LC/MS (ESI) M/z 288 (M+H) ⁺ 。

7-bromo-4, 6-dichloro-1H-pyrazolo [4,3-c]Synthesis of pyridine (A-1-3)

To a stirred suspension of 5-bromo-2, 4, 6-trichloronicotinaldehyde (2.4 g,8.3 mmol) in EtOH (20 mL) was added dropwise hydrazine hydrate (10 mL) at 0deg.C and stirred at room temperature for an additional 3 hours. The solvent was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (etoac=0 to 10% in PE, 10% DCM) to give 7-bromo-4, 6-dichloro-1H-pyrazolo [4,3-c]Pyridine (1.0 g, yield: 45.2%) as a white solid. ¹ H NMR(400MHz,DMSO)δ14.51(s,1H),8.53(s,1H)。

7-bromo-4, 6-dichloro-1- (4-methoxybenzyl) -1H-pyrazolo [4,3-c]Pyridine compound(A-1-4a)Is synthesized by (a)

At 0 ℃ at N ₂ To 7-bromo-4, 6-dichloro-1H-pyrazolo [4,3-c ] under atmosphere]Pyridine (1.0 g,3.8 mmol), (4-methoxyphenyl) methanol (0.8 g,5.7 mmol) and PPh ₃ (1.5 g,5.6 mmol) to a stirred solution of DIAD (1.1 mL,5.6 mmol) in THF (20 mL) was added dropwise and the mixture stirred at room temperature overnight. The mixture was then concentrated under reduced pressure to give the crude product which was purified by silica gel column chromatography (etoac=0 to 10% in PE, 10% DCM) to give 7-bromo-4, 6-dichloro-1- (4-methoxybenzyl) -1H-pyrazolo [4,3-c ]Pyridine [ ]A-1-4a) (0.6 g, yield: 41.4%) as a white solid, LC/MS (ESI) M/z 386/388/390 (M+H) ⁺ And 7-bromo-4, 6-dichloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c]Pyridine [ ]A-1-4b) (0.3 g, yield: 13%) as a white solid, LC/MS (ESI) M/z 386/388/390 (M+H) ⁺ 。

Synthesis of key intermediate A-2-4a

Step 1LDA (220 mL,440 mmol) was added dropwise to a solution of 2,4, 6-trichloro-3- (1, 3-dioxan-2-yl) pyridine (A-1-1) (79 g, 254 mmol) in THF (1L) at-80℃and stirred for 1 hour, then the solution was passed into CO ₂ Bubbling for 1 hour (maintaining the internal temperature below-70 ℃). After warming to room temperature, the mixture was quenched with 1N HCl to ph=5, extracted with EtOAc (500 ml x 3), the combined organic phases were washed with water and brine, over anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave crude product 2,4, 6-trichloro-5- (1, 3-dioxan-2-yl) nicotinic acid (a-2-1) (96 g, quantitative) as a yellow solid which was used without further purification. LC/MS (ESI) M/z 312/314 (M+H) ⁺ 。

Step 2To 2,4, 6-trichloro-5- (1, 3-di) at-5 DEG CTo a solution of oxazolidin-2-yl) nicotinic acid (A-2-1) (39 g,124.78 mmol) and DMF (0.5 mL,6.24 mmol) in THF (400 mL) was added oxalyl chloride (13 mL,149.8 mmol) dropwise and the resulting mixture was stirred for 1 hour, then NH was introduced ₃ Bubbling for 1 hour (maintaining internal temperature<0 ℃). The reaction mixture was then warmed to room temperature, the mixture was diluted with EtOAc (400 mL), filtered, and the filtrate concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel (etoac=0% -10% in DCM) to give the desired product 2,4, 6-trichloro-5- (1, 3-dioxan-2-yl) nicotinamide (30 g, yield: 77.2%) as a pale yellow solid. LC/MS (ESI) M/z 311/313 (M+H) ⁺ ， ¹ H NMR(400MHz,DMSO-d ₆ )δ8.21(br,1H),8.06(br,1H),6.12(s,1H),4.19-4.16(m,2H),3.97-3.94(m,2H),2.12-2.08(m,1H),1.48-1.47(m,1H)。

Step 3To a solution of 2,4, 6-trichloro-5- (1, 3-dioxan-2-yl) nicotinamide (30 g,96.3 mmol) in AcOH (400 mL) was added HCl (200 mL,2.4 mol) at 5℃and the reaction mixture was heated to 50℃for 2 hours. The reaction mixture was cooled to room temperature, the mixture was extracted with EtOAc (400 mL. Times.3) and the combined organic phases were taken up in saturated NaHCO ₃ Washed with water and brine, dried over anhydrous Na ₂ SO ₄ Drying, filtration and concentration under vacuum afforded the crude product, which was purified by silica gel column chromatography (etoac=0% -5% in DCM) to give 2,4, 6-trichloro-5-formylnicotinamide (a-2, 20g, yield: 81.9%) as a white solid. LC/MS (ESI) M/z 253/255 (M+H) ⁺ 。

Step 4:at 10 ℃ to NaHCO ₃ To a solution of (13.3 g,157.81 mmol) and 2,4, 6-trichloro-5-formylnicotinamide (A-2, 20g,78.91mmol, 80%) in THF (600 mL) was added dropwise hydrazine hydrate (7.2 mL,118.39 mmol) and the reaction mixture was stirred at the same temperature for an additional 4 hours. The mixture is then treated with saturated NH ₄ Cl was quenched, extracted with EtOAc (100 mL. Times.3), and the combined organic phases were washed with water and brine over anhydrous Na ₂ SO ₄ Drying, filtration and concentration under vacuum afforded the crude product, which was purified by silica gel column chromatography (etoac=0-50% in DCM) to affordTo the desired product 4, 6-dichloro-1H-pyrazolo [4,3-c]Pyridine-7-carboxamide (A-2-3) (12 g, yield: 65.8%) as a yellow solid. LC/MS (ESI) M/z 231/233 (M+H) +. ¹ H NMR(400MHz,DMSO)δ14.28(s,1H),8.44(s,1H),8.27(br,1H),8.09(br,1H)。

Step 5:at room temperature 4, 6-dichloro-1H-pyrazolo [4,3-c]Pyridine-7-carboxamide (6.0 g,25.97 mmol) and Na ₂ CO ₃ To a solution of (8.3 g,77.91 mmol) in DMF (50 mL) was added dropwise PMBCl (5.3 mL,38.95 mmol) and the reaction mixture was heated to 50deg.C for 2 hours. The reaction mixture was then cooled to room temperature and quenched with H ₂ O (100 mL) was diluted, extracted with EtOAc (100 mL. Times.3), the combined organic phases were washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel column chromatography (etoac=0% -50% in DCM) to give the desired product 4, 6-dichloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (A-2-4 a,4.2g, yield: 46.1%) as a yellow solid. LC/MS (ESI) M/z 351/353 (M+H) ⁺ 。1H NMR(400MHz,DMSO)δ9.06(s,1H),8.08(br,1H),7.85(br,1H),7.39(d,J＝8.7Hz,2H),6.93(d,J＝8.7Hz,2H),5.63(s,2H),3.74(s,3H)。

Synthesis of key intermediate B-1-3a

Step 1To a solution of phenylmethanol (99.7 g, 92mmol) in THF (1L) at 0deg.C was added NaH (44.3 g,1.1 mol), the reaction mixture was stirred under nitrogen atmosphere at 0deg.C for 30 minutes, then 4-bromo-2, 6-difluorobenzonitrile (200 g, 92mmol) in THF (1L) was added dropwise thereto, and stirring was continued for 2 hours. The reaction mixture is treated with NH ₄ Aqueous Cl was quenched, extracted with EtOAc (1 l x 2), and the combined organic phases were washed with water and brine, over Na ₂ SO ₄ Drying and concentration in vacuo gave the crude product 2- (benzyloxy) -4-bromo-6-fluorobenzonitrile (220 g, yield: 78.2%) as a white solid. ¹ H NMR(400MHz,DMSO)δ7.55–7.38(m,7H),5.35(s,2H)。

Step 2To a solution of 2- (benzyloxy) -4-bromo-6-fluorobenzonitrile (220 g,721.31 mmol) in DCM (2L) at-78deg.C was added BBr dropwise ₃ (1057 mL,865.57 mmol) and the reaction mixture was stirred at 0deg.C under nitrogen for 2 hours. The reaction mixture was quenched with MeOH and concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (etoac=1% -5% in PE) to give 4-bromo-2-fluoro-6-hydroxybenzenenitrile (B-1, 145g, yield: 93.5%) as a yellow solid. LC/MS (ESI) M/z 215 (M-H) ⁺ 。

Step 3To a solution of 4-bromo-2-fluoro-6-hydroxybenzonitrile (B-1, 145g,674.41 mmol) in DCM (1.5L) was added DIPEA (232 mL,1.35 mmol) followed by drop MOMCl (59.1 g,741.85 mmol) at 0deg.C. The reaction mixture was stirred at 0 ℃ for 2 hours under nitrogen atmosphere. The reaction mixture was extracted with DCM (500 mL. Times.2) and the combined organic phases were taken up in H ₂ Washing with O and brine, passing through anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give 4-bromo-2-fluoro-6- (methoxymethoxy) benzonitrile (160 g, yield: 91.6%) as a yellow solid, which was used in the next step without further purification. LC/MS (ESI) M/z 477 (M-H) ⁺ ,1H NMR(400MHz,DMSO)δ7.55(dd,J＝8.8,1.5Hz,1H),7.45–7.43(m,1H),5.45(s,2H),3.44(s,3H)

Step 4LDA (401.5 mL,803.09mmol,2M in THF) was added dropwise to a solution of 4-bromo-2-fluoro-6- (methoxymethoxy) benzonitrile (160 g,617.76 mmol) in THF (1.6L) at-78deg.C, the mixture was stirred under nitrogen for 2 hours, then DMF (117.3 g,1606.18 mmol) was added to the mixture, and the internal temperature was kept below-70deg.C, and the reaction mixture was stirred at-78deg.C for another 1 hour. The reaction mixture is treated with NH ₄ Aqueous Cl quench, extraction with EtOAc (2L x 2), extraction with H ₂ O and brine, washed with Na ₂ SO ₄ Drying and concentration in vacuo afforded the crude product, which was purified by silica gel column chromatography (etoac=1% -10% in PE) to afford the desired product 4-bromo-2-fluoro-3-formyl-6- (methoxymethoxy) benzylNitrile (B-1, 115g, yield: 65%) was a yellow solid. LC/MS (ESI) M/z 289 (M-H) ⁺ 。

Step 5To a solution of 4-bromo-2-fluoro-3-formyl-6- (methoxymethoxy) benzonitrile (115 g,400.70 mmol) in MeCN (1.5L) at 0deg.C was added dropwise N ₂ H ₄ .H ₂ O (26 g,400.70mmol,80% in H) ₂ O), the mixture was stirred at 0 ℃ for 1 hour, and then the reaction mixture was heated to 90 ℃ for 12 hours. The reaction mixture was extracted with EtOAc (2 l x 2), the combined organic phases were washed with water and brine, and dried over Na ₂ SO ₄ Drying and concentration gave the crude product, which was purified by silica gel column chromatography (meoh=1% -5% in DCM) to give the desired product 4-bromo-6- (methoxymethoxy) -1H-indazole-7-carbonitrile (65 g, yield: 57.7%) as a white solid. LC/MS (ESI) M/z 281 (M+1) +/283 (M+2) +, ¹ H NMR(400MHz,DMSO)δ14.13(s,1H),8.15(d,J＝1.2Hz,1H),7.47(s,1H),5.48(s,2H),3.47(s,3H)。

step 6:to a solution of 4-bromo-6- (methoxymethoxy) -1H-indazole-7-carbonitrile (27 g,96.09 mmol) in DMF (300 mL) was added K ₂ CO ₃ (26.5 g,192.17 mmol) and PMBCl (17.9 g,115.3 mmol) were stirred at 60℃for 2 hours. The reaction mixture was extracted with EtOAc (500 ml x 2), washed with water and brine, and dried over Na ₂ SO ₄ The crude product was purified by silica gel column chromatography (etoac=1% to 10% in PE) to give 4-bromo-1- (4-methoxybenzyl) -6- (methoxymethoxy) -1H-indazole-7-carbonitrile B-1-3a (12 g, yield: 30%) and 4-bromo-2- (4-methoxybenzyl) -6- (methoxymethoxy) -2H-indazole-7-carbonitrile B-1-3B (21.6 g, yield: 64%) as yellow solids. LC/MS (ESI) M/z 241 (M+H) ⁺

Synthesis of key intermediate 4-bromo-6-hydroxy-2- (4-methoxybenzyl) -2H-indazole-7-carbonitrile (B-1-3 d)

To 4-bromo-2- (4-methoxybenzyl)) To a solution of 6- (methoxymethoxy) -2H-indazole-7-carbonitrile (400 mg,0.99 mmol) in THF (2 mL) was added HCl (2 mL,2 mmol/mL) and the reaction mixture was stirred at 55deg.C for 2 hours. The mixture is treated with H ₂ O (10 mL) was diluted, extracted with EtOAc (10 mL. Times.2), the combined organic phases were washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product 4-bromo-6-hydroxy-2- (4-methoxybenzyl) -2H-indazole-7-carbonitrile (300 mg, 84.9%) as a white solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z 358[ M+1 ]] ⁺

Synthesis of key intermediate B-1-6

Step 1To a stirred solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate (5.0 g,20.4 mmol) and K2CO3 (4.0 g,28.9 mmol) in DMF (30 mL) was slowly added MeI (3.6 g,25.352 mmol) and the reaction mixture was stirred at 60℃for 18 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL. Times.3). The combined organic phases were washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=1% to 10% in PE) to give methyl 5-bromo-2-methoxy-4-methylbenzoate (5.0 g, yield: 94.59%) as a white solid. LC/MS (ESI) M/z 260 (M+H) +.1H NMR (400 MHz, CDCl 3) delta 7.97 (s, 1H), 6.84 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 2.42 (s, 3H).

Step 2H stirring at 0 DEG C ₂ SO ₄ To (30 mL) was added in portions 5-bromo-2-methoxy-4-methylbenzoic acid methyl ester (5.0 g,19.2 mmol). After the solution is clarified, HNO is added dropwise over 30 minutes ₃ (1.25 mL,19.2 mmol) and the mixture was stirred at 0deg.C for an additional 1 hour. The reaction mixture was treated with saturated NaHCO ₃ (200 mL) was diluted and extracted with EtOAc (100 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=0 to 10% in PE) to give methyl 5-bromo-2-methoxy-4-methyl-3-nitrobenzoate (5.2 g, yield: 88.6%) as a pale oil. LC/MS (ESI) M/z 305 (M+H) ⁺ 。1H NMR(400MHz,CDCl ₃ )δ8.16(s,1H),3.93(s,3H),3.91(s,3H),2.35(s,3H)。

Step 3To a stirred solution of 5-bromo-2-methoxy-4-methyl-3-nitrobenzoic acid methyl ester (2 g,6.5 mmol) and iron powder (2 g,35.7 mmol) in EtOH (20 mL) was added HCl (0.2 mL,2.400 mmol) at 25℃and then heated to 80℃and stirred for 18 h. The reaction mixture was cooled to room temperature and filtered, the filtrate was diluted with water (20 mL), the mixture was extracted with EtOAc (30 mL x 3), the combined organic phases were washed with water and brine, over anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=2% -50% in PE) to give methyl 3-amino-5-bromo-2-methoxy-4-methylbenzoate (560 mg, yield: 31.0%) as a yellow solid. LC/MS (ESI) M/z 275 (M+H) ⁺ 。1H NMR(400MHz,CDCl ₃ )δ7.48(s,1H),4.05(s,2H),3.90(s,3H),3.83(s,3H),2.30(s,3H)。

Step 43-amino-5-bromo-2-methoxy-4-methylbenzoic acid methyl ester (300 mg,1.0 mmol) in HBF ₄ To the stirred solution in (2 mL,31.4 mmol) was added dropwise NaNO ₂ (75 mg,1.0mmol in 1mL of water). The reaction mixture was stirred at 10℃for 30 minutes, and a precipitate formed. The cooled reaction mixture was filtered and the solid product was successively purified with small amounts of H ₂ O, meOH and Et ₂ O was washed and dried under high vacuum to give 400mg of diazonium salt as a yellow solid. In another dry flask, 18-crown-6 (289 mg,1.0 mmol) and AcOK (200 mg,2.0 mmol) were pre-dried under high vacuum for 1 hour and CHCl was added ₃ (50 mL). The suspension was stirred at room temperature for 10 minutes. The diazonium salt is then taken a small number of times in N ₂ Adding into the mixed solution under the atmosphere. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL. Times.3). Will be combinedThe combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product which was purified by silica gel column chromatography (etoac=2% -25% in PE) to give 4-bromo-7-methoxy-1H-indazole-6-carboxylic acid methyl ester ((B-1-6, 180mg, yield: 57.7%) as a yellow solid LC/MS (ESI) M/z:285 (m+h) ⁺ 287(M+H+2) ⁺ 。1H NMR(400MHz,CDCl ₃ )δ8.10(s,1H),7.76(s,1H),4.08(s,3H),3.97(s,3H)。

Preparation of boric acid intermediates

N- { [ 3-chloro-4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] methyl } -5-fluoro-2-methoxybenzamide (intermediate A)

Step 1To a solution of sodium hydride (417 mg,10.44 mmol) in dry DMF (10 mL) at 0deg.C was added N- [ (tert-butoxy) carbonyl in portions]Tert-butyl carbamate (7516 mg,3.48 mmol) the resulting mixture was stirred at 0deg.C for 1 hour, followed by the addition of 1-bromo-4- (bromomethyl) -2-chlorobenzene (900 mg,3.17 mmol) and the reaction mixture was stirred at the same temperature for 2 hours. The mixture is then treated with cold saturated NH ₄ Cl quench, extract with EtOAc (40 mL. Times.3), wash with water and brine, over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give N- [ (4-bromo-3-chlorophenyl) methyl]-N- [ (tert-butoxy) carbonyl group]Tert-butyl carbamate (1.6 g, 100%) was used as a white solid without further purification. LC/MS (ESI) M/z 420/422 (M+H) ⁺ 。

Step 2:at 0℃to N- [ (4-bromo-3-chlorophenyl) methyl group]-N- [ (tert-butoxy) carbonyl group]To a solution of tert-butyl carbamate (1.6 g,3.8 mmol) in EtOAc (10 mL) was added HCl (10 mL,4mol/L in 1, 4-dioxane) and the reaction mixture was stirred at room temperature for 2 hours. Then concentrated under reduced pressure to give the crude product (4-bromo-3-chlorophenyl) methylamine hydrochloride (0.7 g, yield: 83.3%) as a yellow solid, which was not fed in The one-step purified was used directly in the next step. LC/MS (ESI) M/z 220/222 (M+H) ⁺ 。

Step 3:to a solution of (4-bromo-3-chlorophenyl) methylamine hydrochloride (0.7 g,3.18 mmol), 5-fluoro-2-methoxybenzoic acid (0.65 g,3.81 mmol) and HATU (1.69 g,4.44 mmol) in DMF (5 mL) was added TEA (1.32 mL,9.52 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture is then treated with H ₂ O (20 mL) was diluted and extracted with EtOAc (30 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give a residue which is purified by silica gel column chromatography (etoac=0% -20% in PE) to give the desired product N- [ (4-bromo-3-chlorophenyl) methyl]-5-fluoro-2-methoxybenzamide (0.8 g, yield: 67.63%) as a white solid. LC/MS (ESI) M/z 372/374 (M+H) ⁺ 。

Step 4To N- [ (4-bromo-3-chlorophenyl) methyl]To a solution of 5-fluoro-2-methoxybenzamide (0.8 g,2.15 mmol) and 4, 5-tetramethyl-2- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (0.82 g,3.22 mmol) in 1, 4-dioxane (20 mL) was added Pd (dppf) Cl ₂ (0.16 g,0.22 mmol) and KOAc (0.42 g,4.29 mmol). The obtained mixed solution is added with N ₂ Heated to 110 ℃ for 12 hours under atmosphere. After cooling to room temperature, the mixture was treated with H ₂ O (10 mL) was diluted, extracted with EtOAc (20 mL. Times.3), the combined organic phases were washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel column chromatography (etoac=0% -20% in PE) to give the desired product N- { [ 3-chloro-4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Methyl } -5-fluoro-2-methoxybenzamide (720 mg, yield: 79.91%) was a pale yellow solid.

Intermediate B:5-fluoro-2- (methoxy-d 3) -N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide

Step 1:4-Bromobenzoic acid (2.0 g,10 mmol) in SOCl ₂ Solution in (10 mL) N ₂ Heated to 85 ℃ for 2 hours under atmosphere. The reaction mixture was then cooled to room temperature, and the solvent was removed under vacuum to give 4-bromobenzoyl chloride (2.2 g, yield: 100%) as a crude product, which was used directly in the next step without purification.

Step 2To a solution of 4-bromo-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (2.2 g,10 mmol) in pyridine (10 mL) was added 4- (trifluoromethyl) pyridin-2-amine (1.6 g,10 mmol). The obtained mixture was subjected to N at 65 DEG C ₂ Stir overnight under an atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product, which was purified by silica gel column chromatography (meoh=0% -3% in DCM) to give the desired product 4-bromo-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (2.7 g, yield: 78.5%) as a white solid. LC/MS (ESI) M/z 345 (M+H) ⁺ 。

Step 3To a stirred solution of 4-bromo-N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (2.7 g,7.85 mmol) and 4,4', 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (3.0 g,11.76 mmol) in dioxane (10 mL) was added KOAc (1.5 g,15.7 mmol) and Pd (dppf) Cl ₂ (0.6 g,0.78 mmol). The obtained mixed solution is added with N ₂ Heated to 110 ℃ for 12 hours under atmosphere. After cooling to room temperature, the mixture was treated with H ₂ O (10 mL) was diluted, extracted with EtOAc (20 mL. Times.3), the combined organic phases were washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=2% -30% in PE) to give 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -N- (4- (trifluoromethyl) pyridin-2-yl) benzamide (2.8 g, yield: 91%) as a white solid. LC/MS (ESI) M/z 393 (M+H) ⁺ 。

Intermediate C:5-fluoro-2- (methoxy-d 3) -N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide

Step 1To a solution of N- (4-bromobenzyl) -5-fluoro-2-methoxybenzamide (2.7 g,8.01 mmol) in DCM (30 mL) at-50deg.C was added BBr over 30 min ₃ (16 mL,16mmol,1M in DCM). The reaction mixture was then stirred at this temperature for 2 hours, quenched with NH4Cl (30 mL), extracted with DCM (30 mL. Times.3), and the combined organic phases were washed with water and brine over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (meoh=0% -3% in DCM) to give the desired product N- (4-bromobenzyl) -5-fluoro-2-hydroxybenzoamide (2.5 g, yield: 96.6%) as a white solid. LC/MS (ESI) M/z 324 (M+H) ⁺ 。

Step 2 to a solution of N- (4-bromobenzyl) -5-fluoro-2-hydroxybenzoamide (2.5 g,7.74 mmol) in MeCN (20 mL) was added K ₂ CO ₃ (1.6 g,11.61 mmol) and CD ₃ I (1.4 g,9.30 mmol). The obtained mixture was then cooled to room temperature under N ₂ Stirring is carried out for 3 hours under an atmosphere. The mixture is treated with H ₂ O (20 mL) was diluted, extracted with EtOAc (20 mL. Times.3), the combined organic phases were washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (meoh=0% -3% in DCM) to give the desired product N- (4-bromobenzyl) -5-fluoro-2- (methoxy-d 3) benzamide (0.8 g, yield: 30.4%) as a white solid. LC/MS (ESI) M/z 341 (M+H) ⁺ 。

Step 3To a stirred solution of N- (4-bromobenzyl) -5-fluoro-2- (methoxy-d 3) benzamide (800 mg,2.35 mmol) and 4,4', 5' -octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (716 mg,2.82 mmol) in dioxane (10 mL) was added AcOK (4631 mg,4.70 mmol) and Pd (d)ppf)Cl ₂ (172 mg,0.24 mmol). The obtained mixed solution is added with N ₂ Heated to 100 ℃ for 12 hours under atmosphere. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL. Times.3), the combined organic phases were washed with water and brine, over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=2% -100% in PE) to give 5-fluoro-2- (methoxy-d 3) -N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide (900 mg, yield: 98.8%) as a white solid. LC/MS (ESI) M/z 389 (M+H) ⁺ 。

Intermediate HTert-butyldiphenyl (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopent-3-enyloxy) silane

Step 1TBDPSCl (25.4 g,92.84 mmol) was added to a solution of cyclopent-3-enol (7.1 g,84.4 mmol) and imidazole (11.5 g,168.8 mmol) in DMF (70 mL) at 0deg.C, and the resulting mixture was stirred at 0deg.C for 2 hours. The mixture is treated with H ₂ O (300 mL) was diluted, extracted with EtOAc (100 mL. Times.3), and the organic layer was then washed with water and brine and the collected organic layer was taken up over Na ₂ SO ₄ Dried and concentrated to give a crude product, which was purified by silica gel column chromatography (pe=100%) to give tert-butyl (cyclopent-3-enyloxy) diphenylsilane (27.2 g, yield: 99.9%) as a colorless oil.

Step 2At room temperature at N ₂ Down tert-butyl (cyclopent-3-enyloxy) diphenylsilane (27.2 g,84.33 mmol) in CCl ₄ Br was added to the solution in (270 mL) ₂ (4.3 mL,84.33 mmol). The mixture was stirred for 3 hours until the starting material was completely consumed. The mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (pe=100%) to obtain tert-butyl (3, 4-dibromocyclopentyloxy) diphenylsilane (33 g, yield: 80.9%) as a colorless oil.

Step 3:to a stirred solution of tert-butyl (3, 4-dibromocyclopentyloxy) diphenylsilane (8 g,17.16 mmol) in THF (100 mL) at 0deg.C was slowly added t-BuOK (9 g,80.37 mmol) and the reaction mixture was stirred at 25deg.C for 18 hours. The reaction mixture was diluted with water (200 mL) at 0 ℃, the mixture was extracted with EtOAc (200 mL x 3), the combined organic phases were washed with water and brine, and the organic phase was dried over anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=5% in PE) to give (3-bromocyclopent-3-enyloxy) (tert-butyl) diphenylsilane (3 g, yield: 45.4%) as a colorless oil.

Step 4Pd (dppf) Cl was slowly added to a stirred solution of (3-bromocyclopent-3-enyloxy) (tert-butyl) diphenylsilane (3 g,7.5 mmol) and 4, 5-tetramethyl-2- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (1.8 g,7.8 mmol) in 1, 4-dioxane (30 mL) at 25 ℃ ₂ (200 mg,0.27 mmol). The obtained mixed solution is added with N ₂ Heated to 100 ℃ for 12 hours under atmosphere. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 ml×3), the combined organic phases were washed with water and brine, over anhydrous Na ₂ SO ₄ Drying, filtration and concentration under vacuum afforded the crude product, which was purified by silica gel column chromatography (etoac=0% -30% in PE) to afford tert-butyldiphenyl (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopent-3-enyloxy) silane (2 g, yield: 59.7%) as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.66(dt,J＝8.0,1.8Hz,4H),7.38(ddd,J＝18.0,9.8,4.7Hz,6H),6.45–6.37(m,1H),4.56(dq,J＝6.4,4.8Hz,1H),2.70–2.44(m,4H),1.26(s,12H),1.04(s,9H)。

Intermediate I:

synthesis of 4, 5-tetramethyl-2- (2-methyl-4, 5-dihydrofuran-3-yl) -1,3, 2-dioxaborolan

Step 1LDA (18.0 mL,36.0 mmol) was added dropwise to a solution of 2-methyloxypentan-3-one (3 g,29.96 mmol) in THF (40 mL) at-78deg.C, the resulting mixture was stirred at-78deg.C under nitrogen for 1 hour, followed by 1, 1-trifluoro-N-phenyl-N-trifluoromethylsulfonyl methanesulfonamide (10.70 g,29.964mmol in THF (10 mL) and the reaction mixture was stirred at-78deg.C for another 1 hour. The mixture was poured into ice-cold NH ₄ Aqueous Cl (20 mL) was extracted with EtOAc (30 mL. Times.3). The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product which was purified by silica gel column chromatography (etoac=1% to 5% in petroleum) to give the desired product 2-methyl-4, 5-dihydrofuran-3-yl triflate (700 mg, yield: 10%) as a yellow oil which was used directly in the next step without further purification. LC/MS (ESI) m/z 233[ M+1 ] ] ⁺

Step 2KOAc (591 mg,6.0 mmol) and Pd (dppf) Cl2 (110 mg,0.15 mmol) were added to a solution of 2-methyl-4, 5-dihydrofuran-3-yl triflate (700 mg,3.0 mmol) and 4, 5-tetramethyl-2- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (766 mg,3.0 mmol) in dioxane (10 mL) and the reaction mixture was stirred at 85℃under nitrogen for 3 hours. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=1% to 5% in petroleum) to give the desired product 4, 5-tetramethyl-2- (2-methyl-4, 5-dihydrofuran-3-yl) -1,3, 2-dioxaborolan (400 mg, yield: 63.1%) as a colorless oil. LC/MS (ESI) m/z 211[ M+1 ]] ⁺

Intermediate K:

synthesis of 2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopent-2-enone

Step 11, 3-DiPEA (1.8 mL,10.83 mmol) in Et to 2-methylcyclopentane-1, 3-dione (0.93 mL,8.92 mmol) at-78deg.C ₂ To the stirred solution in O (30 mL) was slowly added Tf ₂ O (1.6 mL,10 mmol) and the reaction mixture was stirred at-78deg.C under nitrogen for 1.5 h. The reaction mixture was diluted with water (40 mL), the mixture was extracted with EtOAc (60 mL x 3), the combined organic phases were washed with water and brine, and the organic phases were washed with anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave a crude product, which was purified by silica gel column chromatography (pe=0% to 10% in DCM) to give 2-methyl-3-oxocyclopent-1-enyl triflate (1.5 g, yield: 69%) as a colorless oil. LC/MS (ESI) m/z 245[ M+1 ]]+,1H NMR(400MHz,CDCl ₃ )δ2.92(m,2H),2.71–2.60(m,2H),1.79(m,3H)。

Step 2To a stirred solution of 2-methyl-3-oxocyclopent-1-enyl triflate (500 mg,2.048 mmol) and 4, 5-tetramethyl-2- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (0.61 mL,2.36 mmol) in 1, 4-dioxane (10 mL) was slowly added Pd (dppf) Cl at 25 ℃ ₂ (100 mg,0.14 mmol) and KOAc (500 mg,5.09 mmol), and the reaction mixture was stirred at 100℃under nitrogen for 2 hours. The reaction mixture was diluted with water (40 mL), the mixture was extracted with EtOAc (60 mL x 3), the combined organic phases were washed with water and brine, and the organic phases were washed with anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was purified by silica gel column chromatography (pe=0% to 50% in DCM) to give 2-methyl-3- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopent-2-en-1-one (300 mg, yield: 66%) as a colorless oil. LC/MS (ESI) m/z 223[ M+1 ] ] ⁺ , ¹ H NMR(400MHz,CDCl ₃ )δ2.65–2.58(m,2H),2.33(dd,J＝8.6,4.1Hz,2H),1.97–1.91(m,3H),1.31(d,J＝3.3Hz,12H)。

Intermediate L:

synthesis of tert-butyl 5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-pyrrole-1-carboxylate

Step 1In N ₂ To a solution of alanine methyl ester (14.0 g,135.92 mmol) and ethyl acrylate (27.2 g,271.84 mmol) in EtOH (200 mL) was added TEA (27.5 g,271.84 mmol). The reaction mixture was warmed to room temperature overnight. The reaction mixture was diluted with EtOAc (300 mL). The mixture was washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product which was purified by silica gel column chromatography (etoac=10% -20% in PE) to give the desired product ethyl 3- ((1-methoxy-1-oxopropan-2-yl) amino) propionate (11.0 g, yield: 39.87%) as an off-white oil. LC/MS (ESI) M/z 204 (M+H) ⁺

Step 2In N ₂ Boc was added to a solution of ethyl 3- ((1-methoxy-1-oxopropan-2-yl) amino) propionate (11.0 g,54.19 mmol) in DCM (200 mL) ₂ O (23.6 g,108.38 mmol) and TEA (20.2 g,200 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (100 mL). The mixture was washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=10% -20% in PE) to give the desired product ethyl 3- ((tert-butoxycarbonyl) (1-methoxy-1-oxopropan-2-yl) amino) propionate (15.0 g, yield: 91.5%) as an off-white oil. LC/MS (ESI) M/z 304 (M+H) ⁺

Step 3In N ₂ To a solution of ethyl 3- ((tert-butoxycarbonyl) (1-methoxy-1-oxopropan-2-yl) amino) propionate (15.0 g,49.50 mmol) in toluene (150 mL) was added t-BuOK (11.1 g,99 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (150 mL). The mixture was washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtering, and concentrating to obtain crude product, and purifying by silica gel column chromatography(etoac=10% -40% in PE) to give the desired mixture of 5-methyl-4-oxopyrrolidine-1, 3-dicarboxylic acid 1- (tert-butyl) ester 3-ethyl ester and 2-methyl-3-oxopyrrolidine-1, 2-dicarboxylic acid 1- (tert-butyl) ester 2-methyl ester (9.0 g, yield: 70.75%) as an off-white oil. LC/MS (ESI) M/z 258 and 272 (M+H) ⁺

Step 4:to a solution of 1- (tert-butyl) ethyl 5-methyl-4-oxopyrrolidine-1, 3-dicarboxylic acid 1- (tert-butyl) ester and 2-methyl-3-oxopyrrolidine-1, 2-dicarboxylic acid 1- (tert-butyl) ester 2-methyl ester (9.0 g,35.02 mmol) in EtOH (20 mL) was added concentrated HCl (4 mL). The mixture was stirred in a sealed tank at 90℃for 1 hour. After cooling to room temperature, it was diluted with DCM (150 mL). The mixture was washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was used without purification to give the desired 2-methylpyrrolidin-3-one (3.45 g, yield: 100%) as an off-white oil. LC/MS (ESI) M/z 100 (M+H) ⁺

Step 5In N ₂ Boc was added to a solution of 2-methylpyrrolidin-3-one (3.45 g,34.85 mmol) in DCM (20 mL) ₂ O (15.2 g,69.7 mmol) and DIPEA (7 g,69.7 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (100 mL). The mixture was washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product which was purified by silica gel column chromatography (etoac=5% -30% in PE) to give the desired product tert-butyl 2-methyl-3-oxopyrrolidine-1-carboxylate (6.5 g, yield: 93.26%) as an off-white oil. LC/MS (ESI) M/z 200 (M+H) ⁺

Step 6In N ₂ To a solution of tert-butyl 2-methyl-3-oxopyrrolidine-1-carboxylate (3.0 g,15.08 mmol) in THF (20 mL) was added LiHMDS (15.08 mL,2.0mmol/mL,30.16 mmol). The reaction mixture was stirred at-78 ℃ for 1 hour. Then add Tf ₂ O (5.10 g,18.10 mmol) and stirred for a further 2 hours at-78 ℃. The reaction mixture was diluted with DCM (100 mL). The mixture was washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product which was purified by silica gel column chromatography (etoac=5% -30% in PE) to give the desired product tert-butyl 5-methyl-4- (((trifluoromethyl) sulfonyl) oxy) -2, 3-dihydro-1H-pyrrole-1-carboxylate (1.9 g, yield: 38.06%) as an off-white oil. LC/MS (ESI) M/z 332 (M+H) ⁺

Step 7In N ₂ Pd (dppf) Cl was added to a solution of tert-butyl 5-methyl-4- (((trifluoromethyl) sulfonyl) oxy) -2, 3-dihydro-1H-pyrrole-1-carboxylate (1.9 g,5.74 mmol) in dioxane (20 mL) ₂ (0.42 g,0.57 mmol), 4', 5',5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (2.2 g,8.61 mmol) and AcOK (1.1 g,11.48 nnol). The reaction mixture was stirred at 90℃for 3 hours. The reaction mixture was diluted with DCM (100 mL). The mixture was washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product which was purified by silica gel column chromatography (etoac=5% -30% in PE) to give the desired product tert-butyl 5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-pyrrole-1-carboxylate (1.3 g, yield: 73.30%) as an off-white oil. LC/MS (ESI) M/z 310 (M+H) ⁺

Intermediate M3-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) pyridine

Step 1To a solution of 2- (trifluoromethyl) pyridin-4-amine (3 g,18.51 mmol) in MeCN (50 mL) at 0deg.C was added NBS (8.23 g,46.27 mmol) in portions, the resulting mixture was warmed to room temperature and stirred overnight. The mixture is then treated with H ₂ O (50 mL) was diluted, extracted with EtOAc (50 mL. Times.3), washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Drying, filtration and concentration under vacuum afforded the crude product, which was purified by silica gel column chromatography (etoac=0-10% in PE) to afford3, 5-dibromo-2- (trifluoromethyl) pyridin-4-amine (3 g, yield: 50.7%) was a yellow oil. LC/MS: M/z:319/321/323 (M+H) ⁺ 。1H NMR(400MHz,CDCl ₃ )δ8.37(s,1H),5.46(s,2H)。

Step 2Pd/C (10%, 133mg,0.13 mmol) was added to a solution of 3, 5-dibromo-2- (trifluoromethyl) pyridin-4-amine (800 mg,2.50 mmol) in EtOH (20 mL). The mixture was stirred at room temperature for 3 hours. The mixture was then filtered through a pad of celite and the filtrate concentrated in vacuo to give the crude product which was purified by flash chromatography on silica gel (etoac=0 to 50% in PE) to give 3-bromo-2- (trifluoromethyl) pyridin-4-amine (400 mg, yield: 66.4%) as a yellow solid. LC/MS: M/z:241/243 (M+H) ⁺ 。1H NMR(400MHz,DMSO-d ₆ )δ8.07(d,J＝5.6Hz,1H),6.94(d,J＝5.6Hz,1H),5.75(br,2H)。

Step 3To 3-bromo-2- (trifluoromethyl) pyridin-4-amine (400 mg,1.66 mmol) and trimethyl-1,3,5,2,4,6-trioxadiborane (0.95 mL,3.32mmol,3.5M in THF) in 1, 4-dioxane (8 mL) and H ₂ K was added to the mixture of O (2 mL) ₂ CO ₃ (459 mg,3.32 mmol) and Pd (dppf) Cl ₂ (121 mg,0.17 mmol). The obtained mixed solution is added with N ₂ Heated to 80 ℃ for 12 hours under atmosphere. After cooling to room temperature, the mixture was treated with H ₂ O (10 mL) was diluted, extracted with EtOAc (10 mL. Times.3), washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=0-50% in PE) to give 3-methyl-2- (trifluoromethyl) pyridin-4-amine (200 mg, yield: 68.4%) as a yellow solid. LC/MS: M/z:177 (M+H) ⁺ 。

Step 4To a mixture of 3-methyl-2- (trifluoromethyl) pyridin-4-amine (200 mg,1.14 mmol) in MeCN (10 mL) was added tert-butyl nitrite (0.27 mL,2.27 mmol) and CuBr ₂ (803 mg,2.27 mmol). The obtained mixed solution is added with N ₂ Heated to 80 ℃ for 12 hours under atmosphere. After cooling to room temperature, the mixture was treated with H ₂ O (10 mL) was diluted, extracted with EtOAc (10 mL. Times.3), washed with water and brine, and dried Water Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=0 to 5% in PE) to give 4-bromo-3-methyl-2- (trifluoromethyl) pyridine (80 mg, yield: 29.4%) as a yellow oil. LC/MS: M/z:240/242 (M+H) ⁺ 。

Step 5To a mixture of 4-bromo-3-methyl-2- (trifluoromethyl) pyridine (80 mg,0.33 mmol) and 4, 5-tetramethyl-2- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (127 mg,0.50 mmol) in 1, 4-dioxane (10 mL) was added KOAc (65 mg,0.67 mmol) and Pd (dppf) Cl ₂ (24 mg,0.03 mmol). Heating the obtained mixture to 100deg.C, and adding N ₂ Stir overnight under an atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo to give [ 3-methyl-2- (trifluoromethyl) pyridin-4-yl ]]Boric acid (80 mg, yield: 117.2%) was brown oil, which was used directly in the next step without further purification. LC/MS: M/z:206 (M+H) ⁺ 。

Intermediate N, 6-dimethylpyrimidin-5-ylboronic acid

To a solution of 5-bromo-4, 6-dimethylpyrimidine (500 mg,2.67 mmol) in THF (10 mL) was added n-BuLi (1.6 mL,1.6 mmol/mL) dropwise at-78deg.C and stirred under nitrogen for 1 hour at-78deg.C followed by addition of B (OMe) ₃ (780 mg,5.34mmol in 5ml THF) and the reaction mixture was stirred at-78deg.C for 1 hour. The mixture was poured into ice-cold NH ₄ Aqueous Cl (20 mL) was extracted with EtOAc (20 mL. Times.3). The organic phase was treated with anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (meoh=2% -5% in DCM) to give (4, 6-dimethylpyrimidin-5-yl) boronic acid (8 mg, yield: 1.97%) as a yellow solid. LC/MS (ESI) m/z 153[ M+1 ]]+

Table 1. Preparation of borate intermediates. The borates D-G were prepared by a process analogous to intermediate A, B, C; intermediate J was prepared by a procedure analogous to intermediate I, intermediate O-U was prepared by a procedure analogous to intermediate K-N (with variations), starting from commercially available starting materials

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Example 1:

4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-pyrazolo [4,3-c ] pyridine-7-carboxamide (BNB-1049-01)

Step 1To 7-bromo-4, 6-dichloro-1- (4-methoxybenzyl) -1H-pyrazolo [4,3-c]Pyridine (2.2 g,5.7 mmol), 2- (cyclopent-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (1.1 g,5.7 mmol) and Na ₂ CO ₃ (1.2 g, 11.4 mmol) in dioxane (20.0 mL) and H ₂ Pd (PPh) was added to a solution in O (4.0 mL) ₃ ) ₄ (330 mg,0.3 mmol) and the mixture was heated to 60℃under N ₂ Stirring is carried out for 10 hours under an atmosphere. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel column chromatography (etoac=2% -10% in PE) to give the desired product 7-bromo-6-chloro-4- (cyclopent-1-en-1-yl) -1- (4-methoxybenzyl) -1H-pyrazolo [4,3-c]Pyridine (1.1 g, yield: 46.2%) as a white solid. LC/MS (ESI) m/z 418/420[ M+H ]]+, ¹ H NMR(400MHz,CDCl ₃ )δ8.27(s,1H),7.13(d,J＝8.7Hz,2H),6.85–6.79(m,3H),5.94(d,J＝5.7Hz,2H),3.77(s,3H),3.06–2.87(m,2H),2.64(m,2H),2.13–2.03(m,2H)。

Step 2:to 7-bromo-6-chloro-4-cyclopentenyl-1- (4-methoxybenzyl) -1H-pyrazolo [4,3-c]A solution of pyridine (0.3 g,0.7 mmol) in MeOH (5 mL)Pd (dppf) Cl is added into ₂ (52.4 mg,0.1 mmol) and TEA (0.3 mL,2.2 mmol). The resulting mixture was stirred in a sealed tank at 85℃under CO (70 psi) overnight. After cooling to room temperature, the solvent was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (etoac=0 to 50% in DCM) to give 6-chloro-4- (cyclopent-1-en-1-yl) -1- [ (4-methoxy-phenyl) methyl]-1H-pyrazolo [4,3-c]Pyridine-7-carboxylic acid methyl ester (240 mg, yield: 84.2%) as a yellow solid. LC/MS (ESI) M/z 398 (M+H) ⁺ 。

Step 3:to 6-chloro-4- (cyclopent-1-en-1-yl) -1- [ (4-methoxyphenyl) -methyl]-1H-pyrazolo [4,3-c]Pyridine-7-carboxylic acid methyl ester (240 mg,0.6 mmol) in dioxane (8 mL) and H ₂ To a solution in O (2 mL) was added 2- (2-methoxyphenyl) -N- { [4- (4, 5-tetramethyl-1, 3-dioxan-2-yl) phenyl]Methyl } acetamide (231 mg,0.6 mmol), pd (dppf) Cl ₂ (52 mg,0.1 mmol) and K ₂ CO ₃ (250 mg,1.8 mmol). Then the obtained mixed solution is heated to 100 ℃ and N is the same as ₂ Stirring is carried out for 2 hours under an atmosphere. After cooling to room temperature, water (5 mL) was added and extracted with EtOAc (10×3 mL). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product which was purified by silica gel column chromatography (etoac=0-15% in DCM) to give 4- (cyclopent-1-en-1-yl) -6- (4- { [ (2-methoxyphenyl) carboxamido)]Methyl } phenyl) -1- [ (4-methoxyphenyl) methyl]-1H-pyrazolo [4,3-c]Pyridine-7-carboxylic acid methyl ester (260 mg, yield: 71.5%) as yellow solid. LC/MS (ESI) M/z 603 (M+H) ⁺ 。

Step 4:to 4- (cyclopent-1-en-1-yl) -6- (4- { [ (2-methoxyphenyl) -carboxamido)]Methyl } phenyl) -1- [ (4-methoxyphenyl) methyl]-1H-pyrazolo [4,3-c]To a solution of methyl pyridine-7-carboxylate (260 mg,0.4 mmol) in MeOH (5 mL) was added Pd/C (61 mg,20%, wet) and two drops of formic acid. The obtained mixed solution is treated with H at 60 DEG C ₂ Stirred under balloon for 2 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give the crude product which was purified by silica gel column chromatography (etoac=0-20% in DCM) to give the desired product 4-cyclopentyl-6- (4- ((2-methyl) Oxybenzoylamino) methyl) phenyl) -1- (4-methoxybenzyl) -1H-pyrazolo [4,3-c]Pyridine-7-carboxylic acid methyl ester (200 mg, yield: 76.7%) as a yellow solid. LC/MS (ESI) M/z 605 (M+H) ⁺ 。

Step 5:to 4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1- (4-methoxybenzyl) -1H-pyrazolo [4,3-c]To a solution of methyl pyridine-7-carboxylate (250 mg,0.4 mmol) in DCM (5 mL) was added TFA (5 mL). The resulting mixture was stirred at 40℃for 1 hour. After cooling to room temperature, the reaction mixture was diluted with DCM (20 mL) and saturated NaHCO ₃ The solution was pH adjusted. The organic phase was treated with anhydrous Na ₂ SO ₄ Dried and concentrated to give the crude product which was purified by silica gel column chromatography (etoac=0 to 50% in DCM) to give 4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-pyrazolo [4,3-c]Pyridine-7-carboxylic acid methyl ester (100 mg, yield: 49.9%) was a yellow solid. LC/MS (ESI) M/z 485 (M+H) ⁺ 。

Step 6:to 4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-pyrazolo [4,3-c]To a solution of methyl pyridine-7-carboxylate (100 mg,0.2 mmol) in THF (5 mL) was added ammonia (28% in water). The mixture was stirred in a sealed pot at 100℃for 6 hours. After cooling to room temperature, the reaction mixture was concentrated to give the crude product, which was purified by preparative-TLC (DCM: meoh=15:1) to give the desired product 4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-pyrazolo [4,3-c ]Pyridine-7-carboxamide (3 mg, yield: 3.1%) as a pale yellow solid. ¹ H NMR(400MHz,MeOD)δ8.34(s,1H),7.91(dd,J＝7.7,1.8Hz,1H),7.76(d,J＝8.3Hz,2H),7.50(ddd,J＝16.0,8.9,5.1Hz,3H),7.16(d,J＝8.3Hz,1H),7.10–7.04(m,1H),4.69(s,2H),4.58(s,2H),3.97(s,3H),3.76–3.70(m,1H),2.20–2.05(m,4H),1.98–1.89(m,2H),1.81(m,2H)；LC/MS(ESI)m/z:470(M+H) ⁺ 。

Example 2:

6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (4-hydroxycyclohexyl) -1H-pyrazolo [4,3-c ] pyridine-7-carboxamide (BNB-1055-01)

Step 1To 7-bromo-4, 6-dichloro-1- (4-methoxybenzyl) -1H-pyrazolo [4,3-c]Pyridine (560 mg,1.45 mmol), 4, 5-tetramethyl-2- (1, 4-dioxaspiro [ 4.5)]Dec-7-en-8-yl) -1,3, 2-dioxaborolan (365 mg,1.37 mmol) and Na ₂ CO ₃ (460 mg,4.34 mmol) in dioxane (10 mL) and H ₂ Pd (PPh) was added to a solution in O (2.0 mL) ₃ ) ₄ (83 mg,0.01 mmol) and the mixture was taken up in N ₂ Stirring is carried out for 10 hours at 60℃under an atmosphere. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel column chromatography (etoac=2% -10% in PE) to give the desired product 7-bromo-6-chloro-1- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [ 4.5)]Dec-7-en-8-yl) -1H-pyrazolo [4,3-c]Pyridine (510 mg, yield: 72%) as a white solid. ¹ H NMR(400MHz,DMSO)δ9.24(s,1H),7.37(d,J＝8.7Hz,2H),6.93(d,J＝8.7Hz,2H),6.73(t,J＝3.9Hz,1H),5.62(s,2H),3.95(m,4H),3.73(s,3H),2.79–2.68(m,2H),2.51(m,2H),1.84(t,J＝6.5Hz,2H)。

Step 2To 7-bromo-6-chloro-4- {1, 4-dioxaspiro [4.5 ]]Dec-7-en-8-yl } -1- [ (4-methoxyphenyl) methyl]-1H-pyrazolo [4,3-c]To a solution of pyridine (500 mg,1 mmol) in MeOH (10 mL) was added Pd (dppf) Cl ₂ (74.5 mg,0.102 mmol) and TEA (0.43 mL,3.056 mmol). The resulting mixture was stirred at 85℃under CO (70 psi) in a sealed jar overnight. After cooling to room temperature, the solvent was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (etoac=0 to 50% in DCM) to give 6-chloro-4- {1, 4-dioxaspiro [4.5 ]]Dec-7-en-8-yl } -1- [ (4-methoxyphenyl) methyl]-1H-pyrazolo [4,3-c]Pyridine-7-carboxylic acid methyl ester (248 mg, yield: 52%) as a yellow solid. LC/MS (ESI) M/z 470 (M+H) ⁺ 。

Step 3To 6-chloro-1- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [4.5 ]]Dec-7-en-8-yl) -1H-pyrazolo [4,3-c]Pyridine-7-carboxylic acid methyl ester (75 mg,0.16 mmol) and 5-fluoro-2-methoxy-N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan)Pentane-2-yl) benzyl benzamide (74 mg,0.19 mmol) in dioxane (4 mL) and H ₂ K was slowly added to the stirred solution in O (1 mL) ₂ CO ₃ (44 mg,0.32 mmol) and Pd (dppf) Cl ₂ (14 mg,0.02 mmol) of the reaction mixture was reacted under N ₂ Heated to 100 ℃ for 18 hours under atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product which is purified by silica gel column chromatography (etoac=2% -100% in PE) to give 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -1- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [4.5 ] ]Dec-7-en-8-yl) -1H-pyrazolo [4,3-c]Pyridine-7-carboxylic acid methyl ester (80 mg, yield: 72.2%) as a white solid. LC/MS (ESI) M/z 693 (M+H) ⁺ 。

Step 4To 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -1- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [ 4.5)]Dec-7-en-8-yl) -1H-pyrazolo [4,3-c]To a stirred solution of methyl pyridine-7-carboxylate (80 mg,0.12 mmol) in MeOH (10 mL) was added Pd/C (8 mg, 10%). The obtained mixed solution is treated in H ₂ Stirring under atmosphere for 24h, filtering, and concentrating to give the crude product 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -1- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [ 4.5)]Decan-8-yl) -1H-pyrazolo [4,3-c]Pyridine-7-carboxylic acid methyl ester (70 mg, yield: 87.6%) was used as a white solid without further purification. LC/MS (ESI) M/z 695 (M+H) ⁺ 。

Step 5:to 4- {1, 4-dioxaspiro [4.5 ]]Decan-8-yl } -6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido)]Methyl } phenyl) -1- [ (4-methoxyphenyl) methyl]-1H-pyrazolo [4,3-c]Pyridine-7-carboxylic acid methyl ester (70 mg,0.1 mmol) in MeOH (5 mL) and H ₂ NaOH (40 mg,1.01 mmol) was added to a solution of O (1 mL), and the resulting mixture was stirred at 70℃for 5 hours. The pH of the mixture was then adjusted to 5 with 1N HCl, filtered and the filter cake was purified directly by preparative HPLC to give the desired product 4- {1, 4-dioxaspiro [4.5 ] ]Decan-8-yl } -6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido)]Methyl } phenyl) -1- [ (4-methoxyphenyl) methyl]-1H-pyrazolo [4,3-c]Pyridine-7-carboxylic acid (60 mg, yield: 87.5%) was a white solid. LC/MS (ESI) M/z 681 (M+H) ⁺ 。

Step 64- {1, 4-dioxaspiro [4.5 ] at 25 ℃C]Decan-8-yl } -6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido)]Methyl } phenyl) -1- [ (4-methoxyphenyl) methyl]-1H-pyrazolo [4,3-c]To a stirred solution of pyridine-7-carboxylic acid (60 mg,0.09 mmol) and HATU (40 mg,0.11 mmol) in DMF (5 mL) was slowly added DIPEA (34 mg,0.264 mmol) and the reaction mixture was taken up in NH ₃ The mixture was heated to room temperature under an atmosphere for 10 minutes. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave a crude product which was purified by silica gel column chromatography (PE: etoac=50:1 to 3:1) to give 4- {1, 4-dioxaspiro [4.5]Decan-8-yl } -6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido)]Methyl } phenyl) -1- [ (4-methoxyphenyl) methyl]-1H-pyrazolo [4,3-c]Pyridine-7-carboxamide (55 mg, yield: 91.8%) as a white solid. LC/MS (ESI) M/z 680 (M+H) ⁺ 。

Step 7:at N ₂ Downward 4- {1, 4-dioxaspiro [4.5 ]]Decan-8-yl } -6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido)]Methyl } phenyl) -1- [ (4-methoxyphenyl) methyl]-1H-pyrazolo [4,3-c]To a solution of pyridine-7-carboxamide (55 mg,0.08 mmol) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred for 3 hours. The solvent was concentrated under reduced pressure to give the crude product 6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido]Methyl } phenyl) -4- (4-oxocyclohexyl) -1H-pyrazolo [4,3-c]Pyridine-7-carboxamide (40 mg, yield: 96%) was used as yellow solid without further purification. LC/MS (ESI) M/z 516 (M+H) ⁺

Step 8:at N ₂ Downward 6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido)]Methyl } phenyl) -4- (4-oxocyclohexyl) -1H-pyrazolo [4,3-c]To a solution of pyridine-7-carboxamide (40 mg,0.08 mmol) in MeOH (5 mL) was added NaBH ₄ (13 mg,0.39 mmol). After stirring for 3 hours, the reaction mixture was concentrated,the crude product was obtained and purified by preparative-TLC (DCM: meoh=15:1) to give the desired product 6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido)]Methyl } phenyl) -4- (4-hydroxycyclohexyl) -1H-pyrazolo [4,3-c]Pyridine-7-carboxamide (8 mg, yield: 20%) as a white solid. ¹ H NMR(400MHz,MeOD)δ8.40(s,1H),7.75(d,J＝8.2Hz,2H),7.63(dd,J＝9.3,3.2Hz,1H),7.47(d,J＝8.3Hz,2H),7.25(ddd,J＝9.1,7.6,3.3Hz,1H),7.16(dd,J＝9.1,4.2Hz,1H),4.68(s,2H),3.96(s,3H),3.74–3.62(m,1H),3.22(dd,J＝12.9,8.2Hz,1H),2.11(d,J＝11.8Hz,2H),2.06–1.95(m,4H),1.51(dt,J＝17.0,11.6Hz,2H)，LC/MS(ESI)m/z:518(M+H) ⁺ 。

Table 2 compounds of general structure A-1: the compounds in the following table are prepared according to the general procedure (but modified) for synthesis of examples 1 and 2, from key intermediatesA-1-4aPrepared by

Example 6-9 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (3-hydroxycyclopentyl) -1H-pyrazolo [4,3-c ] pyridine-7-carboxamide

Step 1:to 4, 6-dichloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (766 mg,1.71 mmol) and 4, 6-dichloro-1- (4-methoxybenzyl) -1H-pyrazolo [4,3-c ]]Pyridine-7-carboxamide (600 mg,1.71 mmol) in dioxane (20 mL) and H ₂ Pd (dppf) Cl was added to a solution in O (5 mL) ₂ (125 mg,0.17 mmol) and K ₂ CO ₃ (708 mg,5.13 mmol). Heating the obtained mixture to 80 ℃ and adding N ₂ Stirring is carried out for 12 hours under an atmosphere. The reaction mixture was then cooled to room temperature and the mixture was purified with H ₂ O (20 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Drying, filtering, and vacuumConcentration gives the crude product which is purified by column chromatography on silica gel (etoac=0% -70% in PE) to give the desired product 4- (4- (tert-butyldiphenylsiloxy) cyclopent-1-enyl) -6-chloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c ] ]Pyridine-7-carboxamide (870 mg, yield: 79.91%) as a yellow solid. LC/MS (ESI) M/z 637 (M+H) ⁺ 。

Step 2:to 4- (4- (tert-butyldiphenylsiloxy) cyclopent-1-enyl) -6-chloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (870 mg,1.37 mmol) and 5-fluoro-2-methoxy-N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide (631 mg,1.69 mmol) in 1, 4-dioxane (20 mL) and H ₂ Pd (dppf) Cl was added to a solution in O (5 mL) ₂ (100 mg,0.14 mmol) and Cs ₂ CO ₃ (889 mg,2.73 mmol) and the resulting mixture was taken up in N ₂ Heated to 110 ℃ for 12 hours under atmosphere. The reaction mixture was cooled to room temperature and treated with H ₂ O (20 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel column chromatography (etoac=0% -100% in PE) to give the desired product 4- (4- (tert-butyldiphenylsiloxy) cyclopent-1-enyl) -6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -2H-pyrazolo [4, 3-c)]Pyridine-7-carboxamide (600 mg, yield: 51.1%) as a yellow solid. LC/MS (ESI) M/z 860 (M+H) ⁺ 。

Step 3:to 4- (4- (tert-butyldiphenylsiloxy) cyclopent-1-enyl) -6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c ]]Pd/C (74 mg,10%, wet) was added to a solution of pyridine-7-carboxamide (600 mg,0.7 mmol). The obtained mixed solution is treated with H at 50 DEG C ₂ Stirring is carried out for 12 hours under an atmosphere. The reaction mixture was cooled to room temperature, filtered, and the filtrate concentrated in vacuo to give the crude product which was purified by flash chromatography on silica gel (etoac=0% -50% in PE) to give the desired product 4- (3- (tert-butyldiphenylsiloxy) cyclopentyl) -6- (4- ((5-fluoro-)2-methoxybenzoylamino-methyl) phenyl) -2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (500 mg, yield: 83.1%) as a yellow solid. LC/MS (ESI) M/z 862 (M+H) ⁺ 。

Step 4:4- (3- (tert-Butyldiphenylsiloxy) cyclopentyl) -6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c ]]A solution of pyridine-7-carboxamide (500 mg,0.58 mmol) in TFA (4 mL) was heated to 65℃for 4 hours. The reaction mixture was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure to give a crude product of 3- [ 7-carbamoyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] 2, 2-trifluoroacetate ]Methyl } phenyl) -1H-pyrazolo [4,3-c]Pyridin-4-yl]Cyclopentyl ester (300 mg, yield: 86.3%) was used as a yellow solid directly in the next step without further purification. LC/MS (ESI) M/z 600 (M+H) ⁺ 。

Step 53- [ 7-carbamoyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] 2, 2-trifluoroacetate]Methyl } phenyl) -1H-pyrazolo [4,3-c]Pyridin-4-yl]Cyclopentyl ester (400 mg,0.67 mmol) in THF (10 mL) and H ₂ To a solution in O (5 mL) was added NaOH (133 mg,3.34 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 6 with 1N HCl, extracted with EtOAc (10 mL. Times.3), the combined organic phases were washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Drying, filtration and concentration under vacuum gave the crude product which was purified by silica gel column chromatography (meoh=0% -3% in DCM) to give two pairs of enantiomers which were further separated by SFC to give the desired product in four absolute configurations (Waters UPC2 analysis, mobile phase: a CO2, B methanol (0.05% dea), gradient: 10 min @40% B in a, flow rate: 2.0mL/min, back pressure: 100bar, column temperature: 35 ℃). For example 6&Column: chiralPak AD,250 x 4.6mm i.d.,5um; for example 8 &Column: chiralPak IA,250 x 4.6mm i.d.,5um. The absolute configuration of all four compounds was not determined.

Example 6 (obtained from the first eluent, cis-isomer 1): (BNB-1098-01) (15 mg, received)Rate 4.47%) as white solid, LC/MS (ESI) M/z 504 (M+H) ⁺ , ¹ H NMR(400MHz,DMSO-d ₆ )δ13.57(s,1H),8.86(t,J＝6.1Hz,1H),8.47(s,1H),7.83(s,1H),7.72(d,J＝8.2Hz,2H),7.62(s,1H),7.53(dd,J＝9.2,3.3Hz,1H),7.41–7.31(m,3H),7.19(dd,J＝9.1,4.3Hz,1H),5.11(d,J＝5.9Hz,1H),4.56(d,J＝6.1Hz,2H),4.32–4.22(m,1H),3.91(s,3H),3.83–3.71(m,1H),2.32(ddd,J＝14.5,8.9,5.9Hz,1H),2.14–2.03(m,2H),1.96(ddd,J＝12.4,7.4,4.8Hz,1H),1.85(ddd,J＝17.1,11.5,7.2Hz,1H),1.73(td,J＝11.8,6.9Hz,1H)。

Example 7 (from the second eluent, cis-isomer 2): (BNB-1099-01) (25 mg, yield: 7.44%) as a white solid, LC/MS (ESI) M/z:504 (M+H) ⁺ , ¹ H NMR(400MHz,DMSO-d ₆ )δ13.57(s,1H),8.86(t,J＝6.1Hz,1H),8.47(s,1H),7.84(s,1H),7.72(d,J＝8.2Hz,2H),7.62(s,1H),7.53(dd,J＝9.2,3.3Hz,1H),7.40–7.32(m,3H),7.19(dd,J＝9.1,4.3Hz,1H),5.12(d,J＝5.9Hz,1H),4.56(d,J＝6.1Hz,2H),4.27(dd,J＝9.8,4.9Hz,1H),3.91(s,3H),3.81–3.72(m,1H),2.32(ddd,J＝14.6,8.9,5.9Hz,1H),2.08(ddd,J＝16.4,8.0,4.2Hz,2H),1.99–1.92(m,1H),1.89–1.80(m,1H),1.77–1.69(m,1H)。

Example 8 (obtained from the first eluent, trans isomer 3): (BNB-1107-01) (13 mg, yield: 3.87%) as a white solid, LC/MS (ESI) M/z:504 (M+H) ⁺ , ¹ H NMR(400MHz,CD ₃ OD)δ8.35(s,1H),7.76(d,J＝8.1Hz,2H),7.62(dd,J＝9.2,3.2Hz,1H),7.44(dd,J＝20.2,7.9Hz,3H),7.32–7.22(m,2H),7.16(dd,J＝9.1,4.2Hz,1H),4.68(s,2H),4.55–4.51(m,1H),4.09–4.03(m,1H),3.96(s,3H),2.38–2.30(m,2H),2.13(ddd,J＝18.6,12.7,7.0Hz,3H),1.82–1.74(m,1H)。

Example 9 (from the second eluent, trans isomer 4): (BNB-1108-01) (12 mg, yield: 3.57%) as a white solid, LC/MS (ESI) M/z:504 (M+H) ⁺ , ¹ H NMR(400MHz,CD ₃ OD)δ8.25(s,1H),7.67(d,J＝8.3Hz,2H),7.53(dd,J＝9.2,3.2Hz,1H),7.36(d,J＝8.3Hz,2H),7.15(ddd,J＝9.1,7.6,3.3Hz,1H),7.06(dd,J＝9.1,4.2Hz,1H),4.58(s,2H),4.43(ddd,J＝8.2,5.5,2.9Hz,1H),4.01–3.92(m,1H),3.86(s,3H),2.29–2.20(m,2H),2.10–1.95(m,3H),1.72–1.65(m,1H)。

EXAMPLE 10&11 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (4-hydroxycyclohexyl) -1H-pyrazolo [4,3-c ] pyridine-7-carboxamide (stereochemistry not specified)

Step 1To 4, 6-dichloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (630 mg,1.80 mmol) and 4, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5 ]]Dec-7-en-8-yl) -1,3, 2-dioxaborolan (227 mg,1.98 mmol) in dioxane (10 mL) and H ₂ Pd (dppf) Cl was added to the solution in O (3 mL) ₂ (131 mg,0.18 mmol) and K ₂ CO ₃ (497 mg,3.60 mmol). The obtained mixed solution is added with N ₂ Heated to 70 ℃ for 12 hours under atmosphere. The reaction mixture was then cooled to room temperature and the mixture was purified with H ₂ O (20 mL) was diluted, extracted with EtOAc (20 mL. Times.3), the combined organic phases were washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel column chromatography (meoh=0% -3% in DCM) to give the desired product 6-chloro-2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [ 4.5)]Dec-7-en-8-yl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (450 mg, yield: 55.1%) as a white solid. LC/MS (ESI) M/z 455 (M+H) ⁺ 。

Step 26- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [ 4.5)]Dec-7-en-8-yl) -2H-pyrazolo [4,3-c]Synthesis of pyridine-7-carboxamide

To 6-chloro-2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [4.5 ]]Dec-7-en-8-yl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (450 mg,1.0 mmol) and 5-fluoro-2-methoxy-N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide (424 mg,1.10 mmol) in dioxane (10 mL) and H ₂ Pd (dppf) Cl was added to the solution in O (3 mL) ₂ (73 mg,0.10 mmol) andCs ₂ CO ₃ (652 mg,2.0 mmol). The obtained mixed solution is added with N ₂ Heated to 110 ℃ for 12 hours under atmosphere. The reaction mixture was then cooled to room temperature and the mixture was purified with H ₂ O (20 mL) was diluted, extracted with EtOAc (20 mL. Times.3), the combined organic phases were washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel column chromatography (meoh=0% -3% in DCM) to give the desired product 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [4.5 ]]Dec-7-en-8-yl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (450 mg, yield: 66.5%) as a white solid. LC/MS (ESI) M/z 678 (M+H) ⁺ 。

Step 36- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [ 4.5)]Decan-8-yl) -2H-pyrazolo [4,3-c]Synthesis of pyridine-7-carboxamide

To 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [ 4.5)]Dec-7-en-8-yl) -2H-pyrazolo [4,3-c]Pd/C (45 mg,10%, wet) was added to a stirred solution of pyridine-7-carboxamide (450 mg,0.66 mmol) in MeOH (10 mL), and the resulting mixture was then taken up in H at 50 ℃ ₂ Stirring is carried out for 24 hours under an atmosphere. The reaction mixture was filtered and concentrated to give the crude product 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [ 4.5)]Decan-8-yl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (300 mg, yield: 71.1%) was used as a white solid in the next step without further purification. LC/MS (ESI) M/z 680 (M+H) ⁺ 。

Step 46- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (4-oxocyclohexyl) -1H-pyrazolo [4,3-c ]]Synthesis of pyridine-7-carboxamide

6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [ 4.5)]Decan-8-yl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (320 mg,0.47 mmol) in TFA (3 mL)The solution in (2) was stirred at 65℃for 1 hour. After cooling to room temperature, the reaction mixture was diluted with DCM (20 mL) and saturated NaHCO ₃ The pH of the solution was adjusted, the organic phase was collected, and purified by anhydrous Na ₂ SO ₄ Dried and concentrated to give the crude product which was purified by silica gel column chromatography (etoac=0 to 50% in DCM) to give the desired product 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (4-oxocyclohexyl) -1H-pyrazolo [4, 3-c) ]Pyridine-7-carboxamide (220 mg, yield: 90.9%) as a white solid. LC/MS (ESI) M/z 516 (M+H) ⁺ 。

Step 5To 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (4-oxocyclohexyl) -1H-pyrazolo [4,3-c ]]To a solution of pyridine-7-carboxamide (220 mg,0.43 mmol) in MeOH (10 mL) was added NaBH ₄ (33 mg,0.86 mmol). The resulting mixture was stirred at 0℃for 10 minutes. The reaction mixture was diluted with EtOAc (20 mL). The organic phase was treated with anhydrous Na ₂ SO ₄ Dried and concentrated to give the crude product, which was purified by silica gel column chromatography (MeOH in dcm=0 to 5%) to give the product, which was separated by SFC (apparatus: waters UPC2 analysis SFC, column: chiralCel OD,250×4.6mm i.d.,5um, mobile phase: a is CO) ₂ B is methanol (0.05% DEA) gradient 10 min @40% B in A, flow rate 2.0mL/min, back pressure 100bar, column temperature 35 ℃ to give cis and trans products. LC/MS (ESI) M/z 518 (M+H) ⁺ 。

Example 10 (from the first eluent, isomer 1, BNB-1082-01) 10mg (yield: 4.5%) as white solid and ¹ H NMR(400MHz,DMSO)δ13.53(s,1H),8.86(s,1H),8.40(s,1H),7.87(s,1H),7.75(d,J＝7.8Hz,2H),7.62(s,1H),7.53(d,J＝9.4Hz,1H),7.44–7.30(m,3H),7.20(s,1H),4.56(d,J＝5.0Hz,2H),4.41(s,1H),3.91(s,4H),3.24(m,1H),2.21–2.19(m,2H),1.81–1.78(m,2H),1.65–1.62(d,J＝10.7Hz,4H)。

example 11 (from the second eluent, isomer 2, BNB-1083-01) 61mg (yield: 27.4%) as a white solid. ¹ H NMR(400MHz,DMSO)δ13.53(s,1H),8.86(t,J＝6.1Hz,1H),8.45(s,1H),7.85(s,1H),7.72(d,J＝8.2Hz,2H),7.62(s,1H),7.53(dd,J＝9.2,3.3Hz,1H),7.45–7.29(m,2H),7.19(dd,J＝9.1,4.3Hz,1H),4.63(d,J＝4.3Hz,1H),4.55(d,J＝6.0Hz,2H),3.91(s,3H),3.18–3.13(m,1H),3.22–3.11(m,1H),2.05–1.73(m,6H),1.55–1.31(m,2H)。

Table 3 the following compounds were prepared from a-2-4a and the appropriate intermediates according to a similar method (with variations) to examples 6 to 9 and 10& 11:

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Example 40:

6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (3-methylpyridin-4-yl) -1H-pyrazolo [4,3-c ] pyridine-7-carboxamide (BNB-1170-01)

Step 14, 6-dichloro-2- [ (4-methoxyphenyl) methyl group at 25 DEG C]-2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (100 mg,0.29 mmol) and (3-methylpyridin-4-yl) boronic acid (47 mg,0.34 mmol) were slowly added to a stirred solution of dioxane (8 mL) and water (2 mL) in Pd (dppf) Cl ₂ (20 mg,0.028 mmol) and Na ₂ CO ₃ (60 mg,0.57 mmol). Heating the obtained mixture to 80 ℃ and adding N ₂ Stirring is carried out for 12 hours under an atmosphere. The reaction mixture was then cooled to room temperature and the mixture was purified with H ₂ O (10 mL) was diluted and extracted with EtOAc (15 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel column chromatography (etoac=0% -70% in PE) to give the desired product 6-chloro-2- (4-methoxybenzyl) -4- (3-methylpyridin-4-yl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (75 mg,0.26 mmol) as a yellow solid. LC/MS (ESI) M/z 408 (M+H) +.

Step 26-chloro-2- (4-methoxybenzyl) -4- (3-methylpyridin-4-yl) -2H-pyrazolo [4,3-c ] at 25 ℃ ]Pyridine-7-carboxamide (75 mg,0.18 mmol) and 5-fluoro-2-methoxy-N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide (70 mg,0.18 mmol) Pd (dppf) Cl was slowly added to a stirred solution of dioxane (8 mL) and water (2 mL) ₂ (14 mg,0.02 mmol) and K ₂ CO ₃ (51 mg,0.37 mmol). The obtained mixed solution is added with N ₂ Heated to 110 ℃ for 12 hours under atmosphere. The reaction mixture was then cooled to room temperature and the reaction mixture was purified with H ₂ O (20 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel column chromatography (meoh=0-3% in DCM) to give the desired product 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -4- (3-methylpyridin-4-yl) -2H-pyrazolo [4, 3-c)]Pyridine-7-carboxamide (60 mg,0.1 mmol) as a yellow solid. LC/MS (ESI) M/z 631 (M+H) +.

Step 36- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido)]Methyl } phenyl) -2- [ (4-methoxyphenyl) methyl]-4- (3-methylpyridin-4-yl) -2H-pyrazolo [4,3-c]A solution of pyridine-7-carboxamide (60 mg,0.1 mmol) in TFA (2 mL) was stirred at 65℃for 3 hours. The reaction mixture was then cooled to room temperature, the resulting mixture was concentrated in vacuo, the crude product was dissolved in EtOAc (15 mL) and taken up in saturated NaHCO ₃ The solution was adjusted to pH 8. The organic phase was washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative-TLC (meoh=5% in DCM) to give the desired product 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (3-methylpyridin-4-yl) -1H-pyrazolo [4, 3-c)]Pyridine-7-carboxamide (15 mg, yield: 30%) as a white solid. LC/MS (ESI) m/z 511[ M+1 ]] ⁺ ， ¹ H NMR(400MHz,DMSO)δ8.85(s,1H),8.64–8.57(m,2H),8.17(s,2H),7.76(d,J＝8.2Hz,3H),7.56–7.51(m,2H),7.41–7.32(m,3H),7.19(dd,J＝9.2,4.3Hz,1H),4.56(d,J＝6.1Hz,2H),3.90(s,3H),2.37(s,3H)。

Example 41:

6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (pyrimidin-4-yl) -1H-pyrazolo [4,3-c ] pyridine-7-carboxamide (BNB-1186-01)

Step 14, 6-dichloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c ] at 25 DEG C]To a stirred solution of pyridine-7-carboxamide (100 mg,0.29 mmol) and 4- (tributylstannyl) pyrimidine (116 mg,0.31 mmol) in dioxane (5 mL) was added Pd (PPh) ₃ ) ₄ (33 mg,0.028 mmol). Heating the obtained mixture to 80 ℃ and adding N ₂ Stirring is carried out for 18 hours under an atmosphere. The reaction mixture was then cooled to room temperature and the mixture was purified with H ₂ O (10 mL) was diluted and extracted with EtOAc (15 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel column chromatography (etoac=0% -70% in PE) to give the desired product 6-chloro-2- (4-methoxybenzyl) -4- (pyrimidin-4-yl) -2H-pyrazolo [4,3-c ]Pyridine-7-carboxamide (100 mg, yield: 86%) as a yellow solid. LC/MS (ESI) M/z 395 (M+H) +.

Step 2To 6-chloro-2- (4-methoxybenzyl) -4- (pyrimidin-4-yl) -2H-pyrazolo [4,3-c]To a stirred solution of pyridine-7-carboxamide (100 mg,0.25 mmol) and intermediate A (106 mg,0.28 mmol) in dioxane (8 mL) and water (2 mL) was slowly added Pd (dppf) Cl ₂ (15 mg,0.025 mmol) and Cs ₂ CO ₃ (163 mg,0.50 mmol) and the resulting mixture was taken up in N ₂ Heated to 110 ℃ for 12 hours under atmosphere. The reaction mixture was then cooled to room temperature and the reaction mixture was purified with H ₂ O (20 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel column chromatography (meoh=0-3% in DCM) to give the desired product 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -4- (pyrimidin-4-yl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (90 mg, yield: 60%) as a yellow solid. LC/MS (ESI) M/z 618 (M+H) +.

Step 3:6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -4- (pyrimidin-4-yl) -2H-pyrazolo [4,3-c ]A solution of pyridine-7-carboxamide (90 mg,0.15 mmol) in TFA (2 mL) was stirred at 65℃for 3 hours. The reaction mixture was then cooled to room temperature, the resulting mixture was concentrated in vacuo, the crude product was dissolved in EtOAc (15 mL) and the pH was adjusted to 8 with saturated NaHCO ₃ A solution. The organic phase was washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative-TLC (meoh=5% in DCM) to give the desired product 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (pyrimidin-4-yl) -1H-pyrazolo [4,3-c]Pyridine-7-carboxamide (25 mg, yield 34%)) As a white solid. LC/MS (ESI) m/z 498[ M+1 ]] ⁺ ， ¹ H NMR(400MHz,DMSO)δ13.91(s,1H),9.47(d,J＝1.3Hz,1H),9.16–8.94(m,2H),8.89(t,J＝6.1Hz,1H),8.57(dd,J＝5.2,1.4Hz,1H),8.10(s,1H),7.88(d,J＝8.3Hz,2H),7.83(s,1H),7.54(dd,J＝9.2,3.3Hz,1H),7.46(d,J＝8.3Hz,2H),7.35(ddd,J＝9.0,7.9,3.3Hz,1H),7.20(dd,J＝9.1,4.3Hz,1H),4.59(d,J＝6.1Hz,2H),3.92(s,3H)。

TABLE 4 preparation of the following Compounds from A-2-4a and the appropriate intermediate A according to a method analogous to example 40 or 41 (with variations)

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Example 74 (R) -6- (4- ((5-fluoro-2- (methoxy-d 3) benzoylamino) methyl) phenyl) -4- (3-hydroxypyrrolidin-1-yl) -1H-pyrazolo [4,3-c ] pyridine-7-carboxamide (BNB-1091-01)

Step 1:to 4, 6-dichloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c ] at 0deg.C]Pyridine-7-carboxamide (200 mg,0.57 mmol) and K ₂ CO ₃ (157 mg,1.14 mmol) to a solution of MeCN (10 mL) was added dropwise (R) -pyrrolidin-3-ol (52 mg,0.57 mmol), and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was then concentrated under reduced pressure to give the crude product which was purified by silica gel column chromatography (meoh=0% -2% in DCM) to give the desired product (R) -6-chloro-4- (3-hydroxypyrrolidin-1-yl) -2- (4-methoxybenzyl) -2H-pyrazolo [4, 3-c) ]Pyridine-7-carboxamide (150 mg, yield: 65.5%) as a yellow solid. LC/MS (ESI) M/z 402 (M+H) ⁺ 。

Step 2(R) -6- (4- ((5-fluoro-2- (methoxy-d 3) benzoylamino) methyl) phenyl) -4- (3-hydroxypyrrolidin-1-yl) -2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c]Synthesis of pyridine-7-carboxamide

To (R) -6-chloro-4- (3-hydroxypyrrolidin-1-yl) -2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (75 mg,0.19 mmol) and intermediate G (87 mg,0.22 mmol) in dioxane (5 mL) and H ₂ Pd (dppf) Cl was added to a solution in O (1 mL) ₂ (14 mg,0.02 mmol) and Cs ₂ CO ₃ (122 mg,0.37 mmol). The obtained mixed solution is added with N ₂ Heated to 110 ℃ for 12 hours under atmosphere. The reaction mixture was then cooled to room temperature and the mixture was purified with H ₂ O (20 mL) was diluted, extracted with EtOAc (20 mL. Times.3), the combined organic phases were washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel column chromatography (meoh=0% -3% in DCM) to give the desired product (R) -6- (4- ((5-fluoro-2- (methoxy-d 3) benzoylamino) methyl) phenyl) -4- (3-hydroxypyrrolidin-1-yl) -2- (4-methoxybenzyl) -2H-pyrazolo [4, 3-c)]Pyridine-7-carboxamide (70 mg, yield: 59.7%) as a yellow solid. LC/MS (ESI) M/z 628 (M+H) ⁺ 。

Step 3(R) -6- (4- ((5-fluoro-2- (methoxy-d 3) benzoylamino) methyl) phenyl) -4- (3-hydroxypyrrolidin-1-yl) -2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c]Solution in pyridine-7-carboxamide

(70 mg,0.11 mmol) was heated to 65℃in TFA (3 mL) for 2 hours. The reaction mixture was then cooled to room temperature and the resulting mixture was concentrated in vacuo to give the crude product (R) -1- (7-carbamoyl-6- (4- ((5-fluoro-2- (methoxy-d)) ₃ ) Benzamido) methyl) phenyl) -1H-pyrazolo [4,3-c]Pyridin-4-yl) pyrrolidin-3-yl 2, 2-trifluoroacetate (70 mg, quantitative) was a yellow solid which was used without further purification. LC/MS (ESI) M/z 604 (M+H) ⁺ 。

Step 4 to (R) -2, 2-trifluoro-acetic acid 1- (7-carbamoyl-6- (4- ((5-fluoro-2- (methoxy-d) ₃ ) Benzoylamino) -methyl) phenyl) -1H-pyrazolo- [4,3-c]Pyridin-4-yl) pyrrolidin-3-yl ester (70 mg,0.12 mmol) in THF (5 mL) and H ₂ NaOH (46 mg,1.16 mmol) was added to a solution of O (2 mL) and the reaction mixture was heated to 65℃for 1 hour. The resulting mixture was cooled to room temperature and the pH was adjusted to 7 with 1N HCl, extracted with EtOAc (10 mL. Times.3), the combined organic phases were washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to afford the crude product, which was purified by silica gel column chromatography (MeOH in dcm=0% -3%) to afford the crude product, which was purified by preparative-TLC (MeOH in dcm=5%) to afford the desired product (R) -6- (4- ((5-fluoro-2- (methoxy-d) ₃ ) Benzoylamino) methyl) phenyl) -4- (3-hydroxypyrrolidin-1-yl) -1H-pyrazolo [4,3-c]Pyridine-7-carboxamide (15 mg, yield: 25.5%) as a white solid. LC/MS (ESI) M/z 508 (M+H) ⁺ 。1H NMR(400MHz,DMSO-d ₆ )δ12.99(s,1H),8.85(t,J＝6.1Hz,1H),8.20(s,1H),7.64(d,J＝8.1Hz,2H),7.53(dd,J＝9.2,3.3Hz,1H),7.37–7.31(m,3H),7.28–7.13(m,2H),6.92(s,1H),5.04(d,J＝2.9Hz,1H),4.55(d,J＝6.2Hz,2H),4.44–4.41(m,1H),3.84–3.82(m,3H),2.06–1.97(m,2H)。

EXAMPLE 75 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (pyrrolidin-1-yl) -1H-pyrazolo [4,3-c ] pyridine-7-carboxamide (BNB-1075-01)

Step 14, 6-dichloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c ] at 0 DEG C]To a solution of pyridine-7-carboxamide (150 mg,0.43 mmol) in MeCN (10 mL) was added pyrrolidine (37 mg,0.51 mmol) and K ₂ CO ₃ (118 mg,0.86 mmol) and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was then concentrated under reduced pressure to give the crude product which was purified by silica gel column chromatography (meoh=0% -2% in DCM) to give the desired product 6-chloro-2- (4-methoxybenzyl) -4- (pyrrolidin-1-yl) -2H-pyrazolo [4, 3-c)]Pyridine-7-carboxamide (120 mg, yield: 72.5%) as a yellow solid. LC/MS (ESI) M/z 386 (M+H) ⁺ 。

Step 2To 6-chloro-2- (4-methoxybenzyl) -4- (pyrrolidin-1-yl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (120, 0.31 mmol) and intermediate A (143 mg,0.37 mmol) in dioxane (4 mL) and H ₂ Pd (dppf) Cl was added to a solution in O (1 mL) ₂ (22 mg,0.03 mmol) and Cs ₂ CO ₃ (202 mg,0.62 mmol). The obtained mixed solution is added with N ₂ Heated to 110 ℃ for 12 hours under atmosphere. The reaction mixture was then cooled to room temperature and the reaction mixture was purified with H ₂ O (20 mL) was diluted and extracted with EtOAc (20 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel column chromatography (meoh=0% -3% in DCM) to give the desired product 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -4- (pyrrolidin-1-yl) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (30 mg, yield: 15.9%) as a white solid. LC/MS (ESI) M/z 609 (M+H) ⁺ 。

Step 36- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -4- (pyrrolidin-1-yl) -2H-pyrazolo [4,3-c]A solution of pyridine-7-carboxamide (30 mg,0.05 mmol) in TFA (3 mL) was heated to 65℃for 2 hours. The reaction mixture was then cooled to room temperature, and the resulting mixture was concentrated in vacuo to give the crude product, which was dissolved in EtOAc (15 mL) and saturated with NaHCO ₃ The solution was adjusted to pH 8. The organic phase was washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative-TLC (meoh=5% in DCM) to give the desired product 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (pyrrolidin-1-yl) -1H-pyrazolo [4,3-c]Pyridine-7-carboxamide (11 mg, yield: 45%) as a white solid: ¹ H NMR(400MHz,DMSO)δ12.98(s,1H),8.84(t,J＝6.1Hz,1H),8.20(s,1H),7.64(d,J＝8.2Hz,2H),7.53(dd,J＝9.2,3.3Hz,1H),7.33(dd,J＝12.5,5.7Hz,3H),7.28–7.14(m,2H),6.90(s,1H),4.54(d,J＝6.1Hz,2H),3.90(s,3H),3.75(s,4H),1.99(s,4H)；LC/MS(ESI)m/z:489(M+H) ⁺ 。

EXAMPLE 76- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- ((1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazolo [4,3-c ] pyridine-7-carboxamide (BNB-1130-01)

Step 1:at 0 ℃ at N ₂ To a stirred solution of 1, 1-trifluoropropan-2-ol (71 mg,0.6 mmol) in DMF (5 mL) was added NaH (25 mg,0.6mmol, 60%). The resulting mixture was stirred at 0deg.C for 0.5H, followed by the addition of 4, 6-dichloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-c ] in DMF (2 mL)]Pyridine-7-carboxamide (200 mg,0.5 mmol) stirring was continued for a further 2 hours. The reaction mixture was quenched with aqueous NH4Cl, extracted with EtOAc (20 ml x 3), the combined organic phases were washed with water and brine, over anhydrous Na ₂ SO ₄ Drying and concentration in vacuo afforded the crude product, which was purified by silica gel column chromatography (etoac=10% -40% in PE) to afford the desired product 6-chloro-2- (4-methoxybenzyl) -4- ((1, 1-trifluoropropan-2-yl) oxy) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (226 mg, yield: 92.5%) as a grey solid. LC/MS (ESI) M/z 429 (M+H) ⁺

Step 2To 6-chloro-2- (4-methoxybenzyl) -4- ((1, 1-trifluoropropan-2-yl) oxy) -2H-pyrazolo [4,3-c ]]Pyridine-7-carboxamide (226 mg,0.5 mmol) and intermediate A (245 mg,0.6 mmol) in dioxane (10 mL) and H ₂ Cs was added to the stirred solution in O (2 mL) ₂ CO ₃ (487 mg,1.5 mmol) and Pd (dppf) Cl ₂ (38 mg,0.05 mmol) and the reaction mixture was taken up in N at 100deg.C ₂ Stirring is carried out for 10 hours under an atmosphere. The reaction mixture was concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (etoac=30% -50% in PE) to give the desired product 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -4- ((1, 1-trifluoropropan-2-yl) oxy) -2H-pyrazolo [4,3-c]Pyridine-7-carboxamide (90 mg, yield: 26.2%) as a white solid. LC/MS (ESI) M/z 652 (M+1) ⁺ 。

Step 36- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2- (4-methoxybenzyl) -4- ((1, 1-trifluoropropan-2-yl) oxy) -2H-pyrazolo [4,3-c]A solution of pyridine-7-carboxamide (90 mg,0.14 mmol) in TFA (5 mL) was stirred at 65℃for 2 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo to give the crude product, which was dissolved in EtOAc (15 mL) and saturated with NaHCO ₃ The pH was adjusted to 8. The organic phase was washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel column chromatography (meoh=0% -3% in DCM) to give the desired product 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- ((1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazolo [4,3-c]Pyridine-7-carboxamide (65 mg, yield: 88.5%) as a white solid. LC/MS (ESI) M/z 532 (M+H) +, ¹ H NMR(400MHz,DMSO)δ13.65(s,1H),8.90(t,J＝6.1Hz,1H),8.21(s,1H),7.84(s,1H),7.74(d,J＝8.2Hz,2H),7.62(s,1H),7.53(dd,J＝9.2,3.3Hz,1H),7.45–7.27(m,3H),7.19(dd,J＝9.1,4.3Hz,1H),6.27–6.12(m,1H),4.56(d,J＝6.0Hz,2H),3.90(s,3H),1.55(d,J＝6.5Hz,3H)。

TABLE 5 preparation of the following Compounds from A-2-4a and the appropriate intermediates according to examples 74, 75 and 76

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Examples 112 and 113:

6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -4- [ 4-hydroxycyclohexyl ] -1H-indazole-7-carboxamide (BNB-1100-01, 112) and 6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -4- [ 4-hydroxycyclohexyl ] -1H-indazole-7-carboxamide (BNB-1101-01, 113)

Step 1:at N ₂ To 4-bromo-6-hydroxy-2- (4-methoxybenzyl) -2H-indazole-7-carbonitrile (890 mg,2.48 mmol) and 2- {1, 4-dioxaspiro [4.5 ] at atmosphere]Dec-7-en-8-yl } -4, 5-tetramethyl-1, 3, 2-dioxaborolan (727 mg,2.73 mmol) in dioxane (10 mL) and H ₂ Pd (dppf) Cl was added to the solution in O (2 mL) ₂ (181 mg,0.24 mmol) and K ₂ CO ₃ (1.03 g,7.45 mmol). The reaction mixture was stirred at 100℃for 3 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (10 mL). The mixture was washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product which was purified by silica gel column chromatography (etoac=30% -50% in PE) to give the desired product 6-hydroxy-2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [ 4.5)]Dec-7-en-8-yl) -2H-indazole-7-carbonitrile (950 mg, yield: 91.5%) as a yellow solid. LC/MS (ESI) M/z 418 (M+H) +.

Step 2:at-50 ℃ at N ₂ To trifluoro methanesulfonic acid 7-cyano-2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [4.5 ] at atmosphere]To a solution of dec-7-en-8-yl) -2H-indazol-6-yl ester (500 mg,2.27 mmol) and TEA (0.63 mL,4.55 mmol) in DCM (5 mL) was added Tf in DCM (5 mL) ₂ O (0.56 mL,3.41 mmol). The reaction mixture was heated to-50 ℃ for 0.5 hours. The reaction mixture was treated with saturated NaHCO ₃ The solution and brine were washed. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtering, and concentrating to obtain the crude product of 7-cyano-2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [4.5 ] triflate ]Dec-7-en-8-yl) -2H-indazol-6-yl ester (500 mg, yield: 75.9%) as a white solid. LC/MS (ESI) M/z 572 (M+Na) ⁺

Step 3To trifluoro methanesulfonic acid 7-cyano-2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [4.5 ]]Dec-7-en-8-yl) -2H-indazol-6-yl ester (500 mg,0.91 mmol) and 5-fluoro-2-methoxy-N- { [4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]To a solution of methyl } benzamide (420 mg,1.09 mmol) in dioxane (5 mL) and water (1 mL) was added Na ₂ CO ₃ (192 mg,1.82 mmol) and Pd (dppf) Cl ₂ (66 mg,0.091 mmol). The reaction mixture was heated at 100℃for 4 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The mixture was washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product which was purified by silica gel column chromatography (etoac=30% -50% in PE) to give the desired product N- (4- (7-cyano-2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [ 4.5)]Dec-7-en-8-yl) -2H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (599 mg, yield: 99%) was a white solid. LC/MS (ESI) M/z 681 (M+Na) ⁺

Step 4:to N- (4- (7-cyano-2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [ 4.5) ]To a solution of dec-7-en-8-yl) -2H-indazol-6-yl-benzyl) -5-fluoro-2-methoxybenzamide (500 mg,0.75 mmol) in MeOH (15 mL) was added Pd/C10% (50 mg, wt 10%), and the reaction mixture was stirred at room temperature under H ₂ (5 Psi) for 10 hours. The reaction mixture was filtered and concentrated to give the crude product N- (4- (7-cyano-2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [4.5 ])]Decane-8-yl) -2H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (350 mg, yield: 69.7%) was used as a grey solid directly in the next step without further purification. LC/MS (ESI) M/z 661 (M+H) ⁺ 。

Step 5:n- (4- (7-cyano-2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [ 4.5)]A solution of decan-8-yl) -2H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (350 mg,0.53 mmol) in TFA (2 mL) was stirred at 65℃for 3H. The reaction mixture was concentrated under reduced pressure, the residue was dissolved with DCM (15 mL), and saturated NaHCO ₃ The solution (5 mL x 2) was washed. The organic layer was purified by Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product, N- ({ 4- [ 7-cyano-4- (4-oxocyclohexyl) -1H-indazol-6-yl)]Phenyl } methyl) -5-fluoro-2-methoxybenzamide (242 mg,0.48mmol, 92%) as a red solid which was purified directly without further purification Which is used in the next step. LC/MS (ESI) M/z 497 (M+H) ⁺ 。

Step 6(1H-indazol-6-yl) -N- ({ 4- [ 7-cyano-4- (4-oxocyclohexyl) -1H-indazol-6-yl) at 0 ℃C]To a solution of phenyl } methyl) -5-fluoro-2-methoxybenzamide (242 mg,0.48 mmol) in MeOH (3 mL) was added NaBH ₄ (36 mg,0.97 mmol) and the reaction mixture was stirred at 20℃for 0.5 h. The mixture is treated with saturated NH ₄ The Cl solution (5 mL) was quenched and extracted with DCM (15 mL. Times.2). The organic phase was treated with anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product, which is purified by silica gel column chromatography (meoh=1% -5% in DCM) to give the desired product N- ({ 4- [ 7-cyano-4- (4-hydroxycyclohexyl) -1H-indazol-6-yl)]Phenyl } methyl) -5-fluoro-2-methoxybenzamide (162 mg, yield: 66.6%). LC/MS (ESI) M/z 499 (M+H) ⁺

Step 7(1H-indazol-6-yl) -N- ({ 4- [ 7-cyano-4- (4-hydroxycyclohexyl) -1H-indazol-6-yl) at 20 ℃]To a solution of phenyl } methyl) -5-fluoro-2-methoxybenzamide (162 mg,0.32 mmol) in THF (5 mL) and EtOH (5 mL) was added NaOH (2 mL,4 mmol) and H ₂ O ₂ (2 mL) and then the mixture was stirred at 20deg.C for 16 hours. The mixture is treated with H ₂ O (2 mL) was diluted and extracted with EtOAc (10 mL. Times.3), and the combined organic layers were taken up in Na ₂ SO ₄ Drying, filtration and concentration gave a crude product which was purified by preparative-TLC (etoac=100% in PE) and the pure product obtained was separated by SFC analysis using Waters UPC2 (column: chiralCel OJ,250×4.6mm i.d.,5um; mobile phase: a is CO2, B is methanol (0.05% dea); gradient: 8min@40% B in a, flow rate: 2.0mL/min, back pressure: 100bar, column temperature: 35 ℃)

Example 112 was obtained from the first eluent (peak 1) 25mg (yield: 14.9%) LC/MS (ESI) M/z 517 (M+H) +, ¹ HNMR(400MHz,DMSO)δ13.08(s,1H),8.85(t,J＝6.0Hz,1H),8.22(s,1H),7.53(dd,J＝9.3,3.4Hz,2H),7.46(d,J＝8.2Hz,2H),7.42(s,1H),7.39(s,1H),7.37(s,1H),7.33(dd,J＝7.9,3.4Hz,1H),7.19(dd,J＝9.1,4.2Hz,1H),6.91(s,1H),4.55(d,J＝6.1Hz,2H),4.43(d,J＝3.5Hz,1H),3.96-3.94(m,1H),3.91(s,3H),3.03-3.01(m,1H),2.06–1.99(m,2H),1.79-1.77(m,2H),1.67-1.60(m,4H)；LC/MS(ESI)m/z:517(M+H) ⁺ 。

example 113 was obtained from the second eluent (peak 2) 0.8mg (yield: 0.48%) 1H NMR (400 MHz, DMSO). Delta.13.14 (s, 1H), 8.91 (t, J=6.0 Hz, 1H), 8.32 (s, 1H), 7.59 (dd, J=9.2, 3.3Hz, 2H), 7.50 (t, J=9.2 Hz, 3H), 7.45-7.37 (m, 3H), 7.26 (dd, J=9.2, 4.3Hz, 1H), 6.96 (s, 1H), 4.66 (d, J=4.3 Hz, 1H), 4.61 (d, J=6.1 Hz, 2H), 3.97 (s, 3H), 3.61-3.59 (m, 1H), 3.05-2.96 (m, 1H), 2.02-1.93 (m, 4H), 1.80-1.71 (m, 1.41-2H). LC/MS (ESI) M/z 517 (M+H) ⁺ 。

Example 114:

6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (3-hydroxycyclopentyl) -1H-indazole-7-carboxamide (BNB-1080-01)

Step 1To 4-bromo-6-hydroxy-2- (4-methoxybenzyl) -2H-indazole-7-carbonitrile (300 mg,0.84 mmol) and tert-butyldiphenyl ((3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopent-3-en-1-yl) oxy) silane (452 mg,1.01 mmol) in dioxane (4 mL) and H ₂ Pd (dppf) Cl was added to a solution in O (1 mL) ₂ (101 mg,0.12 mmol) and Na ₂ CO ₃ (178 mg,1.68 mmol) and the resulting mixture was stirred at 110℃under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=1% -5% in PE) to give the desired product 4- (4- ((tert-butyldiphenylsilyl) oxy) cyclopent-1-en-1-yl) -6-hydroxy-2- (4-methoxybenzyl) -2H-indazole-7-carbonitrile (380 mg, yield: 75.5%) as a white solid. LC/MS (ESI) m/z 600[ M+1 ] ] ⁺ 。

Step 24- (cyclopent-1-en-1-yl) -6-hydroxy-1- [ (4-methoxyphenyl) methyl at-30deg.C]To a solution of 1H-indazole-7-carbonitrile (380 mg,0.63 mmol) in DCM (5 mL) was added DIPEA (0.22 mL,1.26 mmol) and Tf ₂ O (231 mg,0.82 mmol) and the reaction mixture was stirred at-30℃for 1 hour. The resulting mixture was diluted with water (5 mL) and extracted with DCM (10 mL x 3)). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give 4- (4- ((tert-butyldiphenylsilyl) oxy) cyclopent-1-en-1-yl) -7-cyano-2- (4-methoxybenzyl) -2H-indazol-6-yl triflate (310 mg, yield: 67.3%) as a brown solid without further purification. LC/MS (ESI) m/z 732[ M+1 ]] ⁺

Step 3To 4- (4- ((tert-butyldiphenylsilyl) oxy) cyclopent-1-en-1-yl) -7-cyano-2- (4-methoxybenzyl) -2H-indazol-6-yl triflate (310 mg,0.42 mmol) and 5-fluoro-2-methoxy-N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide (194 mg,0.50 mmol) in dioxane (4 mL) and H ₂ Pd (dppf) Cl was added to a solution in O (1 mL) ₂ (45 mg,0.05 mmol) and Na ₂ CO ₃ (89 mg,0.84 mmol) and the resulting mixture was heated to 110℃under N ₂ Stirring is carried out for 2 hours under an atmosphere. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=1% -10% in PE) to give N- (4- (4- (4- ((tert-butyldiphenylsilyl) oxy) cyclopent-1-en-1-yl) -7-cyano-2- (4-methoxybenzyl) -2H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (260 mg, yield: 73.7%) as a grey solid. LC/MS (ESI) m/z 841[ M+1 ]] ⁺

Step 4To a solution of N- (4- (4- (4- ((tert-butyldiphenylsilyl) oxy) cyclopent-1-en-1-yl) -7-cyano-2- (4-methoxybenzyl) -2H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (260 mg,0.31 mmol) in MeOH (5 mL) was added Pd/C (26 mg, wt10%), and the mixture was stirred at room temperature under H ₂ Stirring is carried out for 6 hours under an atmosphere. The reaction mixture was filtered and concentrated to give the crude product N- (4- (4- (3- ((tert-butyldiphenylsilyl) oxy) cyclopentyl) -7-cyano-2- (4-methoxybenzyl) -2H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (200 mg, yield: 76.6%) as a yellow solid which was used directly in the next step without further purification. LC/MS (ESI) m/z 843[ M+1 ]] ⁺

Step 5At 0 ℃ to N- To a solution of 4- (4- (3- ((tert-butyldiphenylsilyl) oxy) cyclopentyl) -7-cyano-2- (4-methoxybenzyl) -2H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (200 mg,0.24 mmol) in DCM (2 mL) was added TFA (2 mL) dropwise and the mixture was stirred at 40 ℃ for 5 hours. The reaction mixture was concentrated and taken up in saturated NaHCO ₃ (5 mL) was diluted, the mixture was extracted with DCM (10 mL. Times.3), the combined organic phases were washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give N- (4- (7-cyano-4- (2-hydroxycyclopentyl) -1H-indazol-6-yl) benzyl) -2-methoxybenzamide (100 mg,0.21mmol, 85.9%) as a brown solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z 485[ M+1 ]] ⁺

Step 6To a solution of N- (4- (7-cyano-4- (2-hydroxycyclopentyl) -1H-indazol-6-yl) benzyl) -2-methoxybenzamide (100 mg,0.21 mmol) in THF (2 mL) and MeOH (2 mL) at 0deg.C was added dropwise H ₂ O ₂ (1 mL) and NaOH solution (0.04 mL,0.08 mmol), and the mixture was stirred at 60℃for 5 hours. The reaction mixture was treated with H ₂ O (5 mL) was diluted and extracted with EtOAc (10 mL. Times.3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product, which was purified by preparative-TLC (meoh=5% in DCM) to give the desired product 6- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -4- (3-hydroxycyclopentyl) -1H-indazole-7-carboxamide (35 mg, yield: 33.3%) as a white solid. LC/MS (ESI) m/z 503[ M+1 ]] ⁺¹ H NMR(400MHz,DMSO)δ13.09(s,1H),8.86(m,1H),8.33(s,1H),7.53(m,2H),7.45(m,3H),7.39–7.32(m,3H),7.19(dd,J＝9.1,4.3Hz,1H),6.99(s,1H),4.72(d,J＝3.9Hz,1H),4.55(d,J＝6.1Hz,2H),4.30(d,J＝4.2Hz,1H),3.91(s,3H),3.49–3.37(m,1H),2.42–2.41(m,1H),2.02–1.99(m,2H),1.85–1.65(m,3H)。

EXAMPLE 115 4- (2-hydroxycyclopentyl) -6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-indazole-7-carboxamide (BNB-1058-01)

Step 1To 4-bromo-6- (methoxymethoxy) -1- [ (4-methoxyphenyl) methyl]-1H-indazole-7-carbonitrile (500 mg,1.2 mmol) and 2- (cyclopent-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (289 mg,1.49 mmol) in dioxane (4 mL) and H ₂ Pd (dppf) Cl was added to a solution in O (1 mL) ₂ (101 mg,0.12 mmol) and Na ₂ CO ₃ (263 mg,2.5 mmol) and the reaction mixture was stirred at 110℃under N ₂ Stirring is carried out for 2 hours under an atmosphere. The reaction mixture was concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (etoac=1% -5% in PE) to give the desired product 4- (cyclopent-1-en-1-yl) -6- (methoxymethoxy) -1- [ (4-methoxyphenyl) methyl]-1H-indazole-7-carbonitrile (360 mg, yield: 74.4%) as a white solid. LC/MS (ESI) m/z 390[ M+1 ] ] ⁺ 。

Step 2To 4- (cyclopent-1-en-1-yl) -6- (methoxymethoxy) -1- [ (4-methoxyphenyl) methyl]To a solution of 1H-indazole-7-carbonitrile (360 mg,0.92 mmol) in THF (2 mL) was added HCl (2 mL,4 mmol) and the reaction mixture was stirred at 55deg.C for 2 hours. The reaction mixture was treated with H ₂ O (10 mL) was diluted and extracted with EtOAc (10 mL. Times.2). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product 4- (cyclopent-1-en-1-yl) -6-hydroxy-1- [ (4-methoxyphenyl) methyl]-1H-indazole-7-carbonitrile (280 mg, yield: 87.7%) was used as a white solid, directly in the next step without further purification. LC/MS (ESI) m/z 346[ M+1 ]] ⁺

Step 34- (cyclopent-1-en-1-yl) -6-hydroxy-1- [ (4-methoxyphenyl) methyl at-30deg.C]To a solution of 1H-indazole-7-carbonitrile (280 mg,0.81 mmol) in DCM (5 mL) was added DIPEA (0.27 mL,1.62 mmol) followed by Tf ₂ O (0.16 mL,0.97 mmol). The reaction mixture was stirred at-30℃for 1 hour. The reaction mixture was diluted with water (5 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Drying, filtering, and concentrating to give 7-cyano-4- (cyclopent-1-en-1-yl) -1- [ (4-methoxyphenyl) methyl triflate ]-1H-indazol-6-yl ester (260 mg, 67.2%) as brown solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z 478[ M+1 ]] ⁺

Step 4To trifluoro methanesulfonic acid 7-cyano-4- (cyclopent-1-en-1-yl) -1- [ (4-methoxyphenyl) methyl]-1H-indazol-6-yl ester (260 mg,0.55 mmol) and 2-methoxy-N- { [4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Methyl } benzamide (220 mg,0.6 mmol) in dioxane (4 mL) and H ₂ Pd (dppf) Cl was added to a solution in O (1 mL) ₂ (45 mg,0.05 mmol) and Na ₂ CO ₃ (115 mg,1.1 mmol) and the reaction mixture was stirred at 110℃under N ₂ Stirring is carried out for 2 hours under an atmosphere. The reaction mixture was concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (etoac=1% -20% in PE) to give the desired product N- (4- (7-cyano-4- (cyclopent-1-en-1-yl) -1- (4-methoxybenzyl) -1H-indazol-6-yl) benzyl) -2-methoxybenzamide as a grey solid. LC/MS (ESI) m/z 569[ M+1 ]] ⁺

Step 5To a solution of N- (4- (7-cyano-4- (cyclopent-1-en-1-yl) -1- (4-methoxybenzyl) -1H-indazol-6-yl) benzyl) -2-methoxybenzamide (250 mg,0.44 mmol) in THF (5 mL) at 0deg.C was added drop wise BH ₃ .Me ₂ S (0.09 mL,1 mmol/mL), the reaction mixture was stirred at this temperature for 1 hour, then EtOH (1 mL) was added dropwise at 0deg.C, then H ₂ O ₂ (1 mL) and NaOH (0.44 mL,2 mmol/mL) were added sequentially to the solution, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was treated with H ₂ O (10 mL) was diluted and extracted with EtOAc (10 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (meoh=1% -3% in DCM) to give the desired product N- (4- (7-cyano-4- (2-hydroxycyclopentyl) -1- (4-methoxybenzyl) -1H-indazol-6-yl) benzyl) -2-methoxybenzamide (30 mg, yield: 11.5%) as a yellow solid. LC/MS (ESI) m/z 587[ [M+1] ⁺

Step 6:to a solution of N- (4- (7-cyano-4- (2-hydroxycyclopentyl) -1- (4-methoxybenzyl) -1H-indazol-6-yl) benzyl) -2-methoxybenzamide (30 mg,0.06 mmol) in DCM (2 mL) was added TFA (2 mL) dropwise at 0 ℃ and the reaction mixture was stirred at 40 ℃ for 5 hours. The reaction mixture was concentrated and taken up in saturated NaHCO ₃ (5 mL) was diluted, the mixture was extracted with DCM (10 mL. Times.3), the combined organic phases were washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product, N- (4- (7-cyano-4- (2-hydroxycyclopentyl) -1H-indazol-6-yl) benzyl) -2-methoxybenzamide (25 mg, yield: 83.3%), as a brown solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z 467[ M+1 ] ] ⁺

Step 7To a solution of N- (4- (7-cyano-4- (2-hydroxycyclopentyl) -1H-indazol-6-yl) benzyl) -2-methoxybenzamide (25 mg,0.04 mmol) in THF (2 mL) and MeOH (2 mL) at 0deg.C was added dropwise H ₂ O ₂ (1 mL) and 2NNaOH (0.04 mL,0.08 mmol), and the reaction mixture was stirred at 60℃for 5 hours. The reaction mixture was treated with H ₂ O (5 mL) was diluted and extracted with EtOAc (10 mL. Times.3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product, which was purified by preparative-TLC (meoh=5% in DCM) to give the desired product 4- (2-hydroxycyclopentyl) -6- (4- { [ (2-methoxyphenyl) carboxamido)]Methyl } phenyl) -1H-indazole-7-carboxamide (6 mg, yield: 30%) as a white solid. LC/MS (ESI) m/z 485[ M+1 ]] ⁺ ； ¹ H NMR(400MHz,DMSO)δ13.06(s,1H),8.76(t,J＝6.1Hz,1H),8.21(s,1H),7.84–7.72(m,1H),7.52–7.36(m,7H),7.17(d,J＝8.4Hz,1H),7.05(t,J＝7.5Hz,1H),6.92(s,1H),4.82(d,J＝5.4Hz,1H),4.56(d,J＝6.0Hz,2H),4.24(m,1H),3.92(s,3H),3.27(m,1H),2.22–2.14(m,1H),2.0–1.98(m,1H),1.82–1.79(m,3H),1.66–1.58(m,1H)。

Table 6 following compounds were prepared according to examples 112, 113, 114&115 (B-1, pathway 1) using similar methods (with variations) from the appropriate intermediates B-1-3a or B-1-3d and the appropriate boronic acids/esters:

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example 129 4-cyclopentyl-6- (4-phenoxyphenyl) -1H-indazole-7-carboxamide (BNB-1042-01):

step 1To methyl 4-bromo-7-methoxy-1H-indazole-6-carboxylate (3.0 g,10.5 mmol) and 2- (cyclopent-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (3.0 g,15.4 mmol) in dioxane (50 mL) and H at 25 ℃ ₂ K was slowly added to the stirred solution in O (10 mL) ₂ CO ₃ (800 mg,5.7 mmol) and Pd (dppf) Cl ₂ (50 mg,0.7 mmol) the reaction mixture was taken up in N ₂ Heated to 100 ℃ for 24 hours under atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (100 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=2% -25% in PE) to give 4- (cyclopent-1-en-1-yl) -7-methoxy-1H-indazole-6-carboxylic acid methyl ester (1.5 g, yield: 52.4%) as a white solid. LC/MS (ESI) M/z 273 (M+H) ⁺ 。

Step 2:to 4- (cyclopent-1)To a stirred solution of methyl-ene-1-yl) -7-methoxy-1H-indazole-6-carboxylate (1.4 g,5.1 mmol) in MeOH (15 mL) was added Pd/C (150 mg, 10%). The obtained mixed solution is treated in H ₂ Stirring was carried out under an atmosphere for 24 hours, filtering, and concentrating to give crude product 4-cyclopentyl-7-methoxy-1H-indazole-6-carboxylic acid methyl ester (1.2 g, yield: 85.1%) as a white solid, which was used without further purification. LC/MS (ESI) M/z 275 (M+H) ⁺ 。1H NMR(400MHz,CDCl ₃ )δ8.18(s,1H),7.42(s,1H),4.05(s,3H),3.97(s,3H),3.45–3.33(m,1H),2.23–2.11(m,2H),1.97–1.67(m,6H)。

Step 3:to a stirred solution of methyl 4-cyclopentyl-7-methoxy-1H-indazole-6-carboxylate (800 mg,2.9 mmol) in DCM (20 mL) at-50deg.C was added BBr ₃ (5 mL,1M in Tol.) the mixture was stirred at-50℃for 1 hour. The reaction mixture was quenched with MeOH and diluted with water (20 mL) and extracted with EtOAc (15 mL. Times.3). The combined organic phases were washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=2% -25% in PE) to give methyl 4-cyclopentyl-7-hydroxy-1H-indazole-6-carboxylate (500 mg, yield: 60%) as a white solid. LC/MS (ESI) M/z 275 (M+H) ⁺ 。1H NMR(400MHz,CDCl ₃ )δ8.18(s,1H),7.42(s,1H),4.05(s,3H),3.97(s,3H),3.45–3.33(m,1H),2.23–2.11(m,2H),1.97–1.67(m,6H)。

Step 4:to 4-cyclopentyl-7-hydroxy-1H-indazole-6-carboxylic acid methyl ester (500 mg,0.3 mmol) and Tf at 0deg.C ₂ To a stirred solution of O (0.176 mL,1.0 mmol) in DCM (5 mL) was added TEA (100 mg,0.9 mmol) and stirred for 10 min. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=2% -25% in PE) to give methyl 4-cyclopentyl-7- (trifluoromethanesulfonyl oxy) -1H-indazole-6-carboxylate (600 mg, yield: 51%) as a white solid. LC/MS (ESI) M/z 393 (M+H) ⁺ 。1H NMR(400MHz,CDCl ₃ )δ10.54(d,J＝50.9Hz,1H),8.24(d,J＝1.5Hz,1H),7.26(t,J＝1.8Hz,1H),3.99(s,3H),3.47(dd,J＝16.3,7.8Hz,1H),2.21(d,J＝3.9Hz,2H),1.93-1.80(m,6H)。

Step 5:to 4-cyclopentyl-7- (trifluoromethanesulfonyl oxy) -1H-indazole-6-carboxylic acid methyl ester (400 mg,1.0 mmol) and Zn (CN) at 25℃C ₂ (350 mg,2.9 mmol) to a stirred solution of Pd (dppf) Cl in DMF (5 mL) ₂ (100 mg,0.1 mmol) the reaction mixture was heated to 130℃in a microwave reactor under N ₂ Stirring is carried out for 2 hours under an atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=2% -25% in PE) to give methyl 7-cyano-4-cyclopentyl-1H-indazole-6-carboxylate (230 mg, yield: 83.8%) as a white solid. LC/MS (ESI) M/z 270 (M+H) ⁺ 。1H NMR(400MHz,CDCl ₃ )δ11.07(d,J＝55.9Hz,1H),8.26(d,J＝5.4Hz,1H),7.73(s,1H),3.99(s,3H),3.54–3.39(m,1H),2.22–2.12(m,2H),1.91–1.69(m,6H)。

Step 6:to 7-cyano-4-cyclopentyl-1H-indazole-6-carboxylic acid methyl ester (230 mg,0.8 mmol) in MeOH (10 mL)/H ₂ To a solution of O (2 mL) was added LiOH (160 mg,4 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The pH of the mixture was then adjusted to 5 with 1N HCl and extracted with EA (10 mL. Times.3). The combined organic layers were taken up over Na ₂ SO ₄ Dried, concentrated, and purified by preparative-HPLC to give the desired product 7-cyano-4-cyclopentyl-1H-indazole-6-carboxylic acid (170 mg,74.0% yield) as a pale yellow solid. LC/MS (ESI) M/z 256 (M+H) ⁺ 。

Step 7:to a stirred solution of 7-cyano-4-cyclopentyl-1H-indazole-6-carboxylic acid (130 mg,0.5 mmol) and DPPA (150 mg,0.5 mmol) in THF (5 mL) at 25℃was slowly added TEA (105 mg,1 mmol). The reaction mixture was stirred at 25℃under N ₂ Stirring is carried out for 2 hours under an atmosphere. Adding the mixture into H ₂ O (2 mL) and warmed to 65℃for an additional 3 hours. The reaction mixture was diluted with water (20 mL)And extracted with EtOAc (20 ml x 3). The combined organic phases were washed with water and brine, and the organic phases were washed with anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=2% -25% in PE) to give the desired product 6-amino-4-cyclopentyl-1H-indazole-7-carbonitrile (79 mg, yield: 68.6%) as a white solid. LC/MS (ESI) M/z 227 (M+H) ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δ8.01(s,1H),6.43(s,1H),4.66(s,2H),3.38–3.19(m,1H),2.14(dd,J＝14.1,8.7Hz,2H),1.89–1.70(m,6H)。

Step 8:to 6-amino-4-cyclopentyl-1H-indazole-7-carbonitrile (79 mg,0.3 mmol) and CH at 0deg.C ₂ I ₂ (187 mg,0.7 mmol) to a stirred solution in DCM (2.5 mL) and AcOH (0.4 mL,7 mmol) was slowly added NaNO ₂ (120 mg,1.7 mmol) in H ₂ O (2.5 mL), and the reaction mixture was stirred at 0deg.C for 5 min. The reaction mixture was diluted with water (10 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=2% -25% in PE) to give methyl 4- (cyclopent-1-en-1-yl) -7-methoxy-1H-indazole-6-carboxylate (75 mg, yield: 74%) as a white solid. LC/MS (ESI) M/z 338 (M+H) ⁺ 。1H NMR(400MHz,CDCl3)δ10.55(s,1H),8.20(s,1H),7.51(s,1H),3.43(dd,J＝16.9,8.9Hz,1H),2.19(dd,J＝11.4,6.6Hz,2H),1.95–1.74(m,6H)。

Step 9Synthesis of 4-cyclopentyl-6- (4-phenoxyphenyl) -1H-indazole-7-carbonitrile

To 4-cyclopentyl-6-iodo-1H-indazole-7-carbonitrile (30 mg,0.1 mmol) and (4-phenoxyphenyl) boronic acid (45 mg,0.2 mmol) in dioxane (3 mL) and H at 25deg.C ₂ To the stirred solution in O (1 mL) was slowly added NaHCO ₃ (20 mg,0.2 mmol) and Pd (dppf) Cl ₂ (10 mg,0.1 mmol) the reaction mixture was heated to 60℃for 18 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=2% -25% in PE) to give 4-cyclopentyl-6- (4-phenoxyphenyl) -1H-indazole-7-carbonitrile (14 mg, yield: 41.4%) as a white solid. LC/MS (ESI) M/z 380 (M+H) ⁺ 。1H NMR(400MHz,CDCl3)δ10.78(s,1H),8.28(s,1H),7.64–7.57(m,2H),7.44–7.35(m,2H),7.20–7.15(m,2H),7.15–7.08(m,4H),3.57–3.46(m,1H),2.34–2.14(m,2H),1.87(dddd,J＝14.4,9.1,6.8,4.7Hz,6H)。

Step 10To a stirred solution of 4-cyclopentyl-6- (4-phenoxyphenyl) -1H-indazole-7-carbonitrile (14 mg,0.1 mmol) and NaOH (40 mg,1.0 mmol) in THF (2 mL) and MeOH (2 mL) at room temperature was slowly added H ₂ O ₂ (2 mL) and the reaction mixture was stirred at 65deg.C under N ₂ Stirring is carried out for 18 hours under an atmosphere. The mixture was extracted with EtOAc (10 ml x 3) and the combined organic phases were washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was purified by preparative TLC (etoac=30% in PE) to give 4-cyclopentyl-6- (4-phenoxyphenyl) -1H-indazole-7-carboxamide (3 mg, yield: 23.9%) as a white solid. LC/MS (ESI) M/z 398 (M+H) ⁺ 。1H NMR(400MHz,CD ₃ OD)δ8.20(s,1H),7.52–7.47(m,2H),7.42–7.34(m,2H),7.14(t,J＝7.4Hz,1H),7.07–7.02(m,5H),3.53(dd,J＝16.0,8.1Hz,1H),2.25–2.18(m,2H),1.94–1.79(m,6H)。

Table 7 following compounds were prepared according to a similar procedure (B-1, pathway 2) for example 129 (with variations) from B-1-6 and the appropriate boronic acid/ester intermediates:

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EXAMPLE 133 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (pyrrolidin-1-yl) -1H-indazole-7-carboxamide (BNB-1063-01)

Step 1Pd was added to a solution of 4-bromo-1- (4-methoxybenzyl) -6- (methoxymethoxy) -1H-indazole-7-carbonitrile (250 mg,0.61 mmol) and pyrrolidine (66 mg,0.92 mmol) in dioxane (5 mL) ₂ (dba) ₃ (114 mg,0.14 mmol), xant-phos (72 mg,0.14 mmol) and Cs ₂ CO ₃ (405 mg,1.22 mmol) and the reaction mixture was stirred at 110℃under a nitrogen atmosphere for 10 hours. The reaction mixture was concentrated to give the crude product which was purified by silica gel column chromatography (meoh=1-3% in DCM) to give 6- (methoxymethoxy) -1- [ (4-methoxyphenyl) methyl ]-4- (pyrrolidin-1-yl) -1H-indazole-7-carbonitrile (180 mg, yield: 73.8%) as a grey solid, LC/MS (ESI) m/z:393[ M+1 ]] ⁺

Step 2To 6- (methoxymethoxy) -1- [ (4-methoxyphenyl) methyl]To a solution of 4- (pyrrolidin-1-yl) -1H-indazole-7-carbonitrile (180 mg,0.46 mmol) in THF (5 mL) was added 2N HCl (2 mL) and the reaction mixture was stirred at 55deg.C for 2 hours. The reaction mixture was extracted with EtOAc (20 ml x 2), the combined organic phases were washed with water and brine, and dried over Na ₂ SO ₄ Drying and concentrating to obtain crude product 6-hydroxy-1- [ (4-methoxyphenyl) methyl]-4- (pyrrolidin-1-yl) -1H-indazole-7-carbonitrile (140 mg, yield: 87.4%) was used as a yellow solid without further purification in the next step. LC/MS (ESI) m/z 349[ M+1 ]] ⁺

Step 36-hydroxy-1- [ (4-methoxyphenyl) methyl at-30 DEG C]To a solution of 4- (pyrrolidin-1-yl) -1H-indazole-7-carbonitrile (140 mg,0.40 mmol) in DCM (5 mL) was added DIPEA (51 mg,0.40 mmol) followed by Tf ₂ O (112 mg,0.402 mmol) and the reaction mixture was stirred at-30℃for 1 hour. The reaction mixture was extracted with DCM (10 ml x 3), the combined organic phases were washed with water and brine, over Na ₂ SO ₄ Drying and concentrating to obtain crude product of trifluoro methane sulfonic acid 7-cyanogen Methyl-1- [ (4-methoxyphenyl) methyl group]-4- (pyrrolidin-1-yl) -1H-indazol-6-yl ester (110 mg, yield: 57.5%) was used as brown solid in the next step without further purification. LC/MS (ESI) m/z 481[ M+1 ]] ⁺

Step 4To trifluoro methanesulfonic acid 7-cyano-1- [ (4-methoxyphenyl) methyl]-4- (pyrrolidin-1-yl) -1H-indazol-6-yl ester (110 mg,0.23 mmol) and 5-fluoro-2-methoxy-N- { [4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Methyl } benzamide (132 mg,0.34 mmol) in dioxane (4 mL) and H ₂ Pd (dppf) Cl was added to a solution in O (1 mL) ₂ .CH ₂ Cl ₂ (51 mg,0.06 mmol) and Na ₂ CO ₃ (66 mg,0.62 mmol) and the reaction mixture was taken up in N at 100deg.C ₂ Stirring is carried out for 10 hours under an atmosphere. The reaction mixture was concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (etoac=5% -20% in PE) to give the desired product N- [ (4- { 7-cyano-1- [ (4-methoxyphenyl) methyl]-4- (pyrrolidin-1-yl) -1H-indazol-6-yl } phenyl) methyl]-5-fluoro-2-methoxybenzamide (120 mg, yield: 66.7%) as a white solid. LC/MS (ESI) m/z 590[ M+1 ]] ⁺

Step 5To 6-chloro-4- {1, 4-dioxaspiro [4.5 ]]Dec-7-en-8-yl } -1- [ (4-methoxyphenyl) methyl]-1H-pyrazolo [4,3-c ]To a solution of pyridine-7-carboxylic acid methyl ester (65 mg,0.14 mmol) in DCM (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at 40℃for 5 h. The reaction mixture was concentrated in vacuo to give the crude product, N- ({ 4- [ 7-cyano-4- (pyrrolidin-1-yl) -1H-indazol-6-yl)]Phenyl } methyl) -5-fluoro-2-methoxybenzamide (60 mg, yield: 62.8%) was a brown oil, which was used in the next step without further purification. LC/MS (ESI) m/z 470[ M+1 ]] ⁺ 。

Step 6N- ({ 4- [ 7-cyano-4- (pyrrolidin-1-yl) -1H-indazol-6-yl)]Phenyl } methyl) -5-fluoro-2-methoxybenzamide (60 mg,0.13 mmol) in H ₂ SO ₄ The solution in (1 mL) was stirred at 55deg.C for 3 hours. The reaction mixture was poured into ice water, extracted with EtOAc (20 ml x 3) and the combined organic phases were washed with H ₂ Washing with O and brine, passing through anhydrousNa ₂ SO ₄ Drying and concentrating. The crude product was purified by preparative-TLC (meoh=5% in DCM) to give the desired product 6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido)]Methyl } phenyl) -4- (pyrrolidin-1-yl) -1H-indazole-7-carboxamide (6 mg, yield: 9.6%) was a white solid. LC/MS (ESI) m/z 488[ M+1 ]]+,1H NMR(400MHz,CD ₃ OD)δ8.26(s,1H),7.63(dd,J＝9.3,3.2Hz,1H),7.52–7.43(m,5H),7.30–7.23(m,1H),7.17(dd,J＝9.0,4.1Hz,1H),5.93(s,1H),4.68(s,2H),3.97(s,3H),3.73–3.64(m,4H),2.15–2.07(m,4H)。

Example 134 (R) -6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (3-hydroxypyrrolidin-1-yl) -1H-indazole-7-carboxamide (BNB-1072-01)

Step 1In N ₂ Cs was added to a solution of 4-bromo-1- (4-methoxybenzyl) -6- (methoxymethoxy) -1H-indazole-7-carbonitrile (300 mg,0.75 mmol) and (3R) -pyrrolidin-3-ol (78 mg,0.90 mmol) in dioxane (5 mL) ₂ CO ₃ (4816 mg,1.49 mmol), xant-phos (86 mg,0.15 mmol) and Pd ₂ (dba) ₃ (68 mg,0.075 mmol). The resulting mixture was stirred at 110℃overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (etoac=0-100% in PE) to give the desired product (R) -4- (3-hydroxypyrrolidin-1-yl) -1- (4-methoxybenzyl) -6- (methoxymethoxy) -1H-indazole-7-carbonitrile (120 mg, 39.4% yield) as an oil. LC/MS (ESI) M/z 409 (M+H) ⁺ 。

Step 2In N ₂ To a solution of (R) -4- (3-hydroxypyrrolidin-1-yl) -1- (4-methoxybenzyl) -6- (methoxymethoxy) -1H-indazole-7-carbonitrile (120 mg,0.29 mmol) in THF (2 mL) was added 2N HCl (2 mL). The mixture was stirred at 65℃for 3 hours. The solvent was concentrated under reduced pressure to give the crude product (R) -6-hydroxy-4- (3-hydroxypyrrolidin-1-yl) -1- (4-methoxybenzyl) -1H-indazole-7-carbonitrile (70 mg, yield: 65.4%) asYellow solid, which was used directly without further purification. LC/MS (ESI) M/z 365 (M+H) ⁺ 。

Step 3NEt was added to a solution of (R) -6-hydroxy-4- (3-hydroxypyrrolidin-1-yl) -1- (4-methoxybenzyl) -1H-indazole-7-carbonitrile (70 mg,0.19 mmol) in DCM (5 mL) at-50 ℃ ₃ (77.6 mg,0.77 mmol) and trifluoromethanesulfonic anhydride (108 mg,0.38 mmol). The mixture was stirred for 10 minutes. The solvent was concentrated under reduced pressure to give the crude product (R) -trifluoromethanesulfonic acid 7-cyano-4- (3-hydroxypyrrolidin-1-yl) -1- (4-methoxybenzyl) -1H-indazol-6-yl ester (60 mg, yield: 62.9%) as a yellow solid, which was used without further purification. LC/MS (ESI) M/z 497 (M+H) ⁺ 。

Step 4In N ₂ Downward (R) -trifluoromethanesulfonic acid 7-cyano-4- (3-hydroxypyrrolidin-1-yl) -1- (4-methoxybenzyl) -1H-indazol-6-yl ester (60 mg,0.12 mmol) and 5-fluoro-2-methoxy-N- { [4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Methyl } benzamide (51 mg,0.13 mmol) in dioxane (4 mL) and H ₂ K was added to a solution in O (1 mL) ₂ CO ₃ (33 mg,0.24 mmol) and Pd (dppf) Cl ₂ (9 mg,0.012 mmol). The reaction mixture was heated to 90 ℃ for 3 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The mixture was washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product which was purified by silica gel column chromatography (etoac=10% -100% in PE) to give the desired product N- [ (4- { 7-cyano-4- [ (3R) -3-hydroxypyrrolidin-1-yl)]-1- [ (4-methoxyphenyl) methyl group]-1H-indazol-6-yl } phenyl) methyl]-5-fluoro-2-methoxybenzamide (40 mg, yield: 54.7%) as a white solid. LC/MS (ESI) M/z 606 (M+H) ⁺ 。

Step 5To a stirred suspension of (R) -N- (4- (7-cyano-4- (3-hydroxypyrrolidin-1-yl) -1- (4-methoxybenzyl) -1H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (40 mg,0.066 mmol) in TFA (3 mL). The mixture was stirred at 65℃for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc(50 mL. Times.3), the combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give a residue, which was purified by silica gel column chromatography (PE: etoac=100 to 10:1) to give (R) -N- (4- (7-cyano-4- (3-hydroxypyrrolidin-1-yl) -1H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (30 mg, yield: 93.6%) as a white solid. LC/MS (ESI) M/z 486 (M+H) ⁺ 。

Step 6(R) -N- (4- (7-cyano-4- (3-hydroxypyrrolidin-1-yl) -1H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (30 mg,0.062 mmol) in concentrated H ₂ SO ₄ (1 mL) of the suspension. The mixture was stirred at 60℃for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (50 ml×3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE: etoac=100 to 1:10) to give (R) -6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (3-hydroxypyrrolidin-1-yl) -1H-indazole-7-carboxamide (4.4 mg, yield: 14%) as a white solid. LC/MS (ESI) M/z 504 (M+H) ⁺ 。1H NMR(400MHz,DMSO)δ12.60(s,1H),8.86(s,1H),8.21(s,1H),7.53(d,J＝6.6Hz,1H),7.40-7.35(m,5H),7.22—7.21(m,1H),7.07(s,1H),6.08(s,1H),5.80(s,1H),5.04(s,1H),4.56(d,J＝5.3Hz,2H),4.44(s,1H),3.91(s,3H),3.79-3.63(m,3H),3.46-3.44(m,1H),2.05-1.97(m,2H)。

TABLE 8 preparation of the following compounds from B-1-3a and the appropriate boronic acid/ester intermediates according to the procedure (B-2, pathway 1) used to prepare example 133& example 134 (with variations)

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Example 146 (R) -5-chloro-6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (2-methylpyrrolidin-1-yl) -1H-indazole-7-carboxamide (BNB-1119-01)

Step 1Pd was added to a solution of 4-bromo-1- (4-methoxybenzyl) -6- (methoxymethoxy) -1H-indazole-7-carbonitrile (250 mg,0.61 mmol) and (R) -2-methylpyrrolidine (78 mg,0.92 mmol) in dioxane (5 mL) ₂ (dba) ₃ (114 mg,0.14 mmol), xant-phos (72 mg,0.14 mmol) and Cs ₂ CO ₃ (405 mg,1.22 mmol) and the reaction mixture was stirred at 110℃under a nitrogen atmosphere for 10 hours. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (meoh=1% -3% in DCM) to give (R) -1- (4-methoxybenzyl) -6- (methoxymethoxy) -4- (2-methylpyrrolidin-1-yl) -1H-indazole-7-carbonitrile (230 mg, yield: 92.8%) as a grey solid, LC/MS (ESI) m/z:407[ m+1 ] ] ⁺

Step 2To a solution of (R) -1- (4-methoxybenzyl) -6- (methoxymethoxy) -4- (2-methylpyrrolidin-1-yl) -1H-indazole-7-carbonitrile (230 mg,0.57 mmol) in THF (5 mL) was added 2N HCl (2 mL) and the reaction mixture was stirred at 55deg.C for 2 hours. The reaction mixture was extracted with EtOAc (20 ml x 2), the combined organic phases were washed with water and brine, and dried over Na ₂ SO ₄ Drying and concentration gave the crude product (R) -6-hydroxy-1- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-yl) -1H-indazole-7-carbonitrile (200 mg, yield: 96.9%) as a yellow solid which was used in the next step without further purification. LC/MS (ESI) m/z 363[ M+1 ]] ⁺

Step 3To a solution of (R) -6-hydroxy-1- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-yl) -1H-indazole-7-carbonitrile (200 mg,0.55 mmol) in DMF (5 mL) was added NCS (74 mg,0.55 mmol) at-20℃and the mixture was stirred at room temperature for 8 hours. The mixture is treated with H ₂ O (10 mL) was diluted, extracted with EtOAc (10 mL. Times.2), the combined organic phases were washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Drying and passingFiltration and concentration gave the crude product, which was purified by silica gel column chromatography (meoh=1% -5% in DCM) to give the desired product (R) -5-chloro-6-hydroxy-2- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-yl) -2H-indazole-7-carbonitrile (120 mg, yield: 54%) as a white solid. LC/MS (ESI) m/z 397[ M+1 ] ] ⁺

Step 4To a solution of (R) -5-chloro-6-hydroxy-2- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-yl) -2H-indazole-7-carbonitrile (120 mg,0.30 mmol) in DCM (5 mL) was added DIPEA (78 mg,0.60 mmol) dropwise at-30deg.C followed by Tf ₂ O (0.06 mL,0.36 mmol). The mixture was stirred at-30℃for 1 hour. The reaction mixture was treated with H ₂ O (10 mL) was diluted, extracted with DCM (10 mL. Times.2), the combined organic phases were washed with water and brine, and dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give (R) -trifluoromethanesulfonic acid 5-chloro-7-cyano-2- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-yl) -2H-indazol-6-yl ester (110 mg, yield: 68.8%) as a brown solid, which was used directly in the next step without further purification. LC/MS (ESI) M/z 530 (M+H) ⁺

Step 5Pd (dppf) Cl2 (15 mg,0.02 mmol) was added to a solution of (R) -trifluoromethanesulfonic acid 5-chloro-7-cyano-2- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-yl) -2H-indazol-6-yl ester (110 mg,0.21 mmol), 5-fluoro-2-methoxy-N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide (80 mg,0.21 mmol) and Na2CO3 (44 mg,0.42 mmol) in dioxane (4 mL) and H2O (1 mL), and the reaction mixture was concentrated in vacuo to give the crude product as a white solid (R) -N- (4- (5-chloro-7-cyano-2- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-yl) -2H-indazol-6-methoxybenzyl) as a solid (100 mg) by silica gel column chromatography purification of EtOAc=5% -30% in PE. LC/MS (ESI) m/z 639[ M+1 ] ] ⁺

Step 6To a solution of (R) -N- (4- (5-chloro-7-cyano-2- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-yl) -2H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (100 mg,0.16 mmol) in DCM (2 mL) was added TFA (2)mL), the reaction mixture was stirred at 40 ℃ for 5 hours. The reaction mixture was concentrated in vacuo to give the crude product (R) -N- (4- (5-chloro-7-cyano-4- (2-methylpyrrolidin-1-yl) -1H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (65 mg, yield: 63.12%) as a brown solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z 519[ M+1 ]] ⁺

Step 7(R) -N- (4- (5-chloro-7-cyano-4- (2-methylpyrrolidin-1-yl) -1H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (65 mg,0.13 mmol) was reacted in H ₂ SO ₄ The solution in (1 mL) was stirred at 55deg.C for 3 hours. The reaction mixture was poured into ice water, extracted with EtOAc (20 ml x 3) and the combined organic phases were washed with H ₂ Washing with O and brine, passing through anhydrous Na ₂ SO ₄ Drying and concentrating. The crude product was purified by preparative-TLC (meoh=5% in DCM) to give the desired product (R) -5-chloro-6- (4- ((5-fluoro-2-methoxybenzamido) methyl) phenyl) -4- (2-methylpyrrolidin-1-yl) -1H-indazole-7-carboxamide (26 mg, yield: 41.9%) as a white solid: ¹ H NMR(400MHz,DMSO)δ13.16(s,1H),8.88(t,J＝6.2Hz,1H),8.30(s,1H),7.55(dd,J＝9.2,3.3Hz,1H),7.39–7.31(m,3H),7.23(ddd,J＝13.5,11.7,5.6Hz,5H),4.58(d,J＝6.1Hz,2H),4.37(dd,J＝13.7,6.3Hz,1H),3.99(dd,J＝15.6,8.5Hz,1H),3.91(s,3H),3.19(t,J＝6.7Hz,1H),2.24(s,1H),1.90(dd,J＝31.7,21.6Hz,2H),1.61–1.48(m,1H),1.01(d,J＝6.0Hz,3H)；LC/MS(ESI)m/z:537[M+1] ⁺ 。

Example 147 (R) -6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (2-methylpyrrolidin-1-yl) -1H-indazole-7-carboxamide (BNB-1109-01)

Step 1In N ₂ Cs was added to a solution of 4-bromo-6-hydroxy-2- (4-methoxybenzyl) -2H-indazole-7-carbonitrile (400 mg,1.11 mmol) and (2R) -2-methylpyrrolidine (114 mg,1.34 mmol) in dioxane (5 mL) ₂ CO ₃ (727mg，2.23mmol), SPhos (45 mg,0.11 mmol) and Pd ₂ (dba) ₃ (102 mg,0.11 mmol). The resulting mixture was stirred at 110℃for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=50% to 70% in PE) to give the desired product (R) -6-hydroxy-2- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-yl) -2H-indazole-7-carbonitrile (437 mg, yield: 107%) as a yellow solid. LC/MS (ESI) M/z 363 (M+H) ⁺ 。

Step 2To a solution of (R) -6-hydroxy-2- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-yl) -2H-indazole-7-carbonitrile (437 mg,1.20 mmol) in DCM (10 mL) was added DIPEA (0.4 mL,2.41 mmol) and trifluoromethanesulfonic anhydride (0.24 mL,1.40 mmol) at-30deg.C. The mixture was stirred at this temperature for 30 minutes. The solvent was concentrated under reduced pressure to give the crude product (R) -trifluoromethanesulfonic acid 7-cyano-2- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-yl) -2H-indazol-6-yl ester (596 mg, yield: 99.96%) as a yellow solid, which was used directly in the next step without further purification. LC/MS (ESI) M/z 495 (M+H) ⁺ 。

Step 3In N ₂ Downward (R) -trifluoromethanesulfonic acid 7-cyano-2- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-yl) -2H-indazol-6-yl ester (596 mg,1.20 mmol) and 5-fluoro-2-methoxy-N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide (510 mg,1.32 mmol) in dioxane (10 mL) and H ₂ Cs was added to a solution in O (2 mL) ₂ CO ₃ (785 mg,2.41 mmol) and Pd (dppf) Cl ₂ (88 mg,0.12 mmol). The reaction mixture was heated to 90 ℃ for 3 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL), the mixture was washed with water and brine, and the organic phase was washed with anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (etoac=30% to 50% in PE) to give the desired product (R) -N- (4- (7-cyano-2- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-yl) -2H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (342 mg, yield: 47%) as a white solid. LC/MS (ESI) M/z 604 (M+H) ⁺ 。

Step 4A solution of (R) -N- (4- (7-cyano-2- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-yl) -2H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (348 mg,0.56 mmol) in TFA (5 mL) was stirred at 65℃for 3 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo to give the crude product, which was dissolved in EtOAc (15 mL) and saturated with NaHCO ₃ The pH was adjusted to 8. The organic phase was washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=0% to 10% in PE) to give (R) -N- (4- (7-cyano-4- (2-methylpyrrolidin-1-yl) -1H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (150 mg, yield: 54%) as a red solid. LC/MS (ESI) M/z 484 (M+H) ⁺ 。

Step 5(R) -N- (4- (7-cyano-4- (2-methylpyrrolidin-1-yl) -1H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (150 mg,0.31 mmol) was concentrated H ₂ SO ₄ The solution in (3 mL) was stirred at 60℃for 1 hour. After cooling to room temperature, the reaction mixture was poured into ice-water (20 mL) and extracted with EtOAc (20 ml×3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography (etoac=100% in PE) to give example 147 (10.5 mg, yield: 6.75%) as a white solid: ¹ H NMR(400MHz,DMSO)δ12.59(s,1H),8.86(t,J＝6.1Hz,1H),8.17(s,1H),7.53(dd,J＝9.2,3.3Hz,1H),7.45–7.30(m,5H),7.19(dd,J＝9.2,4.3Hz,1H),7.07(s,1H),6.13(s,1H),5.85(s,1H),4.56(d,J＝6.1Hz,2H),4.28(s,1H),3.91(s,3H),3.76(s,1H),3.54(d,J＝8.7Hz,1H),2.06(dd,J＝28.8,21.4Hz,3H),1.72(s,1H),1.19(d,J＝6.1Hz,3H)；LC/MS(ESI)m/z:502(M+H) ⁺ 。

EXAMPLE 148 6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-indazole-7-carboxamide (BNB-1059-01)

Step 1To a solution of 2-fluoro-6-hydroxybenzonitrile (2 g,14.6 mmol) in DCM (20 mL) was added MOMCl (1.41 g,17.5 mmol) and DIPEA (2.8 g,21.9 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was taken up in DCM (20 mL) and saturated Na ₂ CO ₃ And (5) diluting the solution. The organic layer was collected, washed with saturated NaCl solution and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=10% -50% in PE) to give the desired product 2-fluoro-6- (methoxymethoxy) benzonitrile (2.5 g, yield: 94.6%) as a white solid.

Step 2at-78deg.C at N ₂ To a solution of 2-fluoro-6- (methoxymethoxy) benzonitrile (2.5 g,13.8 mmol) in THF (20 mL) was added LDA (10.4 mL,20.7 mmol). The reaction mixture was stirred at the same temperature for 1 hour, followed by addition of DMF (1.2 g,16.7 mmol) and the resulting mixture was kept at-78℃for an additional 1 hour. Saturated NH for the reaction ₄ The Cl solution was quenched and extracted with EtOAc (20 mL. Times.3). The combined organic phases were treated with anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product which was purified by silica gel column chromatography (etoac=10% -30% in PE) to give the desired product 2-fluoro-3-formyl-6- (methoxymethoxy) benzonitrile (1.2 g, yield: 40.9%) as a brown oil. ¹ H NMR(400MHz,CDCl ₃ )δ10.23(s,1H),8.12–7.98(m,1H),7.17(d,J＝9.0Hz,1H),5.40(s,2H),3.54(s,3H)。

Step 3To a solution of 2-fluoro-3-formyl-6- (methoxymethoxy) benzonitrile (400 mg,1.9 mmol) in EtOH (10 mL) was added hydrazine (721 mg,19.1 mmol). The reaction mixture was stirred at 85℃for 12 hours. The resulting yellow solid was collected by filtration. The filter cake was washed with MeCN and then dried to give the crude product 6- (methoxymethoxy) -1H-indazole-7-carbonitrile (360 mg, yield: 92.7%) as a yellow solid which was used directly in the next step without further purification. LCMS ESI m/z 204[ M+H ] ] ⁺ 。

Step 4To 6- (methoxymethoxy) -1H-indazole-7-ATo a solution of nitrile (360 mg,1.8 mmol) in DMF (10 mL) was added PMBCl (0.3 mL,2.1 mmol) and Cs ₂ CO ₃ (808.0 mg,2.5 mmol) and the reaction mixture was stirred at 60℃for 1.5 h. The reaction mixture was diluted with EtOAc (30 mL). The mixture was washed with saturated LiCl solution, water and brine. The organic phase was dried, filtered and concentrated to give the crude product which was purified by silica gel column chromatography (etoac=10% -30% in PE) to give the desired product 6- (methoxymethoxy) -1- [ (4-methoxyphenyl) methyl]-1H-indazole-7-carbonitrile (380 mg, yield: 66.3%) as a yellow oil. LCMS ESI m/z 324[ M+H ]] ⁺ 。

Step 5To 6- (methoxymethoxy) -1- [ (4-methoxyphenyl) methyl]To a solution of 1H-indazole-7-carbonitrile (380 mg,1.2 mmol) in MeOH (5 mL) was added HCl (1 mL,2 mmol) and the resulting mixture was heated to 65℃for 1 hour. The reaction mixture was concentrated to give a crude product which was purified by silica gel column chromatography (etoac=5% -30% in PE) to give the desired product 6-hydroxy-1- [ (4-methoxyphenyl) methyl]-1H-indazole-7-carbonitrile (280 mg, yield: 85.3%) as a yellow oil. LCMS ESI m/z 280[ M+H ] ] ⁺ 。

Step 6To 6-hydroxy-1- [ (4-methoxyphenyl) methyl]To a solution of 1H-indazole-7-carbonitrile (147 mg,0.5 mmol) in DCM (10 mL) was added TEA (80 mg,0.8 mmol) and Tf ₂ O (178 mg,0.6 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (20 mL), the organic phase was washed with water and brine, the collected organic layer was dried, filtered, and concentrated to give the crude product 7-cyano-1- [ (4-methoxyphenyl) methyl triflate]-1H-indazol-6-yl ester (167 mg, yield: 77.1%) as yellow oil, which was used directly in the next step without further purification. LCMS ESI m/z 412[ M+H ]] ⁺ 。

Step 7To trifluoro methanesulfonic acid 7-cyano-1- [ (4-methoxyphenyl) methyl]-1H-indazol-6-yl ester (167 mg,0.4 mmol) and 2-methoxy-N- { [4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Methyl } benzamide (164 mg,0.45 mmol) in dioxane (10 mL) and H ₂ K was added to the solution in O (2 mL) ₂ CO ₃ (112 mg,0.8 mmol) and Pd (dppf) Cl ₂ (29 mg,0.04 mmol) and the reaction mixture was taken up in N at 100deg.C ₂ Stirring is carried out for 2 hours under an atmosphere. The reaction was cooled and concentrated to give the crude product which was purified by silica gel column chromatography (etoac=10% -50% in PE) to give the desired product N- [ (4- { 7-cyano-1- [ (4-methoxyphenyl) methyl ]-1H-indazol-6-yl } phenyl) methyl]-2-methoxybenzamide (182 mg, yield: 89.2%) as a yellow oil. LCMS ESI m/z 503[ M+H ]] ⁺ 。

Step 8:n- [ (4- { 7-cyano-1- [ (4-methoxyphenyl) methyl)]-1H-indazol-6-yl } phenyl) methyl]A solution of 2-methoxybenzamide (120 mg,0.24 mmol) in TFA (2 mL) was heated to 75deg.C for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in EtOAc (15 mL) and taken up in saturated NaHCO ₃ The solution (5 mL. Times.3) was washed. The organic layer was collected, dried, and concentrated to give the crude product N- { [4- (7-cyano-1H-indazol-6-yl) phenyl]Methyl } -2-methoxybenzamide (103 mg, yield: 86.8%) was used as a brown solid directly in the next step without further purification. LCMS: ESI m/z 383[ M+H ]] ⁺ 。

Step 9:to N- { [4- (7-cyano-1H-indazol-6-yl) phenyl]To a solution of methyl } -2-methoxybenzamide (98 mg,0.26 mmol) in EtOH (2 mL) and THF (2 mL) was added NaOH (20 mg,0.5 mmol) and H ₂ O ₂ (1 mL) and the reaction mixture was stirred at 60℃for 2 hours. The reaction mixture was diluted with EtOAc (20 mL). The resulting mixture was washed with water and brine, the collected organic phases were dried, filtered, and concentrated to give the crude product which was purified by silica gel column chromatography (meoh=10% -50% in DCM) to give the desired product 6- (4- { [ (2-methoxyphenyl) carboxamido ]Methyl } phenyl) -1H-indazole-7-carboxamide (17 mg, yield: 34.2%) as a white solid. LCMS ESI m/z 401[ M+H ]] ⁺ 。1HNMR(400MHz,DMSO)δ13.16(s,1H),8.77(t,J＝6.1Hz,1H),8.13(s,1H),7.89–7.74(m,2H),7.65(s,1H),7.50(dd,J＝13.1,4.9Hz,4H),7.39(d,J＝8.1Hz,2H),7.20–7.01(m,3H),4.56(d,J＝6.1Hz,2H),3.92(s,3H)

Example 149:

6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -4- (2-oxopyrrolidin-1-yl) -1H-pyrazolo [4,3-c ] pyridine-7-carboxamide (BNB-1088-01)

Step 14, 6-dichloro-1- [ (4-methoxyphenyl) methyl group at 25 DEG C]-1H-pyrazolo [4,3-c]To a stirred solution of pyridine-7-carboxamide (80 mg,0.23 mmol) and tert-butyl 4-aminobutyrate (50 mg,0.31 mmol) in DMF (2 mL) was added TEA (40 mg,0.40 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water (5 mL), the mixture extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, and dried over Na ₂ SO ₄ Drying, filtration and concentration gave the crude product which was purified by silica gel column chromatography (etoac=10% -50% in PE) to give the desired product 4- ({ 7-carbamoyl-6-chloro-1- [ (4-methoxyphenyl) methyl)]-1H-pyrazolo [4,3-c]Tert-butyl pyridin-4-yl } amino) butyrate (90 mg, yield: 83%) was an off-white oil. LC/MS (ESI) M/z 474 (M+H) ⁺ 。

Step 2To 4- ({ 7-carbamoyl-6-chloro-1- [ (4-methoxyphenyl) methyl) at 25 ℃C ]-1H-pyrazolo [4,3-c]Tert-butyl pyridin-4-yl } amino) butyrate (90 mg,0.19 mmol) and 5-fluoro-2-methoxy-N- { [4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Methyl } benzamide (100 mg,0.26 mmol) in 1, 4-dioxane (5 mL) and H ₂ Pd (dppf) Cl was added to the stirred solution in O (1 mL) ₂ (30 mg,0.041 mmol) and K ₂ CO ₃ (100 mg,0.724 mmol) and the reaction mixture was stirred at 110℃under N ₂ Stirring is carried out for 18 hours under an atmosphere. The reaction mixture was diluted with water (10 mL), the mixture was extracted with EtOAc (15 mL x 3), the combined organic phases were washed with water and brine, and the organic phases were washed with anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=1 in PE0% to 50%) to give the desired product 4- { [ 7-carbamoyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido-e]Methyl } phenyl) -1- [ (4-methoxyphenyl) methyl]-1H-pyrazolo [4,3-c]Pyridin-4-yl]Tert-butyl amino } butyrate (90 mg, yield: 68%) was an off-white oil. LC/MS (ESI) M/z 697 (M+H) ⁺ 。

Step 34- { [ 7-carbamoyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido) at 25 ℃]Methyl } phenyl) -1- [ (4-methoxyphenyl) methyl ]-1H-pyrazolo [4,3-c]Pyridin-4-yl]To a stirred solution of tert-butyl amino } butyrate (90 mg,0.13 mmol) in DCM (5 mL) was added TFA (3 mL) and the reaction mixture was stirred at 50deg.C for 18 h. The reaction mixture was poured into water (5 mL), extracted with EtOAc (60 mL. Times.3) and the combined organic phases were washed with saturated NaHCO ₃ Washing with water and brine, and subjecting the organic phase to anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product which was purified by silica gel column chromatography (meoh=1% -5% in DCM) to give the desired product 4- { [ 7-carbamoyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido)]Methyl } phenyl) -1H-pyrazolo [4,3-c]Pyridin-4-yl]Amino } butyric acid (40 mg, yield: 59.6%) was an off-white solid. LC/MS (ESI) M/z 521 (M+H) ⁺ 。

Step 44- { [ 7-carbamoyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido) at 25 ℃]Methyl } phenyl) -1H-pyrazolo [4,3-c]Pyridin-4-yl]To a stirred solution of amino } butyric acid (45 mg,0.1 mmol) and HATU (50 mg,0.13 mmol) in DMF (2 mL) was added DIPEA (25 mg,0.19 mmol) and the reaction mixture was heated to 50deg.C for 18 hours. The reaction mixture was poured into water (10 mL), the mixture extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, and the organic phases were washed with anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product which was purified by silica gel column chromatography (meoh=1% -5% in DCM) to give the desired product 6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido]Methyl } phenyl) -4- (2-oxopyrrolidin-1-yl) -1H-pyrazolo [4,3c]Pyridine-7-carboxamide (10 mg, yield: 23%) as a white solid. LC/MS (ESI) M/z 503 (M+H) ⁺ 。1H NMR(400MHz,DMSO)δ8.86(t,J＝5.6Hz,1H),8.34(s,1H),7.84(s,1H),7.75(d,J＝8.2Hz,2H),7.64(s,1H),7.52(dd,J＝9.3,3.3Hz,1H),7.43–7.30(m,3H),7.19(dd,J＝9.2,4.3Hz,1H),4.55(d,J＝6.3Hz,2H),4.12(t,J＝7.1Hz,2H),3.90(s,3H),2.67(dd,J＝4.9,3.0Hz,2H),2.19–2.09(m,2H)。

EXAMPLE 150 4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-pyrrolo [3,2-c ] pyridine-7-carboxamide (BNB-1050-01)

Step 1In N ₂ To 2, 6-dichloropyridin-4-amine (25.0 g,153.37 mmol) and Boc with stirring ₂ To a solution of O (100.3 g,460.1 mmol) in DCM (300 mL) was added DMAP (1.87 g,15.3 mmol). The mixture was stirred for 3 hours until the starting material was completely consumed. The reaction mixture was concentrated in vacuo to remove excess DCM. The residue was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layer was dried over MgSO ₄ Drying, filtration, and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=0-2% in PE). The title N- [ (tert-butoxy) carbonyl group]Tert-butyl N- (2, 6-dichloropyridin-4-yl) carbamate (55 g, 99% yield) as a white solid. LC/MS (ESI) M/z 364 (M+H) +.

Step 2at-78deg.C at N ₂ Downwards N- [ (tert-butoxy) carbonyl]To a solution of tert-butyl N- (2, 6-dichloropyridin-4-yl) carbamate (55.0 g,151.4 mmol) in THF (300 mL) was added LDA (227 mL,454.2 mmol). The mixture was stirred for 30 minutes until the starting material was completely consumed. The reaction mixture was warmed to room temperature and saturated NH ₄ The Cl solution was quenched and extracted with EtOAc (100 mL. Times.3). The organic layer was dried over MgSO ₄ Drying, filtration and concentration gave the crude product which was purified by silica gel column chromatography (etoac=0 to 2% in PE) to give the desired product tert-butyl 4- (tert-butoxycarbonylamino) -2, 6-dichloronicotinic acid ester (53 g, 96% yield) as a white solid. LC/MS (ESI) M/z 364 (M+H) ⁺ 。1H NMR(400MHz,DMSO)δ9.84(s,1H),7.63(s,1H),1.60(s,9H),1.52(s,9H)。

Step 3:at N ₂ To a solution of tert-butyl 4- (tert-butoxycarbonylamino) -2, 6-dichloronicotinic acid (2.0 g,5.51 mmol) and 2-cyclopentenyl-4, 5-tetramethyl-1, 3, 2-dioxaborolan (0.96 g,4.96 mmol) in dioxane (15 mL) and water (3 mL) was added K ₂ CO ₃ (1.52 g,11.01 mmol) and Pd (dppf) Cl ₂ (0.2 g,0.28 mmol). The resulting mixture was stirred at 60℃for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (etoac=0-2% in PE) to give the desired product tert-butyl 4- (tert-butoxycarbonylamino) -2-chloro-6-cyclopentenyl nicotinate (1.1 g, 51% yield) as a white solid. LC/MS (ESI) M/z 395 (M+H) ⁺ 。 ¹ HNMR(400MHz,DMSO)δ9.46(s,1H),7.52(s,1H),6.67(s,1H),2.69–2.60(m,2H),2.55(m,2H),2.02–1.97(m,2H),1.54(s,9H),1.46(d,J＝1.7Hz,9H)。

Step 4:to a solution of tert-butyl 4- (tert-butoxycarbonylamino) -2-chloro-6-cyclopentenyl nicotinic acid (1.1 g,2.8 mmol) in EtOAc (20 mL) was added Pt/C (50 mg). The mixture was stirred at room temperature at H ₂ Stirring is carried out for 4 hours under an atmosphere. The resulting reaction mixture was filtered and concentrated to give a crude product, which was purified by silica gel column chromatography (etoac=1 to 4% in PE) to give the desired product, tert-butyl 4- (tert-butoxycarbonylamino) -2-chloro-6-cyclopentylnicotinic acid (540 mg, yield: 49%), as a white solid. LC/MS (ESI) M/z 397 (M+H) ⁺ 。1H NMR(400MHz,DMSO)δ9.40(s,1H),7.38(s,1H),3.08(m,1H),2.06–1.89(m,2H),1.75(m,2H),1.64(m,4H),1.53(s,9H),1.46(s,9H)。

Step 5In N ₂ Downward 4- { [ (tert-butoxy) carbonyl]To a solution of tert-butyl amino } -2-chloro-6-cyclopentylpyridine-3-carboxylate (540 mg,1.3 mmol) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred for 3 hours. The solvent was concentrated under reduced pressure to give the crude product 4-amino-2-chloro-6-cyclopentylpyridine-3-carboxylic acid (280 mg, yield: 89.7%) as a yellow solid, which was used without further purification. LC/MS (ESI) M/z 241 (M+H) ⁺

Step 6In N ₂ To a solution of 4-amino-2-chloro-6-cyclopentylpyridine-3-carboxylic acid (280 mg,1.1 mmol) in DCM (5 mL) was added TMSCHN under an atmosphere ₂ (501 mg,4.4 mmol). The mixture was stirred for 1 hour. The reaction mixture was quenched with AcOH (1 mL) under ice bath. The mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (etoac=2% -10% in PE) to give the desired product, methyl 4-amino-2-chloro-6-cyclopentylpyridine-3-carboxylate (190 mg, yield: 68%), as a white solid. LC/MS (ESI) M/z 255 (M+H) ⁺ 。1H NMR(400MHz,CDCl ₃ )δ6.35(s,1H),5.70(br,2H),3.08–2.88(m,1H),2.00(m,2H),1.84–1.74(m,2H),1.73–1.63(m,4H)。

Step 7NBS (145 mg,0.8 mmol) was added to a solution of methyl 4-amino-2-chloro-6-cyclopentylpyridine-3-carboxylate (190 mg,0.74 mmol) in MeCN (5 mL) at 0deg.C, and the resulting mixture was stirred at 0deg.C for 2 hours. The solvent was removed under reduced pressure to give a crude product, which was purified by silica gel column chromatography (etoac=0 to 5% in PE) to give the desired product, methyl 4-amino-5-bromo-2-chloro-6-cyclopentylpyridine-3-carboxylate (230 mg, yield: 93.3%), as a white solid. LC/MS (ESI) M/z 333/335 (M+H) ⁺

Step 8In N ₂ Downward 4-amino-5-bromo-2-chloro-6-cyclopentylpyridine-3-carboxylic acid methyl ester (200 mg,0.6 mmol) and 2-methoxy-N- { [4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl group]Methyl } benzamide (220 mg,0.6 mmol) in dioxane (6 mL) and H ₂ K was added to the solution in O (2 mL) ₂ CO ₃ (247 mg,1.8 mmol) and Pd (PPh) ₃ ) ₄ (35 mg,0.030 mmol). The reaction mixture was heated to 80 ℃ for 10 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The mixture was washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (etoac=10% -20% in PE) to give the desired product, methyl 4-amino-5-bromo-6-cyclopentyl-2- (4- ((2-methoxybenzoylamino) methyl) phenyl) nicotinate (140 mg, yield: 43.4%), As a white solid. LC/MS (ESI) M/z 538/540 (M+H) ⁺

Step 9In N ₂ Downward 4-amino-5-bromo-6-cyclopentyl-2- (4- ((2-methoxybenzoylamino) methyl) phenyl) nicotinic acid methyl ester (210 mg,0.390 mmol) and 2- [ 2-ethoxyvinyl]-4, 5-tetramethyl-1, 3-dioxolane (78 mg,0.4 mmol) in 1, 4-dioxane (8 mL) and H ₂ K was added to the solution in O (2 mL) ₂ CO ₃ (161 mg,1.2 mmol) and Pd (PPh) ₃ ) ₄ (45 mg,0.04 mmol). The reaction mixture was heated to 60 ℃ for 10 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The mixture was washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (etoac=10% -20% in PE) to give the desired product methyl 4-amino-6-cyclopentyl-2- (4- ((2-methoxybenzamido) methyl) phenyl) -5- (2-methoxyvinyl) nicotinate (140 mg, yield: 67.8%) as a white solid. LC/MS (ESI) M/z 516 (M+H) ⁺

Step 10A solution of methyl 4-amino-6-cyclopentyl-2- (4- ((2-methoxybenzoylamino) methyl) phenyl) -5- (2-methoxyvinyl) nicotinic acid (140 mg,0.3 mmol) in AcOH (5 mL) was heated to 100deg.C in a microwave reactor. The reaction mixture was then concentrated, diluted with EtOAc (20 mL), washed with water and brine. The organic layer was treated with anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product, which is purified by silica gel column chromatography (DCM: meoh=100:1 to 30:1) to give 4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-pyrrolo [3,2-c]Pyridine-7-carboxylic acid methyl ester (100 mg, yield: 78.2%) as a white solid. LC/MS (ESI) M/z 484 (M+H) ⁺

Step 11To 4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-pyrrolo [3,2-c]To a solution of methyl pyridine-7-carboxylate (100 mg,0.206 mmol) in THF (5 mL) was added ammonia solution (5 mL,28% in water). The mixture was stirred in a sealed jar at 100℃for 12 hours. Cooling to room temperature, concentrating the reaction mixture to obtainThe crude product was purified by preparative-TLC (DCM: meoh=15:1) to give the desired product

4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-pyrrolo [3,2-c]Pyridine-7-carboxamide (5.5 mg, yield: 5.69%) as a white solid. LC/MS (ESI) M/z 469 (M+H) ⁺ 。1H NMR(400MHz,MeOD)δ7.91(dd,J＝7.8,1.8Hz,1H),7.70(d,J＝8.2Hz,2H),7.55–7.44(m,4H),7.41(d,J＝3.3Hz,1H),7.16(d,J＝8.3Hz,1H),7.07(t,J＝7.5Hz,1H),6.77(d,J＝3.2Hz,1H),4.68(s,2H),3.97(s,3H),3.69–3.61(m,1H),2.17–2.04(m,4H),1.94(m,2H),1.86–1.70(m,2H)

EXAMPLE 151 4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-pyrrolo [3,2-c ] pyridine-7-carboxamide (BNB-1065-01)

Step 1In N ₂ Downward 4-amino-5-bromo-2-chloro-6-cyclopentylpropionic acid methyl ester (500 mg,1.51 mmol) and 5-fluoro-2-methoxy-N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide (583 mg,1.51 mmol) in dioxane (15 mL) and H ₂ K was added to the solution in O (3 mL) ₂ CO ₃ (417 mg,3.02 mmol) and Pd (PPh) ₃ ) ₄ (173 mg,0.15 mmol). The reaction mixture was heated to 80 ℃ for 10 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The mixture was washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product, which was purified by silica gel column chromatography (etoac=10% -20% in PE) to give the desired product, methyl 4-amino-5-bromo-6-cyclopentyl-2- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) nicotinate (500 mg, yield: 59.9%), as a white solid. LC/MS (ESI) M/z 557/559 (M+H) ⁺

Step 2In N ₂ Downward 4-amino-5-bromo-6-cyclopentyl-2- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) nicotinic acid methyl ester (500 mg,0.90 mmol) and (E) -2- (2-ethyl)Oxyvinyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (178 mg,0.90 mmol) in 1, 4-dioxane (8 mL) and H ₂ K was added to the solution in O (2 mL) ₂ CO ₃ (248 mg,1.80 mmol) and Pd (PPh) ₃ ) ₄ (104 mg,0.09 mmol). The reaction mixture was heated to 60 ℃ for 10 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The mixture was washed with water and brine. The organic phase was treated with anhydrous Na ₂ SO ₄ Drying, filtration and concentration gave the crude product which was purified by silica gel column chromatography (etoac=10% -20% in PE) to give the desired product 4-amino-6-cyclopentyl-5- (2-ethoxyvinyl) -2- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) nicotinic acid ester (430 mg, yield: 87.3%) as a white solid. LC/MS (ESI) M/z 548 (M+H) ⁺

Step 3A solution of 4-amino-6-cyclopentyl-5- (2-ethoxyvinyl) -2- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) nicotinic acid ester (430 mg,0.79 mmol) in AcOH (5 mL) was heated to 100deg.C in a microwave reactor. The reaction mixture was then concentrated, diluted with EtOAc (20 mL), washed with water and brine. The organic layer was treated with anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product, which is purified by silica gel column chromatography (DCM: meoh=100:1 to 30:1) to give 4-cyclopentyl-6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -1H-pyrrolo [3,2-c]Pyridine-7-carboxylic acid methyl ester (220 mg, yield: 55.8%) as a white solid. LC/MS (ESI) M/z:502 (M+H) ⁺

Step 4:to 4-cyclopentyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido)]Methyl } phenyl) -1H-pyrrolo [3,2-c]To a stirred solution of methyl pyridine-7-carboxylate (230 mg,0.46 mmol) in THF (2 mL) and MeOH (2 mL) was added NaOH (184 mg,4.6 mmol). The reaction mixture was stirred at 50℃under N ₂ Stirring is carried out for 18 hours under an atmosphere. The mixture was extracted with EtOAc (10 ml x 3), the combined organic phases were washed with water and brine, and the organic phases were washed with anhydrous Na ₂ SO ₄ Drying, filtration, and concentration gave the crude product which was used without purification to give 4-cyclopentyl-6- (4- { [ (5-fluoro-2)-methoxyphenyl) carboxamido]Methyl } phenyl) -1H-pyrrolo [3,2-c]Pyridine-7-carboxylic acid (200 mg, yield: 89.5%) was a white solid. LC/MS (ESI) M/z 488 (M+H) ⁺ 。

Step 54-cyclopentyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido at 25 ℃ C.)]Methyl } phenyl) -1H-pyrrolo [3,2-c]Pyridine-7-carboxylic acid (200 mg,0.41 mmol) in DMF (5 mL) was added slowly TEA (124 mg,1.23 mmol) and HATU (187 mg,0.49 mmol) and the reaction mixture was taken up in NH at 25 ℃ ₃ Stirring is carried out for 1 hour under an atmosphere. The reaction mixture was diluted with water (20 mL), the mixture was extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, and the organic phases were washed with anhydrous Na ₂ SO ₄ Dried, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (etoac=50:1 to 1:1 in PE) to give 4-cyclopentyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ]Methyl } phenyl) -1H-pyrrolo [3,2-c]Pyridine-7-carboxamide (170 mg, yield: 85.2%) as a white solid. LC/MS (ESI) M/z 487 (M+H) ⁺ 。

Step 6To 4-cyclopentyl-6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -1H-pyrrolo [3,2-c]To a solution of pyridine-7-carboxamide (90 mg,0.19 mmol) in 3mL of AcOH and 3mL of t-BuOH was added PyHBr3 (177 mg,0.56 mmol) which was taken up in N ₂ Stir overnight. Zn (121 mg,1.85 mmol) and AcOH (3 ml) were then added and stirred for 1 hour. The reaction mixture was concentrated in vacuo to remove most of the solvent. The residue was poured into water (6 mL) and extracted with EtOAc (6 mL). The organic layer was dried over MgSO ₄ Dried, filtered, and concentrated. Eluting with etoac=50% in PE by silica gel column chromatography gave the title 4-cyclopentyl-6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -2-oxo-2, 3-dihydro-1H-pyrrolo [3,2-c]Pyridine-7-carboxamide as a white solid (20 mg, yield 21.5%). LC/MS (ESI) M/z 503 (M+H) ⁺ 。1H NMR(400MHz,DMSO)δ10.70(s,1H),8.84(t,J＝6.1Hz,1H),7.75(s,1H),7.64(d,J＝8.2Hz,2H),7.53(dd,J＝9.2,3.3Hz,1H),7.41(s,1H),7.34(dd,J＝13.5,5.7Hz,3H),7.19(dd,J＝9.1,4.3Hz,1H),4.54(d,J＝6.1Hz,2H),3.90(s,3H),3.61(s,2H),3.19–3.08(m,1H),1.93(d,J＝8.0Hz,2H),1.87–1.71(m,4H),1.63(dd,J＝7.1,4.6Hz,2H)。

Biological assay

Biochemical Activity of BTK kinase

The compounds prepared in the above examples were tested for effectiveness as BTK inhibitors using the ADP-Glo method. Enzyme assays using recombinant forms of wild-type BTK (Signalchem, cat#B10-10H-10) and recombinant forms of BTK-C481S (Signalchem, cat#B10-12 CH-10) were performed as follows. Compounds were serially diluted in DMSO at 1:3 in 10-point dose IC50 mode in duplicate. In a solution containing 50mM HEPES, 1mM EGTA and 10mM Mg ²⁺ BTK kinase activity was tested in assay buffer of 0.01% BRIJ35 and 2mM DTT (ph=7.4). mu.L of the diluted compound was mixed with 5. Mu.L of enzyme working solution (Signalchem, cat#B10-10H-10) by Echo (Labcyte, cat#550) and then with 5. Mu.L of substrate working solution (Sigma, cat#P61-58) into 384-well assay plates (Perkin Elmer, cat# 6008280) to initiate the reaction. After incubation at 25℃for 60 minutes, 5. Mu.L of ADP Glo reagent (Promega, cat#V9102) was added and the reaction was stopped by incubation at 25℃for 60 minutes. After adding 10. Mu.L of kinase assay reagent (Promega, cat#V9102) and incubating for 60 minutes at 25℃the US LUM of the plate was read as RLU on an Envision (Perkin Elmer, envision 2104). IC50 values were calculated by fitting the% inhibition values and logarithm (dose response-variable slope) of compound concentration by nonlinear regression using GraphPad Prism 6.0.

MEK1 kinase Activity assay

Enzyme assays using recombinant forms of wild-type MEK1 (Signalchem, cat#M02-10G) were performed using the ADP-Glo method as follows. The compounds prepared in the above examples were serially diluted in DMSO at 1:3 in 10-point doses in IC50 mode in duplicate. In a solution containing 50mM HEPES, 1mM EGTA and 10mM Mg ²⁺ MEK1 kinase activity was tested in assay buffer of 0.01% BRIJ35 and 2mM DTT (ph=7.4). 0.1. Mu.L of the diluted compound was mixed with 5. Mu.L of enzyme working solution (Signalchem, cat#M 02-10G) by Echo (Labcyte, cat#550) and then with 5. Mu.L of substrate working solution (Signalchem, cat#M 29-14G) into 384-well assay plates (Perkin Elmer, cat# 6008280) to initiate the reaction. After incubation at 25℃for 60 minutes, 5. Mu.L of ADP Glo reagent (Promega, cat#V9102) was added and the reaction was stopped by incubation at 25℃for 60 minutes. After addition of 10 μl of kinase assay reagent and incubation at 25 ℃ for 60 min, the plate was read as US LUM on Envision (Perkin Elmer, envision 2104) as RLU. IC50 values were calculated by fitting the% inhibition values and logarithm (dose response-variable slope) of compound concentration by nonlinear regression using GraphPad Prism 6.0.

EGFR kinase Activity assay

Enzyme assays using recombinant forms of wild-type EGFR (Signalchem, cat#E10-11G-10) were performed using the Homogeneous Time Resolved Fluorescence (HTRF) method as follows. The compounds prepared in the above examples were serially diluted in DMSO at 1:3 in 10-point doses in IC50 mode in duplicate. In the presence of 5mM MgCl ₂ 、1mM MnCl ₂ And 1mM DTT in 1x kinase buffer (HTRF KinEASE-TK kit, cisbio, cat#62TK0 PEC). mu.L of the diluted compound was mixed with 5. Mu.L of 2 XEGFR enzyme solution (Signalchem, cat#E10-11G-10) by Echo (Labcyte, cat#550) and incubated at 25℃for 10 minutes. mu.L of TK-substrate-biotin (Cisbio, 61TK0 BLE) and ATP mixture substrate (Promega, cat#V910B) were then added to 384-well assay plates (Labcyte, P-05525-BC) to initiate the reaction. After incubation for 40 min at 25 ℃, 10 μl of 2X Sa-XL 665 and TK-antibody-cryptate (Cisbio, 06A) was added to each well of the assay plate, incubated for 60 min and at 25 ℃ Wen Zhong. Fluorescence signals were read at 615nm (Cryptate) and 665nm (XL 665) on Envision (Perkin Elmer, envision 2104). IC50 values were calculated by fitting the% inhibition values and logarithm (dose response-variable slope) of compound concentration by nonlinear regression using GraphPad Prism 6.0.

OCI-Ly10 cell proliferation assay

Cell proliferation assays using the OCI-Ly10 human DLBCL (diffuse large B-cell lymphoma) cell line (Cobioer Biosciences, CBP 60558) that rely on nfkb signaling were performed using the Celltiter-Glo method as follows. The compounds prepared in the above examples were serially diluted in DMSO at 1:4 in 10-point doses in IC50 mode in duplicate. 10% FBS-supplemented (Invitrogen, cat#1009) suspended in a T75 flask (Corning, cat# 430641) was used9141 1% penicillin-streptomycin (Gibco, cat# 15140-122) and IMDM medium (Gibco, cat# 12440-053). After centrifugation and re-suspension with medium, OCI-Ly10 cells were seeded into 96-well plates (Corning, cat No. 3603) at a density of 8,000 cells/well. Then 5. Mu.L of diluted compound was added to the cell plate and mixed with CO ₂ The cells were incubated in an incubator (ThermoFisher, cat # 371) at 37℃for 72 hours. After 72 hours of compound treatment, 100. Mu.L of cell supernatant was removed and 70. Mu.L of LCelltiter-Glo buffer (Promega, cat #G7573) was added to the cell plate. After incubation at 25 ℃ for 20 minutes, the luminescence signal was measured on an Envision (Perkin Elmer, envision 2104). IC50 values were calculated by fitting the% inhibition values and logarithm (dose response-variable slope) of compound concentration by nonlinear regression using GraphPad Prism 6.0.

PK protocols

ICR mice (male, 6-8 weeks old, 26-30g, each route of administration n=9) were purchased from Shanghai family planning institute (SIPPR) (Shanghai, china). Animals were housed in chambers maintained at a temperature of about 20-26 ℃ and a relative humidity of 40% -70% with a light-dark cycle of 12:12h, free access to food and water. All methods related to animals accord with the Chinese experimental animal management principle. Animal research programs are reviewed and approved by the animal care and use committee. ICR mice received test compounds either intravenously (IV; 1 mg/kg) or orally gavaged (PO; 10 mg/kg) after overnight fast. Food was administered 4 hours after administration. The compounds were formulated in DMA, solutol HS-15 and saline (10:10:80, v/v/v) to give nominal concentrations of 0.2mg/mL (i.v. route) and 1mg/mL (p.o. route) for administration. Blood samples (110 μl) were collected through the jugular sinus at the appropriate time points (each time point n=3). The blood samples were placed in test tubes containing K2EDTA and centrifuged at 5,500rpm for 10 minutes under frozen conditions to separate the plasma. Plasma samples were stored at-20 ℃ prior to analysis. Plasma (20. Mu.L) was mixed with 100. Mu.L of ACN-containing internal standard in 96-well plates to precipitate proteins. After vortexing for 10 seconds, the plates were centrifuged at 3,760rpm for 10 minutes at 4℃and 60. Mu.L of supernatant was diluted with 60. Mu. L H2O prior to LC/MS/MS analysis. Pharmacokinetic parameters were determined using non-compartmental WinNonlin (Pharsight, mountain View, CA, USA) analysis.

Efficacy study

The general procedures for animal care and feeding are in accordance with standard procedures, i.e., the life sciences committee, national research committee. The OCI-LY10 tumor cell line was maintained in vitro as a suspension culture in IMDM medium, modified to supplement 20% heat-inactivated fetal bovine serum, 37℃at 5% CO ₂ In the air. Tumor cells will be routinely subcultured for no more than 4-5 passages. Cells grown in exponential growth phase were harvested and counted for tumor inoculation. Each mouse was inoculated subcutaneously in the right flank with OCI-LY10 tumor cells (1X 10) in 0.1ml IMDM medium and high concentration Matrigel mixture (1:1 ratio) ⁷ ) Can be used for tumor development. Mice were randomly assigned to groups based on tumor volume and body weight, such that the average starting tumor size and body weight were the same for each treatment group. When the average tumor volume reaches about 120-180mm ³ Treatment was started at that time. Tumor size measurements were taken twice weekly with calipers and recorded. Tumor volume (mm) was estimated using the following ³ )：TV＝a×b ² And/2, wherein "a" and "b" are the long and short diameters of the tumor, respectively.

TVs were used to calculate tumor growth inhibition and tumor growth delay. For Tumor Growth Inhibition (TGI), the values were calculated using the following formula:

% T/c= (treatment TVfinal-treatment TVinitial)/(medium TVfinal-medium TVinitial) ×100

% tgi= [1- (treatment TVfinal-treatment VTinitial)/(medium TVfinal-medium TVinitial) ]x100

"TVfinal" and "TVinitial" are average tumor volumes of the last day and the beginning day.

Table 9. Biological Activity of selected examples (A <50nM; B:50 to 100nM; C:100nM to 1000nM; D >1000 nM)

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Claims

1. A compound of formula I:

m is 0 or 1; and is also provided with

n is 1 or 2.

2. The compound of claim 1, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate or pharmaceutically acceptable salt thereof, wherein:

X ₂ is CH;

R ₁ selected from H, 3-8 membered heterocyclyl, 5-12 membered heteroaryl, C _3-8 Cycloalkyl, C _3-8 cycloalkyl-O-, 3-8 membered heterocyclyl-O-, C _6-10 Aryl, C _1-6 Alkyl, C _1-6 Alkoxy, -NH ₂ 、-NH(C _1-6 Alkyl) and-N (C) _1-6 Alkyl group ₂ Wherein each alkyl or alkoxy group is optionally substituted with one or more substituents selected from the group consisting of: halo, -OH, -CN and-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the And wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted with one or more substituents selected from the group consisting of: -OH, -NH ₂ Oxo, halo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -NH (C) _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ 、C _1-6 alkyl-S-, -C _1-6 alkyl-OH, C _3-6 Cycloalkyl and C _3-6 Halogenated cycloalkyl;

m is 0 or 1.

3. The compound of any one of claims 1-2, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein:

X ₁ is CR' or N; r' is H or halo;

X ₂ is CH;

X ₃ selected from CH, C (=o) or N;

R ₁ selected from H, 3-8 membered heterocyclyl, 5-12 membered heteroaryl, C _3-8 Cycloalkyl, C _3-8 cycloalkyl-O-, 3-8 membered heterocyclyl-O-, C _6-10 Aryl, C _1-6 Alkyl, C _1-6 alkoxy-NH ₂ 、-NH(C _1-6 Alkyl) and N (C _1-6 Alkyl group ₂ Wherein each alkyl or alkoxy is optionally substituted with one or more groups selected from halo, -OH, -CN and-NH ₂ Is substituted by a substituent of (a); and wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted with one or more substituents selected from the group consisting of: -OH, -NH ₂ Oxo, halo, -CN, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, -NH (C) _1-6 Alkyl), -N (C) _1-6 Alkyl group ₂ 、C _1-6 alkyl-S-and-C _1-6 alkyl-OH;

m is 0 or 1.

4. A compound according to any one of claims 1 to 3, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate, or a pharmaceutically acceptable salt thereof, wherein X ₃ Is N.

5. The compound of any one of claims 1-4, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein

X ₁ Is CR' or N; r' is H or halo;

X ₂ is CH;

X ₃ is N;

R ₁ selected from 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C _3-8 Cycloalkyl, C _3-8 cycloalkyl-O-, C _6-10 Aryl and N (C) _1-6 Alkyl group ₂ Wherein alkyl is optionally substituted with one or more halo, -OH and-CN; and wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted with one or more groups selected from-OH, halo, CN, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Substitution of the substituent of the alkoxy group;

y is-CH ₂ -NH-C (O) -; and is also provided with

6. The compound of claims 1-5, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein:

ar is

Wherein R is ₃ Is H or halo.

7. The compound of any one of claims 1-6, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein R ₂ Is 2-methoxy-phenyl or 2-methoxy-5-fluoro-phenyl.

8. The compound of any one of claims 1-7, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein R ₁ Selected from 4-6 membered heterocyclyl, 5-10 membered heteroaryl, C _5-6 Cycloalkyl, C _3-6 cycloalkyl-O-and phenyl, each of which is optionally substituted with one or more groups selected from-OH, halo, CN, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Substitution of the substituent of the alkoxy group;

preferably, R ₁ Selected from 5-6 membered heteroaryl groups optionally substituted with one or more groups selected from-OH, halo, CN, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Substitution of the substituent of the alkoxy group;

preferably, R ₁ Is pyridinyl, optionally substituted with one or more groups selected from-OH, halo, CN, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 Substitution of the substituent of the alkoxy group;

more preferably, R ₁ Is pyridin-4-yl which is C-substituted in the 2-position _1-6 Alkyl is optionally further substituted in the 3-position by a member selected from the group consisting of-OH, halo, CN, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 The substituent of the alkoxy group is substituted.

9. The compound of any one of claims 1-7, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, wherein:

R ₁ selected from:

further preferably, R ₁ Selected from:

10. the compound of claim 1, selected from the group consisting of:

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or a pharmaceutically acceptable salt thereof.

11. A compound according to any one of claims 1 to 10, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate, or a pharmaceutically acceptable salt thereof, for use as a medicament.

12. A compound according to any one of claims 1-10, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a BTK-related disease or disorder;

more preferably, the disease or disorder is selected from Acute Lymphoblastic Leukemia (ALL), acute Myeloid Leukemia (AML), acute Promyelocytic Leukemia (APL), chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic Neutrophilic Leukemia (CNL), acute Undifferentiated Leukemia (AUL), anaplastic large cell lymphoma (ALL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T cell ALL, AML with myelodysplasia (AML/TMDS), mixed Lineage Leukemia (MLL), myelodysplastic syndrome (MDSs), myeloproliferative disease (MPD) (e.g., polycythemia Vera (PV), idiopathic thrombocytopenia (ET) and idiopathic primary myelofibrosis), diffuse large B-cell lymphomas (DLBCL) (e.g., activated B-cell like DLBCL (ABC-DLBCL)), follicular lymphomas, mantle cell lymphomas, marginal zone lymphomas (e.g., junction peripheral zone B-cell lymphomas, splenic marginal zone lymphomas), burkitt's lymphoma, waldenstem macroglobulinemia (lymphoplasmacytomer lymphomas (LPL)), primary central nervous system lymphomas, small lymphocytic lymphomas, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myelogenous leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasmacytoma, and Multiple Myeloma (MM); rheumatoid arthritis, osteoarthritis, gouty arthritis and spondylitis; asthma, chronic bronchitis, allergic rhinitis, adult Respiratory Distress Syndrome (ARDS), silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, emphysema, pneumonia, bronchiectasis, pulmonary oxygen poisoning and chronic pneumonic diseases; systemic Lupus Erythematosus (SLE), autoimmune thyroiditis, multiple sclerosis, chronic Obstructive Pulmonary Disease (COPD), myasthenia gravis, psoriasis, inflammatory Bowel Disease (IBD) and idiopathic thrombocytopenic purpura; graft Versus Host Disease (GVHD) and allograft rejection.

13. A pharmaceutical composition comprising a compound according to any one of claims 1-10, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

14. Use of a compound according to any one of claims 1-10, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a BTK-related disease or disorder, or use of a compound according to any one of claims 1-10, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate, or pharmaceutically acceptable salt thereof, for the treatment or prevention of a BTK-related disease or disorder;

15. A method of inhibiting BTK in vivo or in vitro, the method comprising contacting an effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, with BTK.

16. A method of treating or preventing a BTK-related disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-10, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate, or a pharmaceutically acceptable salt thereof;

17. A combination comprising a compound according to any one of claims 1-10, or a stereoisomer, a racemate, a geometric isomer, a tautomer, a hydrate, or a solvate thereof, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably an anti-tumor agent, such as a radiation therapeutic agent, a chemotherapy therapeutic agent, an immunotherapy agent, or a targeted therapeutic agent.

18. A compound selected from:

wherein P is ₁ Is an amino protecting group, preferably P-methoxybenzyl, and P ₂ Is a hydroxy protecting group, preferably methoxymethyl.