CN116348453B

CN116348453B - Heteroaromatic carboxamide compounds and uses thereof

Info

Publication number: CN116348453B
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: 2025-07-04
Anticipated expiration: 2042-04-22
Also published as: CN116348453A; 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) andMacroglobulinemia (WM). However, treatment disruption occurs in up to 30% of ibrutinib patients, which leads to poor clinical results. While second generation BTK inhibitors that provide greater BTK selectivity, such as acartinib (acalabrutinib), zebutinib (zanubrutinib), and tiratinib (tirabrutinib), can limit off-target toxicity, they are irreversible BTK inhibitors. 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 (vecabrutinib), ARQ-531, and LOXO-305, which inhibit BTK activity in the presence of the C481S mutation independent of cysteine-481 interaction with BTK, and clinical evidence began 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、X₂ and X ₃ are each independently CR 'or N, R' is selected from H, C _1-6 alkyl, halo and oxo;

R ₁ is 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) ₂, wherein each alkyl or alkoxy is optionally substituted with one or more substituents selected from deuterium, Halo, -OH, -CN, -NH ₂、-NH(C_1-6 alkyl) and-NH (C _1-6 alkyl) ₂, 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) ₂、C_1-6 alkyl-S-, -C _1-6 alkyl-OH, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -C (O) C _1-6 alkyl, -S (O) _nC_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) 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 halo, C _1-6 alkoxy and C _1-6 alkyl;

y is selected from O、S、-(CH₂)_m-NH-C(O)-、-(CH₂)_m-NH-S(O)_n-、-(CH₂)_m-N(C_1-6 alkyl) -C (O) -, - (CH ₂)_m-N(C_1-6 alkyl )-S(O)_n-、-(CH₂)_m-C(O)-NH-、-(CH₂)_m-S(O)_n-NH-、-(CH₂)_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 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) 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) ₂ and-NHC (O) C _1-6 alkyl;

m is 0 or 1, and

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 is 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) ₂, wherein each alkyl or alkoxy is optionally substituted with one or more substituents selected from deuterium, Halo, -OH, -CN, -NH ₂、-NH(C_1-6 alkyl) and-NH (C _1-6 alkyl) ₂, 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) ₂、C_1-6 alkyl-S-, -C _1-6 alkyl-OH, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, -C (O) C _1-6 alkyl, -S (O) _nC_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) ₂、-NHC(O)C_1-6 alkyl, and 3-6 membered heterocyclyl, optionally substituted with oxo;

m is 0 or 1, and

N is 1 or 2.

Embodiment 2a compound of embodiment 1 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate or a pharmaceutically acceptable salt thereof, wherein X ₁ and X ₃ are each independently CR 'or N, R' is selected from H, C _1-6 alkyl, halo, and oxo.

Embodiment 3a 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 ₂ is CH.

Embodiment 4a 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 5a 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 C _6-10 aryl or 5-6 membered heteroaryl, optionally substituted with 1, 2, or 3 substituents selected from C _1-6 alkoxy, deuterated C _1-6 alkoxy, halo, C _1-6 haloalkyl, -OH, -CN, and-NH ₂.

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 are each independently CR 'or N, R' is selected from H, C _1-6 alkyl, halo and oxo;

x ₂ is CH;

R ₁ is 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) ₂, wherein each alkyl or alkoxy group is optionally substituted with one or more substituents selected from halo, -OH, -CN and-NH ₂, 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), and, -N (C _1-6 alkyl) ₂、C_1-6 alkyl-S-, -C _1-6 alkyl-OH, C _3-6 cycloalkyl and C _3-6 halocycloalkyl;

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 substituents selected from C _1-6 alkoxy, deuterated C _1-6 alkoxy, halo, C _1-6 haloalkyl, -OH, -CN and-NH ₂;

m is 0 or 1.

Embodiment 7a 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 CR 'or N, and R' is H or halo.

Embodiment 8a 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 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 is selected from CH, C (=o) or N;

R ₁ is 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) ₂, wherein each alkyl or alkoxy group is optionally substituted with one or more substituents selected from halo, -OH, -CN and-NH ₂, 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), and, -N (C _1-6 alkyl) 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;

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 substituents selected from C _1-6 alkoxy, deuterated C _1-6 alkoxy, halo, C _1-6 haloalkyl, -OH, -CN and-NH ₂, and

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 is 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) ₂, wherein each alkyl or alkoxy group is optionally substituted with one or more substituents selected from halo, -OH, and-CN, and wherein each heterocyclyl, heteroaryl, cycloalkyl, or aryl group is optionally substituted with one or more substituents selected from-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 is 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) 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 group is optionally substituted with one or more substituents selected from-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 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 Ar is-C _6-10 aryl-Y-R ₂, wherein the aryl is optionally substituted with one or more halo.

Embodiment 12. 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-5-6 membered heteroaryl-Y-R ₂, wherein the heteroaryl is optionally substituted with one or more halo.

Embodiment 13 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 ₂ is C _6-10 aryl or 5-6 membered heteroaryl, optionally substituted with 1,2, or 3 substituents selected from C _1-6 alkoxy, deuterated C _1-6 alkoxy, halo, C _1-6 haloalkyl, and-OH.

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

Embodiment 15 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 ₂ is phenyl, optionally substituted with 1, 2, or 3 substituents selected from C _1-6 alkoxy, deuterated C _1-6 alkoxy, halo, C _1-6 haloalkyl, and-OH.

Embodiment 16 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 ₂ is phenyl or 6-membered heteroaryl, optionally substituted with 1 or 2 substituents selected from C _1-6 alkoxy, deuterated C _1-6 alkoxy, halo, C _1-6 haloalkyl, and-OH.

Embodiment 17 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 ₂ is phenyl, optionally substituted with 1 or 2 substituents selected from C _1-6 alkoxy, deuterated C _1-6 alkoxy, halo, C _1-6 haloalkyl, and-OH.

Embodiment 18 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 ₂ is phenyl, optionally substituted with 1 or 2 substituents selected from C _1-6 alkoxy and halo.

Embodiment 19 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 Y is selected from O, -CH ₂-NH-C(O)-、-CH₂ -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 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 Y is-CH ₂ -NH-C (O) -.

Embodiment 22. 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 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 is selected from the group consisting of 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) 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 alkoxy;

Ar is-C _6-10 aryl-Y-R ₂, wherein each of said C _6-10 aryl groups is optionally substituted with one halo;

y is-CH ₂ -NH-C (O) -, and

R ₂ is C _6-10 aryl substituted with 1,2 or 3 substituents selected from the group consisting of C _1-6 alkoxy, deuterated C _1-6 alkoxy and halo.

Embodiment 24 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 X ₁ is CH.

Embodiment 25 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 X ₃ is N.

Embodiment 26 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 Ar is phenyl-Y-R ₂, wherein said phenyl is optionally substituted with one halo.

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 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 isWherein R ₃ is H or halo.

Embodiment 29 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 phenyl-Y-R ₂.

Embodiment 30 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 ₂ is 2-methoxy-phenyl or 2-methoxy-5-fluoro-phenyl.

Embodiment 31a 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 selected from the group consisting of 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 substituents selected from the group consisting of-OH, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy.

Embodiment 32 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 is selected from 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from-OH, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxy.

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 _1-6 alkyl) ₂ optionally substituted with one or more halo groups, preferably R ₁ is (C _1-6 alkyl) ₂ substituted with one or more halo groups, more preferably R ₁ is

Embodiment 34 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 is selected from 5-6 membered heteroaryl, optionally substituted with one or more substituents selected from-OH, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxy.

Embodiment 35 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 is selected from the group consisting of 5-membered heteroaryl, optionally substituted with one or more substituents selected from-OH, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxy.

Embodiment 36 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 is selected from 6-membered heteroaryl, optionally substituted with one or more substituents selected from-OH, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxy.

Embodiment 37 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 is pyridinyl, optionally substituted with one or more substituents selected from-OH, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxy.

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 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 C _1-6 haloalkyl is CF ₃.

Embodiment 40 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 is pyridinyl, optionally substituted with one or two substituents selected from-OH, methyl, F, OMe, and CF ₃.

Embodiment 41 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 is pyridin-4-yl substituted at the 2-position with C _1-6 alkyl and optionally further substituted at the 3-position with a substituent selected from the group consisting of-OH, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxy.

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 is selected from:

further preferably, R ₁ is selected from:

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

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) Multiple hairy cell leukemia, chronic myelogenous leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasma cell tumor 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 oxyintoxication and chronic pneumonitis 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 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 via oxygen.

The term "alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon group 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 group 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, and "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 from 2 to 6 carbon atoms (C _2-6), more preferably from 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, and "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 -CF₃、-CHF₂、-CH₂F、-CH₂CF₃、-CF₂CF₃、-CF₂CH₃ and the like. Preferably the haloalkyl is a 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, 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, preferably C _1-6 trifluoroalkoxy, more preferably

The term "cycloalkyl" as used herein refers to a saturated cyclic hydrocarbon group having 3 to 10 ring carbon atoms (C _3-10) such as3 to 8 ring carbon atoms (C _3-8), 3 to 7 ring carbon atoms (C _3-7), 3 to 6 ring carbon atoms (C _3-6) or 5 to 6 ring carbon atoms (C _5-6), which 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 a monocyclic C _3-8 cycloalkyl, preferably a monocyclic C _3-6 cycloalkyl, more preferably a monocyclic C _5-6 cycloalkyl. 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 a bicyclic C ₅-C₁₀ cycloalkyl. Examples of bicyclocycloalkyl 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] pentyl, spiro [2.3] hexyl, spiro [2.4] heptyl, spiro [2.5] octyl, and spiro [4.5] decyl. Preferably, the cycloalkyl is a monocyclic C _3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "cycloalkenyl" as used herein refers to a non-aromatic unsaturated cyclic hydrocarbon group having at least one carbon-carbon double bond with 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), 3 to 6 ring carbon atoms (C _3-6) or 5 to 6 ring carbon atoms (C _5-6), which 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 refers to a carbocyclic hydrocarbon group of 6 to 14 carbon atoms (C _6-14), preferably 6 to 10 carbon atoms (C _6-10), consisting of one ring or multiple fused rings, 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 a5 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, of the ring atoms are ring heteroatoms independently selected from N, O and S (preferably N), and the remaining ring atoms are carbon;

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 radical triazolopyridinyl, indazolyl, and triazolopyridinyl radical indazolyl group pyrazolopyrimidinyl, tetrazolopyridinyl, and pharmaceutical compositions containing them tetrahydropyrazolopyridinyl group 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 lineWhen 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 lineWhen 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, the number of the cells to be processed, "optionally substituted with one or more of the following are included herein as defined as" unsubstituted "and" substituted with 1:2, 3 or more substitutions). 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" as used herein means that one or more hydrogen atoms on a given atom or group are 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 valency of the 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 salts" includes, but is not limited to, acid addition salts of the compounds disclosed herein with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, and the like, as well as acid addition salts of the compounds disclosed herein with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, and salts with alkanedicarboxylic acids of the formula HOOC- (CH ₂)_n -COOH (where n is 0-4), and the like, "pharmaceutically acceptable salts" also include base addition salts of the compounds of the invention bearing 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, reduce the size of the tumor, inhibit or prevent infiltration of tumor cells into peripheral organs, including, for example, diffusion of the tumor into soft tissue and bone, inhibit or prevent metastasis of the tumor, inhibit or prevent growth of the tumor, alleviate one or more symptoms associated with the cancer to some extent, reduce morbidity and mortality, improve quality of life, or a combination of the foregoing. 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. By mammal is meant any member of the mammalian class including, but not limited to, humans, non-human primates such as chimpanzees and other apes and monkeys, farm animals such as cows, horses, sheep, goats and pigs, domestic animals such as rabbits, dogs and cats, laboratory animals including rodents such as rats, mice and guinea pigs, and the like. 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 compositions comprise (a) an effective amount of a compound of the invention, (b) a pharmaceutically acceptable excipient (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 a drug (i.e., a 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

1.1 Hematological malignancy (e.g., hematological malignancy that is a BTK-associated tumor) is selected from leukemia, lymphoma (non-Hodgkin's 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 cell leukemia (AUL), anaplastic Large Cell Lymphoma (ALCL), 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 (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 tumor, 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).

1.2 Solid tumors (e.g., solid tumors that are BTK-related tumors). 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, 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 malignancies include 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 (lymphoplasmacytomer lymphoma (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 single joint 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-associated eye diseases;

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;

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. 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, disease states caused by leukocytes;

2.17. cachexia and metastasis, thermal injury, granulocyte transfusion-related syndrome, and cytokine-induced toxicity;

2.18. behcet's disease.

3. Diseases that are 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, C G, 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 (evobrutinib), 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, angstrom 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, radiation therapeutic agents, chemotherapy agents, immunotherapeutic agents, and targeted therapeutic agents.

General synthetic method

General synthetic method for preparing 1H-pyrazolo [4,3-c ] pyridine-7-carboxamide analogs having general structures shown in A-1 and A-2 (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. Or 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 ₁ attached to the ring through C and Rb is R ₁;P₁ or P ₂ attached to the ring through N or O is a protecting group, R ₁ and Ar are as defined herein for formula I.

General synthetic method for preparing 1H-pyrazolo [4,3-c ] pyridine-7-carboxamide analogs having general structures shown in B-1 and B-2 (scheme 2)

Scheme 2

As described in pathway 1, 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). 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.

Or in some cases also use path 2. 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 were measured by Agilent 6120B;Shimadzu LCMS2010. 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 abbreviations 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.

The names of all compounds except the reagent were generated by 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 of the present application, 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

Synthesis of key intermediate A-1-4a

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

Step 1 to a stirred suspension of 2,4, 6-trichloropyridine (9.1 g,49.8 mmol) in THF (100 mL) was added LDA (27.4 mL,54.8 mmol) at-65℃and the resulting mixture stirred under N ₂ for 1 hour, followed by piperidine-1-carbaldehyde (5.6 mL,49.8 mmol) at this temperature. The mixture was stirred at-65 ℃ for 3 hours. The reaction mixture was then quenched with saturated NH ₄ Cl, extracted with EtOAc (60 ml x 3), the combined organic phases were washed with brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated to give 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 (400 MHz, DMSO) δ10.27 (s, 1H), 8.09 (s, 1H).

Step 2 to 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 120℃was added p-TSA (0.7 g,3.9 mmol) and the resulting mixture was stirred under N ₂ 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 ₂SO₄, 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) ⁺.

Synthesis of 5-bromo-2, 4, 6-trichloronicotinaldehyde (A-1-2)

Step 1 to a stirred suspension of 2,4, 6-trichloro-3- (1, 3-dioxan-2-yl) pyridine (A-1-1) (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) at-65℃and the resulting mixture was stirred under N ₂ for 1 hour, followed by 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 quenched with saturated NH ₄ Cl and extracted with EtOAc (50 ml x 3). The combined organic phases were washed with brine, dried over anhydrous Na ₂SO₄, filtered and concentrated to give 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 at 80℃overnight. 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 ₂SO₄, filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (etoac=0-10% 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) ⁺.

Synthesis of 7-bromo-4, 6-dichloro-1H-pyrazolo [4,3-c ] 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 a 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 (400 MHz, DMSO). Delta.14.51 (s, 1H), 8.53 (s, 1H).

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

To a stirred solution of 7-bromo-4, 6-dichloro-1H-pyrazolo [4,3-C ] 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) in THF (20 mL) at 0deg.C under N ₂ was added DIAD (1.1 mL,5.6 mmol) 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-1-4 a) (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-1-4 b) (0.3 g, yield: 13%) as a white solid, LC/MS (ESI) M/z: 388/390 (m+h) ⁺.

Synthesis of key intermediate A-2-4a

Step 1 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) was added dropwise LDA (220 mL,440 mmol) at-80℃and stirred for 1 hour, then the solution was bubbled through CO ₂ 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, dried over anhydrous Na ₂SO₄, filtered, and concentrated to give the 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 directly without further purification. LC/MS (ESI) M/z 312/314 (M+H) ⁺.

Step 2 to a solution of 2,4, 6-trichloro-5- (1, 3-dioxan-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 dropwise oxalyl chloride (13 mL,149.8 mmol) at-5℃and the resulting mixture was stirred for 1 hour, then NH ₃ was bubbled for 1 hour (keeping 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)⁺,¹H NMR(400MHz,DMSO-d₆)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 3 to 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 x 3), the combined organic phases were washed with saturated NaHCO ₃, water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give 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 to a solution of NaHCO ₃ (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) at 10℃and the reaction mixture was stirred at the same temperature for an additional 4 hours. The mixture was then quenched with saturated NH ₄ Cl, extracted with EtOAc (100 ml x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=0-50% in DCM) to give 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)+.¹H NMR(400MHz,DMSO)δ14.28(s,1H),8.44(s,1H),8.27(br,1H),8.09(br,1H).

Step 5 to a solution of 4, 6-dichloro-1H-pyrazolo [4,3-C ] pyridine-7-carboxamide (6.0 g,25.97 mmol) and Na ₂CO₃ (8.3 g,77.91 mmol) in DMF (50 mL) was added dropwise PMBCl (5.3 mL,38.95 mmol) at room temperature and the reaction mixture was heated to 50℃for 2 hours. The reaction mixture was then cooled to room temperature, diluted with H ₂ O (100 mL), extracted with EtOAc (100 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=0% to 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 1 to a solution of phenyl methanol (99.7 g, 92mmol) in THF (1L) at 0℃NaH (44.3 g,1.1 mol) was added, the reaction mixture was stirred under nitrogen atmosphere at 0℃for 30 minutes, then 4-bromo-2, 6-difluorobenzonitrile (200 g, 92mmol) in THF (1L) was added dropwise to the solution, and stirring was continued for 2 hours. The reaction mixture was quenched with aqueous NH ₄ Cl, extracted with EtOAc (1 l x 2), the combined organic phases were washed with water and brine, dried over Na ₂SO₄, and concentrated in vacuo to give the crude product 2- (benzyloxy) -4-bromo-6-fluorobenzonitrile (220 g, yield: 78.2%) as a white solid. ¹ H NMR (400 MHz, DMSO). Delta.7.55-7.38 (m, 7H), 5.35 (s, 2H).

Step 2 to a solution of 2- (benzyloxy) -4-bromo-6-fluorobenzonitrile (220 g,721.31 mmol) in DCM (2L) was added BBr ₃ (1057 mL,865.57 mmol) dropwise at-78℃and the reaction mixture was stirred under nitrogen for 2 hours at 0 ℃. 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-hydroxybenzonitrile (B-1, 145g, yield: 93.5%) as a yellow solid. LC/MS (ESI) M/z 215 (M-H) ⁺.

Step 3 to 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 dropwise addition MOMCl (59.1 g,741.85 mmol) at 0deg.C. The reaction mixture was stirred at 0 ℃ under nitrogen atmosphere for 2 hours. The reaction mixture was extracted with DCM (500 ml x 2), the combined organic phases were washed with H ₂ O and brine, dried over anhydrous Na ₂SO₄, 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 4 LDA (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-78℃and the mixture was stirred under nitrogen for 2 hours at-78℃and then DMF (117.3 g,1606.18 mmol) was added to the mixture and the internal temperature was kept below-70℃and the reaction mixture was stirred for an additional 1 hour at-78 ℃. The reaction mixture was quenched with aqueous NH ₄ Cl, extracted with EtOAc (2 l x 2), washed with H ₂ O and brine, dried over Na ₂SO₄, and concentrated in vacuo to give the crude product which was purified by column chromatography on silica gel (etoac=1% -10% in PE) to give the desired product 4-bromo-2-fluoro-3-formyl-6- (methoxymethoxy) benzonitrile (B-1, 115g, yield: 65%) as a yellow solid. LC/MS (ESI) M/z 289 (M-H) ⁺.

Step 5 to a solution of 4-bromo-2-fluoro-3-formyl-6- (methoxymethoxy) benzonitrile (115 g,400.70 mmol) in MeCN (1.5L) was added dropwise N ₂H₄.H₂ O (26 g,400.70mmol,80% in H ₂ O) at 0℃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, dried over Na ₂SO₄, and concentrated to give the crude product, which was purified by silica gel column chromatography (MeOH in dcm=1% -5%) 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)+,¹H 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 ₂CO₃ (26.5 g,192.17 mmol) and PMBCl (17.9 g,115.3 mmol), and the mixture was stirred at 60℃for 2 hours. The reaction mixture was extracted with EtOAc (500 ml x 2), washed with water and brine, dried over Na ₂SO₄, and 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 a solution of 4-bromo-2- (4-methoxybenzyl) -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 2H. The mixture was diluted with H ₂ O (10 mL), extracted with EtOAc (10 mL x 2), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, 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 1 to 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 dried over anhydrous Na ₂SO₄, filtered and concentrated to give 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(400MHz,CDCl3)δ7.97(s,1H),6.84(s,1H),3.88(s,3H),3.87(s,3H),2.42(s,3H).

Step 2 to stirred H ₂SO₄ (30 mL) was added in portions 5-bromo-2-methoxy-4-methylbenzoic acid methyl ester (5.0 g,19.2 mmol) at 0 ℃. After clarification of the solution, HNO ₃ (1.25 ml,19.2 mmol) was added dropwise over 30 minutes and the mixture was stirred at 0 ℃ for an additional 1 hour. The reaction mixture was diluted with saturated NaHCO ₃ (200 mL) and extracted with EtOAc (100 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered and concentrated to give 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,CDCl₃)δ8.16(s,1H),3.93(s,3H),3.91(s,3H),2.35(s,3H).

Step 3 to 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, dried over anhydrous Na ₂SO₄, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (etoac=2% to 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,CDCl₃)δ7.48(s,1H),4.05(s,2H),3.90(s,3H),3.83(s,3H),2.30(s,3H).

Step 4 to a stirred solution of methyl 3-amino-5-bromo-2-methoxy-4-methylbenzoate (300 mg,1.0 mmol) in HBF ₄ (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, forming a precipitate. The cooled reaction mixture was filtered and the solid product was washed successively with small amounts of H ₂ O, meOH and Et ₂ O 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 ₃ (50 mL) was added. The suspension was stirred at room temperature for 10 minutes. The diazonium salt is then added to the mixture a small number of times under an atmosphere of N ₂. 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). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered and concentrated to give the crude product which was purified by silica gel column chromatography (etoac=2-25% in PE) to give methyl 4-bromo-7-methoxy-1H-indazole-6-carboxylate ((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,CDCl₃)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 1 to a solution of sodium hydride (417 mg,10.44 mmol) in dry DMF (10 mL) was added tert-butyl N- [ (tert-butoxy) carbonyl ] carbamate (7516 mg,3.48 mmol) in portions, the resulting mixture was stirred at 0℃for 1 hour, followed by 1-bromo-4- (bromomethyl) -2-chlorobenzene (900 mg,3.17 mmol) and the reaction mixture was stirred at the same temperature for a further 2 hours. The mixture was then quenched with cold saturated NH ₄ Cl, extracted with EtOAc (40 ml x 3), washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give tert-butyl N- [ (4-bromo-3-chlorophenyl) methyl ] -N- [ (tert-butoxy) carbonyl ] carbamate (1.6 g, 100%) as a white solid, which was used directly without further purification. LC/MS (ESI) M/z 420/422 (M+H) ⁺.

Step 2 to a solution of tert-butyl N- [ (4-bromo-3-chlorophenyl) methyl ] -N- [ (tert-butoxy) carbonyl ] carbamate (1.6 g,3.8 mmol) in EtOAc (10 mL) at 0deg.C 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 used in the next step without further purification. 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 stirred at room temperature for 2 hours. The mixture was then diluted with H ₂ O (20 mL) and extracted with EtOAc (30 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered and concentrated in vacuo to give a residue which was 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 4 to a solution of N- [ (4-bromo-3-chlorophenyl) methyl ] -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) were added Pd (dppf) Cl ₂ (0.16 g,0.22 mmol) and KOAc (0.42 g,4.29 mmol). The resulting mixture was heated to 110 ℃ under an atmosphere of N ₂ for 12 hours. After cooling to room temperature, the mixture was diluted with H ₂ O (10 mL), extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=0% to 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%) as a pale yellow solid.

Intermediate B5-fluoro-2- (methoxy-d 3) -N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide

Step 1A solution of 4-bromobenzoic acid (2.0 g,10 mmol) in SOCl ₂ (10 mL) was heated to 85℃for 2 hours under an atmosphere of N ₂. 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 2 to 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 resulting mixture was stirred overnight at 65 ℃ under an atmosphere of N ₂. 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 ₂SO₄, filtered, and concentrated to give 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 3 to 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 resulting mixture was heated to 110 ℃ under an atmosphere of N ₂ for 12 hours. After cooling to room temperature, the mixture was diluted with H ₂ O (10 mL), extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, 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 C5-fluoro-2- (methoxy-d 3) -N- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) benzamide

Step 1 to a solution of N- (4-bromobenzyl) -5-fluoro-2-methoxybenzamide (2.7 g,8.01 mmol) in DCM (30 mL) was added BBr ₃ (16 mL,16mmol,1M in DCM) at-50℃over 30 min. The reaction mixture was then stirred at this temperature for 2 hours, the mixture was quenched with NH4Cl (30 mL), extracted with DCM (30 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, 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 ₂CO₃ (1.6 g,11.61 mmol) and CD ₃ I (1.4 g,9.30 mmol). The resulting mixture was stirred at room temperature under an atmosphere of N ₂ for 3 hours. The mixture was diluted with H ₂ O (20 mL), extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in dcm=0-3%) 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 3 to 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 (463mg, 4.70 mmol) and Pd (dppf) Cl ₂ (172 mg,0.24 mmol). The resulting mixture was heated to 100 ℃ under an atmosphere of N ₂ for 12 hours. After cooling to room temperature, the 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 ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=2% to 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 H tert-butyldiphenyl (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclopent-3-enyloxy) silane

Step 1 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) was added TBDPSCl (25.4 g,92.84 mmol) at 0deg.C and the resulting mixture was stirred at 0deg.C for 2 hours. The mixture was diluted with H ₂ O (300 mL), extracted with EtOAc (100 mL x 3), then the organic layer was washed with water and brine, the collected organic layer was dried over Na ₂SO₄ and concentrated to give the 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 2 to a solution of tert-butyl (cyclopent-3-enyloxy) diphenylsilane (27.2 g,84.33 mmol) in CCl ₄ (270 mL) was added Br ₂ (4.3 mL,84.33 mmol) at room temperature under N ₂. 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.

Step3 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, the organic phases were dried over anhydrous Na ₂SO₄, filtered, and concentrated to give 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 4 Pd (dppf) Cl ₂ (200 mg,0.27 mmol) 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 ℃. The resulting mixture was heated to 100 ℃ under an atmosphere of N ₂ for 12 hours. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=0% to 30% in PE) to give 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 .¹H NMR(400MHz,CDCl₃)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 1 LDA (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 aqueous NH ₄ Cl (20 mL) and extracted with EtOAc (30 mL x 3). The organic phase was dried over anhydrous Na ₂SO₄, filtered and concentrated to give 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 yellow oil which was used directly in the next step without further purification. LC/MS (ESI) m/z 233[ M+1] ⁺

Step 2 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) was added KOAc (591 mg,6.0 mmol) and Pd (dppf) Cl2 (110 mg,0.15 mmol) and the reaction mixture was stirred under nitrogen at 85℃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 1 to a stirred solution of 2-methylcyclopentane-1, 3-dione (0.93 mL,8.92 mmol) and DIPEA (1.8 mL,10.83 mmol) in Et ₂ O (30 mL) at-78℃Tf ₂ O (1.6 mL,10 mmol) was slowly added and the reaction mixture was stirred under nitrogen for 1.5 hours at-78 ℃. 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, the organic phases were dried over anhydrous Na ₂SO₄, filtered, and concentrated to give the 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 (400 MHz, CDCl ₃) δ2.92 (m, 2H), 2.71-2.60 (m, 2H), 1.79 (m, 3H).

Step 2 Pd (dppf) Cl ₂ (100 mg,0.14 mmol) and KOAc (500 mg,5.09 mmol) were slowly added to 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) at 25℃and the reaction mixture was stirred under nitrogen for 2 hours at 100 ℃. 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, the organic phases were dried over anhydrous Na ₂SO₄, filtered, and concentrated to give 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]⁺,¹H NMR(400MHz,CDCl₃)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 1 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) under N ₂ 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 dried over anhydrous Na ₂SO₄, 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 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 2 to a solution of ethyl 3- ((1-methoxy-1-oxopropan-2-yl) amino) propionate (11.0 g,54.19 mmol) in DCM (200 mL) was added Boc ₂ O (23.6 g,108.38 mmol) and TEA (20.2 g,200 mmol) under N ₂. 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 dried over anhydrous Na ₂SO₄, filtered and concentrated to give the crude product which was purified by silica gel column chromatography (etoac=10% to 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 3 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) under N ₂ 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 dried over anhydrous Na ₂SO₄, filtered and concentrated to give the crude product which was purified by silica gel column chromatography (etoac=10% to 40% in PE) to give the desired mixture of 5-methyl-4-oxopyrrolidine-1, 3-dicarboxylic acid 1- (tert-butyl) 3-ethyl ester and 2-methyl-3-oxopyrrolidine-1, 2-dicarboxylic acid 1- (tert-butyl) 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 3-ethyl 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 dried over anhydrous Na ₂SO₄, filtered, and concentrated to give 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 5 to a solution of 2-methylpyrrolidin-3-one (3.45 g,34.85 mmol) in DCM (20 mL) under N ₂ was added Boc 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 dried over anhydrous Na ₂SO₄, filtered and concentrated to give 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 6 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) under N ₂. The reaction mixture was stirred at-78 ℃ for 1 hour. Tf ₂ O (5.10 g,18.10 mmol) was then added and stirred for an additional 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 dried over anhydrous Na ₂SO₄, filtered and concentrated to give 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 7: 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) was added Pd (dppf) Cl ₂ (0.42 g,0.57 mmol), 4',4',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 dried over anhydrous Na ₂SO₄, filtered and concentrated to give 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 1 to 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 was then diluted with H ₂ O (50 mL), extracted with EtOAc (50 mL x 3), washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=0-10% in PE) to give 3, 5-dibromo-2- (trifluoromethyl) pyridin-4-amine (3 g, yield: 50.7%) as a yellow oil. LC/MS: M/z:319/321/323 (M+H) ⁺.1H NMR(400MHz,CDCl₃) delta 8.37 (s, 1H), 5.46 (s, 2H).

Step 2 to a solution of 3, 5-dibromo-2- (trifluoromethyl) pyridin-4-amine (800 mg,2.50 mmol) in EtOH (20 mL) was added Pd/C (10%, 133mg,0.13 mmol). 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-d₆)δ8.07(d,J＝5.6Hz,1H),6.94(d,J＝5.6Hz,1H),5.75(br,2H).

Step 3 to a mixture of 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 O (2 mL) was added K ₂CO₃ (459 mg,3.32 mmol) and Pd (dppf) Cl ₂ (121 mg,0.17 mmol). The resulting mixture was heated to 80 ℃ under an atmosphere of N ₂ for 12 hours. After cooling to room temperature, the mixture was diluted with H ₂ O (10 mL), extracted with EtOAc (10 mL x 3), washed with water and brine, dried over anhydrous Na ₂SO₄, 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 4 to 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 resulting mixture was heated to 80 ℃ under an atmosphere of N ₂ for 12 hours. After cooling to room temperature, the mixture was diluted with H ₂ O (10 mL), extracted with EtOAc (10 mL x 3), washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=0-5% 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). The resulting mixture was heated to 100 ℃ and stirred overnight under an atmosphere of N ₂. 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 ] boronic acid (80 mg, yield: 117.2%) as a 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-78℃and stirred under nitrogen for 1 hour, followed by B (OMe) ₃ (780 mg,5.34mmol in 5mL of THF) and the reaction mixture stirred at-78℃for another 1 hour. The mixture was poured into ice-cold aqueous NH ₄ Cl (20 mL) and extracted with EtOAc (20 mL x 3). The organic phase was dried over anhydrous Na ₂SO₄, 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 borate D-G was prepared by a procedure analogous to intermediate A, B, C, intermediate J was prepared by a procedure analogous to intermediate I, and intermediate O-U was prepared by a procedure analogous to intermediate K-N (with variations), starting from the commercially available starting materials

Example 1:

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

Step 1 to a solution of 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 ₂CO₃ (1.2 g, 11.4 mmol) in dioxane (20.0 mL) and H ₂ O (4.0 mL) was added Pd (PPh ₃)₄ (330 mg,0.3 mmol), the mixture was stirred at 60℃under an atmosphere of N ₂. 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, 3mmol ] pyridine as a white solid (1.46 g, 1.2.46 g) .LC/MS(ESI)m/z:418/420[M+H]+,¹H NMR(400MHz,CDCl₃)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 a solution of 7-bromo-6-chloro-4-cyclopentenyl-1- (4-methoxybenzyl) -1H-pyrazolo [4,3-c ] pyridine (0.3 g,0.7 mmol) in MeOH (5 mL) was added Pd (dppf) Cl ₂ (52.4 mg,0.1 mmol) and TEA (0.3 mL,2.2 mmol). The resulting mixture was stirred in a sealed jar at 85 ℃ at 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=0-50% in DCM) to give methyl 6-chloro-4- (cyclopent-1-en-1-yl) -1- [ (4-methoxy-phenyl) methyl ] -1H-pyrazolo [4,3-c ] pyridine-7-carboxylate (240 mg, yield: 84.2%) as a yellow solid. LC/MS (ESI) M/z 398 (M+H) ⁺.

Step 3 to a solution of methyl 6-chloro-4- (cyclopent-1-en-1-yl) -1- [ (4-methoxyphenyl) -methyl ] -1H-pyrazolo [4,3-c ] pyridine-7-carboxylate (240 mg,0.6 mmol) in dioxane (8 mL) and H ₂ O (2 mL) was added 2- (2-methoxyphenyl) -N- { [4- (4, 5-tetramethyl-1, 3-dioxolan-2-yl) phenyl ] methyl } acetamide (231 mg,0.6 mmol), pd (dppf) Cl ₂ (52 mg,0.1 mmol) and K ₂CO₃ (250 mg,1.8 mmol). The resulting mixture was then stirred at 100 ℃ for 2 hours under an atmosphere of N ₂. 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 ₂SO₄, filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (etoac=0-15% in DCM) to give methyl 4- (cyclopent-1-en-1-yl) -6- (4- { [ (2-methoxyphenyl) carboxamido ] methyl } phenyl) -1- [ (4-methoxyphenyl) methyl ] -1H-pyrazolo [4,3-c ] pyridine-7-carboxylate (260 mg, yield: 71.5%) as a yellow solid. LC/MS (ESI) M/z 603 (M+H) ⁺.

Step 4 to a solution of methyl 4- (cyclopent-1-en-1-yl) -6- (4- { [ (2-methoxyphenyl) -carboxamido ] methyl } phenyl) -1- [ (4-methoxyphenyl) methyl ] -1H-pyrazolo [4,3-C ] 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 resulting mixture was stirred under a balloon of H ₂ at 60℃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 methyl 4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1- (4-methoxybenzyl) -1H-pyrazolo [4,3-c ] pyridine-7-carboxylate (200 mg, yield: 76.7%) as a yellow solid. LC/MS (ESI) M/z 605 (M+H) ⁺.

Step 5 to a solution of methyl 4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1- (4-methoxybenzyl) -1H-pyrazolo [4,3-c ] 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 pH was adjusted with saturated NaHCO ₃ solution. The organic phase was dried over anhydrous Na ₂SO₄ and concentrated to give the crude product which was purified by silica gel column chromatography (etoac=0-50% in DCM) to give methyl 4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-pyrazolo [4,3-c ] pyridine-7-carboxylate (100 mg, yield: 49.9%) as a yellow solid. LC/MS (ESI) M/z 485 (M+H) ⁺.

Step 6 to a solution of methyl 4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-pyrazolo [4,3-c ] 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 jar 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-methoxybenzamido) methyl) phenyl) -1H-pyrazolo [4,3-c ] pyridine-7-carboxamide (3 mg, yield: 3.1%) as a pale yellow solid .¹H 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 1 Pd (PPh ₃)₄ (83 mg,0.01 mmol) was added to a solution of 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 ₂CO₃ (460 mg,4.34 mmol) in dioxane (10 mL) and H ₂ O (2.0 mL), the mixture was stirred at 60℃for 10 hours under N ₂ atmosphere, the reaction mixture was concentrated, 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-dec-8-yl) -1, 3-C ] pyridine as a white solid (72 mg, 3.01 mg, 3 mmol) in vacuo .¹H 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 2 to a solution of 7-bromo-6-chloro-4- {1, 4-dioxaspiro [4.5] dec-7-en-8-yl } -1- [ (4-methoxyphenyl) methyl ] -1H-pyrazolo [4,3-c ] 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 ℃ in a sealed tank at 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 methyl 6-chloro-4- {1, 4-dioxaspiro [4.5] dec-7-en-8-yl } -1- [ (4-methoxyphenyl) methyl ] -1H-pyrazolo [4,3-c ] pyridine-7-carboxylate (248 mg, yield: 52%) as a yellow solid. LC/MS (ESI) M/z 470 (M+H) ⁺.

Step 3 to a stirred solution of 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-2-yl) benzyl) benzamide (74 mg,0.19 mmol) in dioxane (4 mL) and H ₂ O (1 mL) was slowly added K ₂CO₃ (44 mg,0.32 mmol) and Pd (dppf) Cl ₂ (14 mg,0.02 mmol) and the reaction mixture was heated to 100℃under an atmosphere of N ₂ for 18 hours. 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 ₂SO₄, filtered and concentrated to give the crude product which was purified by silica gel column chromatography (etoac=2-100% in PE) to give methyl 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-carboxylate (80 mg, yield: 72.2%) as a white solid. LC/MS (ESI) M/z 693 (M+H) ⁺.

Step 4 to a stirred solution of methyl 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-carboxylate (80 mg,0.12 mmol) in MeOH (10 mL) was added Pd/C (8 mg, 10%). The resulting mixture was stirred under an atmosphere of H ₂ for 24H, filtered, and concentrated to give the crude product methyl 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-carboxylate (70 mg, yield: 87.6%) as a white solid which was used without further purification. LC/MS (ESI) M/z 695 (M+H) ⁺.

Step 5 to a solution of 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 O (1 mL) was added NaOH (40 mg,1.01 mmol) 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 prep-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%) as a white solid. LC/MS (ESI) M/z 681 (M+H) ⁺.

Step 6 to a stirred solution of 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,0.09 mmol) and HATU (40 mg,0.11 mmol) in DMF (5 mL) at 25℃was slowly added DIPEA (34 mg,0.264 mmol) and the reaction mixture was heated to room temperature under NH ₃ for 10 min. 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 ₂SO₄, filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (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 to a solution of 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,0.08 mmol) in DCM (5 mL) was added TFA (5 mL) under N ₂. 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%) as a yellow solid, which was used without further purification. LC/MS (ESI) M/z 516 (M+H) ⁺

Step 8 to a solution of 6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -4- (4-oxocyclohexyl) -1H-pyrazolo [4,3-c ] pyridine-7-carboxamide (40 mg,0.08 mmol) in MeOH (5 mL) was added NaBH ₄ (13 mg,0.39 mmol) under N ₂. After stirring for 3 hours, 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 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 .¹H 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 Compounds of the following Table are prepared from key intermediates A-1-4a according to the general procedure (but modified) for Synthesis examples 1 and 2

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 a solution of 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 O (5 mL) was added Pd (dppf) Cl ₂ (125 mg,0.17 mmol) and K ₂CO₃ (708 mg,5.13 mmol). The resulting mixture was heated to 80 ℃ and stirred under an atmosphere of N ₂ for 12 hours. The reaction mixture was then cooled to room temperature, diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered and concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (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 a solution of 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) in1, 4-dioxane (20 mL) and H ₂ O (5 mL) was added Pd (dppf) Cl ₂ (100 mg,0.14 mmol) and Cs ₂CO₃ (889 mg,2.73 mmol) and the resulting mixture was heated to 110℃under an atmosphere of N ₂ for 12 hours. The reaction mixture was cooled to room temperature, diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered 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 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 a solution of 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,0.7 mmol) was added Pd/C (74 mg,10%, wet). The resulting mixture was stirred at 50 ℃ under an atmosphere of H ₂ for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel flash chromatography (etoac=0-50% in PE) to give the desired product 4- (3- (tert-butyldiphenylsiloxy) cyclopentyl) -6- (4- ((5-fluoro-2-methoxybenzamido) 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 4A solution of 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,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 the crude product 3- [ 7-carbamoyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazolo [4,3-c ] pyridin-4-yl ] cyclopentyl ester (300 mg, yield: 86.3%) as a yellow solid which was used directly in the next step without further purification. LC/MS (ESI) M/z 600 (M+H) ⁺.

Step 5 to a solution of 3- [ 7-carbamoyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazolo [4,3-c ] pyridin-4-yl ] cyclopentyl ester (400 mg,0.67 mmol) in THF (10 mL) and H ₂ 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 pH adjusted to 6 with 1N HCl, extracted with EtOAc (10 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% -3%) 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 examples 6&7 (cis isomer) column CHIRALPAK AD,250 x 4.6mm i.d.,5um, for examples 8&9 (trans isomer) 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, yield: 4.47%) as a white solid ,LC/MS(ESI)m/z:504(M+H)⁺,¹H NMR(400MHz,DMSO-d₆)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 (obtained 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)⁺,¹H NMR(400MHz,DMSO-d₆)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)⁺,¹H NMR(400MHz,CD₃OD)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 (obtained 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)⁺,¹H NMR(400MHz,CD₃OD)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 1 to a solution of 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 O (3 mL) were added Pd (dppf) Cl ₂ (131 mg,0.18 mmol) and K ₂CO₃ (497 mg,3.60 mmol). The resulting mixture was heated to 70 ℃ under an atmosphere of N ₂ for 12 hours. The reaction mixture was then cooled to room temperature, the mixture was diluted with H ₂ O (20 mL), extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% -3%) 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 2 Synthesis of 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

To a solution of 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 O (3 mL) was added Pd (dppf) Cl ₂ (73 mg,0.10 mmol) and Cs ₂CO₃ (652 mg,2.0 mmol). The resulting mixture was heated to 110 ℃ under an atmosphere of N ₂ for 12 hours. The reaction mixture was then cooled to room temperature, the mixture was diluted with H ₂ O (20 mL), extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% -3%) 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 3 Synthesis of 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

To a stirred solution of 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,0.66 mmol) in MeOH (10 mL) was added Pd/C (45 mg,10%, wet) and the resulting mixture was stirred under an atmosphere of H ₂ at 50 ℃ for 24 hours. The reaction mixture was filtered and concentrated to give the crude product 6- (4- ((5-fluoro-2-methoxybenzamido) 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%) as a white solid which was used directly in the next step without further purification. LC/MS (ESI) M/z 680 (M+H) ⁺.

Step 4 Synthesis of 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (4-oxocyclohexyl) -1H-pyrazolo [4,3-c ] pyridine-7-carboxamide

A solution of 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) was stirred at 65℃for 1 hour. After cooling to room temperature, the reaction mixture was diluted with DCM (20 mL) and pH adjusted with saturated NaHCO ₃ solution, the organic phase was collected, dried over anhydrous Na ₂SO₄ and concentrated to give the crude product, which was purified by silica gel column chromatography (etoac=0-50% in DCM) to give the desired product 6- (4- ((5-fluoro-2-methoxybenzamido) 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 5 to a solution of 6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -4- (4-oxocyclohexyl) -1H-pyrazolo [4,3-c ] 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 dried over anhydrous Na ₂SO₄ and concentrated to give the crude product which was purified by column chromatography on silica gel (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 the 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 a white solid and ¹H 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 .¹H 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:

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 1 to a stirred solution of 4, 6-dichloro-2- [ (4-methoxyphenyl) methyl ] -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) in dioxane (8 mL) and water (2 mL) was slowly added Pd (dppf) Cl ₂ (20 mg,0.028 mmol) and Na ₂CO₃ (60 mg,0.57 mmol) at 25 ℃. The resulting mixture was heated to 80 ℃ and stirred under an atmosphere of N ₂ for 12 hours. The reaction mixture was then cooled to room temperature, diluted with H ₂ O (10 mL) and extracted with EtOAc (15 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered and concentrated in vacuo to give the crude product which was 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 2 to a stirred solution of 6-chloro-2- (4-methoxybenzyl) -4- (3-methylpyridin-4-yl) -2H-pyrazolo [4,3-C ] 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) in dioxane (8 mL) and water (2 mL) was slowly added Pd (dppf) Cl ₂ (14 mg,0.02 mmol) and K ₂CO₃ (51 mg,0.37 mmol) at 25 ℃. The resulting mixture was heated to 110 ℃ under an atmosphere of N ₂ for 12 hours. The reaction mixture was then cooled to room temperature, diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered and concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (MeOH in dcm=0-3%) 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 3A solution of 6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -2- [ (4-methoxyphenyl) methyl ] -4- (3-methylpyridin-4-yl) -2H-pyrazolo [4,3-C ] 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 the pH was adjusted to 8 with saturated NaHCO ₃ solution. The organic phase was washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative-TLC (MeOH in dcm=5%) 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]⁺,¹H 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 1 to a stirred solution of 4, 6-dichloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-C ] 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)) at 25℃and the resulting mixture was heated to 80℃and stirred under an N ₂ atmosphere for 18 hours after which the reaction mixture was cooled to room temperature, the mixture was diluted with H ₂ O (10 mL), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered and concentrated under vacuum to give the crude product which was purified by silica gel column chromatography (EtOAc=0.about.70% in PE) to give the desired product 6-chloro-2- (4-methoxybenzyl) -4- (pyrimidin-4-yl) -pyrazolo [4,3-C ] pyridine (5 mL) as a yellow solid (16 mL: yellow solid, 3:395:86M, 3:95:5:1.g).

Step 2 to a stirred solution of 6-chloro-2- (4-methoxybenzyl) -4- (pyrimidin-4-yl) -2H-pyrazolo [4,3-C ] 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 ₂CO₃ (163 mg,0.50 mmol) and the resulting mixture was heated to 110℃under an atmosphere of N ₂ for 12 hours. The reaction mixture was then cooled to room temperature, diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered and concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (MeOH in dcm=0-3%) 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 3A solution of 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,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 solution. The organic phase was washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative-TLC (MeOH in dcm=5%) 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]⁺,¹H 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)

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 a solution of 4, 6-dichloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-C ] pyridine-7-carboxamide (200 mg,0.57 mmol) and K ₂CO₃ (157 mg,1.14 mmol) in MeCN (10 mL) was added dropwise (R) -pyrrolidin-3-ol (52 mg,0.57 mmol) at 0deg.C 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 to 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 Synthesis of (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

To a solution of (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 O (1 mL) was added Pd (dppf) Cl ₂ (14 mg,0.02 mmol) and Cs ₂CO₃ (122 mg,0.37 mmol). The resulting mixture was heated to 110 ℃ under an atmosphere of N ₂ for 12 hours. The reaction mixture was then cooled to room temperature, the mixture was diluted with H ₂ O (20 mL), extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, 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 (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 solution in (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,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) as a yellow solid which was used without further purification. LC/MS (ESI) M/z 604 (M+H) ⁺.

Step 4 to a solution of (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 O (2 mL) was added NaOH (46 mg,1.16 mmol) 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 x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in dcm=0% to 3%) to give the crude product, which was purified by preparative-TLC (MeOH in dcm=5%) to give 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-d₆)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 1 to a solution of 4, 6-dichloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-C ] pyridine-7-carboxamide (150 mg,0.43 mmol) in MeCN (10 mL) was added pyrrolidine (37 mg,0.51 mmol) and K ₂CO₃ (118 mg,0.86 mmol) at 0deg.C 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 to 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 yellow solid. LC/MS (ESI) M/z 386 (M+H) ⁺.

Step 2 to a solution of 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 O (1 mL) was added Pd (dppf) Cl ₂ (22 mg,0.03 mmol) and Cs ₂CO₃ (202 mg,0.62 mmol). The resulting mixture was heated to 110 ℃ under an atmosphere of N ₂ for 12 hours. The reaction mixture was then cooled to room temperature, diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, 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 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 3A solution of 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,0.05 mmol) in TFA (3 mL) was heated to 65℃for 2 hours. The reaction mixture was then cooled to room temperature, the resulting mixture was concentrated in vacuo to give the crude product, which was dissolved in EtOAc (15 mL) and pH adjusted to 8 with saturated NaHCO ₃ solution. The organic phase was washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative-TLC (MeOH in dcm=5%) 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 :¹H 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 to a stirred solution of 1, 1-trifluoropropan-2-ol (71 mg,0.6 mmol) in DMF (5 mL) at 0deg.C under N ₂ was added NaH (25 mg,0.6mmol, 60%). The resulting mixture was stirred at 0 ℃ for 0.5 hours, followed by the addition of 4, 6-dichloro-2- (4-methoxybenzyl) -2H-pyrazolo [4,3-C ] pyridine-7-carboxamide (200 mg,0.5 mmol) in DMF (2 mL) and stirring was continued for 2 additional 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, dried over anhydrous Na ₂SO₄, concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (etoac=10% -40% in PE) to give 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 2 to a stirred solution of 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 O (2 mL) was added Cs ₂CO₃ (487 mg,1.5 mmol) and Pd (dppf) Cl ₂ (38 mg,0.05 mmol) and the reaction mixture was stirred at 100℃under N ₂ for 10H. 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 3A solution of 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,0.14 mmol) in TFA (5 mL) was stirred at 65℃for 2 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 pH adjusted to 8 with saturated NaHCO ₃. The organic phase was washed with water and brine, dried over anhydrous Na ₂SO₄, filtered and concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (MeOH in dcm=0% -3%) 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)+,¹H 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

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 to a solution of 4-bromo-6-hydroxy-2- (4-methoxybenzyl) -2H-indazole-7-carbonitrile (89mg, 2.48 mmol) and 2- {1, 4-dioxaspiro [4.5] dec-7-en-8-yl } -4, 5-tetramethyl-1, 3, 2-dioxaborolan (727 mg,2.73 mmol) in dioxane (10 mL) and H ₂ O (2 mL) was added Pd (dppf) Cl ₂ (181 mg,0.24 mmol) and K ₂CO₃ (1.03 g,7.45 mmol) under an atmosphere of N ₂. 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 dried over anhydrous Na ₂SO₄, filtered and concentrated to give 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 to a solution of trifluoromethanesulfonic acid 7-cyano-2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [4.5] 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 ₂ O (0.56 mL,3.41 mmol) in DCM (5 mL) at-50℃under N ₂. The reaction mixture was heated to-50 ℃ for 0.5 hours. The reaction mixture was washed with saturated NaHCO ₃ solution and brine. The organic phase was dried over anhydrous Na ₂SO₄, filtered, and concentrated to give the crude product, 7-cyano-2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -2H-indazol-6-yl triflate (500 mg, yield: 75.9%) as a white solid. LC/MS (ESI) M/z 572 (M+Na) ⁺

Step 3 to a solution of trifluoromethanesulfonic 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 ] methyl } benzamide (420 mg,1.09 mmol) in dioxane (5 mL) and water (1 mL) was added Na ₂CO₃ (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 dried over anhydrous Na ₂SO₄, filtered and concentrated to give 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%) as a white solid. LC/MS (ESI) M/z 681 (M+Na) ⁺

Step 4 to a solution of 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 (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] decan-8-yl) -2H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (350 mg, yield: 69.7%) as a grey solid which was used directly in the next step without further purification. LC/MS (ESI) M/z 661 (M+H) ⁺.

Step 5A solution of N- (4- (7-cyano-2- (4-methoxybenzyl) -4- (1, 4-dioxaspiro [4.5] 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 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved with DCM (15 mL) and washed with saturated NaHCO ₃ solution (5 mL x 2). The organic layer was dried over Na ₂SO₄, 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 used directly in the next step without further purification. LC/MS (ESI) M/z 497 (M+H) ⁺.

Step6 to a solution of N- ({ 4- [ 7-cyano-4- (4-oxocyclohexyl) -1H-indazol-6-yl ] phenyl } methyl) -5-fluoro-2-methoxybenzamide (242 mg,0.48 mmol) in MeOH (3 mL) was added NaBH ₄ (36 mg,0.97 mmol) at 0deg.C and the reaction mixture was stirred at 20deg.C for 0.5H. The mixture was quenched with saturated NH ₄ Cl solution (5 mL) and extracted with DCM (15 mL x 2). The organic phase was dried over anhydrous Na ₂SO₄, 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 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 to a solution of N- ({ 4- [ 7-cyano-4- (4-hydroxycyclohexyl) -1H-indazol-6-yl ] phenyl } methyl) -5-fluoro-2-methoxybenzamide (162 mg,0.32 mmol) in THF (5 mL) and EtOH (5 mL) at 20deg.C were added NaOH (2 mL,4 mmol) and H ₂O₂ (2 mL), and the mixture was stirred at 20deg.C for 16H. The mixture was diluted with H ₂ O (2 mL) and extracted with EtOAc (10 mL. Times.3), the combined organic layers were dried over Na ₂SO₄, filtered, and concentrated to give the crude product which was purified by preparative-TLC (EtOAc=100% in PE) and the resulting pure product was separated by Waters UPC2 analysis SFC (column: CHIRALCEL OJ, 250X 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 ℃ C.)

Example 112 was obtained from the first eluent (peak 1): 25mg (yield :14.9％)LC/MS(ESI)m/z:517(M+H)+,¹HNMR(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(400MHz,DMSO)δ13.14(s,1H),8.91(t,J＝6.0Hz,1H),8.32(s,1H),7.59(dd,J＝9.2,3.3Hz,2H),7.50(t,J＝9.2Hz,3H),7.45–7.37(m,3H),7.26(dd,J＝9.2,4.3Hz,1H),6.96(s,1H),4.66(d,J＝4.3Hz,1H),4.61(d,J＝6.1Hz,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,2H),1.50-1.41(m,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 1 to a solution of 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 O (1 mL) were added Pd (dppf) Cl ₂ (101 mg,0.12 mmol) and Na ₂CO₃ (178 mg,1.68 mmol) and the resulting mixture was stirred at 110℃under nitrogen atmosphere 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 2 to a solution of 4- (cyclopent-1-en-1-yl) -6-hydroxy-1- [ (4-methoxyphenyl) methyl ] -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) at-30℃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 ₂SO₄, 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 3 Pd (dppf) Cl ₂ (45 mg,0.05 mmol) and Na ₂CO₃ (89 mg,0.84 mmol) were added to a solution of trifluoromethanesulfonic acid 4- (4- ((tert-butyldiphenylsilyl) oxy) cyclopent-1-en-1-yl) -7-cyano-2- (4-methoxybenzyl) -2H-indazol-6-yl ester (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 O (1 mL) and the resulting mixture was stirred under an atmosphere of N ₂ at 110℃for 2 hours. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (etoac=1-10% 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 4 to 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 an atmosphere of H ₂ for 6 hours. 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 5 to a solution of N- (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 dropwise TFA (2 mL) at 0deg.C and the mixture stirred at 40deg.C for 5H. The reaction mixture was concentrated and diluted with saturated NaHCO ₃ (5 mL), the mixture was extracted with DCM (10 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, 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 6 to 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 ₂O₂ (1 mL) and NaOH solution (0.04 mL,0.08 mmol), and the mixture was stirred at 60deg.C for 5 hours. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with EtOAc (10 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated to give the crude product, which was purified by preparative-TLC (MeOH in dcm=5%) to give the desired product 6- (4- ((5-fluoro-2-methoxybenzoylamino) 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]⁺¹H 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 1 to a solution of 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 O (1 mL) were added Pd (dppf) Cl ₂ (101 mg,0.12 mmol) and Na ₂CO₃ (263 mg,2.5 mmol) and the reaction mixture was stirred at 110℃under an atmosphere of N ₂ 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- (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] ⁺.

Step2 to a solution of 4- (cyclopent-1-en-1-yl) -6- (methoxymethoxy) -1- [ (4-methoxyphenyl) methyl ] -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 55℃for 2 hours. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with EtOAc (10 mL. Times.2). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, 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%) as a white solid which was used directly in the next step without further purification. LC/MS (ESI) m/z 346[ M+1] ⁺

Step 3 to a solution of 4- (cyclopent-1-en-1-yl) -6-hydroxy-1- [ (4-methoxyphenyl) methyl ] -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) dropwise at-30 ℃. 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 ₂SO₄, filtered, and concentrated to give 7-cyano-4- (cyclopent-1-en-1-yl) -1- [ (4-methoxyphenyl) methyl ] -1H-indazol-6-yl triflate (260 mg, 67.2%) as a brown solid which was used directly in the next step without further purification. LC/MS (ESI) m/z 478[ M+1] ⁺

Step 4 to a solution of trifluoromethanesulfonic 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 O (1 mL) were added Pd (dppf) Cl ₂ (45 mg,0.05 mmol) and Na ₂CO₃ (115 mg,1.1 mmol) and the reaction mixture was stirred at 110℃under an atmosphere of N ₂ for 2 hours. The reaction mixture was concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (etoac=1-20% 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 5 to 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) was added drop wise BH ₃.Me₂ S (0.09 mL,1 mmol/mL) at 0℃and the reaction mixture was stirred at this temperature for 1 hour, then EtOH (1 mL) was added drop wise at 0℃and then H ₂O₂ (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 diluted with H ₂ O (10 mL) and extracted with EtOAc (10 mL. Times.3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, 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) at 0deg.C was added TFA (2 mL) dropwise and the reaction mixture stirred at 40deg.C for 5H. The reaction mixture was concentrated and diluted with saturated NaHCO ₃ (5 mL), the mixture was extracted with DCM (10 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, 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 7 to 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 were added dropwise H ₂O₂ (1 mL) and 2NNaOH (0.04 mL,0.08 mmol), and the reaction mixture was stirred at 60deg.C for 5 hours. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with EtOAc (10 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated to give the crude product, which was purified by preparative-TLC (MeOH in dcm=5%) 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]⁺;¹H 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:

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

Step 1 to a stirred solution of 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 ₂ O (10 mL) at 25℃was slowly added K ₂CO₃ (800 mg,5.7 mmol) and Pd (dppf) Cl ₂ (50 mg,0.7 mmol) and the reaction mixture was heated to 100℃for 24 hours under an atmosphere of N ₂. 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 ₂SO₄, filtered, and concentrated to give 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 (1.5 g, yield: 52.4%) as a white solid. LC/MS (ESI) M/z 273 (M+H) ⁺.

Step 2 to a stirred solution of 4- (cyclopent-1-en-1-yl) -7-methoxy-1H-indazole-6-carboxylic acid methyl ester (1.4 g,5.1 mmol) in MeOH (15 mL) was added Pd/C (150 mg, 10%). The resulting mixture was stirred under an atmosphere of H ₂ for 24 hours, filtered, and concentrated to give the crude product methyl 4-cyclopentyl-7-methoxy-1H-indazole-6-carboxylate (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,CDCl₃)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-50℃was added BBr ₃ (5 mL,1M in Tol.) and 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 dried over anhydrous Na ₂SO₄, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (etoac=2% to 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,CDCl₃)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 TEA (100 mg,0.9 mmol) was added to a stirred solution of methyl 4-cyclopentyl-7-hydroxy-1H-indazole-6-carboxylate (500 mg,0.3 mmol) and Tf ₂ O (0.176 mL,1.0 mmol) in DCM (5 mL) at 0deg.C 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 ₂SO₄, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (etoac=2-25% in PE) to give methyl 4-cyclopentyl-7- (trifluoromethylsulfonyloxy) -1H-indazole-6-carboxylate (600 mg, yield: 51%) as a white solid .LC/MS(ESI)m/z:393(M+H)⁺.1H NMR(400MHz,CDCl₃)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 a stirred solution of methyl 4-cyclopentyl-7- (trifluoromethylsulfonyloxy) -1H-indazole-6-carboxylate (400 mg,1.0 mmol) and Zn (CN) ₂ (350 mg,2.9 mmol) in DMF (5 mL) was slowly added Pd (dppf) Cl ₂ (100 mg,0.1 mmol) and the reaction mixture was stirred in a microwave reactor at 130℃under an atmosphere of N ₂ for 2 hours. 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 ₂SO₄, filtered and concentrated to give 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,CDCl₃)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 a solution of methyl 7-cyano-4-cyclopentyl-1H-indazole-6-carboxylate (230 mg,0.8 mmol) in MeOH (10 mL)/H ₂ 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 dried over Na ₂SO₄, concentrated, and purified by prep-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 ℃ for 2 hours under an atmosphere of N ₂. The mixture was added to 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, the organic phases were dried over anhydrous Na ₂SO₄, filtered and concentrated to give 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)⁺;¹H NMR(400MHz,CDCl₃)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 a stirred solution of 6-amino-4-cyclopentyl-1H-indazole-7-carbonitrile (79 mg,0.3 mmol) and CH ₂I₂ (187 mg,0.7 mmol) in DCM (2.5 mL) and AcOH (0.4 mL,7 mmol) at 0deg.C was slowly added a solution of NaNO ₂ (120 mg,1.7 mmol) in H ₂ O (2.5 mL) and the reaction mixture 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 ₂SO₄, filtered, and concentrated to give 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 9 Synthesis of 4-cyclopentyl-6- (4-phenoxyphenyl) -1H-indazole-7-carbonitrile

To a stirred solution of 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 ₂ O (1 mL) at 25 ℃ was slowly added NaHCO ₃ (20 mg,0.2 mmol) and Pd (dppf) Cl ₂ (10 mg,0.1 mmol), and the reaction mixture was heated to 60 ℃ under nitrogen atmosphere for 18 hours. 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 ₂SO₄, filtered and concentrated to give 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 10 to 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 ₂O₂ (2 mL), and the reaction mixture was stirred at 65℃under an atmosphere of N ₂ for 18 hours. 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 dried over anhydrous Na ₂SO₄, filtered, and concentrated to give 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,CD₃OD)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:

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

Step 1 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) were added Pd ₂(dba)₃ (114 mg,0.14 mmol), xant-phos (72 mg,0.14 mmol) and Cs ₂CO₃ (405 mg,1.22 mmol), and the reaction mixture was stirred at 110℃under nitrogen for 10 hours. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (meoh=1 to 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 2 to a solution of 6- (methoxymethoxy) -1- [ (4-methoxyphenyl) methyl ] -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 55℃for 2 hours. The reaction mixture was extracted with EtOAc (20 ml x 2), the combined organic phases were washed with water and brine, dried over Na ₂SO₄, and concentrated to give the crude product 6-hydroxy-1- [ (4-methoxyphenyl) methyl ] -4- (pyrrolidin-1-yl) -1H-indazole-7-carbonitrile (140 mg, yield: 87.4%) as a yellow solid which was used in the next step without further purification. LC/MS (ESI) m/z 349[ M+1] ⁺

Step 3 to a solution of 6-hydroxy-1- [ (4-methoxyphenyl) methyl ] -4- (pyrrolidin-1-yl) -1H-indazole-7-carbonitrile (140 mg,0.40 mmol) in DCM (5 mL) was added drop wise DIPEA (51 mg,0.40 mmol) followed by Tf ₂ O (112 mg,0.402 mmol) at-30℃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, dried over Na ₂SO₄, and concentrated to give the crude product, 7-cyano-1- [ (4-methoxyphenyl) methyl ] -4- (pyrrolidin-1-yl) -1H-indazol-6-yl ester (110 mg, yield: 57.5%) as brown solid which was used in the next step without further purification. LC/MS (ESI) m/z 481[ M+1] ⁺

Step 4 to a solution of trifluoromethanesulfonic 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 O (1 mL) were added Pd (dppf) Cl ₂.CH₂Cl₂ (51 mg,0.06 mmol) and Na ₂CO₃ (66 mg,0.62 mmol) and the reaction mixture was stirred at 100℃under an atmosphere of N ₂ for 10 hours. 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 a solution of methyl 6-chloro-4- {1, 4-dioxaspiro [4.5] dec-7-en-8-yl } -1- [ (4-methoxyphenyl) methyl ] -1H-pyrazolo [4,3-C ] pyridine-7-carboxylate (65 mg,0.14 mmol) in DCM (2 mL) was added TFA (2 mL) and the reaction mixture stirred at 40℃for 5H. 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%), as a brown oil, which was used in the next step without further purification. LC/MS (ESI) m/z 470[ M+1] ⁺.

Step 6A solution of N- ({ 4- [ 7-cyano-4- (pyrrolidin-1-yl) -1H-indazol-6-yl ] phenyl } methyl) -5-fluoro-2-methoxybenzamide (60 mg,0.13 mmol) in H ₂SO₄ (1 mL) was stirred at 55℃for 3 hours. The reaction mixture was poured into ice water, extracted with EtOAc (20 ml x 3), the combined organic phases were washed with H ₂ O and brine, dried over anhydrous Na ₂SO₄, and concentrated. 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%) as a white solid .LC/MS(ESI)m/z:488[M+1]+,1H NMR(400MHz,CD₃OD)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 1 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) was added Cs ₂CO₃ (4816 mg,1.49 mmol), xant-phos (86 mg,0.15 mmol) and Pd ₂(dba)₃ (68 mg,0.075 mmol) under N ₂. 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 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) under N ₂. 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%) as a yellow solid, which was used without further purification. LC/MS (ESI) M/z 365 (M+H) ⁺.

Step 3 NEt ₃ (77.6 mg,0.77 mmol) and trifluoromethanesulfonic anhydride (108 mg,0.38 mmol) were 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 ℃. 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 4 to a solution of (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 O (1 mL) was added K ₂CO₃ (33 mg,0.24 mmol) and Pd (dppf) Cl ₂ (9 mg,0.012 mmol) under N ₂. 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 dried over anhydrous Na ₂SO₄, filtered and concentrated to give 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 ] -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 5 to 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), extracted with EtOAc (50 mL x 3), the combined organic phases were washed with brine, dried over anhydrous Na ₂SO₄, 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 to a stirred suspension of (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 ₂SO₄ (1 mL). 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 ₂SO₄, 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)

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 1 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) were added Pd ₂(dba)₃ (114 mg,0.14 mmol), xant-phos (72 mg,0.14 mmol) and Cs ₂CO₃ (405 mg,1.22 mmol), and the reaction mixture was stirred under nitrogen at 110℃for 10 hours. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (meoh=1 to 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 2 to 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 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, dried over Na ₂SO₄, and concentrated to give 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 3 NCS (74 mg,0.55 mmol) was added to 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) at-20℃and the mixture stirred at room temperature for 8 hours. The mixture was diluted with H ₂ O (10 mL), extracted with EtOAc (10 mL x 2), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated to give the crude product which was purified by silica gel column chromatography (MeOH in DCM = 1% -5%) 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 4 to 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) followed by Tf ₂ O (0.06 mL,0.36 mmol) dropwise at-30 ℃. The mixture was stirred at-30 ℃ for 1 hour. The reaction mixture was diluted with H ₂ O (10 mL), extracted with DCM (10 mL x 2), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated to give (R) -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 5 Pd (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 purified by silica gel column chromatography (EtOAc=5% -30% in PE) to give the desired product (R) -N- (5-chloro-7-cyano-2- (4-methoxybenzyl) -4- (2-methylpyrrolidin-1-H-indazol-2-yl) benzamide (100 mg) as a white solid (5.42 mg). LC/MS (ESI) m/z 639[ M+1] ⁺

Step 6 to 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) and the reaction mixture stirred at 40℃for 5H. 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 7A solution of (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) in H ₂SO₄ (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), the combined organic phases were washed with H ₂ O and brine, dried over anhydrous Na ₂SO₄, and concentrated. 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-methoxybenzoylamino) methyl) phenyl) -4- (2-methylpyrrolidin-1-yl) -1H-indazole-7-carboxamide (26 mg, yield: 41.9%) as a white solid :¹H 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 1 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) was added Cs ₂CO₃ (727 mg,2.23 mmol), SPhos (45 mg,0.11 mmol) and Pd ₂(dba)₃ (102 mg,0.11 mmol) under N ₂. 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 2 to 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-30 ℃. 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 3 to a solution of (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 O (2 mL) was added Cs ₂CO₃ (785 mg,2.41 mmol) and Pd (dppf) Cl ₂ (88 mg,0.12 mmol) under N ₂. 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 dried over anhydrous Na ₂SO₄, filtered and concentrated to give the 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 (349mg, 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 pH adjusted to 8 with saturated NaHCO ₃. The organic phase was washed with water and brine, dried over anhydrous Na ₂SO₄, 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 5A solution of (R) -N- (4- (7-cyano-4- (2-methylpyrrolidin-1-yl) -1H-indazol-6-yl) benzyl) -5-fluoro-2-methoxybenzamide (150 mg,0.31 mmol) in concentrated H ₂SO₄ (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 ₂SO₄, 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 :¹H 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 1 to 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 diluted with DCM (20 mL) and saturated Na ₂CO₃ 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% to 50% in PE) to give the desired product 2-fluoro-6- (methoxymethoxy) benzonitrile (2.5 g, yield: 94.6%) as a white solid.

Step 2 to a solution of 2-fluoro-6- (methoxymethoxy) benzonitrile (2.5 g,13.8 mmol) in THF (20 mL) at-78℃under N ₂ 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. The reaction was quenched with saturated NH ₄ Cl solution and extracted with EtOAc (20 ml x 3). The combined organic phases were dried over anhydrous Na ₂SO₄, filtered and concentrated to give the crude product which was purified by silica gel column chromatography (etoac=10% to 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 .¹H NMR(400MHz,CDCl₃)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 3 to 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 4 to a solution of 6- (methoxymethoxy) -1H-indazole-7-carbonitrile (360 mg,1.8 mmol) in DMF (10 mL) was added PMBCl (0.3 mL,2.1 mmol) and Cs ₂CO₃ (808.0 mg,2.5 mmol), and the reaction mixture was stirred at 60℃for 1.5H. 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% to 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 5 to a solution of 6- (methoxymethoxy) -1- [ (4-methoxyphenyl) methyl ] -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 6 to a solution of 6-hydroxy-1- [ (4-methoxyphenyl) methyl ] -1H-indazole-7-carbonitrile (147 mg,0.5 mmol) in DCM (10 mL) were 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 1H. 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 ] -1H-indazol-6-yl triflate (167 mg, yield: 77.1%) as a yellow oil, which was used directly in the next step without further purification. LCMS: ESI m/z 412[ M+H ] ⁺.

Step 7 to a solution of trifluoromethanesulfonic acid 7-cyano-1- [ (4-methoxyphenyl) methyl ] -1H-indazol-6-yl ester (67 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 O (2 mL) were added K ₂CO₃ (112 mg,0.8 mmol) and Pd (dppf) Cl ₂ (29 mg,0.04 mmol) and the reaction mixture was stirred at 100℃under an atmosphere of N ₂ for 2 hours. 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 8A solution of N- [ (4- { 7-cyano-1- [ (4-methoxyphenyl) methyl ] -1H-indazol-6-yl } phenyl) methyl ] -2-methoxybenzamide (120 mg,0.24 mmol) in TFA (2 mL) was heated to 75℃for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in EtOAc (15 mL) and washed with saturated NaHCO ₃ solution (5 mL x 3). 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%) as a brown solid, which was used directly in the next step without further purification. LCMS: ESI m/z 383[ M+H ] ⁺.

Step 9 to a solution of N- { [4- (7-cyano-1H-indazol-6-yl) phenyl ] methyl } -2-methoxybenzamide (98 mg,0.26 mmol) in EtOH (2 mL) and THF (2 mL) were added NaOH (20 mg,0.5 mmol) and H ₂O₂ (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 1 to a stirred solution of 4, 6-dichloro-1- [ (4-methoxyphenyl) methyl ] -1H-pyrazolo [4,3-C ] pyridine-7-carboxamide (80 mg,0.23 mmol) and tert-butyl 4-aminobutyrate (50 mg,0.31 mmol) in DMF (2 mL) at 25℃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 was extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂SO₄, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (etoac=10% to 50% in PE) to give tert-butyl 4- ({ 7-carbamoyl-6-chloro-1- [ (4-methoxyphenyl) methyl ] -1H-pyrazolo [4,3-c ] pyridin-4-yl } amino) butyrate (90 mg, yield: 83%) as an off-white oil. LC/MS (ESI) M/z 474 (M+H) ⁺.

Step 2 to a stirred solution of tert-butyl 4- ({ 7-carbamoyl-6-chloro-1- [ (4-methoxyphenyl) methyl ] -1H-pyrazolo [4,3-C ] 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 O (1 mL) was added Pd (dppf) Cl ₂ (30 mg, 0.0414 mmol) and K ₂CO₃ (100 mg,0.724 mmol) and the reaction mixture was stirred at 110℃under an atmosphere of N ₂ for 18H. 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, the organic phases were dried over anhydrous Na ₂SO₄, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (etoac=10% to 50% in PE) to give tert-butyl 4- { [ 7-carbamoyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1- [ (4-methoxyphenyl) methyl ] -1H-pyrazolo [4,3-c ] pyridin-4-yl ] amino } butanoate (90 mg, yield: 68%) as an off-white oil. LC/MS (ESI) M/z 697 (M+H) ⁺.

Step 3 to a stirred solution of tert-butyl 4- { [ 7-carbamoyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1- [ (4-methoxyphenyl) methyl ] -1H-pyrazolo [4,3-C ] pyridin-4-yl ] amino } butanoate (90 mg,0.13 mmol) in DCM (5 mL) at 25℃was added TFA (3 mL) and the reaction mixture stirred at 50℃for 18H. The reaction mixture was poured into water (5 mL), extracted with EtOAc (60 mL x 3), the combined organic phases were washed with saturated NaHCO ₃, water and brine, the organic phases were dried over anhydrous Na ₂SO₄, 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%) as an off-white solid. LC/MS (ESI) M/z 521 (M+H) ⁺.

Step 4 to a stirred solution of 4- { [ 7-carbamoyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrazolo [4,3-C ] pyridin-4-yl ] amino } butyric acid (45 mg,0.1 mmol) and HATU (50 mg,0.13 mmol) in DMF (2 mL) at 25℃was added DIPEA (25 mg,0.19 mmol) and the reaction mixture was heated to 50℃for 18H. The reaction mixture was poured into water (10 mL), the mixture was extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, the organic phases were dried over anhydrous Na ₂SO₄, 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 1 to a solution of 2, 6-dichloropyridin-4-amine (25.0 g,153.37 mmol) and Boc ₂ O (100.3 g,460.1 mmol) in DCM (300 mL) under N ₂ with stirring 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, filtered, and concentrated to give the crude product which was purified by silica gel column chromatography (etoac=0-2% in PE). The title tert-butyl N- [ (tert-butoxy) carbonyl ] -N- (2, 6-dichloropyridin-4-yl) carbamate (55 g, 99% yield) was a white solid. LC/MS (ESI) M/z 364 (M+H) +.

Step 2 to a solution of tert-butyl N- [ (tert-butoxy) carbonyl ] -N- (2, 6-dichloropyridin-4-yl) carbamate (55.0 g,151.4 mmol) in THF (300 mL) at-78℃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 quenched with saturated NH ₄ Cl solution and extracted with EtOAc (100 ml x 3). The organic layer was dried over MgSO ₄, filtered and concentrated 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, 6-dichloronicotinic acid (53 g, 96% yield) as a white solid. LC/MS (ESI) M/z 364 (M+H) ⁺. 1H NMR (400 MHz, DMSO). Delta.9.84 (s, 1H), 7.63 (s, 1H), 1.60 (s, 9H), 1.52 (s, 9H).

Step 3 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) under N ₂ was added K ₂CO₃ (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 to 2% in PE) to give the desired product tert-butyl 4- (tert-butoxycarbonylamino) -2-chloro-6-cyclopentenyl nicotinate (1.1 g, yield 51%) as a white solid .LC/MS(ESI)m/z:395(M+H)⁺.¹HNMR(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 under an atmosphere of H ₂ for 4 hours. 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 5 to a solution of tert-butyl 4- { [ (tert-butoxy) carbonyl ] amino } -2-chloro-6-cyclopentylpyridine-3-carboxylate (540 mg,1.3 mmol) in DCM (5 mL) was added TFA (5 mL) under N ₂. 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 6 TMSCHN ₂ (501 mg,4.4 mmol) was added to a solution of 4-amino-2-chloro-6-cyclopentylpyridine-3-carboxylic acid (280 mg,1.1 mmol) in DCM (5 mL) under an atmosphere of N ₂. 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,CDCl₃)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 7 to a solution of methyl 4-amino-2-chloro-6-cyclopentylpyridine-3-carboxylate (190 mg,0.74 mmol) in MeCN (5 mL) was added NBS (145 mg,0.8 mmol) 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 8 to a solution of methyl 4-amino-5-bromo-2-chloro-6-cyclopentylpyridine-3-carboxylate (200 mg,0.6 mmol) and 2-methoxy-N- { [4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] methyl } benzamide (220 mg,0.6 mmol) in dioxane (6 mL) and H ₂ O (2 mL) was added K ₂CO₃ (249 mg,1.8 mmol) and Pd (PPh ₃)₄ (35 mg,0.030 mmol) and 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 dried over anhydrous Na ₂SO₄, filtered and concentrated to give the product which was purified by silica gel column chromatography (EtOAc in PE=10-20%) to give the desired product 4-amino-5-bromo-6-cyclopentyl-2- (4-methoxy-phenyl) methylester (ESI) as a crude solid (538: 4M) and ESI) as a crude solid (43 mg, 40%) as a white solid (43.0.30 mL) ⁺

Step 9 to a solution of methyl 4-amino-5-bromo-6-cyclopentyl-2- (4- ((2-methoxybenzoylamino) methyl) phenyl) nicotinate (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 O (2 mL) under N ₂ was added K ₂CO₃ (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 dried over anhydrous Na ₂SO₄, filtered and concentrated to give the desired product which was purified by column chromatography (EtOAc=10-20% in PE) to give the desired product 4-amino-6-cyclopentyl-2- (methoxybenzoylamino) -phenyl) nicotinate (5:6-methoxymethyl) as a crude solid (ESI: 67:5:5:6:5.m) and ESM (67:5:5:6:6:6:3.Z) (solid, ESI) ⁺

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 100℃in a microwave reactor. The reaction mixture was then concentrated, diluted with EtOAc (20 mL), washed with water and brine. The organic layer was dried over anhydrous Na ₂SO₄, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM: meoh=100:1 to 30:1) to give methyl 4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-pyrrolo [3,2-c ] pyridine-7-carboxylate (100 mg, yield: 78.2%) as a white solid. LC/MS (ESI) M/z 484 (M+H) ⁺

Step 11 to a solution of methyl 4-cyclopentyl-6- (4- ((2-methoxybenzoylamino) methyl) phenyl) -1H-pyrrolo [3,2-c ] pyridine-7-carboxylate (100 mg,0.206 mmol) in THF (5 mL) was added a solution of ammonia (5 mL,28% in water). The mixture was stirred in a sealed jar at 100 ℃ for 12 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-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 1 to a solution of methyl 4-amino-5-bromo-2-chloro-6-cyclopentylpropionate (500 mg,1.51 mmol) and 5-fluoro-2-methoxy-N- (4, 5-dioxaborolan-2-yl) benzyl) benzamide (583 mg,1.51 mmol) in dioxane (15 mL) and H ₂ O (3 mL) was added K ₂CO₃ (417 mg,3.02 mmol) and Pd (PPh ₃)₄ (173 mg,0.15 mmol) under N ₂. 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 dried over anhydrous Na ₂SO₄, filtered and concentrated to give the product which was purified by silica gel column chromatography (EtOAc=10% in PE) to give the desired product, K ₂CO₃ mg,3.02 mmol) and Pd (PPh ₃)₄ (173 mg,0.15 mmol). Sub.15 mmol) as a crude product, i.5-fluoro-cyclopentyl-2-methyl-5-cyclohexanecarbonate (55 mg, 55M) was obtained as a white solid (55 mg, 5M) and ESm-5-methoxy-5-methyl-5-7/55M/g.59M) solid ⁺

Step 2 to a solution of 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-ethoxyvinyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (178 mg,0.90 mmol) in 1, 4-dioxane (8 mL) and H ₂ O (2 mL) under N ₂ were added K ₂CO₃ (248 mg,1.80 mmol) and Pd (PPh ₃)₄ (104 mg,0.09 mmol). The reaction mixture was heated to 60 ℃ C. 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 dried over anhydrous Na ₂SO₄, filtered and concentrated to give the crude product which was purified by column chromatography (EtOAc=10% in PE: 10% to give the desired product, E.3-fluoro-2- (5-methoxybenzoylamino) benzyl) 2- (5-methoxymethyl) at a yield of (5-methoxymethyl) to give 3-5-methoxymethyl) 6-cyclopentyl-nicotinate (ESH-5:5-7.80 mmol) as a solid, i.0.09 mg, i.0.0.0.09 mmol) for 10 ℃ C. 10H, and diluting the mixture with EtOAc (30 mL) ⁺

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 100℃in a microwave reactor. The reaction mixture was then concentrated, diluted with EtOAc (20 mL), washed with water and brine. The organic layer was dried over anhydrous Na ₂SO₄, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM: meoh=100:1 to 30:1) to give methyl 4-cyclopentyl-6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -1H-pyrrolo [3,2-c ] pyridine-7-carboxylate (220 mg, yield: 55.8%) as a white solid. LC/MS (ESI) M/z:502 (M+H) ⁺

Step 4 to a stirred solution of methyl 4-cyclopentyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrrolo [3,2-c ] 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 an atmosphere of N ₂ for 18 hours. The mixture was extracted with EtOAc (10 ml x 3), the combined organic phases were washed with water and brine, the organic phases were dried over anhydrous Na ₂SO₄, filtered, and concentrated to give the crude product 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%) as a white solid. LC/MS (ESI) M/z 488 (M+H) ⁺.

Step 5 to a stirred solution of 4-cyclopentyl-6- (4- { [ (5-fluoro-2-methoxyphenyl) carboxamido ] methyl } phenyl) -1H-pyrrolo [3,2-C ] pyridine-7-carboxylic acid (200 mg,0.41 mmol) in DMF (5 mL) was slowly added TEA (124 mg,1.23 mmol) and HATU (87 mg,0.49 mmol) at 25℃and the reaction mixture stirred under NH ₃ for 1H. 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, the organic phases were dried over anhydrous Na ₂SO₄, 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 6 to a solution of 4-cyclopentyl-6- (4- ((5-fluoro-2-methoxybenzoylamino) methyl) phenyl) -1H-pyrrolo [3,2-c ] pyridine-7-carboxamide (90 mg,0.19 mmol) in 3mL of AcOH and 3mL of t-BuOH was added PyHBr (177 mg,0.56 mmol), which was stirred under N ₂ 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, 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. BTK kinase activity was tested in assay buffer containing 50mM HEPES, 1mM EGTA, 10mM Mg ²⁺, 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#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 60 minutes incubation at 25 ℃, 5 μl ADP Glo reagent (Promega, cat#v9102) was added and the reaction was stopped by incubation at 25 ℃ for 60 minutes. After addition of 10. Mu.L of kinase assay reagent (Promega, cat#V9102) and incubation at 25℃for 60 min, the plate was read as US LUM on an Envision (PERKIN ELMER, envision 2104) as RLU. IC50 values were calculated by non-linear regression fitting the% inhibition values and logarithm of compound concentration (dose response-variable slope) with GRAPHPAD PRISM 6.0.0.

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. MEK1 kinase activity was tested in assay buffer containing 50mM HEPES, 1mM EGTA, 10mM Mg ²⁺, 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), followed by mixing 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 60 minutes incubation at 25 ℃, 5 μl 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 minutes, the US LUM of the plate was read as RLU on Envision (PERKIN ELMER, envision 2104). IC50 values were calculated by non-linear regression fitting the% inhibition values and logarithm of compound concentration (dose response-variable slope) with GRAPHPAD PRISM 6.0.0.

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. EGFR kinase activity was tested in 1 Xkinase buffer (HTRF KINEASE-TK kit, cisbio, cat#62TK0 PEC) containing 5mM MgCl ₂、1mM MnCl₂ and 1mM DTT. mu.L of the diluted compound was mixed with 5. Mu.L of a 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 40 min incubation 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 non-linear regression fitting the% inhibition values and logarithm of compound concentration (dose response-variable slope) with GRAPHPAD PRISM 6.0.0.

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. OCI-Ly10 cells were cultured using IMDM medium (Gibco, cat# 12440-053) supplemented with 10% FBS (Invitrogen, cat# 10099141) and 1% penicillin-streptomycin (Gibco, cat# 15140-122) suspended in a T75 flask (Corning, cat# 430641). 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. mu.L of the diluted compound was then added to the cell plates and incubated at 37℃for 72 hours in a CO ₂ incubator (ThermoFisher, cat#371). After 72 hours of compound treatment, 100. Mu.L of cell supernatant was removed and 70. Mu. LCELLTITER-Glo buffer (Promega, cat #G7573) was added to the cell plate. After incubation at 25 ℃ for 20 minutes, luminescence signals were measured on Envision (PERKIN ELMER, envision 2104). IC50 values were calculated by non-linear regression fitting the% inhibition values and logarithm of compound concentration (dose response-variable slope) with GRAPHPAD PRISM 6.0.0.

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, which was modified to supplement 20% heat-inactivated fetal bovine serum, 37 ℃ in 5% CO ₂ 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 ⁷) in 0.1ml IMDM medium and high concentration Matrigel mixture (1:1 ratio) 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. Treatment was started when the average tumor volume reached about 120-180mm ³. Tumor size measurements were taken twice weekly with calipers and recorded. Tumor volume was estimated using the following formula (mm ³)：TV＝a×b²/2, where "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)/(mediator TVfinal-mediator 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)

Claims

1.A compound of formula I:

Or a stereoisomer, racemate 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;

Ar is-C ₆ aryl-Y-R ₂, wherein each of said C ₆ aryl groups is optionally substituted with one halo;

y is-CH ₂ -NH-C (O) -, and

R ₂ is C ₆ aryl substituted with 1,2 or 3 substituents selected from the group consisting of C _1-6 alkoxy, deuterated C _1-6 alkoxy and halo.

2. The compound of claim 1, or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof, wherein:

Ar is Wherein R ₃ is H or halo.

3. The compound of any one of claims 1-2, or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof, wherein R ₂ is 2-methoxy-phenyl or 2-methoxy-5-fluoro-phenyl.

4. The compound of any one of claims 1-2, or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof, wherein R ₁ is selected from the group consisting of 4-6 membered heterocyclyl, 5-10 membered heteroaryl, C _5-6 cycloalkyl, C _3-6 cycloalkyl-O-, and phenyl, each optionally substituted with one or more substituents selected from-OH, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxy.

5. The compound of any one of claims 1-2, or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof, wherein R ₁ is selected from 5-6 membered heteroaryl, optionally substituted with one or more substituents selected from-OH, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxy.

6. The compound of any one of claims 1-2, or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof, wherein R ₁ is pyridinyl, optionally substituted with one or more substituents selected from-OH, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxy.

7. The compound of any one of claims 1-2, or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof, wherein R ₁ is pyridin-4-yl substituted at the 2-position with C _1-6 alkyl and optionally further substituted at the 3-position with a substituent selected from-OH, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, and C _1-6 alkoxy.

8. The compound of any one of claims 1-2, or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof, wherein:

r ₁ is selected from:

9. The compound of any one of claims 1-2, or a stereoisomer, racemate, or pharmaceutically acceptable salt thereof, wherein R ₁ is selected from:

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

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a stereoisomer, racemate or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

12. Use of a compound according to any one of claims 1-10, or a stereoisomer, racemate or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a BTK related disease or disorder.

13. The use according to claim 12, wherein the disease or disorder is selected from the group consisting of tumors, autoimmune diseases, infectious diseases, inflammatory diseases and neurological disorders.

14. Use according to claim 12, wherein the disease or disorder is selected from hematological malignancies.

15. Use according to claim 12, wherein the disease or disorder is selected from B-cell malignancies.

16. Use according to claim 12, wherein the disease or disorder is selected from leukemia, lymphoma, hodgkin's disease and myeloma.

17. Use according to claim 12, wherein the disease or disorder is selected from 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), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T cell ALL, AML with myelodysplasia (AML/TMDS), mixed Lineage Leukemia (MLL), myelodysplastic syndrome (mds), myeloproliferative disease (MPD), diffuse Large B Cell Lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, berkovic giant globulinemia, primary central nervous system lymphoma, small lymphocytic lymphoma, promyelocytic leukemia (promyelocytic leukemia), hairy cell leukemia, polyahlrab leukemia, myelogenous leukemia, chronic myelogenous leukemia (mals), and anaplastic lymphoma; 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.

18. Use according to claim 12, wherein the disease or disorder is selected from Polycythemia Vera (PV), idiopathic thrombocytopenia (ET), idiopathic primary myelofibrosis, activated B-cell-like DLBCL (ABC-DLBCL), extranodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, and lymphoplasmacytomegalois (LPL).

19. A method of inhibiting BTK in vitro for non-therapeutic and non-diagnostic purposes, the method comprising contacting an effective amount of a compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, with BTK.

20. A combination comprising a compound according to any one of claims 1 to 10, or a stereoisomer, racemate or pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

21. The combination product according to claim 20, wherein the additional therapeutic agent is an antineoplastic agent.

22. The combination product according to claim 20, wherein the additional therapeutic agent is a radiation therapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent or a targeted therapeutic agent.