CN116348453A - Heteroaromatic carboxamide compounds and uses thereof - Google Patents

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

This application claims priority to international application PCT/CN2021/089684 filed on April 25, 2021; the contents of which are incorporated herein by reference in their entirety.

Field of the Invention

The present disclosure provides heteroaromatic carboxamide compounds that inhibit Bruton's tyrosine kinase BTK. The present disclosure also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds to treat BTK-related diseases or disorders.

Background of the Invention

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

巨球蛋白血症(WM)。然而，在高达30％的依鲁替尼患者中发生治疗中断，这导致不良的临床结果。尽管提供更大的BTK选择性的第二代BTK抑制剂，例如阿卡替尼(acalabrutinib)、泽布替尼(zanubrutinib)和替拉鲁替尼(tirabrutinib)，可以限制脱靶毒性，但它们都是不可逆的BTK抑制剂。所述化合物与BTK的ATP结合位点中的半胱氨酸-481共价且不可逆地反应，因此没有克服在30％的持续超过12个月治疗后的患者中发生的依鲁替尼抗性的共同机制。值得注意的是，可逆的BTK抑制剂包括维卡布鲁替尼(vecabrutinib)、ARQ-531和LOXO-305，其不依赖于半胱氨酸-481与BTK相互作用，在C481S突变存在时抑制BTK活性，并且临床证据开始出现以显示它们可以克服对不可逆BTK抑制剂的抗性。另外，目前还没有批准的用于慢性自身免疫适应症的BTK靶向疗法。在自身免疫/炎症性疾病中进展缓慢可能至少部分是由于这些适应症如RA和SLE需求的严格安全性要求。因此，人们一直在努力寻找具有更好的功效和更低毒性的可逆的BTK抑制剂。Significant progress has been made in developing BTK inhibitors as therapeutic agents for targeting hematological malignancies as well as chronic inflammatory diseases. In fact, the first-generation BTK inhibitor ibrutinib (PCI-32765, Imbruvica) has been successful in treating B-cell malignancies and is approved for chronic lymphocytic leukemia (CLL), relapsed or refractory mantle cell lymphoma (MCL), and

Macroglobulinemia (WM). However, treatment interruptions occur in up to 30% of ibrutinib patients, which leads to poor clinical outcomes. Although second-generation BTK inhibitors that provide greater BTK selectivity, such as acalabrutinib, zanubrutinib, and tirabrutinib, can limit off-target toxicity, they are all irreversible BTK inhibitors. The compound covalently and irreversibly reacts with cysteine-481 in the ATP binding site of BTK, and therefore does not overcome the common mechanism of ibrutinib resistance that occurs in 30% of patients who continue to receive treatment for more than 12 months. It is worth noting that reversible BTK inhibitors include vecabrutinib, ARQ-531, and LOXO-305, which do not rely on cysteine-481 to interact with BTK, inhibit BTK activity when C481S mutations are present, and clinical evidence is beginning to appear to show that they can overcome resistance to irreversible BTK inhibitors. Additionally, there are currently no approved BTK-targeted therapies for chronic autoimmune indications. The slow progress in autoimmune/inflammatory diseases may be due, at least in part, to the stringent safety requirements required for these indications, such as RA and SLE. Therefore, efforts have been made to identify reversible BTK inhibitors with improved efficacy and lower toxicity.

SUMMARY OF THE INVENTION

The above-mentioned compounds and the active compounds disclosed in the present invention (including compounds of formula I and specific compounds) or their stereoisomers, racemates, geometric isomers, tautomers, hydrates or solvates or their pharmaceutically acceptable salts 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 a pharmaceutically acceptable salt thereof, wherein:

X ₁ , X ₂ and X ₃ are each independently CR' or N; R' is selected from H, C _1-6 alkyl, halo and oxo;

_R1 is selected from H, deuterium, 3-10 membered heterocyclyl, 5-12 membered heteroaryl, _C3-10 cycloalkyl, _C3-10 cycloalkyl-O-, _C3-10 cycloalkenyl, 3-10 membered heterocyclyl-O-, _C6-10 aryl, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _-C1-6 alkyl- _OC1-6 alkyl, -NH2, -NH(C1-6 alkyl) and N( _C1-6 alkyl) ₂ , wherein each alkyl or alkoxy is optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, -OH _, -CN _{, -NH2} , -NH( _C1-6 alkyl) and -NH( _C1-6 alkyl) ₂ and wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted by 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-OC _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) _n C _1-6 alkyl, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O _{)NH 2 ,} -C(O)NH(C _1-6 alkyl) 2 _1-6 alkyl), -C(O)N(C _1-6 alkyl) ₂ , -NHC(O)C _1-6 alkyl, and a 3-6 membered heterocyclic group optionally substituted by oxo;

Ar is -C _6-10 aryl-YR ₂ or -5-6 membered heteroaryl-YR ₂ , wherein each aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, C _1-6 alkoxy and C _1-6 alkyl;

Y is selected from O, S, -( _CH2 ) _m- NH-C(O)-, -( _CH2 ) _m- NH-S(O) _n- , -( _CH2 ) _m -N( _C1-6 alkyl)-C(O)-, -( _CH2 ) _m -N( _C1-6 alkyl)-S(O) _n- , -( _CH2 ) _m -C(O)-NH-, -( _CH2 ) _m -S(O) _n- NH-, -( _CH2 ) _m -C(O)-N( _C1-6 alkyl)- and -( _CH2 ) _m -S(O) _n -N( _C1-6 alkyl)-;

R ₂ is C _6-10 aryl or 5-10 membered heteroaryl, which is optionally substituted with one or more substituents selected from the group consisting of 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-OC _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-mentioned compounds or their stereoisomers, racemates, geometric isomers, tautomers, hydrates or solvates, or pharmaceutically acceptable salts, as well as active compounds disclosed in the context of the present invention and covered by the scope of the above-mentioned compounds are collectively referred to as "compounds of the present invention".

The disclosure also provides compounds of the invention for use as medicaments.

The present disclosure also provides compounds of the present invention for use in treating or preventing a BTK-related disease or disorder.

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 the pharmaceutical composition of the present invention and instructions for use.

The present disclosure also provides the use of the compounds of the present invention for treating or preventing BTK-related diseases or disorders.

The present disclosure also provides the use of the compounds of the present invention in the preparation of a medicament for treating or preventing a BTK-related disease or disorder.

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

The present disclosure also provides 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.

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

The present disclosure also provides methods for preparing the compounds of the present invention, and intermediates used in preparing the compounds of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present disclosure

Embodiment 1. Compound of formula I:

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

X ₁ , X ₂ and X ₃ are each independently CR' or N; R' is selected from H, C _1-6 alkyl, halo and oxo;

_R1 is selected from H, deuterium, 3-10 membered heterocyclyl, 5-12 membered heteroaryl, _C3-10 cycloalkyl, _C3-10 cycloalkyl-O-, _C3-10 cycloalkenyl, 3-10 membered heterocyclyl-O-, _C6-10 aryl, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _-C1-6 alkyl- _OC1-6 alkyl, -NH2, -NH(C1-6 alkyl) and N( _C1-6 alkyl) ₂ , wherein each alkyl or alkoxy is optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, -OH _, -CN _{, -NH2} , -NH( _C1-6 alkyl) and -NH( _C1-6 alkyl) ₂ and wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted by 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-OC _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) _n C _1-6 alkyl, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O _{)NH 2 ,} -C(O)NH(C _1-6 alkyl) 2 _1-6 alkyl), -C(O)N(C _1-6 alkyl) ₂ , -NHC(O)C _1-6 alkyl and 3-6 membered heterocyclyl, which is optionally substituted by oxo;

Ar is -C _6-10 aryl-YR ₂ or -5-6 membered heteroaryl-YR ₂ , wherein each aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, C _1-6 alkoxy and C _1-6 alkyl;

Y is selected from O, S, -( _CH2 ) _m- NH-C(O)-, -( _CH2 ) _m- NH-S(O) _n- , -( _CH2 ) _m -N( _C1-6 alkyl)-C(O)-, -( _CH2 ) _m -N( _C1-6 alkyl)-S(O) _n- , -( _CH2 ) _m -C(O)-NH-, -( _CH2 ) _m -S(O) _n- NH-, -( _CH2 ) _m -C(O)-N( _C1-6 alkyl)- and -( _CH2 ) _m -S(O) _n -N( _C1-6 alkyl)-;

R ₂ is C _6-10 aryl or 5-10 membered heteroaryl, which is optionally substituted with one or more substituents selected from the group consisting of 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-OC _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.

Embodiment 2. The compound of Embodiment 1 or its stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or pharmaceutically acceptable salt, wherein _X1 and _X3 are each independently CR' or N; R' is selected from H, _C1-6 alkyl, halo and oxo.

Embodiment 3. A compound according to any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein _X2 is CH.

Embodiment 4. The compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof, wherein Y is selected from O, S, -( _CH2 ) _m -NH-C(O)- or -( _CH2 ) _m -C(O)-NH-.

Embodiment 5. 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 R ₂ is C _6-10 aryl or 5-6 membered heteroaryl, which is 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. A compound according to any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof, wherein:

_X1 and _X3 are each independently CR' or N; R' is selected from H, _C1-6 alkyl, halo and oxo;

_X2 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 is optionally substituted with one or more substituents selected from the group consisting of 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), -N(C _1-6 alkyl) ₂ , C 1-6 -C _1-6 alkyl-S-, -C _1-6 alkyl-OH, C _3-6 cycloalkyl and C _3-6 halocycloalkyl;

Ar is -C _6-10 aryl-YR ₂ or -5-6 membered heteroaryl-YR 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, -(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, which is optionally substituted by 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 7. A compound according to 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; R' is H or halo.

Embodiment 8. The compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein X ₃ is selected from CH, C(═O) and N.

Embodiment 9. 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:

_X1 is CR' or N; R' is H or halo;

_X2 is CH;

_X3 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 is optionally substituted with one or more substituents selected from the group consisting of 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), -N(C _1-6 alkyl) ₂ , C 1-6 _1-6 alkyl-S- and -C _1-6 alkyl-OH;

Ar is -C _6-10 aryl-YR ₂ or -5-6 membered heteroaryl-YR ₂ , wherein each aryl or heteroaryl is optionally substituted with one or more halo groups;

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

_R2 is _C6-10 aryl or 5-6 membered heteroaryl, which is optionally substituted with 1, 2 or 3 substituents selected from _C1-6 alkoxy, deuterated _C1-6 alkoxy, halo, _C1-6 haloalkyl, -OH, -CN and _-NH2 ; and

m is 0 or 1.

Embodiment 10. A compound according to 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 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 is optionally substituted with one or more substituents selected from halo, -OH and -CN; and wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted with one or more substituents selected from -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 is optionally substituted with one or more substituents selected from halo; and wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted with one or more substituents selected from: -OH, oxo, halo, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy and -C _1-6 alkyl-OH.

Embodiment 11. The compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein Ar is _-C6-10 aryl- _YR2 , wherein the aryl group is optionally substituted with one or more halo groups.

Embodiment 12. 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 Ar is -5-6 membered heteroaryl- _YR2 , wherein the heteroaryl is optionally substituted with one or more halo groups.

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 _R2 is _C6-10 aryl or 5-6 membered heteroaryl, which is optionally substituted with 1, 2 or 3 substituents selected from _C1-6 alkoxy, deuterated C1-6 alkoxy, halo, _{C1-6 haloalkyl} and -OH.

Embodiment 14. 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 _R2 is a 5-6 membered heteroaryl group, which is optionally substituted with 1, 2 or 3 substituents selected from _C1-6 alkoxy, deuterated _C1-6 alkoxy, halo, _C1-6 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 _R2 is phenyl, which is optionally substituted with 1, 2 or 3 substituents selected from _C1-6 alkoxy, deuterated _C1-6 alkoxy, halo, _C1-6 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 pharmaceutically acceptable salt thereof, wherein _R2 is phenyl or 6-membered heteroaryl, which is optionally substituted with 1 or 2 substituents selected from the group consisting of _C1-6 alkoxy, deuterated _C1-6 alkoxy, halo, _C1-6 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 _R2 is phenyl, which is optionally substituted with 1 or 2 substituents selected from the group consisting of _C1-6 alkoxy, deuterated C1-6 alkoxy, halo _{, C1-6} haloalkyl and -OH.

Embodiment 18. A compound according to 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, which is optionally substituted with 1 or 2 substituents selected from the group consisting of C _1-6 alkoxy and halo.

Embodiment 19. A compound according to any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof, wherein Y is selected from O, _-CH2- NH-C(O)-, _-CH2 -C(O)-NH- and -C(O)-NH-.

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

Embodiment 21. The compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein Y is _-CH2- NH-C(O)-.

Embodiment 22. A compound according to any one of the preceding embodiments, wherein _X3 is N, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof.

Embodiment 23. 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:

_X1 is CR' or N; R' is H or halo;

_X2 is CH;

X ₃ is N;

R ₁ is selected from 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-O-, C _6-10 aryl and N(C _1-6 alkyl) 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 -OH, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy;

Ar is -C _6-10 aryl-YR ₂ , wherein each of the C _6-10 aryl groups is optionally substituted with a halo group;

Y is _-CH2 -NH-C(O)-; and

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

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

Embodiment 25. A compound according to any one of the preceding embodiments, wherein _X3 is N, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof.

Embodiment 26. 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 Ar is phenyl- _YR2 , wherein the 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 pharmaceutically acceptable salt thereof, wherein:

其中R₃是H或卤代基。Ar is

Wherein _R3 is H or halo.

其中R₃是H或卤代基。Embodiment 28. A compound according to any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof, wherein Ar is

Wherein _R3 is H or halo.

Embodiment 29. The compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl- _YR2 .

Embodiment 30. A compound according to any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein _R2 is 2-methoxy-phenyl or 2-methoxy-5-fluoro-phenyl.

Embodiment 31. 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 R ₁ is selected from 4-6 membered heterocyclyl, 5-10 membered heteroaryl, C _5-6 cycloalkyl, C _3-6 cycloalkyl-O- and phenyl, each of which is optionally substituted with one or more substituents selected from -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, which is 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. A compound according to 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 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, which is 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 a 5-membered heteroaryl group, which is 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, which is 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, which is 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 according to any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein the halo group is F or Cl, preferably F.

Embodiment 39. The compound of any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a 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, which is 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, which is 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.

Embodiment 42. 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:

_R is selected from:

Further preferably, R ₁ is selected from:

和H。实施方案43.实施方案1的化合物，其选自:

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. A compound according to any one of Embodiments 1 to 43, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, for use as a medicament.

Embodiment 45. A 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 in treating or preventing a BTK-related disease or disorder;

Preferably, the disease or disorder is selected from a tumor, an autoimmune disease, an infectious disease, an inflammatory disease and a neurological disorder, preferably a hematological malignancy, more preferably a B-cell malignancy, even more preferably a leukemia, a lymphoma, Hodgkin's disease and a myeloma;

More preferably, the disease or disorder is selected from acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid 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 trilineage myeloid dysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential 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, lymphoma, marginal zone lymphoma (e.g., extranodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma), Burkitt lymphoma, Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myeloid leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma (MM); rheumatoid arthritis, monoarticular 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 toxicity and chronic pulmonary inflammatory disease; 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 allogeneic transplant rejection.

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

Embodiment 47. Use of a compound of any one of Embodiments 1-43 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a BTK-related disease or disorder;

Preferably, the disease or disorder is selected from a tumor, an autoimmune disease, an infectious disease, an inflammatory disease and a neurological disorder, preferably a hematological malignancy, more preferably a B-cell malignancy, even more preferably selected from a leukemia, a lymphoma, Hodgkin's disease and a myeloma;

More preferably, the disease or disorder is selected from acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid 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 trilineage myeloid dysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential 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, lymphoma, marginal zone lymphoma (e.g., extranodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma), Burkitt lymphoma, Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myeloid leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma (MM); rheumatoid arthritis, monoarticular 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 toxicity and chronic pulmonary inflammatory disease; 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 allogeneic transplant rejection.

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

Embodiment 49. A method for 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;

Preferably, the disease or disorder is selected from a tumor, an autoimmune disease, an infectious disease, an inflammatory disease and a neurological disorder, preferably a hematological malignancy, more preferably a B-cell malignancy, even more preferably a leukemia, a lymphoma, Hodgkin's disease and a myeloma;

More preferably, the disease or disorder is selected from acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid 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 trilineage myeloid dysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential 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, lymphoma, marginal zone lymphoma (e.g., extranodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma), Burkitt lymphoma, Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myeloid leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma (MM); rheumatoid arthritis, monoarticular 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 toxicity and chronic pulmonary inflammatory disease; 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 allogeneic transplant rejection.

Embodiment 50. A combination comprising 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 and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably an anti-tumor agent, such as a radiotherapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent or a targeted therapeutic agent.

Embodiment 51. A compound selected from:

wherein _P1 is an amino-protecting group, preferably p-methoxybenzyl, and _P2 is a hydroxy-protecting group, preferably methoxymethyl.

Embodiment 52. A compound selected from:

Wherein PMB is p-methoxybenzyl, and MOM is methoxymethyl.

definition

The following words, phrases and symbols used in this disclosure have the meanings described below unless otherwise indicated by the context in which they are used.

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

A hyphen ("-") that is not between two letters or symbols indicates the point of attachment of a substituent. For example, _{C3-8cycloalkyl} -O- is attached to the rest of the molecule through the oxygen.

The term "alkyl" as used herein refers to a straight or branched saturated hydrocarbon group having 1-18 carbon atoms (C _1-18 ), preferably 1-10 carbon atoms (C _1-10 ), preferably 1-6 carbon atoms (C _1-6 ), and more preferably 1-4 carbon atoms (C _1-4 ) or 1-3 carbon atoms (C _1-3 ). For example, "C _1-6 alkyl" means an alkyl group having 1-6 (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 unsaturated hydrocarbon group containing one or more, for example 1, 2 or 3, carbon-carbon double bonds (C=C), and having 2-10 carbon atoms (C _2-10 ), preferably 2-6 carbon atoms (C _2-6 ), and more preferably 2-4 carbon atoms (C _2-4 ). For example, "C _2-6 alkenyl" means an alkenyl having 2-6 (2, 3, 4, 5 or 6) carbon atoms, preferably having 1 or 2 carbon-carbon double bonds; "C _2-4 alkenyl" means an alkenyl having 2-4 carbon atoms, preferably having 1 carbon-carbon double bond. Examples of alkenyl 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 the double bond.

The term "alkynyl" as used herein refers to a straight or branched unsaturated hydrocarbon group containing one or more, for example 1, 2 or 3, carbon-carbon triple bonds (C≡C), and having 2-10 carbon atoms (C _2-10 ), preferably 2-6 carbon atoms (C _2-6 ), and more preferably 2-4 carbon atoms (C _2-4 ). For example, "C _2-6 alkynyl" means an alkynyl having 2-6 (2, 3, 4, 5 or 6) carbon atoms, preferably having 1 or 2 carbon-carbon triple bonds; "C _2-4 alkynyl" means an alkynyl having 2-4 carbon atoms, preferably having 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 the 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 alkyl substituted with halogen is used interchangeably herein and refers to an alkyl as defined herein, wherein one or more hydrogen atoms, such as 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 as defined herein, wherein two or more, such as 2, 3, 4 or 5 hydrogen atoms are replaced by halogen atoms, wherein the halogen atoms are the same as each other. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl as defined herein, wherein two or more, such as 2, 3, 4 or 5 hydrogen atoms are replaced by halogen atoms, wherein the halogen atoms are different from each other. Examples of haloalkyl include, but are not limited to, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CF ₂ CF ₃ , -CF ₂ CH ₃ , etc. Preferably, 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 include, but are not limited to, C _1-6 alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxy, including their isomers. Preferably, the alkoxy is methoxy.

The term "haloalkoxy" or alkoxy substituted by halogen, 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 include, but are not limited to, trifluoroalkoxy, preferably C _1-6 trifluoroalkoxy, more preferably C 1-6 trifluoroalkoxy.

The term "cycloalkyl" as used herein refers to a saturated cyclic hydrocarbon group having 3-10 ring carbon atoms ( _C3-10 ), such as 3-8 ring carbon atoms ( _C3-8 ), 3-7 ring carbon atoms ( _C3-7 ), 3-6 ring carbon atoms ( _C3-6 ) or 5-6 ring carbon atoms ( _C5-6 ), which may have one or more rings, such as 1 or 2 rings. "Cycloalkyl" may include fused rings, bridged rings or spiro rings. For example, the cycloalkyl is a monocyclic cycloalkyl, preferably a monocyclic _C3-8 cycloalkyl, preferably a monocyclic _C3-6 cycloalkyl, more preferably a monocyclic _C5-6 cycloalkyl. Examples of monocyclic cycloalkyls 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 _C5 - _C10 cycloalkyl. Examples of bicyclic cycloalkyls 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 _C3-6 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, which has 3-10 ring carbon atoms ( _C3-10 ), such as 3-8 ring carbon atoms ( _C3-8 ), 3-7 ring carbon atoms ( _C3-7 ), 3-6 ring carbon atoms ( _C3-6 ) or 5-6 ring carbon atoms ( _C5-6 ), which may have one or more rings, such as 1 or 2 rings. For example, the cycloalkenyl is a monocyclic cycloalkenyl. Examples of monocyclic cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cyclohexadienyl.

The term "heterocyclyl" as used herein refers to a saturated or partially unsaturated ring having 3-10 ring atoms (3-10 members), such as 3-8 ring atoms (3-8 members), 5-7 ring atoms (5-7 members), 3-6 ring atoms (3-6 members), 4-6 ring atoms (4-6 members) or 5-6 ring atoms (5-6 members), wherein one or more, such as 1, 2 or 3, preferably 1 or 2 ring atoms are independently selected from N, O and S heteroatoms, and the remaining ring atoms are carbon, and have one or more, such as 1, 2 or 3, preferably 1 or 2 rings, wherein the N or S heteroatom is optionally oxidized to various oxidation states. The point of attachment of the heterocyclyl group can be on the N heteroatom or carbon atom. The ring of the heterocyclyl group also includes fused rings, bridged rings or spiro rings. The ring of the heterocyclyl group can be saturated or contain one or more, such as one or two double bonds (i.e., partially unsaturated), but is not completely conjugated, and is not a 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 heterocyclic groups include, but are not limited to, oxiranyl, aziridinyl, thiirane, oxetanyl, azetidinyl (e.g., azetidin-1-yl, azetidin-2-yl, azetidin-3-yl), thiidine, 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., morpholino (i.e., morpholin-1-yl), morpholin-2-yl, morpholin-3-yl), thiomorpholinyl, piperidinyl (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, tetrahydropyranyl (e.g., tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl), hexahydrothiopyranyl, hexahydropyrimidinyl, and oxazacyclohexyl. Preferably, the heterocyclic group is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholino or tetrahydropyranyl, such as azetidin-1-yl, pyrrolidin-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 consisting of one ring or multiple condensed rings having 6 to 14 carbon atoms ( _C6-14 ), preferably 6 to 10 carbon atoms ( _C6-10 ), wherein at least one ring is an aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, phenanthrenyl, indenyl, indanyl, azulenyl, preferably phenyl and naphthyl, more preferably phenyl.

The term "heteroaryl" as used herein refers to a monocyclic, bicyclic or tricyclic ring system having 5-12 ring atoms (5-12 members), such as 5-10 ring atoms (5-10 members), 8-12 ring atoms (8-12 members), 5-8 ring atoms (5-8 members), 5-7 ring atoms (5-7 members), 5-6 ring atoms (5-6 members), 5 ring atoms (5 members) or 6 ring atoms (6 members), wherein at least one ring is a 5- or 6-membered aromatic ring, wherein one or more, such as 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 heteroatom is optionally oxidized to various oxidation states. For example, heteroaryl is:

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

or

- 8-12 membered bicyclic heteroaryl, i.e. a bicyclic aromatic hydrocarbon radical having 8, 9, 10, 11 or 12 ring atoms (8, 9, 10, 11 or 12 members), 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), 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, imidazopyridyl, imidazopyrrolyl, triazolopyridyl, indazolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, tetrazolopyridinyl, tetrahydropyrazolopyridinyl, benzofuranyl, benzimidazolinyl, or indolyl. Preferably, the heteroaryl group is pyrazolyl, pyridinyl, pyridazinyl or pyrazinyl, more preferably pyrazol-1-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl or pyrazin-3-yl.

As used herein, the term "oxo" refers to the group =0.

When the structures herein contain "(R)" and/or "(S)", it means that the chiral center of the compound labeled by "(R)" or "(S)" is in a single configuration of either R-configuration or S-configuration. For example, the compounds of the present disclosure have 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 means that the compound is an individual stereoisomer, but the absolute or relative configuration of the compound is arbitrarily specified 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," this means that the compound is an individual stereoisomer, and the relative configuration of the compound is cis or trans as indicated, but the configuration is undetermined.

表示的键时，其是指所述化合物的任何比例的异构体的混合物。When the structure of a compound herein contains a wavy line

When a bond is indicated, it refers to a mixture of isomers in any ratio of the compound.

时，波浪线表示该基团与分子其余部分的连接点。When a group carries a wavy line through its bond

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

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

As used herein, the term "substituted" or "substituted by..." means that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents independently selected from the specified substituent group, provided that the normal valence of the given atom is not exceeded. The term "substituted by 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 by one or more (e.g., 1, 2, 3 or 4, preferably 1 or 2) substituents independently selected from the specified substituent group, provided that the normal valence of the specified atom is not exceeded. When the substituent is an oxo group (i.e., =O), two hydrogen atoms on a single atom are replaced. Such combinations are allowed only when the combination of substituents and/or variables results in a chemically correct and stable compound. A chemically correct and stable compound means that the compound is robust enough to be isolated from a reaction mixture.

It will be appreciated by those skilled in the art that some compounds disclosed herein may contain one or more chiral centers or rings, so there are two or more stereoisomers. The racemic mixture of these isomers, a single isomer and a mixture of an enantiomer enrichment, and diastereomers when there are two chiral centers and a mixture of a specific diastereomer part enrichment are all within the scope of the present disclosure. It will also be appreciated by those skilled in the art that the present disclosure includes all individual stereoisomers (e.g., enantiomers, diastereomers, or cis- or trans-isomers) of compounds disclosed herein, racemic mixtures or partially resolved mixtures, and, where appropriate, their individual tautomeric forms.

Racemates or other mixtures of isomers can be used as such or can be resolved into their individual isomers. Stereochemically pure compounds or mixtures enriched in one or more isomers can be obtained by resolution. Methods for separating isomers are well known (e.g., see Allinger N.L. and Eliel E.L., "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971).

The term "pharmaceutically acceptable salt" includes, but is not limited to, acid addition salts of the compounds disclosed herein with inorganic acids, such as hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, etc., and 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-( _CH2 ) _n -COOH (wherein n is 0-4), etc. "Pharmaceutically acceptable salts" also include base addition salts of the compounds of the present invention having an acidic group with pharmaceutically acceptable cations, such as sodium, potassium, calcium, aluminum, lithium, and ammonium.

In addition, if the compounds described herein are obtained in the form of acid addition salts, their free base forms can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is in the form of a free base, its acid addition salt, especially a pharmaceutically acceptable acid addition salt, 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. Those skilled in the art can determine various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable acid addition salts or base addition salts without undue experimentation.

The term "solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap fixed molar ratios of solvent molecules in the solid state, thereby forming a solvate. 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 that is generally used to block or protect a particular functional group when other functional groups on the compound react. For example, an "amino protecting group" is a substituent that blocks or protects the amino functional group in the compound connected to an amino group. Suitable amino protecting groups include p-methoxybenzyl (PMB), benzyl (Bn), trityl (Trt), acetyl, trifluoroacetyl, phthalimido, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent that blocks or protects the hydroxyl of the 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 uses, see T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 5th edition, Wiley, New York, 2014.

As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combination of more than one active agent, and includes fixed and non-fixed combinations of active agents, for example, kits or pharmaceutical compositions. The term "fixed combination" means that the active agents, for example, those disclosed herein and additional active agents, are administered to an individual simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active agents, for example, those disclosed herein and additional active agents, are administered to a patient in need thereof as separate entities simultaneously, concurrently or sequentially without specific time limits, wherein such administration provides an effective level of the compound in the patient's body.

The term "treating" or "treating" a disease refers to administering one or more pharmaceutical substances, particularly a compound of the present invention or a pharmaceutically acceptable salt thereof, to an individual suffering from the disease or disorder, or having symptoms of the disease or disorder, to cure, heal, alleviate, relieve, alter, cure, improve, ameliorate or affect the disease or disorder, or 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, especially a compound of the present invention as defined herein or a pharmaceutically acceptable salt thereof, to an individual who is susceptible to the disease or disorder or who is at risk of developing the disease or disorder, to prevent or slow down the occurrence of the disease or disorder in the 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 present invention described herein or a pharmaceutically acceptable salt thereof that is effective for "treating" or "preventing" a BTK-related disease or disorder as defined above, such as a disease or disorder that responds to inhibition of BTK in an individual. An effective amount may cause any visible or detectable change in the individual described in the "treatment" or "treatment" or "prevention" as defined above. 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 the infiltration of tumor cells into peripheral organs, including, for example, the spread of tumors to soft tissues and bones; inhibit or prevent tumor metastasis; inhibit or prevent tumor growth; alleviate one or more symptoms associated with cancer to a certain extent; reduce morbidity and mortality; improve quality of life; or a combination of the above effects. An effective amount may be an amount sufficient to reduce the symptoms of a BTK-related disease or disorder. The term "effective amount" may also refer to an amount of a compound of the present invention described herein or a pharmaceutically acceptable salt thereof that effectively inhibits the activity of BTK in an individual.

The term "inhibition" refers to a reduction in the baseline activity of a biological activity or process. "BTK inhibition" refers to a reduction in BTK activity as a direct or indirect response to the presence of a compound of the present invention or a pharmaceutically acceptable salt thereof, relative to the BTK activity in the absence of the compound of the present invention or a pharmaceutically acceptable salt thereof. The reduction in activity may be due to a direct interaction of the compound of the present invention or a pharmaceutically acceptable salt thereof with BTK, or due to an interaction of the compound of the present 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 present invention or a pharmaceutically acceptable salt thereof as described herein can reduce BTK activity by directly binding to 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 mammals and non-mammals. Mammals refer to any member of the mammal class, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats and pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs; etc. In some embodiments, the individual is a human. The term "individual" does not indicate a specific age or gender. In some embodiments, the individual is a human. In some embodiments of any method or use described herein, the individual is not treated with a BTK inhibitor. In other embodiments of any method or use described herein, the individual is not treated with a BTK inhibitor.

The term "pharmaceutically acceptable" means that the substances followed by this term can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, especially for human pharmaceutical use.

The term "about" is used herein to mean approximately, within the range of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above or below the numerical values given. Typically, the term "about" is used herein to modify a numerical value above or below a 20% variation of the stated value.

The term "tumor" herein refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, inappropriate ability to 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, leukemias, lymphomas (non-Hodgkin's lymphomas), Hodgkin's disease (also known as Hodgkin's lymphomas), and myeloma. Non-limiting examples of tumors are acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid 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 trilineage myeloid dysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative diseases (MPD) (e.g. Such as, polycythemia vera (PV), idiopathic thrombocytopenia (ET) and idiopathic primary myelofibrosis), 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., extranodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myeloid leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasmacytoma and multiple myeloma (MM). The term "tumor" includes cancers of the skin, tissues, 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" as used herein refers to a disease or condition caused by damage to an individual's own tissues or organs caused by the body's immune response to self-antigens. 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, post-polycythemia vera/essential thrombocythemia myelofibrosis (post-PV/post-ET myelofibrosis).

The term "inflammatory disease" or "inflammatory disorder" refers to a pathological state that results in inflammation, especially 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 pulmonary inflammatory disease, allograft rejection, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD).

All numerical ranges herein are understood to disclose each and all values within the range and each and all value subsets within the range, regardless of whether they are specifically disclosed in addition. For example, when any numerical range is mentioned, it should be considered to refer to each value in the numerical range, for example, each integer in the numerical range. The present disclosure includes all values falling within these ranges, all smaller ranges, and the upper or lower limits of the range.

Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Pharmaceutical compositions and administration

The compounds of the present invention (e.g., any of the compounds in the embodiments herein) alone or in combination with one or more additional active agents can be formulated into pharmaceutical compositions. The pharmaceutical compositions include: (a) an effective amount of a compound of the present 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 ingredients in the composition (in some embodiments, can stabilize the active ingredients) and are harmless to the treated individual. Suitable pharmaceutically acceptable excipients are disclosed in standard reference books in the field (e.g., Remington's Pharmaceutical Sciences, Remington: The Science and Practice of Pharmacy), including one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents and other known additives to provide a good appearance of the drug (i.e., the compound of the present invention or its pharmaceutical composition) or to facilitate the manufacture of the drug product (i.e., medicament).

The compounds of the present invention can be administered in various known ways, such as oral, parenteral, inhalation or implantation. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraspinal, intralesional and intracranial injection or infusion.

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

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

Indications and treatment methods

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 used to treat or prevent a BTK-related disease or disorder.

Preferably, the BTK-related disease or disorder as used herein is selected from tumors, autoimmune diseases, infectious diseases, inflammatory diseases and neurological disorders.

The tumor is a hematological malignancy or a solid tumor. More preferably, the tumor 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 malignancies ( e.g., hematological malignancies that are BTK-related tumors) are selected from leukemias, lymphomas (non-Hodgkin lymphomas), Hodgkin's disease (also known as Hodgkin lymphomas), and myelomas, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid 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 myeloid trilineage dysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplasia syndromes (MDSs), myeloproliferative disorders (MPDs) (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., extranodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myeloid leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma (MM).

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

1.2 Solid tumors (e.g., solid tumors of 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 carcinoma, head and neck cancer, gastric cancer, esophageal cancer, bladder cancer, colorectal cancer, kidney cancer, skin cancer, brain tumors, thyroid cancer, and gliomas. See, for example, Campbell et al., Journal of Clinical Medicine, 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.

1.3 B-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., extranodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (lymphoplasmacytic 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 diseases and autoimmune diseases):

2.1. Arthritis, such as rheumatoid arthritis, monoarticular arthritis, osteoarthritis, gouty arthritis, and spondylitis;

2.2. Infectious diseases, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, Gram-positive sepsis and toxic shock syndrome;

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

2.4. Lung 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 pulmonary inflammatory disease;

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

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

2.7. Autoimmune diseases, including but not limited to systemic lupus erythematosus (SLE), autoimmune thyroiditis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, lupus erythematosus, myasthenia gravis, rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease (IBD), asthma, idiopathic thrombocytopenic purpura and myeloproliferative diseases such as myelofibrosis, myelofibrosis after polycythemia vera/essential thrombocythemia (PV/ET post-myelofibrosis);

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

2.9. Transplant rejection diseases, such as graft-versus-host disease (GVHD) and allogeneic transplant rejection;

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

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

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

2.13. Sjögren's syndrome;

2.14. Diseases involving leukocytic infiltration;

2.15. Alcoholic hepatitis;

2.16. Bacterial pneumonia; diseases mediated by antigen-antibody complexes; hypovolemic shock; type 1 diabetes mellitus; acute and delayed hypersensitivity reactions; disease states caused by leukocytes;

2.17. Cachexia and metastasis; thermal injury; granulocyte transfusion-associated syndrome; and cytokine-induced toxicity;

2.18. Behcet's disease.

3. Diseases resistant to other BTK-related therapies :

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

The compounds of the invention are useful for treating or preventing diseases that are resistant to other BTK-related therapies, either by co-administration or as a subsequent or additional (e.g., follow-up) therapy to an existing drug therapy (e.g., such other BTK kinase inhibitors; e.g., a first and/or second BTK kinase inhibitor). In some embodiments, the first or second BTK kinase inhibitor can be selected from: ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, acalabrutinib, zanubrutinib, spebrutinib, poseltinib, evobrutinib, M7583, tirabrutinib, CG'806, ARQ 531, BIIB068, vecabrutinib, 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, acalabrutinib, zanubrutinib, spebrutinib, poseltinib, evobutinib, M7583, and tirabrutinib. 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, vekabrutinib, AS871, CB 1763, CB988, GDC-0853, RN486, and dasatinib.

Drug combinations

The compounds of the present invention can be used in combination with additional active agents for the treatment of BTK-related diseases or disorders. Additional active agents can be administered separately from the compounds of the present invention, or can be included in a pharmaceutical composition according to the present invention together with the compounds of the present invention, such as a fixed combination product. In some embodiments, the additional active agent is known or found to be effective in treating BTK-related diseases or disorders, such as another BTK inhibitor, or a compound that antagonizes another target associated with the specific disease. The combination can be used to increase the efficacy of the compounds of the present 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 anti-tumor agent. Anti-tumor agents include, but are not limited to, radiotherapeutic agents, chemotherapeutic agents, immunotherapeutic agents, and targeted therapeutic agents.

General synthetic method

Preparation of 1H-pyrazolo[4,3-c]pyridine-7-carboxamide analogs having the general structures shown in A-1 and A-2 By synthetic method (Scheme 1)

Based on the synthesis of similar compounds in the literature (WO 2017042100), A-1-1 was synthesized from commercially available raw material 2,4,6-trichloropyridine, followed by bromination and subsequent deprotection to obtain intermediate A-1-2. Treatment of A-1-2 with hydrazine gave the corresponding cyclized compound A-1-3, which was converted to the key intermediate compound A-1-4a after separation from its regioisomer A-1-4b. Selective and continuous Suzuki reactions were performed on the two chloro groups on the key intermediate A-1-4a 4,6-dichloro-1H-pyrazolo[4,3-c]pyridine-7-carboxamide, followed by multiple steps of functional group transformation to obtain the target compound having the general structure of A-1. Alternatively, compound A-1-1 can be converted to intermediate A-2-2 after carboxylation, amide formation and deprotection. After ring closure and protection, A-2-2 is then converted to the key intermediate A-2-4a. After treating A-2-4a with the corresponding amine and then undergoing Suzuki reaction, the 4-nitrogen analogue having the general structure shown in A-2 can be obtained.

Process 1

wherein Ra is R ₁ connected to the ring via C, and Rb is R ₁ connected to the ring via N or O; P ₁ or P ₂ is a protecting group; R ₁ and Ar are as defined in Formula I herein.

Preparation of 1H-pyrazolo[4,3-c]pyridine-7-carboxamide analogs having the general structures shown in B-1 and B-2 Using the synthetic method (Scheme 2)

Process 2

wherein Ra is R ₁ connected to the ring via C, and Rb is R ₁ connected to the ring via N or O; P ₁ or P ₂ is a protecting group; R ₁ and Ar are as defined in Formula I herein.

As described in route 1, intermediate B-1-1 can be obtained from commercially available 4-bromo-2,6-difluorobenzonitrile according to the two-step method disclosed in WO2010059658 (but modified). After protection, 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 the starting point for the target compounds represented by B-1 or B-2, respectively, prepared in a multi-step sequence.

Alternatively, approach 2 is also used in some cases. According to the improved method disclosed in US20180127370 and WO2004065367, commercially available 5-bromo-2-hydroxy-4-methylbenzoic acid methyl ester is converted into 5-bromo-2-methoxy-4-methyl-3-nitrobenzoic acid methyl ester, which is then converted into compound 3-amino-5-bromo-2-methoxy-4-methylbenzoic acid methyl ester after a reduction step. The subsequent ring closure reaction obtains the key intermediate B-1-6, which is converted into the key intermediate B-1-9 after many bonding and functional group transformation steps. Using the key intermediate B-1-9, the target compound represented by B-1 is prepared.

The various embodiments and features in the various embodiments described in the present disclosure should be understood to be able to be combined with each other in any way, and the various schemes obtained by these combinations are included in the scope of the present disclosure, just as the schemes obtained by these combinations are specifically and one by one listed in this document, unless the context clearly shows otherwise.

All patents, patent applications, publications, and other documents cited or referred to herein are incorporated herein by reference in their entirety to the extent permitted by law. The discussion of these references is intended only to summarize the claims therein. No admission is made that any of the patents, patent applications, publications, or documents, or any portion thereof, are relevant material or prior art. The right to question the accuracy and relevance of any claim that the patents, patent applications, publications, and other documents are relevant material or prior art is specifically reserved.

Example

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

Unless otherwise stated, the temperature is in degrees Celsius and the pressure is atmospheric pressure or near atmospheric pressure. All MS (mass spectrometry) data were obtained by Agilent 6120B; Shimadzu LCMS2010. ¹ H-NMR spectra were obtained using a nuclear magnetic resonance instrument, operating at Bruker AVANCE NEO 400MHz. When indicating the multiplicity of peaks, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartet), br (broad peak), dd (double doublet), dt (double triplet). The coupling constants given are in Hertz (Hz).

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

All compound names except for reagents are generated by Chemdraw. If both the name and the formula are given for a compound, the structure will prevail if the two are inconsistent, unless the context indicates that the structure is incorrect and the name is correct.

In any structural formula herein, if there are vacant valencies on any atom, the vacant valencies are actually hydrogen atoms which are not specifically depicted for the sake of simplicity.

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

The following abbreviations are used in the following examples:

List of abbreviations

Synthesis of key intermediate A-1-4a

Synthesis of 2,4,6-trichloro-3-(1,3-dioxane-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 °C and the resulting mixture was stirred under _N2 for 1 hour, followed by the addition of piperidine-1-carboxaldehyde (5.6 mL, 49.8 mmol) at this temperature. The mixture was stirred at -65 °C for 3 hours. The reaction mixture was then quenched with saturated _NH4Cl , extracted with EtOAc (60 mL x 3), the combined organic phases were washed with brine, dried over anhydrous _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2%) to give 2,4,6-trichloropyridine-3-carboxaldehyde (4.1 g, yield: 39.1%) as a white solid. LC/MS (ESI) m/z: 211 (M+H) ⁺ , ¹ H-NMR (400MHz, DMSO) δ 10.27 (s, 1H), 8.09 (s, 1H).

Step 2 : To a stirred suspension of 2,4,6-trichloropyridine-3-carboxaldehyde (4.1 g, 19.5 mmol) and propane-1,3-diol (2.1 mL, 29.2 mmol) in toluene (40 mL) was added p-TSA (0.7 g, 3.9 mmol) at 120 °C, and the resulting mixture was stirred under _N2 for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over anhydrous _Na2SO4 , filtered, and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc in _PE = 0-10%) to give 2,4,6-trichloro-3-(1,3-dioxane-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-dioxane-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 °C, and the resulting mixture was stirred under _N2 for 1 hour, followed by the addition of 1,2-dibromotetrafluoroethane (4.1 mL, 31.3 mmol). The mixture was stirred at the same temperature for 3 hours. After warming to room temperature, the reaction mixture was quenched with saturated _NH4Cl and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel flash chromatography (EtOAc in PE = 0-10%) to give 3-bromo-2,4,6-trichloro-5-(1,3-dioxane-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-dioxane-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 °C overnight. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0-10%) 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 hydrazine hydrate (10 mL) dropwise at 0°C and stirred for another 3 hours at room temperature. The solvent was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0-10%, containing 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) δ 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-1-4a)

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 _PPh3 (1.5 g, 5.6 mmol) in THF (20 mL) at 0 °C under N2 atmosphere was added DIAD (1.1 mL, 5.6 mmol) dropwise and the mixture was stirred at room temperature overnight. The mixture was then concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0-10%, containing 10% DCM) to give 7-bromo-4,6-dichloro-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine ( A-1-4a ) (0.6 g, yield: 41.4%) as a white solid, LC/MS (ESI) m/z: 386/388/390 (M+H) ⁺ and 7-bromo-4,6-dichloro-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-c]pyridine ( A-1-4b ) (0.3 g, yield: 13%) as a white solid, LC/MS (ESI) m/z: 386/388/390 (M+H) ⁺ .

Synthesis of key intermediate A-2-4a

Step 1 : To a solution of 2,4,6-trichloro-3-(1,3-dioxane-2-yl)pyridine (A-1-1) (79 g, 294 mmol) in THF (1 L) was added LDA (220 mL, 440 mmol) dropwise at -80 °C and stirred for 1 hour, then the solution was bubbled with CO ₂ for 1 hour (maintaining the internal temperature below -70 °C). After warming to room temperature, the mixture was quenched with 1N HCl to pH = 5, extracted with EtOAc (500 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product 2,4,6-trichloro-5-(1,3-dioxane-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-dioxane-2-yl)nicotinic acid (A-2-1) (39 g, 124.78 mmol) and DMF (0.5 mL, 6.24 mmol) in THF (400 mL) was added oxalyl chloride (13 mL, 149.8 mmol) dropwise at -5°C, and the resulting mixture was stirred for 1 hour, and then NH ₃ was bubbled in for 1 hour (maintaining the internal temperature <0°C). The reaction mixture was then warmed to room temperature, the mixture was diluted with EtOAc (400 mL), filtered, and the filtrate was concentrated under vacuum to give a crude product, which was purified by flash chromatography on silica gel (EtOAc in DCM = 0% to 10%) to give the desired product, 2,4,6-trichloro-5-(1,3-dioxane-2-yl)nicotinamide (30 g, yield: 77.2%), as a light yellow solid. LC/MS(ESI)m/z:311/313(M+H) ⁺ , ¹ H NMR(400MHz, DMSO-d ₆ )δ8.21(br,1H),8.06(br,1H),6.12(s,1H),4.19-4.16(m,2H),3.97-3.94(m,2H),2.12-2.08(m, 1H),1.48-1.47(m,1H).

Step 3 : To a solution of 2,4,6-trichloro-5-(1,3-dioxane-2-yl)nicotinamide (30 g, 96.3 mmol) in AcOH (400 mL) was added HCl (200 mL, 2.4 mol) at 5°C, and the reaction mixture was heated to 50°C for 2 hours. The reaction mixture was cooled to room temperature, extracted with EtOAc (400 mL x 3), the combined organic phases were washed with saturated NaHCO ₃ , water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (EtOAc in DCM = 0% to 5%) to give 2,4,6-trichloro-5-formylnicotinamide (A-2-2, 20 g, 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-2-2, 20 g, 78.91 mmol, 80%) in THF (600 mL) was added hydrazine hydrate (7.2 mL, 118.39 mmol) dropwise at 10°C, and the reaction mixture was stirred at the same temperature for another 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 ₂ SO ₄ , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (EtOAc in DCM = 0% to 50%) 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)+. ¹ H NMR (400 MHz, DMSO) δ 14.28 (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 _Na2CO3 (8.3 g, 77.91 mmol) in DMF (50 mL) was added PMBCl (5.3 mL, 38.95 mmol) dropwise at room temperature and the reaction mixture was heated to 50 °C 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 ₂ SO ₄ , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (EtOAc in DCM = 0% to 50%) to give the desired product 4,6-dichloro-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-c]pyridine-7-carboxamide (A-2-4a, 4.2 g, 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 phenylmethanol (99.7 g, 922 mmol) in THF (1 L) was added NaH (44.3 g, 1.1 mol) at 0°C, the reaction mixture was stirred at 0°C under nitrogen atmosphere for 30 minutes, then 4-bromo-2,6-difluorobenzonitrile (200 g, 922 mmol) in THF (1 L) was added dropwise to the solution and stirred for another 2 hours. The reaction mixture was quenched with aqueous NH ₄ Cl solution, extracted with EtOAc (1 L x 2), the combined organic phases were washed with water and brine, dried over Na ₂ SO ₄ , 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 HNMR (400 MHz, DMSO) δ 7.55–7.38 (m, 7H), 5.35 (s, 2H).

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

Step 3 : To a solution of 4-bromo-2-fluoro-6-hydroxybenzonitrile (B-1-1, 145 g, 674.41 mmol) in DCM (1.5 L) was added DIPEA (232 mL, 1.35 mmol), followed by dropwise addition of _MOMCl (59.1 g, 741.85 mmol) at 0°C. The reaction mixture was stirred at 0°C under nitrogen atmosphere for 2 hours. The reaction mixture was extracted with DCM (500 mL x 2), the combined organic phases were washed with _H2O and brine, dried over anhydrous _Na2SO4 , 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(MH) ⁺ ,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 : To a solution of 4-bromo-2-fluoro-6-(methoxymethoxy)benzonitrile (160 g, 617.76 mmol) in THF (1.6 L) was added LDA (401.5 mL, 803.09 mmol, 2 M in THF) dropwise at -78 °C and the mixture was stirred at -78 °C under nitrogen atmosphere for 2 hours. Then DMF (117.3 g, 1606.18 mmol) was added to the mixture and the internal temperature was kept below -70 °C. The reaction mixture was stirred at -78 °C for another hour. The reaction mixture was quenched with NH ₄ Cl aqueous solution, extracted with EtOAc (2 L x 2), washed with H ₂ O and brine, dried over Na ₂ SO ₄ , and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 1% to 10%) to give the desired product, 4-bromo-2-fluoro-3-formyl-6-(methoxymethoxy)benzonitrile (B-1-1, 115 g, yield: 65%), as a yellow solid. LC/MS (ESI) m/z: 289 (MH) ⁺ .

Step 5 : To a solution of 4-bromo-2-fluoro-3-formyl-6-(methoxymethoxy) _{benzonitrile (115 g, 400.70 mmol) in MeCN (1.5 L) was added N2H4.H2O ( 26} g, 400.70 mmol, 80% in _H2O ) dropwise at 0°C, the mixture was stirred at 0°C for 1 hour, and then the reaction mixture was heated to 90°C for 12 hours. The reaction mixture was extracted with EtOAc (2 L x 2), the combined organic phase was washed with water and brine, dried _{over Na2SO4} , and concentrated to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% to 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)+, ¹ HNMR (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) were added _K2CO3 (26.5 g, 192.17 mmol) and PMBCl (17.9 g, 115.3 mmol), and the mixture was stirred at 60 °C for 2 hours. The reaction mixture was extracted with EtOAc (500 mL x 2), washed with water and brine, dried over Na ₂ SO ₄ , and the crude product was purified by silica gel column chromatography (EtOAc in PE = 1% to 10%) 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 the key intermediate 4-bromo-6-hydroxy-2-(4-methoxybenzyl)-2H-indazole-7-carbonitrile (B-1-3d)

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 55°C for 2 hours. The mixture was diluted with _H2O (10 mL), extracted with EtOAc (10 mL x 2), and the combined organic phases were washed with water and brine, dried over _{anhydrous Na2SO4} , 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 5-bromo-2-hydroxy-4-methylbenzoic acid methyl ester (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) at room temperature, and the reaction mixture was stirred at 60 ° C for 18 hours. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL x3). The combined organic phase was washed with water and _brine . The organic phase was dried over anhydrous _Na2SO4 , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 1% to 10%) to give 5-bromo-2-methoxy-4-methylbenzoic acid methyl ester (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 : 5-bromo-2-methoxy-4-methylbenzoic acid methyl ester (5.0 g, 19.2 mmol) was added in portions to stirred H ₂ SO ₄ (30 mL) at 0° C. After the solution was clarified, HNO ₃ (1.25 mL, 19.2 mmol) was added dropwise over 30 minutes and the mixture was stirred at 0° C. for another hour. The reaction mixture was diluted with saturated NaHCO ₃ (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0 to 10%) to give 5-bromo-2-methoxy-4-methyl-3-nitrobenzoic acid methyl ester (5.2 g, yield: 88.6%) as a pale oil. LC/MS(ESI)m/z:305(M+H) ⁺ . 1H NMR (400MHz, CDCl ₃ ) δ 8.16 (s, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 2.35 (s, 3H).

Step 3 : To a stirred solution of methyl 5-bromo-2-methoxy-4-methyl-3-nitrobenzoate (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°C, then heated to 80°C and stirred for 18 hours. 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 _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% to 50%) to give methyl 3-amino-5-bromo-2-methoxy-4-methylbenzoate (560 mg, yield: 31.0%) as a yellow solid. LC/MS(ESI)m/z:275(M+H) ⁺ . 1H NMR (400MHz, CDCl ₃ ) δ7.48 (s, 1H), 4.05 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 2.30 (s, 3H).

Step 4 : To a stirred solution of 3-amino-5-bromo-2-methoxy-4-methylbenzoic acid methyl ester (300 mg, 1.0 mmol) in HBF ₄ (2 mL, 31.4 mmol) was added dropwise NaNO ₂ (75 mg, 1.0 mmol in 1 mL water). The reaction mixture was stirred at 10° C. for 30 minutes to form a precipitate. The cooled reaction mixture was filtered, and the solid product was washed with a small amount of H ₂ O, MeOH and Et ₂ O in sequence and dried under high vacuum to obtain a yellow solid of 400 mg of diazonium salt. 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. Then the diazonium salt was added to the mixture in small amounts and multiple times under N ₂ atmosphere. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% to 25%) to give 4-bromo-7-methoxy-1H-indazole-6-carboxylic acid methyl ester ((B-1-6, 180 mg, yield: 57.7%) as a yellow solid. LC/MS (ESI) m/z: 285 (M+H) ⁺ 287 (M+H+2) ⁺ . 1H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.76 (s, 1H), 4.08 (s, 3H), 3.97 (s, 3H).

Preparation of boronic 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) at 0°C was added tert-butyl N-[(tert-butoxy)carbonyl]carbamate (756 mg, 3.48 mmol) portionwise and the resulting mixture was stirred at 0°C for 1 hour followed by the addition of 1-bromo-4-(bromomethyl)-2-chlorobenzene (900 mg, 3.17 mmol) and the reaction mixture was stirred at the same temperature for another 2 hours. The mixture was then quenched with cold saturated _NH4Cl , extracted with EtOAc (40 mL x 3), washed with water and brine, dried over _{anhydrous Na2SO4} , filtered, and concentrated under vacuum to afford 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) was added HCl (10 mL, 4 mol/L in 1,4-dioxane) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. It was 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 directly 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)methanamine hydrochloride (0.7 g, 3.18 mmol), 5-fluoro-2-methoxybenzoic acid (0.65 g, 3.81 mmol) and HATU (1.69 g, 4.44 mmol) in DMF (5 mL) was added TEA (1.32 mL, 9.52 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was then diluted with H ₂ O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography (EtOAc in PE = 0% to 20%) 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 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (0.82 g, 3.22 mmol) in 1,4-dioxane (20 mL) was added Pd(dppf) _Cl2 (0.16 g, 0.22 mmol) and KOAc (0.42 g, 4.29 mmol). The resulting mixture was heated to 110 °C under _N2 atmosphere for 12 h. After cooling to room temperature, the mixture was diluted with _H2O (10 mL), extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated under vacuum to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0% to 20%) 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 light yellow solid.

Intermediate B: 5-Fluoro-2-(methoxy-d3)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide

Step 1: A solution of 4-bromobenzoic acid (2.0 g, 10 mmol) in _SOCl2 (10 mL) was heated to 85°C under _N2 atmosphere for 2 hours. The reaction mixture was then cooled to room temperature and the solvent was removed under vacuum to give the crude product 4-bromobenzoyl chloride (2.2 g, yield: 100%), 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 at 65 °C under _N2 atmosphere overnight. 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 _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% to 3%) 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 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (3.0 g, 11.76 mmol) in dioxane (10 mL) was added KOAc (1.5 g, 15.7 mmol) and Pd(dppf) _Cl2 (0.6 g, 0.78 mmol). The resulting mixture was heated to 110 °C under _N2 atmosphere for 12 h. After cooling to room temperature, the mixture was diluted with _H2O (10 mL), extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% to 30%) to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (2.8 g, yield: 91%) as a white solid. LC/MS (ESI) m/z: 393 (M+H) ⁺ .

Intermediate C: 5-Fluoro-2-(methoxy-d3)-N-(4-(4,4,5,5-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, 16 mmol, 1 M in DCM) at -50°C over 30 min. The reaction mixture was then stirred at this temperature for 2 h, the mixture was quenched with NH 4 Cl (30 mL), extracted with DCM (30 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% to 3%) to give the desired product, N-(4-bromobenzyl)-5-fluoro-2-hydroxybenzamide (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-hydroxybenzamide (2.5 g, 7.74 mmol) in MeCN (20 mL) was added K ₂ CO ₃ (1.6 g, 11.61 mmol) and CD ₃ I (1.4 g, 9.30 mmol). The resulting mixture was stirred at room temperature under N ₂ atmosphere 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 ₂ SO ₄ , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% to 3%) to give the desired product N-(4-bromobenzyl)-5-fluoro-2-(methoxy-d3)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-d3)benzamide (800 mg, 2.35 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (716 mg, 2.82 mmol) in dioxane (10 mL) was added AcOK (461 mg, 4.70 mmol) and Pd(dppf) _Cl2 (172 mg, 0.24 mmol). The resulting mixture was heated to 100°C under _N2 atmosphere for 12 h. 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 _{Na2SO4 ,} filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% to 100%) to give 5-fluoro-2-(methoxy-d3)-N-(4-(4,4,5,5-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-(4,4,5,5-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 0° C., and the resulting mixture was stirred at 0° C. for 2 hours. The mixture was diluted with H ₂ O (300 mL), extracted with EtOAc (100 mL x 3), and then the organic layer was washed with water and brine, the collected organic layers were dried over Na ₂ SO ₄ , and concentrated to give a crude product, which was purified by silica gel column chromatography (PE=100%) to give tert-butyl(cyclopent-3-enyloxy)diphenylsilane (27.2 g, yield: 99.9%) as a colorless oil.

Step 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 give a crude product, which was purified by silica gel column chromatography (PE=100%) to give tert-butyl(3,4-dibromocyclopentyloxy)diphenylsilane (33 g, yield: 80.9%) as a colorless oil.

Step 3: To a stirred solution of tert-butyl(3,4-dibromocyclopentyloxy)diphenylsilane (8 g, 17.16 mmol) in THF (100 mL) was slowly added t-BuOK (9 g, 80.37 mmol) at 0°C and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was diluted with water (200 mL) at 0°C, 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 Na2SO4} , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 5%) to give (3-bromocyclopent-3-enyloxy)(tert-butyl)diphenylsilane (3 g, yield: 45.4%) as a colorless oil.

Step 4 : To a stirred solution of (3-bromocyclopent-3-enyloxy)(tert-butyl)diphenylsilane (3 g, 7.5 mmol) and 4,4,5,5-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) was slowly added Pd(dppf) _Cl2 (200 mg, 0.27 mmol) at 25° C. The resulting mixture was heated to 100° C. for 12 h under _N2 atmosphere. 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 _{Na2SO4 ,} filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0% to 30%) to give tert-butyldiphenyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-3-enyloxy)silane (2 g, yield: 59.7%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.66 (dt, J＝8.0, 1.8Hz, 4H), 7.38 (ddd, J＝18.0, 9.8, 4.7Hz, 6H), 6.45–6.37 (m, 1H), 4.56 (dq, J＝6.4, 4.8Hz, 1H), 2.70–2.44 (m, 4H ),1.26(s,12H),1.04(s,9H).

Intermediate I:

Synthesis of 4,4,5,5-Tetramethyl-2-(2-methyl-4,5-dihydrofuran-3-yl)-1,3,2-dioxaborolane

Step 1 : To a solution of 2-methyloxolan-3-one (3 g, 29.96 mmol) in THF (40 mL) was added LDA (18.0 mL, 36.0 mmol) dropwise at -78°C, the resulting mixture was stirred at -78°C under nitrogen atmosphere for 1 hour, followed by the addition of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (10.70 g, 29.964 mmol in THF (10 mL)), the reaction mixture was stirred for another 1 hour at -78°C. The mixture was poured into ice-cold NH ₄ Cl aqueous solution (20 mL) and extracted with EtOAc (30 mL x 3). The organic phase was dried over anhydrous _{Na2SO4 ,} filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc in petroleum = 1% to 5%) to give the desired product, 2-methyl-4,5-dihydrofuran-3-yl trifluoromethanesulfonate (700 mg, yield: 10%), as a yellow oil, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 233 [M+1] ⁺

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

Intermediate K:

Synthesis of 2-methyl-3-(4,4,5,5-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 _Et2O (30 mL) was slowly added _Tf2O (1.6 mL, 10 mmol) at -78°C and the reaction mixture was stirred at -78°C under nitrogen atmosphere for 1.5 hours. The reaction mixture was diluted with water (40 mL), the mixture was extracted with EtOAc (60 mL x 3), the combined organic phase was washed with water and _brine , the organic phase was dried over anhydrous _Na2SO4 , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (PE in DCM = 0% to 10%) to give 2-methyl-3-oxocyclopent-1-enyl trifluoromethanesulfonate (1.5 g, yield: 69%) as a colorless oil. LC/MS (ESI) m/z: 245[M+1]+, 1H NMR (400MHz, CDCl ₃ ) δ2.92(m,2H), 2.71–2.60(m,2H), 1.79(m,3H).

Step 2 : To a stirred solution of 2-methyl-3-oxocyclopent-1-enyl trifluoromethanesulfonate (500 mg, 2.048 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (0.61 mL, 2.36 mmol) in 1,4-dioxane (10 mL) was slowly added Pd(dppf) _Cl2 (100 mg, 0.14 mmol) and KOAc (500 mg, 5.09 mmol) at 25 °C and the reaction mixture was stirred at 100 °C under nitrogen atmosphere for 2 h. The reaction mixture was diluted with water (40 mL), the mixture was extracted with EtOAc (60 mL x 3), the combined organic phases were washed with water and brine, the organic phase was dried _over anhydrous _Na2SO4 , filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (PE in DCM = 0% to 50%) to give 2-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one (300 mg, yield: 66%) as a colorless oil. LC/MS (ESI) m/z: 223[M+1] ⁺ , ¹ H NMR (400MHz, CDCl ₃ ) δ2.65–2.58 (m, 2H), 2.33 (dd, J = 8.6, 4.1Hz, 2H), 1.97–1.91 (m, 3H), 1.31 (d, J = 3.3Hz, 12H).

Intermediate L:

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

Step 1 : TEA (27.5 g, 271.84 mmol) was added 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 _N2 . The reaction mixture was heated 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 _Na2SO4 , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 20%) to give the desired product, ethyl 3-((1-methoxy-1-oxopropane-2-yl)amino)propanoate (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-oxopropane-2-yl)amino)propanoate (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 ₂ SO ₄ , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 20%) to give the desired product, ethyl 3-((tert-butoxycarbonyl)(1-methoxy-1-oxopropane-2-yl)amino)propanoate (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-oxopropane-2-yl)amino)propanoate (15.0 g, 49.50 mmol) in toluene (150 mL) was added t-BuOK (11.1 g, 99 mmol) under N2. 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 _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 40%) to give the desired mixed product 5-methyl-4-oxopyrrolidine-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-ethyl ester and 2-methyl-3-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) ester 2-methyl ester (9.0 g, yield: 70.75%) as an off-white oil. LC/MS (ESI) m/z: 258 and 272 (M+H) ⁺

Step 4: To a solution of 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 at 90 ° C for 1 hour in a sealed jar. 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 ₂ SO ₄ , filtered, and concentrated to give a 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) was added Boc ₂ O (15.2 g, 69.7 mmol) and DIPEA (7 g, 69.7 mmol) under _N 2. 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 ₂ SO ₄ , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 5% to 30%) 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, 2.0 mmol/mL, 30.16 mmol) under N2. The reaction mixture was stirred at -78 °C for 1 hour. _Tf2O (5.10 g, 18.10 mmol) was then added and stirred at -78 °C for another 2 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 _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 5% to 30%) 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) _Cl2 (0.42 g, 0.57 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (2.2 g, 8.61 mmol) and AcOK (1.1 g, 11.48 nnol) under N2. The reaction mixture was stirred at 90°C 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 _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 5% to 30%) to give the desired product, 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (1.3 g, yield: 73.30%), as an off-white oil. LC/MS (ESI) m/z: 310 (M+H) ⁺

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

Step 1 : NBS (8.23 g, 46.27 mmol) was added in portions to a solution of 2-(trifluoromethyl)pyridin-4-amine (3 g, 18.51 mmol) in MeCN (50 mL) at 0°C, and 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 ₂ SO ₄ , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0-10%) 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, CDCl ₃ ) δ 8.37 (s, 1H), 5.46 (s, 2H).

Step 2 : Pd/C (10%, 133 mg, 0.13 mmol) was added to a solution of 3,5-dibromo-2-(trifluoromethyl)pyridin-4-amine (800 mg, 2.50 mmol) in EtOH (20 mL). The mixture was stirred at room temperature for 3 hours. The mixture was then filtered through a celite pad and the filtrate was concentrated under vacuum to give a crude product, which was purified by silica gel flash chromatography (EtOAc in PE = 0-50%) to give 3-bromo-2-(trifluoromethyl)pyridin-4-amine (400 mg, yield: 66.4%) as a yellow solid. LC/MS: m/z: 241/243 (M+H) ⁺ . 1H NMR (400MHz, DMSO-d ₆ ) δ 8.07 (d, J = 5.6 Hz, 1H), 6.94 (d, J = 5.6 Hz, 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-trioxatriborinane (0.95 mL, 3.32 mmol, 3.5 M in THF) in 1,4-dioxane ( ₈ mL) and H2O (2 mL) was added _K2CO3 ( ₄₅₉ mg, 3.32 mmol) and Pd(dppf) _Cl2 (121 mg, 0.17 mmol). The resulting mixture was heated to 80°C under _N2 atmosphere for 12 h. After cooling to room temperature, the mixture was diluted with _H2O (10 mL), extracted with EtOAc (10 mL x 3), washed with water and brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0-50%) 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 (363 mg, 2.27 mmol). The resulting mixture was heated to 80 °C under N ₂ atmosphere 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 ₂ SO ₄ , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0-5%) 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 5 : To a mixture of 4-bromo-3-methyl-2-(trifluoromethyl)pyridine (80 mg, 0.33 mmol) and 4,4,5,5-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) _Cl2 (24 mg, 0.03 mmol). The resulting mixture was heated to 100 °C and stirred overnight under _N2 atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under vacuum 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:4,6-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°C and stirred at -78°C under nitrogen atmosphere for 1 hour, followed by the addition of B(OMe) ₃ (780 mg, 5.34 mmol in 5 ml THF), and the reaction mixture was stirred at -78°C for another 1 hour. The mixture was poured into an ice-cold aqueous solution of NH ₄ Cl (20 mL) and extracted with EtOAc (20 mL x 3). The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 2%-5%) 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 boronate intermediates. Boronates D-G were prepared by methods similar to Intermediates A, B, and C; Intermediate J was prepared by methods similar to Intermediate I, and Intermediates O-U were prepared by methods similar to Intermediates K-N (with variations), starting from commercially available starting materials.

Embodiment 1 :

4-Cyclopentyl-6-(4-((2-methoxybenzamido)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)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 g, 5.7 mmol) and _Na2CO3 (1.2 g, 11.4 mmol) in _dioxane (20.0 mL) and _H2O (4.0 mL) was added Pd( _PPh3 ) ₄ (330 mg, 0.3 mmol), and the mixture was stirred at 60°C under _N2 atmosphere for 10 h. The reaction mixture was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (EtOAc in PE = 2% to 10%) to give the desired product, 7-bromo-6-chloro-4-(cyclopent-1-en-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine (1.1 g, yield: 46.2%) as a white solid. LC/MS(ESI)m/z:418/420[M+H]+, ¹ H NMR(400MHz, CDCl ₃ )δ8.27(s,1H),7.13(d,J＝8.7Hz,2H),6.85–6.79(m,3H),5.94(d,J＝5.7Hz,2H),3.77(s,3H),3.06–2 .87(m,2H),2.64(m,2H),2.13–2.03(m,2H).

Step 2: To 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 overnight at 85° C. in a sealed pot under CO (70 psi). After cooling to room temperature, the solvent was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (EtOAc in DCM = 0-50%) to give 6-chloro-4-(cyclopent-1-en-1-yl)-1-[(4-methoxy-phenyl)methyl]-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid methyl ester (240 mg, yield: 84.2%) as a yellow solid. LC/MS (ESI) m/z: 398 (M+H) ⁺ .

Step 3: To a solution of 6-chloro-4-(cyclopent-1-en-1-yl)-1-[(4-methoxyphenyl)-methyl]-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid methyl ester (240 mg, 0.6 mmol) in dioxane (8 mL) and H ₂ O (2 mL) was added 2-(2-methoxyphenyl)-N-{[4-(4,4,5,5-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 ₂ CO ₃ (250 mg, 1.8 mmol). The resulting mixture was then stirred at 100° C. under N ₂ atmosphere for 2 hours. 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 _Na2SO4 , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in DCM = 0-15%) to give methyl 4-(cyclopent-1-en-1-yl)-6-(4-{[(2-methoxyphenyl)formamido]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)-formylamino]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 at 60° C. under a H ₂ balloon for 2 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in DCM = 0-20%) to give the desired product, methyl 4-cyclopentyl-6-(4-((2-methoxybenzamido)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-methoxybenzamido)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 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with DCM (20 mL) and the pH was adjusted with saturated NaHCO ₃ solution. The organic phase was dried over _{anhydrous Na2SO4} and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in DCM = 0-50%) to give methyl 4-cyclopentyl-6-(4-((2-methoxybenzamido)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: Ammonia (28% in water) was added to a solution of methyl 4-cyclopentyl-6-(4-((2-methoxybenzamido)methyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-7-carboxylate (100 mg, 0.2 mmol) in THF (5 mL). The mixture was stirred in a sealed jar at 100 ° C for 6 hours. After cooling to room temperature, the reaction mixture was concentrated to give a 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 light yellow solid. ¹ H NMR (400MHz, MeOD) δ8.34(s,1H),7.91(dd,J＝7.7,1.8Hz,1H),7.76(d,J＝8.3Hz,2H),7.50(ddd,J＝16.0,8.9,5.1Hz,3H),7.16(d,J＝8.3Hz,1H),7.10–7.04 (m,1H),4.69(s,2H),4.58(s,2H),3.97(s,3H),3.76–3.70(m,1H),2.20–2.05(m,4H),1.98–1.89(m,2H),1.81(m,2H); LC/MS(ESI)m/z:470(M+H) ⁺ .

Embodiment 2:

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

Step 1 : To a solution of 7-bromo-4,6-dichloro-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine (560 mg, 1.45 mmol), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (365 mg, 1.37 mmol) and _Na2CO3 (460 _mg , 4.34 mmol) in dioxane (10 mL) and _H2O (2.0 mL) was added Pd( _PPh3 ) ₄ (83 mg, 0.01 mmol) and the mixture was stirred at 60°C for 10 h under _N2 atmosphere. The reaction mixture was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (EtOAc in PE = 2% to 10%) to give the desired product, 7-bromo-6-chloro-1-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrazolo[4,3-c]pyridine (510 mg, yield: 72%) as a white solid. ¹ H NMR (400MHz, DMSO) δ9.24 (s, 1H), 7.37 (d, J = 8.7Hz, 2H), 6.93 (d, J = 8.7Hz, 2H), 6.73 (t, J = 3.9Hz, 1H), 5.62 (s, 2H), 3.95 (m, 4H), 3.73 (s, 3H), 2.79–2.68 (m,2H),2.51(m,2H),1.84(t,J=6.5Hz,2H).

Step 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) _Cl2 (74.5 mg, 0.102 mmol) and TEA (0.43 mL, 3.056 mmol). The resulting mixture was stirred at 85 °C under CO (70 psi) in a sealed pot overnight. After cooling to room temperature, the solvent was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (EtOAc in DCM = 0-50%) 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 methyl 6-chloro-1-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrazolo[4,3-c]pyridine-7-carboxylate (75 mg, 0.16 mmol) and 5-fluoro-2-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide (74 mg, 0.19 mmol) in dioxane (4 mL) and _H2O (1 mL) was slowly added _K2CO3 ( ₄₄ mg, 0.32 mmol) and Pd(dppf) _Cl2 (14 mg, 0.02 mmol) and the reaction mixture was heated to 100°C under _N2 atmosphere for 18 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% to 100%) to give 6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid methyl ester (80 mg, yield: 72.2%) as a white solid. LC/MS(ESI)m/z:693(M+H) ⁺ .

Step 4 : To a stirred solution of methyl 6-(4-((5-fluoro-2-methoxybenzamido)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 _H2 atmosphere for 24 h, filtered, and concentrated to give the crude product methyl 6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazolo[4,3-c]pyridine-7-carboxylate (70 mg, yield: 87.6%) as a white solid, which was used directly without further purification. LC/MS (ESI) m/z: 695 (M+H) ⁺ .

Step 5: To a solution of methyl 4-{1,4-dioxaspiro[4.5]decan-8-yl}-6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[4,3-c]pyridine-7-carboxylate (70 mg, 0.1 mmol) in MeOH (5 mL) and _H2O (1 mL) was added NaOH (40 mg, 1.01 mmol) and the resulting mixture was stirred at 70 °C for 5 h. The pH value of the mixture was then adjusted to 5 with 1N HCl, filtered, and the filter cake was directly purified by preparative HPLC to obtain the desired product, 4-{1,4-dioxaspiro[4.5]decane-8-yl}-6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]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]decane-8-yl}-6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]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) was added DIPEA (34 mg, 0.264 mmol) slowly at 25°C and the reaction mixture was heated to room temperature under _NH3 atmosphere for 10 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (PE:EtOAc = 50:1 to 3:1) to give 4-{1,4-dioxaspiro[4.5]decane-8-yl}-6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]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]decane-8-yl}-6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]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 N2. 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)formamido]methyl}phenyl)-4-(4-oxocyclohexyl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (40 mg, yield: 96%) as a yellow solid, which was used directly without further purification. LC/MS(ESI)m/z:516(M+H) ⁺

Step 8: _To a solution of 6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]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 h, the reaction mixture was concentrated to give a crude product, which was purified by prep-TLC (DCM:MeOH=15:1) to give the desired product 6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-4-(4-hydroxycyclohexyl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (8 mg, yield: ²⁰ %) as a white solid. NMR (400MHz, MeOD) δ8.40(s,1H),7.75(d,J＝8.2Hz,2H),7.63(dd,J＝9.3,3.2Hz,1H),7.47(d,J＝8.3Hz,2H),7.25(ddd,J＝9.1,7.6,3.3Hz,1H),7.16(dd,J＝9.1,4 .2Hz,1H),4. 68(s,2H),3.96(s,3H),3.74–3.62(m,1H),3.22(dd,J＝12.9,8.2Hz,1H),2.11(d,J＝11.8Hz,2H),2.06–1.95(m,4H),1.51(dt,J＝17.0,11.6Hz,2H), LC/ MS(ESI)m/z:518(M+H) ⁺ .

Table 2: Compounds of general structure A-1: The compounds in the following table are prepared from key intermediate A-1-4a according to the general method of Synthesis Example 1 and Example 2 (but with some modifications).

Example 6-9: 6-(4-((5-fluoro-2-methoxybenzamido)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 ₂ CO ₃ (708 mg, 5.13 mmol). The resulting mixture was heated to 80° C. and stirred under N ₂ atmosphere 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×3). The combined organic phases were washed with water and brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0% to 70%) to give the desired product, 4-(4-(tert-butyldiphenylsilyloxy)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-butyldiphenylsilyloxy)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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide (631 mg, 1.69 mmol) in 1,4-dioxane (20 mL) and _H2O (5 mL) was added Pd(dppf) _Cl2 (100 mg, 0.14 mmol) and _Cs2CO3 (889 mg, 2.73 mmol) and _the resulting mixture was heated to 110 °C under _N2 atmosphere for 12 h. The reaction mixture was cooled to room temperature, diluted with H ₂ O (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0% to 100%) to give the desired product 4-(4-(tert-butyldiphenylsilyloxy)cyclopent-1-enyl)-6-(4-((5-fluoro-2-methoxybenzamido)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-butyldiphenylsilyloxy)cyclopent-1-enyl)-6-(4-((5-fluoro-2-methoxybenzamido)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° C. under _H atmosphere for 12 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum to give a crude product, which was purified by silica gel flash chromatography (EtOAc in PE = 0% to 50%) to give the desired product, 4-(3-(tert-butyldiphenylsilyloxy)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 4: A solution of 4-(3-(tert-butyldiphenylsilyloxy)cyclopentyl)-6-(4-((5-fluoro-2-methoxybenzamido)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 °C for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product 3-[7-carbamoyl-6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]cyclopentyl 2,2,2-trifluoroacetate (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)formamido]methyl}phenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]cyclopentyl 2,2,2-trifluoroacetate (400 mg, 0.67 mmol) in THF (10 mL) and _H2O (5 mL) was added NaOH (133 mg, 3.34 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 6 with 1N HCl, extracted with EtOAc (10 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous _{Na2SO4 ,} filtered, and concentrated under vacuum to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% to 3%) to give two pairs of enantiomers, which were further separated by SFC to give four absolute configurations of the desired product (Waters UPC2 analysis, mobile phase: A is CO2, B is methanol (0.05% DEA), gradient: 10 minutes @ 40% B in A, flow rate: 2.0 mL/min, back pressure: 100 bar, column temperature: 35°C). For Examples 6 & 7 (cis isomers): Column: ChiralPak AD, 250×4.6 mm ID, 5um; For Examples 8 & 9 (trans isomers): Column: ChiralPak IA, 250×4.6 mm ID, 5um. The absolute configurations were not determined for all four compounds.

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) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ )δ13.57(s,1H),8.86(t,J＝6.1Hz,1H),8.47(s,1H),7.83(s,1H),7.72(d,J＝8.2Hz,2H),7.62(s,1H),7.53(dd,J＝9.2,3.3Hz,1H),7.41–7.31(m,3H),7 .19(dd,J＝9.1,4.3Hz,1H),5.11(d,J＝5.9Hz,1H),4.56(d,J＝6.1H z,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) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ) δ13.57 (s, 1H), 8.86 (t, J＝6.1 Hz, 1H), 8.47 (s, 1H), 7.84 (s, 1H), 7.72 (d, J＝8.2 Hz, 2H), 7.62 (s, 1H), 7.53 (dd, J＝9.2, 3.3 Hz, 1H), 7.40–7.32 (m, 3H), 7.19 (dd, J＝9.1, 4.3 Hz, 1H), 5.12 (d, J＝5.9 Hz, 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),1.9 9–1.92(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%), white solid, LC/MS (ESI) m/z: 504 (M+H) ⁺ , ¹ H NMR (400 MHz, CD ₃ OD)δ8.35(s,1H),7.76(d,J＝8.1Hz,2H),7.62(dd,J＝9.2,3.2Hz,1H),7.44(dd,J＝20.2,7.9Hz,3H),7.32–7.22(m,2H),7.16(dd,J＝9.1,4.2Hz,1H),4.68(s, 2H),4.55–4.51(m,1H),4.09–4.03(m,1H),3.96(s,3H),2.38–2.30(m,2H),2.13(ddd,J＝18.6,12.7,7.0Hz,3H),1.82–1.74(m,1H).

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

Examples 10 & 11: 6-(4-((5-fluoro-2-methoxybenzamido)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 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (527 mg, 1.98 mmol) in dioxane (10 mL) and _H2O (3 mL) was added Pd(dppf) _Cl2 (131 mg, 0.18 mmol) and _K2CO3 (497 _mg , 3.60 mmol). The resulting mixture was heated to 70°C under _N2 atmosphere for 12 h. The reaction mixture was then cooled to room temperature, diluted with _H2O (20 mL), extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous _{Na2SO4 ,} filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% to 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-methoxybenzamido)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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide (424 mg, 1.10 mmol) in dioxane (10 mL) and _H2O (3 mL) was added Pd(dppf) _Cl2 (73 mg, 0.10 mmol) and _Cs2CO3 (652 mg, 2.0 mmol). The resulting mixture was heated to 110°C under _N2 atmosphere for 12 _h . The reaction mixture was then cooled to room temperature, diluted with _H2O (20 mL), extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, dried over _{anhydrous Na2SO4} , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% to 3%) to give the desired product 6-(4-((5-fluoro-2-methoxybenzamido)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-methoxybenzamido)methyl)phenyl)-2-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]decane-8-yl)-2H-pyrazolo[4,3-c]pyridine-7-carboxamide

To a stirred solution of 6-(4-((5-fluoro-2-methoxybenzamido)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 at 50 °C under _H atmosphere for 24 h. 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]decane-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-methoxybenzamido)methyl)phenyl)-4-(4-oxocyclohexyl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide

A solution of 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 (320 mg, 0.47 mmol) in TFA (3 mL) was stirred at 65 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with DCM (20 mL) and the pH was adjusted with saturated NaHCO ₃ solution. The organic phase was collected, dried over anhydrous Na ₂ SO ₄ , and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in DCM = 0-50%) 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-methoxybenzamido)methyl)phenyl)-4-(4-oxocyclohexyl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (220 mg, 0.43 mmol) in MeOH (10 mL) was added _NaBH4 (33 mg, 0.86 mmol). The resulting mixture was stirred at 0°C for 10 minutes. The reaction mixture was diluted with EtOAc (20 mL). The organic phase was dried over anhydrous _{Na2SO4 and} concentrated to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0-5%) to give the product, which was separated by SFC (equipment: Waters UPC2 analytical SFC, column: ChiralCelOD, 250×4.6mm ID, 5um, mobile phase: A is _CO2 , B is methanol (0.05% DEA), gradient: 10 minutes @ 40% B in A, flow rate: 2.0 mL/min, back pressure: 100 bar, column temperature: 35°C) to give cis and trans products. LC/MS (ESI) m/z: 518 (M+H) ⁺ .

Example 10 (from the first eluent, isomer 1, BNB-1082-01) 10 mg (yield: 4.5%), as a white solid and ¹ H NMR (400MHz, DMSO) δ13.53(s,1H),8.86(s,1H),8.40(s,1H),7.87(s,1H),7.75(d,J＝7.8Hz,2H),7.62(s,1H),7.53(d,J＝9.4Hz,1H),7.44–7.30(m,3H),7. 20(s,1H),4.56(d,J＝5.0Hz,2H),4.41(s,1H),3.91(s,4H),3.24(m,1H),2.21–2.19(m,2H),1.81–1.78(m,2H),1.65–1.62(d,J＝10.7Hz,4H).

Example 11 (obtained from the second eluent, isomer 2, BNB-1083-01) 61 mg (yield: 27.4%), as a white solid. ¹ H NMR (400 MHz, DMSO) δ 13.53 (s, 1H), 8.86 (t, J = 6.1 Hz, 1H), 8.45 (s, 1H), 7.85 (s, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.62 (s, 1H), 7.53 (dd, J = 9.2, 3.3 Hz, 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),1.5 5–1.31(m,2H).

Table 3: The following compounds were prepared from A-2-4a and appropriate intermediates according to methods similar to Examples 6 to 9 and 10 & 11 (with variations):

Embodiment 40:

6-(4-((5-fluoro-2-methoxybenzamido)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 ) _Cl2 (20 mg, 0.028 mmol) and _Na2CO3 (60 mg, 0.57 mmol) at 25°C. The resulting mixture was heated to 80°C and stirred under _N2 atmosphere for 12 hours. The reaction mixture was then cooled to room temperature, diluted with _H2O (10 mL), and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with water and brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0% to 70%) 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-(4,4,5,5-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) _Cl2 (14 mg, 0.02 mmol) and _K2CO3 (51 mg, 0.37 mmol) at 25°C. The resulting mixture was heated to 110°C under _N2 atmosphere for 12 _h . 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 ₂ SO ₄ , filtered, and concentrated under vacuum to give a 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-methoxybenzamido)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 3 : A solution of 6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]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 °C for 3 hours. The reaction mixture was then cooled to room temperature, the resulting mixture was concentrated under vacuum, and 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 _{Na2SO4 ,} filtered, and concentrated under vacuum to give the crude product, which was purified by prep-TLC (MeOH in DCM = 5%) to give the desired product, 6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-4-(3-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (15 mg, yield: 30%) as a white solid. LC/MS(ESI)m/z:511[M+1] ⁺ , ¹ H NMR(400MHz,DMSO)δ8.85(s,1H),8.64–8.57(m,2H),8.17(s,2H),7.76(d,J＝8.2Hz,3H),7.56–7.51(m,2H),7.41–7.32(m ,3H),7.19(dd,J＝9.2,4.3Hz,1H),4.56(d,J＝6.1Hz,2H),3.90(s,3H),2.37(s,3H).

Embodiment 41:

6-(4-((5-fluoro-2-methoxybenzamido)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° C. The resulting mixture was heated to 80° C. and stirred under N ₂ atmosphere for 18 hours. The reaction mixture was then cooled to room temperature, diluted with H ₂ O (10 mL), and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with water and brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0% to 70%) to give the desired product, 6-chloro-2-(4-methoxybenzyl)-4-(pyrimidin-4-yl)-2H-pyrazolo[4,3-c]pyridine-7-carboxamide (100 mg, yield: 86%), as a yellow solid. LC/MS (ESI) m/z: 395 (M+H)+.

Step 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) _Cl2 (15 mg, 0.025 mmol) and _Cs2CO3 (163 mg, 0.50 mmol) and the resulting mixture was heated to 110°C under _N2 atmosphere for 12 _h . The reaction mixture was then cooled to room temperature, diluted with _H2O (20 mL), extracted with EtOAc (20 mL x 3). The combined organic phase was washed with water and brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated under vacuum 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-methoxybenzamido)methyl)phenyl)-2-(4-methoxybenzyl)-4-(pyrimidin-4-yl)-2H-pyrazolo[4,3-c]pyridine-7-carboxamide (90 mg, yield: 60%) as a yellow solid. LC/MS (ESI) m/z: 618 (M+H)+.

Step 3: A solution of 6-(4-((5-fluoro-2-methoxybenzamido)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 °C for 3 hours. The reaction mixture was then cooled to room temperature, the resulting mixture was concentrated under vacuum, 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 _{Na2SO4 ,} filtered, and concentrated under vacuum 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-methoxybenzamido)methyl)phenyl)-4-(pyrimidin-4-yl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (25 mg, yield: 34%) as a white solid. LC/MS (ESI) m/z: 498 [M+1] ⁺ , ¹ H NMR (400MHz, DMSO) δ13.91(s,1H),9.47(d,J＝1.3Hz,1H),9.16–8.94(m,2H),8.89(t,J＝6.1Hz,1H),8.57(dd,J＝5.2,1.4Hz,1H),8.10(s,1H),7.88(d,J＝8.3Hz, 2H),7.83(s,1H),7.54(dd,J＝9.2,3.3Hz,1H),7.46(d,J＝8.3Hz,2H),7.35(ddd,J＝9.0,7.9,3.3Hz,1H),7.20(dd,J＝9.1,4.3Hz,1H),4.59(d,J＝6.1Hz,2H) ,3.92(s,3H).

Table 4: The following compounds were prepared from A-2-4a and the appropriate intermediate A according to a method similar to Example 40 or 41 (with variations).

Example 74: (R)-6-(4-((5-fluoro-2-(methoxy-d3)benzamido)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 ₂ CO ₃ (157 mg, 1.14 mmol) in MeCN (10 mL) was added (R)-pyrrolidin-3-ol (52 mg, 0.57 mmol) dropwise at 0°C and the result was stirred at room temperature for 12 hours. The reaction mixture was then concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% to 2%) 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-d3)benzamido)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) were added Pd(dppf)Cl ₂ (14 mg, 0.02 mmol) and Cs ₂ CO ₃ (122 mg, 0.37 mmol). The resulting mixture was heated to 110° C. under N ₂ atmosphere for 12 h. The reaction mixture was then cooled to room temperature, diluted with _H2O (20 mL), extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous _{Na2SO4 ,} filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% to 3%) to give the desired product (R)-6-(4-((5-fluoro-2-(methoxy-d3)benzamido)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 of (R)-6-(4-((5-fluoro-2-(methoxy-d3)benzamido)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°C in TFA (3 mL) for 2 hours. The reaction mixture was then cooled to room temperature and the resulting mixture was concentrated under vacuum to give the crude product (R)-1-(7-carbamoyl-6-(4-((5-fluoro-2-(methoxy- _d3 )benzamido)methyl)phenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)pyrrolidin-3-yl 2,2,2-trifluoroacetate (70 mg, quantitative) as a yellow solid which was used directly without further purification. LC/MS (ESI) m/z: 604 (M+H) ⁺ .

Step 4: To a solution of (R)-1-(7-carbamoyl-6-(4-((5-fluoro-2-(methoxy- _d3 )benzamido)-methyl)phenyl)-1H-pyrazolo-[4,3-c]pyridin-4-yl)pyrrolidin-3-yl 2,2,2-trifluoroacetate (70 mg, 0.12 mmol) in THF (5 mL) and _H2O (2 mL) was added NaOH (46 mg, 1.16 mmol) and the reaction mixture was heated to 65 °C 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 _{Na2SO4 ,} filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% to 3%) to give a crude product, which was purified by prep-TLC (MeOH in DCM = 5%) to give the desired product (R)-6-(4-((5-fluoro-2-(methoxy- _d3 )benzamido)methyl)phenyl)-4-(3-hydroxypyrrolidin-1-yl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (15 mg, yield: 25.5%) as a white solid. LC/MS (ESI) m/z: 508 (M+H) ⁺ . 1H NMR (400MHz, DMSO-d ₆ ) δ12.99(s,1H),8.85(t,J＝6.1Hz,1H),8.20(s,1H),7.64(d,J＝8.1Hz,2H),7.53(dd,J＝9.2,3.3Hz,1H),7.37–7.31(m,3H),7.28– 7.13(m,2H),6.92(s,1H),5.04(d,J＝2.9Hz,1H),4.55(d,J＝6.2Hz,2H),4.44–4.41(m,1H),3.84–3.82(m,3H),2.06–1.97(m,2H).

Example 75: 6-(4-((5-fluoro-2-methoxybenzamido)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 ₂ CO ₃ (118 mg, 0.86 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was then concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% to 2%) to give the desired product 6-chloro-2-(4-methoxybenzyl)-4-(pyrrolidin-1-yl)-2H-pyrazolo[4,3-c]pyridine-7-carboxamide (120 mg, yield: 72.5%) as a yellow solid. LC/MS (ESI) m/z: 386 (M+H) ⁺ .

Step 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 ₂ CO ₃ (202 mg, 0.62 mmol). The resulting mixture was heated to 110° C. under N ₂ atmosphere 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×3). The combined organic phases were washed with water and brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% to 3%) to give the desired product, 6-(4-((5-fluoro-2-methoxybenzamido)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 3 : A solution of 6-(4-((5-fluoro-2-methoxybenzamido)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 °C for 2 h. The reaction mixture was then cooled to room temperature and the resulting mixture was concentrated under vacuum to give the crude product, which 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 _{Na2SO4 ,} filtered, and concentrated under vacuum to give the crude product, which was purified by prep-TLC (MeOH in DCM = 5%) to give the desired product, 6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-4-(pyrrolidin-1-yl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (11 mg, yield: 45%) as a white solid: ¹ H NMR (400MHz, DMSO) δ12.98(s,1H),8.84(t,J＝6.1Hz,1H),8.20(s,1H),7.64(d,J＝8.2Hz,2H),7.53(dd,J＝9.2,3.3Hz,1H),7.33(dd,J＝12.5,5.7Hz,3H),7.28–7 .14(m,2H),6.90(s,1H),4.54(d,J＝6.1Hz,2H),3.90(s,3H),3.75(s,4H),1.99(s,4H); LC/MS(ESI)m/z:489(M+H) ⁺ .

Example 76: 6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-4-((1,1,1-trifluoropropane-2-yl)oxy)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (BNB-1130-01)

Step 1: To a stirred solution of 1,1,1-trifluoropropane-2-ol (71 mg, 0.6 mmol) in DMF (5 mL) was added NaH (25 mg, 0.6 mmol, 60%) at 0° C. under N _2. The resulting mixture was stirred at 0° C. for 0.5 h, 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 continued stirring for another 2 h. The reaction mixture was quenched with aqueous NH4Cl solution, extracted with EtOAc (20 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous _Na2SO4 , _and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 40%) to give the desired product 6-chloro-2-(4-methoxybenzyl)-4-((1,1,1-trifluoropropane-2-yl)oxy)-2H-pyrazolo[4,3-c]pyridine-7-carboxamide (226 mg, yield: 92.5%) as a gray solid. LC/MS (ESI) m/z: 429 (M+H) ⁺

Step 2 : To a stirred solution of 6-chloro-2-(4-methoxybenzyl)-4-((1,1,1-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 _H2O (2 mL) were added _Cs2CO3 ( ₄₈₇ mg, 1.5 mmol) and Pd(dppf) _Cl2 (38 mg, 0.05 mmol) and the reaction mixture was stirred at 100°C under _N2 atmosphere for 10 h. The reaction mixture was concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 30% to 50%) to give the desired product, 6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-2-(4-methoxybenzyl)-4-((1,1,1-trifluoropropane-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 3 : A solution of 6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-2-(4-methoxybenzyl)-4-((1,1,1-trifluoropropane-2-yl)oxy)-2H-pyrazolo[4,3-c]pyridine-7-carboxamide (90 mg, 0.14 mmol) in TFA (5 mL) was stirred at 65 °C for 2 h. The reaction mixture was then cooled to room temperature and concentrated under vacuum to give the crude product, which was dissolved in EtOAc (15 mL) and the pH was adjusted to 8 with saturated _NaHCO3 . The organic phase was washed with water and brine, dried over anhydrous _{Na2SO4 ,} filtered, and concentrated under vacuum 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-methoxybenzamido)methyl)phenyl)-4-((1,1,1-trifluoropropan-2-yl)oxy)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (65 mg, yield: 88.5%) as a white solid. LC/MS(ESI)m/z:532(M+H)+, ¹ H NMR(400MHz,DMSO)δ13.65(s,1H),8.90(t,J＝6.1Hz,1H),8.21(s,1H),7.84(s,1H),7.74(d,J＝8.2Hz,2H),7.62(s,1H),7.53( dd,J＝9.2,3.3Hz,1H),7.45–7.27(m,3H),7.19(dd,J＝9.1,4.3Hz,1H),6.27–6.12(m,1H),4.56(d,J＝6.0Hz,2H),3.90(s,3H),1.55(d,J＝6.5Hz,3H).

Table 5: The following compounds were prepared from A-2-4a and appropriate intermediates according to Examples 74, 75 and 76

Embodiment 112 and 113:

6-(4-{[(5-fluoro-2-methoxyphenyl)formylamino]methyl}phenyl)-4-[4-hydroxycyclohexyl]-1H-indazole-7-carboxamide (BNB-1100-01, 112) and 6-(4-{[(5-fluoro-2-methoxyphenyl)formylamino]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 (890 mg, 2.48 mmol) and 2-{1,4-dioxaspiro[4.5]dec-7-en-8-yl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (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 ₂ CO ₃ (1.03 g, 7.45 mmol) under N 2 atmosphere. The reaction mixture was stirred at 100 ° C 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 _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 30% to 50%) 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 7-cyano-2-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-2H-indazol-6-yl trifluoromethanesulfonate (500 mg, 2.27 mmol) and TEA (0.63 mL, 4.55 mmol) in DCM (5 mL) was added _Tf2O (0.56 mL, 3.41 mmol) in DCM (5 mL) at -50°C under N2 atmosphere. The reaction mixture was heated to -50°C for 0.5 h. The reaction mixture was washed with saturated _NaHCO3 solution and brine. The organic phase was dried over anhydrous _{Na2SO4 ,} filtered, and concentrated to give the crude product 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, yield: 75.9%) as a white solid. LC/MS (ESI) m/z: 572 (M+Na) ⁺

Step 3 : To a solution of 7-cyano-2-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-2H-indazol-6-yl trifluoromethanesulfonate (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 _Na2CO3 (192 _mg , 1.82 mmol) and Pd(dppf) _Cl2 (66 mg, 0.091 mmol). The reaction mixture was heated at 100°C 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 _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 30% to 50%) 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/C 10% (50 mg, wt 10%) and the reaction mixture was stirred at room temperature under _H2 (5 Psi) for 10 h. The reaction mixture was filtered and concentrated to give the crude product N-(4-(7-cyano-2-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]decane-8-yl)-2H-indazol-6-yl)benzyl)-5-fluoro-2-methoxybenzamide (350 mg, yield: 69.7%) as a gray solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 661 (M+H) ⁺ .

Step 5: A solution of N-(4-(7-cyano-2-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]decane-8-yl)-2H-indazol-6-yl)benzyl)-5-fluoro-2-methoxybenzamide (350 mg, 0.53 mmol) in TFA (2 mL) was stirred at 65 °C 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 x2). The organic layer was dried over Na ₂ SO ₄ , 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, 0.48 mmol, 92%) as a red solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 497 (M+H) ⁺ .

Step 6 : 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 _NaBH4 (36 mg, 0.97 mmol) at 0°C and the reaction mixture was stirred at 20°C for 0.5 h. The mixture was quenched with saturated _NH4Cl solution (5 mL) and extracted with DCM (15 mL x 2). The organic phase was dried over anhydrous _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% to 5%) 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 20°C were added NaOH (2 mL, 4 mmol) and _H2O2 (2 _mL ), and the mixture was stirred at 20°C for 16 hours. The mixture was diluted with _H2O (2mL) and extracted with EtOAc (10mL x 3). The combined organic layers were dried over _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by preparative-TLC (EtOAc in PE = 100%). The obtained pure product was separated by Waters UPC2 analytical SFC (column: ChiralCel OJ, 250×4.6mm ID, 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 obtained from the first eluent (peak 1): 25 mg (yield: 14.9%) LC/MS (ESI) m/z: 517 (M+H)+, ¹ H NMR (400 MHz, DMSO) δ13.08 (s, 1H), 8.85 (t, J=6.0 Hz, 1H), 8.22 (s, 1H), 7.53 (dd, J=9.3, 3.4 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.42 (s, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 7.33 (dd, J=7.9, 3.4 Hz, 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 obtained from the second eluent (peak 2): 0.8 mg (yield: 0.48%) 1H NMR (400 MHz, DMSO) δ 13.14 (s, 1H), 8.91 (t, J = 6.0 Hz, 1H), 8.32 (s, 1H), 7.59 (dd, J = 9.2, 3.3 Hz, 2H), 7.50 (t, J = 9.2 Hz, 3H), 7.45-7.37 (m, 3H), 7.26 (dd, J = 9.2, 4.3 Hz, 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) ⁺ .

Embodiment 114:

6-(4-((5-fluoro-2-methoxybenzamido)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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- _{2-yl)cyclopent-3-en-1-yl)oxy)silane (452 mg, 1.01 mmol) in dioxane (4 mL) and H2O (1 mL) were added Pd(dppf)Cl2 (101 mg, 0.12 mmol) and Na2CO3 ( 178 mg} , 1.68 mmol) and the resulting mixture was stirred at 110°C under nitrogen atmosphere for 2 h. The reaction mixture was concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 1% to 5%) 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 _Tf2O (231 mg, 0.82 mmol) at -30°C and the reaction mixture was stirred for 1 hour at -30°C. 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 Na2SO4} , filtered, and concentrated to give 4-(4-((tert-butyldiphenylsilyl)oxy)cyclopent-1-en-1-yl)-7-cyano-2-(4-methoxybenzyl)-2H-indazol-6-yl trifluoromethanesulfonate (310 mg, yield: 67.3%) as a brown solid without further purification. LC/MS (ESI) m/z: 732 [M+1] ⁺

Step 3 : To a solution of 4-(4-((tert-butyldiphenylsilyl)oxy)cyclopent-1-en-1-yl)-7-cyano-2-(4-methoxybenzyl)-2H-indazol-6-yl trifluoromethanesulfonate (310 mg, 0.42 mmol) and 5-fluoro-2-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide (194 mg, 0.50 mmol) in dioxine (4 mL) and _H2O (1 mL) were added Pd(dppf) _Cl2 (45 mg, 0.05 mmol) and _Na2CO3 (89 mg, 0.84 mmol) and the resulting mixture was stirred at 110°C under _N2 atmosphere for 2 _h . The reaction mixture was concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 1% to 10%) 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 gray 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, wt 10%) and the mixture was stirred at room temperature under _H atmosphere for 6 h. 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 TFA (2 mL) dropwise at 0 °C and the mixture was stirred at 40 °C for 5 h. 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 ₂ SO ₄ , filtered, and concentrated to give N-(4-(7-cyano-4-(2-hydroxycyclopentyl)-1H-indazol-6-yl)benzyl)-2-methoxybenzamide (100 mg, 0.21 mmol, 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) were added _H2O2 ( ₁ mL) and NaOH solution (0.04 mL, 0.08 mmol) dropwise at 0°C and the mixture was stirred at 60°C for 5 hours. The reaction mixture was diluted with _H2O (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by prep-TLC (MeOH in DCM = 5%) to give the desired product 6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-4-(3-hydroxycyclopentyl)-1H-indazole-7-carboxamide (35 mg, yield: 33.3%) as a white solid. LC/MS (ESI) m/z: 503 [M+1] ⁺¹ H NMR(400MHz,DMSO)δ13.09(s,1H),8.86(m,1H),8.33(s,1H),7.53(m,2H),7.45(m,3H),7.39–7.32(m,3H),7.19(dd,J＝9.1,4.3Hz,1H),6.99(s,1H),4.72(d,J＝3.9Hz,1H),4.55(d,J＝6.1Hz,2H),4.30(d,J＝4.2Hz,1H),3.91(s,3H),3.49–3.37(m,1H),2.42–2.41(m,1H),2.02–1.99(m,2H),1.85–1.65(m,3H)。

Example 115: 4-(2-Hydroxycyclopentyl)-6-(4-((2-methoxybenzamido)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)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (289 mg, 1.49 mmol) in dioxane (4 mL) and _H2O (1 mL) were added Pd(dppf) _Cl2 (101 mg, 0.12 mmol) and _Na2CO3 (263 mg, 2.5 mmol) and the reaction mixture was stirred at 110°C under _N2 atmosphere for 2 _h . The reaction mixture was concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 1% to 5%) to give the desired product, 4-(cyclopent-1-en-1-yl)-6-(methoxymethoxy)-1-[(4-methoxyphenyl)methyl]-1H-indazole-7-carbonitrile (360 mg, yield: 74.4%), as a white solid. LC/MS (ESI) m/z: 390 [M+1] ⁺ .

Step 2 : 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 °C for 2 hours. The reaction mixture was diluted with _H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phase was washed with water and brine, dried over anhydrous _Na2SO4 , 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 _Tf2O (0.16 mL, 0.97 mmol) dropwise at -30°C. The reaction mixture was stirred at -30°C 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 Na2SO4} , filtered, and concentrated to give 7-cyano-4-(cyclopent-1-en-1-yl)-1-[(4-methoxyphenyl)methyl]-1H-indazol-6-yl trifluoromethanesulfonate (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 7-cyano-4-(cyclopent-1-en-1-yl)-1-[(4-methoxyphenyl)methyl]-1H-indazol-6-yl trifluoromethanesulfonate (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 _H2O (1 mL) were added Pd(dppf) _Cl2 (45 mg, 0.05 mmol) and _Na2CO3 (115 mg, 1.1 mmol) and the reaction mixture was stirred at 110°C under _N2 atmosphere for 2 _h . The reaction mixture was concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 1% to 20%) 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 gray 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 BH ₃ .Me ₂ S (0.09 mL, 1 mmol/mL) dropwise at 0° C. The reaction mixture was stirred at this temperature for 1 hour, followed by the addition of EtOH (1 mL) dropwise at 0° C., followed by the addition of H ₂ O ₂ (1 mL) and NaOH (0.44 mL, 2 mmol/mL) in sequence 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×3). The combined organic phases were washed with water and brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% to 3%) to give the desired product, N-(4-(7-cyano-4-(2-hydroxycyclopentyl)-1-(4-methoxybenzyl)-1H-indazol-6-yl)benzyl)-2-methoxybenzamide (30 mg, yield: 11.5%) as a yellow solid. LC/MS (ESI) m/z: 587 [M+1] ⁺

Step 6: To a solution of N-(4-(7-cyano-4-(2-hydroxycyclopentyl)-1-(4-methoxybenzyl)-1H-indazol-6-yl)benzyl)-2-methoxybenzamide (30 mg, 0.06 mmol) in DCM (2 mL) was added TFA (2 mL) dropwise at 0°C and the reaction mixture was stirred at 40°C for 5 hours. The reaction mixture was concentrated and diluted with saturated _NaHCO3 (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 _Na2SO4 , 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) were added _H2O2 ( ₁ mL) and 2N NaOH (0.04 mL, 0.08 mmol) dropwise at 0 °C and the reaction mixture was stirred at 60 °C for 5 h. The reaction mixture was diluted with _H2O (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by prep-TLC (MeOH in DCM = 5%) to give the desired product, 4-(2-hydroxycyclopentyl)-6-(4-{[(2-methoxyphenyl)formamido]methyl}phenyl)-1H-indazole-7-carboxamide (6 mg, yield: 30%) as a white solid. LC/MS (ESI) m/z: 485 [M+1] ⁺ ; ¹ H NMR (400MHz, DMSO) δ13.06(s,1H),8.76(t,J＝6.1Hz,1H),8.21(s,1H),7.84–7.72(m,1H),7.52–7.36(m,7H),7.17(d,J＝8.4Hz,1H),7.05(t,J＝7.5Hz,1H),6. 92(s,1 H),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: According to Examples 112, 113, 114 & 115 (B-1, Route 1) using a similar method (with variations) the following compounds were prepared from the appropriate intermediate B-1-3a or B-1-3d and the appropriate boronic acid/ester:

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)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.0 g, 15.4 mmol) in dioxane (50 mL) and H ₂ O (10 mL) was slowly added K ₂ CO ₃ (800 mg, 5.7 mmol) and Pd(dppf)Cl ₂ (50 mg, 0.7 mmol) at 25° C. and the reaction mixture was heated to 100° C. under N ₂ atmosphere for 24 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (100 mL×3). The combined organic phases were washed with water and _brine , dried over anhydrous _Na2SO4 , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% to 25%) 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: Pd/C (150 mg, 10%) was added to a stirred solution of 4-(cyclopent-1-ene-1-yl)-7-methoxy-1H-indazole-6-carboxylic acid methyl ester (1.4 g, 5.1 mmol) in MeOH (15 mL). The resulting mixture was stirred under _H2 atmosphere for 24 h, filtered, and concentrated to give the crude product 4-cyclopentyl-7-methoxy-1H-indazole-6-carboxylic acid methyl ester (1.2 g, yield: 85.1%) as a white solid, which was used directly without further purification. LC/MS (ESI) m/z: 275 (M+H) ⁺ . 1HNMR (400MHz, CDCl ₃ ) δ8.18(s,1H),7.42(s,1H),4.05(s,3H),3.97(s,3H),3.45–3.33(m,1H),2.23–2.11(m,2H),1.97–1.67(m,6H).

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

Step 4: To 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) was added TEA (100 mg, 0.9 mmol) at 0°C and stirred for 10 minutes. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% to 25%) to give methyl 4-cyclopentyl-7-(trifluoromethanesulfonyloxy)-1H-indazole-6-carboxylate (600 mg, yield: 51%) as a white solid. LC/MS (ESI) m/z: 393 (M+H) ⁺ . 1H NMR (400MHz, CDCl ₃ ) δ10.54(d,J＝50.9Hz,1H),8.24(d,J＝1.5Hz,1H),7.26(t,J＝1.8Hz,1H),3.99(s,3H),3.47(dd,J＝16.3,7.8Hz,1H),2.21(d,J＝3.9Hz, 2H),1.93-1.80(m,6H).

Step 5: To a stirred solution of methyl 4-cyclopentyl-7-(trifluoromethanesulfonyloxy)-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) _Cl2 (100 mg, 0.1 mmol) at 25°C and the reaction mixture was stirred at 130°C in a microwave reactor under _N2 atmosphere 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 _Na2SO4 , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% to 25%) 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 (400 MHz, _CDCl3 ) δ 11.07 (d, J = 55.9 Hz, 1H), 8.26 (d, J = 5.4 Hz, 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , concentrated, and purified by preparative-HPLC to give the desired product, 7-cyano-4-cyclopentyl-1H-indazole-6-carboxylic acid (170 mg, 74.0% yield), as a light 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) was slowly added TEA (105 mg, 1 mmol) at 25°C. The reaction mixture was stirred at 25°C under _N2 atmosphere for 2 hours. _H2O (2 mL) was added to the mixture and warmed to 65°C for another 3 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water and brine, and the organic phase was dried over _{anhydrous Na2SO4} , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% to 25%) to give the desired product, 6-amino-4-cyclopentyl-1H-indazole-7-carbonitrile (79 mg, yield: 68.6%), as a white solid. LC/MS (ESI) m/z: 227 (M+H) ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (s, 1H), 6.43 (s, 1H), 4.66 (s, 2H), 3.38-3.19 (m, 1H), 2.14 (dd, J = 14.1, 8.7 Hz, 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 _{CH2I2 (} 187 mg, 0.7 mmol) in DCM (2.5 mL) and AcOH (0.4 mL, 7 mmol) was slowly added a solution of _NaNO2 (120 mg, 1.7 mmol) in _H2O (2.5 mL) at 0°C and the reaction mixture was stirred for 5 min at 0°C. 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 _Na2SO4 , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% to 25%) 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 (400 MHz, CDCl3) δ 10.55 (s, 1H), 8.20 (s, 1H), 7.51 (s, 1H), 3.43 (dd, J = 16.9, 8.9 Hz, 1H), 2.19 (dd, J = 11.4, 6.6 Hz, 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) was slowly added NaHCO ₃ (20 mg, 0.2 mmol) and Pd(dppf)Cl ₂ (10 mg, 0.1 mmol) at 25° C. and the reaction mixture was heated to 60° C. under nitrogen atmosphere for 18 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phases were washed with water and brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% to 25%) 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),2.3 4–2.14(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) was added H ₂ O ₂ (2 mL) slowly at room temperature and the reaction mixture was stirred at 65 °C under N ₂ atmosphere 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 ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by preparative TLC (EtOAc in PE = 30%) to give 4-cyclopentyl-6-(4-phenoxyphenyl)-1H-indazole-7-carboxamide (3 mg, yield: 23.9%) as a white solid. LC/MS(ESI)m/z:398(M+H) ⁺ . 1H NMR (400MHz, CD ₃ OD) δ8.20(s,1H),7.52–7.47(m,2H),7.42–7.34(m,2H),7.14(t,J＝7.4Hz,1H),7.07–7.02(m,5H),3.53(dd,J＝16.0,8.1Hz,1H),2.2 5–2.18(m,2H),1.94–1.79(m,6H).

Table 7: The following compounds were prepared from B-1-6 and the appropriate boronic acid/ester intermediate according to a similar method (B-1, Route 2) as used for Example 129 (with variations):

Example 133: 6-(4-((5-fluoro-2-methoxybenzamido)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 _Pd2 (dba) ₃ (114 mg, _0.14 mmol), Xant-phos (72 mg, 0.14 mmol) and _Cs2CO3 (405 mg, 1.22 mmol), and the reaction mixture was stirred at 110°C under nitrogen atmosphere for 10 hours. The reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% to 3%) to give 6-(methoxymethoxy)-1-[(4-methoxyphenyl)methyl]-4-(pyrrolidin-1-yl)-1H-indazole-7-carbonitrile (180 mg, yield: 73.8%) as a gray 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 °C for 2 hours. The reaction mixture was extracted with EtOAc (20 mL x 2), and the combined organic phase was washed with water and brine, dried over _Na2SO4 , 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 DIPEA (51 mg, 0.40 mmol) followed by _Tf2O (112 mg, 0.402 mmol) dropwise at -30°C and the reaction mixture was stirred for 1 hour at -30°C. The reaction mixture was extracted with DCM (10 mL x 3) and the combined organic phases were washed with water and brine, dried _{over Na2SO4} and concentrated to give the crude product 7-cyano-1-[(4-methoxyphenyl)methyl]-4-(pyrrolidin-1-yl)-1H-indazol-6-yl trifluoromethanesulfonate (110 mg, yield: 57.5%) as a 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 7-cyano-1-[(4-methoxyphenyl)methyl]-4-(pyrrolidin-1-yl)-1H-indazol-6-yl trifluoromethanesulfonate (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 _H2O (1 mL) were added Pd(dppf) _Cl2.CH2Cl2 ( ₅₁ mg, 0.06 mmol ₎ and _Na2CO3 (66 mg, 0.62 mmol) and the reaction mixture was stirred at 100°C under _N2 atmosphere for 10 _h . The reaction mixture was concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (EtOAc in PE = 5% to 20%) 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 5 : To a solution of 6-chloro-4-{1,4-dioxaspiro[4.5]dec-7-ene-8-yl}-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid methyl ester (65 mg, 0.14 mmol) in DCM (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at 40 ° C for 5 hours. 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 6 : A 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 _H2SO4 (1 _mL ) was stirred at 55°C for 3 hours. The reaction mixture was poured into ice water, extracted with EtOAc (20 mL x 3), and the combined organic phases were washed with _H2O and brine, _dried over anhydrous _Na2SO4 , and concentrated. The crude product was purified by prep-TLC (MeOH in DCM = 5%) to give the desired product 6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]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,CD ₃ OD)δ8.26(s,1H),7.63(dd,J＝9.3,3.2Hz,1H),7.52–7.43(m,5H),7.30–7.23(m,1H),7.17(dd,J＝9.0,4.1Hz ,1H),5.93(s,1H),4.68(s,2H),3.97(s,3H),3.73–3.64(m,4H),2.15–2.07(m,4H).

Example 134: (R)-6-(4-((5-fluoro-2-methoxybenzamido)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 _Cs2CO3 ( ₄₈₆ mg, 1.49 mmol), Xant-phos (86 mg, 0.15 mmol) and _Pd2 (dba) ₃ (68 mg, 0.075 mmol) under N2. The resulting mixture was stirred at 110°C overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0-100%) to give the desired product (R)-4-(3-hydroxypyrrolidin-1-yl)-1-(4-methoxybenzyl)-6-(methoxymethoxy)-1H-indazole-7-carbonitrile (120 mg, yield 39.4%) 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 N2. The mixture was stirred at 65 °C 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 directly without further purification. LC/MS (ESI) m/z: 365 (M+H) ⁺ .

Step 3 : 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) was added NEt ₃ (77.6 mg, 0.77 mmol) and trifluoromethanesulfonic anhydride (108 mg, 0.38 mmol) at -50°C. 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-indazole-6-yl ester (60 mg, yield: 62.9%) as a yellow solid, which was used directly without further purification. LC/MS (ESI) m/z: 497 (M+H) ⁺ .

Step 4 : To a solution of ( _R )-7-cyano-4-(3-hydroxypyrrolidin-1-yl)-1-(4-methoxybenzyl)-1H-indazol-6-yl trifluoromethanesulfonate (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 ₂ CO ₃ (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° C. 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 _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 100%) 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) was added. The mixture was stirred at 65 °C 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 _Na2SO4 , 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 _H2SO4 (1 mL). The mixture was stirred at 60°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with _EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous _Na2SO4 , 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-methoxybenzamido)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: The following compounds were prepared from B-1-3a and appropriate boronic acid/ester intermediates according to the method used to prepare Example 133 & Example 134 (B-2, Route 1) (with variations)

Example 146: (R)-5-Chloro-6-(4-((5-fluoro-2-methoxybenzamido)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 _Pd2 (dba) ₃ (114 mg, _0.14 mmol), Xant-phos (72 mg, 0.14 mmol) and _Cs2CO3 (405 mg, 1.22 mmol) and the reaction mixture was stirred at 110°C under nitrogen atmosphere for 10 hours. The reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% to 3%) to give (R)-1-(4-methoxybenzyl)-6-(methoxymethoxy)-4-(2-methylpyrrolidin-1-yl)-1H-indazole-7-carbonitrile (230 mg, yield: 92.8%) as a gray 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 was stirred at 55 °C for 2 hours. The reaction mixture was extracted with EtOAc (20 mL x 2), and the combined organic phase was washed with water and brine, dried _{over Na2SO4} , 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 : 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) was added NCS (74 mg, 0.55 mmol) at -20 °C and the mixture was stirred at room temperature for 8 hours. The mixture was diluted with _H2O (10 mL), extracted with EtOAc (10 mL x 2), the combined organic phases were washed with water and brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% to 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 _Tf2O (0.06 mL, 0.36 mmol) dropwise at -30°C. The mixture was stirred at -30°C for 1 hour. The reaction mixture was diluted with _H2O (10 mL), extracted with DCM (10 mL x 2), the combined organic phases were washed with water and brine, dried over anhydrous _Na2SO4 , filtered, and concentrated to give (R)-trifluoromethanesulfonic acid 5-chloro-7-cyano-2-(4-methoxybenzyl ₎ -4-(2-methylpyrrolidin-1-yl)-2H-indazol-6-yl ester (110 mg, yield: 68.8%) as a brown solid, which was used directly in the next step without further purification. LC/MS (ESI) m/z: 530 (M+H) ⁺

Step 5 : To (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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide (80 mg, 0.21 mmol) and NaCO (44 mg, 0.42 mmol) in dioxane (4 mL) and H O (1 mL) was added a mixture of 1% ethanol and 1% ethanol. Pd(dppf)Cl2 (15 mg, 0.02 mmol) was added to the solution, and the reaction mixture was concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography (EtOAc in PE = 5% to 30%) to obtain the desired product (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, yield: 75.4%) as a white solid. 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 was stirred at 40 °C for 5 hours. The reaction mixture was concentrated in vacuo to give the crude product (R)-N-(4-(5-chloro-7-cyano-4-(2-methylpyrrolidin-1-yl)-1H-indazol-6-yl)benzyl)-5-fluoro-2-methoxybenzamide (65 mg, yield: 63.12%) as a brown solid which was used directly in the next step without further purification. LC/MS (ESI) m/z: 519 [M+1] ⁺

Step 7 : A 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 _H2SO4 (1 mL) was stirred at 55°C for 3 hours. The reaction mixture was poured into ice water, extracted with EtOAc (20 mL x 3), and the combined organic phases were washed with _H2O and _brine , dried over anhydrous _Na2SO4 , and concentrated. The crude product was purified by prep-TLC (MeOH in DCM = 5%) to give the desired product (R)-5-chloro-6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-4-(2-methylpyrrolidin-1-yl)-1H-indazole-7-carboxamide (26 mg, yield: 41.9%) as a ^white solid: 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),4.5 8(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-methoxybenzamido)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 _Cs2CO3 ( ₇₂₇ mg, 2.23 mmol), SPhos (45 mg, 0.11 mmol) and _Pd2 (dba) ₃ (102 mg, 0.11 mmol) under N2. The resulting mixture was stirred at 110°C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 50% to 70%) 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°C. The mixture was stirred at this temperature for 30 minutes. The solvent was concentrated under reduced pressure to give the crude product (R)-trifluoromethanesulfonic acid 7-cyano-2-(4-methoxybenzyl)-4-(2-methylpyrrolidin-1-yl)-2H-indazole-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 )-7-cyano-2-(4-methoxybenzyl)-4-(2-methylpyrrolidin-1-yl)-2H-indazol-6-yl trifluoromethanesulfonate (596 mg, 1.20 mmol) and 5-fluoro-2-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide (510 mg, 1.32 mmol) in dioxane (10 mL) and _H2O (2 mL) was added _Cs2CO3 (785 mg, 2.41 mmol) and Pd(dppf) _Cl2 (88 mg, 0.12 mmol) under _N2 . The reaction mixture was heated to 90°C for 3 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL), washed with water and _brine , and the organic phase was dried over anhydrous _Na2SO4 , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 30% to 50%) 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 4 : A solution of (R)-N-(4-(7-cyano-2-(4-methoxybenzyl)-4-(2-methylpyrrolidin-1-yl)-2H-indazol-6-yl)benzyl)-5-fluoro-2-methoxybenzamide (342 mg, 0.56 mmol) in TFA (5 mL) was stirred at 65° C. for 3 h. The reaction mixture was then cooled to room temperature and concentrated under vacuum to give the crude product, which was dissolved in EtOAc (15 mL) and the pH was adjusted to 8 with saturated NaHCO ₃ . The organic phase was washed with water and brine, dried over anhydrous _{Na2SO4 ,} filtered, and concentrated under vacuum to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0% to 10%) to give (R)-N-(4-(7-cyano-4-(2-methylpyrrolidin-1-yl)-1H-indazol-6-yl)benzyl)-5-fluoro-2-methoxybenzamide (150 mg, yield: 54%) as a red solid. LC/MS (ESI) m/z: 484 (M+H) ⁺ .

Step 5 : A 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 _H2SO4 (3 mL) was stirred at 60°C for 1 hour. After cooling to room temperature, the reaction mixture was poured into ice-water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over anhydrous _{Na2SO4 ,} filtered, and concentrated. The crude product was purified by silica gel column chromatography (EtOAc in PE = 100%) to give Example 147 (10.5 mg, yield: 6.75%) as a white solid: ¹ H NMR (400MHz, DMSO) δ12.59(s,1H),8.86(t,J＝6.1Hz,1H),8.17(s,1H),7.53(dd,J＝9.2,3.3Hz,1H),7.45–7.30(m,5H),7.19(dd,J＝9.2,4.3Hz,1H),7.07(s,1H ),6.13(s,1H),5.85(s, 1H),4.56(d,J＝6.1Hz,2H),4.28(s,1H),3.91(s,3H),3.76(s,1H),3.54(d,J＝8.7Hz,1H),2.06(dd,J＝28.8,21.4Hz,3H),1.72(s,1H),1.19(d,J＝6.1Hz ,3H); LC/MS(ESI)m/z:502(M+H) ⁺ .

Example 148: 6-(4-((2-methoxybenzamido)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 _{Na2CO3 solution} . The organic layer was collected, washed with saturated NaCl solution, and concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 50%) 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) was added LDA (10.4 mL, 20.7 mmol) at -78 °C under _N2 . The reaction mixture was stirred at the same temperature for 1 hour, followed by the addition of DMF (1.2 g, 16.7 mmol) and the resulting mixture was kept at -78 °C for another hour. The reaction was quenched with saturated _NH4Cl solution and extracted with EtOAc (20 mL x 3). The combined organic phases were dried _over anhydrous _Na2SO4 , filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 30%) to give the desired product, 2-fluoro-3-formyl-6-(methoxymethoxy)benzonitrile (1.2 g, yield: 40.9%) as a brown oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.23 (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 ° C 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 ₂ CO ₃ (808.0 mg, 2.5 mmol), and the reaction mixture was stirred at 60° C. for 1.5 hours. 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 a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 30%) 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° C. for 1 hour. The reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 5% to 30%) 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) was added TEA (80 mg, 0.8 mmol) and _Tf2O (178 mg, 0.6 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (20 mL), the organic phase was washed with water and brine, the collected organic layer was dried, filtered, and concentrated to give the crude product trifluoromethanesulfonic acid 7-cyano-1-[(4-methoxyphenyl)methyl]-1H-indazole-6-yl ester (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 7-cyano-1-[(4-methoxyphenyl)methyl]-1H-indazol-6-yl trifluoromethanesulfonate (167 mg, 0.4 mmol) and 2-methoxy-N-{[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}benzamide (164 mg, 0.45 mmol) in dioxane (10 mL) and _H2O (2 mL) were added _K2CO3 (112 mg, 0.8 mmol) and Pd(dppf) _Cl2 (29 mg, 0.04 mmol) and the reaction mixture was stirred at 100°C under _N2 atmosphere for 2 _h . The reaction was cooled and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 50%) to give the desired product, N-[(4-{7-cyano-1-[(4-methoxyphenyl)methyl]-1H-indazol-6-yl}phenyl)methyl]-2-methoxybenzamide (182 mg, yield: 89.2%), as a yellow oil. LCMS: ESI m/z 503 [M+H] ⁺ .

Step 8: A 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 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc (15 mL) and washed with saturated _NaHCO3 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) was added NaOH (20 mg, 0.5 mmol) and H ₂ O ₂ (1 mL), and the reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was diluted with EtOAc (20 mL). The resulting mixture was washed with water and brine, and the collected organic phase was dried, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM=10% to 50%) to give the desired product 6-(4-{[(2-methoxyphenyl)formamido]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)

Embodiment 149:

6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]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) was added TEA (40 mg, 0.40 mmol) at 25° C. 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 _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 50%) to give the desired product, tert-butyl 4-({7-carbamoyl-6-chloro-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)butanoate (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)butanoate (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 _H2O (1 mL) at 25°C was added Pd(dppf) _Cl2 (30 mg, 0.041 mmol) and _K2CO3 (100 mg, 0.724 mmol) and _the reaction mixture was stirred at 110°C under _N2 atmosphere for 18 h. 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 Na2SO4} , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 50%) to give the desired product, tert-butyl 4-{[7-carbamoyl-6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]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)formamido]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) was added TFA (3 mL) at 25 °C and the reaction mixture was stirred at 50 °C for 18 h. 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 ₂ SO ₄ , filtered and concentrated to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% to 5%) to give the desired product, 4-{[7-carbamoyl-6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]methyl}phenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}butanoic 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)formamido]methyl}phenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}butanoic acid (45 mg, 0.1 mmol) and HATU (50 mg, 0.13 mmol) in DMF (2 mL) was added DIPEA (25 mg, 0.19 mmol) at 25 °C and the reaction mixture was heated to 50 °C for 18 h. 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 Na2SO4} , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% to 5%) to give the desired product 6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]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-methoxybenzamido)methyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide (BNB-1050-01)

Step 1 _: DMAP (1.87 g, 15.3 mmol) was added 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 stirring under N 2. 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 a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0-2%). The title N-[(tert-butoxy)carbonyl]-N-(2,6-dichloropyridin-4-yl)carbamic acid tert-butyl ester (55 g, yield 99%) was obtained as 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) was added LDA (227 mL, 454.2 mmol) at -78 °C under N2. 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 _NH4Cl solution and extracted with EtOAc (100 mL x 3). The organic layer was dried over _MgSO4 , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0-2%) to give the desired product, tert-butyl 4-(tert-butoxycarbonylamino)-2,6-dichloronicotinate (53 g, yield 96%) as a white solid. LC/MS(ESI)m/z:364(M+H) ⁺ . 1H NMR (400MHz, DMSO) δ9.84(s,1H),7.63(s,1H),1.60(s,9H),1.52(s,9H).

Step 3: To a solution of tert _-butyl 4-(tert-butoxycarbonylamino)-2,6-dichloronicotinate (2.0 g, 5.51 mmol) and 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.96 g, 4.96 mmol) in dioxane (15 mL) and water (3 mL) was added K ₂ CO ₃ (1.52 g, 11.01 mmol) and Pd(dppf)Cl ₂ (0.2 g, 0.28 mmol) under N 2. The resulting mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0-2%) to give the desired product, 4-(tert-butoxycarbonylamino)-2-chloro-6-cyclopentenylnicotinate (1.1 g, yield 51%), as a white solid. LC/MS (ESI) m/z: 395 (M+H) ⁺ . ¹ HNMR (400 MHz, DMSO) δ 9.46 (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 = 1.7 Hz, 9H).

Step 4: Pt/C (50 mg) was added to a solution of 4-(tert-butoxycarbonylamino)-2-chloro-6-cyclopentenylnicotinate (1.1 g, 2.8 mmol) in EtOAc (20 mL). The mixture was stirred at room temperature under _H2 atmosphere 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 in PE = 1% to 4%) to give the desired product, 4-(tert-butoxycarbonylamino)-2-chloro-6-cyclopentylnicotinate (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 N2. 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 directly without further purification. LC/MS (ESI) m/z: 241 (M+H) ⁺

Step 6 : _TMSCHN2 (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 _N2 atmosphere. The mixture was stirred for 1 hour. The reaction mixture was quenched with AcOH (1 mL) under an ice bath. The mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% to 10%) to give the desired product, 4-amino-2-chloro-6-cyclopentylpyridine-3-carboxylic acid methyl ester (190 mg, yield: 68%), as a white solid. LC/MS (ESI) m/z: 255 (M+H) ⁺ . 1H NMR (400MHz, CDCl ₃ ) δ6.35(s,1H),5.70(br,2H),3.08–2.88(m,1H),2.00(m,2H),1.84–1.74(m,2H),1.73–1.63(m,4H).

Step 7 : NBS (145 mg, 0.8 mmol) was added to a solution of 4-amino-2-chloro-6-cyclopentylpyridine-3-carboxylic acid methyl ester (190 mg, 0.74 mmol) in MeCN (5 mL) at 0°C, and the resulting mixture was stirred at 0°C for 2 hours. The solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0-5%) to obtain the desired product, 4-amino-5-bromo-2-chloro-6-cyclopentylpyridine-3-carboxylic acid methyl ester (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 ₂ CO ₃ (249 mg, 1.8 mmol) and Pd(PPh ₃ ) ₄ (35 mg, 0.030 mmol) under N 2. The reaction mixture was heated to 80° 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 _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 20%) to give the desired product, 4-amino-5-bromo-6-cyclopentyl-2-(4-((2-methoxybenzamido)methyl)phenyl)nicotinate (140 mg, yield: 43.4%) as a white solid. LC/MS (ESI) m/z: 538/540 (M+H) ⁺

Step 9 _: To a solution of methyl 4-amino-5-bromo-6-cyclopentyl-2-(4-((2-methoxybenzamido)methyl)phenyl)nicotinate (210 mg, 0.390 mmol) and 2-[2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3-dioxolane (78 mg, 0.4 mmol) in 1,4-dioxane (8 mL) and H ₂ O (2 mL) was added K ₂ CO ₃ (161 mg, 1.2 mmol) and Pd(PPh ₃ ) ₄ (45 mg, 0.04 mmol) under N 2. 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 _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 20%) to give the desired product, 4-amino-6-cyclopentyl-2-(4-((2-methoxybenzamido)methyl)phenyl)-5-(2-methoxyvinyl)nicotinate (140 mg, yield: 67.8%), as a white solid. LC/MS (ESI) m/z: 516 (M+H) ⁺

Step 10 : A solution of methyl 4-amino-6-cyclopentyl-2-(4-((2-methoxybenzamido)methyl)phenyl)-5-(2-methoxyvinyl)nicotinate (140 mg, 0.3 mmol) in AcOH (5 mL) was heated to 100 °C in a microwave reactor. The reaction mixture _was then concentrated, diluted with EtOAc (20 mL), washed with water and brine. The organic layer was dried over anhydrous _Na2SO4 , filtered, and concentrated to give a 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-methoxybenzamido)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-methoxybenzamido)methyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (100 mg, 0.206 mmol) in THF (5 mL) was added ammonia solution (5 mL, 28% in water). The mixture was stirred in a sealed jar at 100 ° C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated to give a 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-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-methoxybenzamido)methyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide (BNB-1065-01)

Step 1 _: To a solution of 4-amino-5-bromo-2-chloro-6-cyclopentylnicotinate (500 mg, 1.51 mmol) and 5-fluoro-2-methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide (583 mg, 1.51 mmol) in dioxane (15 mL) and H ₂ O (3 mL) was added K ₂ CO ₃ (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° 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 _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 20%) to give the desired product, 4-amino-5-bromo-6-cyclopentyl-2-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)nicotinate (500 mg, yield: 59.9%), as a white solid. LC/MS (ESI) m/z: 557/559 (M+H) ⁺

Step 2 _: To a solution of methyl 4-amino-5-bromo-6-cyclopentyl-2-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)nicotinate (500 mg, 0.90 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (179 mg, 0.90 mmol) in 1,4-dioxane (8 mL) and H ₂ O (2 mL) was added K ₂ CO ₃ (248 mg, 1.80 mmol) and Pd(PPh ₃ ) ₄ (104 mg, 0.09 mmol) under N 2. 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 _{Na2SO4 ,} filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% to 20%) to give the desired product, 4-amino-6-cyclopentyl-5-(2-ethoxyvinyl)-2-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)nicotinate (430 mg, yield: 87.3%), as a white solid. LC/MS (ESI) m/z: 548 (M+H) ⁺

Step 3 : A solution of 4-amino-6-cyclopentyl-5-(2-ethoxyvinyl)-2-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)nicotinate (430 mg, 0.79 mmol) in AcOH (5 mL) was heated to 100 °C in a microwave reactor. The reaction mixture was then concentrated, diluted with EtOAc (20 mL ₎ , washed with water and brine. The organic layer was dried over anhydrous _Na2SO4 , filtered, and concentrated to give a 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-methoxybenzamido)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)formamido]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 °C under _N2 atmosphere for 18 h. 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 _Na2SO4 , filtered, and concentrated to give the crude product which was used without purification to give 4-cyclopentyl-6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]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)formamido]methyl}phenyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (200 mg, 0.41 mmol) in DMF (5 mL) at 25 °C were slowly added TEA (124 mg, 1.23 mmol) and HATU (187 mg, 0.49 mmol) and the reaction mixture was stirred at 25 °C under _NH3 atmosphere for 1 h. 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 Na2SO4} , filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 50:1 to 1:1) to give 4-cyclopentyl-6-(4-{[(5-fluoro-2-methoxyphenyl)formamido]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-methoxybenzamido)methyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide (90 mg, 0.19 mmol) in 3 mL of AcOH and 3 mL of t-BuOH was added PyHBr3 (177 mg, 0.56 mmol) and stirred overnight under _N2 . Zn (121 mg, 1.85 mmol), 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 _MgSO4 , filtered, and concentrated. Silica gel column chromatography eluting with EtOAc in PE = 50% afforded the title 4-cyclopentyl-6-(4-((5-fluoro-2-methoxybenzamido)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 detection

1. Biochemical activity of BTK kinase

The ADP-Glo method was used to determine the effectiveness of the compounds prepared in the above examples as BTK inhibitors. Enzyme assays using recombinant wild-type BTK (Signalchem, Cat#B10-10H-10) and recombinant BTK-C481S (Signalchem, Cat#B10-12CH-10) were performed as follows. The compounds were serially diluted 1:3 in DMSO in a 10-point dose IC50 mode in duplicate. BTK kinase activity was tested in an assay buffer containing 50mM HEPES, 1mM EGTA, 10mM Mg ²⁺ , 0.01% BRIJ35 and 2mMDTT (pH=7.4). 0.1 μL of diluted compound was mixed with 5 μL of enzyme working solution (Signalchem, Cat#B10-10H-10) by Echo (Labcyte, Cat#550), and then mixed with 5 μL of substrate working solution (Sigma, Cat#P61-58) into a 384-well assay plate (Perkin Elmer, Cat#6008280) to initiate the reaction. After incubation at 25°C for 60 minutes, 5 μL of ADP Glo reagent (Promega, Cat#V9102) was added and incubated at 25°C for 60 minutes to terminate the reaction. After adding 10 μL of kinase detection reagent (Promega, Cat#V9102) and incubating at 25°C for 60 minutes, the US LUM of the plate was read on Envision (Perkin Elmer, Envision 2104) as RLU. IC50 values were calculated by nonlinear regression fitting the % inhibition values and logarithm (dose response - variable slope) of compound concentration using GraphPad Prism 6.0.

2. MEK1 kinase activity assay

Enzyme assays using a recombinant form 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 1:3 in DMSO in a 10-point dose IC50 format in duplicate. MEK1 kinase activity was tested in an assay buffer containing 50 mM HEPES, 1 mM EGTA, 10 mM Mg ²⁺ , 0.01% BRIJ35, and 2 mM DTT (pH=7.4). 0.1 μL of the diluted compound was mixed with 5 μL of enzyme working solution (Signalchem, Cat#M02-10G) by Echo (Labcyte, Cat#550), and then mixed with 5 μL of substrate working solution (Signalchem, Cat#M29-14G) into a 384-well assay plate (Perkin Elmer, Cat#6008280) to initiate the reaction. After incubation at 25°C for 60 minutes, 5 μL of ADP Glo reagent (Promega, Cat# V9102) was added and incubated at 25°C for 60 minutes to terminate the reaction. After adding 10 μL of kinase detection reagent and incubating at 25°C for 60 minutes, the US LUM of the plate was read on Envision (Perkin Elmer, Envision 2104) as RLU. IC50 values were calculated by nonlinear regression fitting of % inhibition values and logarithm (dose response-variable slope) of compound concentration using GraphPad Prism 6.0.

3. EGFR kinase activity assay

Enzyme assays using recombinant wild-type EGFR (Signalchem, Cat#E10-11G-10) were performed using a homogeneous time-resolved fluorescence (HTRF) method as follows. The compounds prepared in the above examples were serially diluted 1:3 in DMSO in a 10-point dose IC50 format in duplicate. EGFR kinase activity was tested in 1x kinase buffer (HTRF KinEASE-TK kit, Cisbio, Cat#62TK0PEC) containing 5mM MgCl ₂ , 1mM MnCl ₂ and 1mM DTT. 0.1 μL of the diluted compound was mixed with 5 μL of 2x EGFR enzyme solution (Signalchem, Cat#E10-11G-10) by Echo (Labcyte, Cat#550) and incubated at 25°C for 10 minutes. 5 μL of TK-substrate-biotin (Cisbio, 61TK0BLE) and ATP mixture substrate (Promega, Cat# V910B) were then added to a 384-well assay plate (Labcyte, P-05525-BC) to initiate the reaction. After incubation at 25°C for 40 minutes, 10 μL of 2X Sa-XL 665 and TK-antibody-cryptate (Cisbio, 06A) were added to each well of the assay plate, incubated for 60 minutes and incubated at 25°C. Fluorescence signals were read at 615 nm (Cryptate) and 665 nm (XL 665) on Envision (Perkin Elmer, Envision 2104). IC50 values were calculated by nonlinear regression fitting of % inhibition values and logarithm (dose response-variable slope) of compound concentration using GraphPad Prism 6.0.

4.OCI-Ly10 Cell Proliferation Assay

Cell proliferation assays using the OCI-Ly10 human DLBCL (diffuse large B-cell lymphoma) cell line (Cobioer Biosciences, CBP60558) that relies on NFκB signaling were performed using the Celltiter-Glo method as follows. The compounds prepared in the above examples were serially diluted 1:4 in DMSO in a 10-point dose IC50 format 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 resuspending with culture medium, OCI-Ly10 cells were seeded into 96-well plates (Corning, catalog number 3603) at a density of 8,000 cells/well. 5 μL of diluted compound was then added to the cell plate and cultured for 72 hours at 37°C in a _CO2 incubator (ThermoFisher, Cat#371). After 72 hours of compound treatment, 100 μL of cell supernatant was removed and 70 μL Celltiter-Glo buffer (Promega, Cat#G7573) was added to the cell plate. After 20 minutes of culture at 25°C, the luminescent signal was measured on Envision (Perkin Elmer, Envision 2104). IC50 values were calculated by nonlinear regression fitting of the % inhibition value and logarithm (dose response-variable slope) of the compound concentration using GraphPadPrism 6.0.

PK program

ICR mice (male, 6-8 weeks old, 26-30 g, n = 9 for each route of administration) were purchased from Shanghai Institute of Family Planning (SIPPR) (Shanghai, China). Animals were housed in a room maintained at a temperature of approximately 20-26°C and a relative humidity of 40%-70% under a 12:12 h light-dark cycle, with free access to food and water. All methods involving animals were in accordance with the principles of laboratory animal management in China. Animal research procedures were reviewed and approved by the Animal Care and Use Committee. ICR mice received intravenous (IV; 1 mg/kg) or oral gavage (PO; 10 mg/kg) test compounds after fasting overnight. Food was given 4 hours after administration. The compounds were formulated in DMA, Solutol HS-15 and saline (10:10:80, v/v/v) to produce nominal concentrations of 0.2 mg/mL (i.v. route) and 1 mg/mL (p.o. route) for administration. Blood samples (110 μL) were collected through the jugular sinus at appropriate time points (n=3 for each time point). The blood samples were placed in test tubes containing K2EDTA and centrifuged at 5,500 rpm for 10 minutes under freezing conditions to separate plasma. Plasma samples were stored at -20°C before analysis. Plasma (20 μL) was mixed with 100 μL of internal standard containing ACN in a 96-well plate to precipitate protein. After vortexing for 10 seconds, the plate was centrifuged at 3,760 rpm for 10 minutes at 4°C, and 60 μL of supernatant was diluted with 60 μL H2O before LC/MS/MS analysis. Pharmacokinetic parameters were determined using non-compartmental WinNonlin (Pharsight, Mountain View, CA, USA).

Efficacy studies

The general procedures for animal care and feeding conform to standard operating procedures, i.e., those of the Life Sciences Council, the National Research Council. The OCI-LY10 tumor cell line was maintained in IMDM culture medium as a suspension culture in vitro, the culture medium was modified, supplemented with 20% heat-inactivated fetal bovine serum, 37°C, 5% _CO2 in air. Tumor cells were routinely subcultured, no more than 4-5 generations. Cells growing in the exponential growth phase were harvested and counted for tumor inoculation. Each mouse was subcutaneously inoculated with OCI-LY10 tumor cells ( ^1x107 ) in 0.1ml IMDM culture medium and a high concentration Matrigel mixture (1:1 ratio) under the right flank for tumor development. Based on tumor volume and body weight, mice were randomly assigned to each group so that the average initial tumor size and body weight were the same for each treatment group. Treatment was started when the average tumor volume reached about 120-180mm3. Tumor size was measured and recorded ^twice a week with a caliper. Tumor volume (mm ³ ) was estimated using the following formula: TV = a×b ² /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:

a. %T/C = (treatment TVfinal - treatment TVinitial) / (medium TVfinal - medium TVinitial) * 100

b. %TGI = [1-(treatment TVfinal-treatment VTinitial)/(medium TVfinal-medium TVinitial)]*100

"TVfinal" and "TVinitial" are the average tumor volumes on the final day and the initial day.

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

Claims (18)

1. Compounds of formula I:

or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein: X ₁ , X ₂ and X ₃ are each independently CR' or N; R' is selected from H, C _1-6 alkyl, halo and oxo; _R1 is selected from H, deuterium, 3-10 membered heterocyclyl, 5-12 membered heteroaryl, _C3-10 cycloalkyl, _C3-10 cycloalkyl-O-, _C3-10 cycloalkenyl, 3-10 membered heterocyclyl-O-, _C6-10 aryl, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _-C1-6 alkyl- _OC1-6 alkyl, -NH2, -NH(C1-6 alkyl) and N( _C1-6 alkyl) ₂ , wherein each alkyl or alkoxy is optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, -OH _, -CN _{, -NH2} , -NH( _C1-6 alkyl) and -NH( _C1-6 alkyl) ₂ and wherein each heterocyclyl, heteroaryl, cycloalkyl or aryl is optionally substituted by 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-OC _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) _n C _1-6 alkyl, -C(O)OH, -C(O)OC _1-6 alkyl, -C(O _{)NH 2 ,} -C(O)NH(C _1-6 alkyl) 2 _1-6 alkyl), -C(O)N(C _1-6 alkyl) ₂ , -NHC(O)C _1-6 alkyl, and a 3-6 membered heterocyclic group optionally substituted by oxo; Ar is -C _6-10 aryl-YR ₂ or -5-6 membered heteroaryl-YR 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( _C1-6 alkyl)-C(O)-, -( _CH2 ) _m -N( _C1-6 alkyl)-S(O) _n- , -( _CH2 ) _m -C(O)-NH-, -( _CH2 ) _m -S(O) _n- NH-, -( _CH2 ) _m -C(O)-N( _C1-6 alkyl)- and -( _CH2 ) _m -S(O) _n -N( _C1-6 alkyl)-; R ₂ is C _6-10 aryl or 5-10 membered heteroaryl, which is optionally substituted with one or more substituents selected from the group consisting of 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-OC _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. 2. The compound of claim 1 or its stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or pharmaceutically acceptable salt, wherein: _X1 and _X3 are each independently CR' or N; R' is selected from H, _C1-6 alkyl, halo and oxo; _X2 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 is optionally substituted with one or more substituents selected from the group consisting of 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), -N(C _1-6 alkyl) ₂ , C 1-6 -C _1-6 alkyl-S-, -C _1-6 alkyl-OH, C _3-6 cycloalkyl and C _3-6 halocycloalkyl; Ar is -C _6-10 aryl-YR ₂ or -5-6 membered heteroaryl-YR 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, -(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, which is optionally substituted by 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. 3. A compound according to any one of claims 1 to 2 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein: _X1 is CR' or N; R' is H or halo; _X2 is CH; _X3 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 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 following: -OH, -NH ₂ , oxo, halo, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C 1-6 _1-6 alkyl-S- and -C _1-6 alkyl-OH; Ar is -C _6-10 aryl-YR ₂ or -5-6 membered heteroaryl-YR ₂ , wherein each aryl or heteroaryl is optionally substituted with one or more halo groups; Y is selected from O, S, -(CH ₂ ) _m -NH-C(O)- and -(CH ₂ ) _m -C(O)-NH-; _R2 is _C6-10 aryl or 5-6 membered heteroaryl, which is optionally substituted with 1, 2 or 3 substituents selected from _C1-6 alkoxy, deuterated _C1-6 alkoxy, halo, _C1-6 haloalkyl, -OH, -CN and _-NH2 ; and m is 0 or 1. 4. The compound according to any one of claims 1 to 3, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein X ₃ is N. 5. The compound of any one of claims 1 to 4 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein _X1 is CR' or N; R' is H or halo; _X2 is CH; X ₃ is N; R ₁ is selected from 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-O-, C _6-10 aryl and N(C _1-6 alkyl) 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 -OH, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy; Ar is -C _6-10 aryl-YR ₂ , wherein each of the C _6-10 aryl groups is optionally substituted with a halo group; Y is _-CH2 -NH-C(O)-; and R ₂ is a C _6-10 aryl group substituted with 1, 2 or 3 substituents selected from the group consisting of a C _1-6 alkoxy group, a deuterated C _1-6 alkoxy group and a halo group. 6. A compound according to claim 1 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein: Ar is

Wherein _R3 is H or halo. 7. The compound of any one of claims 1 to 6, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein _R2 is 2-methoxy-phenyl or 2-methoxy-5-fluoro-phenyl. 8. A compound according to any one of claims 1 to 7, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from 4-6 membered heterocyclyl, 5-10 membered heteroaryl, C _5-6 cycloalkyl, C _3-6 cycloalkyl-O- and phenyl, each of which is optionally substituted with one or more substituents selected from -OH, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy; Preferably, R ₁ is selected from 5-6 membered heteroaryl, which is 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; Preferably, R ₁ is pyridyl, which is 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; More preferably, R ₁ is pyridin-4-yl, which is 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. 9. A compound according to any one of claims 1 to 7 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof, wherein: _R is selected from:

Further preferably, R ₁ is selected from:

10. The compound of claim 1 selected from:

or a pharmaceutically acceptable salt thereof. 11. A compound according to any one of claims 1 to 10 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof for use as a medicament. 12. A compound according to any one of claims 1 to 10 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof for use in treating or preventing a BTK-related disease or disorder; Preferably, the disease or disorder is selected from a tumor, an autoimmune disease, an infectious disease, an inflammatory disease and a neurological disorder, preferably a hematological malignancy, more preferably a B-cell malignancy, even more preferably a leukemia, a lymphoma, Hodgkin's disease and a myeloma; More preferably, the disease or disorder is selected from acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid 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 (JML), ML), adult T-cell ALL, AML with trilineage myeloid dysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis), 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., extranodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma), Burkitt lymphoma, Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myeloid leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma (MM); rheumatoid arthritis, monoarticular 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 toxicity and chronic pulmonary inflammatory disease; 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 allogeneic transplant rejection. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier. 14. Use of a compound according to any one of claims 1 to 10 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a BTK-related disease or disorder, or use of a compound according to any one of claims 1 to 10 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof for treating or preventing a BTK-related disease or disorder; Preferably, the disease or disorder is selected from a tumor, an autoimmune disease, an infectious disease, an inflammatory disease and a neurological disorder, preferably a hematological malignancy, more preferably a B-cell malignancy, even more preferably a leukemia, a lymphoma, Hodgkin's disease and a myeloma; More preferably, the disease or disorder is selected from acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid 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 (JML), ML), adult T-cell ALL, AML with trilineage myeloid dysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis), 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., extranodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma), Burkitt lymphoma, Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myeloid leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma (MM); rheumatoid arthritis, monoarticular 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 toxicity and chronic pulmonary inflammatory disease; 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 allogeneic transplant rejection. 15. A method for inhibiting BTK in vivo or in vitro, the method comprising contacting an effective amount of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof with BTK. 16. A method for treating or preventing a BTK-related disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 10 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof; Preferably, the disease or disorder is selected from a tumor, an autoimmune disease, an infectious disease, an inflammatory disease and a neurological disorder, preferably a hematological malignancy, more preferably a B-cell malignancy, even more preferably a leukemia, a lymphoma, Hodgkin's disease and a myeloma; More preferably, the disease or disorder is selected from acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid 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 (JML), ML), adult T-cell ALL, AML with trilineage myeloid dysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis), 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., extranodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma), Burkitt lymphoma, Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myeloid leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasma cell myeloma, plasmacytoma, and multiple myeloma (MM); rheumatoid arthritis, monoarticular 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 toxicity and chronic pulmonary inflammatory disease; 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 allogeneic transplant rejection. 17. A combination comprising a compound according to any one of claims 1 to 10 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably an anti-tumor agent, such as a radiotherapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent or a targeted therapeutic agent. 18. A compound selected from:

wherein _P1 is an amino protecting group, preferably p-methoxybenzyl, and _P2 is a hydroxy protecting group, preferably methoxymethyl.