Heteroaromatic formamide compounds and their uses

Abstract

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

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to International Application PCT / CN2021 / 089684, filed on April 25, 2021; the content of which is incorporated herein by reference in its entirety. Field of the invention

[0003] The present disclosure provides heteroaromatic formamide compounds that inhibit Bruton's tyrosine kinase (BTK). The present disclosure also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of using these compounds to treat BTK - related diseases or disorders. Background of the invention

[0005] 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 signal transduction through the B - cell antigen receptor (BCR) and Fcγ receptor (FcγR) in B cells and myeloid cells, 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 have been demonstrated in different cancers and autoimmune diseases.

[0006] Significant progress has been made in the development of BTK inhibitors as therapeutic agents for targeted blood malignancies and chronic inflammatory diseases. In fact, the first - generation BTK inhibitor ibrutinib (PCI - 32765, Imbruvica) has been successfully used to treat B - cell malignancies and has been approved for the treatment of chronic lymphocytic leukemia (CLL), relapsed or refractory mantle cell lymphoma (MCL), and Waldenström macroglobulinemia (WM). However, treatment interruptions occur in up to 30% of ibrutinib patients, which results in 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 compounds react covalently and irreversibly with cysteine-481 in the ATP-binding site of BTK and thus do not overcome the common mechanism of ibrutinib resistance that occurs in 30% of patients after more than 12 months of treatment. Notably, reversible BTK inhibitors, including vecabrutinib, ARQ-531, and LOXO-305, which do not rely on cysteine-481 to interact with BTK, inhibit BTK activity in the presence of the C481S mutation, and clinical evidence is beginning to emerge 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 strict safety requirements for these indications such as RA and SLE. Therefore, there has been an ongoing effort to find reversible BTK inhibitors with better efficacy and lower toxicity. SUMMARY OF THE INVENTION

[0008] The above compounds, as well as 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 pharmaceutically acceptable salts thereof are collectively referred to as "compounds of the present invention" or "compounds of the present disclosure".

[0009] The present disclosure provides compounds of formula I:

[0010]

[0011] or their stereoisomers, racemates, geometric isomers, tautomers, hydrates or solvates, or pharmaceutically acceptable salts, wherein:

[0012] X1, X2, and X3 are each independently CR' or N; R' is selected from H, C 1-6 alkyl, halo, and oxo;

[0013] R1 is selected from H, deuterium, 3- to 10-membered heterocycloalkyl, 5- to 12-membered heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-O-, C 3-10 cycloalkenyl, 3- to 10-membered heterocycloalkyl-O-, C 6-10 aryl, C 1-6 alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 1-6 Alkyl - O - C 1-6 Alkyl, -NH2, -NH(C 1-6 Alkyl) and N(C 1-6 Alkyl)2, wherein each alkyl or alkoxy is optionally substituted with one or more substituents selected from: deuterium, halo, -OH, -CN, -NH2, -NH(C 1-6 Alkyl) and -NH(C 1-6 Alkyl)2; and wherein each heterocyclic group, heteroaryl, cycloalkyl or aryl is optionally substituted with one or more substituents selected from: -OH, -SH, -NH2, oxo, halo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 1-6 Alkyl - O - C 1-6 Alkyl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl - S -, -C 1-6 Alkyl - OH, C 3-6 Cycloalkyl, C 3-6 Halocycloalkyl, -C(O)C 1-6 Alkyl, -S(O) n C 1-6 Alkyl, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NH(C 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 with oxo;

[0014] Ar is -C 6-10 Aryl - Y - R2 or a 5 - 6 membered heteroaryl - Y - R2, 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;

[0015] Y is selected from O, S, -(CH2) m -NH - C(O)-, -(CH2) m -NH - S(O) n -, -(CH2)m -N(C 1-6 alkyl)-C(O)-, -(CH2) m -N(C 1-6 alkyl)-S(O) n -, -(CH2) m -C(O)-NH-, -(CH2) m -S(O) n -NH-, -(CH2) m -C(O)-N(C 1-6 alkyl)- and -(CH2) m -S(O) n -N(C 1-6 alkyl)-;

[0016] R2 is C 6-10 aryl or a 5- to 10-membered heteroaryl, optionally substituted with one or more substituents selected from: C 1-6 alkoxy, deuterated C 1-6 alkoxy, halo, C 1-6 haloalkyl, -OH, -SH, -CN, -NH2, -NH(C 1-6 alkyl), -NH(C 1-6 alkyl)2, C 1-6 alkyl-S-, -C 1-6 alkyl-O-C 1-6 alkyl, -C(O)C 1-6 alkyl, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 alkyl)2 and -NHC(O)C 1-6 alkyl;

[0017] m is 0 or 1; and

[0018] n is 1 or 2.

[0019] The above-mentioned compounds or their stereoisomers, racemates, geometric isomers, tautomers, hydrates or solvates, or pharmaceutically acceptable salts, as well as the 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 "the compounds of the present invention".

[0020] The present disclosure also provides the compounds of the present invention for use as medicaments.

[0021] The present disclosure also provides the compounds of the present invention for the treatment or prevention of BTK-related diseases or disorders.

[0022] The present disclosure also provides a pharmaceutical composition comprising a compound of the present invention and optionally a pharmaceutically acceptable carrier.

[0023] The present disclosure also provides a kit for treating or preventing BTK-related diseases or disorders, which comprises the pharmaceutical composition of the present invention and an instruction manual.

[0024] The present disclosure also provides the use of the compound of the present invention for treating or preventing BTK-related diseases or disorders.

[0025] The present disclosure also provides the use of the compound of the present invention in the preparation of a drug for treating or preventing BTK-related diseases or disorders.

[0026] The present disclosure also provides a method for inhibiting BTK activity in vivo or in vitro, the method comprising contacting an effective amount of the compound of the present invention with BTK.

[0027] The present disclosure also provides a method for treating or preventing BTK-related diseases or disorders, the method comprising administering an effective amount of the compound of the present invention to a subject in need thereof.

[0028] The present disclosure also provides a combination comprising a compound of the present invention and at least one additional therapeutic agent.

[0029] The present disclosure also provides a method for preparing the compound of the present invention, as well as intermediates for preparing the compound of the present invention. Detailed Description of the Invention

[0031] Embodiments of the present disclosure

[0032] Embodiment 1. Compounds of Formula I:

[0033]

[0034] or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate or pharmaceutically acceptable salt thereof, wherein:

[0035] X1, X2 and X3 are each independently CR' or N; R' is selected from H, C 1-6 alkyl, halo and oxo;

[0036] R1 is selected from H, deuterium, 3- to 10-membered heterocyclic group, 5- to 12-membered heteroaryl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-O-, C 3-10 cycloalkenyl, 3- to 10-membered heterocyclic group-O-, C 6-10 aryl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -C1-6 alkyl-O-C 1-6 alkyl, -NH2, -NH(C 1-6 alkyl) and N(C 1-6 alkyl)2, wherein each alkyl or alkoxy group is optionally substituted with one or more substituents selected from: deuterium, halo, -OH, -CN, -NH2, -NH(C 1-6 alkyl) and -NH(C 1-6 alkyl)2; and wherein each heterocyclic group, heteroaryl group, cycloalkyl group or aryl group is optionally substituted with one or more substituents selected from: -OH, -SH, -NH2, oxo, halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkyl-S-, -C 1-6 alkyl-OH, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, -C(O)C 1-6 alkyl, -S(O) n C 1-6 alkyl, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 alkyl)2, -NHC(O)C 1-6 alkyl and 3-6 membered heterocyclic group, which is optionally substituted with oxo;

[0037] Ar is -C 6-10 aryl-Y-R2 or -5-6 membered heteroaryl-Y-R2, wherein each aryl or heteroaryl group is optionally substituted with one or more substituents selected from: halo, C 1-6 alkoxy and C 1-6 alkyl;

[0038] Y is selected from O, S, -(CH2) m -NH-C(O)-, -(CH2) m -NH-S(O) n -, -(CH2) m -N(C 1-6 alkyl)-C(O)-, -(CH2) m-N(C 1-6 -alkyl)-S(O) n -、-(CH2) m -C(O)-NH-、-(CH2) m -S(O) n -NH-、-(CH2) m -C(O)-N(C 1-6 -alkyl)- and -(CH2) m -S(O) n -N(C 1-6 -alkyl);

[0039] R2 is C 6-10 aryl or a 5- to 10-membered heteroaryl, optionally substituted with one or more substituents selected from: C 1-6 alkoxy, deuterated C 1-6 alkoxy, halo, C 1-6 haloalkyl, -OH, -SH, -CN, -NH2, -NH(C 1-6 -alkyl), -NH(C 1-6 -alkyl)2, C 1-6 -alkyl-S-, -C 1-6 -alkyl-O-C 1-6 -alkyl, -C(O)C 1-6 -alkyl, -C(O)OH, -C(O)OC 1-6 -alkyl, -C(O)NH2, -C(O)NH(C 1-6 -alkyl), -C(O)N(C 1-6 -alkyl)2 and -NHC(O)C 1-6 -alkyl;

[0040] m is 0 or 1; and

[0041] n is 1 or 2.

[0042] Embodiment 2. The compound of Embodiment 1 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof or a pharmaceutically acceptable salt thereof, wherein X1 and X3 are each independently CR' or N; R' is selected from H, C 1-6 -alkyl, halo and oxo.

[0043] Embodiment 3. The compound of any one of the foregoing embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof or a pharmaceutically acceptable salt thereof, wherein X2 is CH.

[0044] Embodiment 4. A compound of any of the foregoing embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein Y is selected from O, S, -(CH2) m -NH-C(O)- or -(CH2) m -C(O)-NH-.

[0045] Embodiment 5. A compound of any of the foregoing embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R2 is C 6-10 aryl or 5- to 6-membered heteroaryl, 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 -NH2.

[0046] Embodiment 6. A compound of any of the foregoing embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0047] X1 and X3 are each independently CR' or N; R' is selected from H, C 1-6 alkyl, halo and oxo;

[0048] X2 is CH;

[0049] R1 is selected from H, 3- to 8-membered heterocyclic group, 5- to 12-membered heteroaryl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-O-, 3- to 8-membered heterocyclic group-O-, C 6-10 aryl, C 1-6 alkyl, C 1-6 alkoxy, -NH2, -NH(C 1-6 alkyl) and N(C 1-6 alkyl)2, wherein each alkyl or alkoxy is optionally substituted by one or more substituents selected from: halo, -OH, -CN and -NH2; and wherein each heterocyclic group, heteroaryl, cycloalkyl or aryl is optionally substituted by one or more substituents selected from: -OH, -NH2, 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 alkyl-S-, -C 1-6 alkyl-OH, C3-6 Cycloalkyl and C 3-6 Halocycloalkyl;

[0050] Ar is -C 6-10 Aryl-Y-R2 or 5- to 6-membered heteroaryl-Y-R2, wherein each aryl or heteroaryl is optionally substituted by one or more substituents selected from halo, C 1-6 Alkoxy and C 1-6 Alkyl;

[0051] Y is selected from O, S, -(CH2) m -NH-C(O)- and -(CH2) m -C(O)-NH-;

[0052] R2 is C 6-10 Aryl or 5- to 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 -NH2;

[0053] m is 0 or 1.

[0054] Embodiment 7. A compound of any one of the foregoing embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein X1 is CR' or N; R' is H or halo.

[0055] Embodiment 8. A compound of any one of the foregoing embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein X3 is selected from CH, C(=O) and N.

[0056] Embodiment 9. A compound of any one of the foregoing embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0057] X1 is CR' or N; R' is H or halo;

[0058] X2 is CH;

[0059] X3 is selected from CH, C(=O) or N;

[0060] R1 is selected from H, 3- to 8-membered heterocycloalkyl, 5- to 12-membered heteroaryl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-O-, 3- to 8-membered heterocycloalkyl-O-, C 6-10 Aryl, C 1-6 Alkyl, C1-6 alkoxy, -NH2, -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 -NH2; and wherein each heterocyclic group, heteroaryl, cycloalkyl, or aryl is optionally substituted with one or more substituents selected from: -OH, -NH2, 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 alkyl-S- and -C 1-6 alkyl-OH;

[0061] Ar is -C 6-10 aryl-Y-R2 or 5-6 membered heteroaryl-Y-R2, wherein each aryl or heteroaryl is optionally substituted with one or more halo substituents;

[0062] Y is selected from O, S, -(CH2) m -NH-C(O)- and -(CH2) m -C(O)-NH-;

[0063] R2 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 -NH2; and

[0064] m is 0 or 1.

[0065] Embodiment 10. The compound of any of the foregoing embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate thereof, or a pharmaceutically acceptable salt, wherein

[0066] R1 is selected from H, 3-8 membered heterocyclic group, 5-12 membered heteroaryl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-O-, 3-8 membered heterocyclic group-O-, C 6-10 aryl, C 1-6 alkyl, C 1-6 alkoxy, and N(C 1-6(alkyl)2, wherein each alkyl or alkoxy group is optionally substituted by one or more substituents selected from halo, -OH, and -CN; and wherein each heterocyclic group, heteroaryl group, cycloalkyl group, or aryl group is optionally substituted by one or more substituents selected from the following: -OH, -NH2, 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;

[0067] Preferably, R1 is selected from H, a 3- to 8-membered heterocyclic group, a 5- to 10-membered heteroaryl group, C 3-8 cycloalkyl, C 3-8 cycloalkyl-O-, 3- to 8-membered heterocyclic group-O-, C 6-10 aryl, C 1-6 alkyl, C 1-6 alkoxy, and N(C 1-6 alkyl)2, wherein each alkyl or alkoxy group is optionally substituted by one or more substituents selected from halo; and wherein each heterocyclic group, heteroaryl group, cycloalkyl group, or aryl group is optionally substituted by one or more substituents selected from the following: -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.

[0068] Embodiment 11. A compound according to any one of the foregoing embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein Ar is -C 6-10 aryl-Y-R2, wherein the aryl is optionally substituted by one or more halo groups.

[0069] Embodiment 12. A compound according to any one of the foregoing embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein Ar is -5- to 6-membered heteroaryl-Y-R2, wherein the heteroaryl is optionally substituted by one or more halo groups.

[0070] Embodiment 13. A compound according to any one of the foregoing embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R2 is C 6-10 aryl or 5- to 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, C1-6 Substituted by haloalkyl and -OH substituents.

[0071] Embodiment 14. A compound of any of the foregoing embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof or a pharmaceutically acceptable salt thereof, wherein R2 is a 5- or 6-membered heteroaryl optionally substituted by 1, 2 or 3 substituents selected from C 1-6 alkoxy, deuterated C 1-6 alkoxy, halogen, C 1-6 Substituted by haloalkyl and -OH substituents.

[0072] Embodiment 15. A compound of any of the foregoing embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof or a pharmaceutically acceptable salt thereof, wherein R2 is a phenyl optionally substituted by 1, 2 or 3 substituents selected from C 1-6 alkoxy, deuterated C 1-6 alkoxy, halogen, C 1-6 Substituted by haloalkyl and -OH substituents.

[0073] Embodiment 16. A compound of any of the foregoing embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof or a pharmaceutically acceptable salt thereof, wherein R2 is a phenyl or 6-membered heteroaryl optionally substituted by 1 or 2 substituents selected from: C 1-6 alkoxy, deuterated C 1-6 alkoxy, halogen, C 1-6 haloalkyl and -OH.

[0074] Embodiment 17. A compound of any of the foregoing embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof or a pharmaceutically acceptable salt thereof, wherein R2 is a phenyl optionally substituted by 1 or 2 substituents selected from: C 1-6 alkoxy, deuterated C 1-6 alkoxy, halogen, C 1-6 haloalkyl and -OH.

[0075] Embodiment 18. A compound of any of the foregoing embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof or a pharmaceutically acceptable salt thereof, wherein R2 is a phenyl optionally substituted by 1 or 2 substituents selected from: C 1-6 alkoxy and halogen.

[0076] Embodiment 19. A compound of any of the foregoing embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein Y is selected from O, -CH2-NH-C(O)-, -CH2-C(O)-NH-, and -C(O)-NH-.

[0077] Embodiment 20. A compound of any of the foregoing embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein Y is O.

[0078] Embodiment 21. A compound of any of the foregoing embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein Y is -CH2-NH-C(O)-.

[0079] Embodiment 22. A compound of any of the foregoing embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein X3 is N.

[0080] Embodiment 23. A compound of any of the foregoing embodiments or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0081] X1 is CR’ or N; R’ is H or a halogen group;

[0082] X2 is CH;

[0083] X3 is N;

[0084] R1 is selected from a 3- to 8-membered heterocyclic group, a 5- to 10-membered heteroaryl group, C 3-8 cycloalkyl, C 3-8 cycloalkyl-O-, C 6-10 aryl, and N(C 1-6 alkyl)2, wherein the alkyl is optionally substituted by one or more halogen groups, -OH, and -CN; and wherein each heterocyclic group, heteroaryl group, cycloalkyl group, or aryl group is optionally substituted by one or more substituents selected from the following: -OH, halogen group, CN, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy;

[0085] Ar is -C 6-10 aryl-Y-R2, wherein each of the C 6-10 aryl groups is optionally substituted by one halogen group;

[0086] Y is -CH2-NH-C(O)-; and

[0087] R2 is C 6-10 an aryl group which is substituted with 1, 2 or 3 substituents selected from C 1-6 alkoxy, deuterated C 1-6 alkoxy and halo groups.

[0088] Embodiment 24. A compound according to any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein X1 is CH.

[0089] Embodiment 25. A compound according to any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein X3 is N.

[0090] Embodiment 26. A compound according to any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl-Y-R2, wherein the phenyl is optionally substituted with one halo group.

[0091] Embodiment 27. A compound according to any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0092] Ar is wherein R3 is H or a halo group.

[0093] Embodiment 28. A compound according to any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein Ar is wherein R3 is H or a halo group.

[0094] Embodiment 29. A compound according to any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl-Y-R2.

[0095] Embodiment 30. A compound according to any one of the preceding embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R2 is 2-methoxyphenyl or 2-methoxy-5-fluorophenyl.

[0096] Embodiment 31. The compound of any one of the foregoing embodiments, or its stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate, or pharmaceutically acceptable salt, wherein R1 is selected from a 4- to 6-membered heterocyclic group, a 5- to 10-membered heteroaryl group, 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, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy.

[0097] Embodiment 32. The compound of any one of the foregoing embodiments, or its stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate, or pharmaceutically acceptable salt, wherein R1 is selected from a 5- to 10-membered heteroaryl group, which is optionally substituted with one or more substituents selected from -OH, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy.

[0098] Embodiment 33. The compound of any one of the foregoing embodiments, or its stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate, or pharmaceutically acceptable salt, wherein R1 is N(C 1-6 alkyl)2 optionally substituted with one or more halogen atoms; preferably, R1 is (C 1-6 alkyl)2 substituted with one or more halogen atoms; more preferably, R1 is

[0099] Embodiment 34. The compound of any one of the foregoing embodiments, or its stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate, or pharmaceutically acceptable salt, wherein R1 is selected from a 5- to 6-membered heteroaryl group, which is optionally substituted with one or more substituents selected from -OH, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy.

[0100] Embodiment 35. The compound of any one of the foregoing embodiments, or its stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate, or pharmaceutically acceptable salt, wherein R1 is selected from a 5-membered heteroaryl group, which is optionally substituted with one or more substituents selected from -OH, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy.

[0101] Embodiment 36. A compound of any of the foregoing embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein R1 is selected from 6-membered heteroaryl, which is optionally substituted by one or more substituents selected from -OH, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy.

[0102] Embodiment 37. A compound of any of the foregoing embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein R1 is pyridyl, which is optionally substituted by one or more substituents selected from -OH, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy.

[0103] Embodiment 38. A compound of any of the foregoing embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein the halo is F or Cl, preferably F.

[0104] Embodiment 39. A compound of any of the foregoing embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein the C 1-6 haloalkyl is CF3.

[0105] Embodiment 40. A compound of any of the foregoing embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein R1 is pyridyl, which is optionally substituted by one or two substituents selected from -OH, methyl, F, OMe, and CF3.

[0106] Embodiment 41. A compound of any of the foregoing embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein R1 is pyridin-4-yl, which is substituted at the 2-position by C 1-6 alkyl and is optionally further substituted at the 3-position by a substituent selected from -OH, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy.

[0107] Embodiment 42. A compound of any of the foregoing embodiments, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, wherein:

[0108] R1 is selected from:

[0109]

[0110] Further preferably, R1 is selected from:

[0111]

[0112]

[0113] and H. Embodiment 43. The compound of Embodiment 1, which is selected from:

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136] or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt.

[0137] Embodiment 44. A compound according to any one of Embodiments 1 - 43, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, for use as a medicament.

[0138] Embodiment 45. A compound according to any one of Embodiments 1 - 43, or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof, or a pharmaceutically acceptable salt, for use in the treatment or prevention of a BTK-related disease or disorder;

[0139] Preferably, the disease or disorder is selected from tumors, autoimmune diseases, infectious diseases, inflammatory diseases and neurological disorders, preferably hematological malignancies, more preferably B-cell malignancies, and even more preferably leukemia, lymphoma, Hodgkin's disease and myeloma;

[0140] More preferably, the disease or disorder is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic 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 myelodysplasia-related changes (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative diseases (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (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 lymphoma, Waldenström 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, plasmacytic 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 type oxygen toxicity and chronic pulmonary inflammatory diseases; systemic lupus erythematosus (SLE), autoimmune thyroiditis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), myasthenia gravis, psoriasis, inflammatory bowel disease (IBD) and idiopathic thrombocytopenic purpura; graft-versus-host disease (GVHD) and allograft rejection.

[0141] Embodiment 46. A pharmaceutical composition comprising a compound according to any one of Embodiments 1-43 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof or a pharmaceutically acceptable salt and optionally a pharmaceutically acceptable carrier.

[0142] Embodiment 47. Use of a compound according to any one of Embodiments 1-43 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof or a pharmaceutically acceptable salt in the manufacture of a medicament for the treatment or prevention of a BTK-related disease or disorder;

[0143] Preferably, the disease or disorder is selected from tumors, autoimmune diseases, infectious diseases, inflammatory diseases, and neurological disorders, preferably hematological malignancies, more preferably B-cell malignancies, and even more preferably selected from leukemia, lymphoma, Hodgkin's disease, and myeloma;

[0144] More preferably, the disease or disorder is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with myelodysplasia-related changes (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative diseases (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (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 lymphoma, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocyte lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myelogenous leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasmacytic 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 type oxygen toxicity, and chronic pulmonary inflammatory diseases; systemic lupus erythematosus (SLE), autoimmune thyroiditis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), myasthenia gravis, psoriasis, inflammatory bowel disease (IBD), and idiopathic thrombocytopenic purpura; graft-versus-host disease (GVHD) and allograft rejection.

[0145] Embodiment 48. A method of 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.

[0146] 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 according to any one of Embodiments 1-43 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof or a pharmaceutically acceptable salt;

[0147] Preferably, the disease or disorder is selected from tumors, autoimmune diseases, infectious diseases, inflammatory diseases and neurological disorders, preferably hematological malignancies, more preferably B-cell malignancies, even more preferably leukemia, lymphoma, Hodgkin's disease and myeloma;

[0148] More preferably, the disease or disorder is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic 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 myelodysplasia-related changes (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative diseases (MPDs) (e.g., polycythemia vera (PV), essential thrombocythemia (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 lymphoma, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocyte lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myeloid leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasmacytic 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 type oxygen toxicity and chronic pulmonary inflammatory diseases; systemic lupus erythematosus (SLE), autoimmune thyroiditis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), myasthenia gravis, psoriasis, inflammatory bowel disease (IBD) and idiopathic thrombocytopenic purpura; graft-versus-host disease (GVHD) and allograft rejection.

[0149] Embodiment 50. A combination comprising a compound of any one of Embodiments 1-43 or a stereoisomer, racemate, geometric isomer, tautomer, hydrate or solvate thereof or a pharmaceutically acceptable salt and at least one additional therapeutic agent, wherein the additional therapeutic agent is preferably an anti-tumor agent, such as a radiotherapy agent, a chemotherapy agent, an immunotherapy agent or a targeted therapy agent.

[0150] Embodiment 51. A compound selected from:

[0151]

[0152] wherein P1 is an amino-protecting group, preferably p-methoxybenzyl, and P2 is a hydroxy-protecting group, preferably methoxymethyl.

[0153] Embodiment 52. A compound selected from:

[0154]

[0155] wherein PMB is p-methoxybenzyl and MOM is methoxymethyl.

[0156] Definitions

[0157] The following words, phrases and symbols used in this disclosure have the meanings set forth below, unless otherwise indicated in the context in which they appear.

[0158] As used herein, the singular forms and "the", "said" are also intended to include the plural forms, unless the context clearly indicates otherwise.

[0159] A short dash ("-") not between two letters or symbols indicates the point of attachment of a substituent. For example, C 3-8 Cycloalkyl-O- is attached to the rest of the molecule through oxygen.

[0160] The term "alkyl" as used herein refers to a straight-chain or branched-chain 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 said alkyl having 1-6 (1, 2, 3, 4, 5 or 6) carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0161] As used herein, the term "alkenyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon group containing one or more, for example, 1, 2 or 3 carbon-carbon double bonds (C═C), and having 2-10 carbon atoms (C 2-10 ), preferably 2-6 carbon atoms (C 2-6 ), more preferably 2-4 carbon atoms (C 2-4 ). For example, "C 2-6 alkenyl" means the alkenyl having 2-6 (2, 3, 4, 5 or 6) carbon atoms, which preferably has 1 or 2 carbon-carbon double bonds; "C 2-4 alkenyl" means the alkenyl having 2-4 carbon atoms, which preferably has 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 can be on the double bond or not on the double bond.

[0162] As used herein, the term "alkynyl" refers to a straight-chain or branched-chain 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 ), more preferably 2-4 carbon atoms (C 2-4 ). For example, "C 2-6 alkynyl" means the alkynyl having 2-6 (2, 3, 4, 5 or 6) carbon atoms, which preferably has 1 or 2 carbon-carbon triple bonds; "C 2-4 alkynyl" means the alkynyl having 2-4 carbon atoms, which preferably has 1 carbon-carbon triple bond. Examples of alkynyl include but are not limited to ethynyl, 2-propynyl and 2-butynyl. The point of attachment of the alkynyl can be on the triple bond or not on the triple bond.

[0163] As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine, and most preferably fluorine.

[0164] 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 halogen atoms, 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, and 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 hydrogen atoms, such as 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, and the halogen atoms are different from each other. Examples of haloalkyl include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CH3, etc. Preferred haloalkyl is C 1-6 trifluoroalkyl, more preferably -CF3.

[0165] 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. Preferred alkoxy is methoxy.

[0166] The term "haloalkoxy" or alkoxy substituted with halogen, which is used interchangeably herein, refers to an alkoxy as defined herein, wherein one or more, 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 halogen atoms, 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

[0167] The term "cycloalkyl" as used herein refers to a saturated cycloalkyl group having 3 - 10 ring carbon atoms (C 3-10 ), such as 3 - 8 ring carbon atoms (C 3-8 ), 3 - 7 ring carbon atoms (C 3-7 ), 3 - 6 ring carbon atoms (C 3-6 ), or 5 - 6 ring carbon atoms (C 5-6 ), 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 C 3-8 cycloalkyl, preferably a monocyclic C 3-6 cycloalkyl, more preferably a monocyclic C 5-6Cycloalkyl. 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 bicyclic C5-C 10 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 monocyclic C 3-6 Cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0168] As used herein, the term "cycloalkenyl" refers to a non-aromatic unsaturated cyclic hydrocarbon group having at least one carbon-carbon double bond, having 3 to 10 ring carbon atoms (C 3-10 ), such as 3 to 8 ring carbon atoms (C 3-8 ), 3 to 7 ring carbon atoms (C 3-7 ), 3 to 6 ring carbon atoms (C 3-6 ), or 5 to 6 ring carbon atoms (C 5-6 ), which may have one or more rings, for example 1 or 2 rings. For example, the cycloalkenyl is a monocyclic cycloalkenyl. Examples of monocyclic cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl.

[0169] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated ring having 3 to 10 ring atoms (3- to 10-membered), such as 3 to 8 ring atoms (3- to 8-membered), 5 to 7 ring atoms (5- to 7-membered), 3 to 6 ring atoms (3- to 6-membered), 4 to 6 ring atoms (4- to 6-membered), or 5 to 6 ring atoms (5- to 6-membered), wherein one or more, such as 1, 2, or 3, preferably 1 or 2, of the ring atoms are heteroatoms independently selected from N, O, and S, the remaining ring atoms are carbon, and having one or more, for example 1, 2, or 3, preferably 1 or 2, rings, wherein an N or S heteroatom is optionally oxidized to various oxidation states. The point of attachment of the heterocyclic group can be on an N heteroatom or a carbon atom. The rings of the heterocyclic group also include fused rings, bridged rings, or spiro rings. The rings of the heterocyclic group can be saturated or contain one or more, for example one or two, double bonds (i.e., partially unsaturated), but are not fully conjugated and are not heteroaryl as defined herein. For example, a "3- to 8-membered heterocyclic group" refers to a heterocyclic group having 3 to 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- to 8-membered heterocyclic group. For example, a "4- to 6-membered heterocyclic group" refers to a heterocyclic group having 4 to 6 ring atoms and containing 1 or 2 ring heteroatoms independently selected from N, O, and S, preferably a saturated monocyclic 4- to 6-membered heterocyclic group, such as a saturated monocyclic 4-, 5-, or 6-membered heterocyclic group. Examples of heterocyclic groups include, but are not limited to, oxiranyl, aziridinyl, thiiranyl, oxetanyl, azetidinyl (e.g., azetidin-1-yl, azetidin-2-yl, azetidin-3-yl), thietanyl, pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), oxopyrrolidinyl (e.g., 2-oxopyrrolidin-1-yl), tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl, tetrahydrofuran-3-yl), dioxolanyl, imidazolidinyl, morpholinyl (e.g., 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 oxaazacyclohexyl. 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.

[0170] As used herein, the term "aryl" refers to a group consisting of one ring or multiple fused rings having 6 to 14 carbon atoms (C 6-14)、Preferably a carbocyclic group having 6 to 10 carbon atoms (C 6-10 ), wherein at least one ring is an aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, phenanthryl, indenyl, indanyl, azulenyl, preferably phenyl and naphthyl, more preferably phenyl.

[0171] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 12 ring atoms (5- to 12-membered), such as 5 to 10 ring atoms (5- to 10-membered), 8 to 12 ring atoms (8- to 12-membered), 5 to 8 ring atoms (5- to 8-membered), 5 to 7 ring atoms (5- to 7-membered), 5 to 6 ring atoms (5- to 6-membered), 5 ring atoms (5-membered) or 6 ring atoms (6-membered), 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:

[0172] - A 5- to 6-membered monocyclic heteroaryl, i.e., a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms (5- or 6-membered), wherein one or more, such as 1, 2 or 3, preferably 1 or 2 ring atoms are ring heteroatoms independently selected from N, O and S (preferably N), and the remaining ring atoms are carbon; preferably a monocyclic aromatic hydrocarbon group having 6 ring atoms (6-membered), wherein 1, 2 or 3, preferably 1 or 2 ring atoms are heteroatoms independently selected from N, O and S, preferably N.

[0173] or

[0174] - An 8- to 12-membered bicyclic heteroaryl, i.e., a bicyclic aromatic hydrocarbon group having 8, 9, 10, 11 or 12 ring atoms (8-, 9-, 10-, 11- or 12-membered), wherein one or more, such as 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.

[0175] Examples of heteroaryl include, but are not limited to, pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl), pyridyl N-oxide, pyrazinyl (e.g., pyrazin-2-yl, pyrazin-3-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl), pyridazinyl (e.g., pyridazin-3-yl, pyridazin-4-yl), pyrazolyl (e.g., pyrazol-1-yl, pyrazol-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl), imidazolyl (e.g., imidazol-1-yl, imidazol-5-yl, imidazol-3-yl, imidazol-4-yl, imidazol-5-yl), oxazolyl, isoxazolyl (e.g., isoxazol-4-yl), oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl, triazinyl, thienyl, furyl, 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, pyrazolopyridyl, pyrazolopyrimidinyl, tetrazolopyridyl, tetrahydropyrazolopyridyl, benzofuryl, benzimidazolinyl or indolyl. Preferably, the heteroaryl is pyrazolyl, pyridyl, 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.

[0176] As used herein, the term "oxo" refers to the group =O.

[0177] When a structure herein contains "(R)" and / or "(S)", it means that the chiral center of the compound labeled by "(R)" or "(S)" is a single configuration of 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).

[0178] When the structure of the present compound is marked as "isomer", it means that the compound is an individual stereoisomer, but the absolute configuration or relative configuration of the compound is arbitrarily specified or unspecified.

[0179] When the structure of the present compound is marked as "cis or trans", it means that the compound is an individual stereoisomer, but the configuration of the compound is arbitrarily specified as cis or trans.

[0180] When the structure of the present compound is marked as "cis" or "trans", it means that the compound is an individual stereoisomer, and the relative configuration of the compound is cis or trans as shown, but the configuration is undetermined.

[0181] When the structure of the present compound contains a bond represented by a wavy line it means a mixture of isomers in any proportion of the said compound.

[0182] When a wavy line is carried on the bond of a group, the wavy line indicates the point of attachment of the group to the rest of the molecule.

[0183] As used herein, the term "optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes the case where the said event or circumstance occurs and the case where the said event or circumstance does not occur. For example, "optionally substituted by one or more..." includes "unsubstituted" as defined herein and "substituted by 1, 2, 3 or more". Those skilled in the art understand that for any group containing one or more substituents, the said group does not include any substitution or substitution pattern that is spatially impracticable, chemically incorrect, synthetically infeasible and / or inherently unstable.

[0184] 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 group of substituents, 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 group of substituents, 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 a combination is allowed only when the combination of each substituent and / or each variable 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 the reaction mixture.

[0185] Those skilled in the art will understand that some of the compounds disclosed herein may contain one or more chiral centers or rings, and thus there are two or more stereoisomers. Racemic mixtures of these isomers, individual isomers, and mixtures enriched in one enantiomer, as well as diastereomers and mixtures enriched in specific diastereomeric moieties when there are two chiral centers, are all within the scope of this disclosure. Those skilled in the art should also understand that this disclosure includes all individual stereoisomers (e.g., enantiomers, diastereomers, or cis- or trans-isomers), racemic mixtures, or partially resolved mixtures of the compounds disclosed herein, and, where appropriate, their individual tautomeric forms.

[0186] Racemates or other mixtures of isomers can be used in their own form or can be resolved into their individual isomers. Resolution can yield stereochemically pure compounds or mixtures enriched in one or more isomers. Methods for separating isomers are well known (e.g., see Allinger N.L. and Eliel E.L., "Topics in Stereochemistry", Volume 6, Wiley Interscience, 1971).

[0187] The term "pharmaceutically acceptable salt" includes, but is not limited to: acid addition salts formed by the compounds disclosed herein with inorganic acids, such as hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, etc.; and acid addition salts formed by the compounds disclosed herein with organic acids, such as formates, acetates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethanesulfonates, benzoates, salicylates, stearates, and salts formed with alkanedicarboxylic acids of the formula HOOC-(CH2) n -COOH (where n is 0 - 4), etc. "Pharmaceutically acceptable salts" also include base addition salts formed by the compounds of the present invention having acidic groups with pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0188] 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 free base form, its acid addition salts, particularly pharmaceutically acceptable acid addition salts, can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid according to the conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art can determine various synthetic methods for preparing non-toxic pharmaceutically acceptable acid addition salts or base addition salts without undue experimentation.

[0189] The term "solvate" refers to a solvate addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to trap solvent molecules in a fixed molar ratio in the solid state, thereby forming a solvate. If the solvent is water, the resulting solvate is a hydrate, and when the solvent is ethanol, the resulting solvate is an ethanolate.

[0190] The term "deuterated" group refers to a group in which one or more, such as 1, 2, or 3, hydrogen atoms are replaced by their isotope deuterium (D).

[0191] The term "protecting group" refers to a substituent that is typically used to block or protect a specific functional group when other functional groups on a compound react. For example, an "amino protecting group" is a substituent that is attached to an amino group and blocks or protects the amino functional group in a compound. Suitable amino protecting groups include p-methoxybenzyl (PMB), benzyl (Bn), trityl (Trt), acetyl, trifluoroacetyl, phthalimido, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent that blocks or protects the hydroxy functional group of a hydroxy 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.

[0192] As used herein, the term "drug 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, such as, for example, a kit or a pharmaceutical composition. The term "fixed combination" refers to an active agent, such as those of the present disclosure and additional active agents, being administered to an individual in the form of a single entity or dose. The term "non-fixed combination" refers to an active agent, such as those of the present disclosure and additional active agents, being administered to a patient in need thereof simultaneously, in parallel, or sequentially without a specific time limit as separate entities, wherein such administration provides an effective level of the compound in the patient's body.

[0193] The term "treating" or "treatment" of a disease refers to administering to an individual having the disease or disorder, or having symptoms of the disease or disorder, one or more pharmaceutically active substances, in particular a compound of the invention or a pharmaceutically acceptable salt thereof, for curing, healing, alleviating, relieving, altering, remedying, improving, ameliorating or affecting the disease or disorder, or the symptoms of the disease or disorder. In some embodiments, the disease is a BTK-related disease or disorder, such as a disease or disorder responsive to inhibition of BTK, preferably cancer.

[0194] The term "preventing" a disease refers to administering to an individual having a predisposition to the disease or disorder, or at risk of developing the disease or disorder, one or more pharmaceutically active substances, in particular a compound of the invention or a pharmaceutically acceptable salt thereof as defined herein, to prevent or slow down the development 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.

[0195] As used herein, the term "effective amount" refers to an amount of a compound of the invention or a pharmaceutically acceptable salt thereof as described herein that is effective to "treat" or "prevent" in an individual a BTK-related disease or disorder, such as a disease or disorder responsive to inhibition of BTK, as defined above. An effective amount can cause any visible or detectable change in the individual as described in "treating" or "treatment" or "preventing" 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 a tumor; inhibit or prevent the invasion of tumor cells into surrounding organs, including, for example, the spread of a tumor into soft tissue and bone; inhibit or prevent the metastasis of a tumor; inhibit or prevent the growth of a tumor; alleviate to some extent one or more symptoms associated with cancer; reduce morbidity and mortality; improve quality of life; or a combination of the above effects. An effective amount can be an amount sufficient to reduce the symptoms of a BTK-related disease or disorder. The term "effective amount" can also refer to an amount of a compound of the invention or a pharmaceutically acceptable salt thereof as described herein that is effective to inhibit BTK activity in an individual.

[0196] The term "inhibition" refers to a decrease in the baseline activity of a biological activity or process. "BTK inhibition" refers to a decrease in BTK activity as a direct or indirect response to the presence of a compound of the invention or a pharmaceutically acceptable salt thereof, relative to BTK activity in the absence of the compound of the invention or a pharmaceutically acceptable salt thereof. The decrease in activity may be due to a direct interaction of the compound of the invention or a pharmaceutically acceptable salt thereof with BTK, or due to an interaction of the compound of the invention or a pharmaceutically acceptable salt thereof with one or more other factors, which in turn affect BTK activity. For example, the presence of a compound of the invention or a pharmaceutically acceptable salt thereof as described herein may decrease BTK activity by directly binding to BTK, by directly or indirectly causing another factor to decrease BTK activity, or by directly or indirectly decreasing the amount of BTK present in a cell or organism.

[0197] As used herein, the term "individual" refers to mammals and non-mammals. Mammals refer to any member of the mammalian class, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; etc. In some embodiments, the individual is a human. The term "individual" does not denote a particular age or sex. In some embodiments, the individual is a human. In some embodiments of any method or use described herein, the individual has not been treated with a BTK inhibitor. In other embodiments of any method or use described herein, the individual has been treated with a BTK inhibitor.

[0198] The term "pharmaceutically acceptable" means that the substance so qualified is suitable for use in the manufacture of a pharmaceutical composition, which is generally safe, non-toxic, and has no undesirable properties, biologically or otherwise, especially for human pharmaceutical use.

[0199] 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 and below the given numerical values. Generally, the term "about" is used herein to modify a variation of 20% above or below the stated value.

[0200] The term "tumor" as used herein refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, the ability to inappropriately invade surrounding tissues, and / or the ability to establish new growths at other sites. The term "tumor" includes, but is not limited to, hematological malignancies and solid tumors, preferably B-cell malignancies. The term "tumor" includes, but is not limited to, leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin disease (also known as Hodgkin lymphoma), and myeloma. Non-limiting examples of tumors are acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with myelodysplasia-related changes (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), and primary idiopathic 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, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myelogenous leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasmacytic myeloma, plasmacytoma, and multiple myeloma (MM). The term "tumor" includes cancers of the skin, tissue, organ, bone, cartilage, blood, and blood vessels. The term "tumor" also includes primary tumors, metastatic tumors, recurrent tumors, and refractory tumors.

[0201] The term "autoimmune disease" as used herein refers to a disease or disorder caused by damage to an individual's own tissues or organs resulting from an immune response of the body against its own 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 disorders such as myelofibrosis, post-polycythemia vera / post-essential thrombocythemia myelofibrosis (post-PV / post-ET myelofibrosis).

[0202] The term "inflammatory disease" or "inflammatory disorder" refers to a pathological condition that causes inflammation, particularly inflammation caused by the 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, Behçet's disease, psoriasis, chronic pulmonary inflammatory diseases, allograft rejection, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD).

[0203] All numerical ranges herein should be understood to disclose every and all values within the range and every and all subsets of values within the range, regardless of whether they are specifically disclosed otherwise. For example, when any numerical range is recited, it should be considered to refer to each and every numerical value within the numerical range, e.g., each integer within the numerical range. This disclosure includes all values falling within these ranges, all smaller ranges, and the upper or lower limits of the range.

[0204] Technical and scientific terms not specifically defined herein have the meanings commonly understood by those skilled in the art to which this invention pertains.

[0205] Pharmaceutical compositions and administrations

[0206] The compounds of the present invention (e.g., any of the compounds in the examples 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.

[0207] A pharmaceutically acceptable excipient refers to an excipient that is compatible with the active ingredient in the composition (and in some embodiments, stabilizes the active ingredient) and is harmless to the individual being treated. Suitable pharmaceutically acceptable excipients are disclosed in standard reference books in the art (e.g., Remington's Pharmaceutical Sciences, Remington: The Science and Practice of Pharmacy) and include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, coloring agents, sweetening agents, flavoring agents, diluents, and other known additives to provide a good appearance for 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., the medicament).

[0208] The compounds of the present invention can be administered in a variety of known ways, such as orally, parenterally, by inhalation or implantation, etc. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intraspinal, intralesional, and intracranial injection or infusion.

[0209] 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 can contain conventional components in pharmaceutical formulations, such as diluents, carriers, pH regulators, sweeteners, fillers, and additional active agents.

[0210] 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, wherein the typical initial range of the compound used is 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms, such as tablets and capsules, contain about 0.1 to about 1000 mg of the compound of the present invention.

[0211] Indications and treatment methods

[0212] The present disclosure relates to methods of treating or preventing BTK-related diseases or disorders, the methods comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

[0213] In one embodiment, the compounds of the present invention are used for treating or preventing BTK-related diseases or disorders.

[0214] Preferably, BTK-related diseases or disorders as used herein are selected from tumors, autoimmune diseases, infectious diseases, inflammatory diseases, and neurological disorders.

[0215] The tumor is a hematological malignancy or a solid tumor. More preferably, the tumor is a B-cell malignancy.

[0216] Non-limiting examples of BTK-related diseases or disorders include:

[0217] 1. Tumors (BTK-related tumors): hematological malignancies, solid tumors, preferably B-cell malignancies

[0218] 1.1 Hematological malignancies (For example, the hematological malignancies related to BTK - associated tumors) are selected from leukemia, lymphoma (non - Hodgkin lymphoma), Hodgkin's disease (also known as Hodgkin lymphoma), and myeloma, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T - cell ALL, AML with myelodysplasia - related changes (AML / TMDS), mixed - lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (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 lymphoma, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocytic lymphoma, precursor B - lymphoblastic leukemia, hairy cell leukemia, chronic myelogenous leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasmacytic myeloma, plasmacytoma, and multiple myeloma (MM).

[0219] The tumors used herein also include transformations in hematological malignancies. Non - limiting examples of transformations in hematological malignancies include Richter transformation, prolymphocytic transformation (e.g., prolymphocytic transformation of CLL), transformed non - Hodgkin lymphoma, and blastoid lymphoma (e.g., blastoid variant of mantle cell lymphoma).

[0220] 1.2 Solid tumors(e.g., for solid tumors of BTK-related tumors). Examples of solid tumors include, for example, bone cancer, bone metastases, 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, the methods described in 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.

[0221] 1.3 B-cell malignancies including B-cell non-Hodgkin lymphoma, Hodgkin lymphoma, or B-cell leukemia. Examples of B-cell malignancies also include Hodgkin 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 lymphoma, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma (LPL)), primary central nervous system lymphoma, small lymphocyte lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia (ALL), B-cell prolymphocytic leukemia, precursor B-lymphoblastic leukemia, or hairy cell leukemia.

[0222] 2. Other BTK-related diseases (including inflammatory diseases and autoimmune diseases):

[0223] 2.1. Arthritis diseases such as rheumatoid arthritis, monoarticular arthritis, osteoarthritis, gouty arthritis, spondylitis;

[0224] 2.2. Infectious diseases, sepsis, septic shock, endotoxic shock, gram-negative sepsis, gram-positive sepsis, and toxic shock syndrome;

[0225] 2.3. Multiple organ damage syndromes secondary to sepsis, trauma, or hemorrhage; ophthalmic diseases such as allergic conjunctivitis, vernal conjunctivitis, uveitis, and thyroid-associated ophthalmopathy; eosinophilic granuloma;

[0226] 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, sarcoidosis, pleurisy, alveolitis, vasculitis, emphysema, pneumonia, bronchiectasis, pulmonary type oxygen toxicity, and chronic pulmonary inflammatory diseases;

[0227] 2.5. Reperfusion injury of the myocardium, brain or extremities;

[0228] 2.6. Fibrosis, such as cystic fibrosis; keloid formation or scar tissue formation; atherosclerosis;

[0229] 2.7. Autoimmune diseases, including but not limited to systemic lupus erythematosus (SLE), autoimmune thyroiditis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, lupus erythematosus, myasthenia gravis, rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease (IBD), asthma, idiopathic thrombocytopenic purpura and myeloproliferative diseases such as myelofibrosis, polycythemia vera / post-essential thrombocythemia myelofibrosis (PV / ET post-myelofibrosis);

[0230] 2.8. Some forms of diabetes and Raynaud's syndrome;

[0231] 2.9. Transplant rejection diseases, such as graft-versus-host disease (GVHD) and allograft rejection;

[0232] 2.10. Chronic glomerulonephritis; inflammatory bowel disease, such as chronic inflammatory bowel disease (CIBD), Crohn's disease, ulcerative colitis and necrotizing enterocolitis;

[0233] 2.11. Inflammatory skin diseases, such as contact dermatitis, atopic dermatitis, psoriasis or urticaria; fever and myalgia caused by infection;

[0234] 2.12. Inflammatory diseases of the central or peripheral nervous system, such as meningitis, encephalitis and brain or spinal cord injury caused by minor trauma;

[0235] 2.13. Sjogren's syndrome;

[0236] 2.14. Diseases involving leukocyte extravasation;

[0237] 2.15. Alcoholic hepatitis;

[0238] 2.16. Bacterial pneumonia; antigen-antibody complex-mediated diseases; hypovolemic shock; type I diabetes; acute and delayed hypersensitivity reactions; disease states caused by leukocytes;

[0239] 2.17. Cachexia and metastasis; thermal injury; granulocyte transfusion-related syndrome; and cytokine-induced toxicity;

[0240] 2.18. Behcet's disease.

[0241] 3. Diseases resistant to other BTK-related treatments :

[0242] Diseases resistant to other BTK-related therapies include tumors with BTK inhibitor-resistant mutations (e.g., which result in increased resistance to a first BTK inhibitor, e.g., substitutions at amino acid position 481, e.g., C481S, C481T, C481R, C481G, and / or one or more BTK inhibitor-resistant mutations).

[0243] The compounds of the present invention are used for treating or preventing diseases resistant to other BTK-related therapies, either by co-administration or as a subsequent or additional (e.g., follow-up) therapy to existing drug therapies (e.g., said other BTK kinase inhibitors; e.g., the first and / or second BTK kinase inhibitors). 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, vicabrutinib, 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 the BTK kinase include, but are not limited to, ibrutinib, PRN1008, PRN473, ABBV-105, AC0058, acalabrutinib, zanubrutinib, spebrutinib, poseltinib, evobrutinib, M7583, and tirabrutinib. In some embodiments, the first or second BTK kinase inhibitor is a non-covalent inhibitor. Exemplary non-covalent inhibitors of the BTK kinase include, but are not limited to, CG'806, ARQ 531, BIIB068, vicabrutinib, AS871, CB 1763, CB988, GDC-0853, RN486, and dasatinib.

[0244] Drug combinations

[0245] The compounds of the present invention can be used in combination with additional active agents for the treatment of BTK-related diseases or disorders. The additional active agent can be administered separately from the compound of the present invention, or can be included together with the compound of the present invention in a pharmaceutical composition according to the present invention, such as a fixed combination product. In some embodiments, the additional active agent is one that is known or found to be effective in treating BTK-related diseases or disorders, such as another BTK inhibitor, or a compound that antagonizes an additional target associated with the specific disease. The combination can be used to increase the efficacy of the compound of the present invention, reduce one or more side effects, or reduce the required dosage.

[0246] 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: radiotherapy agents, chemotherapy agents, immunotherapy agents, targeted therapy agents.

[0247] General synthetic methods

[0248] General synthetic method for preparing 1H-pyrazolo[4,3-c]pyridine-7-carboxamide analogs having the general structures shown in A-1 and A-2 General synthetic method (Scheme 1)

[0249] Based on the synthesis of similar compounds in the literature (WO 2017042100), A-1-1 was synthesized from the commercially available raw material 2,4,6-trichloropyridine, followed by bromination, and then deprotection to obtain the 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 sequential Suzuki reactions were carried out on the two chlorine groups of 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 with the general formula 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 carrying out the Suzuki reaction, the 4-nitrogen analogue with the general formula structure shown in A-2 can be obtained.

[0250] Scheme 1

[0251]

[0252] Wherein Ra is R1 connected to the ring through C, and Rb is R1 connected to the ring through N or O; P1 or P2 is a protecting group; R1 and Ar are as defined in formula I herein.

[0253] General synthetic method for preparing 1H-pyrazolo[4,3-c]pyridine-7-carboxamide analogs having the general formula structures shown in B-1 and B-2 General synthetic method (Scheme 2)

[0254] Scheme 2

[0255]

[0256] Wherein Ra is R1 connected to the ring through C, and Rb is R1 connected to the ring through N or O; P1 or P2 is a protecting group; R1 and Ar are as defined in Formula I herein.

[0257] 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 (with modifications) disclosed in WO2010059658. After protection and formylation, Compound B-1-2 is obtained, which is then separated from its regioisomer B-1-3b and converted to Compound B-1-3a. B-1-3a and its deprotected form B-1-3c, as key intermediates, can be used respectively as starting points for the target compounds represented by B-1 or B-2 prepared according to a multi-step sequence.

[0258] Alternatively, in some cases, Route 2 is also used. According to the improved methods disclosed in US20180127370 and WO2004065367, commercially available methyl 5-bromo-2-hydroxy-4-methylbenzoate is converted to methyl 5-bromo-2-methoxy-4-methyl-3-nitrobenzoate, which is then converted to methyl 3-amino-5-bromo-2-methoxy-4-methylbenzoate after a reduction step. Subsequent ring closure reaction gives the key intermediate B-1-6, which is converted to the key intermediate B-1-9 after many bond-forming and functional group transformation steps. Using the key intermediate B-1-9, the target compound represented by B-1 is prepared.

[0259] Each of the embodiments described in the present disclosure and the features in each embodiment should be understood to be combinable with each other in any way, and each of the combinations thus obtained is included within the scope of the present disclosure as if the combinations were specifically and individually listed herein, unless the context clearly indicates otherwise.

[0260] To the extent permitted by law, the entire contents of all patents, patent applications, publications, and other documents cited or mentioned herein are incorporated herein by reference. The discussions of these references are only intended to summarize the claims therein. No admission is made that any of the patents, patent applications, publications, or documents, or any part thereof, is relevant material or prior art. The right to challenge the accuracy and relevance of any claim that any of the patents, patent applications, publications, and other documents is relevant material or prior art is specifically reserved. Examples

[0261] The following examples are only intended to illustrate the present invention and should not be construed as limiting the present invention in any way.

[0262] Unless otherwise specified, the unit of temperature is degrees Celsius and the pressure is atmospheric pressure or close to atmospheric pressure. All MS (mass spectrometry) data were measured by Agilent 6120B; Shimadzu LCMS2010. 1 The 1H-NMR spectra were obtained using a nuclear magnetic resonance instrument operating at 400 MHz on a Bruker AVANCE NEO. When indicating the multiplicity of peaks, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartet), br (broad peak), dd (doublet of doublets), dt (doublet of triplets). The coupling constants given are in hertz (Hz).

[0263] All reagents and starting materials used in the present invention, except for the intermediates prepared below, are commercially available or prepared according to the prior art.

[0264] The names of all compounds other than reagents were generated by Chemdraw. If both the name and the structural formula of a compound are given and they are inconsistent, the structure of the compound shall prevail, unless the context indicates that the structure of the compound is incorrect while the name is correct.

[0265] In any structural formula of the present application, if there is a vacant valence on any atom, the vacant valence is actually a hydrogen atom that is not specifically depicted for simplicity.

[0266] Unless otherwise specified, if isomers are separated under the same chromatographic separation conditions in the following examples, the isomers are named in the same order as they are eluted.

[0267] The following abbreviations are used in the following examples:

[0268] List of Abbreviations

[0269]

[0270]

[0271]

[0272] Synthesis of key intermediate A-1-4a

[0273]

[0274] Synthesis of 2,4,6-trichloro-3-(1,3-dioxolan-2-yl)pyridine (A-1-1)

[0275] Step 1: At -65 °C, LDA (27.4 mL, 54.8 mmol) was added to a stirred suspension of 2,4,6-trichloropyridine (9.1 g, 49.8 mmol) in THF (100 mL), and the resulting mixture was stirred under N2 for 1 hour. Subsequently, piperidine-1-carbaldehyde (5.6 mL, 49.8 mmol) was added at this temperature. The mixture was stirred at -65 °C for 3 hours. Then the reaction mixture was 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 the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2%) to give 2,4,6-trichloropyridine-3-carbaldehyde (4.1 g, yield: 39.1%) as a white solid. LC / MS (ESI) m / z: 211 (M+H) + , 1 1H-NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 8.09 (s, 1H).

[0276] Step 2 : At 120 °C, p-TSA (0.7 g, 3.9 mmol) was added to a stirred suspension of 2,4,6-trichloropyridine-3-carbaldehyde (4.1 g, 19.5 mmol) and propane-1,3-diol (2.1 mL, 29.2 mmol) in toluene (40 mL), 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 silica gel chromatography (EtOAc in PE = 0 - 10%) to give 2,4,6-trichloro-3-(1,3-dioxan-2-yl)pyridine (A-1-1) (4.2 g, yield: 80.3%) as a white solid. LC / MS (ESI) m / z: 268 (M+H) + 。

[0277] Synthesis of 5-bromo-2,4,6-trichloronicotinaldehyde (A-1-2)

[0278] Step 1 At -65 °C to 2,4,6-trichloro-3-(1,3-dioxan-2-yl)pyridine (A-1-1)(4.2 g, 15.6 mmol) and TMEDA (5.5 mL, 54.7 mmol) were added to a stirred suspension of n-BuLi (31.4 mL, 78.5 mmol) in THF (40 mL), and the resulting mixture was stirred under N₂ for 1 hour. Subsequently, 1,2-dibromotetrafluoroethane (4.1 mL, 31.3 mmol) was added. 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 the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE = 0 - 10%) to give 3-bromo-2,4,6-trichloro-5-(1,3-dioxolan-2-yl)pyridine (4 g, yield: 73.6%) as a white solid. LC / MS (ESI) m / z: 348 / 350 (M + H) + 。

[0279] Step 2: To a stirred suspension of 3-bromo-2,4,6-trichloro-5-(1,3-dioxolan-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 Na₂SO₄, filtered, and concentrated to give the crude product, which was purified by column chromatography on silica gel (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) + 。

[0280] Synthesis of 7-bromo-4,6-dichloro-1H-pyrazolo[4,3-c]pyridine (A-1-3)

[0281] Hydrazine hydrate (10 mL) was added dropwise to a stirred suspension of 5-bromo-2,4,6-trichloronicotinaldehyde (2.4 g, 8.3 mmol) in EtOH (20 mL) at 0 °C, and the mixture was stirred at room temperature for another 3 hours. The solvent was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (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 ¹H NMR (400 MHz, DMSO) δ 14.51 (s, 1H), 8.53 (s, 1H).

[0282] Synthesis of 7-bromo-4,6-dichloro-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine (A-1-4a) Synthesis

[0283] At 0 °C under a N2 atmosphere, DIAD (1.1 mL, 5.6 mmol) was added dropwise 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). The mixture was stirred at room temperature overnight. Then the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0 - 10%, containing 10% DCM) to obtain 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) + .

[0284] Synthesis of key intermediate A-2-4a

[0285]

[0286] Step 1 : At -80 °C, LDA (220 mL, 440 mmol) was added dropwise to a solution of 2,4,6-trichloro-3-(1,3-dioxolan-2-yl)pyridine (A-1-1) (79 g, 294 mmol) in THF (1 L), and the mixture was stirred for 1 hour. Then the solution was bubbled with CO2 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 Na2SO4, filtered, and concentrated to obtain the crude product 2,4,6-trichloro-5-(1,3-dioxolan-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) + .

[0287] Step 2: At -5 °C, oxalyl chloride (13 mL, 149.8 mmol) was added dropwise to a solution of 2,4,6-trichloro-5-(1,3-dioxan-2-yl)nicotinic acid (A-2-1) (39 g, 124.78 mmol) and DMF (0.5 mL, 6.24 mmol) in THF (400 mL). The resulting mixture was stirred for 1 hour and then bubbled with NH3 for 1 hour (maintaining the internal temperature <0 °C). Then the reaction mixture was warmed to room temperature, diluted with EtOAc (400 mL), filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by flash column chromatography on silica gel (EtOAc in DCM = 0% - 10%) to give the desired product 2,4,6-trichloro-5-(1,3-dioxan-2-yl)nicotinamide (30 g, yield: 77.2%), as a pale yellow solid. LC / MS (ESI) m / z: 311 / 313 (M+H) + , 1 1H NMR (400 MHz, DMSO-d6) δ 8.21 (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).

[0288] Step 3 : At 5 °C, HCl (200 mL, 2.4 mol) was added to a solution of 2,4,6-trichloro-5-(1,3-dioxan-2-yl)nicotinamide (30 g, 96.3 mmol) in AcOH (400 mL). 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), and the combined organic phases were washed with saturated NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (EtOAc in DCM = 0% - 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) + .

[0289] Step 4:At 10 °C, hydrazine hydrate (7.2 mL, 118.39 mmol) was added dropwise to a solution of NaHCO3 (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). The reaction mixture was stirred at the same temperature for another 4 hours. Then the mixture was quenched with saturated NH4Cl, extracted with EtOAc (100 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in DCM = 0% - 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 1H NMR (400 MHz, DMSO) δ 14.28 (s, 1H), 8.44 (s, 1H), 8.27 (br, 1H), 8.09 (br, 1H).

[0290] Step 5: At room temperature, PMBCl (5.3 mL, 38.95 mmol) was added dropwise 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). The reaction mixture was heated to 50 °C for 2 hours. Then the reaction mixture was cooled to room temperature, diluted with H2O (100 mL), extracted with EtOAc (100 ml x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in DCM = 0% - 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 (400 MHz, DMSO) δ 9.06 (s, 1H), 8.08 (br, 1H), 7.85 (br, 1H), 7.39 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 5.63 (s, 2H), 3.74 (s, 3H).

[0291] Synthesis of key intermediate B-1-3a

[0292]

[0293] Step 1 : At 0 °C, NaH (44.3 g, 1.1 mol) was added to a solution of phenylmethanol (99.7 g, 922 mmol) in THF (1 L). The reaction mixture was stirred at 0 °C under a nitrogen atmosphere for 30 minutes, and then 4-bromo-2,6-difluorobenzonitrile (200 g, 922 mmol) in THF (1 L) was added dropwise to the solution, and the mixture was stirred for another 2 hours. The reaction mixture was quenched with an aqueous NH4Cl solution and extracted with EtOAc (1 L x 2). The combined organic phases were washed with water and brine, dried over Na2SO4, 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).

[0294] Step 2 : At -78 °C, BBr3 (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). The reaction mixture was stirred at 0 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was quenched with MeOH and concentrated in vacuo. The crude product was purified by silica gel column chromatography (EtOAc in PE = 1% - 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 (M-H) + 。

[0295] Step 3 : DIPEA (232 mL, 1.35 mmol) was added to a solution of 4-bromo-2-fluoro-6-hydroxybenzonitrile (B-1-1, 145 g, 674.41 mmol) in DCM (1.5 L), and then MOMCl (59.1 g, 741.85 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C under a 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 (M-H) +, 1H NMR (400 MHz, DMSO) δ 7.55 (dd, J = 8.8, 1.5 Hz, 1H), 7.45–7.43 (m, 1H), 5.45 (s, 2H), 3.44 (s, 3H)

[0296] Step 4 : At -78 °C, LDA (401.5 mL, 803.09 mmol, 2 M in THF) was added dropwise to a solution of 4-bromo-2-fluoro-6-(methoxymethoxy)benzonitrile (160 g, 617.76 mmol) in THF (1.6 L). The mixture was stirred at -78 °C under a nitrogen atmosphere for 2 hours. Then, DMF (117.3 g, 1606.18 mmol) was added to the mixture, and the internal temperature was maintained below -70 °C. The reaction mixture was stirred at -78 °C for another 1 hour. The reaction mixture was quenched with an aqueous NH4Cl solution, extracted with EtOAc (2 L x 2), washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo to obtain the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 1% - 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 (M-H) + 。

[0297] Step 5 : At 0 °C, N2H4·H2O (26 g, 400.70 mmol, 80% in H2O) was added dropwise to a solution of 4-bromo-2-fluoro-3-formyl-6-(methoxymethoxy)benzonitrile (115 g, 400.70 mmol) in MeCN (1.5 L). 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), and the combined organic phases were washed with water and brine, dried over Na2SO4, and concentrated to obtain the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% - 5%) to give the desired product 4-bromo-6-(methoxymethoxy)-1H-indazole-7-carbonitrile (65 g, yield: 57.7%), as a white solid. LC / MS (ESI) m / z: 281 (M + 1)+ / 283 (M + 2)+, 1 1H NMR (400 MHz, DMSO) δ 14.13 (s, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.47 (s, 1H), 5.48 (s, 2H), 3.47 (s, 3H).

[0298] Step 6:To a solution of 4-bromo-6-(methoxymethoxy)-1H-indazole-7-carbonitrile (27 g, 96.09 mmol) in DMF (300 mL) was added 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 h. The reaction mixture was extracted with EtOAc (500 mL x 2), washed with water and brine, dried over Na2SO4, 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) +

[0299] Synthesis of key intermediate 4-bromo-6-hydroxy-2-(4-methoxybenzyl)-2H-indazole-7-carbonitrile (B-1-3d)

[0300]

[0301] 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 h. 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] +

[0302] Synthesis of key intermediate B-1-6

[0303]

[0304] Step 1: At room temperature, MeI (3.6 g, 25.352 mmol) was slowly added to a stirred solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate (5.0 g, 20.4 mmol) and K2CO3 (4.0 g, 28.9 mmol) in DMF (30 mL). The reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100 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 (EtOAc in PE = 1% to 10%) to give methyl 5-bromo-2-methoxy-4-methylbenzoate (5.0 g, yield: 94.59%) as a white solid. LC / MS (ESI) m / z: 260 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 6.84 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 2.42 (s, 3H).

[0305] Step 2 : Methyl 5-bromo-2-methoxy-4-methylbenzoate (5.0 g, 19.2 mmol) was added portionwise to stirred H2SO4 (30 mL) at 0 °C. After the solution became clear, HNO3 (1.25 mL, 19.2 mmol) was added dropwise over 30 min, and the mixture was stirred at 0 °C for an additional 1 h. The reaction mixture was diluted with saturated NaHCO3 (200 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 the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0 to 10%) to give methyl 5-bromo-2-methoxy-4-methyl-3-nitrobenzoate (5.2 g, yield: 88.6%) as a pale yellow oil. LC / MS (ESI) m / z: 305 (M+H) + . 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 2.35 (s, 3H).

[0306] Step 3: At 25 °C, HCl (0.2 mL, 2.400 mmol) was added 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), and then the mixture was heated to 80 °C and stirred for 18 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water (20 mL), and 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 obtain the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% - 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 (400 MHz, CDCl3) δ 7.48 (s, 1H), 4.05 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 2.30 (s, 3H).

[0307] Step 4 : A solution of sodium nitrite (75 mg, 1.0 mmol in 1 mL of water) was added dropwise to a stirred solution of methyl 3-amino-5-bromo-2-methoxy-4-methylbenzoate (300 mg, 1.0 mmol) in HBF4 (2 mL, 31.4 mmol). The reaction mixture was stirred at 10 °C for 30 min to form a precipitate. The cooled reaction mixture was filtered, and the solid product was washed successively with a small amount of H2O, MeOH, and Et2O and dried under high vacuum to obtain 400 mg of the diazonium salt as a yellow solid. In another dry flask, 18-crown-6 (289 mg, 1.0 mmol) and AcOK (200 mg, 2.0 mmol) were pre-dried under high vacuum for 1 h, and CHCl3 (50 mL) was added. The suspension was stirred at room temperature for 10 min. Then the diazonium salt was added to the mixture in small portions under a N2 atmosphere. The reaction mixture was stirred at room temperature for 3 h. 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 Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% - 25%) to give methyl 4-bromo-7-methoxy-1H-indazole-6-carboxylate ((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, CDCl3) δ 8.10 (s, 1H), 7.76 (s, 1H), 4.08 (s, 3H), 3.97 (s, 3H)。

[0308] Preparation of boric acid intermediate

[0309] N-[(3-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl]-5-fluoro-2-methoxybenzamide (Intermediate A)

[0310]

[0311] Step 1 : At 0 °C, tert-butyl N-[(tert-butoxy)carbonyl]carbamate (756 mg, 3.48 mmol) was added portionwise to a solution of sodium hydride (417 mg, 10.44 mmol) in dry DMF (10 mL). The resulting mixture was stirred at 0 °C for 1 h, then 1-bromo-4-(bromomethyl)-2-chlorobenzene (900 mg, 3.17 mmol) was added. The reaction mixture was stirred at the same temperature for another 2 h. Then the mixture was quenched with cold saturated NH4Cl, extracted with EtOAc (40 mL x 3), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give tert-butyl N-[(4-bromo-3-chlorophenyl)methyl]-N-[(tert-butoxy)carbonyl]carbamate (1.6 g, 100%), as a white solid, which was used directly without further purification. LC / MS (ESI) m / z: 420 / 422 (M+H) + 。

[0312] Step 2: At 0 °C, HCl (10 mL, 4 mol / L in 1,4-dioxane) was added 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). The reaction mixture was stirred at room temperature for 2 h. Then it was concentrated under reduced pressure to give the crude product (4-bromo-3-chlorophenyl)methanamine 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) + 。

[0313] 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 h. Then the mixture was diluted with H2O (20 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 in vacuo to give a residue, which was purified by silica gel column chromatography (EtOAc in PE = 0% - 20%) to afford 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) + 。

[0314] 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-dioxaborolane (0.82 g, 3.22 mmol) in 1,4-dioxane (20 mL) were 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) 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 in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0% - 20%) to afford the desired product N-{[3-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-5-fluoro-2-methoxybenzamide (720 mg, yield: 79.91%), as a pale yellow solid.

[0315] Intermediate B: 5-Fluoro-2-(methoxy-d3)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide

[0316]

[0317] Step 1:A solution of 4-bromobenzoic acid (2.0 g, 10 mmol) in SOCl2 (10 mL) was heated to 85 °C for 2 h under a N2 atmosphere. Then the reaction mixture was cooled to room temperature, and the solvent was removed under vacuum to give crude product 4-bromobenzoyl chloride (2.2 g, yield: 100%), which was used directly in the next step without purification.

[0318] Step 2 : 4-(Trifluoromethyl)pyridin-2-amine (1.6 g, 10 mmol) was added to a solution of 4-bromo-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (2.2 g, 10 mmol) in pyridine (10 mL). The resulting mixture was stirred overnight at 65 °C under a N2 atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% - 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) + 。

[0319] Step 3 : KOAc (1.5 g, 15.7 mmol) and Pd(dppf)Cl2 (0.6 g, 0.78 mmol) were added 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). The resulting mixture was heated to 110 °C for 12 h under a N2 atmosphere. After cooling to room temperature, the mixture was diluted with H2O (10 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% - 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) + 。

[0320] Intermediate C:5-Fluoro-2-(methoxy-d3)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)benzamide

[0321]

[0322] Step 1 : At -50 °C, BBr3 (16 mL, 16 mmol, 1 M in DCM) was added to a solution of N-(4-bromobenzyl)-5-fluoro-2-methoxybenzamide (2.7 g, 8.01 mmol) in DCM (30 mL) over 30 minutes. The reaction mixture was then stirred at this temperature for 2 hours. The mixture was quenched with NH4Cl (30 mL), extracted with DCM (30 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% - 3%) to give the desired product N-(4-bromobenzyl)-5-fluoro-2-hydroxybenzamide (2.5 g, yield: 96.6%) as a white solid. LC / MS (ESI) m / z: 324 (M+H) + 。

[0323] Step 2: K2CO3 (1.6 g, 11.61 mmol) and CD3I (1.4 g, 9.30 mmol) were added to a solution of N-(4-bromobenzyl)-5-fluoro-2-hydroxybenzamide (2.5 g, 7.74 mmol) in MeCN (20 mL). The resulting mixture was stirred at room temperature under a N2 atmosphere for 3 hours. The mixture was diluted with H2O (20 mL), extracted with EtOAc (20 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% - 3%) to give the desired product N-(4-bromobenzyl)-5-fluoro-2-(methoxy-d3)benzamide (0.8 g, yield: 30.4%) as a white solid. LC / MS (ESI) m / z: 341 (M+H) + 。

[0324] 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 in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% - 100%) to afford 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) + 。

[0325] Intermediate H : tert-Butyldiphenyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-3-enyloxy)silane

[0326]

[0327] 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) at 0 °C was added TBDPSCl (25.4 g, 92.84 mmol), and the resulting mixture was stirred at 0 °C for 2 h. The mixture was diluted with H2O (300 mL) and extracted with EtOAc (100 mL x 3). Then the organic layer was washed with water and brine, and the collected organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by silica gel column chromatography (PE = 100%) to afford tert-butyl(cyclopent-3-enyloxy)diphenylsilane (27.2 g, yield: 99.9%) as a colorless oil.

[0328] Step 2: At room temperature under N2, Br2 (4.3 mL, 84.33 mmol) was added to a solution of tert-butyl(cyclopent-3-enyloxy)diphenylsilane (27.2 g, 84.33 mmol) in CCl4 (270 mL). 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.

[0329] Step 3: At 0 °C, t-BuOK (9 g, 80.37 mmol) was slowly added to a stirred solution of tert-butyl(3,4-dibromocyclopentyloxy)diphenylsilane (8 g, 17.16 mmol) in THF (100 mL), and the reaction mixture was stirred at 25 °C for 18 hours. At 0 °C, the reaction mixture was diluted with water (200 mL), the mixture was extracted with EtOAc (200 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 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.

[0330] Step 4 : At 25 °C, Pd(dppf)Cl2 (200 mg, 0.27 mmol) was slowly added to a stirred solution of (3-bromocyclopent-3-enyloxy)(tert-butyl)diphenylsilane (3 g, 7.5 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.8 g, 7.8 mmol) in 1,4-dioxane (30 mL). The resulting mixture was heated to 100 °C under a N2 atmosphere for 12 hours. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3), the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0% - 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. 11H NMR (400 MHz, CDCl3) δ 7.66 (dt, J = 8.0, 1.8 Hz, 4H), 7.38 (ddd, J = 18.0, 9.8, 4.7 Hz, 6H), 6.45–6.37 (m, 1H), 4.56 (dq, J = 6.4, 4.8 Hz, 1H), 2.70–2.44 (m, 4H), 1.26 (s, 12H), 1.04 (s, 9H).

[0331] Intermediate I:

[0332] Synthesis of 4,4,5,5 - tetramethyl - 2 - (2 - methyl - 4,5 - dihydrofuran - 3 - yl)-1,3,2 - dioxaborolane

[0333]

[0334] Step 1 : At - 78 °C, LDA (18.0 mL, 36.0 mmol) was added dropwise to a solution of 2 - methyloxolane - 3 - one (3 g, 29.96 mmol) in THF (40 mL). The resulting mixture was stirred at - 78 °C under a nitrogen atmosphere for 1 hour. Subsequently, 1,1,1 - trifluoro - N - phenyl - N - (trifluoromethylsulfonyl)methanesulfonamide (10.70 g, 29.964 mmol, in THF (10 mL)) was added, and the reaction mixture was stirred at - 78 °C for another 1 hour. The mixture was poured into an ice - cold aqueous NH4Cl solution (20 mL), and extracted with EtOAc (30 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (EtOAc in petroleum ether = 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 could be used directly in the next step without further purification. LC / MS (ESI) m / z: 233 [M + 1] +

[0335] 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-dioxaborolane (766 mg, 3.0 mmol) in dioxane (10 mL) were added KOAc (591 mg, 6.0 mmol) and Pd(dppf)Cl2 (110 mg, 0.15 mmol), and the reaction mixture was stirred at 85 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in petroleum ether = 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] +

[0336] Intermediate K:

[0337] Synthesis of 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-enone

[0338]

[0339] 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) at -78 °C was slowly added Tf2O (1.6 mL, 10 mmol), and the reaction mixture was stirred at -78 °C under a 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 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 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 (400 MHz, CDCl3) δ 2.92 (m, 2H), 2.71–2.60 (m, 2H), 1.79 (m, 3H).

[0340] Step 2: At 25 °C, Pd(dppf)Cl2 (100 mg, 0.14 mmol) and KOAc (500 mg, 5.09 mmol) were slowly added to a stirred solution of 2-methyl-3-oxocyclopent-1-enyl trifluoromethanesulfonate (500 mg, 2.048 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.61 mL, 2.36 mmol) in 1,4-dioxane (10 mL), and the reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with water (40 mL), the mixture was extracted with EtOAc (60 mL x 3), the combined organic phases were washed with water and brine, 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 1H NMR (400 MHz, CDCl3) δ 2.65–2.58 (m, 2H), 2.33 (dd, J = 8.6, 4.1 Hz, 2H), 1.97–1.91 (m, 3H), 1.31 (d, J = 3.3 Hz, 12H).

[0341] Intermediate L:

[0342] 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

[0343]

[0344] Step 1: Under N2, TEA (27.5 g, 271.84 mmol) was added to a solution of methyl alaninate (14.0 g, 135.92 mmol) and ethyl acrylate (27.2 g, 271.84 mmol) in EtOH (200 mL). 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 the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% - 20%) to give the desired product ethyl 3-((1-methoxy-1-oxopropan-2-yl)amino)propanoate (11.0 g, yield: 39.87%), as an off-white oil. LC / MS (ESI) m / z: 204 (M+H) +

[0345] Step 2 : Under N2, Boc2O (23.6 g, 108.38 mmol) and TEA (20.2 g, 200 mmol) were added to a solution of ethyl 3-((1-methoxy-1-oxopropan-2-yl)amino)propanoate (11.0 g, 54.19 mmol) in DCM (200 mL). 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 Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% - 20%) to give the desired product ethyl 3-((tert-butoxycarbonyl)(1-methoxy-1-oxopropan-2-yl)amino)propanoate (15.0 g, yield: 91.5%), as an off-white oil. LC / MS (ESI) m / z: 304 (M+H) +

[0346] Step 3: Under N2, t-BuOK (11.1 g, 99 mmol) was added to a solution of ethyl 3-((tert-butoxycarbonyl)(1-methoxy-1-oxopropan-2-yl)amino)propionate (15.0 g, 49.50 mmol) in toluene (150 mL). 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 obtain the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% - 40%) to obtain the desired mixed products ethyl 1-(tert-butyl) 5-methyl-4-oxopyrrolidine-1,3-dicarboxylate and methyl 1-(tert-butyl) 2-methyl-3-oxopyrrolidine-1,2-dicarboxylate (9.0 g, yield: 70.75%), as an off-white oil. LC / MS (ESI) m / z: 258 and 272 (M+H) +

[0347] Step 4: Concentrated HCl (4 mL) was added to a solution of ethyl 1-(tert-butyl) 5-methyl-4-oxopyrrolidine-1,3-dicarboxylate and methyl 1-(tert-butyl) 2-methyl-3-oxopyrrolidine-1,2-dicarboxylate (9.0 g, 35.02 mmol) in EtOH (20 mL). The mixture was stirred in a sealed tube at 90 °C for 1 hour. After cooling to room temperature, it was diluted with DCM (150 mL). The mixture was washed with water and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was used without purification to obtain the desired 2-methylpyrrolidin-3-one (3.45 g, yield: 100%), as an off-white oil. LC / MS (ESI) m / z: 100 (M+H) +

[0348] Step 5 : Under N2, Boc2O (15.2 g, 69.7 mmol) and DIPEA (7 g, 69.7 mmol) were added to a solution of 2-methylpyrrolidin-3-one (3.45 g, 34.85 mmol) in DCM (20 mL). 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 Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 5% - 30%) to obtain 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) +

[0349] Step 6 : Under N2, LiHMDS (15.08 mL, 2.0 mmol / mL, 30.16 mmol) was added to a solution of tert-butyl 2-methyl-3-oxopyrrolidine-1-carboxylate (3.0 g, 15.08 mmol) in THF (20 mL). The reaction mixture was stirred at -78 °C for 1 hour. Then, Tf2O (5.10 g, 18.10 mmol) was added, and the mixture was 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 obtain the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 5% - 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) +

[0350] Step 7 : Under N2, 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 mmol) were added to a solution of tert-butyl 5-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-pyrrole-1-carboxylate (1.9 g, 5.74 mmol) in dioxane (20 mL). 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 obtain the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 5% - 30%) to give the desired product tert-butyl 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrole-1-carboxylate (1.3 g, yield: 73.30%), as an off-white oil. LC / MS (ESI) m / z: 310 (M+H) +

[0351] Intermediate M: 3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine

[0352]

[0353] Step 1 : At 0 °C, NBS (8.23 g, 46.27 mmol) was added portionwise to a solution of 2-(trifluoromethyl)pyridin-4-amine (3 g, 18.51 mmol) in MeCN (50 mL). The resulting mixture was warmed to room temperature and stirred overnight. Then the mixture was diluted with H2O (50 mL), extracted with EtOAc (50 mL x 3), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the 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 (400 MHz, CDCl3) δ 8.37 (s, 1H), 5.46 (s, 2H).

[0354] 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 h. Then the mixture was filtered through a Celite pad and the filtrate was concentrated in vacuo to give the crude product, which was purified by flash silica gel 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 (400 MHz, DMSO-d6) δ 8.07 (d, J = 5.6 Hz, 1H), 6.94 (d, J = 5.6 Hz, 1H), 5.75 (br, 2H).

[0355] 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) were 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 in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0 - 50%) to afford 3-methyl-2-(trifluoromethyl)pyridin-4-amine (200 mg, yield: 68.4%) as a yellow solid. LC / MS: m / z: 177 (M+H) + 。

[0356] Step 4 : To a mixture of 3-methyl-2-(trifluoromethyl)pyridin-4-amine (200 mg, 1.14 mmol) in MeCN (10 mL) were added tert-butyl nitrite (0.27 mL, 2.27 mmol) and CuBr2 (363 mg, 2.27 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 in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0 - 5%) to afford 4-bromo-3-methyl-2-(trifluoromethyl)pyridine (80 mg, yield: 29.4%) as a yellow oil. LC / MS: m / z: 240 / 242 (M+H) + 。

[0357] 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-dioxaborolane (127 mg, 0.50 mmol) in 1,4-dioxane (10 mL) were 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 in vacuo to give [3-methyl-2-(trifluoromethyl)pyridin-4-yl]boronic acid (80 mg, yield: 117.2%), as a brown oil, which was used directly in the next step without further purification. LC / MS: m / z: 206 (M+H) + 。

[0358] Intermediate N: 4,6-dimethylpyrimidin-5-ylboronic acid

[0359]

[0360] To a solution of 5-bromo-4,6-dimethylpyrimidine (500 mg, 2.67 mmol) in THF (10 mL) at -78 °C was added dropwise n-BuLi (1.6 mL, 1.6 mmol / mL), and the mixture was stirred at -78 °C under nitrogen atmosphere for 1 h. Subsequently, B(OMe)3 (780 mg, 5.34 mmol, in 5 ml THF) was added and the reaction mixture was stirred at -78 °C for another 1 h. The mixture was poured into an ice-cold aqueous solution of NH4Cl (20 mL) and extracted with EtOAc (20 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 (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]+

[0361] Table 1. Preparation of boronic ester intermediates. Boronic esters D-G were prepared by methods similar to those of intermediates A, B, C; intermediate J was prepared by a method similar to that of intermediate I, and intermediates O-U were prepared by methods similar to those of intermediates K-N (with variations), starting from commercially available raw materials

[0362]

[0363]

[0364] Example 1 :

[0365] 4-Cyclopentyl-6-(4-((2-methoxybenzamido)methyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (BNB-1049-01)

[0366]

[0367] 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 a N2 atmosphere for 10 hours. The reaction mixture was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (EtOAc in PE = 2% - 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 (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.13 (d, J = 8.7 Hz, 2H), 6.85–6.79 (m, 3H), 5.94 (d, J = 5.7 Hz, 2H), 3.77 (s, 3H), 3.06–2.87 (m, 2H), 2.64 (m, 2H), 2.13–2.03 (m, 2H).

[0368] Step 2:To a solution of 7-bromo-6-chloro-4-cyclopenten-1-yl-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridine (0.3 g, 0.7 mmol) in MeOH (5 mL) was added Pd(dppf)Cl2 (52.4 mg, 0.1 mmol) and TEA (0.3 mL, 2.2 mmol). The resulting mixture was stirred overnight in a sealed tube at 85 °C under CO (70 psi). After cooling to room temperature, the solvent was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (EtOAc in DCM = 0 - 50%) to afford methyl 6-chloro-4-(cyclopent-1-en-1-yl)-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[4,3-c]pyridine-7-carboxylate (240 mg, yield: 84.2%) as a yellow solid. LC / MS (ESI) m / z: 398 (M+H) + 。

[0369] Step 3: To a solution of methyl 6-chloro-4-(cyclopent-1-en-1-yl)-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[4,3-c]pyridine-7-carboxylate (240 mg, 0.6 mmol) in dioxane (8 mL) and H2O (2 mL) were 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)Cl2 (52 mg, 0.1 mmol) and K2CO3 (250 mg, 1.8 mmol). The resulting mixture was then stirred at 100 °C under N2 atmosphere for 2 h. After cooling to room temperature, water (5 mL) was added and the mixture was extracted with EtOAc (10 x 3 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc in DCM = 0 - 15%) to afford 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) + 。

[0370] Step 4:To a solution of methyl 4-(cyclopent-1-en-1-yl)-6-(4-{[(2-methoxyphenyl)-carbamoylamino]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 H2 balloon for 2 h. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated to give the 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) + 。

[0371] 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 h. After cooling to room temperature, the reaction mixture was diluted with DCM (20 mL) and the pH was adjusted with saturated NaHCO3 solution. The organic phase was dried over anhydrous Na2SO4 and concentrated to give the 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) + 。

[0372] Step 6: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) was added ammonia (28% in water). The mixture was stirred in a sealed tube at 100 °C for 6 h. After cooling to room temperature, the reaction mixture was concentrated to give the crude product, which was purified by preparative-TLC (DCM:MeOH = 15:1) to afford the desired product, 4-cyclopentyl-6-(4-((2-methoxybenzamido)methyl)phenyl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (3 mg, yield: 3.1%), as a pale yellow solid. 1 H NMR (400 MHz, MeOD) δ 8.34 (s, 1H), 7.91 (dd, J = 7.7, 1.8 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.50 (ddd, J = 16.0, 8.9, 5.1 Hz, 3H), 7.16 (d, J = 8.3 Hz, 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) + 。

[0373] Example 2:

[0374] 6-(4-((5-Fluoro-2-methoxybenzamido)methyl)phenyl)-4-(4-hydroxycyclohexyl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (BNB-1055-01)

[0375]

[0376] 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). The mixture was stirred at 60 °C for 10 h under a N2 atmosphere. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel column chromatography (EtOAc in PE = 2% - 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 (400 MHz, DMSO) δ 9.24 (s, 1H), 7.37 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.73 (t, J = 3.9 Hz, 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 = 6.5 Hz, 2H).

[0377] 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 in a sealed tube at 85 °C under CO (70 psi) overnight. After cooling to room temperature, the solvent was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (EtOAc 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) + 。

[0378] 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). 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 phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% - 100%) to give 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, yield: 72.2%) as a white solid. LC / MS (ESI) m / z: 693 (M+H) + 。

[0379] 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) + 。

[0380] Step 5:To a solution of methyl 4-{1,4-dioxaspiro[4.5]dec-8-yl}-6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]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. Then the pH of the mixture was adjusted to 5 with 1N HCl, filtered, and the filter cake was purified directly by preparative-HPLC to give the desired product 4-{1,4-dioxaspiro[4.5]dec-8-yl}-6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]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) + .

[0381] Step 6 : To a stirred solution of 4-{1,4-dioxaspiro[4.5]dec-8-yl}-6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]methyl}phenyl)-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid (60 mg, 0.09 mmol) and HATU (40 mg, 0.11 mmol) in DMF (5 mL) at 25 °C was slowly added DIPEA (34 mg, 0.264 mmol), and the reaction mixture was heated to room temperature in an 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 phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the 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]dec-8-yl}-6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]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) + .

[0382] Step 7:Under N2, TFA (5 mL) was added to a solution of 4-{1,4-dioxaspiro[4.5]decan-8-yl}-6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]methyl}phenyl)-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (55 mg, 0.08 mmol) in DCM (5 mL). The mixture was stirred for 3 hours. The solvent was concentrated under reduced pressure to give the crude product 6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]methyl}phenyl)-4-(4-oxocyclohexyl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (40 mg, yield: 96%), which was a yellow solid and was used directly without further purification. LC / MS (ESI) m / z: 516 (M+H) +

[0383] Step 8: Under N2, NaBH4 (13 mg, 0.39 mmol) was added to a solution of 6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]methyl}phenyl)-4-(4-oxocyclohexyl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (40 mg, 0.08 mmol) in MeOH (5 mL). After stirring for 3 hours, the reaction mixture was concentrated to give the crude product, which was purified by preparative-TLC (DCM:MeOH = 15:1) to give the desired product 6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]methyl}phenyl)-4-(4-hydroxycyclohexyl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (8 mg, yield: 20%), which was a white solid. 1 1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.63 (dd, J = 9.3, 3.2 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.25 (ddd, J = 9.1, 7.6, 3.3 Hz, 1H), 7.16 (dd, J = 9.1, 4.2 Hz, 1H), 4.68 (s, 2H), 3.96 (s, 3H), 3.74–3.62 (m, 1H), 3.22 (dd, J = 12.9, 8.2 Hz, 1H), 2.11 (d, J = 11.8 Hz, 2H), 2.06–1.95 (m, 4H), 1.51 (dt, J = 17.0, 11.6 Hz, 2H), LC / MS (ESI) m / z: 518 (M+H) + 。

[0384] Table 2: Compounds of general formula A-1: The compounds in the following table were prepared from the key intermediate according to the general methods of Synthesis Examples 1 and 2 (with modifications). A-1-4a Prepared

[0385]

[0386] Examples 6 - 9: 6-(4-((5-Fluoro-2-methoxybenzamido)methyl)phenyl)-4-(3-hydroxycyclopentyl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0387]

[0388] 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 H2O (5 mL) was added Pd(dppf)Cl2 (125 mg, 0.17 mmol) and K2CO3 (708 mg, 5.13 mmol). The resulting mixture was heated to 80 °C and stirred under a N2 atmosphere for 12 h. The reaction mixture was then cooled to room temperature, diluted with H2O (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 in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0% - 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) + .

[0389] 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). The resulting mixture was heated to 110 °C under N2 atmosphere for 12 h. The reaction mixture was cooled to room temperature, diluted with H2O (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 in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0% - 100%) to afford 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) + 。

[0390] 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 H2 atmosphere for 12 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel flash chromatography (EtOAc in PE = 0% - 50%) to afford 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) + 。

[0391] 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 h. 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)carbamoyl]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) + 。

[0392] Step 5 : To a solution of 3-[7-carbamoyl-6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]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 h. The pH of the reaction mixture was adjusted to 6 with 1N HCl 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 in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% - 3%) to give two pairs of enantiomers, which were further separated by SFC to give the desired product in four absolute configurations (Waters UPC2 analysis, mobile phase: A was CO2, B was methanol (0.05% DEA), gradient: 10 min @ 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 I.D., 5um; For Examples 8 & 9 (trans isomers): column: ChiralPak IA, 250×4.6 mm I.D., 5um. The absolute configurations of all four compounds were not determined.

[0393] Example 6 (from the first eluate, cis isomer 1): (BNB-1098-01) (15 mg, yield: 4.47%), as a white solid, LC / MS (ESI) m / z: 504 (M+H) + , 11H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 8.86 (t, J = 6.1 Hz, 1H), 8.47 (s, 1H), 7.83 (s, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.62 (s, 1H), 7.53 (dd, J = 9.2, 3.3 Hz, 1H), 7.41–7.31 (m, 3H), 7.19 (dd, J = 9.1, 4.3 Hz, 1H), 5.11 (d, J = 5.9 Hz, 1H), 4.56 (d, J = 6.1 Hz, 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, 5.9 Hz, 1H), 2.14–2.03 (m, 2H), 1.96 (ddd, J = 12.4, 7.4, 4.8 Hz, 1H), 1.85 (ddd, J = 17.1, 11.5, 7.2 Hz, 1H), 1.73 (td, J = 11.8, 6.9 Hz, 1H).

[0394] Example 7 (obtained from the second eluate, cis-isomer 2): (BNB-1099-01) (25 mg, yield: 7.44%), a white solid, LC / MS (ESI) m / z: 504 (M+H) + , 1 1H NMR (400 MHz, DMSO-d6) δ 13.57 (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 = 6.1 Hz, 2H), 4.27 (dd, J = 9.8, 4.9 Hz, 1H), 3.91 (s, 3H), 3.81–3.72 (m, 1H), 2.32 (ddd, J = 14.6, 8.9, 5.9 Hz, 1H), 2.08 (ddd, J = 16.4, 8.0, 4.2 Hz, 2H), 1.99–1.92 (m, 1H), 1.89–1.80 (m, 1H), 1.77–1.69 (m, 1H).

[0395] Example 8 (obtained from the first eluate, trans-isomer 3): (BNB-1107-01) (13 mg, yield: 3.87%), a white solid, LC / MS (ESI) m / z: 504 (M+H) + ,1 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.62 (dd, J = 9.2, 3.2 Hz, 1H), 7.44 (dd, J = 20.2, 7.9 Hz, 3H), 7.32–7.22 (m, 2H), 7.16 (dd, J = 9.1, 4.2 Hz, 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, 7.0 Hz, 3H), 1.82–1.74 (m, 1H).

[0396] Example 9 (obtained from the second eluate, trans isomer 4): (BNB-1108-01) (12 mg, yield: 3.57%), a white solid, LC / MS (ESI) m / z: 504 (M + H) + , 1 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.53 (dd, J = 9.2, 3.2 Hz, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.15 (ddd, J = 9.1, 7.6, 3.3 Hz, 1H), 7.06 (dd, J = 9.1, 4.2 Hz, 1H), 4.58 (s, 2H), 4.43 (ddd, J = 8.2, 5.5, 2.9 Hz, 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).

[0397] 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)

[0398]

[0399] 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) were 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 a N2 atmosphere for 12 h. Then the reaction mixture was cooled to room temperature, diluted with H2O (20 mL), extracted with EtOAc (20 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% - 3%) to afford 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) + .

[0400] 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

[0401] 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. Then the reaction mixture was cooled to room temperature, the mixture was 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 in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% - 3%) to give the desired product 6-(4-((5-fluoro-2-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) + .

[0402] Step 3 : Synthesis of 6-(4-((5-Fluoro-2-methoxybenzamido)methyl)phenyl)-2-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]dec-8-yl)-2H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0403] To a stirred solution of 6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-2-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]deca-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 a H2 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) + 。

[0404] Step 4 : Synthesis of 6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-4-(4-oxocyclohexyl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide

[0405] A solution 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 (320 mg, 0.47 mmol) in TFA (3 mL) was stirred at 65 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with DCM (20 mL) and the pH was adjusted with saturated NaHCO3 solution. The organic phase was collected, dried over anhydrous Na2SO4 and concentrated to give the 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) + 。

[0406] 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 the 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: ChiralCel OD, 250×4.6 mm I.D., 5 μm, mobile phase: A was CO2, B was 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 the cis and trans products. LC / MS (ESI) m / z: 518 (M+H) + 。

[0407] Example 10 (from the first eluate, isomer 1, BNB-1082-01) 10 mg (yield: 4.5%), a white solid and 1 1H NMR (400 MHz, DMSO) δ 13.53 (s, 1H), 8.86 (s, 1H), 8.40 (s, 1H), 7.87 (s, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.62 (s, 1H), 7.53 (d, J = 9.4 Hz, 1H), 7.44–7.30 (m, 3H), 7.20 (s, 1H), 4.56 (d, J = 5.0 Hz, 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 = 10.7 Hz, 4H).

[0408] Example 11 (from the second eluate, isomer 2, BNB-1083-01) 61 mg (yield: 27.4%), a white solid. 11H 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, 4.3 Hz, 1H), 4.63 (d, J = 4.3 Hz, 1H), 4.55 (d, J = 6.0 Hz, 2H), 3.91 (s, 3H), 3.18–3.13 (m, 1H), 3.22–3.11 (m, 1H), 2.05–1.73 (m, 6H), 1.55–1.31 (m, 2H).

[0409] Table 3: The following compounds were prepared from A-2-4a and the appropriate intermediates according to a method (with variations) similar to that of Examples 6 to 9 and 10 & 11:

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417] Example 40:

[0418] 6-(4-((5-Fluoro-2-methoxybenzamido)methyl)phenyl)-4-(3-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (BNB-1170-01)

[0419]

[0420] Step 1: At 25 °C, Pd(dppf)Cl2 (20 mg, 0.028 mmol) and Na2CO3 (60 mg, 0.57 mmol) were slowly added 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). The resulting mixture was heated to 80 °C and stirred under a N2 atmosphere for 12 h. Then the reaction mixture was 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 in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0% - 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)+.

[0421] Step 2 : At 25 °C, Pd(dppf)Cl2 (14 mg, 0.02 mmol) and K2CO3 (51 mg, 0.37 mmol) were slowly added 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). The resulting mixture was heated to 110 °C under a N2 atmosphere for 12 h. Then the reaction mixture was cooled to room temperature, diluted with H2O (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 in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0 - 3%) to give the desired product 6-(4-((5-fluoro-2-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)+.

[0422] Step 3 : A solution of 6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]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 h. Then the reaction mixture was cooled to room temperature, and the resulting mixture was concentrated in vacuo. The crude product obtained was dissolved in EtOAc (15 mL), and the pH was adjusted to 8 with saturated NaHCO3 solution. The organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative-TLC (MeOH in DCM = 5%) to give the desired product 6-(4-((5-fluoro-2-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 1H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.64–8.57 (m, 2H), 8.17 (s, 2H), 7.76 (d, J = 8.2 Hz, 3H), 7.56–7.51 (m, 2H), 7.41–7.32 (m, 3H), 7.19 (dd, J = 9.2, 4.3 Hz, 1H), 4.56 (d, J = 6.1 Hz, 2H), 3.90 (s, 3H), 2.37 (s, 3H).

[0423] Example 41:

[0424] 6-(4-((5-Fluoro-2-methoxybenzamido)methyl)phenyl)-4-(pyrimidin-4-yl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (BNB-1186-01)

[0425]

[0426] Step 1: At 25 °C, Pd(PPh3)4 (33 mg, 0.028 mmol) was added 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). The resulting mixture was heated to 80 °C and stirred for 18 h under a N2 atmosphere. Then the reaction mixture was 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 in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0% - 70%) to afford 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)+.

[0427] 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). The resulting mixture was heated to 110 °C for 12 h under a N2 atmosphere. Then the reaction mixture was cooled to room temperature, diluted with H2O (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 in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0 - 3%) to afford 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)+.

[0428] 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 h. Then the reaction mixture was cooled to room temperature, and the resulting mixture was concentrated in vacuo. The crude product was dissolved in EtOAc (15 mL), and the pH was adjusted to 8 with saturated NaHCO3 solution. The organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude product, which was purified by preparative-TLC (MeOH in DCM = 5%) to afford 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 1H NMR (400 MHz, DMSO) δ 13.91 (s, 1H), 9.47 (d, J = 1.3 Hz, 1H), 9.16–8.94 (m, 2H), 8.89 (t, J = 6.1 Hz, 1H), 8.57 (dd, J = 5.2, 1.4 Hz, 1H), 8.10 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.83 (s, 1H), 7.54 (dd, J = 9.2, 3.3 Hz, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.35 (ddd, J = 9.0, 7.9, 3.3 Hz, 1H), 7.20 (dd, J = 9.1, 4.3 Hz, 1H), 4.59 (d, J = 6.1 Hz, 2H), 3.92 (s, 3H).

[0429] Table 4: The following compounds were prepared from A-2-4a and the appropriate intermediate A according to a method similar to that of Example 40 or 41 (with variations)

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437] 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)

[0438]

[0439] 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 K2CO3 (157 mg, 1.14 mmol) in MeCN (10 mL) at 0 °C was added dropwise (R)-pyrrolidin-3-ol (52 mg, 0.57 mmol), and the resulting mixture was stirred at room temperature for 12 h. Then the reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% - 2%) to afford 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) + 。

[0440] 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

[0441] 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 H2O (1 mL) was added Pd(dppf)Cl2 (14 mg, 0.02 mmol) and Cs2CO3 (122 mg, 0.37 mmol). The resulting mixture was heated at 110 °C under a N2 atmosphere for 12 h. Then the reaction mixture was cooled to room temperature, the mixture was 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 in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% - 3%) to give the desired product (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) + .

[0442] Step 3 : in a 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

[0443] (70 mg, 0.11 mmol) was heated at 65 °C in TFA (3 mL) for 2 h. Then the reaction mixture was cooled to room temperature, the resulting mixture was concentrated in vacuo 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) + .

[0444] Step 4: To a solution of (R)-2,2,2-trifluoroacetic acid 1-(7-carbamoyl-6-(4-((5-fluoro-2-(methoxy-d3)benzamido)-methyl)phenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)pyrrolidin-3-yl ester (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 h. The resulting mixture was cooled to room temperature, and the pH was adjusted to 7 with 1N HCl, 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 in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% - 3%) to give the crude product, which was further purified by preparative-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 (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.85 (t, J = 6.1 Hz, 1H), 8.20 (s, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.53 (dd, J = 9.2, 3.3 Hz, 1H), 7.37–7.31 (m, 3H), 7.28–7.13 (m, 2H), 6.92 (s, 1H), 5.04 (d, J = 2.9 Hz, 1H), 4.55 (d, J = 6.2 Hz, 2H), 4.44–4.41 (m, 1H), 3.84–3.82 (m, 3H), 2.06–1.97 (m, 2H).

[0445] 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)

[0446]

[0447] Step 1: At 0 °C, pyrrolidine (37 mg, 0.51 mmol) and K2CO3 (118 mg, 0.86 mmol) were added 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). The resulting mixture was stirred at room temperature for 12 hours. Then the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% - 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) + 。

[0448] 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 H2O (1 mL) were added Pd(dppf)Cl2 (22 mg, 0.03 mmol) and Cs2CO3 (202 mg, 0.62 mmol). The resulting mixture was heated to 110 °C under N2 atmosphere for 12 hours. Then the reaction mixture was cooled to room temperature, diluted with H2O (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 in vacuo to obtain 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-(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) + 。

[0449] 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. Then the reaction mixture was cooled to room temperature, and the resulting mixture was concentrated in vacuo to give the crude product, which was dissolved in EtOAc (15 mL), and the pH was adjusted to 8 with saturated NaHCO3 solution. The organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative-TLC (MeOH in DCM = 5%) to give the desired product 6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-4-(pyrrolidin-1-yl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (11 mg, yield: 45%) as a white solid: 1 1H NMR (400 MHz, DMSO) δ 12.98 (s, 1H), 8.84 (t, J = 6.1 Hz, 1H), 8.20 (s, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.53 (dd, J = 9.2, 3.3 Hz, 1H), 7.33 (dd, J = 12.5, 5.7 Hz, 3H), 7.28–7.14 (m, 2H), 6.90 (s, 1H), 4.54 (d, J = 6.1 Hz, 2H), 3.90 (s, 3H), 3.75 (s, 4H), 1.99 (s, 4H); LC / MS (ESI) m / z: 489 (M + H) + 。

[0450] Example 76: 6-(4-((5-Fluoro-2-methoxybenzamido)methyl)phenyl)-4-((1,1,1-trifluoropropan-2-yl)oxy)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (BNB-1130-01)

[0451]

[0452] Step 1:At 0 °C under N2, NaH (25 mg, 0.6 mmol, 60%) was added to a stirred solution of 1,1,1-trifluoropropan-2-ol (71 mg, 0.6 mmol) in DMF (5 mL). The resulting mixture was stirred at 0 °C for 0.5 h, then 4,6-dichloro-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-c]pyridine-7-carboxamide (200 mg, 0.5 mmol) in DMF (2 mL) was added, and stirring was continued for another 2 h. The reaction mixture was quenched with an aqueous NH4Cl solution and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% - 40%) to give the desired product 6-chloro-2-(4-methoxybenzyl)-4-((1,1,1-trifluoropropan-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) +

[0453] 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). The reaction mixture was stirred at 100 °C under a 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 = 30% - 50%) to give the desired product 6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-2-(4-methoxybenzyl)-4-((1,1,1-trifluoropropan-2-yl)oxy)-2H-pyrazolo[4,3-c]pyridine-7-carboxamide (90 mg, yield: 26.2%) as a white solid. LC / MS (ESI) m / z: 652 (M+1) + 。

[0454] Step 3: A solution of 6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-2-(4-methoxybenzyl)-4-((1,1,1-trifluoropropan-2-yl)oxy)-2H-pyrazolo[4,3-c]pyridine-7-carboxamide (90 mg, 0.14 mmol) in TFA (5 mL) was stirred at 65 °C for 2 h. Then the reaction mixture was cooled to room temperature and concentrated in vacuo 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 in vacuo to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 0% - 3%) to give the desired product 6-(4-((5-fluoro-2-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 1H NMR (400 MHz, DMSO) δ 13.65 (s, 1H), 8.90 (t, J = 6.1 Hz, 1H), 8.21 (s, 1H), 7.84 (s, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.62 (s, 1H), 7.53 (dd, J = 9.2, 3.3 Hz, 1H), 7.45–7.27 (m, 3H), 7.19 (dd, J = 9.1, 4.3 Hz, 1H), 6.27–6.12 (m, 1H), 4.56 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H), 1.55 (d, J = 6.5 Hz, 3H).

[0455] Table 5: The following compounds were prepared from A-2-4a and the appropriate intermediates according to Examples 74, 75 and 76

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464] Examples 112 and 113:

[0465] 6-(4-{[(5-Fluoro-2-methoxyphenyl)carbamoyl]methyl}phenyl)-4-[4-hydroxycyclohexyl]-1H-indazole-7-carboxamide (BNB-1100-01, 112) and 6-(4-{[(5-Fluoro-2-methoxyphenyl)carbamoyl]methyl}phenyl)-4-[4-hydroxycyclohexyl]-1H-indazole-7-carboxamide (BNB-1101-01, 113)

[0466]

[0467] Step 1: Under a N2 atmosphere, Pd(dppf)Cl2 (181 mg, 0.24 mmol) and K2CO3 (1.03 g, 7.45 mmol) were added 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 H2O (2 mL). 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% - 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)+.

[0468] Step 2:At -50 °C under a N2 atmosphere, trifluoromethanesulfonic acid 7-cyano-2-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)-2H-indazol-6-yl ester (500 mg, 2.27 mmol) and TEA (0.63 mL, 4.55 mmol) in DCM (5 mL) were added to Tf2O (0.56 mL, 3.41 mmol) in DCM (5 mL). 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]deca-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) +

[0469] Step 3 : To a solution of trifluoromethanesulfonic acid 7-cyano-2-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)-2H-indazol-6-yl ester (500 mg, 0.91 mmol) and 5-fluoro-2-methoxy-N-{[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}benzamide (420 mg, 1.09 mmol) in dioxane (5 mL) and water (1 mL) were 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 h. 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 the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 30% - 50%) to give the desired product N-(4-(7-cyano-2-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]deca-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) +

[0470] Step 4:To a solution of N-(4-(7-cyano-2-(4-methoxybenzyl)-4-(1,4-dioxaspiro[4.5]deca-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%). 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) + .

[0471] 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 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (15 mL) and washed with saturated NaHCO3 solution (5 mL x 2). The organic layer was dried over Na2SO4, 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) + .

[0472] Step 6: At 0 °C, NaBH4 (36 mg, 0.97 mmol) was added 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). 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 the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% - 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) +

[0473] Step 7 : At 20 °C, NaOH (2 mL, 4 mmol) and H2O2 (2 mL) were added 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). Then the mixture was stirred at 20 °C for 16 h. The mixture was diluted with H2O (2 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative-TLC (EtOAc in PE = 100%). The pure product obtained was separated by SFC analysis on Waters UPC2 (column: ChiralCel OJ, 250×4.6 mm I.D., 5um; mobile phase: A was CO2, B was methanol (0.05% DEA); gradient: 8 min @ 40% B in A, flow rate: 2.0 mL / min, back pressure: 100 bar, column temperature: 35 °C)

[0474] Example 112 was obtained from the first eluate (peak 1): 25 mg (yield: 14.9%) LC / MS (ESI) m / z: 517 (M+H)+, 1HNMR(400MHz, DMSO) δ 13.08 (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, 4.2 Hz, 1H), 6.91 (s, 1H), 4.55 (d, J = 6.1 Hz, 2H), 4.43 (d, J = 3.5 Hz, 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) + 。

[0475] Example 113 Obtained from the second eluate (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 = 4.3 Hz, 1H), 4.61 (d, J = 6.1 Hz, 2H), 3.97 (s, 3H), 3.61 - 3.59 (m, 1H), 3.05 - 2.96 (m, 1H), 2.02 - 1.93 (m, 4H), 1.80 - 1.71 (m, 2H), 1.50 - 1.41 (m, 2H). LC / MS(ESI) m / z: 517 (M + H) + 。

[0476] Example 114:

[0477] 6-(4-((5-Fluoro-2-methoxybenzamido)methyl)phenyl)-4-(3-hydroxycyclopentyl)-1H-indazole-7-carboxamide (BNB-1080-01)

[0478]

[0479] 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) was added Pd(dppf)Cl2 (101 mg, 0.12 mmol) and Na2CO3 (178 mg, 1.68 mmol). The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 1% - 5%) to afford 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] + .

[0480] 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) at -30 °C was added DIPEA (0.22 mL, 1.26 mmol) and Tf2O (231 mg, 0.82 mmol). The reaction mixture was stirred at -30 °C for 1 hour. The resulting mixture was diluted with water (5 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous 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] +

[0481] 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 dioxene (4 mL) and H2O (1 mL) was 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 the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 1% - 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] +

[0482] Step 4 : To a solution of N-(4-(4-(4-((tert-butyldiphenylsilyl)oxy)cyclopent-1-en-1-yl)-7-cyano-2-(4-methoxybenzyl)-2H-indazol-6-yl)benzyl)-5-fluoro-2-methoxybenzamide (260 mg, 0.31 mmol) in MeOH (5 mL) was added Pd / C (26 mg, wt10%), and the mixture was stirred at room temperature under H2 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] +

[0483] Step 5: At 0 °C, TFA (2 mL) was added dropwise 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). The 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 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] +

[0484] Step 6 : At 0 °C, H2O2 (1 mL) and NaOH solution (0.04 mL, 0.08 mmol) were added dropwise 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). 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 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-(3-hydroxycyclopentyl)-1H-indazole-7-carboxamide (35 mg, yield: 33.3%), as a white solid. LC / MS (ESI) m / z: 503 [M+1] +11H NMR (400 MHz, DMSO) δ 13.09 (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, 4.3 Hz, 1H), 6.99 (s, 1H), 4.72 (d, J = 3.9 Hz, 1H), 4.55 (d, J = 6.1 Hz, 2H), 4.30 (d, J = 4.2 Hz, 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).

[0485] Example 115: 4-(2-Hydroxycyclopentyl)-6-(4-((2-methoxybenzamido)methyl)phenyl)-1H-indazole-7-carboxamide (BNB-1058-01)

[0486]

[0487] 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). The reaction mixture was stirred at 110 °C under a N2 atmosphere for 2 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 1%–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] + 。

[0488] 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 h. The reaction mixture was diluted with H2O (10 mL) and 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 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] +

[0489] Step 3 : At -30 °C, DIPEA (0.27 mL, 1.62 mmol) and then Tf2O (0.16 mL, 0.97 mmol) were added dropwise 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). The reaction mixture was stirred at -30 °C for 1 h. 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] +

[0490] Step 4: To a solution of 7-cyano-4-(cyclopent-1-en-1-yl)-1-[(4-methoxyphenyl)methyl]-1H-indazole-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) was added Pd(dppf)Cl2 (45 mg, 0.05 mmol) and Na2CO3 (115 mg, 1.1 mmol). The reaction mixture was stirred at 110 °C under N2 atmosphere for 2 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 1% - 20%) to afford the desired product N-(4-(7-cyano-4-(cyclopent-1-en-1-yl)-1-(4-methoxybenzyl)-1H-indazol-6-yl)benzyl)-2-methoxybenzamide as a grey solid. LC / MS (ESI) m / z: 569 [M+1] +

[0491] 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) at 0 °C was added dropwise BH3·Me2S (0.09 mL, 1 mmol / mL). The reaction mixture was stirred at this temperature for 1 h, then EtOH (1 mL) was added dropwise at 0 °C, and then H2O2 (1 mL) and NaOH (0.44 mL, 2 mmol / mL) were added to the solution successively. The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with H2O (10 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 the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% - 3%) to afford 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] +

[0492] Step 6:At 0 °C, TFA (2 mL) was added dropwise 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). 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] +

[0493] Step 7 : At 0 °C, H2O2 (1 mL) and 2N NaOH (0.04 mL, 0.08 mmol) were added dropwise 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). The reaction 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 the crude product, which was purified by preparative-TLC (MeOH in DCM = 5%) to give the desired product 4-(2-hydroxycyclopentyl)-6-(4-{[(2-methoxyphenyl)carbamoyl]methyl}phenyl)-1H-indazole-7-carboxamide (6 mg, yield: 30%), as a white solid. LC / MS (ESI) m / z: 485 [M+1] + ; 11H NMR (400 MHz, DMSO) δ 13.06 (s, 1H), 8.76 (t, J = 6.1 Hz, 1H), 8.21 (s, 1H), 7.84–7.72 (m, 1H), 7.52–7.36 (m, 7H), 7.17 (d, J = 8.4 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.92 (s, 1H), 4.82 (d, J = 5.4 Hz, 1H), 4.56 (d, J = 6.0 Hz, 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).

[0494] Table 6: The following compounds were prepared from the appropriate intermediate B-1-3a or B-1-3d and the appropriate boric acid / ester using a similar method (with variations) according to Examples 112, 113, 114 & 115 (B-1, Route 1):

[0495]

[0496]

[0497]

[0498]

[0499] Example 129 4-Cyclopentyl-6-(4-phenoxyphenyl)-1H-indazole-7-carboxamide (BNB-1042-01):

[0500]

[0501] Step 1: At 25 °C, K2CO3 (800 mg, 5.7 mmol) and Pd(dppf)Cl2 (50 mg, 0.7 mmol) were slowly added 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 H2O (10 mL). The reaction mixture was heated to 100 °C under a N2 atmosphere for 24 h. 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 the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% - 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) + .

[0502] Step 2: Pd / C (150 mg, 10%) was added to a stirred solution of methyl 4-(cyclopent-1-en-1-yl)-7-methoxy-1H-indazole-6-carboxylate (1.4 g, 5.1 mmol) in MeOH (15 mL). The resulting mixture was stirred under a H2 atmosphere for 24 h, filtered, and concentrated to give the crude product methyl 4-cyclopentyl-7-methoxy-1H-indazole-6-carboxylate (1.2 g, yield: 85.1%) as a white solid, which was used directly without further purification. LC / MS (ESI) m / z: 275 (M+H) + . 1H NMR (400 MHz, CDCl3) δ 8.18 (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).

[0503] Step 3:At -50 °C, BBr3 (5 mL, 1 M in Tol.) was added to a stirred solution of methyl 4-cyclopentyl-7-methoxy-1H-indazole-6-carboxylate (800 mg, 2.9 mmol) in DCM (20 mL). The mixture was stirred at -50 °C for 1 h. The reaction mixture was quenched with MeOH and diluted with water (20 mL), then extracted with EtOAc (15 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 (EtOAc in PE = 2% - 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 (400 MHz, CDCl3) δ 8.18 (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).

[0504] Step 4: At 0 °C, TEA (100 mg, 0.9 mmol) was added to a stirred solution of methyl 4-cyclopentyl-7-hydroxy-1H-indazole-6-carboxylate (500 mg, 0.3 mmol) and Tf2O (0.176 mL, 1.0 mmol) in DCM (5 mL), and the mixture was stirred for 10 min. 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 Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% - 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 (400 MHz, CDCl3) δ 10.54 (d, J = 50.9 Hz, 1H), 8.24 (d, J = 1.5 Hz, 1H), 7.26 (t, J = 1.8 Hz, 1H), 3.99 (s, 3H), 3.47 (dd, J = 16.3, 7.8 Hz, 1H), 2.21 (d, J = 3.9 Hz, 2H), 1.93 - 1.80 (m, 6H).

[0505] Step 5:At 25 °C, Pd(dppf)Cl2 (100 mg, 0.1 mmol) was slowly added 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). The reaction mixture was stirred in a microwave reactor at 130 °C under a N2 atmosphere for 2 h. 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 the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% - 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).

[0506] Step 6: To a solution of methyl 7-cyano-4-cyclopentyl-1H-indazole-6-carboxylate (230 mg, 0.8 mmol) in MeOH (10 mL) / H2O (2 mL) was added LiOH (160 mg, 4 mmol). The resulting mixture was stirred at room temperature for 2 h. Then the pH of the mixture was adjusted to 5 with 1N HCl and extracted with EA (10 mL x 3). The combined organic layers were dried over Na2SO4, concentrated, and purified by preparative-HPLC to give the desired product 7-cyano-4-cyclopentyl-1H-indazole-6-carboxylic acid (170 mg, 74.0% yield) as a pale yellow solid. LC / MS (ESI) m / z: 256 (M+H) + .

[0507] Step 7:At 25 °C, TEA (105 mg, 1 mmol) was slowly added 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). The reaction mixture was stirred at 25 °C under a N2 atmosphere for 2 h. The mixture was added to H2O (2 mL), and warmed to 65 °C for an additional 3 h. 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 the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% - 25%) to afford 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 1H NMR (400 MHz, CDCl3) 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).

[0508] Step 8: At 0 °C, a solution of NaNO2 (120 mg, 1.7 mmol) in H2O (2.5 mL) was slowly added 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). The reaction mixture was stirred at 0 °C for 5 min. The reaction mixture was diluted with water (10 mL) and extracted with DCM (15 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% - 25%) to afford 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).

[0509] Step 9 : Synthesis of 4-Cyclopentyl-6-(4-phenoxyphenyl)-1H-indazole-7-carbonitrile

[0510] At 25 °C, NaHCO3 (20 mg, 0.2 mmol) and Pd(dppf)Cl2 (10 mg, 0.1 mmol) were slowly added 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 H2O (1 mL). The reaction mixture was heated to 60 °C under a nitrogen atmosphere for 18 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% - 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 (400 MHz, CDCl3) δ 10.78 (s, 1H), 8.28 (s, 1H), 7.64–7.57 (m, 2H), 7.44–7.35 (m, 2H), 7.20–7.15 (m, 2H), 7.15–7.08 (m, 4H), 3.57–3.46 (m, 1H), 2.34–2.14 (m, 2H), 1.87 (dddd, J = 14.4, 9.1, 6.8, 4.7 Hz, 6H).

[0511] Step 10 : At room temperature, H2O2 (2 mL) was slowly added 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), and the reaction mixture was stirred at 65 °C under a N2 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 Na2SO4, 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 (400 MHz, CD3OD) δ 8.20 (s, 1H), 7.52–7.47 (m, 2H), 7.42–7.34 (m, 2H), 7.14 (t, J = 7.4 Hz, 1H), 7.07–7.02 (m, 5H), 3.53 (dd, J = 16.0, 8.1 Hz, 1H), 2.25–2.18 (m, 2H), 1.94–1.79 (m, 6H).

[0512] 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) (with variations) used for Example 129:

[0513]

[0514]

[0515] Example 133: 6-(4-((5-Fluoro-2-methoxybenzamido)methyl)phenyl)-4-(pyrrolidin-1-yl)-1H-indazole-7-carboxamide (BNB-1063-01)

[0516]

[0517] 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) was added Pd2(dba)3 (114 mg, 0.14 mmol), Xant-phos (72 mg, 0.14 mmol), and Cs2CO3 (405 mg, 1.22 mmol). The reaction mixture was stirred at 110 °C under a nitrogen atmosphere for 10 hours. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% - 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] +

[0518] 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 h. The reaction mixture was extracted with EtOAc (20 mL x 2), and the combined organic phases were 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] +

[0519] Step 3 : At -30 °C, DIPEA (51 mg, 0.40 mmol) was added dropwise 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), followed by Tf2O (112 mg, 0.402 mmol), and the reaction mixture was stirred at -30 °C for 1 h. 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] +

[0520] Step 4: To a solution of 7-cyano-1-[(4-methoxyphenyl)methyl]-4-(pyrrolidin-1-yl)-1H-indazole-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) was added Pd(dppf)Cl2·CH2Cl2 (51 mg, 0.06 mmol) and Na2CO3 (66 mg, 0.62 mmol). The reaction mixture was stirred at 100 °C under a 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 = 5% - 20%) to afford the desired product N-[(4-{7-cyano-1-[(4-methoxyphenyl)methyl]-4-(pyrrolidin-1-yl)-1H-indazole-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] +

[0521] Step 5 : To a solution of methyl 6-chloro-4-{1,4-dioxaspiro[4.5]dec-7-en-8-yl}-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[4,3-c]pyridine-7-carboxylate (65 mg, 0.14 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at 40 °C for 5 h. The reaction mixture was concentrated in vacuo to give a crude product N-({4-[7-cyano-4-(pyrrolidin-1-yl)-1H-indazole-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] + 。

[0522] 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 h. The reaction mixture was poured into ice water and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by preparative-TLC (MeOH in DCM = 5%) to give the desired product 6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]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 (400 MHz, CD3OD) δ 8.26 (s, 1H), 7.63 (dd, J = 9.3, 3.2 Hz, 1H), 7.52–7.43 (m, 5H), 7.30–7.23 (m, 1H), 7.17 (dd, J = 9.0, 4.1 Hz, 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).

[0523] Example 134: (R)-6-(4-((5-Fluoro-2-methoxybenzamido)methyl)phenyl)-4-(3-hydroxypyrrolidin-1-yl)-1H-indazole-7-carboxamide (BNB-1072-01)

[0524]

[0525] Step 1: Under N2, Cs2CO3 (486 mg, 1.49 mmol), Xant-phos (86 mg, 0.15 mmol), and Pd2(dba)3 (68 mg, 0.075 mmol) were added to a solution of 4-bromo-1-(4-methoxybenzyl)-6-(methoxymethoxy)-1H-indazole-7-carbonitrile (300 mg, 0.75 mmol) and (3R)-pyrrolidin-3-ol (78 mg, 0.90 mmol) in dioxane (5 mL). The resulting mixture was stirred at 110 °C overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0 - 100%) to afford 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) + 。

[0526] Step 2 : 2N HCl (2 mL) was added 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) under N2. The mixture was stirred at 65 °C for 3 h. 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) + 。

[0527] Step 3 : NEt3 (77.6 mg, 0.77 mmol) and trifluoromethanesulfonic anhydride (108 mg, 0.38 mmol) were added to a solution of (R)-6-hydroxy-4-(3-hydroxypyrrolidin-1-yl)-1-(4-methoxybenzyl)-1H-indazole-7-carbonitrile (70 mg, 0.19 mmol) in DCM (5 mL) at -50 °C. The mixture was stirred for 10 min. The solvent was concentrated under reduced pressure to give the crude product (R)-7-cyano-4-(3-hydroxypyrrolidin-1-yl)-1-(4-methoxybenzyl)-1H-indazol-6-yl trifluoromethanesulfonate (60 mg, yield: 62.9%) as a yellow solid, which was used directly without further purification. LC / MS (ESI) m / z: 497 (M+H) + 。

[0528] Step 4 : Under N2, 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 H2O (1 mL) was added K2CO3 (33 mg, 0.24 mmol) and Pd(dppf)Cl2 (9 mg, 0.012 mmol). 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 the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% - 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) + 。

[0529] Step 5 : To a stirred suspension of (R)-N-(4-(7-cyano-4-(3-hydroxypyrrolidin-1-yl)-1-(4-methoxybenzyl)-1H-indazol-6-yl)benzyl)-5-fluoro-2-methoxybenzamide (40 mg, 0.066 mmol) in TFA (3 mL). The mixture was stirred at 65 °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), and 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) + 。

[0530] Step 6:(R)-N-(4-(7-Cyano-4-(3-hydroxypyrrolidin-1-yl)-1H-indazol-6-yl)benzyl)-5-fluoro-2-methoxybenzamide (30 mg, 0.062 mmol) was added to a stirred suspension 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 (400 MHz, DMSO) δ 12.60 (s, 1H), 8.86 (s, 1H), 8.21 (s, 1H), 7.53 (d, J = 6.6 Hz, 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 = 5.3 Hz, 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).

[0531] Table 8: The following compounds were prepared from B-1-3a and the appropriate boronic acid / ester intermediate according to the method (B-2, route 1) (with variations) used for the preparation of Example 133 & Example 134

[0532]

[0533]

[0534] 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)

[0535]

[0536] 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). The reaction mixture was stirred at 110 °C under a nitrogen atmosphere for 10 h. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% - 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] +

[0537] 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). The reaction mixture was stirred at 55 °C for 2 h. The reaction mixture was extracted with EtOAc (20 mL x 2). The combined organic phases were 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] +

[0538] Step 3: At -20 °C, NCS (74 mg, 0.55 mmol) was added to a solution of (R)-6-hydroxy-1-(4-methoxybenzyl)-4-(2-methylpyrrolidin-1-yl)-1H-indazole-7-carbonitrile (200 mg, 0.55 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 8 hours. The mixture was diluted with H2O (10 mL) and 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 the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% - 5%) to give the desired product (R)-5-chloro-6-hydroxy-2-(4-methoxybenzyl)-4-(2-methylpyrrolidin-1-yl)-2H-indazole-7-carbonitrile (120 mg, yield: 54%) as a white solid. LC / MS (ESI) m / z: 397 [M+1] +

[0539] Step 4 : At -30 °C, DIPEA (78 mg, 0.60 mmol) was added dropwise 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), followed by Tf2O (0.06 mL, 0.36 mmol). The mixture was stirred at -30 °C for 1 hour. The reaction mixture was diluted with H2O (10 mL) and 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)-5-chloro-7-cyano-2-(4-methoxybenzyl)-4-(2-methylpyrrolidin-1-yl)-2H-indazol-6-yl trifluoromethanesulfonate (110 mg, yield: 68.8%) as a brown solid, which could be used directly in the next step without further purification. LC / MS (ESI) m / z: 530 (M+H) +

[0540] Step 5: To a solution of (R)-5-chloro-7-cyano-2-(4-methoxybenzyl)-4-(2-methylpyrrolidin-1-yl)-2H-indazol-6-yl trifluoromethanesulfonate (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 Na2CO3 (44 mg, 0.42 mmol) in dioxane (4 mL) and H2O (1 mL) was added Pd(dppf)Cl2 (15 mg, 0.02 mmol). The reaction mixture was concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (EtOAc in PE = 5% - 30%) to afford 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] +

[0541] 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). The reaction mixture was stirred at 40 °C for 5 h. 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 could be used directly in the next step without further purification. LC / MS (ESI) m / z: 519 [M+1] +

[0542] Step 7(R)-N-(4-(5-chloro-7-cyano-4-(2-methylpyrrolidin-1-yl)-1H-indazol-6-yl)benzyl)-5-fluoro-2-methoxybenzamide (65 mg, 0.13 mmol) in H2SO4 (1 mL) was stirred at 55 °C for 3 h. The reaction mixture was poured into ice water and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by preparative-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: 1 H NMR (400 MHz, DMSO) δ 13.16 (s, 1H), 8.88 (t, J = 6.2 Hz, 1H), 8.30 (s, 1H), 7.55 (dd, J = 9.2, 3.3 Hz, 1H), 7.39–7.31 (m, 3H), 7.23 (ddd, J = 13.5, 11.7, 5.6 Hz, 5H), 4.58 (d, J = 6.1 Hz, 2H), 4.37 (dd, J = 13.7, 6.3 Hz, 1H), 3.99 (dd, J = 15.6, 8.5 Hz, 1H), 3.91 (s, 3H), 3.19 (t, J = 6.7 Hz, 1H), 2.24 (s, 1H), 1.90 (dd, J = 31.7, 21.6 Hz, 2H), 1.61–1.48 (m, 1H), 1.01 (d, J = 6.0 Hz, 3H); LC / MS (ESI) m / z: 537 [M+1] + .

[0543] Example 147 (R)-6-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-4-(2-methylpyrrolidin-1-yl)-1H-indazole-7-carboxamide (BNB-1109-01)

[0544]

[0545] Step 1: Under N2, Cs2CO3 (727 mg, 2.23 mmol), SPhos (45 mg, 0.11 mmol), and Pd2(dba)3 (102 mg, 0.11 mmol) were added to a solution of 4-bromo-6-hydroxy-2-(4-methoxybenzyl)-2H-indazole-7-carbonitrile (400 mg, 1.11 mmol) and (2R)-2-methylpyrrolidine (114 mg, 1.34 mmol) in dioxane (5 mL). 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 the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 50% to 70%) to afford 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) + 。

[0546] Step 2 : At -30 °C, DIPEA (0.4 mL, 2.41 mmol) and trifluoromethanesulfonic anhydride (0.24 mL, 1.40 mmol) were added 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). The mixture was stirred at this temperature for 30 min. The solvent was concentrated under reduced pressure to give the crude product (R)-7-cyano-2-(4-methoxybenzyl)-4-(2-methylpyrrolidin-1-yl)-2H-indazol-6-yl trifluoromethanesulfonate (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) + 。

[0547] Step 3: Under N2, Cs2CO3 (785 mg, 2.41 mmol) and Pd(dppf)Cl2 (88 mg, 0.12 mmol) were added 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). The reaction mixture was heated to 90 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 mL), washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the 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) + .

[0548] 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 hours. Then the reaction mixture was cooled to room temperature and concentrated in vacuo 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 in vacuo 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) + .

[0549] 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 (400 MHz, DMSO) δ 12.59 (s, 1H), 8.86 (t, J = 6.1 Hz, 1H), 8.17 (s, 1H), 7.53 (dd, J = 9.2, 3.3 Hz, 1H), 7.45–7.30 (m, 5H), 7.19 (dd, J = 9.2, 4.3 Hz, 1H), 7.07 (s, 1H), 6.13 (s, 1H), 5.85 (s, 1H), 4.56 (d, J = 6.1 Hz, 2H), 4.28 (s, 1H), 3.91 (s, 3H), 3.76 (s, 1H), 3.54 (d, J = 8.7 Hz, 1H), 2.06 (dd, J = 28.8, 21.4 Hz, 3H), 1.72 (s, 1H), 1.19 (d, J = 6.1 Hz, 3H); LC / MS (ESI) m / z: 502 (M+H) + 。

[0550] Example 148: 6-(4-((2-Methoxybenzamido)methyl)phenyl)-1H-indazole-7-carboxamide (BNB-1059-01)

[0551]

[0552] 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 in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% - 50%) to give the desired product 2-fluoro-6-(methoxymethoxy)benzonitrile (2.5 g, yield: 94.6%), as a white solid.

[0553] Step 2 : At -78 °C under N2, LDA (10.4 mL, 20.7 mmol) was added to a solution of 2-fluoro-6-(methoxymethoxy)benzonitrile (2.5 g, 13.8 mmol) in THF (20 mL). The reaction mixture was stirred at the same temperature for 1 h, then DMF (1.2 g, 16.7 mmol) was added, and the resulting mixture was kept at -78 °C for another 1 h. 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% - 30%) to give the desired product 2-fluoro-3-formyl-6-(methoxymethoxy)benzonitrile (1.2 g, yield: 40.9%) as a brown oil. 1 1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 8.12–7.98 (m, 1H), 7.17 (d, J = 9.0 Hz, 1H), 5.40 (s, 2H), 3.54 (s, 3H).

[0554] Step 3 : Hydrazine (721 mg, 19.1 mmol) was added to a solution of 2-fluoro-3-formyl-6-(methoxymethoxy)benzonitrile (400 mg, 1.9 mmol) in EtOH (10 mL). The reaction mixture was stirred at 85 °C for 12 h. 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] + 。

[0555] 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 Cs2CO3 (808.0 mg, 2.5 mmol), and the reaction mixture was stirred at 60 °C for 1.5 h. The reaction mixture was diluted with EtOAc (30 mL). The mixture was washed with saturated LiCl solution, water, and brine. The organic phase was dried, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% - 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] + 。

[0556] 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 h. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 5% - 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] + 。

[0557] 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 h. The reaction mixture was diluted with DCM (20 mL), the organic phase was washed with water and brine, and the collected organic layer was dried, filtered, and concentrated to give the crude product 7-cyano-1-[(4-methoxyphenyl)methyl]-1H-indazol-6-yl trifluoromethanesulfonate (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] + 。

[0558] Step 7To 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) was added K2CO3 (112 mg, 0.8 mmol) and Pd(dppf)Cl2 (29 mg, 0.04 mmol). The reaction mixture was stirred at 100 °C under N2 atmosphere for 2 h. The reaction was cooled and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% - 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] + .

[0559] 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 h. 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] + .

[0560] 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 H2O2 (1 mL), and the reaction mixture was stirred at 60 °C for 2 h. 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 the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 10% - 50%) to give the desired product 6-(4-{[(2-methoxyphenyl)carbamoyl]methyl}phenyl)-1H-indazole-7-carboxamide (17 mg, yield: 34.2%), as a white solid. LCMS: ESI m / z 401 [M+H] + 1H NMR (400 MHz, DMSO) δ 13.16 (s, 1H), 8.77 (t, J = 6.1 Hz, 1H), 8.13 (s, 1H), 7.89–7.74 (m, 2H), 7.65 (s, 1H), 7.50 (dd, J = 13.1, 4.9 Hz, 4H), 7.39 (d, J = 8.1 Hz, 2H), 7.20–7.01 (m, 3H), 4.56 (d, J = 6.1 Hz, 2H), 3.92 (s, 3H)

[0561] Example 149:

[0562] 6-(4-{[(5-Fluoro-2-methoxyphenyl)carbamoyl]methyl}phenyl)-4-(2-oxopyrrolidin-1-yl)-1H-pyrazolo[4,3-c]pyridine-7-carboxamide (BNB-1088-01)

[0563]

[0564] Step 1: At 25 °C, TEA (40 mg, 0.40 mmol) was added 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). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was poured into water (5 mL), and 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 the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% - 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)butyrate (90 mg, yield: 83%), as an off-white oil. LC / MS (ESI) m / z: 474 (M+H) + 。

[0565] Step 2 : At 25 °C, Pd(dppf)Cl2 (30 mg, 0.041 mmol) and K2CO3 (100 mg, 0.724 mmol) were added to a stirred solution of tert-butyl 4-({7-carbamoyl-6-chloro-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[4,3-c]pyridin-4-yl}amino)butyrate (90 mg, 0.19 mmol) and 5-fluoro-2-methoxy-N-{[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}benzamide (100 mg, 0.26 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL). The reaction mixture was stirred at 110 °C under a N2 atmosphere for 18 h. The reaction mixture was diluted with water (10 mL), and the mixture was extracted with EtOAc (15 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 the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% - 50%) to give the desired product tert-butyl 4-{[7-carbamoyl-6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]methyl}phenyl)-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}butyrate (90 mg, yield: 68%), as an off-white oil. LC / MS (ESI) m / z: 697 (M+H) + 。

[0566] Step 3: To a stirred solution of tert-butyl 4-{[7-carbamoyl-6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]methyl}phenyl)-1-[(4-methoxyphenyl)methyl]-1H-pyrazolo[4,3-c]pyridin-4-yl]amino}butanoate (90 mg, 0.13 mmol) in DCM (5 mL) at 25 °C was added TFA (3 mL), 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), and the combined organic phases were washed with saturated NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% - 5%) to afford the desired product 4-{[7-carbamoyl-6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]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) + .

[0567] Step 4 : To a stirred solution of 4-{[7-carbamoyl-6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]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) at 25 °C was added DIPEA (25 mg, 0.19 mmol), and the reaction mixture was heated to 50 °C for 18 h. The reaction mixture was poured into water (10 mL), and the mixture was extracted with EtOAc (20 mL x3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (MeOH in DCM = 1% - 5%) to afford the desired product 6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]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 (400 MHz, DMSO) δ 8.86 (t, J = 5.6 Hz, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.64 (s, 1H), 7.52 (dd, J = 9.3, 3.3 Hz, 1H), 7.43–7.30 (m, 3H), 7.19 (dd, J = 9.2, 4.3 Hz, 1H), 4.55 (d, J = 6.3 Hz, 2H), 4.12 (t, J = 7.1 Hz, 2H), 3.90 (s, 3H), 2.67 (dd, J = 4.9, 3.0 Hz, 2H), 2.19–2.09 (m, 2H)。

[0568] Example 150: 4-Cyclopentyl-6-(4-((2-methoxybenzamido)methyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide (BNB-1050-01)

[0569]

[0570] Step 1 : Under N2 and with stirring, 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 Boc2O (100.3 g, 460.1 mmol) in DCM (300 mL). The mixture was stirred for 3 h until the starting materials were completely consumed. The reaction mixture was concentrated in vacuo to remove the excess DCM. The residue was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layer was dried over MgSO4, filtered, and concentrated to give the 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)+.

[0571] Step 2: At -78 °C under N2, LDA (227 mL, 454.2 mmol) was added 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). 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 the 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, 96% yield) as a white solid. LC / MS (ESI) m / z: 364 (M+H) + . 1H NMR (400 MHz, DMSO) δ 9.84 (s, 1H), 7.63 (s, 1H), 1.60 (s, 9H), 1.52 (s, 9H).

[0572] Step 3: Under N2, K2CO3 (1.52 g, 11.01 mmol) and Pd(dppf)Cl2 (0.2 g, 0.28 mmol) were added 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). The resulting mixture was stirred at 60 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0 - 2%) to give the desired product tert-butyl 4-(tert-butoxycarbonylamino)-2-chloro-6-cyclopentenylnicotinate (1.1 g, 51% yield) as a white solid. LC / MS (ESI) m / z: 395 (M+H) + . 1 1H NMR (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).

[0573] Step 4:To a solution of tert-butyl 4-(tert-butoxycarbonylamino)-2-chloro-6-cyclopentenylnicotinate (1.1 g, 2.8 mmol) in EtOAc (20 mL) was added Pt / C (50 mg). The mixture was stirred at room temperature under H2 atmosphere for 4 h. The resulting reaction mixture was filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 1% - 4%) to give the desired product tert-butyl 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 (400 MHz, DMSO) δ 9.40 (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).

[0574] Step 5 : Under N2, 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). The mixture was stirred for 3 h. 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) +

[0575] Step 6 : Under N2 atmosphere, to a solution of 4-amino-2-chloro-6-cyclopentylpyridine-3-carboxylic acid (280 mg, 1.1 mmol) in DCM (5 mL) was added TMSCHN2 (501 mg, 4.4 mmol). The mixture was stirred for 1 h. The reaction mixture was quenched with AcOH (1 mL) in an ice bath. The mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 2% - 10%) to give the desired product methyl 4-amino-2-chloro-6-cyclopentylpyridine-3-carboxylate (190 mg, yield: 68%) as a white solid. LC / MS (ESI) m / z: 255 (M+H) + . 1H NMR (400 MHz, CDCl3) δ 6.35 (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).

[0576] Step 7 : At 0 °C, NBS (145 mg, 0.8 mmol) was added to a solution of methyl 4-amino-2-chloro-6-cyclopentylpyridine-3-carboxylate (190 mg, 0.74 mmol) in MeCN (5 mL). The resulting mixture was stirred at 0 °C for 2 h. The solvent was removed under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 0 - 5%) to give the desired product, methyl 4-amino-5-bromo-2-chloro-6-cyclopentylpyridine-3-carboxylate (230 mg, yield: 93.3%), as a white solid. LC / MS (ESI) m / z: 333 / 335 (M+H) +

[0577] Step 8 : Under N2, K2CO3 (249 mg, 1.8 mmol) and Pd(PPh3)4 (35 mg, 0.030 mmol) were added 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 H2O (2 mL). The reaction mixture was heated to 80 °C for 10 h. 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 obtain the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% - 20%) to give the desired product, methyl 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) +

[0578] Step 9: Under N2, 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 H2O (2 mL) were added K2CO3 (161 mg, 1.2 mmol) and Pd(PPh3)4 (45 mg, 0.04 mmol). The reaction mixture was heated to 60 °C for 10 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The mixture was washed with water and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% - 20%) to give the desired product methyl 4-amino-6-cyclopentyl-2-(4-((2-methoxybenzamido)methyl)phenyl)-5-(2-methoxyvinyl)nicotinate (140 mg, yield: 67.8%), as a white solid. LC / MS (ESI) m / z: 516 (M+H) +

[0579] 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. Then the reaction mixture was concentrated, diluted with EtOAc (20 mL), and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 30:1) to give methyl 4-cyclopentyl-6-(4-((2-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) +

[0580] 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 tube at 100 °C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated to give the crude product, which was purified by preparative-TLC (DCM:MeOH = 15:1) to give the desired product

[0581] 4-Cyclopentyl-6-(4-((2-methoxybenzamido)methyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide (5.5 mg, yield: 5.69%), a white solid. LC / MS (ESI) m / z: 469 (M+H) + 1H NMR (400 MHz, MeOD) δ 7.91 (dd, J = 7.8, 1.8 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.55–7.44 (m, 4H), 7.41 (d, J = 3.3 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.77 (d, J = 3.2 Hz, 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)

[0582] Example 151: 4-Cyclopentyl-6-(4-((2-methoxybenzamido)methyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide (BNB-1065-01)

[0583]

[0584] Step 1 : Under N2, to a solution of methyl 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 H2O (3 mL) was added K2CO3 (417 mg, 3.02 mmol) and Pd(PPh3)4 (173 mg, 0.15 mmol). The reaction mixture was heated to 80 °C for 10 h. 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 the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10%–20%) to give the desired product methyl 4-amino-5-bromo-6-cyclopentyl-2-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)nicotinate (500 mg, yield: 59.9%), a white solid. LC / MS (ESI) m / z: 557 / 559 (M+H) +

[0585] Step 2 : Under N2, 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 H2O (2 mL) were added K2CO3 (248 mg, 1.80 mmol) and Pd(PPh3)4 (104 mg, 0.09 mmol). The reaction mixture was heated to 60 °C for 10 h. 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 the crude product, which was purified by silica gel column chromatography (EtOAc in PE = 10% - 20%) to afford the desired product, methyl 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) +

[0586] Step 3 : A solution of methyl 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. Then the reaction mixture was concentrated, diluted with EtOAc (20 mL), and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 30:1) to afford 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) +

[0587] Step 4:To a stirred solution of methyl 4-cyclopentyl-6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]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 a N2 atmosphere for 18 h. The mixture was extracted with EtOAc (10 mL x 3), and the combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product which was used without purification to afford 4-cyclopentyl-6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]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) + 。

[0588] Step 5 : To a stirred solution of 4-cyclopentyl-6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]methyl}phenyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (200 mg, 0.41 mmol) in DMF (5 mL) at 25 °C was 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 an NH3 atmosphere for 1 h. The reaction mixture was diluted with water (20 mL), and 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 the crude product which was purified by silica gel column chromatography (EtOAc in PE = 50:1 to 1:1) to afford 4-cyclopentyl-6-(4-{[(5-fluoro-2-methoxyphenyl)carbamoyl]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) + 。

[0589] 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 the mixture was stirred overnight under N2. Then Zn (121 mg, 1.85 mmol) and AcOH (3 ml) were added, and the mixture was 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. Elution with 50% EtOAc in PE through silica gel column chromatography gave 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 (400 MHz, DMSO) δ 10.70 (s, 1H), 8.84 (t, J = 6.1 Hz, 1H), 7.75 (s, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.53 (dd, J = 9.2, 3.3 Hz, 1H), 7.41 (s, 1H), 7.34 (dd, J = 13.5, 5.7 Hz, 3H), 7.19 (dd, J = 9.1, 4.3 Hz, 1H), 4.54 (d, J = 6.1 Hz, 2H), 3.90 (s, 3H), 3.61 (s, 2H), 3.19–3.08 (m, 1H), 1.93 (d, J = 8.0 Hz, 2H), 1.87–1.71 (m, 4H), 1.63 (dd, J = 7.1, 4.6 Hz, 2H).

[0590] Biological detection

[0591] 1. Biochemical activity of BTK kinase

[0592] The effectiveness of the compounds prepared in the above examples as BTK inhibitors was determined using the ADP-Glo method. Enzyme assays using recombinant forms of 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 10-fold in DMSO in a 1:3 ratio in an IC50 mode, in duplicate. In a solution containing 50 mM HEPES, 1 mM EGTA, 10 mM Mg 2+The BTK kinase activity was tested in an assay buffer containing 0.01% BRIJ35 and 2 mM DTT (pH = 7.4). 0.1 μL of the diluted compound was mixed with 5 μL of the enzyme working solution (Signalchem, Cat#B10-10H-10) by Echo (Labcyte, Cat#550), and then mixed with 5 μL of the 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 the 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 the RLU. The IC50 value was calculated by fitting the % inhibition value of the compound concentration and the logarithm (dose response - variable slope) using GraphPad Prism 6.0 by non-linear regression.

[0593] 2. MEK1 Kinase Activity Assay

[0594] The enzyme assay using the recombinant form of wild-type MEK1 (Signalchem, Cat#M02-10G) was performed using the ADP-Glo method as follows. The compounds prepared in the above examples were serially diluted 10-fold in DMSO in a 1:3 IC50 mode in duplicate. In a solution containing 50 mM HEPES, 1 mM EGTA, 10 mM Mg 2+The MEK1 kinase activity was tested in an assay buffer containing 0.01% BRIJ35 and 2 mM DTT (pH = 7.4). 0.1 μL of the diluted compound was mixed with 5 μL of the enzyme working solution (Signalchem, Cat#M02-10G) by Echo (Labcyte, Cat#550), and then mixed with 5 μL of the 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 the 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 the RLU. The IC50 value was calculated by fitting the % inhibition value of the compound concentration and the logarithm (dose response - variable slope) with GraphPad Prism 6.0.

[0595] 3. EGFR Kinase Activity Assay

[0596] The enzyme assay using the recombinant form of wild-type EGFR (Signalchem, Cat#E10-11G-10) was performed as follows using the homogeneous time-resolved fluorescence (HTRF) method. The compounds prepared in the above examples were serially diluted 10-fold in DMSO in a 1:3 ratio in an IC50 mode, in duplicate. The EGFR kinase activity was tested in 1x kinase buffer (HTRF KinEASE-TK kit, Cisbio, Cat#62TK0PEC) containing 5 mM MgCl2, 1 mM MnCl2, and 1 mM 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. Subsequently, 5 μL of the TK-substrate-biotin (Cisbio, 61TK0BLE) and ATP mixture substrate (Promega, Cat#V910B) were added to a 384-well assay plate (Labcyte, P-05525-BC) to initiate the reaction. After incubating 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 and incubated at 25 °C for 60 minutes. Fluorescence signals were read at 615 nm (Cryptate) and 665 nm (XL 665) on an Envision (Perkin Elmer, Envision 2104). The IC50 value was calculated by fitting the % inhibition value of the compound concentration and the logarithm (dose response - variable slope) using GraphPad Prism 6.0.

[0597] 4. OCI-Ly10 Cell Proliferation Assay

[0598] The cell proliferation assay using the OCI-Ly10 human DLBCL (Diffuse Large B-Cell Lymphoma) cell line (Cobioer Biosciences, CBP60558), which depends on NFκB signaling, was performed as follows using the Celltiter-Glo method. The compounds prepared in the above examples were serially diluted 10-fold in DMSO in an IC50 mode of 1:4 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 resuspension with the medium, the OCI-Ly10 cells were seeded into a 96-well plate (Corning, catalog number 3603) at a density of 8,000 cells / well. Then, 5 μL of the diluted compound was added to the cell plate, and the cells were cultured at 37 °C in a CO2 incubator (ThermoFisher, Cat#371) for 72 hours. After 72 hours of compound treatment, 100 μL of the cell supernatant was removed, and 70 μL of Celltiter-Glo buffer (Promega, Cat#G7573) was added to the cell plate. After culturing at 25 °C for 20 minutes, the luminescence signal was measured on an Envision (Perkin Elmer, Envision 2104). The IC50 value was calculated by fitting the % inhibition value of the compound concentration and the logarithm (dose response - variable slope) using GraphPad Prism 6.0 by non-linear regression.

[0599] PK scheme

[0600] ICR mice (male, 6 - 8 weeks old, 26 - 30 g, n = 9 for each administration route) were purchased from Shanghai Institute of Planned Parenthood Research (SIPPR) (Shanghai, China). Under a 12:12 h light - dark cycle, the animals were housed in a room with the temperature maintained at approximately 20 - 26 °C and relative humidity of 40% - 70%, with free access to food and water. All methods involving animals complied with the principles of laboratory animal management in China. The animal research procedures were reviewed and approved by the Animal Care and Use Committee. After an overnight fast, the ICR mice received the test compound either intravenously (IV; 1 mg / kg) or by oral gavage (PO; 10 mg / kg). Food was given 4 hours after dosing. The compound was 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 from the jugular venous sinus at appropriate time points (n = 3 for each time point). The blood samples were placed in 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 ACN - containing internal standard in a 96 - well plate to precipitate proteins. After vortexing for 10 seconds, the plate was centrifuged at 3,760 rpm for 10 minutes at 4 °C, and 60 μL of the supernatant was diluted with 60 μL of H2O before LC / MS / MS analysis. Pharmacokinetic parameters were determined using non - compartmental WinNonlin (Pharsight, Mountain View, CA, USA).

[0601] Efficacy research

[0602] General procedures for animal care and feeding conformed to standard operating procedures, i.e., those of the Life Sciences Committee, National Research Council. The OCI - LY10 tumor cell line was maintained in IMDM medium as a suspension culture in vitro. The medium was modified by supplementing with 20% heat - inactivated fetal bovine serum, at 37 °C, in 5% CO2 air. The tumor cells were sub - cultured routinely, not exceeding 4 - 5 passages. Cells growing in the exponential growth phase were harvested and counted for tumor inoculation. Each mouse was subcutaneously inoculated in the right flank with OCI - LY10 tumor cells (1x10 7 ) in a mixture of 0.1 ml IMDM medium and high - concentration Matrigel (1:1 ratio) for tumor development. Based on tumor volume and body weight, the mice were randomly assigned to groups such that the mean starting tumor size and body weight were the same for each treatment group. Treatment was initiated when the mean tumor volume reached approximately 120 - 180 mm 3 . Tumor size was measured twice a week using calipers and recorded. Tumor volume (mm3 ):TV = a × b 2 / 2, where "a" and "b" are the long and short diameters of the tumor, respectively.

[0603] TVs are used to calculate tumor growth inhibition and tumor growth delay. For tumor growth inhibition (TGI), the value is calculated using the following formula:

[0604] a. %T / C = (treated TVfinal - treated TVinitial) / (vehicle TVfinal - vehicle TVinitial) * 100

[0605] b. %TGI = [1 - (treated TVfinal - treated VTinitial) / (vehicle TVfinal - vehicle TVinitial)] * 100

[0606] "TVfinal" and "TVinitial" are the average tumor volumes on the last day and the starting day, respectively.

[0607] Table 9. Bioactivity of selected examples (A < 50 nM; B: 50 to 100 nM; C: 100 nM to 1000 nM; D > 1000 nM)

[0608]

[0609]

Claims

1. A compound of formula I: or a stereoisomer, racemate or pharmaceutically acceptable salt thereof, wherein: X1 is CR’ or N; R’ is H or a halogen substituent; X2 is CH; X3 is N; R1 is selected from 3- to 8-membered heterocyclic groups, 5- to 10-membered heteroaryl groups, C 3-8 cycloalkyl groups, C 3-8 cycloalkyl-O-, C 6-10 aryl groups, and N(C 1-6 alkyl)2, wherein the alkyl is optionally substituted with one or more halogen atoms, -OH, and -CN; and wherein each heterocyclic group, heteroaryl group, cycloalkyl group, or aryl group is optionally substituted with one or more substituents selected from -OH, halogen atoms, CN, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy; Ar is -C6 aryl - Y - R2, wherein each said C6 aryl is optionally substituted by a halogen substituent; Y is -CH2-NH-C(O)-; and R2 is a C6 aryl group which is substituted with 1, 2 or 3 substituents selected from C 1-6 alkoxy, deuterated C 1-6 alkoxy and halo groups.

2. The compound of claim 1 or a stereoisomer, racemate or pharmaceutically acceptable salt thereof, wherein: Ar is wherein R3 is H or a halogen group.

3. The compound of any one of claims 1 - 2 or a stereoisomer, racemate or pharmaceutically acceptable salt thereof, wherein R2 is 2 - methoxyphenyl or 2 - methoxy - 5 - fluorophenyl.

4. A compound according to any one of claims 1-2, or a stereoisomer, racemate or pharmaceutically acceptable salt thereof, wherein R1 is selected from a 4-6 membered heterocyclic group, a 5-10 membered heteroaryl group, a C 5-6 cycloalkyl group, a C 3-6 cycloalkyl-O- and a phenyl group, 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.

5. The compound of any one of claims 1-2, or its stereoisomer, racemate or pharmaceutically acceptable salt, wherein R1 is selected from 5- to 6-membered heteroaryl, which is optionally substituted by one or more substituents selected from -OH, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy.

6. A compound according to any one of claims 1-2, or a stereoisomer, racemate or pharmaceutically acceptable salt thereof, wherein R1 is pyridyl, which is optionally substituted by one or more substituents selected from -OH, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy.

7. The compound according to any one of claims 1-2, or a stereoisomer, racemate or pharmaceutically acceptable salt thereof, wherein R1 is pyridin-4-yl which is substituted at the 2-position by C 1-6 alkyl and optionally further substituted at the 3-position by a substituent selected from -OH, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy.

8. The compound of any one of claims 1 - 2 or a stereoisomer, racemate or pharmaceutically acceptable salt thereof, wherein: R1 is selected from:

9. The compound of any one of claims 1 - 2 or a stereoisomer, racemate or pharmaceutically acceptable salt thereof, wherein R1 is selected from:

10. The compound of claim 1, which is selected from: or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

17. Use according to claim 12, wherein the disease or disorder is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with myelodysplasia-related changes (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPDs), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, Waldenström macroglobulinemia, primary central nervous system lymphoma, small lymphocyte lymphoma, precursor B-lymphoblastic leukemia, hairy cell leukemia, chronic myelogenous leukemia, anaplastic large cell lymphoma, MALT lymphoma, plasmacytic 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 type oxygen toxicity, and chronic pulmonary inflammatory diseases; systemic lupus erythematosus (SLE), autoimmune thyroiditis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), myasthenia gravis, psoriasis, inflammatory bowel disease (IBD), and idiopathic thrombocytopenic purpura; graft-versus-host disease (GVHD) and allograft rejection.

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

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

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

21. The combination product according to claim 20, wherein the additional therapeutic agent is an anti-tumor drug.

22. The combination product according to claim 20, wherein the additional therapeutic agent is a radiotherapy agent, a chemotherapy agent, an immunotherapy agent, or a targeted therapy agent.

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