Menin-MLL inhibitor, preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a Menin-MLL inhibitor, a preparation method therefor and the use thereof. The inhibitor can be used for the treatment of related diseases (in particular, hematological tumors (such as leukemia) and diabetes), and has excellent application prospects and research value.

Description

A Menin-MLL inhibitor, its preparation method and application Technical Field

[0001] This invention relates to the field of chemical pharmaceutical technology, specifically to a Menin-MLL inhibitor, its preparation method, and its application. Background Technology

[0002] The MLL gene, also known as the KMT2A gene, is a driver gene for MLL fusion gene-positive leukemia (MLL leukemia). Studies have shown that when the MLL gene undergoes a translocation mutation, it expresses an MLL fusion protein. This fusion protein is formed by the N-terminus of the MLL protein (uniprot ID: Q03164) fusing with a fusion partner (more than 70 have been identified so far), promoting the transformation of leukemia cells through different mechanisms (depending on the type of fusion partner). Although the downstream mechanisms differ, the menin protein (uniprot ID: O00255) can directly interact with the N-terminal segment of any of the aforementioned fusion proteins that belongs to MLL, forming a complex; this interaction is considered a key step in the MLL fusion protein-mediated transformation of leukemia cells. Therefore, menin-MLL inhibitors (including inhibitors that inhibit the interaction between menin and MLL protein, and inhibitors that inhibit the interaction between menin and MLL fusion protein) show promise in the treatment of diseases, especially leukemia. Summary of the Invention

[0003] To overcome the shortcomings of the prior art, the present invention provides a Menin-MLL inhibitor, its preparation method and application.

[0004] In a first aspect of the invention, a compound, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, is provided, said compound having the following structure:

[0005] in,

[0006] Ring A is a 4-10 membered carbon ring or a heterocyclic ring;

[0007] R1 is one or more independent substituents on ring A, each R1 being independently selected from: H, D, =O, halogen, C1-C. 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C1-C 10Cyanoalkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C3-C 10 Deuterated cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -OR 101 -C(O)R 101 -C(O)OR 101 -NR 102 C(O)OR 101 -OC(O)R 101 -NR 102 SO2R 101 -SO2NR 101 R 102 -NR 102 C(O)R 101 -C(O)NR 101 R 102 -NR 101 R 102 -SR 101 -S(O)R 101 -S(O)2R 101 -SO3H; each R 101 R 102 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic);

[0008] R 2a R 2b R 2c R 2d Independently selected from: H, D, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C1-C 10 Cyanoalkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C3-C 10Deuterated cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -OR 201 -C(O)R 201 -C(O)OR 201 -NR 202 C(O)OR 201 -OC(O)R 201 -NR 202 SO2R 201 -SO2NR 201 R 202 -NR 202 C(O)R 201 -C(O)NR 201 R 202 -NR 201 R 202 -SR 201 -S(O)R 201 -S(O)2R 201 -SO3H; each R 201 R 202 Independently selected from: H, D, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic);

[0009] R3 is selected from: H, D, halogens, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C1-C 10 Cyanoalkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C3-C 10 Deuterated cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -OR 301 -C(O)R 301 -C(O)OR301 -NR 302 C(O)OR 301 -OC(O)R 301 -NR 302 SO2R 301 -SO2NR 301 R 302 -NR 302 C(O)R 301 -C(O)NR 301 R 302 -NR 301 R 302 -SR 301 -S(O)R 301 -S(O)2R 301 -SO3H; each R 301 R 302 Independently selected from: H, D, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic); or, R 301 R 302 Together with the atoms they are attached to, they form heterocycles;

[0010] L1 and L2 are independently selected from: single bonds, C1-C 10 Alkylene, -(C0-C 10 alkylene)-Q-(C0-C 10 Alkylene), Q is selected from: -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R) La )-、-N(R La )C(O)-、-N(R La )C(O)O-、-N(R La )C(O)N(R La )-、-N(R La -, -S(O)2-, -S(O)2N(R) La )-、-N(R La -S(O)2-, -S(O)-, -S(O)N(R) La )-、-N(R La )S(O)-、-C(=NR La )-、-C(=NR La )-NRLa -、C3-C 10 Cycloalkylene, 4-10 membered heterocyclic alkylene; R La Selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic);

[0011] The E ring is a 3-10 membered carbon ring or a heterocyclic ring;

[0012] R4 is one or more independent substituents on the E ring, each R4 being independently selected from: H, D, halogen, =O, C1-C. 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C1-C 10 Cyanoalkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C3-C 10 Deuterated cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -OR 401 -C(O)R 401 -C(O)OR 401 -NR 102 C(O)OR 401 -OC(O)R 401 -NR 402 SO2R 401 -SO2NR 401 R 402 -NR 402 C(O)R 401 -C(O)NR 401 R 402 -NR 401 R 402 -SR 401 -S(O)R 401 -S(O)2R 401 -SO3H; each R 401 R 402 Independently selected from: H, D, C1-C10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic);

[0013] Y is selected from: H, D, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C3-C 10 Deuterated cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-12 membered heterocyclic); which may optionally be surrounded by one or more R Y Group substitution, R Y Selected from: H, D, =O, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C1-C 10 Cyanoalkyl, -OR7, -C(O)R7, -C(O)OR7, -NR8C(O)OR7, -OC(O)R7, -NR8SO2R7, -SO2NR7R8, -NR7C(O)R8, -C(O)NR7R8, -NR7R8, -SR7, -S(O)R7, -S(O)2R7, -SO3H, -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C3-C 10 Deuterated cycloalkyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein, the C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10The aryl and 4-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: D, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl) (C3-C 10 cycloalkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 Alkyl), -O (C3-C) 10 cycloalkyl), -S(C 0-10 Alkyl), -S(C3-C 10 cycloalkyl), -SO(C 0-10 alkyl), -SO2(C 0-10 Alkyl group), -SO2 (C3-C) 10 cycloalkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -SO2N(C 0-10 Alkyl) (C3-C 10 cycloalkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CON(C) 0-10 Alkyl) (C3-C 10 cycloalkyl), -CO(C 0-10 alkyl);

[0014] Each of R7 and R8 is independently selected from: H, D, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10cycloalkyl), -(C0-C6 alkylene)-(C3-C 10 Deuterated cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic);

[0015] In this embodiment, the H atom on each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclic group is optionally substituted with a group selected from the following: H, D, halogen, cyano, C1-C6 cyanoalkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic).

[0016] Specifically, each R1 is independently selected from: H, halogen (such as F), C1-C6 alkyl, C1-C6 haloalkyl (such as CF3).

[0017] Specifically, R 2a Selected from: H, halogens (such as F), C1-C6 alkyl groups, C1-C6 haloalkyl groups (such as CF3), and C1-C6 deuteralkyl groups (such as CD3). In some embodiments of the present invention, R 2a It can be H, methyl, or CD3.

[0018] Specifically, R 2b Selected from: H, halogens (such as F), C1-C6 alkyl groups, C1-C6 haloalkyl groups (such as CF3), and C1-C6 deuteralkyl groups (such as CD3). In some embodiments of the present invention, R 2b It is either methyl or CD3.

[0019] Specifically, R 2c Selected from: H, halogens (such as F), C1-C6 alkyl groups, C1-C6 haloalkyl groups (such as CF3), and C1-C6 deuteralkyl groups (such as CD3). In some embodiments of the present invention, R 2c For H.

[0020] Specifically, R 2d Selected from: H, halogens (such as F), C1-C6 alkyl groups, C1-C6 haloalkyl groups (such as CF3), and C1-C6 deuteralkyl groups (such as CD3). In some embodiments of the present invention, R 2d It can be H, methyl, or CD3.

[0021] In some embodiments of the present invention, R3 is -NR. 302C(O)R 301 or -C(O)NR 301 R 302 Among them, R 301 R 302 Independently selected from: H, D, C1-C6 alkyl (especially ethyl, isopropyl), C1-C6 deuterated alkyl, C3-C6 cycloalkyl (e.g. cyclopropyl, cyclobutyl), C3-C6 deuterated cycloalkyl, -(C1-C3 alkylene)-(C3-C6 cycloalkyl), C1-C6 haloalkyl (e.g. -CHF2, -CF3, -CH2-CHF2, -CH2-CF3), -(C1-C3 alkylene)-O-(C0-C3 alkyl), -(C1-C3 alkylene)-NH-(C0-C3 alkyl); or, R 301 and R 302 Together with the atoms to which it is attached, it forms a 4-8 membered saturated heterocycle, wherein the H on the heterocycle is optionally substituted by a group selected from the following: H, D, =O, halogen (e.g., F), C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 hydroxyalkyl.

[0022] More specifically, R 301 Selected from: C1-C6 alkyl (especially ethyl, isopropyl) and C1-C6 deuterated alkyl (e.g. deuterated isopropyl).

[0023] More specifically, R 302 Selected from: C1-C6 alkyl (especially ethyl, isopropyl), C1-C6 deuterated alkyl (e.g. deuterated ethyl), C3-C6 cycloalkyl, C3-C6 deuterated cycloalkyl, C1-C6 haloalkyl.

[0024] In some embodiments of the present invention, R3 is selected from:

[0025] In some embodiments of the invention, R3 is a phenyl or a 4-8 membered nitrogen-containing heterocyclic group, wherein the H on the phenyl or nitrogen-containing heterocyclic group is optionally substituted by a group selected from: H, halogen (e.g., F), C1-C6 alkyl (e.g., methyl, ethyl, isopropyl), C1-C6 haloalkyl (e.g., -CHF2, -CH2F, -CF3), C3-C6 cycloalkyl (e.g., ...

[0026] In some embodiments of the present invention, R3 is selected from:

[0027] In some embodiments of the present invention, ring A is a benzene ring.

[0028] Specifically, A part can have the following structure: For example Among them, R 1a For H or halogens (e.g., F, Cl), R 1b R is one or more independent substituents on the benzene ring, having the definition of R1 above. In some embodiments of the invention, R 1b For H. In some embodiments of the present invention, Some have the following structure:

[0029] In some embodiments of the present invention, ring A is a 4-10 membered heterocycle, such as a 5- or 6-membered heteroaromatic ring or a 4- or 10-membered saturated nitrogen-containing heterocycle, for example.

[0030] Specifically, A part can have the following structure:

[0031] In some embodiments of the present invention, L1 is a single bond. In other embodiments of the present invention, L1 is a C1-C3 alkylene group, such as a methylene group.

[0032] Specifically, the E ring is a 4-10 saturated or partially saturated carbon ring or a nitrogen-containing heterocycle.

[0033] In some embodiments of the present invention Part of (The left end of this structure is connected to the 6-position of the imidazopyridine ring, and the right end N is connected to L2), n1 is 1 or 2, and n2 is 1, 2, 3, or 4. Specifically, Part of For example For example

[0034] Specifically, R4 is selected from: H, D, halogen (e.g., F), hydroxyl, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy; more specifically, R4 is selected from: H, F, hydroxyl.

[0035] In some embodiments of the present invention, the compound has the following structure:

[0036] Specifically, L2 is a C1-C6 alkylene or -(C0-C6 alkylene)-Q-(C0-C6 alkylene)-, and Q is a C3-C6 cycloalkylene, wherein the H atom in the alkylene may optionally be substituted with the following groups: H, C1-C3 alkyl, halogen, cyano, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C6 alkylamine, C3-C6 cycloalkyl, 3-6 membered heterocyclic groups (e.g., ... C1-C3 alkyl-substituted 3-6 membered heterocyclic groups (such as C1-C3 alkyl-substituted 3-6 membered heterocyclic groups)

[0037] In some embodiments of the present invention, L2 is selected from: methylene, -C(O)-、

[0038] Specifically, Y is selected from: -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-12 membered heterocyclic); wherein the H on the cycloalkyl, aryl, or heterocyclic group is optionally replaced by one or more R Y Group substitution; in some embodiments of the invention, Y is Among them, YⅠ ring is a 3-8 member saturated or partially saturated aliphatic ring, benzene ring, or 4-12 member saturated or partially saturated heterocycle, R Y0 R is one or more independent substituents on the ring. Y0 R Y1 With R Y Definition of a functional group.

[0039] In some embodiments of the present invention, the compound has the following structure:

[0040] Among them, YⅠ ring is a 3-8 member saturated or partially saturated aliphatic ring, benzene ring, or 4-12 member saturated or partially saturated nitrogen-containing heterocycle, R Y0 It is one or more independent substituents on the ring, which have the above-described definition of the present invention.

[0041] In some embodiments of the present invention, Y is...

[0042] Specifically, R Y0 Selected from: H, D, halogen (e.g., F), C1-C3 alkyl (e.g., methyl), C1-C3 haloalkyl, C1-C3 deuteralkyl, hydroxyl, C1-C3 alkoxy.

[0043] Specifically, R Y1Selected from: -OR7, -C(O)R7, -C(O)OR7, -NR8C(O)OR7, -OC(O)R7, -NR8SO2R7, -SO2NR7R8, -NR7C(O)R8, -C(O)NR7R8, -NR7R8, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); each R7 and R8 is independently selected from: H, D, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, -(C0-C6 alkylene)-(4-10 membered heterocyclic). Alkyl)-(C3-C6 cycloalkyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the H on the alkyl, cycloalkyl, or heterocyclic group is optionally substituted by a group selected from the following: D, halogen, cyano, C1-C6 cyanoalkyl, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, amino, C1-C6 alkylamine, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)N(C0-C6 alkyl)(C0-C6 alkyl).

[0044] In some embodiments of the present invention, R Y1 Selected from:

[0045] In some embodiments of the present invention, R Y1 Selected from:

[0046] In some embodiments of the present invention, R Y1 Selected from:

[0047] In some embodiments of the present invention, R Y1 Selected from:

[0048] In some embodiments of the present invention, R Y1 Selected from:

[0049] In some embodiments of the present invention, R Y1 Selected from:

[0050] In some embodiments of the present invention, R Y1 Selected from:

[0051] In some embodiments of the present invention, R Y1Selected from:

[0052] In some embodiments of the present invention, R Y1 Selected from: H, D, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated hydroxyalkyl, C1-C6 alkoxyalkyl.

[0053] In some embodiments of the present invention, Y is selected from:

[0054] In some embodiments of the present invention, Y is selected from:

[0055] In some embodiments of the present invention, the compound has the following structure:

[0056] In some embodiments of the present invention, the compound has the following structure:

[0057] In some embodiments of the present invention, ring A is a benzene ring, and the compound has the following structure:

[0058] In some embodiments of the present invention, ring A is a heterocyclic ring, and the compound has the following structure:

[0059] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0060] In a second aspect of the invention, a pharmaceutical composition is provided comprising the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, as well as a pharmaceutically acceptable excipient.

[0061] Specifically, pharmaceutically acceptable excipients may be selected from one or more of the following: disintegrants, binders, lubricants, suspending agents, stabilizers, fillers, absorption enhancers, surfactants, flavoring agents, antioxidants, and preservatives.

[0062] Specifically, the pharmaceutical composition can be administered via any suitable route of administration, such as gastrointestinal administration (e.g., oral, sublingual, rectal administration) or non-gastrointestinal administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.).

[0063] Specifically, the pharmaceutical composition can be any suitable dosage form, such as gastrointestinal dosage forms, including, but not limited to, tablets, pills, powders, granules, capsules, lozenges, syrups, liquids, emulsions, suspensions, etc.; non-gastrointestinal dosage forms, such as injectable dosage forms: such as injections (e.g., for subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection); respiratory dosage forms: such as sprays, aerosols, powder inhalers, etc.; skin dosage forms: such as topical solutions, lotions, ointments, plasters, pastes, patches, etc.; mucosal dosage forms: such as eye drops, ophthalmic ointments, nasal drops, mouthwashes, sublingual tablets, etc.; cavity dosage forms: such as suppositories, aerosols, effervescent tablets, drops, pills, etc., for use in the rectum, vagina, urethra, nasal cavity, ear canal, etc.

[0064] Specifically, in the pharmaceutical composition, the compound described in the first aspect or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates, and deuterated compounds may be used alone or in combination with other types of active ingredients.

[0065] Specifically, the various dosage forms of the above-mentioned pharmaceutical compositions can be prepared according to conventional pharmaceutical manufacturing methods. For example, the active ingredient can be mixed with one or more pharmaceutically acceptable excipients and then formulated into the desired dosage form.

[0066] Specifically, in the above-mentioned pharmaceutical composition, the weight percentage of the compound described in the first aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound may be 0.1-99.5%, for example 0.5%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, particularly 1-30%.

[0067] In a third aspect of the invention, the use of the compound described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, in the preparation of a medicament for inhibiting the interaction between Menin and MLL is provided.

[0068] In a fourth aspect of the invention, the use of the compound described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, in the preparation of a medicament for the prevention and / or treatment of Menin-MLL interaction-mediated diseases is provided.

[0069] In some embodiments of the present invention, the disease is a tumor, including, but not limited to, hematologic malignancies (e.g., leukemia, lymphoma), bladder cancer, brain cancer (e.g., glioma, diffuse endogenous pontine glioma (DIPG)), breast cancer (e.g., triple-negative breast cancer, estrogen receptor-positive breast cancer (i.e., ER+ breast cancer)), colorectal cancer (e.g., colon cancer, rectal cancer, colorectal cancer), gastrointestinal stromal tumor (GIST), cervical cancer, gastric cancer, genitourinary cancer, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer (e.g., castration-resistant prostate cancer), kidney cancer (e.g., renal cell carcinoma), skin cancer, thyroid cancer (e.g., papillary thyroid carcinoma), testicular cancer, glioblastoma, sarcoma (e.g., Ewing's sarcoma), and AIDS-related cancers.

[0070] In some embodiments of the present invention, the tumor is a hematologic tumor, such as leukemia, lymphoma, myeloma, etc.

[0071] In some embodiments of the present invention, the tumor is a solid tumor, such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, or glioblastoma.

[0072] In some embodiments of the present invention, the diseases include, but are not limited to, mixed-lineage leukemia (MLL), MLL-associated leukemia, MLL-related leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed-lineage leukemia (MLL-r), leukemia associated with MLL rearrangement or MLL gene rearrangement, acute leukemia, chronic leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myeloid leukemia, childhood leukemia, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia. Leukemia (AML), acute myeloid leukemia, acute non-lymphocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), treatment-related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), myeloproliferative neoplasm (MPN), plasmacytoma, multiple myeloma, spinal dysplasia, cutaneous T-cell lymphoma, lymphoid tumor, hairy cell leukemia, leukemic meningitis, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma (malignant lymphoma).

[0073] In some embodiments of the present invention, the disease is diabetes, insulin resistance, or hyperglycemia. More specifically, the disease is diabetes.

[0074] In some embodiments of the present invention, the disease is an autoimmune disease.

[0075] In some embodiments of the present invention, the disease is non-alcoholic hepatitis.

[0076] In a fifth aspect of the invention, a method for preventing and / or treating Menin-MLL interaction-mediated diseases is provided, comprising administering to a subject in need the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, or the pharmaceutical composition of the second aspect.

[0077] Specifically, the disease has the definition described in the fourth aspect of this invention.

[0078] Specifically, the subjects were mammals, particularly humans.

[0079] This invention prepares a series of new compounds that can be used as menin-MLL inhibitors for the treatment of related diseases (especially hematological malignancies such as leukemia and diabetes), and have very good application prospects and research value. Attached Figure Description

[0080] Figure 1 shows the changes in blood glucose levels in mice after a 6-hour fast (blood glucose was measured at 5 predetermined time points during the study).

[0081] Figure 2 shows the results of random blood glucose level changes over time in mice (postprandial blood glucose levels were measured at 5 predetermined time points during the study period).

[0082] Figure 3 shows the changes in C-peptide levels in mouse plasma (PD index) (C-peptide levels were measured on day 28 after drug administration, and one-way ANOVA was used for intergroup comparisons with the solvent control group as a reference).

[0083] Figure 4 shows the changes in blood glucose levels in mice after a 6-hour fast (blood glucose was measured at 5 predetermined time points during the study).

[0084] Figure 5 shows the results of random blood glucose level changes over time in mice (postprandial blood glucose levels were measured at 5 predetermined time points during the study period).

[0085] Figure 6 shows the changes in C-peptide levels in mouse plasma (PD index) (C-peptide levels were measured on day 28 after drug administration, and one-way ANOVA was used for intergroup comparisons with the solvent control group as a reference).

[0086] Figure 7 shows the changes in glucose-stimulated insulin secretion (GSIS) in mice on day 1.

[0087] Figure 8 shows the changes in glucose-stimulated insulin secretion (GSIS) in mice on day 28. Detailed Implementation

[0088] Unless otherwise defined, all scientific and technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0089] In this invention, the term "aliphatic group" refers to a straight-chain or branched hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a cyclic hydrocarbon group (also referred to herein as a "carbocyclic ring" or "aliphatic ring") that is fully saturated or contains one or more unsaturated units, connected to other parts of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkyl)alkenyl, etc. Typical aliphatic groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms.

[0090] The term "alkyl" refers to a straight-chain or branched hydrocarbon radical that does not contain unsaturated bonds and is connected to the rest of the molecule by single bonds. Typical alkyl groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. If the alkyl group is replaced by a cycloalkyl group, it is referred to as a "cycloalkylalkyl," such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. Typical cycloalkylalkyl groups are usually C3-C. 10 Cycloalkyl alkyl groups, such as -(C1-C3 alkylene)-(C3-C6 cycloalkyl). If the alkyl group is substituted with an aryl group, then it is correspondingly "aralkyl", such as benzyl, diphenylmethyl, or phenethyl. If the alkyl group is substituted with a heterocyclic group, then it is correspondingly "heterocyclic alkyl". In this invention, CO alkyl refers to H, i.e., CO-C 10 Alkyl groups include H and C1-C 10 alkyl.

[0091] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by the loss of two hydrogen atoms from an alkane molecule. It can be straight-chain or branched and is connected to the rest of the molecule by a single bond. Typical alkylene groups described herein have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, etc. In this invention, CO alkylene refers to a single bond, i.e., CO-C. 10 Alkyl groups include single bonds and C1-C bonds. 10 Alkylene.

[0092] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 monocyclic and / or fused rings, containing 3 to 18 carbon atoms, preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl.

[0093] The term "alkoxy" refers to a substituent formed when the hydrogen in a hydroxyl group is replaced by an alkyl group, such as alkoxy groups containing 1-10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, etc.

[0094] The term "alkylamine" refers to a substituent formed when one or two hydrogen atoms of an amino group (-NH2) are replaced by an alkyl group, such as an alkylamine group containing 1-10 carbon atoms, for example...

[0095] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0096] The term "halogenated alkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with a halogen atom (such as fluorine, chlorine, bromine or iodine), such as -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0097] The term "aryl" refers to a monocyclic or polycyclic free radical, including polycyclic free radicals containing a monoaryl group and / or a fused aryl group, such as those containing 1-3 monocyclic or fused rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms, as described in this invention (C6-C). 12 The aryl group refers to an aryl group containing 6-12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indene, etc.

[0098] The term "heterocyclic group" refers to a 3- to 18-membered ring group containing 2 to 17 carbon atoms and 1 to 10 heteroatoms selected from N, O, or S atoms. Heterocyclic groups can be monocyclic, bicyclic, tricyclic, or tetracyclic polycyclic systems, which can include fused (two rings sharing two ring atoms), helical (two rings sharing one ring atom), or bridged (two rings sharing three or more ring atoms) ring systems (excluding tandem rings). Heterocyclic groups can be partially saturated (heteroaryl) or fully saturated (heterocyclic alkyl). Suitable heteroaryl groups in the compounds of the present invention contain one, two, or three heteroatoms selected from N, O, or S atoms. These heteroaryl groups include, for example, coumarins, including 8-coumarins; quinolinyl groups, including 8-quinolinyl, isoquinolinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrroloyl, thiopheneyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazoleyl, indolyl, isoyndolyl, indazoleyl, inazinyl, phthalazinyl, pteridinyl, purineyl, oxadiazolyl, thiadiazolyl, furazolidyl, pyridazinyl, triazinyl; cenolinyl, benzimidazolyl, benzofuranyl, benzofuranyl, benzothiopheneyl, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphridinyl, and furanopyridinyl. Suitable heterocyclic alkyl groups in the compounds of the present invention contain one, two, or three heteroatoms selected from N, O, or S atoms. The heterocyclic alkyl groups include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran, tetrahydrothiophenyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, oxothiohexacyclohexyl, piperazine, aziridine, oxothiohexacyclo ... Heptyl, triacetyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, dithiaalkyl, dithiopentyl, dihydropyranyl, dihydrothiophenyl, pyrazolinyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinazinyl. In this invention, for optionally substituted heterocyclic groups, the substituted position can be any suitable carbon atom or heteroatom, for example, for The substitution position of R can be any suitable carbon or nitrogen atom, and it can be, for example...

[0099] The term "optionally substituted" can be halogen, -CN, -NO2, -OR', -NR'R", -S(O)t-R', -S(O)t-NR'R", -COR', -C(O)OR', -C(O)NR'R", -C(O)N(R')OR", -OC(O)R', -OC(O)NR'R", -NR'C(O)R", -N(R')C(O)NR'R', -N(R')C(NR')NR'R', -NR'-S(O)t-R', -NR'-S(O)t-NR'R', -N=S(O)R'R", -S(NR')(O)R", -N(R')CN, -P(O)(R')NR'R", -P(O)(R')OR" or -P(O)R'R", C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 3-6 cycloalkyl, C 4-10 cycloalkylalkyl, C 6-10 Aryl, C 6-10 Arylalkyl, C 3-8 Heterocyclic group, C 3-8 Heterocyclic alkyl; t is 0, 1 or 2; each R' and R" is independently selected from: H, halogen, -CN, -NO2, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, heterocyclic alkyl; or, R' and R" connected to the same nitrogen atom form a heterocycle together with the nitrogen atom.

[0100] The term "pharmaceutically acceptable salt" includes acid addition salts and base addition salts.

[0101] The term "acid addition salt" includes, but is not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, as well as salts derived from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids, such as acetates, salicylates, decanoates, stearates, oleates, hexanoates, malates, glycolates, ethanesulfonates, hydroxyethylsulfonates, etc. Therefore, these salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, iodates, acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, amygdalinates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, tartrates, and methanesulfonates, as well as salts of amino acids such as arginine salts, gluconates, galacturons, aspartate salts, and glutamate salts. Acid addition salts can be prepared by contacting a sufficient amount of the desired acid in a conventional manner to form a salt. The free base can be regenerated by contacting the salt with a base, and the free base can be separated in a conventional manner.

[0102] The term "base addition salt" refers to a salt formed with a metal or amine, such as hydroxides of alkali metals and alkaline earth metals, or with an organic amine. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Suitable amines include, but are not limited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucosamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid form can be regenerated by contacting the salt form with an acid, and the free acid can be separated in a conventional manner.

[0103] The term "stereoisomer" includes enantiomers, diastereomers, and geometric isomers. Some compounds of the present invention have cyclic hydrocarbon groups that can be substituted on more than one carbon atom; in this case, all their geometric forms, including cis and trans, and mixtures thereof, are within the scope of the present invention.

[0104] The term "solvent" refers to the physical bond between the compound of this invention and one or more solvent molecules. This physical bond includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvents include solution phases and separable solvates. Representative solvates include ethanolides, methanolides, etc.

[0105] The term "deuterated compound" refers to a compound in which one or more hydrogen atoms, such as 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by deuterium atoms (D).

[0106] It should be recognized that, depending on the source of the chemical materials used in the synthesis, there are variations in the natural isotopic abundance in the synthesized compounds. Therefore, the compounds of the present invention will inherently contain small amounts of deuterated isotopes. Despite this variation, the concentrations of these naturally abundant stable hydrogen and carbon isotopes are low and insignificant compared to the degree of stable isotopic substitution in the compounds of the present invention. See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0107] In the compounds of this invention, any atom not specifically designated as deuterium is present at its natural isotopic abundance. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", that position should be understood as having hydrogen according to its natural abundance isotopic composition. Similarly, unless otherwise stated, when a position is specifically designated as "D" or "deuterium", that position should be understood as having deuterium at an abundance at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium doping).

[0108] The term “isotope enrichment coefficient” used in this article refers to the ratio between the isotopic abundance of a particular isotope and its natural abundance.

[0109] In other embodiments, the compounds of the present invention have an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping at each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping).

[0110] The term "isotope" refers to a substance whose chemical structure differs from that of a specific compound of the present invention only in terms of its isotopic composition.

[0111] The term "prodrug" refers to a Formula I compound that is suitable for administration to patients without excessive toxicity, irritation, or allergic reactions, and is effective for its intended purpose. Prodrugs include acetals, esters, and zwitterionic forms. Prodrugs are converted in the body, such as through hydrolysis in the blood, to yield the parent compound.

[0112] The terms “patient” or “subject”, etc., are used interchangeably herein to refer to any animal or its cells, whether in vitro or in situ, treated according to the methods described herein. Specifically, the aforementioned animals include mammals, such as rats, mice, guinea pigs, rabbits, dogs, monkeys, and humans, especially humans.

[0113] The term "treatment" refers to the prevention, cure, reversal, reduction, mitigation, minimization, suppression, cessation, and / or cessation of one or more clinical symptoms of a disease after its onset.

[0114] The term "prevention" refers to the treatment taken before a disease develops to avoid, minimize, or prevent the disease from developing or progressing.

[0115] The term "tumor" refers to a new growth formed by the proliferation of local tissue cells under the influence of various carcinogenic factors. Based on the cellular characteristics of the new growth and the degree of harm it causes to the body, tumors are further divided into two main categories: benign tumors and malignant tumors. "Malignant tumors" are defined as diseases characterized by uncontrollable growth and spread of malignant cells and tissue infiltration, and which, according to pathological examination, meet the criteria for malignant tumors as published by the Ministry of Health of China.

[0116] In specific embodiments, the compounds of the present invention are used to treat leukemia associated with MLL rearrangement, acute lymphoblastic leukemia associated with MLL rearrangement, acute lymphoblastic leukemia associated with MLL rearrangement, acute lymphoblastic leukemia associated with MLL rearrangement, acute myeloid leukemia associated with MLL rearrangement, or acute myeloid leukemia associated with MLL rearrangement. As used herein, "MLL rearrangement" means rearrangement of the MLL gene.

[0117] The term "autoimmune disease" refers to diseases caused by damage to one's own tissues due to an immune response to self-antigens. These diseases can be divided into organ-specific autoimmune diseases (primarily affecting a single organ) and systemic autoimmune diseases (affecting multiple tissues or organs throughout the body). The American Autoimmune Related Diseases Association (AAAA) has compiled a comprehensive list of autoimmune diseases, including common ones such as systemic lupus erythematosus, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, psoriasis, celiac disease, ulcerative colitis, and Crohn's disease.

[0118] The term "diabetes" refers to a group of metabolic diseases characterized by chronic hyperglycemia, mainly caused by insulin secretion defects or impaired insulin action leading to glucose metabolism disorders. These include: type 1 diabetes, type 2 diabetes, gestational diabetes, adult-onset diabetes in young adults, steroid diabetes, dual diabetes, LADA diabetes (late-onset autoimmune diabetes in adults, also known as "type 1.5 diabetes"), and especially type 2 diabetes and LADA diabetes.

[0119] Unless otherwise stated, numerical ranges expressed in the form of "from x to y" or "xy" should be understood to include both x and y. When multiple preferred ranges are described in the form of "from x to y" or "xy" for a particular feature, it should be understood that combinations of all ranges with different endpoints may also be considered.

[0120] All publications, patents, and published patent specifications cited in this article are incorporated herein in their entirety through citation.

[0121] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0122] Synthesis Examples

[0123] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0124] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), or a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0125] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 high-performance liquid chromatograph.

[0126] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0127] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0128] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0129] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0130] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0131] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0132] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0133] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0134] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0135] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0136] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0137] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0138] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0139] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0140] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0141] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0142] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included: A: n-hexane / ethyl acetate system, B: dichloromethane / methanol system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0143] Examples 1-1, 1-2

[0144] 2-(6-{1-[(1S)-1-[1-(2-cyanoacetyl)piperidin-4-yl]ethyl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 1-1

[0145] 2-(6-{1-[(1R)-1-[1-(2-cyanoacetyl)piperidin-4-yl]ethyl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 1-2

[0146] first step

[0147] 2-Bromo-N-ethyl-5-fluoro-N-isopropylbenzamide 1b

[0148] N-Ethylpropyl-2-amine (12 g, 137.67 mmol) and triethylamine (27.72 g, 273.96 mmol) were added to a solution of 2-bromo-5-fluorobenzoic acid 1a (20 g, 91.32 mmol) in dichloromethane (250 mL), followed by the slow addition of HATU (52.08 g, 136.98 mmol). The mixture was stirred at 25 °C for 12 hours. The mixture was washed with saturated sodium carbonate aqueous solution (100 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (A: petroleum ether, B: ethyl acetate, 0% B to 15% B in A, thin-layer chromatography (petroleum ether: ethyl acetate = 1:1, Rf = 0.35) to give title product 1b (24 g, 83.29 mmol, yield 91.20%) as a white solid.

[0149] MS m / z(ESI): 289.8 [M+1]

[0150] 1 H NMR (400MHz, DMSO-d6) δ7.80-7.61(m,1H),7.38-7.29(m,1H),7.22(dt,J=3.0,8.6Hz,1H),3.57-3.38 (m,2H),3.26(qd,J=7.0,13.8Hz,1H),1.25-1.17(m,6H),1.06(d,J=6.6Hz,2H),0.96(t,J=7.1Hz,1H)

[0151] Step 2

[0152] N-Ethyl-5-fluoro-N-isopropyl-2-(tetramethyl-1,3,2-dioxaborane-2-yl)benzamide 1c

[0153] Compound 1b (13 g, 45.11 mmol), potassium acetate (13.3 g, 135.52 mmol), and pinacol diboronate (35 g, 137.83 mmol) were dissolved in DMSO (200 mL). Pd(dppf)Cl2·DCM (3.30 g, 4.51 mmol) was added under a nitrogen atmosphere, and the mixture was stirred at 110 °C for 12 hours. After cooling to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (A: petroleum ether, B: ethyl acetate, 0% B to 20% B in A, thin-layer chromatography (petroleum ether: ethyl acetate = 3:1, Rf = 0.2)) to give the title product 1c (10 g, 29.83 mmol, yield: 66.12%).

[0154] MS m / z(ESI): 336.2 [M+1]

[0155] 1 H NMR (400MHz, DMSO-d6) δ7.73 (dd, J=6.5, 8.1Hz, 1H), 7.20 (dt, J=2.4, 8.7Hz, 1H), 7.09 (br dd,J=2.4,9.4Hz,1H),3.54(td,J=6.6,13.2Hz,1H),3.31-3.27(m,2H),1.28-1.20(m,16H),1.16(s,4H)

[0156] Step 3

[0157] 6-Bromo-8-chloro-3-methylimidazo[1,5-a]pyridine 1e

[0158] Compound 1d (10.0 g, 45.15 mmol) was dissolved in acetic anhydride (100 mL), and p-toluenesulfonic acid (4.0 g, 23.23 mmol) was added. The reaction mixture was stirred at 100 °C for 12.0 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Diluted with dichloromethane (40 mL), and the pH of the mixture was adjusted to 8 with saturated sodium carbonate aqueous solution. The mixture was extracted with dichloromethane (60 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate as the elution system to give the title product 1e (8.0 g, 32.6 mmol, yield: 72.2%). MS m / z (ESI): 246.7 [M+1]

[0159] Step 4

[0160] 3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-carboxylic acid tert-butyl ester 1f

[0161] Under nitrogen protection, 1,2-dibromoethane (120.77 mg, 642.87 μmol) was dissolved in DMAc (8.0 mL), and zinc powder (388.04 mg, 5.93 mmol) was added. The mixture was stirred at 70 °C for 10 minutes, then cooled to room temperature. TMSCl (53.72 mg, 494.51 μmol) was slowly added dropwise to the reaction. After the addition was complete, the reaction was stirred at 25 °C for 30 minutes. Then, a DMAc solution of 1.4 g (4.95 mmol) in tert-butyl 1-iodozacyclobutane-1-carboxylic acid was added dropwise to the reaction. The reaction solution was heated to 40 °C and stirred for 1 hour, until no obvious solid precipitate was observed. The reaction solution was cooled to 25°C, and then compound 1e (1.09 g, 4.45 mmol), Pd2(dba)3 (284.35 mg, 494.51 μmol), and tris(2-furanyl)phosphine (114.81 mg, 494.51 μmol) were added to the reaction mixture. Nitrogen gas was purged three times, and the reaction mixture was heated to 70°C and stirred for 12 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added. Extraction was performed with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the elution system to give the title product 1f (560 mg, 1.74 mmol, yield: 35.19%) as a brown oil. MS m / z (ESI): 321.9 [M+1]

[0162] Step 5

[0163] 1 g of 3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane

[0164] Compound 1f (330 mg, 1.03 mmol) was dissolved in dichloromethane (5.0 mL), and trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) was added at 25 °C. The reaction mixture was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure, and dichloromethane (20 mL) was added. The pH was adjusted to 11 with 10% sodium hydroxide aqueous solution, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1 g of crude product (200 mg, 902.18 μmol, yield: 87.98%) as a yellow solid. The crude product was used directly in the next reaction without purification.

[0165] Step 6

[0166] 4-[1-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester 1i

[0167] 1 g (2 g, 9.02 mmol) of compound and 1 h (2.26 g, 9.92 mmol) of 4-acetylpiperidin-1-carboxylic acid tert-butyl ester were dissolved in methanol (20 mL), and zinc chloride (2.46 g, 18.04 mmol) was added. The mixture was stirred at 50 °C for 1.0 h. Sodium cyanoborohydride (1.70 g, 27.07 mmol) was added, and the mixture was stirred at 50 °C for 11 h. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (50 mL), filtered, and extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate / methanol as the elution system to give the title product 1i (1.8 g, 4.16 mmol, yield: 46.08%) as a yellow solid.

[0168] MS m / z(ESI): 433.3 [M+1]

[0169] Step 7

[0170] 4-[(1S)-1-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)ethyl]piperidin-1-carboxylic acid tert-butyl ester 1i-1

[0171] 4-[(1R)-1-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)ethyl]piperidin-1-carboxylic acid tert-butyl ester 1i-2

[0172] Compound 1i (1.8 g, 4.16 mmol) was purified by chiral preparative HPLC (chiral preparative column: Chiral-Cellulose-2-30-Phenomenex-Cellulose-2 (250 mm * 30 mm, 10 μm); mobile phase: CO2-EtOH:CAN [7:3 (0.1% NH3H2O)], elution gradient: 45%; the corresponding fractions were collected and concentrated under reduced pressure to give the title product 1i-1 (800 mg, 1.85 mmol, yield: 44.44%) and 1i-2 (800 mg, 1.85 mmol, yield: 44.44%).

[0173] Single-configuration compound 1i-1:

[0174] MS m / z(ESI): 433.3 [M+1]

[0175] Chiral SFC analysis: retention time 0.566 min; column: Cellulose-2 50x4.6mm ID, 3µm; mobile phase: CO2 / EtOH+ACN (0.05% DEA), elution gradient: 40%.

[0176] Single-configuration compound 1i-2:

[0177] MS m / z(ESI): 433.3 [M+1]

[0178] Chiral SFC analysis: retention time 0.871 min; column: Cellulose-2 50x4.6mm ID, 3µm; mobile phase: CO2 / EtOH+ACN (0.05% DEA), elution gradient: 40%.

[0179] Step 8

[0180] 4-[(1S)-1-[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)azacyclobutane-1-yl]ethyl]piperidin-1-carboxylic acid tert-butyl ester 1j-1

[0181] Compound 1i-1 (540 mg, 1.25 mmol) and compound 1c (501.69 mg, 1.50 mmol) were dissolved in dioxane (10.0 mL) and water (2.5 mL). Potassium phosphate (794.19 mg, 3.74 mmol) and Xphos Pd G4 (107.31 mg, 124.72 μmol) were added, and the mixture was stirred at 95 °C for 1 h under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 1j-1 (690 mg, 1.14 mmol, yield: 91.33%).

[0182] MS m / z (ESI): 606.6 [M+1]

[0183] Step 9

[0184] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(1S)-1-(piperidin-4-yl)ethyl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 1k-1

[0185] Compound 1j-1 (540 mg, 891.41 μmol) was dissolved in dioxane (3.0 mL) and trifluoroacetic acid (1.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure, the pH of the solution was adjusted to 10 with 10% NaOH aqueous solution, and extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 1k-1 (450 mg, 889.91 μmol, yield: 99.83%). The crude product was used directly in the next reaction without purification.

[0186] MS m / z (ESI): 506.3 [M+1]

[0187] Step 10

[0188] 2-(6-{1-[(1S)-1-[1-(2-cyanoacetyl)piperidin-4-yl]ethyl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 1-1

[0189] 2-Cyanoacetic acid (30.28 mg, 355.96 μmol), triethylamine (90.05 mg, 889.91 μmol), and HATU (135.35 mg, 355.96 μmol) were dissolved in dichloromethane (2.0 mL), and compound 1k-1 (150 mg, 296.64 μmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 24%–54%) to give the title product 1-1 (33.73 mg, 58.89 μmol, yield: 19.85%) as a white solid.

[0190] MS m / z(ESI): 573.4 [M+1]

[0191] Chiral SFC analysis: retention time 1.467 min; column: Chiralcel OD-3 50×4.6mm ID, 3µm; mobile phase: CO2 / MeOH (0.05% DEA), elution gradient: 5%–40%.

[0192] 1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.72-7.58(m,1H),7.42-7.27(m,2H),7.09-7.00(m,1H),6.89-6.64(m,1H),4.48-4.30(m,1H),4.01(br d,J=9.2Hz,2H),3.71-3.62(m,1H),3.58-3.40(m,4H),3.13-3.02(m,2H),3.00-2.84(m,2H ),2.59(d,J=1.6Hz,3H),2.25-2.16(m,1H),1.82-1.31(m,4H),1.30-0.96(m,3H),0.90(br d,J=6.4Hz,3H),0.82-0.21(m,9H).

[0193] Step 11

[0194] 4-[(1R)-1-[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)azacyclobutane-1-yl]ethyl]piperidin-1-carboxylic acid tert-butyl ester 1j-2

[0195] Compound 1i-2 (500 mg, 1.15 mmol) and compound 1c (425.81 mg, 1.27 mmol) were dissolved in dioxane (2.0 mL) and water (0.5 mL). Potassium phosphate (735.36 mg, 3.46 mmol) and Xphos Pd G4 (99.37 mg, 115.48 μmol) were added, and the mixture was stirred at 95 °C for 1 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 1j-2 (400 mg, 660.30 μmol, yield: 57.18%).

[0196] MS m / z (ESI): 606.5 [M+1]

[0197] Step Twelve

[0198] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(1R)-1-(piperidin-4-yl)ethyl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 1k-2

[0199] Compound 1j-2 (400 mg, 660.30 μmol) was dissolved in dioxane (5.0 mL) and trifluoroacetic acid (3.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure and extracted with 10% NaOH aqueous solution (20 mL) and dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 1k-2 (310 mg, 613.05 μmol, yield: 92.84%). The crude product was used directly in the next reaction without purification.

[0200] MS m / z (ESI): 506.3 [M+1]

[0201] Step Thirteen

[0202] 2-(6-{1-[(1R)-1-[1-(2-cyanoacetyl)piperidin-4-yl]ethyl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 1-2

[0203] 2-Cyanoacetic acid (7.07 mg, 83.06 μmol), triethylamine (21.01 mg, 207.65 μmol), and HATU (31.58 mg, 83.06 μmol) were dissolved in dichloromethane (1.0 mL), and compound 1k-2 (35.00 mg, 69.22 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate aqueous solution (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 24%–54%) to give title product 1-2 (37.00 mg, 64.60 μmol, yield: 93.34%) as a yellow solid.

[0204] MS m / z(ESI): 573.4 [M+1]

[0205] Chiral SFC analysis: retention time 1.464 min; column: Chiralcel OD-3 50×4.6mm ID, 3µm; mobile phase: CO2 / MeOH (0.05% DEA), elution gradient: 5%–40%.

[0206] 1H NMR (400MHz, DMSO-d6) δ7.96-7.90(m,1H),7.72-7.65(m,1H),7.42-7.27(m,2H),7.06-7.00(m,1H),6.86-6.69(m,1H),4.40(br d,J=12.6Hz,1H),4.09-3.93(m,2H),3.72-3.63(m,1H),3.60-3.35(m,4 H),3.31-3.25(m,1H),3.15-2.87(m,4H),2.62-2.55(m,3H),2.55-2.52( m,1H),2.49-2.41(m,1H),2.26-2.16(m,1H),1.78-1.40(m,3H),1.34-0 .95(m,3H),0.90(d,J=6.4Hz,2H),0.83-0.72(m,6H),0.30-0.21(m,2H).

[0207] Following similar steps to those in the above embodiments, the following compounds were prepared and characterized:

[0208] Examples 3-1, 3-2

[0209] 2-(6-{1-[(1S)-1-(4-ethanesulfonamidocyclohexyl)ethyl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 3-1

[0210] 2-(6-{1-[(1R)-1-(4-ethanesulfonamidocyclohexyl)ethyl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 3-2

[0211] first step

[0212] N-[(1r,4r)-4-[1-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)ethyl]cyclohexyl]tert-butyl carbamate 3b

[0213] 1 g (900 mg, 4.06 mmol) of compound N-(4-acetylcyclohexyl)carbamate tert-butyl ester 1a (979.73 mg, 4.06 mmol) was dissolved in methanol (10 mL), and zinc chloride (1.11 g, 8.12 mmol) was added. The mixture was stirred at 50 °C for 0.5 h. Sodium cyanoborohydride (637.81 mg, 10.15 mmol) was added, and the mixture was stirred at 50 °C for 12 h. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), filtered, and extracted with dichloromethane (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give title product 3b (1.0 g) as a yellow solid.

[0214] MS m / z(ESI): 447.4 [M+1]

[0215] Step 2

[0216] N-[(1S,4r)-4-[(1S)-1-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)ethyl]cyclohexyl]tert-butyl carbamate 3b-1

[0217] N-[(1R,4r)-4-[(1R)-1-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)ethyl]cyclohexyl]tert-butyl carbamate 3b-2

[0218] Compound 3b (500 mg) was purified by chiral preparative HPLC (chiral column: DAICL CHIRALCEL OD-H (250 mm * 30 mm, 5 μm); mobile phase: CO2-MeOH (0.1% NH3H2O); elution gradient: 35%; the corresponding fractions were collected and concentrated under reduced pressure to give the title products 3b-1 (240 mg, 536.90 μmol) and 3b-2 (240 mg, 536.90 μmol).

[0219] The single-configuration compound 3b-1:

[0220] MS m / z(ESI): 447.4 [M+1]

[0221] Chiral SFC analysis: retention time 0.701 min; column: Chiralcel OX-3 50x4.6mm ID, 3µm; mobile phase: CO2 / MeOH (0.05% DEA), elution gradient: 40%.

[0222] The single-configuration compound 3b-2:

[0223] MS m / z(ESI): 447.4 [M+1]

[0224] Chiral SFC analysis: retention time 0.971 min; column: Chiralcel OX-3 50x4.6mm ID, 3µm; mobile phase: CO2 / MeOH (0.05% DEA), elution gradient: 40%.

[0225] Step 3

[0226] N-[(1S,4r)-4-[(1S)-1-[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)azacyclobutane-1-yl]ethyl]cyclohexyl]tert-butyl carbamate 3c-1

[0227] Compound 3b-1 (140 mg, 313.19 μmol) and compound 1c (137 mg, 408.69 μmol) were dissolved in dioxane (2.0 mL) and water (0.4 mL). Potassium phosphate (167 mg, 786.75 μmol) and Pd(dtbpf)Cl2 (21 mg, 32.22 μmol) were added, and the reaction was stirred at 95 °C for 2.0 h under a nitrogen atmosphere. The reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 3c-1 (180 mg, 290.41 μmol, yield: 92.73%).

[0228] MS m / z (ESI): 620.5 [M+1]

[0229] Step 4

[0230] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(1S)-1-[(1r,4S)-4-aminocyclohexyl]ethyl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 3d-1

[0231] Compound 3c-1 (180.00 mg, 290.41 μmol) was dissolved in dioxane (3.0 mL) and trifluoroacetic acid (1.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure, the pH of the solution was adjusted to 11 with 10% NaOH aqueous solution, and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 3d-1 (150 mg, 288.63 μmol, yield: 99.39%). The crude product was used directly in the next reaction without purification.

[0232] MS m / z (ESI): 520.5 [M+1]

[0233] Step 5

[0234] 2-(6-{1-[(1S)-1-(4-ethanesulfonamidocyclohexyl)ethyl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 3-1

[0235] Compound 3d-1 (150.00 mg, 288.63 μmol) and triethylamine (88 mg, 869.65 μmol) were dissolved in dichloromethane (2.0 mL), and ethylsulfonyl chloride (56 mg, 435.53 μmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), and extracted with dichloromethane (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 30%–60%) to give the title product 3d-1 (79.02 mg, 129.16 μmol, yield: 44.75%) as a yellow solid.

[0236] MS m / z(ESI): 612.3 [M+1]

[0237] Chiral SFC analysis: retention time 1.296 min; column: Chiralcel OD-3 50×4.6mm ID, 3µm; mobile phase: CO2 / MeOH (0.05% DEA), elution gradient: 5%–40%.

[0238] 1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.75-7.63(m,1H),7.45-7.24(m,2H),7.09-6.93(m,2H),6.88-6.67(m,1H),4.32-3.42(m,4H),3.28-2 .74(m,7H),2.59(s,3H),2.21-2.10(m,1H),1.96-1.83(m,2H),1.79-1 .61(m,1H),1.53-1.41(m,1H),1.26-0.70(m,18H),0.30-0.25(m,2H).

[0239] Step 6

[0240] N-[(1R,4r)-4-[(1R)-1-[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)azacyclobutane-1-yl]ethyl]cyclohexyl]tert-butyl carbamate 3c-2

[0241] Compound 3b-2 (140 mg, 313.19 μmol) and compound 1c (140 mg, 417.64 μmol) were dissolved in dioxane (2.0 mL) and water (0.5 mL). Potassium phosphate (167 mg, 786.75 μmol) and Pd(dtbpf)Cl2 (21 mg, 32.22 μmol) were added, and the reaction was stirred at 95 °C for 2.0 h under a nitrogen atmosphere. The reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 3c-2 (180 mg, 290.41 μmol, yield: 92.73%).

[0242] MS m / z (ESI): 620.4 [M+1]

[0243] Step 7

[0244] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(1R)-1-[(1r,4R)-4-aminocyclohexyl]ethyl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 3d-2

[0245] Compound 3c-2 (180 mg, 290.41 μmol) was dissolved in dioxane (3.0 mL) and trifluoroacetic acid (1.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure, the pH of the solution was adjusted to 11 with 10% NaOH aqueous solution, and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 3d-2 (150 mg, 288.63 μmol, yield: 99.39%). The crude product was used directly in the next reaction without purification.

[0246] MS m / z(ESI): 520.4 [M+1]

[0247] Step 8

[0248] 2-(6-{1-[(1S)-1-(4-ethanesulfonamidocyclohexyl)ethyl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 3-2

[0249] Compound 3d-2 (150.00 mg, 288.63 μmol) and triethylamine (88 mg, 869.65 μmol) were dissolved in dichloromethane (2.0 mL), and ethylsulfonyl chloride (56 mg, 435.53 μmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), and extracted with dichloromethane (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 30%–60%) to give the title product 3d-2 (76.05 mg, 124.30 μmol, yield: 43.07%) as a yellow solid.

[0250] MS m / z(ESI): 612.3 [M+1]

[0251] Chiral SFC analysis: retention time 1.313 min; column: Chiralcel OD-3 50×4.6mm ID, 3µm; mobile phase: CO2 / MeOH (0.05% DEA), elution gradient: 5%–40%.

[0252] 1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.75-7.62(m,1H),7.44-7.25(m,2H),7.09-6.93(m,2H),6.87-6.68(m,1H),4.31-3.42(m,4H),3.27-2 .71(m,7H),2.59(s,3H),2.21-2.08(m,1H),1.97-1.82(m,2H),1.79-1 .62(m,1H),1.55-1.39(m,1H),1.26-0.71(m,18H),0.30-0.25(m,2H).

[0253] Examples 4-1, 4-2

[0254] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(2R)-1-[(1r,4r)-4-(acrylamido)cyclohexyl]propyl-2-yl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 4-1

[0255] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(2S)-1-[(1r,4r)-4-(acrylamido)cyclohexyl]propyl-2-yl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 4-2

[0256] first step

[0257] N-[(1r,4r)-4-{[methoxy(methyl)carbamoyl]methyl}cyclohexyl]tert-butyl carbamate 4b

[0258] 2-[(1r,4r)-4-{[(tert-butoxy)carbonyl]amino}cyclohexyl]acetic acid 4a (500 mg, 1.94 mmol) and triethylamine (589.85 mg, 5.83 mmol) were dissolved in dichloromethane (8.0 mL), and EDCI (744.98 mg, 3.89 mmol) and HOBt (525.11 mg, 3.89 mmol) were added. The mixture was stirred at room temperature for 30 minutes, and N-methoxymethylamine (227.44 mg, 2.33 mmol, hydrochloride) was added. The reaction mixture was stirred at room temperature for 12 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the elution system to give the title product 4b (525 mg, 1.75 mmol, yield: 89.95%) as a white solid.

[0259] 1 H NMR(400MHz, CDCl3)δ4.39(s,1H),3.67(s,3H),3.46-3.30(m,1H),3.18(s, 3H),2.31(m,2H),1.99(m,2H),1.81(m,3H),1.44(s,9H),1.21-1.00(m,4H).

[0260] Step 2

[0261] N-[(1r,4r)-4-(2-oxopropyl)cyclohexyl]tert-butyl carbamate 4c

[0262] Compound 4b (525 mg, 1.75 mmol) was dissolved in tetrahydrofuran (19.94 mL), cooled to 0 °C, and a solution of methylmagnesium bromide in tetrahydrofuran (3 M, 640.83 μL) was added. The reaction mixture was stirred at room temperature for 12 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product of title product 4c (82 mg, 321.13 μmol, yield: 18.37%) as a white solid.

[0263] 1 H NMR (400MHz, CDCl3) δ4.42-4.32(m,1H),3.44-3.30(m,1H),2.32(d,J=6.4Hz,2H), 2.13(s,3H),2.03-1.95(m,2H),1.79-1.71(m,3H),1.44(s,9H),1.19-0.95(m,4H).

[0264] Step 3

[0265] 3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)azacyclobutane-1-carboxylic acid tert-butyl ester 4a

[0266] Compound 1f (400 mg, 1.24 mmol), compound 1c (909.12 mg, 1.49 mmol), and potassium phosphate (791.54 mg, 3.73 mmol) were dissolved in dioxane (8.0 mL) and water (2.0 mL). Pd(dtbpf)Cl2 (81.01 mg, 124.30 μmol) was added. The reaction mixture was stirred at 90 °C for 12 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and extracted with water (30 mL) and ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative column chromatography with petroleum ether / ethyl acetate as the elution system to give the title product 4d (584 mg, 1.18 mmol, yield: 94.99%).

[0267] MS m / z(ESI): 495.2 [M+1]

[0268] 1 H NMR (400MHz, DMSO-d6) δ8.03(br s,1H),7.77-7.59(m,1H),7.46-7.25(m,2H),7.05(s,1H),6.67(br s,1H),4.20(br d,J=5.4Hz,2H),3.98-3.72(m,3H),3.48(br s,1H),3.29(br d,J=7.1Hz,1H),3.07-2.86(m,1H),2.59(s,3H),1.40(s,9H),1.21-1.11(m,1H),0.97-0.70(m,6H),0.32(br d,J=6.1Hz,2H).

[0269] Step 4

[0270] 2-[6-(azacyclobutane-3-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 4e

[0271] Compound 4d (150 mg, 303.28 μmol) was dissolved in dioxane (3.0 mL), and trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 11 with 10% sodium hydroxide aqueous solution. The solution was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 4e (100 mg). The crude product was used directly in the next reaction without purification.

[0272] MS m / z(ESI): 395.3 [M+1]

[0273] Step 5

[0274] N-[(1r,4r)-4-{2-[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)azacyclobutane-1-yl]propyl}cyclohexyl]tert-butyl carbamate 4f

[0275] Compound 4e (500 mg, 1.27 mmol) and compound 4c (388.38 mg, 1.52 mmol) were dissolved in methanol (10 mL), and zinc chloride (345.50 mg, 2.53 mmol) was added. The mixture was stirred at 50 °C for 1.0 h. Sodium cyanoborohydride (238.95 mg, 3.80 mmol) was added, and the mixture was stirred at 50 °C for 11 h. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted to 10 with 10% sodium hydroxide aqueous solution. The mixture was extracted with dichloromethane (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 4f (200 mg, 315.54 μmol, yield: 24.89%) as a yellow solid.

[0276] MS m / z (ESI): 634.3 [M+1]

[0277] Step 6

[0278] N-[(1r,4r)-4-[(2R)-2-[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)azacyclobutane-1-yl]propyl]cyclohexyl]carbamate 4f-1

[0279] N-[(1r,4r)-4-[(2S)-2-[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)azacyclobutane-1-yl]propyl]cyclohexyl]carbamate 4f-2

[0280] Compound 4f (200 mg, 315.54 μmol) was purified by chiral preparative HPLC (chiral preparative column: Chiral-AD-30-DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: CO2-IPA (0.1% NH3H2O); elution gradient: 28%). The corresponding fractions were collected and concentrated under reduced pressure to give the title products 4f-1 (71 mg, 112.02 μmol, yield: 8.84%) and 4f-2 (81 mg, 127.79 μmol, yield: 10.08%).

[0281] The single-configuration compound 4f-1:

[0282] MS m / z (ESI): 634.5 [M+1]

[0283] Chiral SFC analysis: retention time 3.822 min; column: Cellulose-2 50X 4.6mm ID, 3µm; mobile phase: n-hexane / IPA+ACN (0.1% IPAm), elution gradient: 10%.

[0284] The single-configuration compound 4f-2:

[0285] MS m / z (ESI): 634.5 [M+1]

[0286] Chiral SFC analysis: retention time 4.850 min; column: Cellulose-2 50X 4.6mm ID, 3µm; mobile phase: n-hexane / IPA+ACN (0.1% IPAm), elution gradient: 10%.

[0287] Step 7

[0288] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(2R)-1-[(1r,4r)-4-aminocyclohexyl]propyl-2-yl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 4g-1

[0289] Compound 4f-1 (71.00 mg, 112.02 μmol) was dissolved in dioxane (3.0 mL) and trifluoroacetic acid (1.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure, the pH of the solution was adjusted to 10 with 10% NaOH aqueous solution, and extracted with dichloromethane / isopropanol (10:1; 10 mL x 5). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 4f-1 (59 mg, 110.54 μmol, yield: 98.69%). The crude product was used directly in the next reaction without purification.

[0290] MS m / z (ESI): 534.6 [M+1]

[0291] Step 8

[0292] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(2R)-1-[(1r,4r)-4-(acrylamido)cyclohexyl]propyl-2-yl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 4-1

[0293] Acrylic acid (7.97 mg, 110.54 μmol), compound 4g-1 (59.00 mg, 110.54 μmol), and triethylamine (33.56 mg, 331.63 μmol) were dissolved in dichloromethane (5.0 mL), and HATU (84.06 mg, 221.09 μmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography with dichloromethane / methanol as the elution system to give the title product 4-1 (40.28 mg, 68.53 μmol, yield: 61.99%) as a white solid.

[0294] MS m / z(ESI): 588.3 [M+1]

[0295] Chiral SFC analysis: retention time 1.256 min; column: Chiralcel OD-3 50×4.6mm ID, 3µm; mobile phase: CO2 / MeOH (0.05% DEA), elution gradient: 5%–40%.

[0296] 1 H NMR (400MHz, CDCl3) δ7.65-7.55(m,1H),7.48(br s,1H),7.18-7.02(m,3H),6.87-6.74(m,1H),6.19(br d,J=17.0Hz,1H),6.05-5.92(m,1H),5.55(d,J=10.3Hz,1H),5.28(br d,J=6.8Hz,1H),3.99-3.66(m,4H),3.47-2.79(m,5H),2.08-1.79(m,4H),1.35-1.16(m ,5H),1.13-1.03(m,4H),1.02-0.84(m,10H),0.84-0.68(m,2H),0.20(t,J=6.9Hz,2H).

[0297] Step 9

[0298] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(2S)-1-[(1r,4r)-4-aminocyclohexyl]propyl-2-yl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 4g-2

[0299] Compound 4f-2 (81 mg, 127.79 μmol) was dissolved in dioxane (4.0 mL) and trifluoroacetic acid (1.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 10 with 10% NaOH aqueous solution, and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 4f-2 (50 mg, 93.68 μmol). The crude product was used directly in the next reaction without purification.

[0300] MS m / z (ESI): 534.4 [M+1]

[0301] Step 10

[0302] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(2S)-1-[(1r,4r)-4-(acrylamido)cyclohexyl]propyl-2-yl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 4-2

[0303] Acrylic acid (10.13 mg, 140.52 μmol), compound 4g-2 (50.00 mg, 93.68 μmol), and triethylamine (28.44 mg, 281.05 μmol) were dissolved in dichloromethane (2.0 mL), and HATU (71.24 mg, 187.36 μmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 28%–58%) to give the title product 4g-2 (8.74 mg, 14.87 μmol, yield: 15.87%) as a white solid.

[0304] MS m / z (ESI): 588.6 [M+1]

[0305] Chiral SFC analysis: retention time 1.312 min; column: Chiralcel OD-3 50×4.6mm ID, 3µm; mobile phase: CO2 / MeOH (0.05% DEA), elution gradient: 5%–40%.

[0306] 1H NMR (400MHz, DMSO-d6) δ7.96-7.84(m,2H),7.72-7.64(m,1H),7.38(dt,J=2.8,8.4 Hz,1H),7.31(dd,J=2.8,9.2Hz,1H),7.02(d,J=5.6Hz,1H),6.73(d,J=16.4Hz,1H), 6.25-6.10(m,1H),6.09-6.01(m,1H),5.54(dd,J=2.0,10.0Hz,1H),3.55-3.43(m, 5H),3.30-3.24(m,1H),3.09-2.88(m,3H),2.59(s,3H),2.32-2.22(m,1H),1.79(br d,J=9.6Hz,3H),1.69(br d,J=12.4Hz,1H),1.28-1.08(m,5H),1.04-0.95(m,2H),0.90(br d,J=6.4Hz,3H),0.85(br d,J=6.0Hz,4H),0.82-0.71(m,3H),0.31-0.27(m,2H).

[0307] Examples 5-1, 5-2

[0308] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(2S)-1-[1-(acryloyl)piperidin-4-yl]propyl-2-yl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 5-1

[0309] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(2S)-1-[1-(acryloyl)piperidin-4-yl]propyl-2-yl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 5-2

[0310] first step

[0311] 4-{2-[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)azacyclobutane-1-yl]propyl}piperidine-1-carboxylic acid tert-butyl ester 5b

[0312] 4-[1-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester 1i

[0313] Compound 4e (1.0 g, 2.53 mmol) and tert-butyl 4-(2-oxopropyl)piperidine-1-carboxylic acid ester 5a (734.10 mg, 3.04 mmol) were dissolved in methanol (20 mL), and zinc chloride (691.01 mg, 5.07 mmol) was added. The mixture was stirred at 50 °C for 1.0 h. Sodium cyanoborohydride (477.90 mg, 7.60 mmol) was added, and the mixture was stirred at 50 °C for 15 h. The reaction mixture was quenched with saturated potassium carbonate aqueous solution (100 mL), filtered, and extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 5b (1.64 g, 2.65 mmol, yield: 104.38%) as a yellow solid.

[0314] MS m / z (ESI): 620.5 [M+1]

[0315] Step 2

[0316] 4-[(2S)-2-[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)azacyclobutane-1-yl]propyl]piperidine-1-carboxylic acid tert-butyl ester 5b-1

[0317] 4-[(2R)-2-[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)azacyclobutane-1-yl]propyl]piperidine-1-carboxylic acid tert-butyl ester 5b-2

[0318] Compound 5b (500 mg, 806.70 μmol) was purified by chiral preparative HPLC (chiral preparative column: Chiral-OD-30-DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm); mobile phase: CO2-IPA (0.1% NH3H2O); elution gradient: 20%). The corresponding fractions were collected and concentrated under reduced pressure to give the title products 5b-1 (133 mg, 214.58 μmol, yield: 26.6%) and 5b-2 (187 mg, 301.71 μmol, yield: 37.40%).

[0319] Single-configuration compound 5b-1:

[0320] MS m / z (ESI): 620.5 [M+1]

[0321] Chiral SFC analysis: retention time 2.201 min; column: Chiralcel OD-3 50x4.6mm ID, 3µm; mobile phase: CO2 / IPA (0.05% DEA), elution gradient: 5%–20%.

[0322] The single-configuration compound 5b-2:

[0323] MS m / z (ESI): 620.5 [M+1]

[0324] Chiral SFC analysis: retention time 2.376 min; column: Chiralcel OD-3 50x4.6mm ID, 3µm; mobile phase: CO2 / IPA (0.05% DEA), elution gradient: 5%–20%.

[0325] Step 3

[0326] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(2S)-1-(piperidin-4-yl)prop-2-yl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 5c-1

[0327] Compound 5b-1 (133 mg, 214.58 μmol) was dissolved in dioxane (1.0 mL) and trifluoroacetic acid (1.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure, the pH of the solution was adjusted to 10 with 10% NaOH aqueous solution, and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 5c-1 (92 mg, 177.26 μmol, yield: 82.88%). The crude product was used directly in the next reaction without purification.

[0328] MS m / z(ESI): 520.3 [M+1]

[0329] Step 4

[0330] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(2S)-1-[1-(acryloyl)piperidin-4-yl]propyl-2-yl]azacyclobutane-3-yl}imidazo[1,5-a]pyridine-8-

[0331] 5-1 (N-(isopropyl)benzamide)

[0332] Compound 5c-1 (35 mg, 67.35 μmol) was dissolved in dichloromethane (0.5 mL), and acrylic acid (9.71 mg, 134.69 μmol), triethylamine (20.44 mg, 202.04 μmol), and HATU (38.41 mg, 101.02 μmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 26%–56%) to give the title product 5-1 (4.28 mg, 7.46 μmol, yield: 11.08%) as a white solid.

[0333] MS m / z(ESI): 574.4 [M+1]

[0334] Chiral SFC analysis: retention time 1.358 min; column: Chiralcel OD-3 50×4.6mm ID, 3µm; mobile phase: CO2 / MeOH (0.05% DEA), elution gradient: 5%–40%.

[0335] 1 H NMR (400MHz, CDCl3) δ7.59-7.75(m,1H)7.52(br d,J=3.60Hz,1H)7.08-7.24(m,3H)6.79-6.95(m,1H)6.50-6.65(m,1H)6.19-6.30(m,1H)5.66(br d,J=10.40Hz,1H)4.55-4.71(m,1H)3.62-4.08(m,4H)3.22-3.57(m,3H)2.88-3.11(m,2H)2.52-2.76(m,5H)1.75(br d,J=0.80Hz,2H)1.01-1.43(m,9H)0.68-1.00(m,7H)0.25(br d,J=6.40Hz,2H).

[0336] Step 5

[0337] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(2S)-1-(piperidin-4-yl)prop-2-yl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 5c-2

[0338] Compound 5b-2 (187 mg, 301.71 μmol) was dissolved in dioxane (1.5 mL) and trifluoroacetic acid (1.5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure and extracted with 10% NaOH aqueous solution (20 mL) and dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 5c-2 (130 mg, 250.15 μmol, yield: 86.67%). The crude product was used directly in the next reaction without purification.

[0339] MS m / z(ESI): 520.3 [M+1]

[0340] Step 6

[0341] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(2S)-1-[1-(acryloyl)piperidin-4-yl]propyl-2-yl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 5-2

[0342] Compound 5c-2 (55 mg, 105.83 μmol) was dissolved in dichloromethane (1.0 mL), and acrylic acid (15.25 mg, 211.66 μmol), triethylamine (32.13 mg, 317.49 μmol), and HATU (60.36 mg, 158.75 μmol) were added. The reaction mixture was stirred at room temperature for 1.0 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate aqueous solution (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 27%–57%) to give the title product 5-2 (11.76 mg, 20.50 μmol, yield: 19.37%) as a yellow solid.

[0343] MS m / z (ESI): 574.5 [M+1]

[0344] Chiral SFC analysis: retention time 1.391 min; column: Chiralcel OD-3 50×4.6mm ID, 3µm; mobile phase: CO2 / MeOH (0.05% DEA), elution gradient: 5%–40%.

[0345] 1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.71-7.64(m,1H),7.41-7.28(m,2H),7.07-7.00(m,1H), 6.83-6.71(m,2H),6.05(dd,J=2.0,16.4Hz,1H),5.63(dd,J=1.6,10.2Hz,1H),4.44-4.31(m,1 H),4.05-3.93(m,1H),3.55-3.42(m,4H),3.11-2.89(m,4H),2.65-2.60(m,1H),2.58(s,3H),2 .34-2.28(m,1H),1.80-1.54(m,3H),1.27-1.19(m,1H),1.08-0.69(m,14H),0.30-0.26(m,2H).

[0346] Following similar steps to those in the above embodiments, the following compounds were prepared and characterized:

[0347] Examples 7-1, 7-2

[0348] N-Ethyl-5-fluoro-2-(6-{1-[(1S)-1-{3-[(2-methoxyethyl)(methyl)amino]cyclobutyl}-2-methylpropyl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 7-1

[0349] N-Ethyl-5-fluoro-2-(6-{1-[(1R)-1-{3-[(2-methoxyethyl)(methyl)amino]cyclobutyl}-2-methylpropyl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 7-2

[0350] first step

[0351] N-Methoxy-N-methyl-3-oxocyclobutane-1-formamide 7b

[0352] 3-Oxocyclobutane-1-carboxylic acid 7a (10 g, 87.64 mmol) and triethylamine (26.61 g, 262.93 mmol) were dissolved in dichloromethane (200 mL), and EDCI (20.16 g, 105.17 mmol) and HOBt (14.21 g, 105.17 mmol) were added. The mixture was stirred at room temperature for 5.0 min, and N-methoxymethylamine (10.26 g, 105.17 mmol, hydrochloride) was added. The reaction mixture was stirred at room temperature for 12 h. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate as the elution system to give the title product 195b (8.5 g, 54.08 mmol, yield: 61.71%) as a yellow liquid.

[0353] 1 H NMR (400MHz, CDCl3) δ3.73(s,3H),3.63-3.53(m,1H),3.52-3.41(m,2H),3.29-3.14(m,5H).

[0354] Step 2

[0355] N,3,3-Trimethoxy-N-methylcyclobutane-1-carboxamide 7c

[0356] Compound 7b (4.0 g, 25.45 mmol) was dissolved in methanol (50 mL), and trimethyl orthoformate (5.40 g, 50.90 mmol) and 4-toluenesulfonic acid monohydrate (484.12 mg, 2.55 mmol) were added. The mixture was stirred at 50 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (60 mL) and washed with saturated sodium bicarbonate aqueous solution (30 mL × 3) and saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title product 7c (4.5 g, 22.14 mmol, yield: 87%) as a colorless liquid.

[0357] 1 H NMR (400MHz, CDCl3) δ3.66 (s, 3H), 3.20-3.14 (m, 10H), 2.39 (br d, J = 8.9Hz, 4H).

[0358] Step 3

[0359] 1-(3,3-Dimethoxycyclobutyl)-2-methylpropane-1-one 7d

[0360] Under nitrogen protection, compound 7c (2.0 g, 9.84 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to 0 °C. Isopropyl magnesium chloride solution (2 M, 14.76 mL) was added dropwise to the reaction mixture. After the addition was complete, the mixture was slowly heated to room temperature and stirred for 2.0 h. A saturated ammonium chloride aqueous solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate as the elution system to give the title product 7d (1.1 g, 5.91 mmol, yield: 60.02%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ3.19 (s, 3H), 3.16-3.09 (m, 4H), 2.65 (td, J = 6.9, 13.9Hz, 1H), 2.39-2.27 (m, 4H), 1.10 (d, J = 6.9Hz, 6H).

[0361] Step 4

[0362] 3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}-1-[1-(3,3-dimethoxycyclobutyl)-2-methylpropyl]azacyclobutane 7e

[0363] Compound 1 g (2 g, 9.02 mmol) and compound 7d (2.00 g, 10.74 mmol) were dissolved in methanol (10 mL), and zinc chloride (2.46 g, 18.04 mmol) was added. The mixture was stirred at 50 °C for 1.0 h. Sodium cyanoborohydride (1.70 g, 27.07 mmol) was added, and the mixture was stirred at 50 °C for 11 h. The reaction mixture was filtered, and the filtrate was quenched with saturated sodium bicarbonate aqueous solution (25 mL). The mixture was extracted with dichloromethane / methanol (10:1; 50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title product 7e (1.3 g, 3.32 mmol, yield: 36.77%) as a yellow oil.

[0364] MS m / z(ESI): 392.1 [M+1]

[0365] Step 5

[0366] 3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}-1-[(1S)-1-(3,3-dimethoxycyclobutyl)-2-methylpropyl]azacyclobutane 7e-1

[0367] 3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}-1-[(1R)-1-(3,3-dimethoxycyclobutyl)-2-methylpropyl]azacyclobutane 7e-2

[0368] Compound 7e (1.3 g, 3.32 mmol) was purified by chiral preparative HPLC (chiral preparative column: Chiral-AD-30-DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: CO2-IPA (0.1% NH3H2O); elution gradient: 25%). The corresponding fractions were collected and concentrated under reduced pressure to give the title products 7e-1 (300 mg, 765.44 μmol, yield: 23.08%) and 7e-2 (300 mg, 765.44 μmol, yield: 23.08%).

[0369] The single-configuration compound 7e-1:

[0370] MS m / z(ESI): 392.0 [M+1]

[0371] Chiral SFC analysis: retention time 1.311 min; column: Chiralpak AD-3 50x4.6mm ID, 3µm; mobile phase: CO2 / IPA (0.05% DEA), elution gradient: 5%–40%.

[0372] The single-configuration compound 7e-2:

[0373] MS m / z(ESI): 392.1 [M+1]

[0374] Chiral SFC analysis: retention time 1.549 min; column: Chiralpak AD-3 50x4.6mm ID, 3µm; mobile phase: CO2 / IPA (0.05% DEA), elution gradient: 5%–40%.

[0375] Step 6

[0376] 2-(6-{1-[(1S)-1-(3,3-dimethoxycyclobutyl)-2-methylpropyl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 7f-1

[0377] Compound 7e-1 (280 mg, 714.41 μmol) and compound 1c (263.43 mg, 785.85 μmol) were dissolved in dioxane (4.0 mL) and water (1.0 mL). Potassium phosphate (454.93 mg, 2.14 mmol) and Xphos Pd G4 (61.47 mg, 71.44 μmol) were added, and the mixture was stirred at 95 °C for 1 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 7f-1 (390 mg, 690.59 μmol, yield: 96.67%).

[0378] MS m / z (ESI): 565.4 [M+1]

[0379] Step 7

[0380] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(1S)-2-methyl-1-(3-oxocyclobutyl)propyl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 7g-1

[0381] Compound 7f-1 (300 mg, 531.23 μmol) was dissolved in dioxane (10 mL) and trifluoroacetic acid (1.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure, the pH of the solution was adjusted to 7 with saturated sodium carbonate aqueous solution, and extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 7f-1 (270 mg, 520.57 μmol, yield: 97.99%). The crude product was used directly in the next reaction without purification.

[0382] MS m / z (ESI): 519.5 [M+1]

[0383] Step 8

[0384] N-Ethyl-5-fluoro-2-(6-{1-[(1S)-1-{3-[(2-methoxyethyl)(methyl)amino]cyclobutyl}-2-methylpropyl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 7-1

[0385] Compound 7 g-1 (135 mg, 260.28 μmol) and 2-methoxy-N-methylethylamine (23.20 mg, 260.28 μmol) were dissolved in methanol (4.0 mL), and acetic acid (15.63 mg, 260.28 μmol) was added. The mixture was stirred at 50 °C for 0.5 h. Sodium cyanoborohydride (49.07 mg, 780.85 μmol) was added, and the mixture was stirred at 50 °C for 12 h. The reaction mixture was cooled to room temperature, and the reaction was quenched with saturated sodium bicarbonate aqueous solution (20 mL). The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 40%-70%) to obtain the title product 7-1 (73.72 mg, 124.57 μmol, yield: 47.86%), which was a yellow solid.

[0386] MS m / z(ESI): 592.4 [M+1]

[0387] Chiral SFC analysis: retention time 2.019 min; column: Chiralpak IK-3 50x4.6mm ID, 3µm; mobile phase: CO2 / MeOH (0.05% DEA), elution gradient: 5%–40%.

[0388] 1 H NMR(400MHz,DMSO-d6)δ7.96-7.87(m,1H),7.75-7.63(m,1H),7.45-7.24(m,2 H),7.07-7.01(m,1H),6.86-6.69(m,1H),3.57-3.35(m,5H),3.30-2.67(m,8H ),2.62-2.56(m,3H),2.34-2.27(m,2H),2.14-1.98(m,6H),1.88-1.76(m,1H) ,1.73-1.59(m,2H),1.52-1.39(m,1H),1.16-0.64(m,14H),0.32-0.25(m,2H).

[0389] Step 9

[0390] 2-(6-{1-[(1R)-1-(3,3-dimethoxycyclobutyl)-2-methylpropyl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 7f-2

[0391] Compound 7e-2 (230 mg, 586.83 μmol) and compound 1c (255.73 mg, 762.88 μmol) were dissolved in dioxane (2.0 mL) and water (0.5 mL). Potassium phosphate (311.41 mg, 1.47 mmol) and Pd(dtbpf)Cl2 (38.25 mg, 58.68 μmol) were added, and the reaction was stirred at 95 °C for 2.0 h under a nitrogen atmosphere. The reaction solution was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 7f-2 (300 mg, 531.23 μmol, yield: 90.52%).

[0392] MS m / z (ESI): 565.4 [M+1]

[0393] Step 10

[0394] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(1R)-2-methyl-1-(3-oxocyclobutyl)propyl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 7g-2

[0395] Compound 7f-2 (300 mg, 531.23 μmol) was dissolved in dioxane (5.0 mL) and trifluoroacetic acid (1.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 11 with saturated sodium carbonate aqueous solution, and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 7f-2 (250 mg, 482.01 μmol, yield: 90.74%). The crude product was used directly in the next reaction without purification.

[0396] MS m / z (ESI): 519.4 [M+1]

[0397] Step 11

[0398] N-Ethyl-5-fluoro-2-(6-{1-[(1R)-1-{3-[(2-methoxyethyl)(methyl)amino]cyclobutyl}-2-methylpropyl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 7-2

[0399] Compound 7 g-2 (150 mg, 289.20 μmol) and 2-methoxy-N-methylethylamine (38.67 mg, 433.81 μmol) were dissolved in methanol (2.0 mL), and acetic acid (34.73 mg, 578.41 μmol) was added. The mixture was stirred at 25 °C for 0.5 h. Sodium cyanoborohydride (54.52 mg, 867.61 μmol) was added, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was cooled to room temperature, and the reaction was quenched with saturated sodium bicarbonate aqueous solution (20 mL). The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 34%-64%) to obtain the title product 7-2 (8.06 mg, 13.62 μmol, yield: 4.71%), which was a yellow solid.

[0400] MS m / z(ESI): 592.4 [M+1]

[0401] Chiral SFC analysis: retention time 1.121 min; column: Chiralpak OD-3 50x4.6mm ID, 3µm; mobile phase: CO2 / MeOH (0.05% DEA), elution gradient: 5%–40%.

[0402] 1 H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.74-7.64(m,1H),7.43-7.27(m,2H),7 .08-7.00(m,1H),6.89-6.69(m,1H),4.39-3.41(m,5H),3.32-2.83(m,8H),2 .62-2.56(m,3H),2.34-2.27(m,2H),2.15-1.98(m,6H),1.86-1.76(m,1H),1 .72-1.59(m,2H),1.51-1.40(m,1H),1.09-0.68(m,14H),0.30-0.25(m,2H).

[0403] Following similar steps to those in the above embodiments, the following compounds were prepared and characterized:

[0404] Example 9

[0405] 2-[6-(1-{[1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl]methyl}azacyclobutane-3-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 9

[0406] first step

[0407] [1-(5,6-Dimethoxypyridazin-3-yl)piperidin-4-yl]methanol 9c

[0408] Compound 6-chloro-3,4-dimethoxypyridazine 9a (200 mg, 1.15 mmol) and compound (piperidin-4-yl)methanol 9b (197.91 mg, 1.72 mmol) were dissolved in dioxane (8.0 mL). Cesium carbonate (746.50 mg, 2.29 mmol) and Pd-PEPPSI-IHept-Cl (111.44 mg, 114.56 μmol) were added, and the reaction was carried out under nitrogen atmosphere at 100 °C with stirring for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 9c (272 mg, 1.07 mmol, yield: 93.74%).

[0409] MS m / z(ESI): 254.2 [M+1]

[0410] Step 2

[0411] 1-(5,6-Dimethoxypyridazine-3-yl)piperidine-4-carboxaldehyde 9d

[0412] Compound 9c (270 mg, 1.07 mmol) was dissolved in dichloromethane (6.0 mL), and DMP oxidant (678.17 mg, 1.60 mmol) was added. The mixture was stirred at 25 °C for 1.0 h. The reaction solution was quenched with saturated sodium carbonate aqueous solution (20 mL) and extracted with dichloromethane (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 9d (96 mg, 382.04 μmol, yield: 35.84%).

[0413] MS m / z(ESI): 252.1 [M+1]

[0414] Step 3

[0415] 2-[6-(1-{[1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl]methyl}azacyclobutane-3-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 9

[0416] Compound 4e (85 mg, 215.47 μmol) and compound 9d (60 mg, 238.78 μmol) were dissolved in methanol (2.0 mL), and acetic acid (12.94 mg, 215.47 μmol) was added. The mixture was stirred at 50 °C for 0.5 h. Sodium cyanoborohydride (40.62 mg, 646.41 μmol) was added, and the mixture was stirred at 50 °C for 12 h. The reaction mixture was cooled to room temperature, and the reaction was quenched with saturated sodium bicarbonate aqueous solution (10 mL). The mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 22%-52%) to give title product 9 (83.89 mg, 133.21 μmol, yield: 61.82%) as a white solid.

[0417] MS m / z (ESI): 630.4 [M+1]

[0418] 1 H NMR(400MHz,DMSO-d6)δ7.95-7.91(m,1H),7.72-7.65(m,1H),7.41-7.29(m,2H),7.05-7.00(m,1H),6.85- 6.72(m,2H),4.21-4.11(m,2H),3.89-3.85(m,3H),3.84-3.81(m,3H),3.61-3.52(m,3H),3.49-3.40(m,1H ),3.31-3.25(m,1H),3.18-3.07(m,2H),2.98-2.85(m,1H),2.79-2.70(m,2H),2.61-2.57(m,3H),2.37-2. 29(m,2H),1.83-1.69(m,2H),1.59-1.46(m,1H),1.26-1.00(m,3H),0.92-0.73(m,6H),0.30-0.25(m,2H).

[0419] Example 13

[0420] 2-(6-{1-[(1S)-1-[1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl]ethyl}azacyclobutane-3-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 13

[0421] first step

[0422] [1-(5,6-Dimethoxypyridazin-3-yl)piperidin-4-yl]methanol 9c

[0423] Compound 6-chloro-3,4-dimethoxypyridazine 9a (16.57 mg, 94.92 μmol) and compound 1k-1 (40 mg, 79.10 μmol) were dissolved in dioxane (2.0 mL). Cesium carbonate (51.55 mg, 158.21 μmol) and Pd-PEPPSI-IHept-Cl (7.69 mg, 7.91 μmol) were added, and the reaction was stirred at 100 °C for 4.0 h under a nitrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 30%-50%) to give title product 13 (14.18 mg, 22.03 μmol, yield: 27.84%) as a white solid. MS m / z (ESI): 644.5 [M+1]

[0424] 1 H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.73-7.63(m,1H),7.45-7.21(m,2H),7.10-6.9 6(m,1H),6.92-6.62(m,2H),4.30-4.19(m,2H),3.92-3.73(m,6H),3.59-3.43(m,5H), 3.15-3.04(m,2H),2.98-2.87(m,1H),2.76-2.62(m,2H),2.61-2.56(m,3H),2.28-2.1 8(m,1H),1.79-1.45(m,3H),1.39-1.02(m,3H),0.96-0.63(m,9H),0.32-0.23(m,2H).

[0425] Example 14

[0426] 2-{4-[4-(3-{8-[2-(4-cyclopropylpyrimidin-5-yl)-6-fluoropyridin-3-yl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazin-1-yl}ethanol 14

[0427] first step

[0428] (6-{1-[(tert-butoxy)carbonyl]azacyclobutane-3-yl}-3-methylimidazol[1,5-a]pyridin-8-yl)boronic acid 14a

[0429] Compound 1f (500 mg, 1.55 mmol), pinacol borate (434.01 mg, 1.71 mmol), and potassium acetate (457.47 mg, 4.66 mmol) were dissolved in dioxane (10.0 mL). Pd(dppf)Cl2 (126.89 mg, 155.38 μmol) was added. The reaction mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The reaction solution was cooled without further treatment and used directly in the next reaction. LC-MS analysis yielded the title product 14a.

[0430] MS m / z(ESI): 332.1 [M+1]

[0431] Step 2

[0432] 3-[8-(2-chloro-6-fluoropyridin-3-yl)-3-methylimidazo[1,5-a]pyridin-6-yl]azacyclobutane-1-carboxylic acid tert-butyl ester 14b

[0433] Compound 3-bromo-2-chloro-6-fluoropyridine (317.71 mg, 1.51 mmol) and potassium phosphate (961.43 mg, 4.53 mmol) were dissolved in the compound 14a solution obtained in the previous step and water (2.0 mL). Pd(dppf)Cl2 (123.29 mg, 150.98 μmol) was added. The reaction was stirred at 95 °C for 2 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure after cooling. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 30%-30%) to give the title product 14b (220 mg, 527.74 μmol, yield: 34.95%) as a yellow solid.

[0434] MS m / z(ESI): 417.2 [M+1]

[0435] Step 3

[0436] 4-Cyclopropyl-5-(4,4,5,5-Tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)pyrimidine 14d

[0437] Compound 5-bromo-4-cyclopropylpyrimidine 14c (2 g, 10.05 mmol), pinacol borate (3.83 g, 15.07 mmol), and potassium acetate (2.96 g, 30.14 mmol) were dissolved in dioxane (20.0 mL). Pd(dppf)Cl2 (367.60 mg, 502.39 μmol) was added. The reaction was stirred at 95 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the elution system to give the title product 14d (2.5 g, 10.16 mmol, yield: 101.10%).

[0438] MS m / z(ESI): 247.0 [M+1]

[0439] Step 4

[0440] 6-Chloro-2-methylhexane-3-one 14f

[0441] 4-Chlorobutyryl chloride 14e (30 g, 212.77 mmol) was dissolved in anhydrous tetrahydrofuran (500 mL), and a tetrahydrofuran solution of acetylacetone iron(III) (1.80 g, 5.11 mmol) (100 mL) was added. The mixture was stirred for 10 minutes. The solution was cooled to 0 °C, and isopropyl magnesium chloride (2 M, 107 mL) was slowly added dropwise. The reaction mixture was stirred at 0 °C for 0.5 hours. Then, a saturated aqueous solution of ammonium chloride (100 mL) was slowly added, and the mixture was stirred thoroughly. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, and the remaining aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the elution system to give the title product 14f (21.4 g, 143.98 mmol, yield: 67.67%) as a colorless oil.

[0442] 1 H NMR (400MHz, CDCl3) δ3.55-3.61(m,2H),2.53-2.71(m,3H),2.01-2.09(m,2H),1.10(d,J=7.20Hz,6H).

[0443] Step 5

[0444] 6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylhexane-3-one 14g

[0445] Compound 14f (11.4 g, 69.03 mmol) was dissolved in acetonitrile (120 mL), and 2-(piperazin-1-yl)ethanol (8.99 g, 69.03 mmol) and DIPEA (26.68 g, 206.44 mmol) were added. The reaction mixture was stirred at 80 °C for 16.0 h under a nitrogen atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was added to a saturated aqueous potassium carbonate solution (200 mL), and the mixture was extracted with dichloromethane (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 14 g (17.4 g, 71.80 mmol, yield: 104%) as a brown oil.

[0446] MS m / z(ESI): 243.1 [M+1]

[0447] 1 H NMR (400MHz, DMSO-d6) δ4.36(br s,1H),3.46(br s,2H),2.57-2.65(m,1H),2.45(br t,J=6.80Hz,2H),2.22-2.40(m,10H),2.18(br t,J=7.20Hz,2H),1.59(br t,J=6.80Hz,2H),0.99(d,J=6.80Hz,6H).

[0448] Step 6

[0449] 3-{8-[2-(4-cyclopropylpyrimidin-5-yl)-6-fluoropyridin-3-yl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-carboxylic acid tert-butyl ester

[0450] 14h

[0451] Compound 14b (100 mg, 239.88 μmol), compound 14d (70.84 mg, 287.86 μmol), and potassium phosphate (152.76 mg, 719.64 μmol) were dissolved in dioxane (4.0 mL) and water (1.0 mL). Pd(dtbpf)Cl2 (15.63 mg, 23.99 μmol) was added. The reaction mixture was stirred at 80 °C for 4 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure after cooling. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate as the elution system. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.225% formic acid), elution gradient: 15%-45%) to give the title product 14h (25 mg, 49.94 μmol, yield: 20.82%) as a yellow solid.

[0452] MS m / z(ESI): 501.3 [M+1]

[0453] Step 7

[0454] 5-{3-[6-(azacyclobutane-3-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-6-fluoropyridin-2-yl}-4-cyclopropylpyrimidine 14i

[0455] Compound 14h (25 mg, 49.94 μmol) was dissolved in dioxane (1.0 mL), and trifluoroacetic acid (296.00 mg, 2.60 mmol, 0.2 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 10 with 10% sodium hydroxide aqueous solution. The solution was extracted with dichloromethane (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product of title product 14i (20 mg, 49.94 μmol, yield: 100%). The crude product was used directly in the next reaction without purification.

[0456] MS m / z(ESI): 401.2 [M+1]

[0457] Step 8

[0458] 2-{4-[4-(3-{8-[2-(4-cyclopropylpyrimidin-5-yl)-6-fluoropyridin-3-yl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazin-1-yl}ethanol 14

[0459] Compound 14i (20 mg, 49.94 μmol) and compound 14g (14.53 mg, 59.93 μmol) were dissolved in methanol (1.0 mL), and acetic acid (3.00 mg, 49.94 μmol) was added. The mixture was stirred at 50 °C for 0.5 h. Sodium cyanoborohydride (9.42 mg, 149.83 μmol) was added, and the mixture was stirred at 50 °C for 4.0 h. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate aqueous solution (10 mL), and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.05% ammonia), elution gradient: 23%-43%) to give title product 14 (3.32 mg, 5.30 μmol, yield: 10.61%) as a white solid.

[0460] MS m / z(ESI): 627.5 [M+1]

[0461] 1H NMR(400MHz,DMSO-d6)δ8.91-8.74(m,1H),8.59-8.43(m,1H),8.40-8.26(m,1H),7.94-7.71(m,1H),7.52- 7.44(m,1H),7.11-6.97(m,1H),6.68-6.23(m,1H),4.44-4.23(m,1H),3.50-3.39(m,7H),2.78-2.73(m,1H ),2.71-2.66(m,1H),2.57-2.54(m,3H),2.37-2.29(m,7H),2.23-2.18(m,2H),1.93-1.88(m,1H),1.80-1. 72(m,1H),1.68-1.59(m,1H),1.45-1.35(m,2H),1.27-1.06(m,3H),0.87-0.73(m,8H),0.64-0.46(m,2H).

[0462] Example 15

[0463] 2-{4-[4-(3-{8-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenyl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazin-1-yl}ethanol 15

[0464] Compound 15a (71 mg, 177.74 μmol, synthesized via the same route as compound 14i, replacing 3-bromo-2-chloro-6-fluoropyridine with 2-bromo-4-fluoro-1-iodobenzene) and compound 14 g (43.08 mg, 177.74 μmol) were dissolved in methanol (2.0 mL), and acetic acid (16.01 mg, 266.61 μmol) was added. The mixture was stirred at 50 °C for 0.5 h. Sodium cyanoborohydride (33.51 mg, 533.22 μmol) was added, and the mixture was stirred at 50 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with water (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.05% ammonia), elution gradient: 25%-55%) to obtain the title product 15 (16.84 mg, 26.91 μmol, yield: 15.14%), which was a white solid.

[0465] MS m / z(ESI): 627.5 [M+1]

[0466] 1H NMR (400MHz, DMSO-d6) δ8.84-8.76(m,1H),8.47(d,J=17.6Hz,1H),7.81-7.72(m,2H),7.54-7.44(m,2H),7.03(d,J=6 .4Hz,1H),6.35(d,J=12.0Hz,1H),4.43-4.28(m,1H),3.46(t,J=6.0Hz,2H),3.39-3.35(m,3H),2.82-2.60(m,2H),2. 55(s,3H),2.41-2.27(m,9H),2.23-2.18(m,2H),1.93-1.86(m,1H),1.69-1.61(m,2H),1.46-1.36(m,2H),1.24-1.08 (m,2H),1.01-0.93(m,1H),0.84(dd,J=2.0,6.8Hz,4H),0.78(t,J=6.4Hz,4H),0.55-0.36(m,1H),0.20--0.07(m,1H).

[0467] Examples 15-1, 15-2

[0468] 2-{4-[(4R)-4-(3-{8-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenyl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazin-1-yl}ethanol 15-1

[0469] 2-{4-[(4S)-4-(3-{8-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenyl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazin-1-yl}ethanol 15-2

[0470] first step

[0471] 4-Cyclopropyl-5-(2-bromo-5-fluorophenyl)pyrimidine 15b

[0472] 1-Bromo-4-fluoro-2-iodobenzene (500 mg, 1.66 mmol) was dissolved in dioxane (6.0 mL) and water (1.5 mL). Compound 14d (408.97 mg, 1.66 mmol), potassium carbonate (688.97 mg, 4.99 mmol), and Pd(dppf)Cl2 (121.59 mg, 166.17 μmol) were added. The reaction mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane / ethyl acetate as the elution system to give the title product 15b (200 mg, 682.28 μmol, yield: 41.06%) as a white solid.

[0473] MS m / z(ESI): 293.0 [M+1]

[0474] Step 2

[0475] 4-Cyclopropyl-5-[5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)phenyl]pyrimidine 15c

[0476] Compound 15b (200 mg, 682.28 μmol), pinacol borate (327.37 mg, 1.36 mmol), and potassium acetate (200.88 mg, 2.05 mmol) were dissolved in dioxane (2.0 mL). Pd(dppf)Cl2 (49.92 mg, 68.23 μmol) was added. The reaction mixture was stirred at 100 °C for 3.0 h under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane / ethyl acetate as the elution system to give the title product 15c (200 mg, 587.89 μmol, yield: 86.17%). LCMS showed that the purity of the product was 50%, containing 48% debromination byproducts. The mixture was used directly in the next reaction without further purification.

[0477] MS m / z(ESI): 341.2 [M+1]

[0478] Step 3

[0479] 2-{4-[4-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazin-1-yl}-ethanol 15d

[0480] Compound 1 g (7.0 g, 31.58 mmol) and compound 14 g (9.18 g, 37.89 mmol) were dissolved in methanol (150.0 mL), and acetic acid (2.84 g, 47.36 mmol) was added. The mixture was stirred at 50 °C for 1.0 h. After cooling to room temperature, sodium cyanoborohydride (5.95 g, 94.73 mmol) was added, and the mixture was stirred at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and extracted with dichloromethane (100 mL x 3) after adding saturated potassium carbonate aqueous solution. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by reversed-phase chromatography (preparative column: CD27-Phenomenex luna C18 250*70mm, 10µm; mobile phase: acetonitrile-water (10mM ammonium bicarbonate); elution gradient: 20%–50%) to give the title product 15d (7.1g, 15.85mmol, yield: 75.53%).

[0481] MS m / z (ESI): 448.4 [M+1]

[0482] Step 4

[0483] 2-{4-[(4R)-4-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazin-1-yl}-ethanol 15d-12-{4-[(4S)-4-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazin-1-yl}-ethanol 15d-2

[0484] Compound 15d (1 g, 2.23 mmol) was purified by chiral SFC (preparative column: Chiral-IG-30-Daicel ChiralPak IG (250*30 mm, 10 μm), mobile phase: carbon dioxide-isopropanol (0.1% ammonia); elution gradient: 43%) to obtain the title products 15d-1 (490 mg, 1.09 mmol, yield: 49%) and 15d-2 (490 mg, 1.09 mmol, yield: 49%).

[0485] The single-configuration compound 15d-1:

[0486] MS m / z(ESI): 448.1 [M+1]

[0487] Chiral HPLC analysis: retention time 0.675 min; column: Chiralpak IG-3 50x4.6mm ID, 3µm; mobile phase: carbon dioxide-isopropanol (0.05% diethylamine); elution gradient: 5%–40%.

[0488] The single-configuration compound 15d-2:

[0489] MS m / z(ESI): 448.1 [M+1]

[0490] Chiral HPLC analysis: retention time 1.108 min; column: Chiralpak IG-3 50x4.6mm ID, 3µm; mobile phase: carbon dioxide-isopropanol (0.05% diethylamine); elution gradient: 5%–40%.

[0491] Step 5

[0492] 2-{4-[(4R)-4-(3-{8-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenyl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazin-1-yl}ethanol 15-1

[0493] Compound 15d-1 (60.00 mg, 133.92 μmol) and compound 15c (100.23 mg, 147.31 μmol) were dissolved in dioxane (2.0 mL) and water (0.5 mL). Potassium phosphate (85.28 mg, 401.75 μmol) and Xphos Pd G4 (11.52 mg, 13.39 μmol) were added, and the reaction was stirred at 95 °C for 2.0 h under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography with dichloromethane / methanol as the elution system. The crude product was then purified by reversed-phase column chromatography (preparative column: C18, 20g; mobile phase: acetonitrile, water (0.1% trifluoroacetic acid); elution gradient: 20%-40%) to obtain the title product 15-1 (43.41 mg, 69.37 μmol, yield: 51.80%) as a yellow solid.

[0494] MS m / z (ESI): 626.7 [M+1]

[0495] Chiral HPLC analysis: retention time 1.735 min; column: Chiralpak AD-3 50x4.6mm ID, 3µm; mobile phase: carbon dioxide-isopropanol (0.05% diethylamine); elution gradient: 5%–40%.

[0496] 1H NMR (400MHz, DMSO-d6) δ10.73-10.47(m,0.98H),8.81(br d,J=9.2Hz,1H),8.71-8.56(m,1H),8.24(br s,1H),7.82-7.68(m,1H),7.62-7.52(m,2H),7.41(br d,J=10.0Hz,1H),6.89(br d,J=8.4Hz,1H),4.45-4.06(m,5H),4.00-3.92(m,1H),3.28(br s,6H),3.20-3.06(m,4H),2.92-2.79(m,2H),2.69(s,4H),2.00(br s,1H),1.77-1.37(m,6H),1.02-0.95(m,4H),0.94-0.78(m,5H),0.53-0.33(m,1H).

[0497] Step 6

[0498] 2-{4-[(4S)-4-(3-{8-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenyl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazin-1-yl}ethanol 15-2

[0499] Compound 15d-2 (100.00 mg, 223.19 μmol) and compound 15c (75.93 mg, 223.19 μmol) were dissolved in dioxane (2.0 mL) and water (0.5 mL). Potassium phosphate (142.13 mg, 669.58 μmol) and Xphos Pd G4 (19.21 mg, 22.32 μmol) were added, and the mixture was stirred at 95 °C for 12.0 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with dichloromethane / methanol as the elution system. The crude product was purified by preparative high performance liquid chromatography (mobile phase: acetonitrile, water (10 mM ammonium bicarbonate), elution gradient: 25%-55%) to give the title product 15-2 (9.40 mg, 15.02 μmol, yield: 6.73%) as a yellow solid.

[0500] MS m / z (ESI): 626.5 [M+1]

[0501] Chiral HPLC analysis: retention time 1.818 min; column: Chiralpak AD-3 50x4.6mm ID, 3µm; mobile phase: carbon dioxide-isopropanol (0.05% diethylamine); elution gradient: 5%–40%. 1H NMR(400 MHz, DMSO-d6)δ8.90-8.77(m,1H),8.58-8.40(m,1H),7.82-7.73(m,2H),7.54-7.45(m,2H),7.05-6.99( m,1H),6.39-6.33(m,1H),4.36-4.32(m,1H),3.49-3.43(m,2H),3.40-3.34(m,3H),2.82-2.60(m,2H),2. 55-2.52(m,3H),2.41-2.28(m,9H),2.24-2.19(m,2H),1.93-1.88(m,1H),1.69-1.59(m,2H),1.44-1.36 (m,2H),1.24-1.09(m,2H),1.01-0.93(m,1H),0.88-0.74(m,8H),0.55-0.37(m,1H),0.23--0.11(m,1H).

[0502] Example 16

[0503] 3-[6-(1-{[1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl]methyl}azacyclobutane-3-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-N-(isopropyl)thiophene-2-carboxamide 16

[0504] first step

[0505] 3-Bromo-N-ethyl-N-(isopropyl)thiophene-2-carboxamide 16b

[0506] N-Ethylpropyl-2-amine (420.99 mg, 4.83 mmol) and triethylamine (1.47 g, 14.49 mmol) were added to a solution of 3-bromothiophene-2-carboxylic acid 16a (1 g, 4.83 mmol) in dichloromethane (10 mL), followed by the slow addition of HATU (3.67 g, 9.66 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction was quenched with 1N hydrochloric acid aqueous solution (10 mL), diluted with ethyl acetate (20 mL), and the organic phase was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the elution system to give the title product 16b (1.1 g, 3.98 mmol, yield: 82.46%) as a white solid.

[0507] MS m / z(ESI): 276.0 / 278.0 [M+1]

[0508] Step 2

[0509] N-Ethyl-N-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)thiophene-2-carboxamide 16c

[0510] Compound 16b (200 mg, 724.13 μmol), potassium acetate (213.20 mg, 2.17 mmol), and pinacol diboronate (275.83 mg, 1.09 mmol) were dissolved in dioxane (10 mL). Pd(dppf)Cl₂ (52.99 mg, 72.41 μmol) was added under a nitrogen atmosphere, and the mixture was stirred at 100 °C for 12 hours. The reaction solution was not further purified and was used directly in the next reaction. LC-MS showed that the title product 16c was obtained.

[0511] MS m / z(ESI): 324.2 [M+1]

[0512] Step 3

[0513] 3-(8-{2-[ethyl(isopropyl)carbamoyl]thiophen-3-yl}-3-methylimidazo[1,5-a]pyridin-6-yl)azacyclobutane-1-carboxylic acid tert-butyl ester 16d

[0514] Compound 1f (116.47 mg, 361.94 μmol), compound 16c (117 mg, 361.94 μmol), and potassium phosphate (230.48 mg, 1.09 mmol) were dissolved in dioxane (10.0 mL) and water (2.0 mL). Pd(dtbpf)Cl2 (23.59 mg, 36.19 μmol) was added. The reaction mixture was stirred at 100 °C for 12 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water (10 mL) was added, followed by extraction with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 16d (150 mg, 310.79 μmol, yield: 85.87%).

[0515] MS m / z(ESI): 483.1 [M+1]

[0516] Step 4

[0517] 3-[6-(azacyclobutane-3-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-N-(isopropyl)thiophene-2-carboxamide 16e

[0518] Compound 16d (150 mg, 310.79 μmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) was added at 25 °C. The reaction mixture was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure, and dichloromethane (10 mL) was added. The pH was adjusted to 10 with 10% sodium hydroxide aqueous solution, and the mixture was extracted with dichloromethane / methanol (10:1; 10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product of title product 16e (118 mg, 308.48 μmol, yield: 99.26%). The crude product was used directly in the next reaction without purification.

[0519] MS m / z(ESI): 383.0 [M+1]

[0520] Step 5

[0521] 3-[6-(1-{[1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl]methyl}azacyclobutane-3-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-N-(isopropyl)thiophene-2-carboxamide 16

[0522] Compound 16e (118 mg, 308.48 μmol) and compound 9d (142.11 mg, 339.33 μmol) were dissolved in methanol (5.0 mL), and acetic acid (1.85 mg, 30.85 μmol) was added. The mixture was stirred at 40 °C for 1.0 h. Sodium cyanoborohydride (38.77 mg, 616.96 μmol) was added, and the mixture was stirred at 40 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (20 mL), and washed with 10 mL each of saturated sodium bicarbonate aqueous solution, water, and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.05% ammonia), elution gradient: 26%-56%) to give the title product 16 (24.00 mg, 38.85 μmol, yield: 12.59%) as a yellow solid.

[0523] MS m / z(ESI): 618.3 [M+1]

[0524] 1H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.81(d,J=4.8Hz,1H),7.40(d,J=5.2Hz,1H),7.16(s,1H),6.84(s,1H),6.74(s,1H),4.17(br d,J=12.8Hz,2H),3.84(d,J=13.6Hz,6H),3.78-3.65(m,1H),3.62-3.54(m,3H ),3.27-3.07(m,4H),2.74(s,2H),2.59(s,3H),2.34(d,J=6.8Hz,2H),1.77(br d,J=11.2Hz,2H),1.56-1.43(m,1H),1.25-0.88(m,6H),0.78-0.61(m,5H).

[0525] Example 17

[0526] N-Ethyl-5-fluoro-2-[6-(1-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylhexane-3-yl}azacyclobutane-3-yl)-3,7-dimethylimidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 17

[0527] first step

[0528] 3,5-Dibromo-4-methylpyridin-2-onitrile 17b

[0529] 2,3,5-Tribromo-4-methylpyridine (5 g, 15.16 mmol) was dissolved in NMP (20 mL), and cuprous cyanide (1.63 g, 18.19 mmol) was added. The mixture was stirred at 130 °C for 12 hours. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate aqueous solution (20 mL) was added. Extraction was performed with dichloromethane (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate as the elution system to give the title product 17b (2.5 g, 9.06 mmol, yield 59.76%) as a yellow solid.

[0530] MS m / z(ESI): 274.9 [M+1]

[0531] Step 2

[0532] 1-(3,5-Dibromo-4-methylpyridin-2-yl)methylamine 17c

[0533] Compound 17b (2.5 g, 9.06 mmol) was dissolved in dichloromethane (40 mL) as solution 1 and in DIBAL-H (1 M, 27.18 mL) as solution 2. Solutions 1 and 2 were reacted in a flow reactor. Solution 1 was pumped into the reactor at a rate of 8.037 mL / min, and solution 2 was pumped into the reactor at a rate of 5.575 mL / min. The reaction was carried out for 5 minutes. After the reaction mixture and solution were collected, the reaction was quenched with water (1.0 mL), 15% sodium hydroxide aqueous solution (1.0 mL), and water (10 mL). The mixture was directly concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 17c (2.2 g, 7.86 mmol, yield: 86.73%).

[0534] MS m / z(ESI): 280.9 [M+1]

[0535] Step 3

[0536] 6,8-Dibromo-3,7-dimethylimidazo[1,5-a]pyridine 17d

[0537] Compound 17c (2 g, 7.14 mmol) was dissolved in acetic anhydride (20 mL), and p-toluenesulfonic acid (1.36 g, 7.14 mmol) was added. The mixture was stirred at 100 °C for 1.0 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 17d (2.0 g, 6.58 mmol, yield: 92.10%).

[0538] MS m / z(ESI): 302.9 [M+1]

[0539] Step 4

[0540] 3-{8-bromo-3,7-dimethylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-carboxylic acid tert-butyl ester 17e

[0541] Under nitrogen protection, compound 17d (1 g, 3.29 mmol), tert-butyl 3-iodozacyclobutane-1-carboxylate (854.38 mg, 3.62 mmol), nickel dichloride (108.42 mg, 493.45 μmol), manganese powder (542.19 mg, 9.87 mmol), sodium iodide (123.28 mg, 822.42 μmol), and pyridine-2,6-bis(formamidinium) dihydrochloride (116.50 mg, 493.45 μmol) were dissolved in DMF (10.0 mL). Trifluoroacetic acid (37.51 mg, 328.97 μmol) was added under nitrogen atmosphere. The mixture was stirred at 60 °C for 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system. The crude product was then purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.225% formic acid), elution gradient: 18%-48%) to obtain the title product 17e (100 mg, 262.97 μmol, yield: 7.99%) as a white solid.

[0542] MS m / z(ESI): 382.0 [M+1]

[0543] Step 5

[0544] 3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3,7-dimethylimidazo[1,5-a]pyridin-6-yl)azacyclobutane-1-carboxylic acid tert-butyl ester 17f

[0545] Compound 17e (80 mg, 210.37 μmol), compound 1c (70.52 mg, 210.37 μmol), and potassium phosphate (133.96 mg, 631.12 μmol) were dissolved in dioxane (2.0 mL) and water (0.5 mL). Xphos Pd G4 (18.10 mg, 21.04 μmol) was added. The reaction mixture was stirred at 95 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and extracted with water (10 mL) and ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative column chromatography with petroleum ether / ethyl acetate as the elution system to give the title product 17f (100 mg, 196.61 μmol, yield: 93.46%) as a yellow solid.

[0546] MS m / z (ESI): 509.4 [M+1]

[0547] Step 6

[0548] 2-[6-(azacyclobutane-3-yl)-3,7-dimethylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 17g

[0549] Compound 17f (50 mg, 98.30 μmol) was dissolved in dioxane (2.0 mL), and trifluoroacetic acid (740.00 mg, 6.49 mmol, 0.5 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 10 with 10% sodium hydroxide aqueous solution. The solution was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 17 g of crude product (40 mg, 97.92 μmol, yield: 99.61%). The crude product was used directly in the next reaction without purification.

[0550] MS m / z(ESI): 409.4 [M+1]

[0551] Step 7

[0552] N-Ethyl-5-fluoro-2-[6-(1-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylhexane-3-yl}azacyclobutane-3-yl)-3,7-dimethylimidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 17

[0553] Compound 17 g (40 mg, 97.92 μmol) and compound 14 g (47.46 mg, 195.83 μmol) were dissolved in methanol (1.0 mL), and acetic acid (3.00 mg, 49.94 μmol) was added. The mixture was stirred at 50 °C for 1.0 h. Sodium cyanoborohydride (18.46 mg, 293.75 μmol) was added, and the mixture was stirred at 50 °C for 12 h. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate aqueous solution (10 mL), and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.05% ammonia), elution gradient: 24%-54%) to give title product 17 (6.25 mg, 9.84 μmol, yield: 10.05%) as a yellow solid.

[0554] MS m / z (ESI): 635.5 [M+1]

[0555] 1H NMR(400MHz,DMSO-d6)δ7.77-7.65(m,1H),7.41-7.27(m,3H),6.60-6.48(m,1 H),4.37-4.32(m,1H),3.74-3.41(m,7H),3.19-3.11(m,1H),2.97-2.89(m,1H ),2.82-2.71(m,1H),2.60-2.56(m,3H),2.45-2.25(m,9H),2.23-2.18(m,2H) ,1.98-1.73(m,5H),1.52-1.12(m,5H),1.00-0.63(m,13H),0.15-0.03(m,2H).

[0556] Example 24

[0557] (1R,2R,5S)-3-[6-(1-{[1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl]methyl}azacyclobutane-3-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-N-(isopropyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide 24

[0558] first step

[0559] (1R,2R,5S)-2-[ethyl(isopropyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 24b

[0560] N-Ethylpropyl-2-amine (46.03 mg, 528.04 μmol) and triethylamine (89.05 mg, 880.06 μmol) were added to a solution of (1R,2R,5S)-2-[(tert-butoxy)carbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid 24a (100 mg, 440.03 μmol) in dichloromethane (2.0 mL), followed by the slow addition of T4P condensing agent (380.46 mg, 528.04 μmol, 50% purity). The mixture was stirred at 25 °C for 2 hours. The reaction was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate as the elution system to give the title product 24b (110 mg, 371.12 μmol, yield: 84.34%) as a yellow solid.

[0561] MS m / z(ESI): 297.1 [M+1]

[0562] 1H NMR (400MHz, CDCl3) δ4.74-4.16(m,2H),3.82-3.67(m,1H),3.63-3.51(m,1H),3.49-3.13(m,2H),1.79-1. 48(m,2H),1.46-1.37(m,9H),1.36-1.25(m,5H),1.21-1.14(m,4H),0.79-0.68(m,1H),0.44-0.24(m,1H).

[0563] Step 2

[0564] (1R,2R,5S)-N-ethyl-N-(isopropyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide 24c

[0565] Compound 24b (110 mg, 371.12 μmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) was added at 25 °C. The reaction mixture was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure, and dichloromethane (10 mL) was added. The pH was adjusted to 10 with 10% sodium hydroxide aqueous solution, and the mixture was extracted with dichloromethane / methanol (10:1; 10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product of title product 24c (70 mg, 356.62 μmol, yield: 96.09%) as a yellow solid. The crude product was used directly in the next reaction without purification.

[0566] MS m / z(ESI): 197.0 [M+1]

[0567] Step 3

[0568] 3-{8-[(1R,2R,5S)-2-[ethyl(isopropyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-yl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-carboxylic acid tert-butyl ester 24d

[0569] Compound 1f (114.76 mg, 356.62 μmol), compound 24c (70 mg, 356.62 μmol), and sodium tert-butoxide (102.82 mg, 1.07 mmol) were dissolved in dioxane. Pd-PEPPSI-IHept-Cl (34.69 mg, 35.66 μmol) was added. The reaction mixture was stirred at 95 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and extracted with water (10 mL) and ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate as the elution system to give the title product 24d (80 mg, 166.10 μmol, yield: 46.58%).

[0570] MS m / z(ESI): 482.3 [M+1]

[0571] Step 4 (1R,2R,5S)-3-[6-(azacyclobutane-3-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-N-(isopropyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide 24e

[0572] Compound 24d (80 mg, 166.10 μmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (740.00 mg, 6.49 mmol, 0.5 mL) was added at 25 °C. The reaction mixture was stirred at room temperature for 1.0 h. The reaction solution was concentrated under reduced pressure, and dichloromethane (10 mL) was added. The pH was adjusted to 10 with 10% sodium hydroxide aqueous solution, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product of title product 24e (60 mg, 157.27 μmol, yield: 94.68%). The crude product was used directly in the next reaction without purification.

[0573] MS m / z(ESI): 382.2 [M+1]

[0574] Step 5

[0575] (1R,2R,5S)-3-[6-(1-{[1-(5,6-dimethoxypyridazin-3-yl)piperidin-4-yl]methyl}azacyclobutane-3-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-N-(isopropyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide 24

[0576] Compound 24e (60 mg, 157.27 μmol) and compound 9d (98.80 mg, 235.90 μmol) were dissolved in methanol (2.0 mL), and acetic acid (9.44 mg, 157.27 μmol) was added. The mixture was stirred at 50 °C for 1.0 h. Sodium cyanoborohydride (29.65 mg, 471.81 μmol) was added, and the mixture was stirred at 50 °C for 12 h. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate aqueous solution (10 mL), and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.05% ammonia), elution gradient: 24%-54%) to give the title product 24 (9.44 mg, 15.30 μmol, yield: 9.73%) as a yellow solid.

[0577] MS m / z (ESI): 617.5 [M+1]

[0578] 1 H NMR(400MHz,DMSO-d6)δ7.34(s,1H),7.26-7.10(m,1H),6.77-6.71(m,1H),5.58-5.41(m,1H),5 .16-4.77(m,1H),4.54-4.25(m,1H),4.23-3.92(m,3H),3.88-3.86(m,3H),3.84-3.82(m,3H),3 .79-3.51(m,3H),3.49-3.42(m,1H),3.16-3.01(m,3H),2.81-2.67(m,2H),2.48-2.44(m,3H),2 .36-2.28(m,2H),1.79-1.48(m,5H),1.40-1.02(m,10H),0.97-0.75(m,3H),0.47-0.37(m,1H).

[0579] Example 26

[0580] N-Ethyl-5-fluoro-2-(6-{1-[(3R)-6-[4-(hydroxymethyl)-4-methylpiperidin-1-yl]-2-methylhexane-3-yl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 26

[0581] first step

[0582] 2-(6-{1-[1-(1,3-dioxolane-2-yl)-4-methylpentan-3-yl]azacyclobutan-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 26b

[0583] Compound 4e (400 mg, 1.01 mmol) and 1-(1,3-dioxolane-2-yl)-4-methylpentan-3-one 26a (261.94 mg, 1.52 mmol) were dissolved in methanol (8.0 mL), and ZnCl2 (276.40 mg, 2.03 mmol) was added. The mixture was stirred at 55 °C for 1.0 h. After cooling to room temperature, sodium cyanoborohydride (191.16 mg, 3.04 mmol) was added, and the mixture was stirred at 55 °C for 11 h. The reaction mixture was then added to a saturated aqueous sodium carbonate solution (20 mL), stirred for 30 min, and extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 26b (500 mg, 907.93 μmol, yield: 89.54%).

[0584] MS m / z (ESI): 551.3 [M+1]

[0585] Step 2

[0586] 2-(6-{1-[(3S)-1-(1,3-dioxolane-2-yl)-4-methylpentan-3-yl]azacyclobutan-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 26b-1

[0587] 2-(6-{1-[(3R)-1-(1,3-dioxolane-2-yl)-4-methylpentan-3-yl]azacyclobutan-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 26b-2

[0588] Compound 26b (500 mg, 907.93 μmol) was purified by chiral SFC (preparative column: Daicel Chiralcel OD (250*30 mm, 10 μm), mobile phase: carbon dioxide-isopropanol (0.1% ammonia); elution gradient: 35%) to obtain the title products 26b-1 (165 mg, 299.62 μmol, yield: 33%) and 26b-2 (155 mg, 281.46 μmol, yield: 31%).

[0589] Single-configuration compound 26b-1:

[0590] MS m / z (ESI): 551.2 [M+1]

[0591] Chiral HPLC analysis: retention time 1.456 min; column: Chiralcel OD-3 50x4.6mm ID, 3µm; mobile phase: carbon dioxide-isopropanol (0.05% diethylamine); elution gradient: 5%–40%.

[0592] Single-configuration compound 26b-2:

[0593] MS m / z (ESI): 551.2 [M+1]

[0594] Chiral HPLC analysis: retention time 1.7-10 min; column: Chiralcel OD-3 50x4.6mm ID, 3µm; mobile phase: carbon dioxide-isopropanol (0.05% diethylamine); elution gradient: 5%–40%.

[0595] Step 3

[0596] N-Ethyl-5-fluoro-2-(3-methyl-6-{1-[(3R)-2-methyl-6-oxohexane-3-yl]azacyclobutane-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 26c-2

[0597] Compound 26b-2 (155.00 mg, 281.46 μmol) was dissolved in acetonitrile (3.0 mL), and hydrochloric acid solution (1.0 M; 1.0 mL) was added. The reaction mixture was stirred at 50 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane (5 mL) and water (5 mL) were added. The pH of the solution was adjusted to ≥7 with 10% NaOH aqueous solution, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 26c-2 (142 mg, 280.27 μmol, yield: 99.58%). The crude product was used directly in the next reaction without purification.

[0598] The single-configuration compound 26c-2:

[0599] MS m / z (ESI): 507.3 [M+1]

[0600] Step 4

[0601] N-Ethyl-5-fluoro-2-(6-{1-[(3R)-6-[4-(hydroxymethyl)-4-methylpiperidin-1-yl]-2-methylhexane-3-yl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 26

[0602] The crude product of compound 26c-2 (90 mg, 177.64 μmol) and (4-methyl-4-piperidinyl)methanol (22.95 mg, 177.64 μmol) were dissolved in methanol (2.0 mL), and acetic acid (10.67 mg, 177.64 μmol) was added. The mixture was stirred at 50 °C for 1.0 h. Sodium cyanoborohydride (33.49 mg, 532.91 μmol) was added, and the reaction was carried out at 50 °C for 12.0 h under nitrogen protection. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate aqueous solution (10 mL) was added. The mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (HPLC) (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 24%-54%) to give the title product 26 (45.07 mg, 72.71 μmol, yield: 40.93%) as a yellow solid. MS m / z (ESI): 620.6 [M+1]

[0603] Chiral SFC: retention time 1.422 min; column: Chiralcel OD-3 50×4.6mm ID, 3µm; mobile phase: CO2 / EtOH (0.05% DEA); elution gradient: 5%–40%.

[0604] 1 H NMR(400MHz,DMSO-d6)δ7.95-7.90(m,1H),7.72-7.64(m,1H),7.41-7.26(m,2H),7.06-7.00(m,1H),6.87-6.67 (m,1H),4.44-4.38(m,1H),3.60-3.41(m,4H),3.32-3.24(m,1H),3.17-3.02(m,4H),2.98-2.85(m,1H),2.61-2 .56(m,3H),2.45-2.36(m,2H),2.25-2.18(m,2H),2.16-2.07(m,2H),2.05-1.99(m,1H),1.76-1.66(m,1H),1.4 8-1.36(m,4H),1.28-1.03(m,5H),0.92-0.88(m,2H),0.87-0.77(m,12H),0.76-0.71(m,1H),0.30-0.25(m,2H).

[0605] Following similar steps to those in the above embodiments, the following compounds were prepared and characterized:

[0606] Examples 27-1, 27-2

[0607] {1-[(4R)-4-(3-{8-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenyl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]-4-methylpiperidin-4-yl}methanol27-1

[0608] {1-[(4S)-4-(3-{8-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenyl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]-4-methylpiperidin-4-yl}methanol 27-2

[0609] first step

[0610] 4-Cyclopropyl-5-[2-(6-{1-[1-(1,3-dioxolane-2-yl)-4-methylpentan-3-yl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-5-fluorophenyl]pyrimidine 27a

[0611] Compound 15a (230 mg, 575.77 μmol) and 1-(1,3-dioxolane-2-yl)-4-methylpentan-3-one 26a (128.91 mg, 748.51 μmol) were dissolved in methanol (4.0 mL), and acetic acid (69.15 mg, 1.15 mmol) was added. The mixture was stirred at 50 °C for 1.0 h. After cooling to room temperature, sodium cyanoborohydride (108.55 mg, 1.73 mmol) was added, and the mixture was stirred at 50 °C for 12 h. The reaction mixture was then extracted with saturated sodium bicarbonate aqueous solution (10 mL) and dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography using dichloromethane / methanol as the elution system to give the title product 27a (80 mg, 143.97 μmol, yield: 25%).

[0612] MS m / z (ESI): 556.4 [M+1]

[0613] Step 2

[0614] 4-Cyclopropyl-5-[2-(6-{1-[(3R)-1-(1,3-dioxolane-2-yl)-4-methylpentan-3-yl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-5-fluorophenyl]pyrimidine 27a-1

[0615] 4-Cyclopropyl-5-[2-(6-{1-[(3S)-1-(1,3-dioxolane-2-yl)-4-methylpentan-3-yl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-5-fluorophenyl]pyrimidine 27a-2

[0616] Compound 27a (110 mg, 197.95 μmol) was purified by chiral preparation using an SFC (preparative column: Chiral-AD-30-DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm), mobile phase: carbon dioxide-isopropanol (0.1% ammonia); elution gradient: 55%) to obtain the title products 27a-1 (50 mg, 89.98 μmol, yield: 45.45%) and 27a-2 (52 mg, 93.58 μmol, yield: 47.27%).

[0617] Single-configuration compound 27a-1:

[0618] MS m / z (ESI): 556.3 [M+1]

[0619] Chiral HPLC analysis: retention time 1.902 min; column: Chiralcel OD-3 50x4.6mm ID, 3µm; mobile phase: carbon dioxide-isopropanol (0.05% diethylamine); elution gradient: 5%–40%.

[0620] Single-configuration compound 27a-2:

[0621] MS m / z (ESI): 556.3 [M+1]

[0622] Chiral HPLC analysis: retention time 1.667 min; column: Chiralcel OD-3 50x4.6mm ID, 3µm; mobile phase: carbon dioxide-isopropanol (0.05% diethylamine); elution gradient: 5%–40%.

[0623] Step 3

[0624] (4R)-4-(3-{8-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenyl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexanal 27b-1

[0625] Compound 27a-1 (40.00 mg, 71.98 μmol) was dissolved in dichloromethane (4.0 mL), and trifluoroacetic acid (740.00 mg, 6.49 mmol, 0.5 mL) was added. The reaction mixture was stirred at 20 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane (5 mL) and water (5 mL) were added. The pH of the solution was adjusted to 10 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 27b-1 (36 mg, 70.36 μmol, yield: 97.75%). The crude product was used directly in the next reaction without purification.

[0626] Single-configuration compound 27b-1:

[0627] MS m / z (ESI): 512.5 [M+1]

[0628] Step 4

[0629] {1-[(4R)-4-(3-{8-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenyl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]-4-methylpiperidin-4-yl}methanol27-1

[0630] Compound 27b-1 (70.00 mg, 136.82 μmol) and (4-methyl-4-piperidinyl)methanol (22 mg, 170.28 μmol) were dissolved in methanol (2.0 mL), and acetic acid (17 mg, 283.10 μmol) was added. The mixture was stirred at 45 °C for 0.5 h. Sodium cyanoborohydride (25 mg, 397.82 μmol) was added, and the reaction was carried out at 45 °C for 12.0 h under nitrogen protection. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate aqueous solution (10 mL) was added. The mixture was extracted with dichloromethane (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (HPLC) (mobile phase: acetonitrile, water (10 mM ammonium bicarbonate), elution gradient: 27%–57%) to give the title product 27-1 (24.58 mg, 39.34 μmol, yield: 28.75%) as a white solid. MS m / z (ESI): 625.5 [M+1]

[0631] Chiral SFC: retention time 1.585 min; column: Chiralcel OD-3 50×4.6mm ID, 3µm; mobile phase: CO2 / EtOH (0.05% DEA); elution gradient: 5%–40%.

[0632] 1H NMR(400MHz,DMSO-d6)δ8.79(d,J=4.0Hz,1H),8.53-8.41(m,1H),7.83-7.72(m,2H),7.5 4-7.43(m,2H),7.02(d,J=6.4Hz,1H),6.40-6.30(m,1H),4.41(t,J=5.2Hz,1H),3.36(br s,3H),3.13-3.09(m,2H),2.80-2.59(m,2H),2.55(s,3H),2.47-2.39(m,2H),2.25-2.12(m,4H),1.93-1.87(m,1H), 1.70-1.59(m,2H),1.46-1.37(m,4H),1.22-1.08(m,4H),1.00-0.93(m,1H),0.85-0.76(m,10H),0.55-0.00(m,2H).

[0633] Step 5

[0634] (4S)-4-(3-{8-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenyl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexanal 27b-2

[0635] Compound 27a-2 (40.00 mg, 71.98 μmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (740.00 mg, 6.49 mmol, 0.5 mL) was added. The reaction mixture was stirred at 20 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane (5 mL) and water (5 mL) were added. The pH of the solution was adjusted to 10 with saturated potassium carbonate aqueous solution, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 27b-2 (36 mg, 70.36 μmol, yield: 97.75%). The crude product was used directly in the next reaction without purification.

[0636] Single-configuration compound 27b-2:

[0637] MS m / z(ESI): 512.4 [M+1]

[0638] Step 6

[0639] {1-[(4S)-4-(3-{8-[2-(4-cyclopropylpyrimidin-5-yl)-4-fluorophenyl]-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]-4-methylpiperidin-4-yl}methanol 27-2

[0640] The crude product of compound 27b-2 (70.00 mg, 136.82 μmol) and (4-methyl-4-piperidinyl)methanol (22.00 mg, 170.28 μmol) were dissolved in methanol (2.0 mL), and acetic acid (16.43 mg, 273.63 μmol) was added. The mixture was stirred at 45 °C for 0.5 h. Sodium cyanoborohydride (25.79 mg, 410.45 μmol) was added, and the reaction was carried out at 45 °C for 12.0 h under nitrogen protection. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate aqueous solution (10 mL) was added. The mixture was extracted with dichloromethane (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (10 mM ammonium bicarbonate), elution gradient: 27%-57%) to give the title product 27-2 (27.68 mg, 44.30 μmol, yield: 32.38%) as a white solid.

[0641] MS m / z (ESI): 625.5 [M+1]

[0642] Chiral SFC: retention time 1.559 min; column: Chiralcel OD-3 50×4.6mm ID, 3µm; mobile phase: CO2 / EtOH (0.05% DEA); elution gradient: 5%–40%.

[0643] 1 H NMR(400MHz, DMSO-d6)δ8.79(d,J=4.0Hz,1H),8.54-8.42(m,1H),7.84-7.72(m,2H),7.55-7.44(m,2H),7 .02(d,J=6.4Hz,1H),6.41-6.30(m,1H),4.41(t,J=5.6Hz,1H),3.36(s,3H),3.15-3.07(m,2H),2.81-2.7 2(m,1H),2.67-2.57(m,1H),2.55(s,3H),2.46-2.39(m,2H),2.24-2.11(m,4H),1.94-1.86(m,1H),1.69- 1.59(m,2H),1.46-1.37(m,4H),1.23-1.09(m,4H),0.97(m,1H),0.85-0.76(m,10H),0.55--0.02(m,2H).

[0644] Following similar steps to those in the above embodiments, the following compounds were prepared and characterized:

[0645] Example 30

[0646] 2-[6-(1-{[4-(5,6-dimethoxypyridazin-3-yl)cyclohexyl-3-en-1-yl]methyl}azacyclobutane-3-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 30

[0647] first step

[0648] 4-(5,6-Dimethoxypyridazine-3-yl)cyclohexene-1-carboxylic acid ethyl ester 30b

[0649] Compound 6-chloro-3,4-dimethoxypyridazine 9a (747.78 mg, 4.28 mmol) and compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)cyclohex-3-en-1-carboxylic acid ethyl ester 9b (1 g, 3.57 mmol) were dissolved in dioxane (10.0 mL) and water (2.5 mL). Potassium phosphate (2.27 g, 10.71 mmol) and X-Phos Pd G4 (307.13 mg, 356.93 μmol) were added, and the reaction was stirred at 95 °C for 2.0 h under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 30b (800 mg, 2.74 mmol, yield: 76.67%).

[0650] MS m / z(ESI): 293.5 [M+1]

[0651] Step 2

[0652] 4-(5,6-Dimethoxypyridazine-3-yl)cyclohexyl-3-ene-1-carboxaldehyde 30c

[0653] Compound 30b (200 mg, 684.16 μmol) was dissolved in dichloromethane (5.0 mL), cooled to -78 °C, and DIBAL-H (1 M, 1.37 mL) solution was slowly added dropwise. The reaction mixture was stirred at -78 °C for 2.0 h. Methanol (2.0 mL) was added dropwise to the reaction mixture under nitrogen protection, followed by quenching with a saturated aqueous solution of sodium potassium tartrate. The mixture was stirred for 30 min and extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 30c (96 mg, 382.04 μmol, yield: 35.84%). The crude product was used directly in the next reaction without further purification.

[0654] MS m / z(ESI): 248.9 [M+1]

[0655] Step 3

[0656] 2-[6-(1-{[4-(5,6-dimethoxypyridazin-3-yl)cyclohexyl-3-en-1-yl]methyl}azacyclobutane-3-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 30

[0657] Compound 4e (150 mg, 380.24 μmol) and compound 30c (113.29 mg, 456.29 μmol) were dissolved in methanol (2.0 mL), and acetic acid (22.83 mg, 380.24 μmol) was added. The mixture was stirred at 50 °C for 1.0 h. Sodium cyanoborohydride (71.69 mg, 1.14 mmol) was added, and the mixture was stirred at 50 °C for 12 h. The reaction mixture was cooled to room temperature, and the reaction was quenched with saturated sodium bicarbonate aqueous solution (10 mL). The mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.05% ammonia), elution gradient: 30%-60%) to give the title product 30 (141.94 mg, 226.47 μmol, yield: 59.56%) as a yellow solid.

[0658] MS m / z (ESI): 627.4 [M+1]

[0659] 1 H NMR(400MHz,DMSO-d6)δ7.98-7.91(m,1H),7.73-7.64(m,1H),7.43-7.25(m,3H),7.08-7.01(m,1H),6.87- 6.75(m,1H),6.64-6.57(m,1H),4.03-3.94(m,3H),3.92-3.84(m,3H),3.64-3.55(m,3H),3.53-3.38(m,1H ),3.32-3.26(m,1H),3.22-3.06(m,2H),2.98-2.85(m,1H),2.77-2.68(m,1H),2.62-2.56(m,3H),2.45-2. 32(m,4H),2.01-1.83(m,2H),1.68-1.54(m,1H),1.37-1.01(m,2H),0.93-0.72(m,6H),0.30-0.26(m,2H).

[0660] Examples 37, 38

[0661] N-Ethyl-5-fluoro-2-(6-{1-[(3R)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylhexane-3-yl]azacyclobutane-3-yl}-1,3-dimethylimidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 37

[0662] 2-(1-bromo-6-{1-[(3R)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylhex-3-yl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 38

[0663] first step

[0664] N-Ethyl-5-fluoro-2-(6-{1-[(3R)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylhexane-3-yl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 37-1

[0665] Compound 26c-2 (180 mg, 355.27 μmol) and 2-piperazin-1-ylethanol (92.50 mg, 710.55 μmol) were dissolved in methanol (4.0 mL), and acetic acid (21.33 mg, 355.27 μmol) was added. The mixture was stirred at room temperature for 0.5 h. Sodium cyanoborohydride (66.98 mg, 1.07 mmol) was added, and the reaction was carried out at 25 °C for 15.0 h under nitrogen protection. The reaction mixture was extracted with saturated sodium carbonate aqueous solution (15 mL) and dichloromethane (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system. The crude product was then purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 36%-66%) to obtain the title product 37-1 (85.12 mg, 137.10 μmol, yield: 38.59%) as a yellow solid.

[0666] MS m / z(ESI): 621.8 [M+1]

[0667] 1H NMR(400MHz,DMSO-d6)δ7.96-7.86(m,1H),7.73-7.61(m,1H),7.43-7.26(m,2H),7.10- 6.93(m,1H),6.86-6.67(m,1H),4.35-4.24(m,1H),3.58-3.41(m,6H),3.19-2.77(m,4H ),2.61-2.55(m,3H),2.41-2.26(m,9H),2.23-2.18(m,2H),2.06-1.98(m,1H),1.77-1. 66(m,1H),1.50-1.36(m,2H),1.32-1.02(m,3H),0.95-0.68(m,13H),0.30-0.25(m,2H).

[0668] Step 2

[0669] 2-(1-bromo-6-{1-[(3R)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylhex-3-yl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 38

[0670] Compound 37-1 (50 mg, 80.54 μmol) was dissolved in DCM (2 mL), and NBS (17.20 mg, 96.64 μmol) was added at 0 °C. The temperature was then slowly increased to 25 °C, and the reaction was stirred at 25 °C for 2 hours under nitrogen protection.

[0671] The reaction solution was cooled to 0°C, quenched with saturated sodium sulfite solution (10 mL), and extracted with dichloromethane (10 mL x 2). The organic phase was collected and evaporated to dryness to obtain the crude product. The crude product was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.225% formic acid), elution gradient: 6%-66%) to obtain the title product 38 (13.05 mg, 18.65 μmol, yield: 23.16%) as a yellow solid.

[0672] MS m / z(ESI): 701.5 [M+1]

[0673] Chiral HPLC analysis: retention time 1.59 min; column: Chiralpak OD-3 50x4.6 mm ID, 3 μm; mobile phase: carbon dioxide-ethanol (0.05% diethylamine); elution gradient: 5%–40%.

[0674] 1H NMR(400MHz,DMSO-d6)δ8.21(s,2.197H),8.01(br d,J=3.2Hz,1H),7.50-7.41(m,1H),7.36-7.25(m,2H),6.89-6.74(m,1H),4. 30-4.10(m,1H),3.73-3.63(m,1H),3.61-3.44(m,5H),3.40-3.28(m,1H),3. 26-2.94(m,3H),2.92-2.78(m,1H),2.59(s,3H),2.47-2.28(m,9H),2.28-1. 92(m,4H),1.79-1.62(m,1H),1.51-1.35(m,2H),1.33-1.06(m,3H),0.91(br d,J=6.4Hz,2H),0.87-0.70(m,9H),0.23(br d,J=6.4Hz,2H).

[0675] Step 3

[0676] N-Ethyl-5-fluoro-2-(6-{1-[(3R)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylhexane-3-yl]azacyclobutane-3-yl}-1,3-dimethylimidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 37

[0677] Compound 38 (90 mg, 128.62 μmol) and methylboronic acid (38.50 mg, 643.10 μmol) were dissolved in dioxane (2.0 mL). Potassium phosphate (81.90 mg, 385.86 μmol) and Pd-PEPPSI-IPent (10.21 mg, 12.86 μmol) were added, and the mixture was stirred at 95 °C for 2.0 h under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography with dichloromethane / methanol as the elution system, and further purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.05% ammonia), elution gradient: 25%-55%) to give the title product 37 (7.40 mg, 11.6 μmol, yield: 9.1%) as a yellow solid.

[0678] MS m / z (ESI): 635.7 [M+1]

[0679] Chiral HPLC analysis: retention time 1.385 min; column: Chiralpak OD-3 50x4.6 mm ID, 3 μm; mobile phase: carbon dioxide-ethanol (0.05% diethylamine); elution gradient: 5%–40%.

[0680] 1 H NMR (400MHz, CD3OD) δ7.84-7.73(m,1H),7.50(dd,J=5.2,8.4Hz,1H),7.36-7.29(m,1H),7.27-7.19(m,1H),6.73(br d,J=2.0Hz,1H),3.76(br d,J=3.2Hz,1H),3.71-3.61(m,5H),3.53-3.44(m,1H),3.26-3.21(m,1H),3.0 0(td,J=6.8,13.6Hz,1H),2.66-2.48(m,13H),2.36(q,J=8.0Hz,3H),2.27(br s,1H),2.02(s,3H),1.92-1.79(m,2H),1.66-1.55(m,2H),1.45-1.37(m,1H),1.20-1.05(m,2H),1.01(br d,J=6.8Hz,2H),0.97-0.87(m,10H),0.30(d,J=6.8Hz,2H).

[0681] Following similar steps to those in Example 38 above, the following compounds were prepared and characterized:

[0682] Example 42

[0683] N-[(1,1,2,2,2-pentadeuterated)ethyl]-5-fluoro-2-(6-{1-[(3R)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylhexane-3-yl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 42

[0684] first step

[0685] 2-Bromo-5-fluoro-N-isopropylbenzamide 42a

[0686] Propyl-2-amine (8.10 g, 136.98 mmol) and triethylamine (23.10 g, 228.30 mmol) were added to a solution of 2-bromo-5-fluorobenzoic acid 1a (25 g, 114.15 mmol) in dichloromethane (500 mL), followed by the slow addition of HATU (52.08 g, 136.98 mmol). The mixture was stirred at 25 °C for 12 hours. The mixture was washed with saturated sodium carbonate aqueous solution (500 mL). The organic layer was washed with 1M hydrochloric acid aqueous solution (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the elution system to give the title product 42a as a pale yellow solid.

[0687] MS m / z(ESI): 262.0 [M+1]

[0688] Step 2

[0689] 2-Bromo-N-[(1,1,2,2,2-pentadeuterated)ethyl]-5-fluoro-N-(isopropyl)benzamide 42b

[0690] Potassium hydroxide (16.18 g, 288.35 mmol) was dissolved in DMSO (500 mL), and 1,1,2,2,2-pentadeuterated iodoethane (37.14 g, 230.68 mmol) was added. Compound 42a (50 g, 192.23 mmol) was slowly added. The mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the filtrate was diluted with 1000 mL of H2O, and 100 mL of water was added. The mixture was extracted with ethyl acetate (500 mL × 3). The organic phase was washed with water (500 mL), saturated ammonium chloride aqueous solution (500 mL), and saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate as the elution system to give the title product 42b as a white solid.

[0691] MS m / z(ESI): 295.0 [M+1]

[0692] Step 3

[0693] N-[(1,1,2,2,2-pentadeuterated)ethyl]-5-fluoro-N-(isopropyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzamide 42c: Compound 42b (25 g, 85.27 mmol), potassium acetate (25.11 g, 255.81 mmol), and pinacol diboronate (43.35 g, 170.71 mmol) were dissolved in dioxane (500 mL). A WXPS1004 palladium catalyst (19.23 g, 5.50 mmol) was added under a nitrogen atmosphere, and the reaction mixture was stirred at 95 °C for 48 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was filtered and concentrated. The crude product was dissolved in ethyl acetate (200 mL), then washed with water (200 mL × 2) and saturated brine (200 mL). The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized to obtain the target product 42c, which was a white solid.

[0694] MS m / z(ESI): 340.3 [M+1]

[0695] Step 4

[0696] N-[(1,1,2,2,2-pentadeuterated)ethyl]-5-fluoro-2-(6-{1-[(3R)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylhexane-3-yl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 42

[0697] Compound 15d-1 (1 g, 2.23 mmol) and compound 42c (850.00 mg, 2.50 mmol) were dissolved in ethanol (12.0 mL) and water (2.0 mL). Potassium phosphate (1.18 g, 5.58 mmol) and Xphos Pd G4 (192.05 mg, 223.19 μmol) were added, and the reaction was stirred at 80 °C for 2.0 h under a nitrogen atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was added to water (10 mL) and then extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (preparative column: CD03-Welch Xtimate C18 150*25mm*5um; mobile phase: acetonitrile, water (0.05% hydrochloric acid), elution gradient: 0%-15%). The preparative solution was concentrated under reduced pressure to remove acetonitrile. The pH of the solution was adjusted to 10 with potassium carbonate. The solution was extracted with dichloromethane (50mL×3). After drying, filtration, and rotary evaporation, the product was lyophilized to obtain the title product 42 (484.11mg, 773.50μmol, yield: 34.66%) as a yellow-green solid.

[0698] MS m / z(ESI): 626.9 [M+1]

[0699] Chiral HPLC analysis: retention time 1.735 min; column: Chiralpak AD-3 50x4.6mm ID, 3µm; mobile phase: carbon dioxide-isopropanol + acetonitrile (0.05% diethylamine); elution gradient: 15%–30%.

[0700] 1 H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.75-7.59(m,1H),7.46-7.23(m,2H), 7.10-6.97(m,1H),6.88-6.70(m,1H),4.37-4.27(m,1H),3.61-3.38(m,6H) ,3.21-3.01(m,2H),2.58(s,3H),2.45-1.89(m,13H),1.76-1.66(m,1H),1. 49-1.37(m,2H),1.27-1.16(m,2H),1.10-0.74(m,10H),0.30-0.25(m,2H).

[0701] Example 45

[0702] N-[(1,1,2,2,2-pentadeuterated)ethyl]-5-fluoro-2-(6-{1-[(3R)-6-{4-[2-hydroxy(1,1,2,2-tetradeuterated)ethyl]piperazin-1-yl}-2-methylhexane-3-yl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 45

[0703] first step

[0704] 4-(5-methyl-4-oxohexyl)piperazine-1-carboxylic acid tert-butyl ester 45a

[0705] Compound 14f (4.0 g, 26.91 mmol) was dissolved in acetonitrile (60 mL), and piperazine-1-carboxylic acid tert-butyl ester (6.01 g, 32.29 mmol), potassium carbonate (7.44 g, 53.82 mmol), and sodium iodide (403.40 mg, 2.69 mmol) were added at 25 °C. The reaction mixture was heated to 85 °C and stirred for 12 hours. The reaction solution was cooled to room temperature, filtered, and washed with ethyl acetate (50 mL x 3). The combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 45a (4 g, 13.40 mmol, yield: 49.81%) as a colorless oil.

[0706] 1 H NMR(400MHz, CDCl3)δ3.43-3.39(m,4H),2.61(br d,J=6.9Hz,1H),2.48(t,J=7.1Hz,2H),2.38-2.31(m,6H),1.81-1.74(m,2H),1.45(s,9H),1.09(d,J=6.9Hz,6H).

[0707] Step 2

[0708] 4-[4-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazine-1-carboxylic acid tert-butyl ester 45b

[0709] Compound 1 g (2 g, 9.02 mmol) and compound 45a (2.96 g, 9.92 mmol) were dissolved in methanol (20.0 mL), and ZnCl2 (3.69 g, 27.07 mmol) was added. The mixture was stirred at 50 °C for 1.0 h. After cooling to room temperature, sodium cyanoborohydride (1.70 g, 27.07 mmol) was added, and the mixture was stirred at 50 °C for 12.0 h. The reaction mixture was extracted with saturated sodium bicarbonate aqueous solution (30 mL) and dichloromethane (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 45b (3.4 g, 6.74 mmol, yield: 74.76%) as a yellow solid.

[0710] MS m / z (ESI): 504.3 [M+1]

[0711] Step 3

[0712] 4-[(4R)-4-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazine-1-carboxylic acid tert-butyl ester 45b-1

[0713] 4-[(4S)-4-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazine-1-carboxylic acid tert-butyl ester 45b-2

[0714] Compound 45b (3.4 g, 6.74 mmol) was purified by chiral SFC (preparative column: DAICL CHIRALCEL OD (250 mm * 30 mm, 10 μm), mobile phase: carbon dioxide-isopropanol (0.1% ammonia); elution gradient: 30%). Title products 45b-1 (1.65 g, 3.27 mmol, yield: 48.53%) and 45b-2 (1.6 g, 3.17 mmol, yield: 47.06%) were obtained as yellow solids.

[0715] Single-configuration compound 45b-1:

[0716] MS m / z(ESI): 504.2 [M+1]

[0717] Chiral HPLC analysis: retention time 1.446 min; column: Chiralcel AD-3 50x4.6mm ID, 3µm; mobile phase: carbon dioxide-isopropanol (0.05% diethylamine); elution gradient: 5%–40%.

[0718] Single-configuration compound 45b-2:

[0719] MS m / z (ESI): 504.3 [M+1]

[0720] Chiral HPLC analysis: retention time 1.645 min; column: Chiralcel AD-3 50x4.6mm ID, 3µm; mobile phase: carbon dioxide-isopropanol (0.05% diethylamine); elution gradient: 5%–40%.

[0721] Step 4

[0722] 1-[(4R)-4-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazine 45c-1

[0723] Compound 45b-1 (150 mg, 297.56 μmol) was dissolved in dichloromethane (1.0 mL), and trifluoroacetic acid (444.00 mg, 3.89 mmol, 300.00 μL) was added. The reaction mixture was stirred at 25 °C for 1.0 h. The reaction solution was concentrated under reduced pressure to obtain the crude product 45c-1. The crude product was used directly in the next reaction without purification.

[0724] MS m / z(ESI): 404.2 [M+1]

[0725] Step 5

[0726] 2-{4-[(4R)-4-(3-{8-chloro-3-methylimidazo[1,5-a]pyridin-6-yl}azacyclobutane-1-yl)-5-methylhexyl]piperazin-1-yl}(1,1,2,2-tetradeuterated)ethane-1-ol 45d-1

[0727] The crude product of compound 45c-1 was dissolved in acetonitrile (1.0 mL), and 2-bromo-1,1,2,2-tetradeuterated ethanol (50 mg, 387.63 μmol) and DIPEA (116 mg, 897.53 μmol, 156.33 μL) were added. The mixture was stirred at 80 °C for 12 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 45d-1 (70 mg, 154.84 μmol, two-part yield: 52.04%) as a colorless oil.

[0728] MS m / z(ESI): 452.2 [M+1]

[0729] Step 6

[0730] N-[(1,1,2,2,2-pentadeuterated)ethyl]-5-fluoro-2-(6-{1-[(3R)-6-{4-[2-hydroxy(1,1,2,2-tetradeuterated)ethyl]piperazin-1-yl}-2-methylhexane-3-yl]azacyclobutane-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 45

[0731] Compound 45d-1 (70 mg, 154.84 μmol), compound 42c (115 mg, 236.59 μmol), and potassium phosphate (98.60 mg, 464.53 μmol) were dissolved in dioxane (2.0 mL) and water (0.4 mL). X-Phos Pd G4 (15 mg, 17.43 μmol) was added. The reaction mixture was stirred at 90 °C for 1.0 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water (10 mL) was added, followed by extraction with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system. The crude product was then purified by preparative HPLC (preparative column: CD02-Waters Xbridge BEH C18 100*25mm*10um, mobile phase: acetonitrile-water (0.05% ammonia); elution gradient: 26%–56%) to obtain the title product 45 (40.07 mg, 63.61 μmol, yield: 41.08%).

[0732] MS m / z(ESI): 630.6 [M+1]

[0733] Chiral HPLC analysis: retention time 1.418 min; column: Chiralpak OD-3 50x4.6mm ID, 3µm; mobile phase: carbon dioxide-ethanol (0.05% diethylamine); elution gradient: 5%–40%.

[0734] 1 H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.74-7.62(m,1H),7.43-7.26(m,2H),7. 08-6.98(m,1H),6.87-6.71(m,1H),4.27(s,1H),3.61-3.38(m,4H),3.19-3.00 (m,2H),2.59(s,3H),2.46-2.09(m,10H),2.07-1.99(m,1H),1.77-1.66(m,1H ),1.52-1.35(m,2H),1.30-0.99(m,3H),0.92-0.79(m,9H),0.30-0.25(m,2H).

[0735] Example 47

[0736] N-[(1,1,2,2,2-pentadeuterated)ethyl]-5-fluoro-2-(3-methyl-6-{1-[(3R)-2-methyl-6-(piperazin-1-yl)hexan-3-yl]azacyclobutan-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 47

[0737] first step

[0738] 4-[(4R)-4-{3-[8-(2-{(1,1,2,2,2-5-deuterated)ethylcarbamoyl}-4-fluorophenyl)-3-methylimidazo[1,5-a]pyridin-6-yl]azacyclobutane-1-yl}-5-methylhexyl]piperazine-1-carboxylic acid tert-butyl ester 47a

[0739] Compound 45b-1 (200 mg, 396.74 μmol), compound 42c (337.48 mg, 793.48 μmol), and potassium phosphate (210.54 mg, 991.85 μmol) were dissolved in dioxane (5 mL) and water (1 mL). Xphos-Pd-G4 (34.14 mg, 39.67 μmol) was added. The reaction mixture was stirred at 95 °C for 2.0 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water (10 mL) was added, followed by extraction with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the elution system to give the title product 47a (150 mg, 219.96 μmol, yield: 55.44%).

[0740] MS m / z(ESI): 682.6 [M+1]

[0741] Step 2

[0742] N-[(1,1,2,2,2-pentadeuterated)ethyl]-5-fluoro-2-(3-methyl-6-{1-[(3R)-2-methyl-6-(piperazin-1-yl)hexan-3-yl]azacyclobutan-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 47

[0743] Compound 47a (150 mg, 219.96 μmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (740.00 mg, 6.49 mmol, 0.5 mL) was added. The reaction mixture was stirred at 25 °C for 1.0 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (preparative column: CD52-Wepure Prepulite Platinum C18 150*25*7 μm; mobile phase: acetonitrile, water (0.225% formic acid), elution gradient: 0%-30%). The preparative solution was concentrated under reduced pressure to remove acetonitrile, the pH of the solution was adjusted to 10 with potassium carbonate, and the product was extracted with dichloromethane (10 mL × 3). After drying, filtration, and rotary evaporation, the product was lyophilized to obtain the title product 47 (3.61 mg, 6.20 μmol, yield: 2.82%) as a yellow solid.

[0744] MS m / z(ESI): 582.4 [M+1]

[0745] 1H NMR(400MHz,DMSO-d6)δ7.92(m,1H),7.76-7.60(m,1H),7.45-7.24(m,2H),7.11-6.98(m,1H),6.90-6.68(m,1H),4.37-3.45(m, 5H),3.17-3.05(m,2H),2.75-2.55(m,7H),2.33(m,6H),2.02(m,1H),1.71(m,1H),1.43(m,2H),1.19-0.77(m,12H),0.27(m,2H).

[0746] Test Implementation Examples

[0747] Experimental Example 1: Determination of Menin-MLL Binding Inhibition

[0748] This experiment used fluorescence polarization (FP) assays to evaluate the ability of the compounds to inhibit the binding of Menin to MLL.

[0749] Using a buffer containing 20 mM HEPES (pH 7.5), 50 mM NaCl, 1 mM DTT, and 0.01% BSA, 150 nM His-Menin protein (BIORTUS, BP9210) and different concentrations of the test compound (two replicates per concentration) were added to a 384-well plate. After thorough mixing, the plate was pre-incubated at 25°C for 15 minutes. Then, 15 nM FITC-MLL1 was added. 4-43 Fluorescently labeled peptides (purchased from GenScript, C491HFF190-3 / PE1324). After centrifugation, the reaction was carried out at 25°C for 60 minutes. The fluorescence polarization (mP) value of each well was measured using a multi-mode microplate reader.

[0750] Plotting the logarithm of compound concentration on the X-axis and the fluorescence polarization mP value on the Y-axis, a four-parameter logistic model was used for nonlinear regression analysis to calculate the half-maximal inhibitory concentration (IC50) for the compound to inhibit Menin-MLL binding. 50 Values. The experimental results are shown in Table 1.

[0751] Table 1: Inhibitory activity of compounds on the binding between Menin and MLL

[0752] Experimental Example 2: Determination of the inhibitory activity of the compound on the proliferation of human leukemia cells (MOLM-13)

[0753] This experiment aims to evaluate the inhibitory effect of the compounds of this invention on the proliferation of the human acute myeloid leukemia cell line MOLM-13 carrying MLL-AF9.

[0754] MOLM-13 cells (purchased from COBIOER BIOSCIENCES CO.,LTD, CBP60678) were maintained in an environment containing 20% ​​fetal bovine serum, 100 U·ml⁻¹ penicillin, and 100 μg·mL⁻¹ of penicillin. -1 Streptomycin was incubated in RPMI-1640 medium at 37°C with 5% CO2. Cell suspensions were prepared using complete culture medium and seeded into 96-well plates at a density of 4000 cells / well. The test drug was serially diluted with DMSO and then prepared into working solutions of various concentrations using complete culture medium. 100 μl of working solution containing twice the final concentration of the test compound was added to each well, with two replicates for each concentration. The control group was treated with culture medium containing 0.1% DMSO. After 7 days of drug treatment, Alamar blue assay reagent (MedChemExpress) was added to each well, and the fluorescence intensity of each well was measured using a multi-mode microplate reader.

[0755] Cell wells containing only 0.1% DMSO on day 7 were used as high-reading controls (100% proliferation); cell well reads on the day of drug administration (day 0) were used as low-reading controls. The logarithm of compound concentration was plotted on the X-axis, and the cell proliferation inhibition rate on the Y-axis. A four-parameter logistic model was used for nonlinear regression analysis to calculate the 50% growth inhibition concentration (GI) of the compound that inhibited cell proliferation. 50 The experimental results are shown in Table 2.

[0756] Table 2: Inhibitory activity of compounds on the proliferation of human leukemia cells

[0757] Experimental Example 3: In vivo pharmacodynamic evaluation of compound 42 in a ZDF rat model of diabetes

[0758] The Zucker diabetic adipose-derived (ZDF) rat model, combined with a high-fat diet (HFD), was used to simulate human obesity-associated type 2 diabetes (Obese T2D) characterized by insulin resistance, to verify the therapeutic potential of candidate compounds in improving insulin resistance and supporting the recovery of β-cell function.

[0759] Female ZDF rats (3-5 weeks old) were purchased from Viton Lever Laboratories. Upon arrival, the animals were initially fed a standard maintenance diet. After three weeks, except for the normal control group, the remaining rats were switched to a high-fat diet to induce a diabetes model. Lean animals were culled based on weight gain. All procedures performed on the animals in this experiment strictly adhered to the standard operating procedures (SOPs) for laboratory animal handling and were approved by the Institute of Laboratory Animal Care and Use (IACUC), complying with relevant animal welfare regulations.

[0760] The experimental grouping and administration adopted a sequential enrollment design. Animals meeting the criteria were enrolled in batches according to the time of achievement of the criteria (six animals per group), and the day of enrollment and administration was recorded as Day 1. There were three experimental groups: Group A was the normal diet control group (fed standard maintenance diet, without drug intervention); Group B was the model control group / solvent group, fed a high-fat diet and administered an equal volume of blank solvent (such as 0.5% methylcellulose solution) by gavage daily; Group C was the compound 42 administration group, fed a high-fat diet and administered the test compound (as in Example 42) by gavage daily at a dose of 15 mg / kg. Administration was once daily for 28 consecutive days. On days 0, 7, 14, 21, and 28, after fasting for 6 hours, fasting blood glucose was measured using a glucometer via tail vein sampling, and random blood glucose was measured on days 1, 8, 15, 22, and 29. Plasma samples were collected on days 0, 7, 14, 21, and 28 after a 6-hour fast, and the concentration of C-peptide in the plasma was measured using a rat C-peptide ELISA kit.

[0761] In an obese ZDF diabetic rat model, compound 42 exhibited robust glycemic control in both fasting and postprandial states, achieving dual control of fasting (Figure 1) and postprandial blood glucose (Figure 2). Compound 42 not only demonstrated strong glycemic control capabilities but was also validated by improved C-peptide levels (Figure 3), suggesting that it does not simply promote insulin release but rather supports endogenous insulin production and β-cell function recovery.

[0762] Experimental Example 4: In vivo pharmacodynamic study of compound 42 in a low-dose STZ-induced diabetic rat model combined with a high-fat diet.

[0763] A low-dose STZ-induced diabetic rat model combined with a high-fat diet was used to simulate lean type 2 diabetes (T2D) and latent autoimmune adult-onset diabetes mellitus (LADA, T1D subtype) in humans, to evaluate the pharmacodynamic characteristics of candidate compounds in a diabetic phenotype characterized by impaired β-cell function. All animal procedures in this experiment strictly adhered to the standard operating procedures (SOPs) related to laboratory animal handling and were approved by the Institute of Laboratory Animal Care and Use (IACUC), complying with relevant animal welfare regulations.

[0764] Male Wistar rats were fed a high-fat diet for more than 3 weeks. A diabetic model was established by a single intraperitoneal injection of streptozotocin (STZ, 30 mg / kg) into rats induced by the high-fat diet. Blood glucose was continuously monitored, and rats with fasting blood glucose ≥13 mmol / L were selected as successful models for drug administration. All experimental groups were fed a high-fat diet continuously during the experiment. The experiment consisted of 3 groups, with 6 animals in each group: Group A was the high-fat diet control group, without STZ injection; Group B was the model control group, consisting of rats successfully modeled with high-fat diet plus STZ, which were given an equal volume of blank solvent by gavage daily; Group C was the test compound group, consisting of rats successfully modeled with high-fat diet plus STZ, which were given compound 42 (30 mg / kg) by gavage daily. Administration was once daily for 28 consecutive days.

[0765] Compound 42 showed a time-dependent increasing trend in improving hyperglycemia, with both fasting and non-fasting blood glucose levels decreasing significantly over time, supporting its therapeutic effect through gradual improvement of β-cell function (Figures 4 and 5). In the STZ model control group (Vehicle), compared to the control animals fed only a high-fat diet, C-peptide levels were significantly decreased (p<0.01), suggesting a gradual loss of β-cell function (Figure 6). Compound 42 significantly enhanced endogenous insulin secretion (p<0.01), reaching levels comparable to the normal control group, and completely restored the maximum secretory capacity of β-cells.

[0766] Glucose-stimulated insulin secretion (GSIS) serves as a "stress test" for pancreatic function, assessing the ability of β-cells to sense elevated blood glucose and secrete insulin. GSIS analysis (Figures 7-8) showed that on day 1, the GSIS AUC levels in the compound 42 group and the solvent control group were similar, indicating that the initial β-cell response to glucose stimulation was similar. By day 28, the GSIS AUC in the solvent control group had slightly decreased, reflecting impaired β-cell function; while the GSIS AUC in the compound 42 group had significantly increased, indicating that compound 42 effectively restored the glucose sensing and insulin secretion capabilities of β-cells. The dynamic recovery of GSIS validated that the newly generated β-cells not only existed but also functioned normally.

[0767] In summary, compound 42 improved fasting and postprandial blood glucose, increased C-peptide and GSIS AUC in diabetic rats, and rapidly and sustainably restored β-cell function, demonstrating its potential therapeutic value in type 2 and LADA diabetes.

[0768] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

[0769] The foregoing embodiments and methods described in this invention may vary based on the capabilities, experience, and preferences of those skilled in the art.

[0770] Listing the steps of the method in a certain order in this invention does not constitute any restriction on the order of the method steps.

Claims

1. A compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, said compound having the following structure: in, Ring A is a 4-10 membered carbon ring or a heterocyclic ring; R1 is one or more independent substituents on ring A, each R1 being independently selected from: H, D, =O, halogen, C1-C. 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C1-C 10 Cyanoalkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C3-C 10 Deuterated cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -OR 101 -C(O)R 101 -C(O)OR 101 -NR 102 C(O)OR 101 -OC(O)R 101 -NR 102 SO2R 101 -SO2NR 101 R 102 -NR 102 C(O)R 101 -C(O)NR 101 R 102 -NR 101 R 102 -SR 101 -S(O)R 101 -S(O)2R 101 -SO3H; each R 101 R 102 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); R 2a R 2b R 2c R 2d Independently selected from: H, D, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C1-C 10 Cyanoalkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C3-C 10 Deuterated cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -OR 201 -C(O)R 201 -C(O)OR 201 -NR 202 C(O)OR 201 -OC(O)R 201 -NR 202 SO2R 201 -SO2NR 201 R 202 -NR 202 C(O)R 201 -C(O)NR 201 R 202 -NR 201 R 202 -SR 201 -S(O)R 201 -S(O)2R 201 -SO3H; each R 201 R 202 Independently selected from: H, D, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); R3 is selected from: H, D, halogens, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C1-C 10 Cyanoalkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C3-C 10 Deuterated cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -OR 301 -C(O)R 301 -C(O)OR 301 -NR 302 C(O)OR 301 -OC(O)R 301 -NR 302 SO2R 301 -SO2NR 301 R 302 -NR 302 C(O)R 301 -C(O)NR 301 R 302 -NR 301 R 302 -SR 301 -S(O)R 301 -S(O)2R 301 -SO3H; each R 301 R 302 Independently selected from: H, D, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic); or, R 301 R 302 Together with the atoms they are attached to, they form heterocycles; L1 and L2 are independently selected from: single bonds, C1-C 10 Alkylene, -(C0-C 10 alkylene)-Q-(C0-C 10 Alkylene), Q is selected from: -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R) La )-、-N(R La )C(O)-、-N(R La )C(O)O-、-N(R La )C(O)N(R La )-、-N(R La -, -S(O)2-, -S(O)2N(R) La )-、-N(R La -S(O)2-, -S(O)-, -S(O)N(R) La )-、-N(R La )S(O)-、-C(=NR La )-、-C(=NR La )-NR La -、C3-C 10 Cycloalkylene, 4-10 membered heterocyclic alkylene; R La Selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); The E ring is a 3-10 membered carbon ring or a heterocyclic ring; R4 is one or more independent substituents on the E ring, each R4 being independently selected from: H, D, halogen, =O, C1-C. 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C1-C 10 Cyanoalkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C3-C 10 Deuterated cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -OR 401 -C(O)R 401 -C(O)OR 401 -NR 102 C(O)OR 401 -OC(O)R 401 -NR 402 SO2R 401 -SO2NR 401 R 402 -NR 402 C(O)R 401 -C(O)NR 401 R 402 -NR 401 R 402 -SR 401 -S(O)R 401 -S(O)2R 401 -SO3H; each R 401 R 402 Independently selected from: H, D, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); Y is selected from: H, D, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C3-C 10 Deuterated cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-12 membered heterocyclic); which may optionally be surrounded by one or more R Y Group substitution, R Y Selected from: H, D, =O, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C1-C 10 Cyanoalkyl, -OR7, -C(O)R7, -C(O)OR7, -NR8C(O)OR7, -OC(O)R7, -NR8SO2R7, -SO2NR7R8, -NR7C(O)R8, -C(O)NR7R8, -NR7R8, -SR7, -S(O)R7, -S(O)2R7, -SO3H, -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C3-C 10 Deuterated cycloalkyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein, the C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups may optionally be substituted by one or more groups selected from the following: D, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), halogen, cyano, nitro, azide, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, -N(C) 0-10 Alkyl)(C 0-10 alkyl), -N(C) 0-10 Alkyl) (C3-C 10 cycloalkyl), -N(C) 0-10 Alkyl)CO(C 0-10 alkyl), -N(C) 0-10 Alkyl)CON(C 0-10 alkyl), -N(C) 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C) 0-10 Alkyl), -O (C3-C) 10 cycloalkyl), -S(C 0-10 Alkyl), -S(C3-C 10 cycloalkyl), -SO(C 0-10 alkyl), -SO2(C 0-10 Alkyl group), -SO2 (C3-C) 10 cycloalkyl), -SO2N(C 0-10 Alkyl)(C 0-10 alkyl), -SO2N(C 0-10 Alkyl) (C3-C 10 cycloalkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C) 0-10 Alkyl)(C 0-10 Alkyl), -CON(C) 0-10 Alkyl) (C3-C 10 cycloalkyl), -CO(C 0-10 alkyl); Each of R7 and R8 is independently selected from: H, D, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C3-C 10 Deuterated cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); In this embodiment, the H atom on each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclic group is optionally substituted with a group selected from the following: H, D, halogen, cyano, C1-C6 cyanoalkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic).

2. The compound according to claim 1, characterized in that, Ring A is a benzene ring or a 4-10 membered heterocycle; Preferably, Some are selected from the following structure: or, 3. The compound according to claim 1 or 2, characterized in that, R1 is independently selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl; and / or, R 2a Selected from: H, halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 deuteralkyl groups; and / or, R 2b Selected from: H, halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 deuteralkyl groups; and / or, R 2c Selected from: H, halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 deuteralkyl groups; and / or, R 2d Selected from: H, halogens, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl.

4. The compound according to any one of claims 1-3, characterized in that, R3 is -NR 302 C(O)R 301 or -C(O)NR 301 R 302 ; Among them, R 301 R 302 Independently selected from: H, D, C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C3-C6 deuterated cycloalkyl, -(C1-C3 alkylene)-(C3-C6 cycloalkyl), C1-C6 haloalkyl, -(C1-C3 alkylene)-O-(C0-C3 alkyl), -(C1-C3 alkylene)-NH-(C0-C3 alkyl); or, R 301 and R 302 Together with the atoms to which it is attached, it forms a 4-8 membered saturated heterocycle, wherein the H on the heterocycle is optionally substituted with a group selected from: H, D, =O, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 hydroxyalkyl; or, R3 is a phenyl or a 4-8 membered nitrogen-containing heterocyclic group, wherein the H on the phenyl or nitrogen-containing heterocyclic group is optionally substituted by a group selected from the following groups: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl; Preferably, R3 is selected from:

5. The compound according to any one of claims 1-4, characterized in that, L1 is a single bond or a C1-C3 alkylene bond.

6. The compound according to any one of claims 1-5, characterized in that, The E ring is a 4-10 member saturated or partially saturated carbon ring or a nitrogen-containing heterocycle; Preferably, Part of n1 is 1 or 2, and n2 is 1, 2, 3 or 4; More preferably, Part of For example For example Preferably, R4 is selected from: H, D, halogen, hydroxyl, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy.

7. The compound according to any one of claims 1-6, characterized in that, L2 is a C1-C6 alkylene group or -(C0-C6 alkylene group)-Q-(C0-C6 alkylene group)-, where Q is a C3-C6 cycloalkylene group, wherein the H atom in the alkylene group may optionally be substituted with the following groups: H, C1-C3 alkyl, halogen, cyano, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C6 alkylamine, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted with C1-C3 alkyl; Preferably, L2 is selected from: methylene, -C(O)-、 8. The compound according to any one of claims 1-7, characterized in that, Y is Among them, YⅠ ring is a 3-8 member saturated or partially saturated aliphatic ring, benzene ring, or 4-12 member saturated or partially saturated nitrogen-containing heterocycle, R Y0 R is one or more independent substituents on the ring. Y0 R Y1 With R Y Definition of a functional group; Preferably, Y is selected from: Preferably, R Y0 Selected from: H, D, halogen (e.g., F), C1-C3 alkyl (e.g., methyl), C1-C3 haloalkyl, C1-C3 deuteralkyl, hydroxyl, C1-C3 alkoxy; Preferably, R Y1 Selected from: H, D, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated hydroxyalkyl, C1-C6 alkoxyalkyl, -OR7, -C(O)R7, -C(O)OR7, -NR8C(O)OR7, -OC(O)R7, -NR8SO2R7, -SO2NR7R8, -NR7C(O)R8, -C(O)NR7R8, -NR7R8, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); each R7 and R8 is independently selected from: H, D, C1-C6 alkyl, C1-C 6-Deuterated alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the H on the alkyl, cycloalkyl, or heterocyclic group is optionally substituted by a group selected from the following: D, halogen, cyano, C1-C6 cyanoalkyl, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, amino, C1-C6 alkylamine, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)N(C0-C6 alkyl)(C0-C6 alkyl); More preferably, R Y1 Selected from:

9. The compound according to any one of claims 1-7, characterized in that, Y is selected from:

10. The compound according to claim 1, characterized in that, The compound is selected from the following structures: Preferably, the stereoisomers of the compound are selected from the following structures:

11. A pharmaceutical composition comprising the compound of any one of claims 1-10 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, and a pharmaceutically acceptable excipient.

12. The use of the compound of any one of claims 1-10 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof in the preparation of a medicament for the prevention and / or treatment of Menin-MLL interaction-mediated diseases; Preferably, the disease is selected from: tumors, diabetes, insulin resistance, hyperglycemia, autoimmune diseases, and non-alcoholic hepatitis; More preferably, the tumor is a hematologic malignancy, particularly leukemia.

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