Benzamide compound and pharmaceutical use thereof

Abstract

The present disclosure relates to a benzamide compound and the pharmaceutical use thereof. Specifically, the present disclosure relates to a compound as represented by formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, the use thereof as a therapeutic agent, and the use thereof in the preparation of a drug for treating and / or preventing diseases or conditions associated with SARM1.

Description

Benzamide compounds and their applications in medicine Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a compound of formula (I), a method for its preparation, a pharmaceutical composition containing the compound, and its use as a therapeutic agent. Background Technology

[0002] Axonal degeneration occurs after nerve injury and is a hallmark of various neurological diseases, including peripheral nerve disorders, traumatic brain injury, and neurodegenerative diseases. Due to the disruption of neural circuit integrity, it leads to progressive loss of neurological function in patients. Wallerian degeneration, as a form of programmed subcellular death, promotes axonal breakdown in disease and injury and is an intrinsic axonal damage-activating molecular pathway. SARM1 (sterile alpha and TIR motif containing 1) is one of the main regulators of active axonal destruction in this pathway.

[0003] SARM1, a Toll-like receptor adaptor protein, is a complex multi-domain protein with an ARM (Armadillo / HEAT repeat) domain, a SAM (Sterile alpha motif) domain, and a TIR (Toll / interleukin-receptor) domain. SARM1 can regulate the NF-κB signaling pathway after activating the Toll-like receptor. Its intrinsic NADase activity within the TIR domain can also catalyze the generation of ADPR (Adenosine 5-diphosphate ribose) and cyclic cADPR (Cyclic adenosine 5-diphosphate ribose) from NAD+. SARM1 activation is tightly regulated. In healthy neurons, SARM1 is inactive. However, in response to various pathological triggers, a decrease in the level of the axonal maintenance factor NMNAT2 (Nicotinamide mononucleotide adenylyl transferase 2) leads to SARM1 activation. Damaged axons actively drive their own destruction through the SAM domain and TIR motif, resulting in Ca2+ depletion. 2+ It enters, activates calpapsin, and breaks down the cytoskeleton, playing an important pro-degenerative role in programmed axonal death (Wallerian degeneration).

[0004] Axonal degeneration is a common feature of a variety of acute, chronic, sporadic, and familial neurological diseases. SARM1, as a regulator of active axonal destruction, can serve as a target for axon-specific therapeutic interventions. This disclosure aims to provide a novel compound that inhibits SARM1, offering a potential treatment for such diseases for which effective clinical interventions are currently lacking. Summary of the Invention

[0005] In a first aspect, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0006] in

[0007] Ring B is an N-containing six-membered heteroaryl group optionally substituted with one or more R3 groups, wherein the R3 groups are independently selected from halogens, hydroxyl groups, cyano groups, and C-membered heteroaryl groups. 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1- 6-alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups;

[0008] R1 is selected from hydrogen, C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1- 6-alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups;

[0009] The condition is that when ring B is pyridyl, R1 is not hydrogen;

[0010] R2 is selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups;

[0011] N is 0, 1, 2, 3 or 4;

[0012] Z represents a single bond or C optionally replaced by one or more R4 bonds. 1-9 Alkylene, wherein each R4 is independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups;

[0013] Y is a single bond or CR6R7, wherein R6 and R7 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each optionally substituted by one or more Ra groups; or the R6 and R7 groups together with the linked carbon atom form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group, each optionally substituted by one or more R5 groups, wherein the R5 groups are independently selected from halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1- 6-alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups;

[0014] Ring A is selected from 5-8-membered heteroaryl, 5-8-membered heterocyclic alkyl, phenyl, fused ring of 5-8-membered heterocyclic alkyl and phenyl, and fused ring of 5-8-membered heterocyclic alkyl and pyridine; each of the 5-8-membered heteroaryl, 5-8-membered heterocyclic alkyl, phenyl, fused ring of 5-8-membered heterocyclic alkyl and phenyl, and fused ring of 5-8-membered heterocyclic alkyl and pyridine is independently optionally substituted by one or more R8s, wherein R8s are independently selected from halogens, cyano groups, oxo groups, C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups;

[0015] Each Ra is independently selected from halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, 3-6 membered cycloalkyl, and 3-6 membered heterocycloalkyl;

[0016] Excluding the following structure

[0017] In some embodiments, the compound as described in formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a six-membered heteroaryl group containing one or two N atoms optionally substituted with one or more R3s as defined in formula (I).

[0018] In some embodiments, the compound as described in formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is selected from pyridinyl, pyridazinyl and pyrimidinyl, each of which is independently and optionally substituted by one or more R3s as defined in formula (I).

[0019] In some embodiments, the compound as described in formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is pyridinyl or pyridazinyl, wherein the pyridinyl and pyridazinyl groups are each optionally substituted independently by one or more R3 groups as defined in formula (I).

[0020] In some embodiments, the compound as described in formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a pyridinyl group, which is optionally substituted with one or more R3 groups as defined in formula (I).

[0021] In some embodiments, the compound or its pharmaceutically acceptable salt as described in formula (I) is wherein ring B is a pyridazinyl group, which is optionally substituted with one or more R3 groups as defined in formula (I).

[0022] In some embodiments, the compound as described in formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a pyrimidinyl group, which is optionally substituted with one or more R3 groups as defined in formula (I).

[0023] In some embodiments, the compound as described in formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is R3 is defined in equation (I), where m is 0, 1, 2, 3, or 4.

[0024] In some embodiments, the compound as described in formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is R3 is defined in equation (I), where m is 0, 1, 2, 3, or 4.

[0025] In some embodiments, the compound as described in formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is R3 is defined in equation (I), where m is 0, 1, 2, 3, or 4.

[0026] This disclosure also provides a compound of formula (II-A) or formula (II-B) or a pharmaceutically acceptable salt thereof.

[0027] R1, R2, R3, m, n, Z, Y and ring A are defined as in equation (I).

[0028] In some embodiments, compounds or pharmaceutically acceptable salts thereof, such as those of formula (I), (II-A), and (II-B), wherein ring A is a 5-8 heteroaryl group, which is optionally substituted with one or more R8 groups as defined in formula (I).

[0029] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B) or pharmaceutically acceptable salts thereof are used, wherein ring A is selected from thiazolyl, isoxazolyl, and pyridinyl, each of which is optionally substituted independently by one or more R8s as defined in formula (I).

[0030] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), or pharmaceutically acceptable salts thereof, wherein ring A is selected from... p is 0, 1, 2, 3 or 4, and R8 is as defined in equation (I).

[0031] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B) or pharmaceutically acceptable salts thereof are used, wherein ring A is a 5-8 membered heterocyclic alkyl group, which is optionally substituted with one or more R8 groups as defined in formula (I).

[0032] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), or pharmaceutically acceptable salts thereof, wherein ring A is E1 is selected from single bonds, O and C(R8)2, p is 0, 1, 2, 3 or 4, and R8 is defined as in equation (I).

[0033] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B) or pharmaceutically acceptable salts thereof are used, wherein ring A is tetrahydropyranyl or tetrahydrofuranyl, wherein the tetrahydropyranyl and tetrahydrofuranyl are each optionally substituted independently by one or more R8s as defined in formula (I).

[0034] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), or pharmaceutically acceptable salts thereof, wherein ring A is p is 0, 1, 2, 3 or 4, and R8 is as defined in equation (I).

[0035] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), or pharmaceutically acceptable salts thereof, wherein ring A is p is 0, 1, 2, 3 or 4, and R8 is as defined in equation (I).

[0036] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), or pharmaceutically acceptable salts thereof, wherein ring A is p is 0, 1, 2, 3 or 4, and R8 is as defined in equation (I).

[0037] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), or pharmaceutically acceptable salts thereof, wherein ring A is selected from... p is 0, 1, 2, 3 or 4, and R8 is as defined in equation (I).

[0038] In some embodiments, compounds or pharmaceutically acceptable salts thereof, such as those of formula (I), (II-A), and (II-B), wherein ring A is a phenyl group, which is optionally substituted with one or more R8 groups as defined in formula (I).

[0039] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), or pharmaceutically acceptable salts thereof, wherein ring A is p is 0, 1, 2 or 3, and R8 is as defined in equation (I).

[0040] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B) or pharmaceutically acceptable salts thereof are used, wherein ring A is a fused ring of a 5-8 membered heterocyclic alkyl group and a phenyl group; the fused ring of the 5-8 membered heterocyclic alkyl group and the phenyl group is optionally substituted with one or more R8 groups as defined in formula (I).

[0041] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), or pharmaceutically acceptable salts thereof, wherein ring A is E2 is selected from single bonds, O and C(R8)2, p is 0, 1, 2, 3 or 4, and R8 is defined as in equation (I).

[0042] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), or pharmaceutically acceptable salts thereof, wherein ring A is E2 is a single bond or O, p is 0, 1, 2, 3 or 4, and R8 is as defined in equation (I).

[0043] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), or pharmaceutically acceptable salts thereof, wherein ring A is p is 0, 1, 2, 3 or 4, and R8 is as defined in equation (I).

[0044] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), or pharmaceutically acceptable salts thereof, wherein ring A is Preferred p is 0, 1, 2, 3 or 4, and R8 is as defined in equation (I).

[0045] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), or pharmaceutically acceptable salts thereof, wherein ring A is Preferred p is 0, 1, 2, 3 or 4, and R8 is as defined in equation (I).

[0046] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B) or pharmaceutically acceptable salts thereof are used, wherein ring A is a fused ring of a 5-8 membered heterocyclic alkyl group and pyridine, the fused ring of the 5-8 membered heterocyclic alkyl group and pyridine optionally being replaced by one or more R8s as defined in formula (I).

[0047] In some embodiments, the compound or its pharmaceutically acceptable salt, as shown in formula (I), formula (II-A), formula (II-B), is used, wherein Z is a single bond.

[0048] In some embodiments, compounds of formula (I), (II-A), and (II-B), or pharmaceutically acceptable salts thereof, wherein Z is a C4 optionally substituted with one or more R4 groups. 1-9 Alkylene, R4 as defined in formula (I).

[0049] In some embodiments, compounds of formula (I), (II-A), and (II-B), or pharmaceutically acceptable salts thereof, wherein Z is a C4 optionally substituted with one or more R4 groups. 1-6 Alkylene, R4 as defined in formula (I).

[0050] In some embodiments, compounds of formula (I), (II-A), and (II-B), or pharmaceutically acceptable salts thereof, wherein Z is a C4 optionally substituted with one or more R4 groups. 1-3 Alkylene, R4 as defined in formula (I).

[0051] In some embodiments, the compound or its pharmaceutically acceptable salt represented by formula (I), formula (II-A), formula (II-B) or formula (II-C) is used, wherein each R4 is independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups as defined in formula (I).

[0052] In some embodiments, compounds of formula (I), (II-A), and (II-B), or pharmaceutically acceptable salts thereof, wherein each R4 is independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 Each alkoxy group may be independently substituted by one or more Ra groups, as defined in formula (I).

[0053] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B) or pharmaceutically acceptable salts thereof are used, wherein each R4 is independently selected from halogen, hydroxyl and cyano groups.

[0054] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), or pharmaceutically acceptable salts thereof, wherein each R4 is independently selected from C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups as defined in formula (I).

[0055] In some embodiments, the compound or its pharmaceutically acceptable salt, as shown in formula (I), formula (II-A), formula (II-B), is used, wherein Y is a single bond.

[0056] In some embodiments, the compound or its pharmaceutically acceptable salt as shown in formula (I), formula (II-A), formula (II-B) is used, wherein Y is CR6R7, and R6 and R7 are as defined in formula (I).

[0057] This disclosure also provides compounds or pharmaceutically acceptable salts thereof as shown in formulas (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), and (III-H).

[0058] R1, R2, R3, R6, R7, R8, m, n and p are defined as in equation (I).

[0059] This disclosure also provides compounds or pharmaceutically acceptable salts thereof as shown in formulas (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), and (IV-H).

[0060] R1, R2, R3, R6, R7, R8, m, n and p are defined as in equation (I).

[0061] This disclosure also provides a compound or a pharmaceutically acceptable salt thereof as shown in formulas (VA), (VB), (VC), and (VD).

[0062] R1, R2, R3, R6, R7, R8, m, n and p are defined as in equation (I).

[0063] In some embodiments, compounds of formula (I), (II-A), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein R1 is selected from hydrogen, C 1- 6-alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups as defined in formula (I).

[0064] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein R1 is selected from C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1- 6-alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups as defined in formula (I).

[0065] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein R1 is C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy group may be independently substituted by one or more Ra groups, as defined in formula (I).

[0066] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein R1 is C 1-3 Alkyl, the C 1-3 The alkyl group may optionally be replaced by one or more Ra groups as defined in formula (I).

[0067] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein R1 is a methyl group, which is optionally substituted with one or more Ra groups; Ra is as defined in formula (I).

[0068] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein R1 is methyl, preferably selected from... R1 is preferably selected from

[0069] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-C), (III-D), (III-E), (III-G), (IV-C), (IV-D), (IV-E), (IV-G), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein R6 is selected from hydrogen, halogens, and C. 1-6 Alkyl, the C 1-6 The alkyl group may optionally be replaced by one or more Ra groups as defined in formula (I).

[0070] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-C), (III-D), (III-E), (III-G), (IV-C), (IV-D), (IV-E), (IV-G), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein R7 is selected from hydrogen, halogens, and C. 1-6 Alkyl, the C 1-6 The alkyl group may optionally be replaced by one or more Ra groups as defined in formula (I).

[0071] In some embodiments, compounds or pharmaceutically acceptable salts thereof, such as those shown in formula (I), formula (II-A), formula (II-B), formula (III-C), formula (III-D), formula (III-E), formula (III-G), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-G), formula (VC), and formula (VD), are used, wherein R6 and R7 are both hydrogen.

[0072] In some embodiments, compounds or pharmaceutically acceptable salts thereof, such as those shown in formula (I), formula (II-A), formula (II-B), formula (III-C), formula (III-D), formula (III-E), formula (III-G), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-G), formula (VC), and formula (VD), are used, wherein R6 and R7 are halogens.

[0073] In some embodiments, compounds or pharmaceutically acceptable salts thereof, such as those represented by formulas (I), (II-A), (II-B), (III-C), (III-D), (III-E), (III-G), (IV-C), (IV-D), (IV-E), (IV-G), (VC), and (VD), are used, wherein R6 is hydrogen and R7 is carbon. 1-6 Alkyl, the C 1-6 The alkyl group may optionally be replaced by one or more Ra groups as defined in formula (I).

[0074] In some embodiments, compounds or pharmaceutically acceptable salts thereof, such as those shown in formula (I), formula (II-A), formula (II-B), formula (III-C), formula (III-D), formula (III-E), formula (III-G), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-G), formula (VC), and formula (VD), wherein R6 and R7 form a 3-6 membered cycloalkyl group, wherein the 3-6 membered cycloalkyl group is optionally substituted with one or more R5 groups as defined in formula (I).

[0075] In some embodiments, compounds or pharmaceutically acceptable salts thereof, such as those of formula (I), (II-A), (II-B), (III-C), (III-D), (III-E), (III-G), (IV-C), (IV-D), (IV-E), (IV-G), (VC), and (VD), are used, wherein R6 and R7 together with the linked carbon atom form a 3-6 membered heterocyclic alkyl group, wherein the 3-6 membered heterocyclic alkyl group is optionally substituted with one or more R5s as defined in formula (I).

[0076] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-C), (III-D), (III-E), (III-G), (IV-C), (IV-D), (IV-E), (IV-G), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein R5 is independently selected from halogens, cyano groups, oxo groups, C... 1-6 Alkyl, C 1-6alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups as defined in formula (I).

[0077] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-C), (III-D), (III-E), (III-G), (IV-C), (IV-D), (IV-E), (IV-G), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein R5 is independently selected from halogens, cyano groups, oxo groups, C... 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 Each alkoxy group may be independently substituted by one or more Ra groups, as defined in formula (I).

[0078] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein R3 is a halogen or C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be replaced by one or more Ra groups as defined in formula (I).

[0079] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein R3 is C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be replaced by one or more Ra groups as defined in formula (I).

[0080] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (III-G), formula (III-H), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (VA), formula (VB), formula (VC), and formula (VD), or pharmaceutically acceptable salts thereof, wherein m is 0, 1, or 2; preferably m is 0 or 1.

[0081] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein p is 0, 1, or 2; preferably p is 0 or 1.

[0082] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein R2 is a halogen or C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be replaced by one or more Ra groups as defined in formula (I).

[0083] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein R2 is C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be replaced by one or more Ra groups as defined in formula (I).

[0084] In some embodiments, the compound or pharmaceutically acceptable salt thereof is represented by formula (I), formula (II-A), formula (II-B), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (III-G), formula (III-H), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (VA), formula (VB), formula (VC), and formula (VD), wherein R2 is a halogen.

[0085] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein n is 0, 1, or 2; preferably n is 0 or 1.

[0086] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein each R8 is independently selected from halogens, oxo groups, and C. 1-6 Alkyl, the C 1-6 The alkyl group may optionally be replaced by one or more Ra groups as defined in formula (I).

[0087] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein each R8 is independently a halogen or C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be replaced by one or more Ra groups as defined in formula (I).

[0088] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (III-G), formula (III-H), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (VA), formula (VB), formula (VC), and formula (VD), or pharmaceutically acceptable salts thereof, wherein each R8 is independently a halogen.

[0089] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein each R8 is independently C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be replaced by one or more Ra groups as defined in formula (I).

[0090] In some embodiments, compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, wherein each Ra is independently selected from halogens, hydroxyl groups, cyano groups, oxo groups, C... 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and hydroxy C 1-6 Alkyl group.

[0091] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (III-G), formula (III-H), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (VA), formula (VB), formula (VC), and formula (VD), or pharmaceutically acceptable salts thereof, wherein each Ra is independently selected from halogens, hydroxyl groups, and cyano groups.

[0092] In some embodiments, compounds of formula (I), formula (II-A), formula (II-B), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (III-G), formula (III-H), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (VA), formula (VB), formula (VC), and formula (VD), or pharmaceutically acceptable salts thereof, wherein each Ra is independently a halogen or a hydroxyl group.

[0093] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof, including but not limited to:

[0094] This disclosure also provides an isotopic substitute of a compound or a pharmaceutically acceptable salt thereof as described in formulas (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), preferably, the isotopic substitute is a deuterium-substituted product.

[0095] This disclosure also provides a pharmaceutical composition comprising at least one compound of formula (I), formula (II-A), formula (II-B), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (III-G), formula (III-H), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (VA), formula (VB), formula (VC), and formula (VD) or a pharmaceutically acceptable salt thereof or an isotopic substitute thereof, and a pharmaceutically acceptable excipient.

[0096] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0097] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0099] This disclosure provides that compounds of formulas (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, the aforementioned isotope substitutes, and the aforementioned pharmaceutical compositions, all exhibit significant inhibitory activity against SARM1; the compound IC of this disclosure 50 ≤1000nM, preferably the compound IC described in this disclosure 50 ≤800 nM, preferably the compound IC described in this disclosure 50 ≤600 nM, preferably the compound IC described in this disclosure 50 ≤500nM.

[0100] This disclosure also provides the use of compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD) or pharmaceutically usable salts thereof, isotope substitutes as described above, and pharmaceutical compositions as described above, for use as a medicine.

[0101] This disclosure also provides the use of the compounds described above as of formula (I), formula (II-A), formula (II-B), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (III-G), formula (III-H), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (VA), formula (VB), formula (VC), and formula (VD), or pharmaceutically acceptable salts thereof, isotope substitutes as described above, or pharmaceutical compositions as described above, for the treatment and / or prevention of diseases or conditions associated with SARM1.

[0102] This disclosure also provides the use of the compounds described above as of formula (I), formula (II-A), formula (II-B), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (III-G), formula (III-H), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (VA), formula (VB), formula (VC) and formula (VD), or pharmaceutically acceptable salts thereof, the aforementioned isotope substitutes, and the aforementioned pharmaceutical compositions for the treatment and / or prevention of diseases or conditions related to axonal degeneration.

[0103] This disclosure also provides the following as described above: formulas (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD). The use of compounds or their pharmaceutically usable salts, isotope substitutes as described above, and pharmaceutical compositions as described above for the treatment and / or prevention of chemotherapy-induced peripheral neuropathy (CIPN), painful diabetic neuropathy (PDN), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), demyelinating diseases, Parkinson's disease (PD), Alzheimer's disease (AD), ocular neuropathy, peripheral neuropathy, traumatic brain injury (TBI), sciatica, sciatic nerve injury, traumatic nerve injury, nerve injury-related neuropathy, peroneal muscular atrophy (CMT Charcot-Marie-Tooth), hereditary spastic paraplegia, ischemia, stroke, glaucoma, carpal tunnel syndrome, retinal degeneration, optic nerve injury-related diseases, viral infections, and viral encephalitis.

[0104] This disclosure also provides the use of compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD) as described above, or pharmaceutically acceptable salts thereof, isotope substitutes as described above, or pharmaceutical compositions as described above, in the preparation of medicaments for the treatment and / or prevention of diseases or conditions associated with SARM1.

[0105] This disclosure also provides the use of compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD) as described above, or pharmaceutically acceptable salts thereof, isotope substitutes as described above, or pharmaceutical compositions as described above, in the preparation of a medicament for the treatment and / or prevention of diseases or conditions associated with axonal degeneration.

[0106] This disclosure also provides compounds of formula (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD) as described above, or their derivatives thereof. The use of pharmaceutical salts, isotope substitutes as described above, and pharmaceutical compositions as described above in the preparation of a medicament for the treatment and / or prevention of chemotherapy-induced peripheral neuropathy (CIPN), painful diabetic neuropathy (PDN), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), demyelinating diseases, Parkinson's disease (PD), Alzheimer's disease (AD), ocular neuropathy, peripheral neuropathy, traumatic brain injury (TBI), sciatica, sciatic nerve injury, traumatic nerve injury, nerve injury-related neuropathy, peroneal muscular atrophy (CMT Charcot-Marie-Tooth), hereditary spastic paraplegia, ischemia, stroke, glaucoma, carpal tunnel syndrome, retinal degeneration, optic nerve injury-related diseases, viral infections, and viral encephalitis.

[0107] This disclosure also provides methods for treating and / or preventing diseases or conditions associated with SARM1, comprising administering to a desired patient a compound or pharmaceutically acceptable salt thereof as described above, such as formula (I), formula (II-A), formula (II-B), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (III-G), formula (III-H), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (VA), formula (VB), formula (VC), and formula (VD), isotope substitutes as described above, or pharmaceutical compositions as described above.

[0108] This disclosure also provides methods for treating and / or preventing diseases or conditions associated with axonal degeneration, comprising administering to a desired patient a compound as described above, such as formula (I), formula (II-A), formula (II-B), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-E), formula (III-F), formula (III-G), formula (III-H), formula (IV-A), formula (IV-B), formula (IV-C), formula (IV-D), formula (IV-E), formula (IV-F), formula (IV-G), formula (IV-H), formula (VA), formula (VB), formula (VC), and formula (VD), or a pharmaceutically acceptable salt thereof, an isotope substitute as described above, or a pharmaceutical composition as described above.

[0109] This disclosure also provides treatments and / or preventions for chemotherapy-induced peripheral neuropathy (CIPN), painful diabetic neuropathy (PDN), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), demyelinating diseases, Parkinson's disease (PD), Alzheimer's disease (AD), ocular neuropathy, peripheral neuropathy, traumatic brain injury (TBI), sciatica, sciatic nerve injury, traumatic nerve injury, nerve injury-related neuropathy, and peroneal muscular atrophy (CMT). Methods of treating conditions such as Charcot-Marie-Tooth, hereditary spastic paraplegia, ischemia, stroke, glaucoma, carpal tunnel syndrome, retinal degeneration, optic nerve injury-related diseases, viral infections, and viral encephalitis, comprising administering to the desired patient the compounds described above as of formulas (I), (II-A), (II-B), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-A), (IV-B), (IV-C), (IV-D), (IV-E), (IV-F), (IV-G), (IV-H), (VA), (VB), (VC), and (VD), or pharmaceutically acceptable salts thereof, isotope substitutes as described above, or pharmaceutical compositions as described above.

[0110] This disclosure also provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0111] It includes the step of reacting a compound of formula (M1) or a pharmaceutically acceptable salt thereof with a compound of formula (M2) or a pharmaceutically acceptable salt thereof to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, R1, R2, Z, Y and n are as defined in formula (I).

[0112] In some embodiments, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein M1 and M2 react in the presence of a condensing agent.

[0113] In some embodiments, the preparation of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the condensing agent is selected from 1-n-propylphosphonic anhydride (PPACA, T3P), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) and carbonyldiimidazole (CDI).

[0114] This disclosure also provides a compound of formula (M1) or a pharmaceutically acceptable salt thereof.

[0115] The rings B, R1, R2, and n are defined as in equation (I).

[0116] In some embodiments, the compound represented by formula (M1) or a pharmaceutically acceptable salt thereof is used for the preparation of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0117] This disclosure also provides compounds of the following formula or pharmaceutically acceptable salts thereof.

[0118] This disclosure also provides the use of compounds of the following formula or pharmaceutically acceptable salts thereof for the preparation of compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0119] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0120] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0121] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0122] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. In the chemical structure of the compounds described in this disclosure, the bonds... No configuration was specified, i.e., key The configuration can be E-type or Z-type, or it can contain both E-type and Z-type configurations.

[0123] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerizations. Exemplary examples of isomerizations containing a lactam-lactamimide structure are, for example, between A and B as shown below.

[0124] All compounds disclosed herein may be designated as type A or type B. All tautomers are within the scope of this invention. The nomenclature of compounds does not exclude any tautomers.

[0125] This disclosure also includes compounds identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0126] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or even higher. This disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of compounds of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used to prepare the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0127] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1- "6-alkyl" means that a halogen or cyano group may or may not be present. This description includes cases where the alkyl group is substituted by a halogen or cyano group and cases where the alkyl group is not substituted by a halogen or cyano group.

[0128] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertment of its biological activity.

[0129] "Pharmaceutical-acceptable excipients" include, but are not limited to, any adjuvant, carrier, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration (FDA) for use in humans or livestock.

[0130] The term "effective amount" or "effective therapeutic amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0131] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. The alkyl group can be substituted or unsubstituted; when substituted, it can be substituted at any usable connection point.

[0132] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylenes). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C12). 1- 12 Alkylenes, more preferably alkylenes having 1 to 6 carbon atoms (i.e., C16-164 ... 1-6Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker.

[0133] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C). 2-6 Alkenyl groups. Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point.

[0134] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C64). 2-6 Alynyl group. Non-limiting examples include: ethynyl, propynyl, butynyl, pentylyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker.

[0135] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be replaced at any usable connection point.

[0136] Similarly, the "alkoxy" in "cycloalkoxy" and "heterocycloalkoxy" is the same as the "alkoxy" defined above.

[0137] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl includes spirocyclic, fused, and bridged cycloalkyl. The cycloalkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any usable connection point.

[0138] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 7 ring atoms, of which 1 to 3 are heteroatoms; even more preferably, it contains 5 to 8 ring atoms, of which 1 to 2 are heteroatoms.

[0139] Non-limiting examples of "heterocyclic alkyl" include: etc.

[0140] The heterocyclic alkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocyclic alkyl ring, and non-limiting examples include:

[0141] wait.

[0142] Heterocyclic alkyl groups can be optionally substituted or unsubstituted.

[0143] A "monovalent group" refers to a compound in which one monovalent atom or group is "formally" eliminated. A "subunit" refers to a compound in which two monovalent or one divalent atom or group is "formally" eliminated.

[0144] In some embodiments, heterocyclic alkyl groups and heteroaryl groups can be monovalent or divalent, and those skilled in the art will recognize from the context the number of available valences.

[0145] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0146] Aryl groups can be substituted or unsubstituted.

[0147] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 6 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrole, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazole, benzimidazolyl, etc. wait.

[0148] The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0149] The heteroaryl group can be optionally substituted or unsubstituted.

[0150] The term "spirocyclic" refers to a polycyclic system in which the rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms (e.g., nitrogen, oxygen, and sulfur, wherein the nitrogen may be optionally oxidized to form nitrogen oxides; and the sulfur may be optionally oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocyclic rings). The spirocyclic ring is preferably a spirocyclic ring with 6 to 14 ring atoms (i.e., 6 to 14-membered spirocyclic rings), and more preferably a spirocyclic ring with 7 to 10 ring atoms (i.e., 7 to 10-membered spirocyclic rings). The spiral rings include single spiral rings and multi-spiral rings (such as double spiral rings), preferably single spiral rings or double spiral rings, and more preferably single spiral rings of 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan.

[0151] Non-restrictive examples include: Its connection point can be anywhere.

[0152] The term "hydroxyl group" refers to the -OH group.

[0153] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0154] The term "cyano" refers to -CN.

[0155] The term "amino" refers to -NH2.

[0156] The term "nitro" refers to -NO2.

[0157] The term "oxo" refers to the =O substituent.

[0158] The term "carboxyl group" refers to -COOH.

[0159] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0160] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0161] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0162] The term "hydroxyalkoxy" refers to an alkoxy group that is replaced by one or more hydroxyl groups, where the alkoxy group is as defined above.

[0163] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently replaced by the corresponding number of substituents. When the substituent is a ketone or an oxo (i.e., =O), two (2) hydrogen atoms on the atom are replaced.

[0164] When the groups described in this disclosure are substituted, unless otherwise defined, the substituents may be the same or different from each other, and are independently selected from the following groups:

[0165] Halogen, carboxyl, cyano, nitro, amino, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2- 6-olefin, C 2-6 Alkyne group, 3- to 6-membered cycloalkoxy group, 3- to 6-membered heterocycloalkoxy group, C 3-8 Cycloalkenyloxy, aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl C 1-6 Alkylene, 3- to 6-membered heterocyclic alkyl and 3- to 6-membered heterocyclic alkyl C 1-6 Alkylene, the C 1-6 Alkyl, C 1-6Alkoxy, C 2-6 alkenyloxy group, C 2-6 Acryloxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered heterocycloalkoxy, 3- to 8-membered cycloalkenoxy, aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl C 1-6 Alkylene, 3- to 6-membered heterocyclic alkyl and 3- to 6-membered heterocyclic alkyl C 1-6 Each alkylene group is independently and optionally selected from one or more groups chosen from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups. Detailed Implementation

[0166] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0167] Example

[0168] 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 measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0169] MS measurements were performed using a Finnigan LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0170] 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.

[0171] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0172] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0173] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0174] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0175] 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.

[0176] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0177] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0178] 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.

[0179] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0180] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0181] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0182] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0183] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0184] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0185] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0186] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0187] 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: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate 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.

[0188] Example 1

[0189] 4,4-Difluoro-N-(4-(1-(3-methylpyridazin-4-yl)ethyl)phenyl)tetrahydro-2H-pyran-3-carboxamide (1)

[0190] Step 1

[0191] 1-(3-methylpyridazin-4-yl)ethyl-1-one 1a (540 mg, 3.96 mmol) was dissolved in methanol (15 mL), and p-toluenesulfonyl hydrazine 1b (1.1 g, 5.94 mmol) was added. The mixture was stirred in an oil bath at 70 °C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to silica gel column chromatography (0-20% ethyl acetate / petroleum ether) to give 4-methyl-N'-(1-(3-methylpyridazin-4-yl)ethylidene)benzenesulfonyl hydrazine 1c (660 mg, yield 54%).

[0192] MS m / z (ESI): 305.1 [M+H] + .

[0193] Step 2

[0194] Compound 1c (660 mg, 2.16 mmol) and 4-bromophenylboronic acid 1d (653 mg, 3.25 mmol) were dissolved in dioxane (15 mL), and potassium carbonate (600 mg, 4.33 mmol) was added. The mixture was stirred in an oil bath at 100 °C for 6 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to silica gel column chromatography (0-20% ethyl acetate / petroleum ether) to give 4-(1-(4-bromophenyl)ethyl)-3-methylpyridazine 1e (300 mg, 50% yield).

[0195] MS m / z(ESI): 277.0 [M+H] + .

[0196] Step 3

[0197] Compound 1e (300 mg, 1.08 mmol) and tert-butyl carbamate (190 mg, 1.62 mmol) were dissolved in dioxane (5 mL), and potassium tert-butoxide (182 mg, 1.62 mmol) was added. The mixture was placed in a microwave reactor at 100 °C and reacted for 1 hour. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was subjected to silica gel column chromatography (10-30% ethyl acetate / petroleum ether) to give (4-(1-(3-methylpyridazin-4-yl)ethyl)phenyl)tert-butyl carbamate 1f (220 mg, yield 65%).

[0198] MS m / z (ESI): 314.5 [M+H] + .

[0199] Step 4

[0200] Compound 1f (220 mg, 0.702 mmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (2 mL) was added. The mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure to obtain the crude product. The crude product was subjected to silica gel column chromatography (0-5% methanol / dichloromethane) to give 4-(1-(3-methylpyridazin-4-yl)ethyl)aniline 1h (135 mg, 90% yield).

[0201] MS m / z (ESI): 214.4 [M+H] + .

[0202] Step 5

[0203] Compound 1h (40 mg, 0.188 mmol) and 4,4-difluorotetrahydro-2H-pyran-3-carboxylic acid 1i (37 mg, 0.225 mmol) were dissolved in dichloromethane (1 mL), and 1-n-propylphosphoric anhydride (1 mL) and N-methylimidazole (30 mg, 0.375 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with 5 mL of water, and extracted twice with dichloromethane (10 mL). The dichloromethane phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was used to prepare the target compound 1 (20 mg, yield 31%) by HPLC.

[0204] MS m / z(ESI): 362.2 [M+H] + .

[0205] 1H NMR (400MHz, DMSO) δ10.12(s,1H),9.03(d,J=5.2Hz,1H),7.52(dd,J=10.3,6.9Hz,3H),7.13(d,J=8.5Hz,2H),4.26(q,J=7.0Hz,1H),4.01–3. 88(m,1H),3.86–3.75(m,2H),3.71–3.59(m,1H),3.15–3.01(m,1H),2. 49(s,3H),2.38–2.21(m,1H),2.06–1.86(m,1H),1.52(d,J=7.1Hz,3H).

[0206] Example 2

[0207] N-(4-(1-(pyridazin-4-yl)ethyl)phenyl)-2,3-dihydrobenzo[b][1,4]dioxin-2-carboxamide (2)

[0208] Step 1

[0209] At room temperature, 1-(pyridazin-4-yl)ethyl-1-one 2a (1 g, 8.2 mmol) and p-toluenesulfonyl hydrazine 1b (1.8 g, 9.8 mmol) were dissolved in methanol (20 mL). The reaction mixture was gradually heated to 80 °C and stirred for 3 hours under nitrogen protection. The reaction solution was filtered to obtain 4-methyl-N'-(1-(pyridazin-4-yl)ethylidene)benzenesulfonyl hydrazine 2b (750 mg, yield 32%).

[0210] MS(ESI)m / z = 291.2[M+H] + .

[0211] Step 2

[0212] Compound 2b (750 mg, 2.6 mmol), 4-bromophenylboronic acid 1d (778 mg, 3.9 mmol), and potassium carbonate (714 mg, 5.2 mmol) were dissolved in dioxane (20 mL) at room temperature. The reaction mixture was gradually heated to 110 °C and stirred overnight under nitrogen protection. The reaction solution was washed with saturated NaCl aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 2), the organic phases were combined, dried, concentrated, and the residue was separated by column chromatography to give 4-(1-(4-bromophenyl)ethyl)pyridazine 2c (230 mg, yield 34%).

[0213] MS(ESI)m / z = 263.2[M+H] + .

[0214] Step 3

[0215] Compound 2c (100 mg, 0.38 mmol) and tert-butyl carbamate (67 mg, 0.75 mmol) were dissolved in anhydrous dioxane (3 mL) at room temperature. tBuXPhos-Pd-G3 (30 mg, 0.03 mmol) and potassium tert-butoxide (85 mg, 0.76 mmol) were added. The mixture was microwaved under nitrogen protection, heated to 100 °C, and stirred for 1 hour. The reaction solution was washed with saturated NaCl aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 2), the organic phases were combined, dried, concentrated, and the residue was separated by column chromatography to give (4-(1-(pyridazin-4-yl)ethyl)phenyl)carbamate tert-butyl 2d (80 mg, 70% yield).

[0216] MS(ESI)m / z = 300.3[M+H] + .

[0217] Step 4

[0218] Compound 2d (80 mg, 0.27 mmol) was dissolved in dioxane hydrochloride solution (4.0 M, 2 mL) at room temperature and stirred for 2 hours. The reaction solution was concentrated and separated by column chromatography to give 4-(1-(pyridazin-4-yl)ethyl)aniline 2e (50 mg, yield 88%).

[0219] MS(ESI)m / z = 200.3[M+H] + .

[0220] Step 5

[0221] Compound 2e (80 mg, 0.4 mmol), 2,3-dihydrobenzo[b][1,4]dioxin-2-carboxylic acid 2f (87 mg, 0.48 mmol), and compound 2e were dissolved in DMF (5 mL) at room temperature. TEA (0.12 mL, 0.8 mmol) and HATU (230 mg, 0.60 mmol) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was washed with saturated NaCl aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 2), the organic phases were combined, dried, and the residue was concentrated. The residue was separated by column chromatography to obtain a crude product, which was then purified by HPLC to obtain target compound 2 (25 mg, yield 17.3%).

[0222] MS m / z(ESI):362.3[M+H]+.

[0223] 1H NMR (400MHz, DMSO) δ10.14(s,1H),9.21(s,1H),9.14(d,J=5.3Hz,1H),7.66–7.55(m,3H),7.28(d,J=8.3Hz,2H),7.08–7.00( m,1H),6.90–6.81(m,3H),4.98–4.95(m,1H),4.46–4.40(m,1H),4.36–4.30(m,1H),4.28–4.21(m,1H),1.60(d,J=7.2Hz,3H).

[0224] Example 3

[0225] 4,4-Difluoro-N-(4-(1-(pyridazin-4-yl)ethyl)phenyl)tetrahydro-2H-pyran-3-carboxamide (3)

[0226] Step 1

[0227] At room temperature, compound 2e (20 mg, 0.09 mmol), 4,4-difluorotetrahydro-2H-pyran-3-carboxylic acid 1i (23 mg, 0.14 mmol), and N-methylimidazole (15 mg, 0.18 mmol) and T3P (50% in EA, 1 mL) were dissolved in DCM (2 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was washed with saturated NaCl aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 2), the organic phases were combined, dried, and the residue was concentrated. The crude product was separated by column chromatography, and then purified by HPLC to obtain target compound 3 (5 mg, 15% yield).

[0228] MS m / z(ESI): 348.3[M+H]+.

[0229] 1 H NMR (400MHz, CDCl3) δ9.08(s,2H),7.95(s,1H),7.51(d,J=8.2Hz,2H),7.15(d,J=8.2Hz,2H),4.23–4.10( m,2H),4.02–3.90(m,2H),3.83–3.72(m,1H),3.12–2.97(m,1H),2.32–2.08(m,2H),1.67(d,J=7.1Hz,3H).

[0230] Step 2

[0231] Compound 3 was purified by SFC (separation conditions: column: ChiralPak AD (250×30 mm, 5 μm); mobile phase: phase A: supercritical carbon dioxide, phase B: ethanol (0.1% NH3); gradient: B%: 50%), yielding fraction 1 (3-P1), fraction 2 (3-P2), and fraction 3. SFC detection (column: ChiralPak AD, 100×4.6 mm ID, 3 μm; mobile phase: phase A: supercritical carbon dioxide, phase B: ethanol (0.1% DEA); gradient: B%: 45%) showed that 3-P1 had a retention time of 1.180 min (MS m / z (ESI): 348.22 [M+H)). + The retention time of 3-P2 was 1.411 min (MS m / z(ESI): 348.18 [M+H]+), and the retention time of component 3 was 4.942 min.

[0232] Component 3 was further purified by SFC (separation conditions: column: ChiralPak As, 250×25mm ID, 10μm; mobile phase: phase A: supercritical carbon dioxide, phase B: methanol (0.1% NH3); gradient: B%: 20%), yielding component A (3-P3) and component B (3-P4). SFC detection (column: ChiralPak AS, 100×4.6mm ID, 3μm; mobile phase: phase A: supercritical carbon dioxide, phase B: methanol (0.1% DEA); gradient: B%: 20%) showed a retention time of 2.230 min for 3-P3 (MS m / z (ESI): 348.22 [M+H)). + The retention time of 3-P4 was 2.484 min (MS m / z (ESI): 348.22 [M+H]). + ).

[0233] The structure and characterization of 3-P1 are as follows:

[0234] Compound 3-P1: 1 H NMR (400MHz, DMSO) δ10.12(s,1H),9.15(s,1H),9.09(d,1H),7.60–7.47(m,3H),7.25(d,2H),4.20(q,1H),4.01–3.91 (m,1H),3.88–3.77(m,2H),3.72–3.60(m,1H),3.21–3.01(m,1H),2.40–2.22(m,1H),2.05–1.93(m,1H),1.59(d,3H).

[0235] 3-P2, 3-P3, and 3-P4 are selected from the following structures:

[0236] Example 4

[0237] 2,2-Difluoro-N-(4-(1-(pyridazin-4-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide (4)

[0238] Step 1

[0239] Ethyl 3-pyridine 4a (4.1 g, 24.8 mmol) was dissolved in tetrahydrofuran (74 mL), purged with nitrogen, and cooled to -78 °C. Lithium bis(trimethylsilylamine)amine (34.3 mL, 34.3 mmol) was added dropwise, and the reaction was allowed to proceed for half an hour. A tetrahydrofuran (74 mL) solution of N-fluorobis(phenyl)sulfonamide (10.80 g, 34.3 mmol) was slowly added dropwise to the reaction mixture, and the reaction was allowed to proceed at -78 °C for 5 hours. After the reaction was complete, the reaction mixture was quenched with methanol, concentrated, and purified by normal phase to give 2,2-difluoro-2-(pyridin-3-yl)acetic acid 4b (930 mg, yield 21.64%).

[0240] MS m / z(ESI): 173.90 [M+H] + .

[0241] Step 2

[0242] N-methylimidazole (0.030 mL, 0.376 mmol) and T3P (50% in EA) (0.067 mL, 0.226 mmol) were added to a dichloromethane (5 mL) solution of compound 2e (15 mg, 0.075 mmol) and compound 4b (30 mg, 0.173 mmol), and the reaction was carried out for 3 hours. After the reaction was completed, the reaction solution was concentrated, purified by normal phase and then purified by HPLC to obtain the target compound 4 (2.9 mg, yield 10.9%).

[0243] MS m / z (ESI): 355.54 [M+H] + .

[0244] 1H NMR (400MHz, DMSO) δ10.87(s,1H),9.16(dd,J=2.5,1.2Hz,1H),9.10(dd,J=5.4,1.3Hz,1H),8.88(d,J=2.4Hz,1H),8.79(dd,J=4.8,1.5Hz,1H) ,8.08(dt,J=8.1,2.0Hz,1H),7.66–7.57(m,3H),7.55(dd,J=5.4,2.5Hz,1H),7.35–7.28(m,2H),4.23(q,J=7.2Hz,1H),1.60(d,J=7.2Hz,3H).

[0245] Example 5

[0246] 2,2-Difluoro-N-(4-(1-(3-methylpyridazin-4-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide (5)

[0247] Compound 5 was synthesized using the method described in Example 4.

[0248] MS m / z(ESI): 369.2 [M+H] + .

[0249] Example 6

[0250] N-(4-(1-(pyridazin-4-yl)ethyl)phenyl)-2-(tetrahydrofuran-3-yl)acetamide (6)

[0251] The synthesis of Example 6 was obtained by referring to Example 2.

[0252] MS m / z (ESI): 312.5 [M+H] + .

[0253] 1H NMR (400MHz, CDCl3) δ9.15–9.02(m,2H),7.50(d,J=8.4Hz,2H),7.41(s,1H),7.34( dd,J=5.0,2.0Hz,1H),7.13(d,J=8.4Hz,2H),4.15(q,J=7.1Hz,1H),4.01–3.85(m, 2H),3.77(dd,J=15.6,7.7Hz,1H),3.50(dd,J=8.6,5.9Hz,1H),2.84–2.72(m,1H), 2.47(d,J=7.4Hz,2H),2.22–2.14(m,1H),1.67(d,J=7.2Hz,3H),1.65–1.57(m,1H).

[0254] Example 7

[0255] 2-(2,3-Dihydrobenzofuran-3-yl)-N-(4-(1-(pyridazin-4-yl)ethyl)phenyl)acetamide (7)

[0256] Step 1

[0257] At room temperature, 2-(2,3-dihydrobenzofuran-3-yl)acetic acid 7a (30 mg, 0.17 mmol) and compound 2e (30 mg, 0.15 mmol) were dissolved in anhydrous DMF (1 mL), and HATU (77 mg, 0.2 mmol) and DIEA (0.06 mL, 44 mg, 0.34 mmol) were added. The mixture was stirred overnight at room temperature under nitrogen protection. The reaction solution was washed with saturated NaCl aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 2), the organic phases were combined, dried, concentrated, and the residue was separated by column chromatography to obtain the crude product. The crude product was then purified by HPLC to obtain the target compound 7 (10 mg, yield 16.5%).

[0258] MS(ESI)m / z = 360.2[M+H] + .

[0259] 1H NMR(400MHz, CDCl3)δ8.97(s,2H),7.53(s,1H),7.47–7.36(m,2H),7.23–7.16(m,1H),7.13–7.00(m,4H),6.82–6.69(m,2H),4.6 8(m,1H),4.29–4.20(m,1H),4.11–3.99(m,1H),3.97–3.87(m,1H),2.77–2.66(m,1H),2.63–2.53(m,1H),1.58(d,J=7.2Hz,3H).

[0260] Example 8

[0261] 4,4-Difluoro-N-(4-(1-(pyridin-4-yl)ethyl)phenyl)tetrahydro-2H-pyran-3-carboxamide (8)

[0262] Compound 8 was synthesized using the method described in Example 1.

[0263] MS m / z(ESI): 347.3[M+H]+.

[0264] 1 H NMR (400MHz, DMSO) δ10.11(s,1H),8.44(d,J=5.4Hz,2H),7.51(d,J=8.4Hz,2H),7.28–7.15(m,4H),4.13(q,J=7.1Hz,1H),4.01–3 .90(m,1H),3.86–3.76(m,1H),3.71–3.60(m,1H),3.17–3.02(m,1H),2.40–2.23(m,1H),2.07–1.88(m,1H),1.55(d,J=7.2Hz,2H).

[0265] Reference point 1

[0266] 4,4-Difluoro-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)tetrahydro-2H-pyran-3-carboxamide

[0267] Step 1:

[0268] (S)-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)aniline (350 mg, 1.73 mmol) and 4,4-difluorotetrahydro-2H-pyran-3-carboxylic acid 1i (317 mg, 1.91 mmol) were dissolved in dichloromethane (7 mL), and n-butylphosphine anhydride (1.4 mL) and N-methylimidazolium (285 mg, 3.47 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with 10 mL of water, and extracted twice with dichloromethane (20 mL). The dichloromethane phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was used to prepare 4,4-difluoro-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)tetrahydro-2H-pyran-3-carboxamide (reference 1) (530 mg, yield 87%) by HPLC.

[0269] MS m / z (ESI): 350.3 [M+H] + .

[0270] Step 2:

[0271] Reference 1 was purified by SFC (separation conditions: column: ChiralPak AD (250×30 mm, 5 μm); mobile phase: phase A: supercritical carbon dioxide, phase B: ethanol (0.1% NH3); gradient: B%: 40%), yielding fraction 1 (reference 1-P1) and fraction 2 (reference 1-P2). SFC detection (column: ChiralPak AD, 100×4.6 mm ID, 3 μm; mobile phase: phase A: supercritical carbon dioxide, phase B: ethanol (0.1% DEA); gradient: B%: 40%) showed a retention time of 0.779 min (MS m / z (ESI): 349.95 [M+H)). + The retention time of reference 1-P2 was 1.406 min (MS m / z(ESI): 349.91 [M+H]+).

[0272] Reference object 1-P1 and reference object 1-P2 are selected from the following structures:

[0273] Reference material 1-P1: ¹H NMR (400MHz, DMSO) δ 10.15 (s, ¹H), 7.53 (d, 2H), 7.22 (d, ¹H), 7.13 (d, 2H), 6.76 (d, ¹H), 5.40 (q, ¹H), 4.00–3.91 (m, ¹H), 3.87–3.76 (m, 2H), 3.71–3.60 (m, ¹H), 3.15–3.03 (m, ¹H), 2.40–2.24 (m, ¹H), 2.19 (s, 3H), 2.06–1.94 (m, ¹H), 1.70 (d, 3H).

[0274] Reference material 1-P2: ¹H NMR (400MHz, DMSO) δ 10.16 (s, ¹H), 7.53 (d, 2H), 7.22 (d, ¹H), 7.13 (d, 2H), 6.77 (s, ¹H), 5.40 (q, ¹H), 4.00–3.91 (m, ¹H), 3.88–3.76 (m, 2H), 3.72–3.60 (m, ¹H), 3.18–3.03 (m, ¹H), 2.39–2.23 (m, ¹H), 2.19 (s, 3H), 2.04–1.92 (m, ¹H), 1.70 (d, 3H).

[0275] Bioactivity test

[0276] The present disclosure is further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0277] Test Example 1. Inhibitory activity of the disclosed compound against SARM1

[0278] 1.1 Experimental Procedure

[0279] a) The 408-724 amino acid sequence of SARM1 was overexpressed in the NRK1-293T293 cell line (source: Shenzhou Yiqiao) to obtain cell lysates containing the SAM-TIR domain of SARM1.

[0280] b) Dilute the cell lysis buffer with PBS to a 2X SAM-TIR lysis buffer of 240 μg / mL.

[0281] c) Prepare and dilute the test compound to concentrations of 10 μM, 3.3 μM, 1.1 μM, 0.37 μM, 0.123 μM, 0.041 μM, 0.014 μM, 0.005 μM, 0.0015 μM, and 0.0005 μM.

[0282] d) Using an ECHO pipetting system, transfer 20 nL of the compound solution to a 384-well plate, then add 10 μL of 2X SAM-TIR lysis buffer and incubate at room temperature for 30 min. Add 10 μL of 10 μM NAD solution, seal the 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate at 25 °C for 2 h. Then, add 40 μL of 7.5% trichloroacetic acid to terminate the reaction, vortex to mix for 30 s, centrifuge at 4000 rpm for 10 min, and take 40 μL of the supernatant. Add 25 μL of 1% ammonia to adjust the pH to 3-4.

[0283] e) Finally, the concentration of ADPR was detected by HPLC-MS / MS.

[0284] The compounds described in this disclosure all exhibit significant inhibitory activity against SARM1.

[0285] Table 1. Inhibitory activity of the compounds disclosed herein against SARM1 (IC50) 50 ,nM)

[0286] Compound 3-P1 was tested according to the experimental procedure described in 1.1 above, and the results are shown in Table 2.

[0287] Table 2. Inhibitory activity of the compounds disclosed herein against SARM1 (IC50) 50 ,nM)

[0288] The results show that compound 3-P1 has good inhibitory activity against SARM1.

[0289] Test Example 2. Stability test of the test compound in hepatocytes

[0290] 1. Experimental Procedure

[0291] 1) Prepare a high-concentration stock solution of the test substance and the control drug verapamil powder with DMSO. Before use, dilute with DMSO to a working solution of 100 μM. The final concentration of the test substance and verapamil is 1 μM.

[0292] 2) Take a tube of cryopreserved hepatocytes, ensuring that the hepatocytes remain frozen before thawing. Quickly place the hepatocytes in a 37°C water bath and gently shake until all ice crystals are dispersed. Spray with 70% ethanol and transfer to a biosafety cabinet.

[0293] 3) Pour the contents of hepatocyte tubules from different species into centrifuge tubes containing 50 mL of resuscitation medium and centrifuge at 100 g for 10 minutes. After centrifugation, aspirate the resuscitation medium and add sufficient incubation medium to obtain a cell density of approximately 1.0 × 10⁻⁶ cells / year. 6 Cell suspension of cells per mL.

[0294] 4) Use Cellometer Vision to count hepatocytes and determine viable cell density. The hepatocyte viability must be greater than 75%. Dilute the hepatocyte suspension with incubation medium to a viable cell density of 0.5 × 10⁻⁶ cells / day. 6 Cells / mL.

[0295] 5) Transfer 198 μL of live cell suspension to a 96-well deep-well plate, place the plate on a vortex and preheat in an incubator for 10 minutes. Perform double parallel incubation.

[0296] 6) Add 2 μL of 100 μM test substance or verapamil to each well to initiate the reaction, and then place the deep well plate back onto the incubator vortex.

[0297] 7) Incubate the sample. At 0, 15, 30, 60, 90, and 120 minutes, respectively, take 25 μL of the suspension and add 150 μL of acetonitrile containing the internal standard to terminate the reaction. Vortex for 10 minutes, then centrifuge at 3220 g and 4 °C for 45 minutes. Transfer 100 μL of the supernatant to the sample plate, add 100 μL of pure water and mix well for UPLC-MS / MS analysis.

[0298] 2. Data Analysis

[0299] All calculations were performed using Microsoft Excel. Peak areas were detected by extracting ion spectra. The in vitro half-life (T0) of the parent drug was determined by linearly fitting the natural logarithm of the elimination percentage of the parent drug to time. 1 / 2 ).

[0300] In vitro half-life (T 1 / 2 ) Calculated by slope: In vitro T 1 / 2 =0.693 / k

[0301] In vitro clearance rate (unit: μL / min / 10) 6 (per cell) is calculated using the following formula: In vitro CL int =kV / N

[0302] V = Incubation volume per well (0.2 mL);

[0303] N = Number of cells per well (0.1 × 10⁻⁶) 6 (cells)

[0304] Table 3. Metabolic clearance rate of the tested compounds in different hepatocytes CL int (μL / min / 10 6 (cells)

[0305] Reference 1 is Example 220 in patent application WO2024126777. The results show that compound 3-P1 exhibits better stability in mouse and human hepatocytes than reference 1-P1.

[0306] Test Example 3. Testing the inhibitory activity of compounds against human CYP450 (CYP1A2, CYP2C9, CYP2C19 and CYP3A).

[0307] 1. Equipment, materials and reagents

[0308] 1) Human liver microsomes (HLM)

[0309] Human liver microsomes (from BD Gentest) are stored at -80°C. Before use, remove the human liver microsomes from the freezer and preheat them in a 37°C water bath until thawed, then place them on ice until ready to use.

[0310] 2) Substrate

[0311] The preparation details of the substrate mixture are as follows: the substrate mixture consists of 50% pure water and 50% organic solvent. The prepared substrate mixture is stored in a -20°C refrigerator. Before use, it is taken out of the refrigerator and heated to room temperature, vortexed for 30 seconds, and then used.

[0312] Table 4. Substrate mixtures of CYP1A2, CYP2C9, CYP2C19 and CYP3A

[0313] 3) Phosphate buffer (100 mmol / L, pH 7.4)

[0314] Disodium hydrogen phosphate (analytical grade) and potassium dihydrogen phosphate (analytical grade) were purchased from a local supplier. Solution A preparation: Accurately weigh 7.098 g of disodium hydrogen phosphate and add it to 500 ml of pure water, then sonicate. Solution B preparation: Accurately weigh 3.400 g of potassium dihydrogen phosphate and add it to 250 ml of pure water, then sonicate. Add solution B to solution A; the final pH is 7.4.

[0315] 4) 10 mmol / L NADPH solution

[0316] NADPH (MW: 833.4 g / mol) was purchased from MCE. Dissolve 8.334 mg / mL in phosphate buffer.

[0317] 2. Experimental Procedure

[0318] 1) Preparation of incubation solution

[0319] The incubation system for the substrate and human liver microsome mixture is as follows:

[0320] 2) Compound dilution

[0321] 15 μL of a 10 mmol / L DMSO solution of the test compound was added to a deep-well plate with sequence labels. The dilution steps are as follows:

[0322] 3) Incubation

[0323] Each well of the 96-well deep plate contains 179 μL of substrate and human liver microsomal phosphate-buffered saline solution, and 1 μL of test sample or blank solution. Pre-incubate the plate in a 37°C water bath for 5 minutes, then add 20 μL of 10 mM NADPH to initiate the reaction. After adding the NADPH solution, incubate the plate at 37°C for another 5 minutes.

[0324] 4) Reaction quenching

[0325] Quenching was performed by adding 300 μL of acetonitrile solution containing 3% formic acid and 200 nM tolbutamide, 200 nM alprazolam, and 200 nM labetalol. The mixture was then centrifuged at 3,220 g for 50 minutes, and 200 μL of the supernatant was analyzed by LC / MS / MS.

[0326] 3. Data Processing

[0327] The system automatically calculates the peak area and internal standard peak area of ​​all samples and imports them into Excel software.

[0328] Calculate the percentage of remaining activity using the following formula:

[0329] Area ratio = peak area 受试物 / peak area 内标

[0330] Remaining activity percentage (%) = area ratio 受试物 / area ratio 空白 *100

[0331] Calculate IC using Excel XLfit 5.3.1.3 50 Value (concentration of the test substance at which 50% inhibition is achieved)

[0332] Table 5. IC50 inhibitory activity of the test compounds against CYP450 in this experiment 50 (μM)

[0333] The results showed that compound 3-P1 did not inhibit CYP1A2, CYP2C9, CYP2C19, and CYP3A (IC50). 50>30 μM). Compared with compound 8, compound 3-P1 significantly improved the inhibition risk on CYP1A2, CYP2C9, CYP2C19 and CYP3A.

[0334] Test Example 4. Testing the permeability of the compound in MDCKII-MDR1

[0335] 1. Purpose

[0336] The aim of this study was to evaluate the bidirectional permeability and sensitivity of the test compounds to efflux transporter substrates. Samples were analyzed by LC / MS / MS to estimate the apparent permeability (Papp) of MDCKII-MDR1 cell monolayers and derive the efflux ratio (ER). Propranolol, prazosin, and quinidine were used as control compounds.

[0337] 2. Materials and Reagents

[0338] 1) The MDCKII-MDR1 cell line was purchased from the Netherlands Cancer Institute (NKI).

[0339] 2) Hepes, penicillin-streptomycin premixed solution (100×), and dimethyl sulfoxide were purchased from Beijing Solarbio Science & Technology Co., Ltd. G418 was purchased from MCE. Minimum Essential Medium Eagle (MEM), Hanke Balanced Salt Solution (HBSS), trypsin / EDTA, and GlutaMAX were also used. TM -I was purchased from Gibco. Serum was purchased from AusGeneX.

[0340] 3) HTS-96-well Transwell plates were purchased from Corning Incorporated (Cambridge, MA). The Millicell transmembrane thyristor was purchased from Millipore. Electrodes for measuring resistance were purchased from World Precision Instruments (Salasota, Florida), and the MTS2 / 4 vortex oscillator was purchased from IKA (Stauffen, Germany).

[0341] 4) Acetonitrile and methanol were purchased from Merck.

[0342] 5) Other reagents were purchased from local suppliers.

[0343] 3. Experimental Procedure

[0344] 3.1 Preparation of monolayer membranes

[0345] 1) MDCKII-MDR1 cells were cultured in MEM medium supplemented with 10% fetal bovine serum and 1% GlutaMAX. TM-I, 400 μg / mL G418 and 1% penicillin-streptomycin premixed solution were used for cell culture.

[0346] 2) Before cell seeding, add 50 μL of cell culture medium to each well in the upper chamber of the Transwell and 25 mL of cell culture medium to the lower culture plate.

[0347] 3) After incubating the culture plate in a 37°C, 5% CO2 incubator for 1 hour, it can be used for cell inoculation.

[0348] 4) Cells are cultured in T-75 cell culture flasks, with the incubator set to 37℃, 5% CO2, and 95% relative humidity. Cells can be inoculated with Transwell when the confluence reaches 80%-90%.

[0349] 5) Wash the cells cultured in the T-75 culture flask with 10 mL PBS, then add 3 mL trypsin / EDTA for digestion, incubate at 37°C for 5-10 minutes until the cells are separated and suspended, and add 10 mL of excess serum-containing culture medium to inactivate trypsin / EDTA.

[0350] 6) After cell digestion, transfer the cell suspension to a round-bottom centrifuge tube and centrifuge at 900 rpm for 5 minutes.

[0351] 7) Resuspend the cells in culture medium to a final concentration of 1.56 × 10⁻⁶. 6 Cells / mL.

[0352] 8) Change the medium 24 hours after inoculation, and change the medium every other day until 3-8 days of culture.

[0353] 3.2 Assessment of cell monolayer membrane integrity

[0354] 1) First discard the receiving plate and the culture medium in the Transwell chamber.

[0355] 2) Add 75 μL and 25 mL of preheated cell culture medium to the Transwell chamber and the receiving plate, respectively.

[0356] 3) Measure the resistance of the monolayer membrane using a Millicell transmembrane osmometer. Measure the resistance of each well, record the data, and then return the cell plate to the incubator.

[0357] 4) The formula for calculating TEER (transmembrane resistance) is as follows. The TEER value for each aperture should not be less than 42 ohms·cm. 2 .

[0358] Measure resistance (ohms) × film area (cm²) 2 ) = TEER value (ohm·cm)2 )

[0359] 3.3 Experimental Procedure

[0360] 1) Remove the MDCKII-MDR1 cell culture plate from the incubator. Rinse the cell monolayer twice with pre-warmed transport buffer HBSS (25mM HEPES, pH 7.4) and incubate at 37°C for 30 minutes.

[0361] 2) Propranolol, prazosin, and quinidine were used as control compounds. The stock solution of the control compound propranolol was diluted to 1 mM with DMSO, and then diluted with HBSS (25 mM HEPES, pH 7.4) to obtain a 5 μM working solution. The stock solutions of the other control compounds and the test compound were diluted to 200 μM with DMSO, and then diluted with HBSS (25 mM HEPES, pH 7.4) to obtain a 1 μM working solution. The final concentration of DMSO was 0.5%.

[0362] 3) To determine the drug transport rate from the top to the base, 150 μL of working solution was pipetted to the top of the Transwell chamber, and immediately 50 μL of sample was removed from the top and quenched in a quenching plate pre-filled with 200 μL of pre-cooled quencher as the initial dosing end sample (AB). The sample was vortexed at 1000 rpm for 10 min. 300 μL of buffer solution (HBSS buffer containing 0.5% DMSO) was added to the receiving end (base end).

[0363] 4) To determine the drug transport rate from the base to the top, pipette 350 μL of working solution into the base of the Transwell chamber, and immediately remove 50 μL of sample from the base into a quenching plate pre-filled with 200 μL of pre-cooled quencher for quenching, as the initial dosing end sample (BA), and vortex at 1000 rpm for 10 min. Add 100 μL of buffer solution (HBSS buffer containing 0.5% DMSO) to the top of the Transwell chamber.

[0364] 5) Both tip-to-base and base-to-tip transport need to be performed simultaneously to initiate bidirectional transport. Then, incubate the cell plate in an incubator at 37°C, 5% CO2 and saturated relative humidity for 2 hours.

[0365] 6) After 2 hours, 50 μL of sample was aspirated from both the dosing and receiving ends into the quenching plate. Four times the sample volume of pre-cooled quenching agent was added to each well of the quenching plate. After vortexing for 10 minutes, the sample was centrifuged at 4000 rpm and 4°C for 30 minutes. 100 μL of sample from each well was mixed with 100 μL of pure water for LC / MS / MS analysis. All samples were analyzed in duplicate.

[0366] 7) To determine the leakage of fluorescein after 2 hours of incubation, the fluorescein stock solution was diluted with blank buffer to a final concentration of 100 μM. 100 μL of fluorescein solution was added to the top side, and 300 μL of blank buffer was added to the bottom side. After incubation at 37°C for 30 minutes, 80 μL was transferred directly from both the top and bottom sides to a new 96-well plate. Fluorescence values ​​were measured using a microplate reader at an excitation wavelength of 480 nM and an emission wavelength of 530 nM.

[0367] 4. Data Processing

[0368] All calculations were performed using Microsoft Excel. Peak areas were determined using the extracted ion chromatograms.

[0369] Apparent permeability coefficient (P) app Unit: cm / s × 10 -6 For drug transport testing, the calculation formula is as follows:

[0370] In the formula: V A The volume of the receiving solution is 0.3 mL for A→B and 0.1 mL for B→A. Area is the membrane area of ​​the Transwell-96-well plate (0.143 cm²). 2 Time is the incubation time (in seconds), [Drug] acceptor [Drug]initial and donor represent the initial drug concentration at the receiving end and the initial drug concentration at the dosing end, respectively.

[0371] Table 6. Permeability of the test compounds in MDCKII-MDR1 in this experiment

[0372] The results show that compound 3-P1 has higher permeability in MDCKII-MDR1 compared to reference compound 1-P1.

[0373] Test Example 5. Pharmacokinetic Experiment in Mice

[0374] C57BL6J mice (from SiBeiFu) were used as test animals. The plasma drug concentrations at different time points after gavage administration of reference compound 1 (WO2024126777, Example 220) and the compound from the examples were determined using LC / MS / MS. The pharmacokinetic behavior of reference compound 1 and the compound from the examples in mice was studied to evaluate their pharmacokinetic characteristics.

[0375] Experimental animals: Two healthy male mice (20-30g) aged 6-8 weeks per group.

[0376] Drug preparation: Weigh a certain amount of the drug and prepare a colorless and clear solution of 1 mg / mL (solvent: 2.5% DMSO / 10% Cremphor EL / 87.5% physiological saline).

[0377] Administration: administered by gavage. The dosage for both reference compound 1-P1 and the compound in the examples was 10 mg / kg.

[0378] Procedure: Reference compound 1-P1 and the compound of the example were administered to mice by gavage. At 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, approximately 0.03 mL of blood was collected by peripheral vein puncture and placed in a test tube containing EDTA-K2. The plasma was separated by centrifugation at 4000g per minute for 5 minutes at approximately 4°C and stored at -75°C.

[0379] To determine the content of the target compound in mouse plasma after oral administration of different concentrations of the drug: 10 μL of mouse plasma was collected at each time point after administration, 5 μL of blank solution and 200 μL of acetonitrile solution containing internal standard dexamethasone were added, vortexed for 30 s, centrifuged for 15 minutes (3900 rpm), and 12 μL of the supernatant of the plasma sample was analyzed by LC / MS / MS.

[0380] Table 7. Pharmacokinetic parameters of reference 1-P1 and compound 3-P1

[0381] Note: All values ​​listed are averages of two animals. Reference 1 is Example 220 in patent application WO2024126777.

[0382] The results show that Example 3-P1 has better oral PK in mice, with significantly higher blood drug exposure, indicating that the pharmacokinetic properties of the compound disclosed herein are superior to those of reference compound 1-P1.

Claims

1. The compound shown in formula (I) or a pharmaceutically acceptable salt thereof, in Ring B is pyridinyl or pyridazinyl, each of which is independently and optionally substituted by one or more R3 groups, wherein the R3 groups are independently selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups; R1 is selected from hydrogen, C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1- 6-alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups; The condition is that when ring B is pyridyl, R1 is not hydrogen; R2 is selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups; n can be 0, 1, 2, 3, or 4; Z represents a single bond; Y is a single bond or CR6R7, wherein R6 and R7 are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each optionally substituted by one or more Ra groups; or the R6 and R7 groups together with the linked carbon atom form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group, each optionally substituted by one or more R5 groups, wherein the R5 groups are independently selected from halogen, cyano, oxo, C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1- 6-alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups; Ring A is selected from 5-8-membered heteroaryl, 5-8-membered heterocyclic alkyl, and fused rings of 5-8-membered heterocyclic alkyl and phenyl; each of the 5-8-membered heteroaryl, 5-8-membered heterocyclic alkyl, and fused rings of 5-8-membered heterocyclic alkyl and phenyl is independently optionally substituted by one or more R8s, wherein the R8s are independently selected from halogens, cyano groups, oxo groups, C... 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups; Each Ra is independently selected from halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl.

2. The compound or its pharmaceutically acceptable salt according to claim 1, wherein the compound or its pharmaceutically acceptable salt represented by formula (I) is a compound or its pharmaceutically acceptable salt represented by formula (II-A) or formula (II-B). Where m is 0, 1, 2 or 3; preferably m is 0, 1 or 2; preferably m is 0 or 1; R3, R1, R2, n, Z, Y, and ring A are as defined in claim 1.

3. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein the compound or a pharmaceutically acceptable salt thereof represented by formula (I) is a compound or a pharmaceutically acceptable salt thereof represented by formula (III-A), (III-B), (III-C), (III-D), (III-E), or (IV-A). Where p is 0, 1, 2, 3 or 4, preferably p is 0, 1, 2 or 3, more preferably p is 0, 1 or 2, and even more preferably p is 0 or 1; R1, R2, R3, R6, R7, R8, m, and n are as defined in claim 1.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C 1-6 Alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl and 3-6 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 The alkoxy group, the 3-6 membered cycloalkyl group, and the 3-6 membered heterocycloalkyl group are each independently and optionally substituted by one or more Ra groups; R1 is preferably C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy group can be independently and optionally replaced by one or more Ra groups; More preferably, R1 is C 1-3 Alkyl, the C 1-3 The alkyl group may optionally be replaced by one or more Ra groups; More preferably, R1 is More preferably, R1 is Ra is as defined in claim 1.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R6 and R7 are each independently selected from hydrogen, halogens, and C. 1-6 Alkyl, the C 1-6 The alkyl group may optionally be replaced by one or more Ra groups; Alternatively, both R6 and R7 may be hydrogen; Or both R6 and R7 are halogens; Alternatively, R6 could be hydrogen and R7 could be carbon. 1-6 alkyl; Ra is as defined in claim 1.

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein R3 is a halogen or C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be substituted with one or more Ra groups as defined in claim 1.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein R2 is a halogen or C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be substituted with one or more Ra groups as defined in claim 1.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein R8 is a halogen or C 1-6 Alkyl, the C 1-6 The alkyl group may optionally be substituted with one or more Ra groups as defined in claim 1.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein each Ra is independently selected from halogen, hydroxyl, cyano, oxo, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1- 6-alkoxy, halogenated C 1-6 Alkoxy and hydroxy C 1-6 Alkoxy; Preferably, each Ra is independently selected from halogen, hydroxyl, and cyano groups; Preferably, each Ra is independently halogenated or hydroxyl-containing.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein the compound or a pharmaceutically acceptable salt thereof represented by formula (I) is selected from the compounds or pharmaceutically acceptable salts thereof represented by the following formula.

11. The compound according to any one of claims 1-10, or an isotopic substitute of the pharmaceutically acceptable salt thereof, preferably, the isotopic substitute is a deuterium-substituted compound.

12. A pharmaceutical composition comprising at least one compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, or an isotope substitute according to claim 11, and a pharmaceutically acceptable excipient.

13. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-10, or the isotope substitute according to claim 11, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating and / or preventing diseases or conditions associated with SARM1.

14. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-10, or the isotopic substitute according to claim 11, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating and / or preventing diseases or conditions related to axonal degeneration.

15. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-10, or the isotope substitute according to claim 11, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for the treatment and / or prevention of chemotherapy-induced peripheral neuropathy (CIPN), painful diabetic neuropathy (PDN), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), demyelinating diseases, Parkinson's disease (PD), Alzheimer's disease (AD), ocular neuropathy, peripheral neuropathy, traumatic brain injury (TBI), sciatica, sciatic nerve injury, traumatic nerve injury, nerve injury-related neuropathy, peroneal muscular atrophy (CMT), hereditary spastic paraplegia, ischemia, stroke, glaucoma, carpal tunnel syndrome, retinal degeneration, optic nerve injury-related diseases, viral infections, and viral encephalitis.

16. The compound represented by formula (M1) or a pharmaceutically acceptable salt thereof, Wherein rings B, R1, R2, and n are as defined in claim 1.

17. A compound or its pharmaceutically acceptable salt,

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