Diaryl compounds as tubulin-SRC dual-target inhibitors

Abstract

The present invention discloses diaryl compounds as tubulin-SRC dual target inhibitors. The present invention further provides diaryl compounds represented by formula I, their tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs. The diaryl compounds can be used as dual target inhibitors of tubulin and Src kinase, or as individual tubulin or Src kinase inhibitors. The compounds of the present invention can significantly inhibit the polymerization of tubulin monomers and inhibit cell proliferation. [Formula 1] TIFF2025502293000142.tif35170

Description

Detailed description of the invention

[0001] This application claims priority to Chinese patent application 202210044016.7, filed on 14 January 2022; Chinese patent application 202210399397.0, filed on 15 April 2022; Chinese patent application 202211139978.7, filed on 19 September 2022; and Chinese patent application 202310020643.1, filed on 6 January 2023. This application incorporates the full text of the above Chinese patent applications.

[0002] [Technical field] This invention relates to diaryl compounds as tubulin-SRC dual-target inhibitors.

[0003] [Background technology] Microtubules are essential components of the eukaryotic cell cytoskeleton and play a crucial role in various cellular functions, including maintaining cell morphology, signal transduction, organelle transport, cell movement, cell division, and mitosis (Jordan MA et al. Nature Reviews Cancer, 2004, 4(4):253-265).

[0004] Microtubules are composed of two tubulin subunits, α-tubulin and β-tubulin, which together form tubulin heterodimers, the basic units of microtubule aggregation. Microtubule-targeting agents (MTAs) can disrupt the dynamic stability and structure of microtubules, interfere with spindle formation during mitosis, induce cell cycle arrest at the G2 / M phase, and promote apoptosis (Shuai W et al. Journal of Medicinal Chemistry, 2021, 64(12)).

[0005] Microtubules are involved in many important cellular processes and are one of the most important drug targets in the treatment of hyperproliferative diseases. Several microtubule-targeted drugs approved by the US FDA, such as vinblastine and taxane compounds, are widely used to treat several solid tumors and hematological malignancies. However, drug resistance and dose-limiting toxicity of microtubule-targeted drugs limit their clinical efficacy. Dual-target inhibitors can overcome drug resistance and improve therapeutic efficacy compared to single-target drugs and have become a hot spot in research. Examples include tubulin-SRC dual-target inhibitors, tubulin-receptor tyrosine kinase (RTK) dual-target inhibitors, and tubulin-histone deacetylase (HDAC) dual-target inhibitors (Shuai W et al. Journal of Medicinal Chemistry, 2021, 64(12)).

[0006] Actinic keratosis (AK) is a skin condition associated with prolonged exposure to ultraviolet light. It is the second most common disease among dermatologists in the United States and is characterized by uncontrolled proliferation of mutated keratinocytes. It is considered a precancerous condition and, if left untreated, can progress to cutaneous squamous cell carcinoma (SCC) in 20% of cases. Currently, the tubulin-SRC dual-target inhibitor tirbanibulin (NCT03285477) has shown significant clinical efficacy in the topical treatment of AK and is approved for sale by the FDA. This suggests that the development of new tubulin-SRC dual-target inhibitors with superior efficacy in the topical treatment of AK may be a promising direction.

[0007] [Overview of the prefecture] The object of the present invention is to provide diaryl compounds as tubulin-SRC dual-target inhibitors, and a method for preparing and using the same, wherein the diaryl compound has the structure of Formula I described in the present invention. The diaryl compound can be used as a dual-target inhibitor of tubulin and Src kinase, or as a separate tubulin or Src kinase inhibitor.

[0008] In a first aspect of the present invention, diaryl compounds represented by formula I having the following structure, tautomers, stereoisomers, solvates (e.g., hydrates), pharmaceutically acceptable salts, or prodrugs are provided.

[0009] [ka]

[0010] However, W is selected from -O-, -S-, -NH-, and -N(C1~C6 alkyl)-. L is a C1-C6 alkylene, V is either absent or selected from -O-, -S-, -NH-, -N(C1~C6 alkyl)-. If V does not exist, Q is a ring A that is unsubstituted or substituted with m R3s, and a ring B that is unsubstituted or substituted with m R3s. If V is selected from -O-, -S-, -NH-, and -N(C1~C6 alkyl)-, then Q is an unsubstituted or m R3-substituted ring C. The ring A is a 6- to 15-membered heterocyclic group, and if ring A is a 6-membered heterocyclic group, then ring A is

[0011] [ka] And,

[0012] The aforementioned ring B is a 6-12 membered sulfonyl-containing heterocyclic group, The aforementioned ring C is a 4-15 member heterocyclic group or a 6-12 member sulfonyl-containing heterocyclic group. R1, R2, and R3 are each independently hydrogen, or halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-C1-C6 alkyl, -COO-C1-C6 alkyl, -CO-C1-C6 alkyl, or -C(O)NR 11 R 12 -COO-3~6 member cycloalkyl, -CO-3~6 member cycloalkyl, -S(O)2-C1~C6 alkyl, -S(O)2-3~6 member cycloalkyl, -C(O)-C1~C6 alkyl-NR 11 R 12 Selected from, Here, R 11 , R 12 Each is independently hydrogen or a C1-C6 alkyl, or R 11 and R 12 These, together with the N atoms linked to them, form a 4-6 membered ring. R1, R2, and R3 are optionally substituted with one or more substituents selected from halogens, hydroxyls, aminos, cyanos, C1-C6 alkyls, and 3-6 membered cycloalkyls, and if there are multiple substituents, the substituents may be the same or different. n is 1, 2, or 3, and if there are multiple R1s, then the R1s are the same or different. p is 1, 2, or 3, and if there are multiple R2s, then the R2s are the same or different. m is 1, 2, or 3, and if there are multiple R3s, then the R3s are the same or different. The condition is that if Q is ring A, then R1 and R2 are not both hydrogen atoms. The aforementioned ring A

[0013] [ka] In that case, R3 is also not hydrogen,

[0014] Alternatively, the ring A is

[0015] [ka] When it is, at least one of R1 and R2 is cyano, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)NR 11 R 12 selected from the following.

[0016] In the present invention, the definition of a specific substituent in the diaryl compound represented by the formula I, its tautomer, stereoisomer, solvate (e.g., hydrate), pharmaceutically acceptable salt or prodrug may be as follows, and the definition of substituents not mentioned is as described in any one of the schemes of this application (hereinafter referred to as "in a preferred embodiment", "in a preferred embodiment" or "in a preferred scheme").

[0017] However, W is selected from -O-, -S-, -NH-, -N(C1-C6 alkyl)-, L is C1-C6 alkylene, V does not exist or is selected from -O-, -S-, -NH-, -N(C1-C6 alkyl)-, When V does not exist, Q is ring A which is unsubstituted or substituted by m R3s, or ring B which is unsubstituted or substituted by m R3s, When V is selected from -O-, -S-, -NH-, -N(C1-C6 alkyl)-, Q is ring C which is unsubstituted or substituted by m R3s, The ring A is a 6- to 15-membered heterocyclic group, and when the ring A is a 6-membered heterocyclic group, the ring A is

[0018]

Chemical formula

[0019] The ring B is a 6- to 12-membered sulfonyl-containing heterocyclic group, The ring C is a 4- to 15-membered heterocyclic group or a 6- to 12-membered sulfonyl-containing heterocyclic group, R1, R2, and R3 are each independently hydrogen, or halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-C1-C6 alkyl, -COO-C1-C6 alkyl, -CO-C1-C6 alkyl, or -C(O)NR 11 R 12 -COO-3~6 member cycloalkyl, -CO-3~6 member cycloalkyl, -S(O)2-C1~C6 alkyl, -S(O)2-3~6 member cycloalkyl, -C(O)-C1~C6 alkyl-NR 11 R 12 Selected from, Here, R 11 , R 12 Each is independently hydrogen or a C1-C6 alkyl, or R 11 and R 12 These, together with the N atoms linked to them, form a 4-6 membered ring. R1, R2, and R3 are optionally substituted with one or more substituents selected from halogens, hydroxyls, aminos, cyanos, C1-C6 alkyls, and 3-6 membered cycloalkyls, and if there are multiple substituents, the substituents may be the same or different. n is 1, 2, or 3, and if there are multiple R1s, then the R1s are the same or different. p is 1, 2, or 3, and if there are multiple R2s, then the R2s are the same or different. m is 1, 2, or 3, and if there are multiple R3s, then the R3s are the same or different. The diaryl compounds represented by formula I are (1) V is selected from -O-, -S-, -NH-, -N(C1~C6 alkyl)-, (2) Q is a heterocyclic group containing 6-12 member sulfonyl groups that is unsubstituted or substituted with m R3 groups. (3) R1 is hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-C1-C6 alkyl, -COO-C1-C6 alkyl, -CO-C1-C6 alkyl, -C(O)NR 11 R 12-COO-3~6 member cycloalkyl, -CO-3~6 member cycloalkyl, -S(O)2-C1~C6 alkyl, -S(O)2-3~6 member cycloalkyl, -C(O)-C1~C6 alkyl-NR 11 R 12 It is selected from the following, or R1 is a halogen and ring A, ring B, or ring C satisfies one, two, or three of the following conditions: R1 is a halogen and ring A, ring B, or ring C is a fused ring, a bridging ring, or a spiro ring.

[0020] In a preferred embodiment, V is selected from -O-, -S-, -NH-, and -N(C1-C6 alkyl)-. In a preferred embodiment, V is selected from -NH-.

[0021] In a preferred embodiment, Q is an unsubstituted or 6-12 membered sulfonyl-containing heterocyclic group substituted with m R3 groups. In a preferred embodiment, Q is an unsubstituted 6-12 membered sulfonyl-containing heterocyclic group.

[0022] In preferred embodiments, R1 is hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-C1-C6 alkyl, -COO-C1-C6 alkyl, -CO-C1-C6 alkyl, -C(O)NR 11 R 12 -COO-3~6 member cycloalkyl, -CO-3~6 member cycloalkyl, -S(O)2-C1~C6 alkyl, -S(O)2-3~6 member cycloalkyl, -C(O)-C1~C6 alkyl-NR 11 R 12 Selected from.

[0023] In a preferred embodiment, R1 is selected from cyano, C1-C6 alkyl, and C2-C6 alkynyl. In a preferred embodiment, R1 is a halogen, and ring A, ring B, or ring C is a fused ring, a bridging ring, or a spiro ring.

[0024] In a preferred embodiment, the diaryl compound represented by formula I is

[0025] [ka] And,

[0026] m is either 1 or 2. R3 can be a halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-C1-C6 alkyl, -COO-C1-C6 alkyl, -CO-C1-C6 alkyl, or -C(O)NR 11 R 12 Selected from the following, R1 is cyano, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)NR 11 R 12 Selected from.

[0027] In a preferred embodiment, the diaryl compound represented by formula I is

[0028] [ka] Therefore, m is 1, and R3 is a C1-C6 alkyl group.

[0029] In a preferred embodiment, the diaryl compound represented by formula I is

[0030] [ka] m is 1, R3 is C1-C6 alkyl, and R1 is cyano, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)NR 11 R 12 Selected from.

[0031] In a preferred embodiment, the condition is that when Q is ring A, R1 and R2 are not both hydrogen atoms. Furthermore, the ring A

[0032] [ka] If so, R3 is not hydrogen, or at least one of R1 and R2 is cyano, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)NR 11 R 12 Selected from.

[0033] In a preferred embodiment, W is selected from -O-. In a preferred embodiment, L is a C1-C6 alkylene. In a preferred embodiment, V is absent or selected from -NH-, If V does not exist, Q is a ring A that is unsubstituted or substituted with m R3s, and a ring B that is unsubstituted or substituted with m R3s. If V is selected from -NH-, then Q is an unsubstituted or m R3-substituted ring C. The ring A is a 6- to 15-membered heterocyclic group, and if ring A is a 6-membered heterocyclic group, then ring A is

[0034] [ka] And,

[0035] The aforementioned ring B is a 6-12 membered sulfonyl-containing heterocyclic group, The aforementioned ring C is a 4-15 member heterocyclic group or a 6-12 member sulfonyl-containing heterocyclic group. m is 1, 2, or 3, and if there are multiple R3s, then the R3s are the same or different. R3 is a C1-C6 alkyl or -CO-C1-C6 alkyl, and R3 is optionally substituted with one or more 3-6 membered cycloalkyl groups. If there are multiple substituents, the substituents may be the same or different.

[0036] In a preferred embodiment, n is 1, 2, or 3, and if there are multiple R1s, the R1s are the same or different. R1 is hydrogen, halogen, cyano, unsubstituted C1-C6 alkyl, or unsubstituted C2-C6 alkynyl.

[0037] In a preferred embodiment, n is 1, R1 is hydrogen, halogen, cyano, unsubstituted C1-C6 alkyl, or unsubstituted C2-C6 alkynyl.

[0038] In a preferred embodiment, p is 1, 2, or 3, and if there are multiple R2s, the R2s are the same or different. R2 is either hydrogen or a halogen.

[0039] In a preferred embodiment, p is 1 and R2 is hydrogen. In a preferred embodiment, the diaryl compound represented by formula I is (1) V is selected from -NH-, (2) Q is a heterocyclic group containing 6-12 member sulfonyl groups that is unsubstituted or substituted with m R3 groups. (3) R1 is a cyano, an unsubstituted C1-C6 alkyl, or an unsubstituted C2-C6 alkynyl, or R1 is a halogen and ring A, ring B, or ring C is a fused ring, a bridging ring, or a spiro ring, satisfying one, two, or three of these conditions.

[0040] In a preferred embodiment, W is selected from -O-, L is a C1-C6 alkylene, V does not exist, or it is selected from -NH-. If V does not exist, Q is a ring A that is unsubstituted or substituted with m R3s, and a ring B that is unsubstituted or substituted with m R3s. If V is selected from -NH-, then Q is an unsubstituted or m R3-substituted ring C. The ring A is a 6- to 15-membered heterocyclic group, and if ring A is a 6-membered heterocyclic group, then ring A is

[0041] [ka] And,

[0042] The aforementioned ring B is a 6-12 membered sulfonyl-containing heterocyclic group, The aforementioned ring C is a 4-15 member heterocyclic group or a 6-12 member sulfonyl-containing heterocyclic group. n is 1, 2, or 3, and if there are multiple R1s, then the R1s are the same or different. R1 is hydrogen, halogen, cyano, unsubstituted C1-C6 alkyl, or unsubstituted C2-C6 alkynyl. p is 1, 2, or 3, and if there are multiple R2s, then the R2s are the same or different. R2 is hydrogen or halogen. m is 1, 2, or 3, and if there are multiple R3s, then the R3s are the same or different. R3 is a C1-C6 alkyl or -CO-C1-C6 alkyl, and R3 is optionally substituted with one or more 3-6 membered cycloalkyl groups. If there are multiple substituents, the substituents may be the same or different. The diaryl compounds represented by formula I are (1) V is selected from -NH-, (2) Q is a heterocyclic group containing 6-12 member sulfonyl groups that is unsubstituted or substituted with m R3 groups. (3) R1 is a cyano, an unsubstituted C1-C6 alkyl, or an unsubstituted C2-C6 alkynyl, or R1 is a halogen and ring A, ring B, or ring C is a fused ring, a bridging ring, or a spiro ring, satisfying one, two, or three of these conditions.

[0043] In a preferred embodiment, W is selected from -O-, L is a C1-C6 alkylene, V does not exist, or it is selected from -NH-. If V does not exist, Q is a ring A that is unsubstituted or substituted with m R3s, and a ring B that is unsubstituted or substituted with m R3s. If V is selected from -NH-, then Q is an unsubstituted or m R3-substituted ring C. The ring A is a 6- to 15-membered heterocyclic group, and if ring A is a 6-membered heterocyclic group, then ring A is

[0044] [ka] And,

[0045] The aforementioned ring B is a 6-12 membered sulfonyl-containing heterocyclic group, The aforementioned ring C is a 4-15 member heterocyclic group or a 6-12 member sulfonyl-containing heterocyclic group. n is 1, R1 is hydrogen, halogen, cyano, unsubstituted C1-C6 alkyl, or unsubstituted C2-C6 alkynyl. p is 1, R2 is hydrogen, m is 1, 2, or 3, and if there are multiple R3s, then the R3s are the same or different. R3 is a C1-C6 alkyl or -CO-C1-C6 alkyl, and R3 is optionally substituted with one or more 3-6 membered cycloalkyl groups. If there are multiple substituents, the substituents may be the same or different. The diaryl compounds represented by formula I are (1) V is selected from -NH-, (2) Q is a heterocyclic group containing 6-12 member sulfonyl groups that is unsubstituted or substituted with m R3 groups. (3) R1 is a cyano, an unsubstituted C1-C6 alkyl, or an unsubstituted C2-C6 alkynyl, or R1 is a halogen and ring A, ring B, or ring C is a fused ring, a bridging ring, or a spiro ring, satisfying one, two, or three of these conditions.

[0046] In a preferred embodiment, L is -CH2-, -CH2CH2-, -CH2CH2CH2-, and preferably L is -CH2CH2-. In a preferred embodiment, in ring A, the 6-15 membered heterocyclic group is a 6-8 membered heterocyclic group.

[0047] In a preferred embodiment, in ring A, the 6- to 15-membered heterocyclic group is a monocyclic ring, a fused ring, a bridging ring, or a spirocyclic ring. In a preferred embodiment, the 6-15 membered heterocyclic group in ring A is a saturated ring.

[0048] In a preferred embodiment, in ring A, the heteroatoms of the 6-15 membered heterocyclic group are N and / or O. In a preferred embodiment, in ring A, the heteroatoms of the 6-15 membered heterocyclic group are N and O.

[0049] In a preferred embodiment, in ring A, the 6-15 membered heterocyclic group is linked to V via an N atom. In a preferred embodiment, ring A is

[0050] [ka] (for example,

[0051] [ka] ),

[0052] [ka] That is the case.

[0053] In a preferred embodiment, in ring C, the 4- to 15-membered heterocyclic group is a 6- to 8-membered heterocyclic group. In a preferred embodiment, in ring C, the 4- to 15-membered heterocyclic group is a monocyclic ring, a fused ring, a bridging ring, or a spirocyclic ring.

[0054] In a preferred embodiment, the 4- to 15-membered heterocyclic group in ring C is a saturated ring. In a preferred embodiment, in the ring C, the heteroatoms of the 4- to 15-membered heterocyclic group are N and / or O.

[0055] In a preferred embodiment, in the ring C, the heteroatoms of the 4- to 15-membered heterocyclic group are N and O. In a preferred embodiment, in the ring C, the 4- to 15-membered heterocyclic group is linked to V via an N atom.

[0056] In a preferred embodiment, in the ring C, the 4- to 15-membered heterocyclic group is

[0057] [ka] (for example,

[0058] [ka] ),

[0059] [ka] That is the case.

[0060] In a preferred embodiment, in ring B, the 6-12 member sulfonyl-containing heterocyclic group is a 6-8 member sulfonyl-containing heterocyclic group. In a preferred embodiment, in ring B, the 6-12 member sulfonyl-containing heterocyclic group is a monocyclic ring, a fused ring, a crosslinked ring, or a spirocyclic ring.

[0061] In a preferred embodiment, in ring B, the 6-12 member sulfonyl-containing heterocyclic group is a monocyclic or spirocyclic ring. In a preferred embodiment, the 6-12 membered sulfonyl-containing heterocyclic group in ring B is a saturated ring.

[0062] In a preferred embodiment, in ring B, the complex of the 6-12 member sulfonyl-containing heterocyclic group is -S(=O)2- and / or N. In a preferred embodiment, in ring B, the complex of the 6-12 member sulfonyl-containing heterocyclic group is -S(=O)2- and N.

[0063] In a preferred embodiment, in ring B, the 6-12 member sulfonyl-containing heterocyclic group is linked to V via an N atom. In a preferred embodiment, in ring B, the 6-12 member sulfonyl-containing heterocyclic group is

[0064] [ka] That is the case.

[0065] In a preferred embodiment, in ring C, the 6-12 member sulfonyl-containing heterocyclic group is a 6-8 member sulfonyl-containing heterocyclic group. In a preferred embodiment, in ring C, the 6-12 member sulfonyl-containing heterocyclic group is a monocyclic ring, a fused ring, a crosslinked ring, or a spirocyclic ring.

[0066] In a preferred embodiment, the 6-12 membered sulfonyl-containing heterocyclic group in ring C is a monocyclic or spirocyclic ring. In a preferred embodiment, the 6-12 membered sulfonyl-containing heterocyclic group in ring C is a saturated ring.

[0067] In a preferred embodiment, in the ring C, the complex of the 6-12 member sulfonyl-containing heterocyclic group is -S(=O)2- and / or N. In a preferred embodiment, in the ring C, the complex of the 6-12 member sulfonyl-containing heterocyclic group is -S(=O)2- and N.

[0068] In a preferred embodiment, in the ring C, the 6-12 member sulfonyl-containing heterocyclic group is linked to V via the N atom. In a preferred embodiment, in ring C, the 6-12 member sulfonyl-containing heterocyclic group is

[0069] [ka] That is the case.

[0070] In a preferred embodiment, the halogen in R1 is fluorine or chlorine. In a preferred embodiment, in R1, the C1-C6 alkyl groups are methyl or ethyl.

[0071] In a preferred embodiment, in R1, the C2-C6 alkynyl is ethynyl or propynyl. In a preferred embodiment, in R2, the halogen is fluorine or chlorine.

[0072] In a preferred embodiment, in R3, the C1-C6 alkyl group is methyl or ethyl. In a preferred embodiment, in R3, the C1-C6 alkyl in "-CO-C1-C6 alkyl" is methyl or ethyl.

[0073] In a preferred embodiment, R 11 and R 12 The 4-6 membered rings formed together with the N atoms linked to them may be 4-6 membered N-containing heterocycloalkyl or 5-6 membered heteroaryl.

[0074] In a preferred embodiment, W is selected from -O-, -S-, and -NH-, and preferably W is -O-. In a preferred embodiment, L is -CH2-, -CH2CH2-, -CH2CH2CH2-, and preferably L is -CH2CH2-.

[0075] In a preferred embodiment, V is either absent or -NH-. In a preferred embodiment, ring A is a 7-15 member monocyclic, fused, bridging, or spirocyclic heterocyclic group. Preferably, the ring A comprises one, two, or three heteroatoms selected from N, O, or S, and if there are multiple heteroatoms, the heteroatoms are the same or different, preferably the ring A comprises one N atom and one O atom.

[0076] In a preferred embodiment, the ring A is structure

[0077] [ka] It has, where Z represents C or N, preferably Z is N, preferably the ring A further contains one O atom, preferably

[0078] [ka] teeth

[0079] [ka] That is the case.

[0080] In preferred embodiments, ring B is a 6-12 member sulfonyl-containing monocyclic, fused, spirocyclic, or crosslinked heterocyclic group, preferably a 6-8 member sulfonyl-containing monocyclic heterocyclic group, and preferably a 7-12 member sulfonyl-containing fused, spirocyclic, or crosslinked heterocyclic group.

[0081] In a preferred embodiment, ring B is

[0082] [ka] And, where K represents C or N.

[0083] In preferred embodiments, the diaryl compound, its tautomers, stereoisomers, solvates (e.g., hydrates), pharmaceutically acceptable salts, or prodrugs have a structure represented by formula Ia, Ib, or Ic.

[0084] [ka]

[0085] However, K represents C or N, The definitions of ring A, ring B, m, n, p, R1, R2, and R3 are as described in the first aspect of the present invention.

[0086] In a preferred embodiment,

[0087] [ka] is structure

[0088] [ka] It has.

[0089] In a preferred embodiment, ring A is a 7-10 member monocyclic heterocyclic group, or a 7-12 member fused, bridging, or spirocyclic heterocyclic group. In a preferred embodiment, ring A is

[0090] [ka] Selected from,

[0091] Preferably,

[0092] [ka] teeth,

[0093] [ka] That is the case.

[0094] In a preferred embodiment, R1 and R2 are each independently hydrogen, or selected from halogens, hydroxyl, amino, C1-C6 alkyl, and -O-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogens, and R3 is selected from halogens, hydroxyl, amino, C1-C6 alkyl, and -O-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogens, and R1 and R2 are not simultaneously hydrogen. Preferably, R1, R2, and R3 are each independently selected from halogens and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more halogens. More preferably, R1, R2, and R3 are each independently selected from fluorine, methyl, ethyl, and propyl, and the methyl, ethyl, and propyl are optionally substituted with one or more halogens. Preferably, the halogen is F.

[0095] In preferred embodiments, ring B is a 6-12 member monocyclic, fused, spirocyclic, or bridging heterocyclic group, preferably a 6-8 member monocyclic heterocyclic group, and preferably a 7-12 member fused, spirocyclic, or bridging heterocyclic group.

[0096] In a preferred embodiment, ring B is

[0097] [ka] Selected from.

[0098] In a preferred embodiment, R1, R2, and R3 are each independently hydrogen, or halogen, hydroxyl, amino, cyano, C1-C6 alkyl, -O-C1-C6 alkyl, or -C(O)NR 11 R 12 Selected from, R 11 , R 12 Each of these is independently hydrogen or a C1-C6 alkyl group. The C1-C6 alkyl groups are optionally substituted with one or more halogens. Preferably, R1, R2, and R3 are each independently selected from halogens and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more halogens. More preferably, R1, R2, and R3 are each independently selected from fluorine, methyl, ethyl, and propyl, the C1-C6 alkyl groups are optionally substituted with one or more fluorine atoms, and preferably the halogen is F.

[0099] In a preferred embodiment, n is 1. In preferred embodiments, R1 is hydrogen, or selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. Preferably, R1 is hydrogen, or selected from halogen, cyano, C1-C6 alkyl, or C2-C6 alkynyl. More preferably, R1 is hydrogen, or selected from fluorine, chlorine, cyano, methyl, and -C≡C-CH3.

[0100] In a preferred embodiment, R2 is hydrogen. In a preferred embodiment, R3 is hydrogen. In preferred embodiments, the diaryl compound, its tautomers, stereoisomers, solvates (e.g., hydrates), pharmaceutically acceptable salts, or prodrugs have structure Id,

[0101] [ka]

[0102] However, m is 1 or 2, preferably m is 1. R3 is hydrogen, or a halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-C1-C6 alkyl, -COO-C1-C6 alkyl, -CO-C1-C6 alkyl, or -C(O)NR 11 R 12 Selected from the following, R1 is cyano, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)NR 11 R 12 Selected from, Alternatively, R1 and R3 can independently be halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-C1-C6 alkyl, -COO-C1-C6 alkyl, -CO-C1-C6 alkyl, or -C(O)NR 11 R 12 Selected from, Here, R 11 , R 12 Each is independently hydrogen or a C1-C6 alkyl, or R 11 and R 12 These, together with the N atoms linked to them, form a 4-6 membered ring. R3 is optionally substituted with one or more substituents selected from halogen, hydroxyl, amino, cyano, and C1-C6 alkyl groups, and if there are multiple substituents, the substituents may be the same or different.

[0103] In preferred embodiments, R3 is hydrogen, or a halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-C1-C6 alkyl, -COO-C1-C6 alkyl, -CO-C1-C6 alkyl, or -C(O)NR 11 R 12 Selected from the following, R1 is cyano, C2-C3 alkenyl, C2-C3 alkynyl, -C(O)NR 11 R 12 Selected from, Alternatively, R1 and R3 are independently selected from halogens and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxyls, aminos, cyanos, and C1-C6 alkyl groups, and if there are multiple substituents, the substituents may be the same or different. Preferably, R3 is hydrogen or selected from halogens, methyl, ethyl, or propyl, and the methyl, ethyl, or propyl is optionally substituted with one or more halogens, and R1 is selected from cyano, C2-C3 alkenyl, or C2-C3 alkynyl, more preferably R3 is hydrogen and R1 is selected from cyano, C2-C3 alkenyl, or C2-C3 alkynyl. Preferably, R1 and R3 are each independently selected from halogen, methyl, ethyl, and propyl, and the methyl, ethyl, and propyl are optionally substituted with one or more halogens, preferably the halogen being fluorine.

[0104] In preferred embodiments, the diaryl compound, its tautomers, stereoisomers, solvates (e.g., hydrates), pharmaceutically acceptable salts, or prodrugs have structure Ie or If.

[0105] [ka]

[0106] However, the definitions of rings C, R1, R2, n, and p are as described in the first aspect of the present invention. R3 is C1-C6 alkyl, -CO-C1-C6 alkyl, -C(O)NR 11 R 12 , 3-6 member cycloalkyl, -COO-C1-C6 alkyl, -COO-3-6 member cycloalkyl, -CO-3-6 member cycloalkyl, -S(O)2-C1-C6 alkyl, -S(O)2-3-6 member cycloalkyl, -C(O)-C1-C6 alkyl-NR 11 R 12 And, Here, R 11 , R12 Each is independently hydrogen or a C1-C6 alkyl, or R 11 and R 12 These, together with the N atoms linked to them, form a 4-6 membered ring. The aforementioned R3 is optionally substituted with one or more substituents selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and 3-6 membered cycloalkyl groups, and if there are multiple substituents, the substituents may be the same or different. Preferably, ring C is a 4- to 8-membered heterocyclic group, preferably ring C is a 4- to 6-membered heterocyclic group, and more preferably ring C is a 4-membered ring. Preferably, R3 is a -CO-C1~C6 alkyl group. Preferably, R3 is optionally substituted with one or more substituents selected from halogens and 3- to 6-membered cycloalkyl groups. More preferably, R3 is -CO-C1~C3 alkyl-cyclopropyl or -CO-C1~C3 alkyl-cyclobutyl.

[0107] In preferred embodiments, diaryl compounds represented by formula I, Ia, Ib, Ic, Id, Ie, or If, R1 is hydrogen, or selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. Preferably, R1 is hydrogen, or selected from halogen, cyano, C1-C6 alkyl, or C2-C6 alkynyl. More preferably, R1 is hydrogen, or selected from fluorine, chlorine, cyano, methyl, and -C≡C-CH3.

[0108] In preferred embodiments, the diaryl compound, its tautomers, stereoisomers, solvates (e.g., hydrates), pharmaceutically acceptable salts, or prodrugs, the diaryl compound is one of the following compounds.

[0109] [ka] TIFF0007897940000035.tif127170

[0110] In preferred embodiments, the diaryl compound, its tautomers, stereoisomers, solvates (e.g., hydrates), pharmaceutically acceptable salts, or prodrugs, the diaryl compound is one of the following compounds.

[0111] [ka]

[0112] Preferably,

[0113] [ka] teeth,

[0114] [ka] And, Preferably,

[0115] [ka] teeth,

[0116] [ka] That is the case.

[0117] In a second embodiment of the present invention, compound B having the following structure is provided.

[0118] [ka]

[0119] However, the definitions of Q, L, W, R1, and n are as described in the first aspect. X is a halogen or substituent G, The substituent G is selected from a borate ester group, a borate group, an alkyltin group, a trifluoromethanesulfonic acid group, a methanesulfonic acid group, and a p-toluenesulfonic acid group. Preferably, the halogen is chlorine, bromine, or iodine.

[0120] In a preferred embodiment, compound B has the following structure:

[0121] [ka]

[0122] However, K represents C or N, The definitions of ring A, ring B, m, n, p, R1, R2, and R3 are as described in the first aspect. X is a halogen or substituent G, In preferred embodiments, the substituent G is selected from a borate ester group, a borate group, an alkyltin group, a trifluoromethanesulfonic acid group, a methanesulfonic acid group, and a p-toluenesulfonic acid group. Preferably, the halogen is chlorine, bromine, or iodine.

[0123] In a second embodiment of the present invention, an intermediate B having the following structure is provided.

[0124] [ka]

[0125] However, the definitions of Q, L, W, R1, and n are as described in the first aspect. X is a halogen or substituent G, The substituent G is selected from a borate ester group, a borate group, an alkyltin group, a trifluoromethanesulfonic acid group, a methanesulfonic acid group, and a p-toluenesulfonic acid group. Preferably, the halogen is chlorine, bromine, or iodine.

[0126] In a preferred embodiment, the intermediate B has the following structure:

[0127] [ka]

[0128] However, K represents C or N, The definitions of ring A, ring B, m, n, p, R1, R2, and R3 are as described in the first aspect. X is a halogen or substituent G, In preferred embodiments, the substituent G is selected from a borate ester group, a borate group, an alkyltin group, a trifluoromethanesulfonic acid group, a methanesulfonic acid group, and a p-toluenesulfonic acid group. Preferably, the halogen is chlorine, bromine, or iodine.

[0129] In a preferred embodiment, ring A is a 7-15 member monocyclic, fused, bridging, or spirocyclic heterocyclic group. Preferably, the ring A is a 7-10 member monocyclic heterocyclic group, or a 7-12 member fused, bridging, or spirocyclic heterocyclic group. Preferably, the ring A contains one N atom and one O atom.

[0130] In preferred embodiments, the borate ester group is selected from bis(pinacolate)diborone, bis(catecolate)diborone, bis(3,3-dimethylpentane-2,4-glycolate)diborone, triethanolamine borate, trimethyl borate, triisopropyl borate, triethyl borate, tributyl borate, and bis(neopentylglycolate)diborone.

[0131] In preferred embodiments, ring B is a 6-12 member monocyclic, fused, spirocyclic, or bridging heterocyclic group, preferably a 6-8 member monocyclic heterocyclic group, and preferably a 7-12 member fused, spirocyclic, or bridging heterocyclic group.

[0132] In preferred embodiments, the alkyltin is butyltin, isopropyltin, or propyltin. In preferred embodiments, R1, R2, and R3 are each independently halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-C1-C6 alkyl, -COO-C1-C6 alkyl, -CO-C1-C6 alkyl, or -C(O)NR 11 R 12 Selected from, Here, R 11 , R 12 Each is independently hydrogen or a C1-C6 alkyl, or R 11 and R 12 These, together with the N atoms linked to them, form a 4-6 membered ring. R3 is optionally substituted with one or more substituents selected from halogen, hydroxyl, amino, cyano, and C1-C6 alkyl groups, and if there are multiple substituents, the substituents may be the same or different.

[0133] In preferred embodiments, R3 is hydrogen, or a halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -O-C1-C6 alkyl, -COO-C1-C6 alkyl, -CO-C1-C6 alkyl, or -C(O)NR 11 R 12 Selected from the following, R1 is cyano, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)NR 11 R 12 Selected from.

[0134] Preferably, R3 is hydrogen, or selected from halogen, methyl, ethyl, or propyl, and the methyl, ethyl, or propyl is optionally substituted with one or more halogens, and R1 is selected from cyano, C2-C3 alkenyl, or C2-C3 alkynyl. In a preferred embodiment, R1, R2, and R3 are each independently selected from halogens and C1-C6 alkyl groups, and the C1-C6 alkyl groups are optionally substituted with one or more substituents selected from halogens, hydroxyls, aminos, cyanos, and C1-C6 alkyl groups, and if there are multiple substituents, the substituents may be the same or different. Preferably, R1 and R3 are each independently selected from halogen, methyl, ethyl, and propyl, and the methyl, ethyl, and propyl are optionally substituted with one or more halogens, preferably the halogen being fluorine.

[0135] In a preferred embodiment, R3 is C1-C6 alkyl, -CO-C1-C6 alkyl, -C(O)NR 11 R 12 , 3-6 member cycloalkyl, -COO-C1-C6 alkyl, -COO-3-6 member cycloalkyl, -CO-3-6 member cycloalkyl, -S(O)2-C1-C6 alkyl, -S(O)2-3-6 member cycloalkyl, -C(O)-C1-C6 alkyl-NR 11 R 12 And here, R 11 , R 12 Each is independently either hydrogen or a C1-C6 alkyl group, or R 11 and R 12 These, together with the N atoms linked to them, form a 4-6 membered ring. R3 is optionally substituted with one or more substituents selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, and 3-6 membered cycloalkyl groups, and if there are multiple substituents, the substituents may be the same or different.

[0136] Preferably, the ring C is a 4- to 8-membered heterocyclic group, preferably, the ring C is a 4- to 6-membered heterocyclic group, more preferably,

[0137] [ka] And,

[0138] Preferably, R3 is -CO-C1-C6 alkyl, and preferably, the R3 is optionally substituted by one or more substituents selected from halogen, 3- to 6-membered cycloalkyl, More preferably, R3 is -CO-C1-C3 alkyl-cyclopropyl, -CO-C1-C3 alkyl-cyclobutyl.

[0139] A compound having any one of the following structures.

[0140]

Chemical formula

[0141] In a third aspect of the present invention, there is provided a method for preparing a diaryl compound, a tautomer, a stereoisomer, a solvate (e.g., hydrate), a pharmaceutically acceptable salt or a prodrug thereof according to any one of the first aspects, which comprises reacting intermediate B and intermediate C according to any one of the second aspects under alkaline conditions to obtain the diaryl compound.

[0142]

Chemical formula

[0143] However, the definitions of R2 and p are as described in the first aspect, Y is halogen or substituent G, The substituent G is selected from a borate ester group, a boric acid group, an alkyltin, a trifluoromethanesulfonic acid group, a methanesulfonic acid group, a p-toluenesulfonic acid group, When X of intermediate B is halogen, Y is G, When X of intermediate B is G, X is halogen, Preferably, the halogen is chlorine, bromine or iodine, Preferably, intermediate C has the structure

[0144]

Chemical formula

[0145] In preferred embodiments, the borate ester group is selected from bis(pinacolate)diborone, bis(catecolate)diborone, bis(3,3-dimethylpentane-2,4-glycolate)diborone, triethanolamine borate, trimethyl borate, triisopropyl borate, triethyl borate, tributyl borate, and bis(neopentylglycolate)diborone.

[0146] In preferred embodiments, the alkyltin is butyltin, isopropyltin, or propyltin. In a preferred embodiment, the reaction requires protection by an inert gas, which includes, but is not limited to, nitrogen gas, helium gas, neon gas, and argon gas.

[0147] In a preferred embodiment, the reaction is carried out under palladium-catalyzed conditions, and preferably the palladium catalyst is selected from the following: The reactions in each step of the present invention are preferably carried out in an inert solvent, which includes, but is not limited to, toluene, benzene, water, methanol, ethanol, isopropyl alcohol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, trichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or combinations thereof.

[0148] Preferably, the palladium catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium(0)(Pd2(dba)3), tetrakis(triphenylphosphine)palladium(0)(Pd(PPh3)4), palladium acetate, palladium chloride, bis(triphenylphosphine)palladium(II) dichloride, palladium trifluoroacetate(II), bis(triphenylphosphine)palladium(II) diacetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis(tri-o-tolylphosphine)palladium(II) dichloride, [1,2-bis(diphenylphosphino)ethane]palladium(II) dichloride, or combinations thereof.

[0149] Preferably, the borate ester group is selected from the group consisting of bis(pinacolate)diborone, bis(catecholate)diborone, bis(3,3-dimethylpentane-2,4-glycolate)diborone, triethanolamine borate, trimethyl borate, triisopropyl borate, triethyl borate, tributyl borate, and bis(neopentylglycolate)diborone.

[0150] A fourth aspect of the present invention provides a pharmaceutical composition comprising a diaryl compound described in the first aspect, its tautomers, stereoisomers, solvates (e.g., hydrates), pharmaceutically acceptable salts, or prodrugs.

[0151] The present invention provides a pharmaceutical composition comprising a diaryl compound described in the first embodiment, its tautomers, stereoisomers, solvates (e.g., hydrates), pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable carriers and / or other active pharmaceutical ingredients.

[0152] In a fifth embodiment of the present invention, 1) Inhibiting tubulin polymerization and / or Src kinase, 2) To prevent and / or treat diseases related to tubulin polymerization and / or Src kinase, 3) To prepare tubulin polymerization and / or Src kinase inhibitors. 4) The present invention provides the use of diaryl compounds, tautomers, stereoisomers, solvates (e.g., hydrates), pharmaceutically acceptable salts or prodrugs thereof, as described in the first embodiment, or the use of pharmaceutical compositions as described in the fourth embodiment, comprising preparing pharmaceuticals, pharmaceutical compositions or formulations for the prevention and / or treatment of diseases related to tubulin polymerization and / or Src kinase.

[0153] Preferably, the use includes inhibiting tubulin polymerization and / or preventing and / or treating diseases mediated by tubulin polymerization and / or preparing tubulin polymerization inhibitors and / or preparing pharmaceuticals, pharmaceutical compositions or formulations for preventing and / or treating tubulin polymerization-mediated diseases.

[0154] Preferably, the use includes inhibiting src kinase and / or preventing and / or treating diseases mediated by src kinase and / or preparing src kinase inhibitors and / or preparing pharmaceuticals, pharmaceutical compositions or formulations for preventing and / or treating src kinase-mediated diseases.

[0155] Preferably, the pharmaceutical is a topical preparation. Preferably, the pharmaceutical is administered transdermally. Preferably, the diseases associated with tubulin polymerization and / or Src kinase include tumors and skin diseases.

[0156] A sixth aspect of the present invention provides the use of diaryl compounds, tautomers, stereoisomers, solvates (e.g., hydrates), pharmaceutically acceptable salts, or prodrugs described in the first aspect in the preparation of pharmaceuticals for treating tumors and / or skin diseases, or the use of pharmaceutical compositions described in the fourth aspect in the preparation of pharmaceuticals for treating tumors and / or skin diseases.

[0157] Preferably, the pharmaceutical is a topical preparation. Preferably, the medicament is a medicament for transdermal administration. In a seventh aspect of the invention, there is provided the use of at least one of the diaryl compounds, tautomers, stereoisomers, solvates (e.g., hydrates), pharmaceutically acceptable salts or prodrugs according to the first aspect, or the pharmaceutical composition according to the fourth aspect, in the treatment or prevention of tumors and / or skin diseases.

[0158] In a preferred embodiment, the tumors include solid tumors, sarcomas, and blood cancers. Preferably, the tumors include breast cancer, ovarian cancer, prostate cancer, cervical cancer, testicular cancer, colon cancer, colorectal cancer, liver cancer, non-small cell lung cancer, squamous cell carcinoma (e.g., cutaneous squamous cell carcinoma), small cell lung cancer, gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, bladder cancer, germ cell tumor, mastocytoma, mastocytosis, glioblastoma, neuroblastoma, astrocytoma, melanoma, B-cell lymphoma, T-cell lymphoma, indolent lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, myeloma and / or myelodysplastic syndrome.

[0159] In a preferred embodiment, the skin diseases include actinic keratosis, psoriasis vulgaris, atopic dermatitis, psoriasis, vitiligo, roseola and / or systemic lupus erythematosus. In an eighth aspect of the invention, there is provided a method of inhibiting Src kinase, or a method of preventing and / or treating a disease associated with (or mediated by) Src kinase, comprising the step of administering to a subject in need of the compound, tautomer, stereoisomer, solvate (e.g., hydrate), pharmaceutically acceptable salt or prodrug according to the first aspect of the invention, or the pharmaceutical composition according to the fourth aspect of the invention.

[0160] A ninth aspect of the present invention provides a method for inhibiting tubulin, or a method for preventing and / or treating a tubulin-related (or tubulin-mediated) disease, comprising the step of administering to a subject requiring a compound described in the first aspect of the present invention, its tautomers, stereoisomers, solvates (e.g., hydrates), pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition described in the fourth aspect of the present invention.

[0161] Additional aspects and advantages of the present invention are given in part in the following description, will become apparent from the following description, or can be understood through the practice of the present invention. Terms and Definitions Unless otherwise specified, the definitions of groups and terms described in the specification and claims of this application include illustrative definitions, exemplary definitions, preferred definitions, definitions listed in tables, and definitions of specific compounds in examples, and can be arbitrarily combined with each other. Such combinations and combined definitions of groups and structures of compounds should fall within the scope described in the specification of this application.

[0162] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as generally understood by those skilled in the art to whom the categories of claims belong. Unless otherwise specified, all patents, patent applications, and published materials cited herein are incorporated herein by reference in their entirety. If there are multiple definitions of a term herein, the definition in this chapter shall prevail.

[0163] Please understand that the brief description above and the detailed description below are illustrative and descriptive only and do not limit the categories of the present invention in any way. In this application, unless otherwise specified, the use of the singular includes the plural. Please note that unless otherwise clearly indicated by the context, the singular as used herein and in the claims includes the plural of the object being referred to. Also note that unless otherwise specified, the words "or" and "or" used mean "and / or". Furthermore, the use of the term "include" and other forms such as "contain," "include," and "contain" is not limiting.

[0164] For definitions of standard chemical terms, refer to the references (e.g., Carey and Sundberg, “ADVANCED ORGANIC CHEMISTRY 4THED,” Vols. A(2000) and B(2001), Plenum Press, New York). Unless otherwise specified, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy, and pharmacological methods, are used. Unless otherwise specified, terms used herein in relation to analytical chemistry, synthetic organic chemistry, pharmaceutical and medical chemistry are known in the art. Standard techniques can be used for chemical synthesis, chemical analysis, preparation, formulation and delivery of pharmaceuticals, and treatment of patients. For example, reactions and purifications can be carried out using the instructions of the kit manufacturer, or by methods known in the art or described herein. The above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various general and more specific literature cited and discussed herein. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural parts and compounds.

[0165] When substituents are written from left to right in a standard chemical formula, chemically equivalent substituents when the structural formula is written from right to left are also included. For example, CH2O is equivalent to OCH2. As used herein,

[0166] [ka] This indicates the binding site of the group.

[0167] Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described herein. All documents or parts of documents cited herein, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0168] In addition to the above, when used in the specification and claims of this application, the following terms have the meanings set forth below unless otherwise specified. With respect to numerical ranges described in the specification and claims of this application, if such numerical ranges are understood as "integers," they should be understood to include the two endpoints of the range and each integer within that range. For example, "integers from 1 to 6" should be understood to include the integers 1, 2, 3, 4, 5, and 6.

[0169] In this application, when used alone or as part of other substituents, the term "halogen" refers to fluorine, chlorine, bromine, and iodine. When used alone or as part of another substituent, "sulfonyl"

[0170] [ka] It refers to the base.

[0171] As used herein, when used alone or as part of other substituents, the term "alkyl" refers to a linear or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturated bonds, and having, for example, 1 to 6 carbon atoms, linked to the rest of the molecule by single bonds. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. Alkyls may also be naturally abundant isotopic isomers of alkyls that are rich in carbon and / or hydrogen isotopes (i.e., deuterium or tritium).

[0172] As used herein, the term "alkenyl" means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.

[0173] When used alone or as part of other substituents, the term "C1-C6 alkyl" should be understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl groups are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. In particular, the group has one, two, or three carbon atoms ("C1-C3 alkyl"), and is, for example, methyl, ethyl, n-propyl, or isopropyl.

[0174] When used alone or as part of another substituent, the term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group. Examples of alkylene groups include methylene (-CH2-), ethylene (including -CH2CH2- or -CH(CH3)-), and isopropylene (including -CH(CH3)CH2- or -C(CH3)2-).

[0175] When used alone or as part of another substituent, the terms "cycloalkyl" or "carbocyclyl" mean cyclic alkyl. "m-n member cycloalkyl" or "C m ~C n The term "cycloalkyl" should be understood to mean a saturated, unsaturated, or partially saturated carbon ring having m to n atoms. For example, "3-15 member cycloalkyl" or "C3-C 15 "Cycloalkyl" refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6, or 3 to 5 carbon atoms, and may contain 1 to 4 rings. "5 to 8 membered cycloalkyl" refers to a cyclic alkyl group containing 5 to 8 carbon atoms. This includes monocyclic, dicyclic, tricyclic, spirocyclic, or bridging rings. Examples of unsubstituted cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as the decahydronaphthalene ring. Cycloalkyls may be substituted with one or more substituents. In some embodiments, the cycloalkyl may be a cycloalkyl group condensed to an aryl or heteroaryl. The term "C3-C6 cycloalkyl" should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including condensed or bridging polycyclic systems. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0176] When used alone or as part of another substituent, “haloalkyl” refers to a branched and linear saturated aliphatic hydrocarbon group having a specific number of carbon atoms substituted by one or more halogens (e.g., -CvFw, where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyls include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0177] When used alone or as part of another substituent, "m-n membered heterocyclyl" is understood to mean a saturated, unsaturated, or partially saturated monocyclic, fused (including bicyclic and tricyclic), spirocyclic, or bridging cyclic compound having m-n atoms, preferably a saturated heterocycle.

[0178] For example, "7-15 membered heterocyclil" should be understood to mean a saturated, unsaturated, or partially saturated monocyclic, fused (including bicyclic and tricyclic), spirocyclic, or bridging cyclic ring having 7 to 15 atoms, preferably a saturated heterocyclic ring. Here, 1, 2, 3, 4, or 5 ring atoms are selected from N, O, and S. If the total number of S and O atoms in the heterocyclil exceeds 1, it should be understood that these heteroatoms are not adjacent to each other. If the heterocyclil is monocyclic, it must not be aromatic. Examples of heterocyclyls include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroindolyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridine-2-one, and 2,5-dioxoimidazolidinyl. "6-12 membered heterocyclyl" refers to a saturated, unsaturated, or partially saturated monocycle, fused ring (including dicyclic and tricyclic rings), spirocycle, or bridging ring having 6 to 12 atoms.

[0179] The term "condensed ring" refers to a cyclic hydrocarbon in which any two rings in a compound share two carbon atoms through direct bonding. These are classified into bicyclic, tricyclic, and tetracyclic hydrocarbons depending on the number of rings they comprise. A non-restrictive example is:

[0180] [ka] It includes.

[0181] The term "spiro ring" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between monocyclic rings, and may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, it is 6-12 membered, more preferably 7-8 membered. Depending on the number of spiro atoms shared between the rings, spirocycloalkyls are classified as monospirocycloalkyls, bisspirocycloalkyls, or polyspirocycloalkyls, preferably monospirocycloalkyls and bisspirocycloalkyls. More preferably, they are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyls. Non-limiting examples of spirocycloalkyls include:

[0182] [ka] It includes.

[0183] Furthermore, this also includes spirocycloalkyls in which monospirocycloalkyls and heterocycloalkyls share a spiro atom, and non-limiting examples include:

[0184] [ka] It includes.

[0185] The term "bridged ring" refers to a cyclic hydrocarbon in a compound where any two rings share two carbon atoms that are not directly bonded. These are classified into bicyclic, tricyclic, and tetracyclic hydrocarbons depending on the number of rings they comprise. A non-restrictive example is:

[0186] [ka] It includes.

[0187] When used alone or as part of another substituent, "C2-C6 alkenyl" should be understood to mean a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, or 6 carbon atoms, preferably, for example, 2 or 3 carbon atoms (i.e., a C2-C3 alkenyl). If the alkenyl contains two or more double bonds, it should be understood that the double bonds may be separated from each other or conjugated. The aforementioned alkenyls are, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-buto-2-enyl, (Z)-buto-2-enyl, (E)-buto-1-enyl, (Z)-buto-1-enyl, pento-4-enyl, (E)-pento-3-enyl, (Z)-pento-3-enyl, (E)-pento-2-enyl, (Z)-pento-2-enyl, (E)-pento-1- Enyl, (Z)-pento-1-enyl, hexa-5-enyl, (E)-hexa-4-enyl, (Z)-hexa-4-enyl, (E)-hexa-3-enyl, (Z)-hexa-3-enyl, (E)-hexa-2-enyl, (Z)-hexa-2-enyl, (E)-hexa-1-enyl, (Z)-hexa-1-enyl, isopropenyl, 2-methylpropa-2-enyl, 1-methylpropa-2-enyl Nyl, 2-methylpropa-1-enyl, (E)-1-methylpropa-1-enyl, (Z)-1-methylpropa-1-enyl, 3-methylbutato-3-enyl, 2-methylbutato-3-enyl, 1-methylbutato-3-enyl, 3-methylbutato-2-enyl, (E)-2-methylbutato-2-enyl, (Z)-2-methylbutato-2-enyl, (E)-1-methylbutato-2-enyl, (Z)-1-methylbutato-2-enyl These are rubto-2-enyl, (E)-3-methylbuto-1-enyl, (Z)-3-methylbuto-1-enyl, (E)-2-methylbuto-1-enyl, (Z)-2-methylbuto-1-enyl, (E)-1-methylbuto-1-enyl, (Z)-1-methylbuto-1-enyl, 1,1-dimethylpropa-2-enyl, 1-ethylpropa-1-enyl, 1-propyl vinyl, and 1-isopropyl vinyl.

[0188] The term "C2-C6 alkynyl" should be understood to mean a linear or branched monovalent hydrocarbon group (C2-C3 alkynyl) containing one or more triple bonds and having 2, 3, 4, 5, or 6 carbon atoms, preferably, for example, 2 or 3 carbon atoms. The aforementioned alkynyls include, for example, ethinyl, propa-1-inyl, propa-2-inyl, buto-1-inyl, buto-2-inyl, buto-3-inyl, pento-1-inyl, pento-2-inyl, pento-3-inyl, pento-4-inyl, hexa-1-inyl, hexa-2-inyl, hexa-3-inyl, hexa-4-inyl, hexa-5-inyl, 1-methylpropa-2-inyl, 2-methylbuto-3-inyl, 1-methylbuto-3-inyl, 1-methylbuto-2-inyl, 3-methylbuto-1-inyl, and 1-ethylpropa-2 These include -inyl, 3-methylpento-4-inyl, 2-methylpento-4-inyl, 1-methylpento-4-inyl, 2-methylpento-3-inyl, 1-methylpento-3-inyl, 4-methylpento-2-inyl, 1-methylpento-2-inyl, 4-methylpento-1-inyl, 3-methylpento-1-inyl, 2-ethylbuto-3-inyl, 1-ethylbuto-3-inyl, 1-ethylbuto-2-inyl, 1-propylpropa-2-inyl, 1-isopropylpropa-2-inyl, and 2,2-dimethylbuto-3-inyl. In particular, the alkynyl is ethinyl, propa-1-inyl, or propa-2-inyl.

[0189] In examples of the present invention, the proton may occupy two or more positions in the heterocyclic system in a cyclic form, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. The tautomer form may be in equilibrium or sterically fixed into a single form by appropriate substitution. For example,

[0190] [ka] That is the case.

[0191] Due to resonance, the hydrogen atoms of the nitrogen on the triazole can be present on any of the three nitrogen atoms; therefore, although they are named differently, these three forms actually represent the same compound. The compounds provided herein include intermediates that can be used in the preparation of the compounds provided herein, and include reactive functional groups (e.g., carboxyl, hydroxyl, and amino moieties, but not limited to these), and protected derivatives thereof. “Protected derivatives” are those compounds in which one or more reaction sites are blocked by one or more protecting groups (also called protecting groups). Suitable carboxyl moiety protecting groups include benzyl, tert-butyl, and isotopes. Suitable amino and amide protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, and benzyloxycarbonyl. Suitable hydroxyl protecting groups include benzyl. Other suitable protecting groups are well known to those skilled in the art.

[0192] In this application, "optional" or "optionally" means that the event or situation described thereafter may or may not occur, and the description includes both cases where the event or situation occurs and where it does not. For example, "optionally substituted aryl" means that the aryl is substituted or not substituted, and the description includes both substituted and non-substituted aryls.

[0193] In this application, the terms “salt” or “pharmaceutically acceptable salt” include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term “pharmaceutically acceptable” applies to those compounds, materials, compositions and / or dosage forms which are within the bounds of reliable medical judgment, suitable for contact with human and animal tissues, with little toxicity, irritation, allergic reaction or other problem or complication, and which meet a reasonable benefit / risk ratio.

[0194] "Pharmacologically acceptable acid addition salts" mean salts formed with inorganic or organic acids that can retain the biological efficacy of a free base without other side effects. "Pharmacologically acceptable base addition salts" mean salts formed with inorganic or organic bases that can retain the biological efficacy of a free acid without other side effects. In this invention, other salts are also considered in addition to pharmaceutically acceptable salts. These may act as intermediates in the purification of the compound or the preparation of other pharmaceutically acceptable salts, or they may be used in the identification, characterization, or purification of the compound of this invention.

[0195] The term "amine salt" refers to a product obtained by neutralizing an alkyl primary, secondary, or tertiary amine with an acid. The acid includes the inorganic or organic acids described in this application.

[0196] The term "stereoisomer" refers to isomers that arise from differences in the spatial arrangement of atoms within a molecule, including cis-trans isomers, enantiomers, diastereomers, and structural isomers.

[0197] Depending on the selection of starting materials and methods, the compounds of the present invention may exist in the form of one or a mixture thereof of possible isomers, for example, as pure optical isomers, or as mixtures of isomers, for example, as racemates and mixtures of diastereomers, depending on the number of chiral carbon atoms. When describing optically active compounds, the prefixes D and L, or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) within the molecule. The prefixes D and L, or (+) and (-) are symbols used to specify the rotation of plane polarization by the compound, where (-) or L means that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.

[0198] When the bond with a chiral carbon in the formula of this invention is described as a straight line, it should be understood that both the (R) and (S) configurations of the chiral carbon, and the resulting enantiomerically pure compounds and mixtures, are within the scope of this general formula. The graphical representation of racemates or enantiomerically pure compounds in this specification is from Maehr, J. Chem. Ed. 1985, 62:114-120. The absolute configuration of the stereocenter is represented by wedge-shaped bonds and dashed-line bonds.

[0199] The term "tautomer" refers to a functional isomer resulting from the rapid movement of atoms between two positions within a molecule. The compounds of the present invention can exhibit the phenomenon of tautomerism. Tautomer compounds can exist as two or more interconvertible species. Prototropic tautomers arise from the movement of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium, and attempting to isolate a single tautomer usually yields a mixture whose physicochemical properties match those of the compound mixture. The equilibrium position depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant, while in phenols, the enol form is dominant. The present invention encompasses all tautomer forms of compounds.

[0200] In this application, “pharmaceutical composition” means a formulation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The object of the pharmaceutical composition is to facilitate administration to a living organism, to facilitate the absorption of the active ingredient, and thereby to exert biological activity.

[0201] In this application, “pharmaceutically acceptable carrier” includes, but is not limited to, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, fragrances, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers approved by the relevant government regulatory body as acceptable for use in humans or livestock.

[0202] The term "solvate" means that the compound or salt thereof of the present invention contains a stoichiometric or non-stoichiometric solvent bonded by intermolecular non-covalent forces, and if the solvent is water, it is a hydrate.

[0203] The term "prodrug" refers to the compounds of the present invention that can be converted into biologically active compounds under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying the functional groups in the compound, and this modification can be removed by normal procedures or in vivo to obtain the parent compound. Prodrugs include compounds formed by the bonding of a hydroxyl or amino group in the compound of the present invention to any group, and when a prodrug of the compound of the present invention is administered to a mammalian organism, the prodrug is cleaved to form free hydroxyl and free amino groups, respectively.

[0204] The compounds of the present invention may contain unnatural proportions of atomic isotopes in one or more of the atoms constituting the compound. For example, the compound may contain deuterium ( 2 H), tritium ( 3 H), Iodine-125( 125 I) or C-14 ( 14 It can be labeled with radioactive isotopes such as C). All isotopic transformations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0205] The term "excipient" refers to a pharmaceutically acceptable inert component. Examples of types of "excipients" include, but are not limited to, binders, disintegrants, lubricants, flow enhancers, stabilizers, fillers, and diluents. Excipients can improve the handling properties of pharmaceutical formulations, that is, they can make formulations more suitable for direct compression by increasing their fluidity and / or tackiness.

[0206] The term “treatment” and other similar synonyms as used herein include: (i) To prevent the occurrence of diseases or conditions in mammals, in particular in mammals that are susceptible to such diseases or conditions but have not yet been diagnosed with them. (ii) To inhibit a disease or symptom, that is, to prevent its progression. (iii) To alleviate a disease or symptom, that is, to resolve the state of the disease or symptom, or (iv) This includes alleviating the symptoms caused by the disease or condition.

[0207] In each step of the reaction, the reaction temperature can be appropriately selected depending on the solvent, starting materials, reagents, etc., and the reaction time can also be appropriately selected depending on the reaction temperature, solvent, starting materials, reagents, etc. After the reaction in each step is complete, the target compound can be separated and purified from the reaction system by conventional methods such as filtration, extraction, recrystallization, washing, and silica gel column chromatography. Alternatively, the target compound can be directly added to the next step's reaction without separation or purification, without affecting the reaction of the next step.

[0208] Based on the fact that it does not contradict common sense in the field, each of the above preferred conditions can be arbitrarily combined to obtain each preferred example of the present invention. All reagents and raw materials used in this invention are commercially available.

[0209] A significant progressive effect of the present invention is that, as a result of extensive and meticulous research, the inventors have unexpectedly developed diaryl compounds as tubulin-SRC dual-target inhibitors, as well as methods for their preparation and use, wherein the diaryl compounds have the structure of Formula I described in the present invention. The diaryl compounds can be used as dual-target inhibitors of tubulin and Src kinase, or as individual tubulin or Src kinase inhibitors. The compounds of the present invention can significantly inhibit the polymerization of tubulin monomers and inhibit cell proliferation. They have good pharmacokinetic properties for topical administration to the skin and have good drug discovery potential. They have the advantages of rapid metabolism and few side effects, and can be used in the preparation of topical skin preparations. [Brief explanation of the drawing]

[0210] [Figure 1] This is the polymerization curve of tubulin monomer using the compound from Test Example 1. [Figure 2] This is the result of inhibiting the Src signaling pathway by the compound. [Modes for carrying out the invention]

[0211] The present invention will be further described below based on specific examples. It should be understood that the following description represents only the most preferred embodiments of the present invention and should not be considered to limit the scope of protection of the present invention. Based on a full understanding of the present invention, in experimental methods for which specific conditions are not shown in the following examples, a person skilled in the art may make non-essential modifications to the technical solutions of the present invention, usually according to conventional conditions or conditions recommended by the manufacturer, and such modifications should be considered to fall within the scope of protection of the present invention.

[0212] Preparation of intermediate A1: N-benzyl-2-(5-bromopyridine-2-yl)acetamide The synthesis route is as follows:

[0213] [ka]

[0214] Step 1: Preparation of 2-(5-bromopyridine-2-yl)acetonitrile At room temperature, acetonitrile (19.6 g, 477 mmol) was added to anhydrous tetrahydrofuran (500 mL), cooled to -78°C, and n-butyllithium (170 mL, 426 mmol) was slowly added dropwise. The reaction solution was stirred at -78°C for 1 hour, then 5-bromo-2-fluoropyridine (30 g, 170 mmol) in tetrahydrofuran (100 mL) was added dropwise. After the addition was complete, the temperature was slowly raised to room temperature and the mixture was stirred for 2 hours. After detecting the end of the reaction with a spot plate, the reaction solution was poured into saturated ammonium chloride solution / ethyl acetate (300 mL / 300 mL), the liquids were separated, the aqueous phase was extracted with ethyl acetate (200 mL x 3), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified using a thin-layer silica gel plate to obtain compound A1-2 (22.5 g, yield: 67%).

[0215] Step 2: Preparation of methyl 2-(5-bromopyridine-2-yl)acetate At room temperature, compound A1-2 (30 g, 152 mmol) was added to anhydrous methanol (200 mL), concentrated sulfuric acid (25 mL, 457 mmol) was slowly added dropwise, and the mixture was heated under reflux and stirred for 24 hours. After detecting the end of the reaction with a spot plate, the reaction solution was concentrated under reduced pressure to remove methanol, the residue was dissolved in dichloromethane (500 mL), the organic phase was sequentially washed with water (200 mL), saturated sodium bicarbonate solution (200 mL), and saturated brine (200 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified using a thin-layer silica gel plate to obtain compound A1-3 (31 g, yield: 88%).

[0216] Step 3: Preparation of N-benzyl-2-(5-bromopyridine-2-yl)acetamide At room temperature, benzylamine (39.1 g, 365 mmol) was added to compound A1-3 (28 g, 122 mmol), then heated to 125°C and stirred for 15 hours. After detecting the end of the reaction with a spot plate, the reaction solution was cooled to room temperature, and ethyl acetate / petroleum ether (100 mL / 100 mL) was slowly added while stirring. The precipitated solid was filtered to obtain compound A1 (yellow solid, 28.5 g, yield: 77%).

[0217] 1 H NMR (400 MHz, DMSO-d6): δ 8.66-8.53 (m, 2H), 7.97 (dd, J = 8.3, 2.5 Hz, 1H), 7.38-7.19 (m, 6H), 4.26 (d, J = 5.9 Hz, 2H), 3.66 (s, 2H). LC-MS, M / Z (ESI): 306.9 [M+H] + .

[0218] Preparation of intermediate A2: N-benzyl-2-(5-(tributylstannyl)pyridine-2-yl)acetamide The synthesis route is as follows:

[0219] [ka]

[0220] At room temperature, intermediate A1 (15 g, 49.2 mmol) was added to 1,4-dioxane (300 mL), followed by the addition of lithium chloride (6.2 g, 147 mmol). Under nitrogen gas protection, 1,1,1,2,2,2-hexabutyldistannane (29.8 mL, 59.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.84 g, 2.46 mmol) were added. Then, the mixture was heated to 110 °C and stirred for 15 hours. After detecting the completion of the reaction by spot plate, the reaction solution was cooled to room temperature, the solvent was concentrated under reduced pressure, water (500 mL) was added for dilution, and the mixture was extracted with ethyl acetate (200 mL × 3). The layers were separated, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain intermediate A2 (10.5 g, yield: 41.5%).

[0221] 1 H NMR (400 MHz, CDCl3): δ 8.01 (s, 3H), 7.71 (dd, J = 7.5, 1.6 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.24 - 7.20 (m, 3H), 4.47 (d, J = 5.8 Hz, 2H), 3.74 (s, 2H), 1.56 - 1.47 (m, 5H), 1.31 (ddd, J = 22.6, 14.9, 7.3Hz, 7H), 1.08 (dd, J = 9.5, 6.8 Hz, 6H), 0.87 (t, J = 7.3 Hz, 9H). LC-MS, M / Z (ESI): 517.3 [M+H] + 。

[0222] Example 1 Preparation of Compound I-1 The synthetic route is as follows:

[0223]

Chemical Structure

[0224] Step 1: Preparation of 1-bromo-4-(2-bromoethoxy)-2-fluorobenzene 4-Bromo-3-fluorophenol (1 g, 5.24 mmol), 1,2-dibromoethane (5.90 g, 31.4 mmol), and potassium carbonate (4.41 g, 31.9 mmol) were dissolved in acetone (30 mL), and the mixture was heated to 80°C and reacted for 18 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was separated by column chromatography (petroleum ether:ethyl acetate (V / V) = 30:1) to obtain 1-bromo-4-(2-bromoethoxy)-2-fluorobenzene (1.3 g, colorless oil, yield: 83%).

[0225] Step 2: Preparation of (3aR,6aS)-5-(2-(4-bromo-3-fluorophenoxy)ethyl)hexahydro-1H-fl[3,4-c]pyrrole 1-Bromo-4-(2-bromoethoxy)-2-fluorobenzene (1.3 g, 4.36 mmol) was dissolved in dry acetonitrile (30 mL), and (3aR,6aS)-hexahydro-1H-fl[3,4-c]pyrrole hydrochloride (718 mg, 4.80 mmol) and potassium carbonate (1.809 g, 13.09 mmol) were added. The mixture was heated to 80°C and reacted for 20 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain (3aR,6aS)-5-(2-(4-bromo-3-fluorophenoxy)ethyl)hexahydro-1H-fl[3,4-c]pyrrole (1.1 g, yellow oily substance, yield: 76%).

[0226] LC-MS, M / Z (ESI): 330.0 [M+H] + . Step 3: Preparation of N-benzyl-2-(5-(2-fluoro-4-(2-((3aR,6aS)-tetrahydro-1H-fluoro[3,4-c]pyrrole-5(3H)-yl)ethoxy)phenyl)pyridine-2-yl)acetamide (I-1)

[0227] [ka]

[0228] (3aR,6aS)-5-(2-(4-bromo-3-fluorophenoxy)ethyl)hexahydro-1H-fl[3,4-c]pyrrole (150 mg, 0.454 mmol) was dissolved in dried 1,4-dioxane (5 mL), and N-benzyl-2-(5-(tributylstannyl)pyridine-2-yl)acetamide (281 mg, 0.545 mmol) and bis(triphenylphosphine)palladium(II) dichloride (31.9 mg, 0.045 mmol) were added. The mixture was purged three times with argon gas, and the temperature was raised to 100°C under argon gas protection and the mixture was reacted for 4 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), extracted with dichloromethane (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated by silica gel plate (ethyl acetate:methanol (V / V) = 20:1, NH3·H2O) to obtain N-benzyl-2-(5-(2-fluoro-4-(2-((3aR,6aS)-tetrahydro-1H-furan[3,4-c]pyrrole-5(3H)-yl)ethoxy)phenyl)pyridine-2-yl)acetamide(I-1) (25 mg, yield: 11.57%).

[0229] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (br,2H),7.86 (m,1H),7.49~6.92(m,9H),4.30(m,2H),4.12(m,2H),3.72(m,4H),3.39(m,2H),2.75~2.68(m,6H),2.39(m,2H). LC-MS, M / Z (ESI): 476.2 [M+H] + .

[0230] Example 2 Preparation of Compound I-2 The synthesis route is as follows:

[0231] [ka]

[0232] Step 1: Synthesis of 1-bromo-4-(2-bromoethoxy)-2-methylbenzene 4-bromo-3-methylphenol (1 g, 5.37 mmol), 1,2-dibromoethane (5.99 g, 32.2 mmol), and potassium carbonate (4.45 g, 32.2 mmol) were dissolved in acetone (30 mL), heated to 80°C, and refluxed for 18 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was separated by column chromatography (petroleum ether:ethyl acetate (V / V) = 30:1) to obtain 1-bromo-4-(2-bromoethoxy)-2-methylbenzene (1.3 g, colorless oil, yield: 82.8%).

[0233] Step 2: (3aR,6aS)-5-(2-(4-bromo-3-methylphenoxy)ethyl)hexahydro-1H-fl[3,4-c]pyrrole 1-Bromo-4-(2-bromoethoxy)-2-methylbenzene (1.3 g, 4.45 mmol) was dissolved in dry acetonitrile (30 mL), and (3aR,6aS)-hexahydro-1H-fl[3,4-c]pyrrole hydrochloride (730 mg, 4.90 mmol) and potassium carbonate (1.844 g, 13.36 mmol) were added. The mixture was heated to 80°C and reacted for 20 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain (3aR,6aS)-5-(2-(4-bromo-3-methylphenoxy)ethyl)hexahydro-1H-fl[3,4-c]pyrrole (1.0 g, yellow oily substance, yield: 69.1%).

[0234] LC-MS, M / Z (ESI): 326.0 [M+H] + . Step 3: N-benzyl-2-(5-(2-methyl-4-(2-((3aR,6aS)-tetrahydro-1H-fluoro[3,4-c]pyrrole-5(3H)-yl)ethoxy)phenyl)pyridine-2-yl)acetamide(I-2)

[0235] [Chemical formula]

[0236] (3aR,6aS)-5-(2-(4-Bromo-3-methylphenoxy)ethyl)hexahydro-1H-furo[3,4-c]pyrrole (150 mg, .460 mmol) was dissolved in dry 1,4-dioxane (5 mL), and N-benzyl-2-(5-(tributylstannyl)pyridin-2-yl)acetamide (355 mg, 0.690 mmol) and bis(triphenylphosphine)palladium(II) dichloride (32.3 mg, 0.046 mmol) were added. The mixture was purged with argon gas three times and then heated to 100 °C under argon gas protection and reacted for four hours. The reaction solution was cooled to room temperature, diluted by adding water (50 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the residue was separated by silica gel plate (ethyl acetate:methanol (V / V) = 20:1, NH3·H2O) to obtain N-benzyl-2-(5-(2-methyl-4-(2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)ethoxy)phenyl)pyridin-2-yl)acetamide (I-2) (20 mg, yield: 9.22%).

[0237] 1 H NMR (400 MHz, DMSO-d6): δ 8.62 (t, 1H), 8.41 (d, 1H), 7.70 - 6.83 (m, 10H), 4.30 (d, 2H), 4.07 (t, 2H), 3.78 - 3.62 (m, 4H), 3.39 - 3.37 (m, 2H), 2.75 - 2.61 (m, 6H), 2.39 - 2.37 (m, 2H), 2.21 (s, 3H). LC-MS, M / Z (ESI): 472.2 [M+H] + .

[0238] Example 3 Preparation of Compound I-3 The synthetic route is as follows:

[0239] [ka]

[0240] Step 1: Preparation of 4-(2-(4-bromophenoxy)ethyl)thiomorpholine 1,1-dioxide At room temperature, 1-bromo-4-(2-bromoethoxy)benzene (2.8 g, 10.0 mmol), K2CO3 (4.14 g, 30 mmol), and thiomorpholine 1,1-dioxide (1.5 g, 11.0 mmol) were added to acetonitrile (30 ml) and stirred at 85°C for 12 hours under nitrogen gas protection. After the reaction was complete, the mixture was diluted with water (100 mL), extracted with ethyl acetate (30 mL x 3), the liquid was separated, and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified on a thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V) = 2:3) to obtain 4-(2-(4-bromophenoxy)ethyl)thiomorpholine 1,1-dioxide (2.5 g, white solid, yield: 75%).

[0241] Step 2: Preparation of 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)thiomorpholine 1,1-dioxide Compounds 4-(2-(4-bromophenoxy)ethyl)thiomorpholine 1,1-dioxide (2.0 g, 6.0 mmol), bis(pinacolate)diborone (2.28 g, 9.0 mmol), potassium acetate (1.76 g, 18.0 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.4 g, 0.6 mmol) were added to 1,4-dioxane (20 mL), the mixture was purged with nitrogen gas, the temperature was raised to 85°C, and the mixture was stirred for 10 hours. The mixture was diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3), the liquids were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified using a thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V) = 1:2) to obtain 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)thiomorpholine 1,1-dioxide (1.1 g, white solid, yield: 70%).

[0242] Step 3: Preparation of N-benzyl-2-(5-(4-(2-(1,1-dioxothiomorpholine)ethoxy)phenyl)pyridine-2-yl)acetamide

[0243] [ka]

[0244] 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)thiomorpholine 1,1-dioxide (300 mg, 0.79 mmol), N-benzyl-2-(5-bromopyridine-2-yl)acetamide (287 mg, 0.95 mmol), tetrakis(triphenylphosphine)palladium (0) (80 mg, 0.071 mmol), and sodium carbonate (254 mg, 2.40 mmol) were added to ethylene glycol dimethyl ether (3 ml) and water (0.5 ml), and the mixture was heated to 100°C and stirred for 12 hours. The mixture was diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the liquid was separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified using a thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V) = 1:2), and then purified by preparative liquid chromatography to obtain the product N-benzyl-2-(5-(4-(2-(1,1-dioxothiomorpholine)ethoxy)phenyl)pyridine-2-yl)acetamide(I-3) (70 mg, yield: 46.4%).

[0245] 1 H NMR (400 MHz, CDCl3) δ 8.70 (d, 1H), 7.81 (dd, 1H), 7.59 (s, 1H), 7.50 (t, 2H), 7.35 - 7.30 (m, 2H), 7.25 (d, 4H), 6.99 (d, 2H), 4.49 (d, 2H), 4.14 (t, 2H), 3.82 (s, 2H), 3.22 - 3.14 (m, 4H), 3.12 - 3.05 (m, 4H), 3.02 (t, 2H). LC-MS, M / Z (ESI): 480.2[M+H] + .

[0246] Example 4 Preparation of Compound I-4 The synthesis route is as follows:

[0247] [ka]

[0248] Step 1: Preparation of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol At room temperature, the compounds 4-bromo-3-fluorophenol (5.0 g, 24.10 mmol), KOAc (9.99 g, 72.3 mmol), bis(pinacolate)diborone (12.24 g, 48.2 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.76 g, 2.41 mmol) were added to dioxane (80 mL), and the mixture was stirred at 85°C for 12 hours under nitrogen gas protection. After the reaction was complete, the mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), separated the liquid, combined with the organic phase, dried the organic phase over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified using a thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V) = 2:3) to obtain compound 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.8 g, white solid, yield: 60.1%).

[0249] Step 2: Preparation of N-benzyl-2-(5-(2-fluoro-4-hydroxyphenyl)pyridine-2-yl)acetamide The compounds 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.1 g, 8.25 mmol), N-benzyl-2-(5-bromopyridine-2-yl)acetamide (2.77 g, 9.08 mmol), potassium carbonate (3.42 g, 24.75 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.065 g, 0.089 mmol) were added to dioxane (30 mL), the mixture was purged with nitrogen gas, the temperature was raised to 85°C, and the mixture was stirred for 10 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (30 mL x 3), the liquids were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by chromatography column chromatography (petroleum ether:ethyl acetate (V / V) = 3:2) to obtain the compound N-benzyl-2-(5-(2-fluoro-4-hydroxyphenyl)pyridine-2-yl)acetamide (2.6 g, white solid, yield: 42.4%).

[0250] LC-MS, M / Z (ESI): 337.3[M+H] + . Step 3: Preparation of N-benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridine-2-yl)acetamide N-benzyl-2-(5-(2-fluoro-4-hydroxyphenyl)pyridine-2-yl)acetamide (0.14 g, 0.416 mmol), 1,2-dibromoethane (0.469 g, 2.497 mmol), and potassium carbonate (0.345 g, 2.497 mmol) were placed in acetonitrile (3 mL), heated to 85°C, and stirred for 12 hours. The mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL x 3), the liquid was separated, and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain the compound N-benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridine-2-yl)acetamide (0.14 g, white solid, yield: 76%).

[0251] Step 4: Preparation of 2-(5-(4-(2-(2-oxo-6-azapiro[3.3]heptan-6-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-benzylacetamide (I-4)

[0252] [ka]

[0253] N-benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridine-2-yl)acetamide (0.14 g, 0.316 mmol), 2-oxa-6-azaspiro[3.3]heptane (0.063 g, 0.632 mmol), and potassium carbonate (0.131 g, 0.947 mmol) were added to acetonitrile (3 mL), and the reaction solution was heated to 85°C and stirred for 12 hours. The mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL x 3), the liquids were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by preparative high-performance liquid chromatography to obtain compound 2-(5-(4-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-2-fluorophenyl)pyridine-2-yl)-N-benzylacetamide (I-4) (8.6 mg, yield: 5.9%).

[0254] 1 H NMR (400 MHz,CDCl3) δ 8.64 (s, 1H), 7.80 (d, 1H), 7.67 (s, 1H), 7.33 (dd, 2H), 7.30 (d, 1H), 7.28 (s, 1H), 7.24 (dt, 3H), 6.75 (m, 2H), 4.75 (s, 4H), 4.47 (t, 2H), 3.98 (t, 2H), 3.82 (s, 2H), 3.49 (s, 4H), 2.80 (t, 2H). LC-MS, M / Z (ESI): 462.1 [M+H] + .

[0255] Example 5: Preparation of Compound I-5 The synthesis route is as follows:

[0256] [ka]

[0257] Step 1: Preparation of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol At room temperature, 4-bromo-3-methylphenol (5 g, 26.7 mmol) and bis(pinacolate)diborone (10.2 g, 40.1 mmol) were added to 1,4-dioxane (70 mL), then potassium acetate (6.56 g, 66.8 mmol) was added, and under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (950 mg, 1.3 mmol) was added, and the mixture was heated to 95 °C and stirred for 6 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified using a thin-layer silica gel plate (petroleum ether:ethyl acetate (V / V) = 5:1) to obtain compound 2-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butan-2-ol (6.1 g, yield: 97%).

[0258] Step 2: Preparation of N-benzyl-2-(5-(4-hydroxy-2-methylphenyl)pyridine-2-yl)acetamide At room temperature, the compounds 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.15 g, 4.92 mmol) and N-benzyl-2-(5-bromopyridine-2-yl)acetamide (1.0 g, 3.33 mmol) were added to 1,4-dioxane / water (10 mL / 1 mL), then potassium fluoride (0.760 g, 13.1 mmol) was added, and under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (117 mg, 0.16 mmol) was added, and the mixture was heated to 90°C and stirred for 10 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (CH2Cl2:MeOH(V / V)=95:5) to obtain compound N-benzyl-2-(5-(4-(3-hydroxy-3-methylbutoxy)phenyl)pyridine-2-yl)acetamide (850 mg, yield: 78%).

[0259] Step 3: Preparation of N-benzyl-2-(5-(4-(2-bromoethoxy)-2-methylphenyl)pyridine-2-yl)acetamide At room temperature, N-benzyl-2-(5-(2-methyl-4-hydroxyphenyl)pyridine-2-yl)acetamide (0.6 g, 1.8 mmol) and potassium carbonate (1.5 g, 10.7 mmol) were added to anhydrous acetonitrile (15 mL), heated to 80°C, and stirred for 1 hour. Then, 1,2-dibromoethane (2.01 g, 10.7 mmol) was added, and the mixture was stirred at 80°C for 10 hours. The reaction solution was cooled to room temperature, concentrated, and the solvent was removed to obtain the crude product. This crude product was separated and purified by silica gel column chromatography (DCM:MeOH(V / V)=95:5) to obtain the compound N-benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridine-2-yl)acetamide (0.55 g, yield: 69%).

[0260] Step 4: Preparation of 2-(5-(4-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)-N-benzylacetamide (I-5)

[0261] [ka]

[0262] N-benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridine-2-yl)acetamide (500.0 mg, 1.14 mmol) was dissolved in acetonitrile (5.0 mL) in a 100.0 mL neck flask, then potassium carbonate (786.4 mg, 5.69 mmol) was added, followed by the dropwise addition of 2-oxa-6-azaspiro[3.3]heptane (124.1 mg, 1.25 mmol). The reaction system was then heated to 85°C and stirred for 16 hours. After the reaction was complete, the mixture was filtered, the mother liquor was spin-dried, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1 to 1:1) to obtain 2-(5-(4-(2-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethoxy)-2-methylphenyl)pyridine-2-yl)-N-benzylacetamide (340.0 mg, yield: 65.3%).

[0263] 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (t, 1H), 8.42 (d, 1H), 7.70 (dd, 1H), 7.39 (d, 1H), 7.36 - 7.19 (m, 5H), 7.14 (d, 1H), 6.88 (d, 1H), 6.83 (dd, 1H), 4.60 (s, 4H), 4.31 (d, 2H), 3.93 (t, 2H), 3.73 (s, 2H), 3.35 (s, 4H), 2.68 (t, 2H), 2.22 (s, 3H). LC-MS, M / Z (ESI): 458.05[M+H] + .

[0264] The following compounds were prepared by referring to the preparation methods for other compounds of the present invention.

[0265] [Table 1] TIFF0007897940000069.tif245170TIFF0007897940000070.tif222170TIFF0007897940000071.tif191170

[0266] Example 18 Preparation of Compound I-18 The synthesis route is as follows:

[0267] [ka]

[0268] Step 1: Preparation of N-benzyl-2-(5-(4-(2-bromoethoxy)phenyl)pyridine-2-yl)acetamide N-benzyl-2-(5-(4-hydroxyphenyl)pyridine-2-yl)acetamide (0.5 g, 1.56 mmol), 1,2-dibromoethane (1.75 g, 9.35 mmol), and potassium carbonate (1.29 g, 9.35 mmol) were added to acetonitrile (6 mL), and the reaction solution was heated to 85°C and stirred for 12 hours. The mixture was diluted with water (10 mL), extracted with ethyl acetate (5 mL x 3), the liquid was separated, and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain compound N-benzyl-2-(5-(4-(2-bromoethoxy)phenyl)pyridine-2-yl)acetamide (0.4 g, white solid, yield: 60.0%).

[0269] Step 2: Preparation of 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide At room temperature, 2-thia-6-azaspiro[3.3]heptane-6-carboxylic acid tert-butyl ester 2,2-dioxide (0.2 g, 0.81 mmol) was added to anhydrous dichloromethane (2 mL), then trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, the solvent was concentrated to obtain the crude product 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide trifluoroacetate (0.21 g, yield: 100%), which was used directly in the next step.

[0270] Step 3: Preparation of N-benzyl-2-(5-(4-(2-(2,2-dioxide-2-thia-6-azapiro[3.3]heptan-6-yl)ethoxy)phenyl)pyridine-2-yl)acetamide (I-18)

[0271] [ka]

[0272] At room temperature, N-benzyl-2-(5-(4-(2-bromoethoxy)phenyl)pyridine-2-yl)acetamide (0.1 g, 0.23 mmol) was added to DMF (2 mL), then triethylamine (91 mg, 0.9 mmol), potassium iodide (150 mg, 0.9 mmol), and the crude product 2-thia-6-azaspiro[3.3]heptan-2,2-dioxidetrifluoroacetate (120 mg, 0.47 mmol) were added. The mixture was then stirred at 60°C for 8 hours, and after monitoring the completion of the reaction by TLC, the compound was purified by preparative high-performance liquid chromatography to obtain the compound N-benzyl-2-(5-(4-(2-(2,2-dioxide-2-thia-6-azaspiro[3.3]heptan-6-yl)ethoxy)phenyl)pyridine-2-yl)acetamide (68.1 mg, yield: 59%).

[0273] 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, 1H), 8.61 (t, 1H), 7.96 (dd, 1H), 7.64 (d, 2H), 7.39 (d, 1H), 7.34 - 7.20 (m, 5H), 7.02 (d, 2H), 4.37-4.25 (m, 6H), 3.99 (t, 2H), 3.70 (s, 2H), 3.42 (s, 4H), 2.77 (t, 2H). LC-MS, M / Z (ESI): 492.2 [M+H] + .

[0274] Example 24 Preparation of compounds I-24A and I-24B The synthesis route is as follows:

[0275] [ka]

[0276] Step 1: Preparation of N-benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridine-2-yl)acetamide At room temperature, N-benzyl-2-(5-(2-fluoro-4-hydroxyphenyl)pyridine-2-yl)acetamide (0.6 g, 1.8 mmol) and potassium carbonate (1.5 g, 10.7 mmol) were added to anhydrous acetonitrile (15 mL), heated to 80°C, and stirred for 1 hour. Then, 1,2-dibromoethane (2.01 g, 10.7 mmol) was added, and the mixture was continued to heat and stirred at 80°C for 10 hours. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, evaporated using a rotary evaporator, and the solvent was concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography to obtain the compound N-benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridine-2-yl)acetamide (0.55 g, yield: 69%).

[0277] Step 2: Preparation of (S)-N-benzyl-2-(5-(2-fluoro-4-(2-(3-methylmorpholino)ethoxy)phenyl)pyridine-2-yl)acetamide

[0278] [ka]

[0279] At room temperature, N-benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridine-2-yl)acetamide (0.1 g, 0.23 mmol) was added to N,N-dimethylformamide (2 mL), then triethylamine (91 mg, 0.9 mmol), potassium iodide (150 mg, 0.9 mmol), and (S)-3-methylmorpholine (34 mg, 0.34 mmol). The mixture was then stirred at 60°C for 8 hours, and the reaction solution was purified by preparative high-performance liquid chromatography to obtain the compound (S)-N-benzyl-2-(5-(2-fluoro-4-(2-(3-methylmorpholino)ethoxy)phenyl)pyridine-2-yl)acetamide (I-24A) (18.9 mg, yield: 18%).

[0280] 1 H NMR (400 MHz, DMSO-d6)δ 8.68 - 8.56 (m, 2H), 7.86 (d, 1H), 7.50 (t, 1H), 7.43(d, 1H), 7.36 - 7.19 (m, 5H), 7.03 - 6.88 (m, 2H), 4.30 (d, 2H), 4.13 (t, 2H), 3.72 (s, 2H), 3.70 - 3.64 (m, 1H), 3.59 (dd, 1H), 3.52 - 3.43 (m, 1H), 3.06 (ddd, 2H), 2.80 (dt, 1H), 2.68 - 2.56 (m, 1H), 2.47 - 2.34 (m, 2H), 0.93 (t, 3H). LC-MS, M / Z (ESI): 464.3 [M+H] + Step 3: Preparation of (R)-N-benzyl-2-(5-(2-fluoro-4-(2-(3-methylmorpholino)ethoxy)phenyl)pyridine-2-yl)acetamide

[0281] [ka]

[0282] At room temperature, N-benzyl-2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridine-2-yl)acetamide (0.1 g, 0.23 mmol) was added to DMF (2 mL), then triethylamine (91 mg, 0.9 mmol), potassium iodide (150 mg, 0.9 mmol), and (R)-3-methylmorpholine (34 mg, 0.34 mmol). The mixture was then stirred at 60°C for 8 hours. After monitoring the completion of the reaction by TLC, the compound (R)-N-benzyl-2-(5-(2-fluoro-4-(2-(3-methylmorpholino)ethoxy)phenyl)pyridine-2-yl)acetamide (I-24B) (19.9 mg, yield: 19%).

[0283] 1H NMR (400 MHz, DMSO-d6) δ 8.63 (dd, J = 11.8, 5.6 Hz, 2H), 7.86 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 9.0Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.35 - 7.20 (m, 5H), 6.99 (dd, J = 12.9, 2.2 Hz, 1H), 6.92 (dd, J = 8.6,2.1 Hz, 1H), 4.30 (d, J = 5.9 Hz, 2H), 4.13 (t, J = 5.9 Hz, 2H), 3.73 (s, 2H), 3.67 (d, J = 11.1 Hz, 1H),3.59 (dd, J = 11.0, 2.9 Hz, 1H), 3.47 (td, J = 11.7, 5.6 Hz, 1H), 3.14 - 3.00 (m, 2H), 2.80 (d, J = 11.8 Hz,1H), 2.61 (dt, J = 13.5, 5.6 Hz, 1H), 2.47 - 2.35 (m, 2H), 0.94 (d, J = 6.2 Hz, 3H) LC-MS, M / Z (ESI): 464.3 [M+H] + .

[0284] Example 26 Preparation of Compound I-26 The synthesis route is as follows:

[0285] [ka]

[0286] Step 1: Preparation of tert-butyl(1-(2-cyclopropylacetyl)azetidine-3-yl)carbamate At room temperature, add 2-cyclopropylacetic acid (0.35 g, 3.5 mmol) to anhydrous dichloromethane (15 mL), then add 3-(((ethylimino)methylene)amino)-N,N-dimethylpropane-1-amine hydrochloride (0.67 g, 3.5 mmol) and 1H-benzo[d][1,2,3]triazole-1-ol (0.54 g, 3.5 mmol), stir at room temperature for 10 minutes, then add tert-butylazetidine-3-ylcarbamate (0.5 g, 2.9 mmol) The mixture was then mixed with ) and stirred at room temperature for 5 hours. After detecting the end of the reaction on a spot plate, the reaction solution was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate solution / saline solution (50 mL / 50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified using a thin-layer silica gel plate to obtain the compound tert-butyl(1-(2-cyclopropylacetyl)azetidine-3-yl)carbamate (0.6 g, yield: 81%).

[0287] Step 2: Preparation of 1-(3-aminoazetidine-1-yl)-2-cyclopropylethane-1-one At room temperature, tert-butyl(1-(2-cyclopropylacetyl)azetidine-3-yl)carbamate (0.6 g, 2.4 mmol) was added to anhydrous 1,4-dioxane (2 mL), and then hydrochloric acid / 1,4-dioxane (4.7 mL, 4 M) was added while stirring. The mixture was stirred at room temperature for 2 hours, and after detecting the end of the reaction with a spot plate, the solvent was concentrated by evaporation using a rotary evaporator to obtain compound 1-(3-aminoazetidine-1-yl)-2-cyclopropylethane-1-one hydrochloride (0.45 g, yield: 100%).

[0288] Step 3: Preparation of 1-(3-((2-(4-bromophenoxy)ethyl)amino)azetidine-1-yl)-2-cyclopropylethane-1-one At room temperature, 1-(3-aminoazetidine-1-yl)-2-cyclopropylethane-1-one hydrochloride (0.45 g, 2.4 mmol) was added to acetonitrile (5 mL), then potassium carbonate (0.98 g, 7.2 mmol) and 1-bromo-4-(2-bromoethoxy)benzene (0.73 g, 2.6 mmol) were added, and the mixture was stirred at 30°C for 8 hours. After detecting the end of the reaction with a spot plate, the solvent was concentrated by evaporation using a rotary evaporator, the residue was diluted with ethyl acetate (50 mL), washed with water / saline solution (50 mL / 50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by thin-layer silica gel column chromatography to obtain compound 1-(3-((2-(4-bromophenoxy)ethyl)amino)azetidine-1-yl)-2-cyclopropylethane-1-one (0.2 g, yield: 24%).

[0289] Step 4: Preparation of N-benzyl-2-(5-(4-(2-((1-(2-cyclopropylacetyl)azetidine-3-yl)amino)ethoxy)phenyl)pyridine-2-yl)acetamide (I-26)

[0290] [ka]

[0291] At room temperature, the compounds 1-(3-((2-(4-bromophenoxy)ethyl)amino)azetidine-1-yl)-2-cyclopropylethane-1-one (60 mg, 0.17 mmol) and N-benzyl-2-(5-(tributylstannyl)pyridine-2-yl)acetamide (110 mg, 0.21 mmol) were added to toluene (2 mL), and under nitrogen gas protection, tetrakis(triphenylphosphine)palladium (0) (20 mg, 0.017 mmol) was added, and the mixture was heated to 100 °C and stirred for 10 hours. The solution was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was prepared by basic preparation to obtain compound N-benzyl-2-(5-(4-(3-hydroxy-3-methylbutoxy)phenyl)pyridine-2-yl)acetamide (I-26) (10.7 mg, yield: 9.1%).

[0292] 1 H NMR (400 MHz, CDCl3) δ8.71 (dd, J = 8.1, 2.2 Hz, 1H), 7.85 - 7.78 (m, 1H), 7.62 (s, 1H), 7.50 (d, J= 8.7 Hz, 2H), 7.32 (dd, J = 14.5, 7.3 Hz, 3H), 7.24 (d, J = 2.3 Hz, 2H), 7.00 (t, J = 9.2 Hz, 2H), 4.49 (d, J= 5.8 Hz, 2H), 4.34 - 4.18 (m, 2H), 4.11 (t, J = 5.0 Hz, 2H), 3.85 (dd, J = 8.9, 4.6 Hz, 1H), 3.82 (s, 2H),3.80 - 3.71 (m, 2H), 3.01 (h, J = 9.3 Hz, 2H), 2.04 (t, J = 6.6 Hz, 2H), 1.10 - 1.00 (m, 1H), 0.60 - 0.51(m, 2H), 0.15 (q, J = 4.8 Hz, 2H). LC-MS, M / Z (ESI): 499.2 [M+H] + .

[0293] Example 27 Preparation of Compound I-27 The synthesis route is as follows:

[0294] [ka]

[0295] Step 1: Preparation of 2-bromo-5-(2-morpholinoethoxy)benzonitrile 4-(2-chloroethyl)morpholine (0.783 g, 4.21 mmol), 2-bromo-5-hydroxybenzonitrile (1 g, 5.05 mmol), and potassium carbonate (2.036 g, 14.73 mmol) were dissolved in acetonitrile (10 mL), and the mixture was heated to 80°C and reacted for 10 hours. The reaction solution was cooled to room temperature, and aqueous sodium chloride (100 mL) and ethyl acetate (100 mL) were added. The liquid was separated, the organic phase was concentrated, and then separated by column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain compound 2-bromo-5-(2-morpholinoethoxy)benzonitrile (1.21 g, brown solid, yield: 92%).

[0296] Step 2: N-benzyl-2-(5-(2-cyano-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide

[0297] [ka]

[0298] 2-Bromo-5-(2-morpholinoethoxy)benzonitrile (100 mg, 0.32 mmol), N-benzyl-2-(5-(tributylstannyl)pyridine-2-yl)acetamide (248 mg, 0.482 mmol), and bis(triphenylphosphine)palladium(II) dichloride (22.56 mg, 0.032 mmol) were dissolved in dried 1,4-dioxane (15 mL), nitrogen gas was added for protection, and the mixture was heated to 90°C and reacted for 10 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was then purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain N-benzyl-2-(5-(2-cyano-4-(2-morpholinoethoxy)phenyl)pyridine-2-yl)acetamide (I-27) (5 mg, yield: 3.41%).

[0299] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (dd, J = 14.2, 3.9 Hz, 2H), 7.93 (dd, J = 8.0, 2.3 Hz, 1H), 7.58 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.40 (dd, J = 8.7, 2.6 Hz, 1H), 7.34 - 7.26 (m, 4H), 7.23 (t, J = 7.0 Hz, 1H), 4.31 (d, J = 5.8 Hz, 2H), 4.21 (t, J = 5.6 Hz, 2H), 3.76 (s, 2H), 3.56 (dd, J = 14.5, 10.0 Hz, 4H), 2.71 (t, J = 5.6 Hz, 2H), 2.50 - 2.45 (m, 4H). LC-MS, M / Z (ESI): 457.2 [M+H] + .

[0300] Example 28 Preparation of Compound I-28

[0301] [ka]

[0302] The compound N-benzyl-2-(5-(4-(2-morpholinoethoxy)-2-(prop-1-in-1-yl)phenyl)pyridine-2-yl)acetamide (I-28) was prepared by referring to the preparation method for compound I-27. LC-MS, M / Z (ESI): 470.2[M+H] + .

[0303] Example 29 Preparation of Compound I-29 The synthesis route is as follows:

[0304] [ka]

[0305] Step 1: Preparation of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol At room temperature, 4-bromo-3,5-dimethylphenol (2 g, 9.95 mmol), potassium acetate (2.93 g, 29.8 mmol), bis(pinacolate)diborone (3.8 g, 14.9 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (364 mg, 0.49 mmol) were added to a reaction flask, purged three times with nitrogen gas, then 40 mL of the solvent dioxane was added, and the mixture was heated to 100°C and stirred for 10 hours. The completion of the reaction was monitored by TLC. The mixture was then cooled to room temperature, evaporated using a rotary evaporator to concentrate the solvent, dissolved the residue in ethyl acetate (100 mL), washed with water (50 mL) and saturated brine (50 mL), dried the organic layer over anhydrous sodium sulfate, evaporated using a rotary evaporator to obtain the crude N-benzyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)acetamide product (2.4 g, yield: 100%), and the crude product was used directly in the next step.

[0306] Step 2: Preparation of N-benzyl-2-(5-(4-hydroxy-2,6-dimethylphenyl)pyridine-2-yl)acetamide At room temperature, N-benzyl-2-(5-bromopyridine-2-yl)acetamide (0.45 g, 1.5 mmol), N-benzyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)acetamide crude product (0.55 g, 2.2 mmol), potassium fluoride (0.34 g, 5.9 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (108 mg, 0.15 mmol) The reaction flask was purged three times with nitrogen gas, then 20 mL of the solvent dioxane was added, and the mixture was heated to 85°C and stirred for 10 hours. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, and the solvent was concentrated by evaporation using a rotary evaporator to obtain the crude product. This crude product was purified by preparative high-performance liquid chromatography to obtain N-benzyl-2-(5-(4-hydroxy-2,6-dimethylphenyl)pyridine-2-yl)acetamide (0.35 g, yield: 68%).

[0307] Step 3: Preparation of N-benzyl-2-(5-(4-(2-bromoethoxy)-2,6-dimethylphenyl)pyridine-2-yl)acetamide At room temperature, N-benzyl-2-(5-(4-hydroxy-2,6-dimethylphenyl)pyridine-2-yl)acetamide (0.2 g, 0.58 mmol) and potassium carbonate (0.48 g, 3.46 mmol) were added to anhydrous acetonitrile (15 mL), heated to 85°C, and stirred for 1 hour. Then, 1,2-dibromoethane (0.65 g, 3.46 mmol) was added, and the mixture was continued to heat and stirred at 85°C for 10 hours. After monitoring the completion of the reaction by TLC, the mixture was cooled to room temperature, evaporated using a rotary evaporator, and the solvent was concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography to obtain the compound N-benzyl-2-(5-(4-(2-bromoethoxy)-2,6-dimethylphenyl)pyridine-2-yl)acetamide (0.2 g, yield: 76%).

[0308] Step 4: N-benzyl-2-(5-(2,6-dimethyl-4-(2((3aR,6aS)-tetrahydro-1H-fluoro[3,4-c]pyrrole-5(3H)-yl)ethoxy)phenyl)pyridine-2-yl)acetamide

[0309] [ka]

[0310] At room temperature, N-benzyl-2-(5-(4-(2-bromoethoxy)-2,6-dimethylphenyl)pyridine-2-yl)acetamide (0.2 g, 0.47 mmol) was added to N,N-dimethylformamide (2 mL), followed by triethylamine (191 mg, 1.81 mmol), potassium iodide (312 mg, 1.81 mmol), and (3aR,6aS)-hexahydro-1H-furan[3,4-c]pyrrole (53 mg, 0.47 mmol) was added, and the mixture was stirred at 60°C for 8 hours. After monitoring the completion of the reaction by TLC, the compound was purified by preparative high-performance liquid chromatography to obtain the compound N-benzyl-2-(5-(2,6-dimethyl-4-(2-((3aR,6aS)-tetrahydro-1H-fluoro[3,4-c]pyrrole-5(3H)-yl)ethoxy)phenyl)pyridine-2-yl)acetamide (59.5 mg, yield: 26%).

[0311] 1 H NMR (400 MHz,DMSO-d6) δ 8.64 (t, 1H), 8.25 (d, 1H), 7.53 (dd, 1H), 7.42 (d, 1H), 7.34 - 7.19 (m, 4H), 6.74 (s, 2H), 4.32 (d, 2H), 4.06 (t, 2H), 3.77 - 3.66 (m, 4H), 3.39 (dd, 2H), 2.74 (t, 2H), 2.71 - 2.66 (m, 2H),2.66 - 2.60 (m, 2H), 2.40 (dd, 2H), 1.95 (s, 6H). LC-MS, M / Z (ESI): 486.2 [M+H] +.

[0312] Example 30 Preparation of Compound I-30 The synthesis route is as follows:

[0313] [ka]

[0314] Step 1: Preparation of 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol At room temperature, the compounds 4-bromo-3-chlorophenol (5.0 g, 24.10 mmol), K2CO3 (9.99 g, 72.3 mmol), bis(pinacolate)diborone (12.24 g, 48.2 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.76 g, 2.41 mmol) were added to dioxane (80 mL), and the mixture was stirred at 85°C for 12 hours under nitrogen gas protection. After the reaction was complete, the mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), separated the liquid, combined with the organic phase, dried the organic phase over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate (V / V) = 2:3) to obtain compound 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.6 g, white solid, yield: 42.4%).

[0315] Step 2: Preparation of N-benzyl-2-(5-(2-chloro-4-hydroxyphenyl)pyridine-2-yl)acetamide The compounds 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.1 g, 8.25 mmol), N-benzyl-2-(5-bromopyridine-2-yl)acetamide (2.77 g, 9.08 mmol), potassium carbonate (3.42 g, 24.75 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.065 g, 0.089 mmol) were added to dioxane (30 mL), the mixture was purged with nitrogen gas, the temperature was raised to 85°C, and the mixture was stirred for 10 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (30 mL x 3), the liquids were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by chromatography column chromatography (petroleum ether:ethyl acetate (V / V) = 3:2) to obtain the compound N-benzyl-2-(5-(2-chloro-4-hydroxyphenyl)pyridine-2-yl)acetamide (2.6 g, white solid, yield: 42.4%).

[0316] Step 3: N-benzyl-2-(5-(4-(2-bromoethoxy)-2-chlorophenyl)pyridine-2-yl)acetamide N-benzyl-2-(5-(2-chloro-4-hydroxyphenyl)pyridine-2-yl)acetamide (0.55 g, 1.56 mmol), 1,2-dibromoethane (1.75 g, 9.35 mmol), and potassium carbonate (1.29 g, 9.35 mmol) were added to acetonitrile (6 mL), and the reaction solution was heated to 85°C and stirred for 12 hours. The mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL x 3), the liquid was separated, and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by chromatography column (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain the compound N-benzyl-2-(5-(4-(2-bromoethoxy)-2-chlorophenyl)pyridine-2-yl)acetamide (0.4 g, white solid, yield: 55.8%).

[0317] Step 4: N-benzyl-2-(5-(2-chloro-4-(2-((3aR,6aS)-tetrahydro-1H-fluoro[3,4-c]pyrrole-5(3H)-yl)ethoxy)phenyl))pyridine-2-yl)acetamide(I-30)

[0318] [ka]

[0319] N-benzyl-2-(5-(4-(2-bromoethoxy)-2-chlorophenyl)pyridine-2-yl)acetamide (0.2 g, 0.435 mmol), (3aR,6aS)-hexahydro-1H-fl[3,4-c]pyrrole (0.054 g, 0.479 mmol), and potassium carbonate (0.180 g, 1.30 mmol) were dissolved in acetonitrile (3 mL), heated to 85°C, and stirred for 12 hours. The mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL x 3), the liquids were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative high-performance liquid chromatography to obtain the compound N-benzyl-2-(5-(2-chloro-4-(2-((3aR,6aS)-tetrahydro-1H-fluoro[3,4-c]pyrrole-5(3H)-yl)ethoxy)phenyl))pyridine-2-yl)acetamide(I-30) (0.1 g, yield: 46.7%).

[0320] 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, 1H), 7.75 (dd, 1H), 7.68 (s, 1H), 7.28 (ddt, 6H), 7.06 (d, J = 2.5 Hz, 1H), 6.91 (dd, 1H), 4.50 (d, 2H), 4.13 (t, 2H), 3.83 (s, 2H), 3.77 (dd, 2H), 3.65 - 3.60 (m, 2H), 2.89 (t, 2H), 2.87 - 2.80 (m, 4H), 2.41 (dd, 2H). LC-MS, M / Z (ESI): 492.3 [M+H]+ .

[0321] Example 31 Preparation of Compound I-31 The synthesis route is as follows:

[0322] [ka]

[0323] Step 1: Preparation of 2-(5-bromopyridine-2-yl)-N-(2-fluorobenzyl)acetamide 30.0 g, 130.40 mmol of methyl 2-(5-bromopyridine-2-yl)acetate and 48.96 g, 391.20 mmol of 2-fluorobenzylamine were placed in a round-bottom flask, heated to 120°C, and stirred for 12 hours. The reaction solution was cooled to room temperature, petroleum ether / ethyl acetate (V / V = 3:1, 500 mL) was added, and the mixture was allowed to form a slurry at room temperature for 2 hours. The mixture was filtered, the cake was collected, and it was vacuum-dried to obtain 2-(5-bromopyridine-2-yl)-N-(2-fluorobenzyl)acetamide (35.2 g, yield: 83.0%).

[0324] LC-MS, M / Z (ESI): 323.1 [M+H] + . Step 2: Preparation of 2-(5-(2-fluoro-4-hydroxyphenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide 3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5.5 g, 21.61 mmol), 2-(5-bromopyridine-2-yl)-N-(2-fluorobenzyl)acetamide (6.98 g, 21.61 mmol), potassium carbonate (8.96 g, 64.83 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.96 g, 2.73 mmol) were dissolved in dioxane (120 mL) and water (3 mL), and the mixture was heated to 85°C and stirred for 12 hours. The mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL x 3), the liquid was separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by chromatography column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain 2-(5-(2-fluoro-4-hydroxyphenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (4.0 g, yield: 58.4%).

[0325] LC-MS, M / Z (ESI): 355.1 [M+H] + . Step 3: Preparation of 2-(5-(4-(2-bromoethoxy)-2-phenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide 2-(5-(2-fluoro-4-hydroxyphenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (5.0 g, 13.48 mmol), 1,2-dibromoethane (15.20 g, 80.90 mmol), and potassium carbonate powder (11.18 g, 80.90 mmol) were placed in acetonitrile (50.0 mL), and the reaction solution was heated to 85°C and stirred for 12 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), the liquids were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by chromatography column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain 2-(5-(4-(2-bromoethoxy)-2-phenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (3.0 g, yield: 58.0%).

[0326] LC-MS, M / Z (ESI): 461.1 [M+H] + . Step 4: Preparation of (R)-2-(5-(2-fluoro-4-(2-(3-methylmorpholino)ethoxy)phenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (I-31) At room temperature, 2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (0.6 g, 1.3 mmol) was added to MeCN (20 mL), then K2CO3 (540 mg, 3.9 mmol), potassium iodide (26 mg, 0.13 mmol), and (R)-3-methylmorpholine (170 mg, 1.7 mmol) were added sequentially, and the reaction solution was stirred at 80°C for 8 hours. After monitoring the disappearance of the starting materials by TLC, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH(V / V)=20:1) to obtain compound (R)-2-(5-(2-fluoro-4-(2-(3-methylmorpholino)ethoxy)phenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (I-31) (217.2 mg, yield: 34.6%).

[0327] 1 H NMR(400 MHz, DMSO-d6)δ 8.67 (s, 1H), 7.84 - 7.69 (m, 2H), 7.37 - 7.27(m, 3H), 7.25 - 7.20 (m, 1H), 7.10 - 6.99 (m, 2H), 6.83- 6.70 (m, 2H), 4.51 (dd, 2H), 4.16 - 4.06 (m, 2H), 3.85 - 3.78 (m, 3H), 3.73 - 3.62 (m, 2H), 3.27(dd, 1H), 3.20- 3.11 (m,1H), 2.90 - 2.81 (m, 1H), 2.80 - 2.70 (m, 1H), 2.62 - 2.51 (m, 2H), 1.04 (d, 3H). LC-MS, M / Z (ESI): 482.1 [M+H] + .

[0328] Example 32 Preparation of Compound I-32 The synthesis route is as follows:

[0329] [ka]

[0330] 2-(5-(4-(2-bromoethoxy)-2-fluorophenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (2.0 g, 4.19 mmol) and (S)-3-methylmorpholine (0.47 g, 4.19 mmol) were dissolved in acetonitrile (20.0 mL), potassium carbonate (1.74 g, 12.56 mmol) was added, and the reaction solution was heated to 85°C and stirred for 12 hours. The reaction solution was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), the liquids were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain (S)-2-(5-(2-fluoro-4-(2-(3-methylmorpholino)ethoxy)phenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (I-32) (200 mg, yield: 10%).

[0331] 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.83 - 7.78 (m, 1H), 7.77 - 7.70 (m, 1H), 7.37 - 7.19 (ddd, 4H), 7.10 - 6.99 (m, 2H), 6.78 (ddd, 2H), 4.53 (d, 2H), 4.16 - 4.08 (m, 2H), 3.86 - 3.75 (m, 3H), 3.73 - 3.62 (m, 2H), 3.27 (dd, 1H), 3.16 (dt, 1H), 2.85 (dt, 1H), 2.75 (dt, 1H), 2.61 - 2.50 (m, 2H), 1.04 (d, 3H). LC-MS, M / Z (ESI): 482.5 [M+H] + .

[0332] Example 33 Preparation of Compound I-33 The synthesis route is as follows:

[0333] [ka]

[0334] Step 1: N-(2-fluorobenzyl)-2-(5-(4-hydroxy-2-methylphenyl)pyridine-2-yl)acetamide At room temperature, the compounds 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.15 g, 4.92 mmol) and 2-(5-bromopyridine-2-yl)-N-(2-fluorobenzyl)acetamide (1.0 g, 3.33 mmol) were added to 1,4-dioxane / water (10 mL / 1 mL), then potassium fluoride (0.760 g, 13.1 mmol) was added, and under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (117 mg, 0.16 mmol) was added, and the reaction solution was heated to 90°C and stirred for 10 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3), the liquid was separated, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH(V / V)=95:5) to obtain compound N-(2-fluorobenzyl)-2-(5-(4-hydroxy-2-methylphenyl)pyridine-2-yl)acetamide (840 mg, yield: 76%).

[0335] LC-MS, M / Z (ESI): 351.4 [M+H] + . Step 2: Preparation of 2-(5-(4-(2-bromoethoxy)-2-methylphenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide At room temperature, N-(2-fluorobenzyl)-2-(5-(4-hydroxy-2-methylphenyl)pyridine-2-yl)acetamide (0.8 g, 2.3 mmol) and potassium carbonate (1.89 g, 13.7 mmol) were added to anhydrous acetonitrile (15 mL), heated to 80°C, and stirred for 1 hour. Then, 1,2-dibromoethane (2.55 g, 13.7 mmol) was added, and the reaction solution was stirred at 80°C for 10 hours. The reaction solution was cooled to room temperature, concentrated to remove the solvent, and the crude product was separated and purified by silica gel column chromatography (DCM:MeOH(V / V)=20:1) to obtain 2-(5-(4-(2-bromoethoxy)-2-methylphenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (0.6 g, yield: 69%).

[0336] Step 3: Preparation of N-(2-fluorobenzyl)-2-(5-(2-methyl-4-(2-((3aR,6aS)-tetrahydro-1H-fluoro[3,4-c]pyrrole-5(3H)-yl))ethoxy)phenyl)pyridine-2-yl)acetamide

[0337] [ka]

[0338] At room temperature, 2-(5-(4-(2-bromoethoxy)-2-methylphenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (0.6 g, 1.31 mmol) was added to MeCN (20 mL), then K2CO3 (543 mg, 3.94 mmol), potassium iodide (33 mg, 0.2 mmol), and (3aR,6aS)-hexahydro-1H-fl[3,4-c]pyrrole hydrochloride (255 mg, 1.7 mmol) were added, and the mixture was stirred at 80°C for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM:MeOH(V / V)=20:1) to obtain N-(2-fluorobenzyl)-2-(5-(2-methyl-4-(2-((3aR,6aS)-tetrahydro-1H-fluoro[3,4-c]pyrrole-5(3H)-yl))ethoxy)phenyl)pyridine-2-yl)acetamide(I-33) (248.3 mg, yield: 39%).

[0339] 1 H NMR(400 MHz,DMSO-d6)δ8.63 (t, 1H), 8.43 - 8.39 (m, 1H), 7.69 (m, 1H), 7.40 - 7.26 (m, 3H), 7.20 - 7.08 (m, 3H), 6.91 (d, 1H), 6.85 (m, 1H),4.34 (d, 2H), 4.07 (t, 2H), 3.75 - 3.64 (m, 4H), 3.38 (m, 2H), 2.74(t, 2H), 2.70 - 2.60 (m, 4H), 2.38 (dd, 2H), 2.21 (s, 3H) LC-MS, M / Z (ESI): 490.4 [M+H] + .

[0340] Example 34 Preparation of Compound I-34 The synthesis route is as follows:

[0341] [ka]

[0342] Step 1: Preparation of 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 4-Bromo-3-chlorophenol (6.0 g, 28.92 mmol), bis(pinacolate)diborone (11.02 g, 43.38 mmol), potassium acetate (8.582 g, 86.77 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.96 g, 2.73 mmol) were dissolved in dioxane (120 mL) and water (3 mL). The reaction solution was heated to 85°C and stirred for 12 hours. The mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL x 3), the liquids were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain a white solid 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5.5 g, yield: 74.0%).

[0343] LC-MS, M / Z (ESI): 255.1 [M+H] + . Step 2: Preparation of 2-(5-(2-chloro-4-hydroxyphenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide 3-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5.5 g, 21.61 mmol), 2-(5-bromopyridine-2-yl)-N-(2-fluorobenzyl)acetamide (6.98 g, 21.61 mmol), potassium carbonate (8.96 g, 64.83 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.96 g, 2.73 mmol) were added to 1,4-dioxane (120 mL) and water (3 mL). The reaction solution was heated to 85°C and stirred for 12 hours. The mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL x 3), the liquids were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to obtain a white solid 2-(5-(2-chloro-4-hydroxyphenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (5.0 g, yield: 62.4%).

[0344] LC-MS, M / Z (ESI): 371.1 [M+H] + . Step 3: Preparation of 2-(5-(4-(2-bromoethoxy)-2-chlorophenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (A6)

[0345] [ka]

[0346] 2-(5-(2-chloro-4-hydroxyphenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (5.0 g, 13.48 mmol), 1,2-dibromoethane (15.20 g, 80.90 mmol), and potassium carbonate powder (11.18 g, 80.90 mmol) were placed in acetonitrile (50 mL), and the reaction solution was heated to 85°C and stirred for 12 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), the liquids were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by chromatography column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain 2-(5-(4-(2-bromoethoxy)-2-chlorophenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (A6, 4.0 g, yield: 62.1%).

[0347] LC-MS, M / Z (ESI): 477.1 [M+H] + . Step 4: Preparation of 2-(5-(2-chloro-4-(2-((3aR,6aS)-tetrahydro-1H-fluoro[3,4-c]pyrrole-5(3H)-yl)ethoxy)phenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide

[0348] [ka]

[0349] 2-(5-(4-(2-bromoethoxy)-2-chlorophenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (A6, 2.0 g, 4.19 mmol), (3aR,6aS)-hexahydro-1H-fluoro[3,4-C]pyrrole hydrochloride (0.63 g, 4.19 mmol), and potassium carbonate (1.74 g, 12.56 mmol) were dissolved in acetonitrile (20.0 mL), and the reaction solution was heated to 85°C and stirred for 12 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), the liquids were separated, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was sequentially separated and purified by chromatography column chromatography (petroleum ether:ethyl acetate (V / V) = 1:1), and further purified by preparative high-performance liquid chromatography to obtain 2-(5-(2-chloro-4-(2-((3aR,6aS)-tetrahydro-1H-fluoro[3,4-c]pyrrole-5(3H)-yl)ethoxy)phenyl)pyridine-2-yl)-N-(2-fluorobenzyl)acetamide (I-34, 150 mg, yield: 7%).

[0350] 1 H NMR (400 MHz, CDCl3) δ 8.57 (d, 1H), 7.80 - 7.69 (m, 2H), 7.37 - 7.27 (m, 2H), 7.25 - 7.19 (m, 2H), 7.10 - 6.98 (m, 3H), 6.91 (dd, 1H), 4.54 (d, 2H), 4.14 (t, 2H), 3.82 (s, 2H), 3.79 - 3.72 (m, 2H), 3.64 (dd, 2H), 2.97 - 2.83 (m, 6H), 2.41 (dd, 2H). In the test examples of the present invention, control compound I (trade name: Tirbanibulin) is a dual-action inhibitor of Src kinase and tubulin polymerization, and has been approved by the FDA and the European Union as a topical treatment for actinic keratosis of the face or scalp. The preparation of control compound I was carried out with reference to patent WO2008 / 002676A2, and the structure of control compound I is as follows.

[0351] [ka]

[0352] Test Example 1: Inhibition of tubulin monomer polymerization Compound inhibition tests for tubulin monomer polymerization were performed using the Tubulin Polymerization Assay Kit (cytoskeleton, catalog number: BK011P).

[0353] Before testing, first place the 96-well plate (Corning Costar, catalog number: 3686) included in the kit into a microplate reader (MD, SpectraMax M5), heat to 37°C, maintain for 10 minutes, remove the 96-well plate, add 5 μL of 12.5 μM compound solution or blank solution, then place the 96-well plate back into the microplate reader and incubate at 37°C for 1 minute to raise the compound solution temperature to 37°C, remove the 96-well plate, and quickly add 50 μL of the reaction mixture prepared according to the supplier's instructions to each well, completing sample addition within 1 minute to avoid bubble formation, then immediately place the 96-well plate back into the microplate reader, shake for 5 seconds, and perform continuous detection at 37°C for 30-60 minutes using Kinetic mode, detecting every 30 seconds under conditions of 360 nm excitation light and 420 nm emission light, with detection time on the X axis and fluorescence signal value on the Y axis to obtain a tubulin monomer polymerization curve. As shown in Figure 1 and Table 1, the larger the Vmax value of the polymerization curve and the higher the maximum fluorescence signal value, the lower the inhibition efficiency of the compound.

[0354] [Table 2]

[0355] The results of the inhibition tests of the compounds against tubulin polymerization are shown in Figure 1 and Table 1. The results show that the Vmax value and maximum fluorescence signal value of the polymerization curve corresponding to the compounds of the present invention are significantly smaller, indicating that the compounds of the present invention significantly inhibit the polymerization of tubulin monomer and have superior inhibitory activity compared to control compound I.

[0356] Test Example 2: Cell proliferation inhibition test using compounds The inhibitory effects of small molecule compounds on cell proliferation were detected using proliferation tests of human cutaneous squamous cell carcinoma cells A-431 (ATCC, CRL-1555) and HT 297.T (ATCC, CRL-7782) derived from patients with actinic keratosis.

[0357] A-431 cells and HT297.T cells were cultured in DMEM medium containing 10% fetal bovine serum and grown in a 37°C, 5% CO2 incubator. Logarithmic phase cells were inoculated into 96-well cell culture plates at a rate of 1000 cells / well and 100 mL / well, and cultured overnight in a 37°C, 5% CO2 incubator. The following day, 100 mL of a gradient-diluted 2× test compound solution was added to each well, with DMSO as the positive control and 10 mL of staurosporine (Aladdin, S102392) as the negative control. The plates with the added compounds were cultured for 4 days in a 37°C, 5% CO2 incubator. After culture completion, fluorescence signal values ​​were measured using an Envision 2104 Multilabel Reader with a Steady-Glo® luciferase assay system (Promega, G9243) according to the supplier's instructions. The inhibition rate is calculated using the formula below, a curve is drawn with the logarithm of the inhibitor concentration on the X axis and the inhibition rate on the Y axis, and IC is generated using Graphpad 8.0. 50 I calculated it.

[0358] Inhibition % = (Signal in positive control group - Signal in test well) / (Signal in positive control group - Signal in negative control group) × 100

[0359] [Table 3]

[0360] [Table 4]

[0361] The results of the inhibition tests of the compounds against cell proliferation are shown in Tables 2 and 3. The results show that the compounds of the present invention can significantly inhibit cell proliferation, and in particular, their inhibitory effect on HT297.T cells derived from patients with actinic keratosis is significantly superior to that of control compound I. This indicates that the compounds of the present invention have a superior therapeutic effect against actinic keratosis.

[0362] Test Example 3: Thermodynamic Solubility Test A pH 7.4 phosphate buffer (PBS), a pH 6.5 FeSSIF solution, and a pH 1.6 FaSSGF solution were prepared. The compounds were accurately weighed and added to the prepared pH 7.4 phosphate buffer, pH 6.5 FeSSIF solution, and pH 1.6 FaSSGF solution to prepare a 4 mg / mL solution. The solutions were shaken at 1000 rpm for 1 hour and then incubated overnight at room temperature. The cultured solutions were centrifuged at 12000 rpm for 10 minutes to remove undissolved particles, and the supernatant was transferred to a new centrifuge tube. After appropriately diluting the supernatant, an acetonitrile solution containing an internal standard was added, and the concentration was quantified using a calibration curve prepared with the same matrix.

[0363] [Table 5]

[0364] The results of the thermodynamic solubility test are shown in Table 4. The results indicate that the compound of the present invention has greater thermodynamic solubility under neutral conditions and exhibits good drug discovery potential compared to control compound I.

[0365] Test Example 4: Pharmacokinetic Study For the pharmacokinetic study in mice, three male ICR mice weighing 20-25 g were used. After fasting overnight, they were administered via tail vein injection (1 mg / kg or 5 mg / kg), and blood samples were collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. Three other mice were taken and administered orally (5 mg / kg), and blood samples were collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. Blood samples were centrifuged at 6800 g at 2-8°C for 6 minutes to collect plasma, which was then stored at -80°C. Plasma was collected at each time point, mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm at 4°C for 10 minutes, the supernatant was collected, 3 times the volume of water was added and mixed, and an appropriate amount of the mixed solution was collected and subjected to LC-MS / MS analysis. Key pharmacokinetic parameters were analyzed using a non-compartment model in WinNonlin 7.0 software.

[0366] [Table 6]

[0367] [Table 7]

[0368] [Table 8]

[0369] The results of the mouse pharmacokinetic studies are shown in Tables 5, 6, and 7. The results showed that the compound of the present invention exhibited rapid metabolism, low potential systemic toxicity, and good drug discovery potential in mice compared to control compound I.

[0370] Test Example 5: Human Liver Microsome Stability Test Human liver microsome stability testing was performed by co-culturing the compound with human liver microsomes in vitro. First, the compound to be tested was prepared as a 10 mM stock solution in DMSO solvent, and then diluted to 0.5 mM with acetonitrile. Human liver microsomes (Corning) were diluted in microsome / buffer using PBS, and this solution was used to dilute the 0.5 mM compound to prepare the working solution. The concentration of the compound in the working solution was 1.5 μM, and the concentration of human liver microsomes was 0.75 mg / mL. Deep well plates were taken, 30 μL of the working solution was added to each well, and then 15 μL of preheated 6 mM NADPH solution was added to initiate the reaction, and the cells were incubated at 37°C. At 0, 5, 15, 30, and 45 minutes of incubation, 135 μL of acetonitrile was added to the corresponding well to stop the reaction. After stopping the reaction with acetonitrile at the last 45 minutes, the deep-well plate was vortex-shaked for 10 minutes (600 rpm / min), then centrifuged for 15 minutes. After centrifugation, the supernatant was taken, purified water was added in a 1:1 ratio, and LC-MS / MS detection was performed. The ratio of the peak area of ​​the compound to the peak area of ​​the internal standard at each time point was determined, and the peak area ratios of the compound at 5, 15, 30, and 45 minutes were compared to the peak area ratio at 0 minutes to calculate the remaining percentage of the compound at each time point. The results were then analyzed using Graphpad 5 software. 1 / 2 I calculated it.

[0371] [Table 9]

[0372] The results of the human liver microsome stability test are shown in Table 8. The results indicated that the human liver microsomes of the compound of the present invention exhibited rapid metabolism, low potential systemic toxicity, and good drug discovery potential.

[0373] Test Example 6: Inhibition of the Src signaling pathway by a compound Western blotting was used to detect p-SRC inhibition of compounds against A-431 skin cancer cells (ATCC, CRL-1555) and to evaluate the inhibitory effect of the compounds on the SRC signaling pathway.

[0374] A-431 cells were cultured in DMEM medium containing 10% fetal bovine serum and grown in a 37°C, 5% CO2 incubator. 500,000 cells / well were inoculated into 12-well cell culture plates and incubated overnight in a 37°C, 5% CO2 incubator. The following day, the medium was changed, and different concentrations of compounds were added for treatment. DMSO was used as a control, and the culture plates with the added compounds were incubated for 24 hours in a 37°C, 5% CO2 incubator. Cells were washed once with PBS, lysed at low temperature for 30 minutes using RIPA lysis solution (R0010, Solarbio), and the protein lysis solution was collected in a centrifuge tube. The centrifuge was centrifuged at 14,000 g at 4°C for 10 minutes, and the supernatant was transferred to a new tube. Protein concentration was detected and calculated using a BCA protein concentration detection kit (P0009, Beyotime Biotechnology). Protein levels in each sample were consistently quantified using 5× protein loading buffer, boiled at 100°C for 5 minutes, and Western blotting was performed to detect p-SRC levels. The p-SRC antibody (Ab185617) was purchased from Abcam, and the GAPDH antibody (60004-1-Ig) was purchased from Proteintech.

[0375] The test results are shown in Figure 2. The results indicate that the compound of the present invention can significantly inhibit SRC phosphorylation at 80 nM, exhibiting superior p-SRC inhibitory activity compared to control compound I, and can block the downstream signaling pathway of SRC.

[0376] Although embodiments of the present invention have been shown and described above, these embodiments are illustrative and should not be interpreted as limiting the present invention. Those skilled in the art should understand that modifications, alterations, substitutions, and variations of the above embodiments can be carried out within the scope of the present invention.

Claims

1. A diaryl compound represented by formula I having the following structure. 【Chemistry 1】 (However, W is -O-, L is C １ ~C ６ It is alkylene, V does not exist, Q is either unsubstituted or m R ３ Ring B is substituted by, Ring B is, 【Chemistry 2】 And, However, K represents C or N, Furthermore, ring B is a 6-8 member monocyclic sulfonyl-containing heterocyclic group or a 7-12 member fused cyclic or spirocyclic sulfonyl-containing heterocyclic group. R １ is each independently hydrogen, halogen, hydroxyl, amino, cyano, C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, -O-C １ to C ６ alkyl, or -CO-C １ to C ６ alkyl, and is selected from R ２ , R ３ Each of these is independently hydrogen, halogen, hydroxyl, amino, cyano, and C. １ ~C ６ Alkyl, -O-C １ ~C ６ Alkyl, or -CO-C １ ~C ６ Selected from alkyl groups, The aforementioned R １ , R ２ , R ３ These are halogen, hydroxyl, amino, cyano, and C. １ ~C ６ It is unsubstituted or substituted with one or more substituents selected from alkyl or 3- to 6-membered cycloalkyl groups, and if there are multiple substituents, the substituents may be the same or different. n is 1, 2, or 3, and R １ If there are multiple instances, the R １ They are the same or different. p is 1, 2, or 3, R ２ If there are multiple instances, the R ２ They are the same or different. m is 1, 2, or 3, R ３ If there are multiple instances, the R ３ They are either the same or different.

2. L is -CH ２ CH ２ The diaryl compound according to claim 1, characterized by being -.

3. It has a structure represented by formula Ic, 【Transformation 3】 However, K represents C or N, Ring B, m, n, p, R １ , R ２ , R ３ The diaryl compound according to claim 1, characterized in that the definition is as described in claim 1. 【Request Item 4】 【Chemistry 4】 is structure 【Transformation 5】 The diaryl compound according to claim 1, characterized by having the following characteristics.

5. The aforementioned ring B is 【Transformation 6】 A diaryl compound according to claim 1, characterized by being selected from among.

6. R １ , R ２ These are, independently, hydrogen, halogen, hydroxyl, amino, and C. １ ~C ６ Alkyl, -O-C １ ~C ６ Selected from alkyl, the C １ ~C ６ Alkyls are unsubstituted or substituted with one or more halogens. R ３ is halogen, hydroxyl, amino, C １ ~C ６ Alkyl, -O-C １ ~C ６ Selected from alkyl, the C １ ~C ６ Alkyl is unsubstituted or substituted with one or more halogens, and R １ , R ２ The diaryl compound according to claim 1, characterized in that it is not hydrogen at the same time.

7. R １ , R ２ , R ３ The diaryl compound according to claim 6, characterized in that each of the elements is independently selected from fluorine, methyl, ethyl, and propyl, and the methyl, ethyl, and propyl elements are unsubstituted or substituted with one or more halogens.

8. The diaryl compound according to claim 1, characterized in that the diaryl compound is one of the following compounds. 【Transformation 7】

9. Compound B has the following structure. 【Transformation 8】 (However, Q, L, W, R １ The definition of n is as described in any one of claims 1 to 8, X is a halogen or substituent G, The substituent G is selected from a borate ester group, a borate group, an alkyltin group, a trifluoromethanesulfonic acid group, a methanesulfonic acid group, and a p-toluenesulfonic acid group.

10. Compound B according to claim 9, characterized by having the following structure. 【Chemistry 9】 (However, K represents C or N, Ring B, m, n, R １ , R ３ The definition is as described in any one of claims 1 to 8, X is a halogen or substituent G, The substituent G is selected from a borate ester group, a borate group, an alkyltin group, a trifluoromethanesulfonic acid group, a methanesulfonic acid group, and a p-toluenesulfonic acid group.

11. The present invention includes obtaining the diaryl compound by reacting intermediate B and intermediate C described in claim 9 under alkaline conditions, 【Chemistry 10】 However, R ２ The definitions of and p are as described in any one of claims 1 to 8, Y is a halogen or substituent G, The substituent G is selected from a borate ester group, a borate group, an alkyltin group, a trifluoromethanesulfonic acid group, a methanesulfonic acid group, and a p-toluenesulfonic acid group. If X in intermediate B is a halogen, then Y is G. A method for preparing a diaryl compound according to any one of claims 1 to 8, characterized in that when X of intermediate B is G, Y is a halogen.

12. diaryl compounds according to any one of claims 1 to 8, and A pharmaceutical composition comprising a pharmaceutically acceptable carrier and / or other active pharmaceutical agent.

13. 1) To prepare tubulin polymerization and / or Src kinase inhibitors. 2) To prepare pharmaceuticals, pharmaceutical compositions, or formulations for the prevention and / or treatment of diseases related to tubulin polymerization and / or Src kinase, or 3) Use of a diaryl compound according to any one of claims 1 to 8 for preparing a medicament for the treatment of tumors and / or skin diseases.

14. Satisfying any one of the following conditions (1) to (4): (1) The disease associated with tubulin polymerization and / or Src kinase is a tumor or a skin disease. (2) The pharmaceutical product is an external preparation. (3) The pharmaceutical product is administered transdermally. (4) The tumor is at least one selected from the group consisting of solid tumors, sarcomas and hematological carcinomas. The use described in claim 13.

15. The aforementioned tumor is at least one selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, cervical cancer, testicular cancer, colon cancer, colorectal cancer, liver cancer, non-small cell lung cancer, squamous cell carcinoma, small cell lung cancer, gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, bladder cancer, germ cell tumor, mast cell tumor, mastocytosis, glioblastoma, neuroblastoma, astrocytoma, melanoma, B-cell lymphoma, T-cell lymphoma, slowly progressive lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, myeloma, and myelodysplastic syndrome. The use according to claim 14, wherein the skin disease is at least one selected from the group consisting of actinic keratosis, psoriasis vulgaris, atopic dermatitis, psoriasis, vitiligo, roseola, and systemic lupus erythematosus.

Images