The present application claims the right of the priorities of Chinese patent application 202111372073X filed on Nov. 18, 2021, Chinese patent application 2022108370158 filed on Jul. 15, 2022, and Chinese patent application 2022114082124 filed on Nov. 10, 2022. The contents of the above Chinese patent applications are incorporated herein by reference in their entireties.

TECHNICAL FIELD

The present disclosure belongs to the field of medicine, specifically, the present disclosure relates to a 15-PGDH inhibitor and a use thereof.

BACKGROUND

The 15-hydroxyprostaglandin dehydrogenase (15-PGDH) gene spans approximately 31 kb on the 4q34 to q35 of chromosome 4 and contains 7 exons with a molecular weight of 29 kD. 15-PGDH consists of 266 amino acids and belongs to the short-chain dehydrogenases (SDR) family, which is a dimer composed of two identical subunits, but some people believe that 15-PGDH only has enzymatic activity when 15-PGDH exists as a monomer. 15-PGDH is a key enzyme in the degradation and inactivation of prostaglandins (PGs) and related eicosane bioactive substances, which is widely found in normal tissues such as lungs, kidneys, gastrointestinal tracts, thyroids, prostates, and placentas in humans and mammals. On the one hand, 15-PGDH can catalyze the oxidation of active 15-hydroxyprostaglandin into 15-keto-prostaglandin with greatly reduced activity, and on the other hand, 15-PGDH can degrade a number of other non-prostaglandin polycyclic aromatic hydrocarbons in the presence of NAD⁺coenzyme factors, reducing carcinogens and procarcinogens produced under physiological or pathological conditions through oxidative reactions.

There are currently no drugs on the market for the treatment of numerous conditions including fibrosis through the 15-PGDH inhibitory pathway. Therefore, the development of novel compounds that can inhibit the activity of 15-PGDH is of positive significance for the treatment of diseases.

Content of the Present Invention

The technical problem to be solved by the present disclosure is to overcome the shortcomings of the prior art in that there are no drugs for the treatment of numerous conditions including fibrosis through the 15-PGDH inhibitory pathway, and therefore a 15-PGDH inhibitor and a use thereof is provided. The compounds of the present disclosure have good inhibitory effect on 15-PGDH.

The present disclosure solves the above technical problem by the following technical solutions.

The purpose of the present disclosure is to provide a novel compound for use as a 15-PGDH inhibitor.

A first aspect of the present disclosure provides a heterocyclic compound of formula I, a solvate, a pharmaceutically acceptable salt, a solvate of the pharmaceutically acceptable salt, or a prodrug thereof:

[Image Omitted]

- wherein
- Z¹, Z², Z³, Z⁴, and Z⁵each independently represent a ring atom;
- Z¹, Z², Z³, Z⁴, and Z⁵are each independently N, NH, O, S, CH₂, CH, or C;
- R¹and R²are each independently hydrogen, C₁-C₆alkyl, or C₃-C₈cycloalkyl,
- or, R¹and R²together with the N atom to which they are attached form a 3- to 11-membered heterocycloalkyl ring; wherein the 3- to 11-membered heterocycloalkyl ring is further substituted by 0, 1, or more than one (e.g., 2 or 3) R^1-1groups; when there is more than one substituent, the substituents are the same or different;
- each R^1-1is independently halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (═O), carboxyl, C₁-C₆alkyl, C₂-C₆alkynyl, halo-C₁-C₆alkyl, hydroxy-C₁-C₆alkyl, C₁-C₆alkylcarbonyl, C₁-C₆alkoxy, halo-C₁-C₆alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆alkylcarbonyloxy, C₁-C₆alkoxy-C₁-C₆alkyl, C₁-C₆alkoxycarbonyl-C₁-C₆alkyl, C₃-C₅cycloalkyl, C₃-C₅cycloalkylcarbonyl, C₃-C₅cycloalkoxy, aminocarbonyl optionally having 1 or 2 C₁-C₆alkyl groups, C₁-C₆alkylsulfonyl, aminosulfonyl optionally having 1 or 2 C₁-C₆alkyl groups, C₁-C₆alkylsulfonylamino, or amino optionally having 1 or 2 C₁-C₆alkyl groups; R^aand R^bare each independently halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (═O), carboxyl, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₂-C₆alkynyl, halo-C₁-C₆alkyl, hydroxy-C₁-C₆alkyl, C₁-C₆alkylcarbonyl, C₁-C₆alkoxy, or halo-C₁-C₆alkoxy;
- m and n are each independently 0, 1, 2, or 3;
- X¹, X², X³, X⁴, and X⁵each independently represent a ring atom;
- X¹, X², X³, X⁴, and X⁵are each independently N, O, S, CH₂, CH, or C;
- the bond between X⁴and X⁵is a single bond or a double bond;
- R³is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (═O), carboxyl, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₂-C₆alkynyl, halo-C₁-C₆alkyl, hydroxy-C₁-C₆alkyl, C₁-C₆alkylcarbonyl, C₁-C₆alkoxy, halo-C₁-C₆alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆alkoxy-C₁-C₆alkyl, C₁-C₆alkoxycarbonyl-C₁-C₆alkyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkylcarbonyl, C₃-C₈cycloalkoxy, aminocarbonyl optionally having 1 or 2 C₁-C₆alkyl groups, C₁-C₆alkylsulfonyl, aminosulfonyl optionally having 1 or 2 C₁-C₆alkyl groups, C₁-C₆alkylsulfonylamino, or amino optionally having 1 or 2 C₁-C₆alkyl groups;
- in the group moiety

[Image Omitted]

formed by the connection of X⁴and X⁵, A is absent, or A together with the ring atoms X⁴and X⁵forms a 3- to 11-membered heterocycloalkyl ring, 5-membered heteroaromatic ring, or 6-membered heteroaromatic ring; the heteroatom is independently selected from one or more than one of N, O, and S;

- when A is absent, X⁴and X⁵are each independently substituted by R⁴or R⁵;
- when A is present, the A is further substituted by R^3-1; the R^3-1substitution is one or more than one substitution, and when there is more than one substituent, the substituents are the same or different;
- R⁴and R^3-1are each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (═O), carboxyl, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₂-C₆alkynyl, halo-C₁-C₆alkyl, hydroxy-C₁-C₆alkyl, C₁-C₆alkylcarbonyl, C₁-C₆alkoxy, halo-C₁-C₆alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆alkylcarbonyloxy, C₁-C₆alkoxy-C₁-C₆alkyl, C₁-C₆alkoxycarbonyl-C₁-C₆alkyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkylcarbonyl, C₃-C₈cycloalkoxy, aminocarbonyl optionally having 1 or 2 C₁-C₆alkyl groups, C₁-C₆alkylsulfonyl, aminosulfonyl optionally having 1 or 2 C₁-C₆alkyl groups, C₁-C₆alkylsulfonylamino, or amino optionally having 1 or 2 C₁-C₆alkyl groups;
- R⁵is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (═O), carboxyl, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₂-C₆alkynyl, halo-C₁-C₆alkyl, hydroxy-C₁-C₆alkyl, C₁-C₆alkylcarbonyl, C₁-C₆alkoxy, halo-C₁-C₆alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆alkylcarbonyloxy, C₁-C₆alkoxy-C₁-C₆alkyl, C₁-C₆alkoxycarbonyl-C₁-C₆alkyl, C₃-C₅cycloalkyl, C₃-C₅cycloalkylcarbonyl, C₃-C₅cycloalkoxy, aminocarbonyl optionally substituted by 1 or 2 R^5-1groups, C₁-C₆alkylsulfonyl, aminosulfonyl optionally having 1 or 2 C₁-C₆alkyl groups, C₁-C₆alkylsulfonylamino, or amino optionally having 1 or 2 C₁-C₆alkyl groups;
- each R^5-1is independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (═O), carboxyl, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₂-C₆alkynyl, halo-C₁-C₆alkyl, hydroxy-C₁-C₆alkyl, C₁-C₆alkylcarbonyl, C₁-C₆alkoxy, halo-C₁-C₆alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆alkylcarbonyloxy, C₁-C₆alkoxy-C₁-C₆alkyl, C₁-C₆alkoxycarbonyl-C₁-C₆alkyl, C₃-C₅cycloalkyl, C₃-C₅cycloalkylcarbonyl, C₃-C₅cycloalkoxy, C₁-C₆alkylsulfonyl, aminosulfonyl optionally having 1 or 2 C₁-C₆alkyl groups, C₁-C₆alkylsulfonylamino, or amino optionally having 1 or 2 C₁-C₆alkyl groups.

A second aspect of the present disclosure provides a compound of formula I′, a solvate, a pharmaceutically acceptable salt, a solvate of the pharmaceutically acceptable salt, or a prodrug thereof:

[Image Omitted]

- in formula I′, Z¹, Z², Z³, Z⁴, and Z⁵each independently represent a ring atom;

Z¹, Z², Z³, Z⁴, and Z⁵are each independently N or C;

- R¹and R²are each independently hydrogen, C₁-C₆alkyl, or C₃-C₈cycloalkyl;
- or, R¹and R²together with the N atom to which they are attached form a 3- to 11-membered heterocycloalkyl ring; wherein the C₃-C₈cycloalkyl or 3- to 11-membered heterocycloalkyl ring is further substituted by R^1-1;
- each R^1-1is independently halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (═O), carboxyl, C₁-C₆alkyl, C₂-C₆alkynyl, halo-C₁-C₆alkyl, hydroxy-C₁-C₆alkyl, C₁-C₆alkylcarbonyl, C₁-C₆alkoxy, halo-C₁-C₆alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆alkoxy-C₁-C₆alkyl, C₁-C₆alkoxycarbonyl-C₁-C₆alkyl, C₃-C₅cycloalkyl, C₃-C₅cycloalkylcarbonyl, C₃-C₅cycloalkoxy, aminocarbonyl optionally having 1 or 2 C₁-C₆alkyl groups, C₁-C₆alkylsulfonyl, aminosulfonyl optionally having 1 or 2 C₁-C₆alkyl groups, C₁-C₆alkylsulfonylamino, or amino optionally having 1 or 2 C₁-C₆alkyl groups;

R^aand R^bare each independently halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (═O), carboxyl, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₂-C₆alkynyl, halo-C₁-C₆alkyl, hydroxy-C₁-C₆alkyl, C₁-C₆alkylcarbonyl, C₁-C₆alkoxy, or halo-C₁-C₆alkoxy;

- m and n are each independently 0, 1, 2, or 3;
- X¹, X², X³, X⁴, and X⁵each independently represent a ring atom;
- X¹, X², X³, X⁴, and X⁵are each independently N or C;
- each R³is independently halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (═O), carboxyl, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₂-C₆alkynyl, halo-C₁-C₆alkyl, hydroxy-C₁-C₆alkyl, C₁-C₆alkylcarbonyl, C₁-C₆alkoxy, or halo-C₁-C₆alkoxy;
- in the group moiety

[Image Omitted]

formed by the connection of X⁴and X⁵, A is absent, or A together with the ring atoms X⁴and X⁵forms a 3- to 11-membered heterocycloalkyl ring, 5-membered heteroaromatic ring, or 6-membered heteroaromatic ring; the heteroatom is selected from one or more than one of N, O, and S;

- when A is absent, X⁴and X⁵are each independently substituted by R⁴or R⁵;
- when A is present, the A is further substituted by R^3-1; the R^3-1substitution is one or more than one substitution, and when there is more than one substituent, the substituents are the same or different;
- R⁴, R⁵, and R^3-1are each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (═O), carboxyl, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₂-C₆alkynyl, halo-C₁-C₆alkyl, hydroxy-C₁-C₆alkyl, C₁-C₆alkylcarbonyl, C₁-C₆alkoxy, halo-C₁-C₆alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆alkoxy-C₁-C₆alkyl, C₁-C₆alkoxycarbonyl-C₁-C₆alkyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkylcarbonyl, C₃-C₈cycloalkoxy, aminocarbonyl optionally having 1 or 2 C₁-C₆alkyl groups, C₁-C₆alkylsulfonyl, aminosulfonyl optionally having 1 or 2 C₁-C₆alkyl groups, C₁-C₆alkylsulfonylamino, or amino optionally having 1 or 2 C₁-C₆alkyl groups.

In the present disclosure, the definitions of some substituents in the heterocyclic compound of formula I may be described as follows, and the definitions of unmentioned substituents are as described in any one of the above embodiments.

In a preferred embodiment of the present disclosure, the heteroatom in the 3- to 11-membered heterocycloalkyl ring, 5-membered heteroaromatic ring, and 6-membered heteroaromatic ring is one or more than one of N, O, or S, and the number of heteroatoms is 1, 2, 3, or 4.

In a preferred embodiment of the present disclosure,

[Image Omitted]

is phenyl or “a 6-membered heteroaromatic ring having 1, 2, or 3 heteroatoms selected from one or more than one of N, O, and S”.

In a preferred embodiment of the present disclosure,

[Image Omitted]

is phenyl or “a 6-membered heteroaromatic ring having 1, 2, or 3 heteroatoms selected from one or more than one of N, O, and S”, such as a pyridine ring.

In a preferred embodiment of the present disclosure,

[Image Omitted]

is “a 6-membered heteroalkyl ring substituted by cyclopropane having 1 heteroatom selected from N and O”.

In a preferred embodiment of the present disclosure,

[Image Omitted]

is “a 6-membered heteroalkyl ring substituted by cyclopropane having 1 heteroatom selected from N and O” or “a 6-membered heteroalkyl ring substituted by cyclopropane having 1 heteroatom selected from N”, such as a pyridine ring.

In a preferred embodiment of the present disclosure,

[Image Omitted]

In a preferred embodiment of the present disclosure, the rings of

[Image Omitted]

are connected to form or

[Image Omitted]

In a preferred embodiment of the present disclosure, the heterocyclic compound of formula I has a structure of formula I-1 or formula I-2:

[Image Omitted]

In a preferred embodiment of the present disclosure, the solvate is a hydrate.

In a preferred embodiment of the present disclosure, the R¹and R²together with the N atom to which they are attached form a 3- to 11-membered heterocycloalkyl ring, in which the heterocycloalkyl ring is a monocyclic heterocycloalkyl ring, a bridged bicyclic heterocycloalkyl ring, or a spiro bicyclic heterocycloalkyl ring.

In a preferred embodiment of the present disclosure, the R¹and R²together with the N atom to which they are attached form a 3- to 11-membered heterocycloalkyl ring, in which the heteroatom is one or more than one of N, O, or S, and the number of heteroatoms is 1, 2, 3, or 4.

In a preferred embodiment of the present disclosure, the R¹and R²together with the N atom to which they are attached form a 3- to 11-membered heterocycloalkyl ring further substituted by one or more than one R^1-1.

In a preferred embodiment of the present disclosure, the R¹and R²together with the N atom to which they are attached form a 3- to 8-membered heterocycloalkyl ring.

Preferably, the 3- to 8-membered heterocycloalkyl ring is a monocyclic 3- to 8-membered heterocycloalkyl ring, a fused bicyclic 3- to 8-membered heterocycloalkyl ring, or a 3- to 8-membered heterocycloalkyl ring optionally comprising a bridged or spiro bicyclic ring.

Preferably, the 3- to 8-membered heterocycloalkyl ring further has 1 to 3 heteroatoms selected from one or more than one of N, O, and S.

Preferably, the 3- to 8-membered heterocycloalkyl ring is further substituted by halogen or halo-C₁-C₆alkyl, or the 3- to 8-membered heterocycloalkyl ring is further substituted by halogen and/or halo-C₁-C₆alkyl.

Further preferably, the 3- to 8-membered heterocycloalkyl ring is a monocyclic 3- to 6-membered heterocycloalkyl ring, a bridged bicyclic 6- to 8-membered heterocycloalkyl ring, or a spiro bicyclic 8-membered heterocycloalkyl ring, and the heterocycloalkyl ring has 1 or 2 heteroatoms being N and/or 0, such as azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolidinyl-fused cyclopropyl, oxazaspiro[2.5]octyl, azaspiro[2.5]octyl, or octahydrocyclopenta[c]pyrrolidinyl.

In a preferred embodiment of the present disclosure, the 3- to 8-membered heterocycloalkyl ring is further substituted by C₁-C₆alkyl. Preferably, the substitutions are 0, 1, 2, or 3.

In a preferred embodiment of the present disclosure, in R^1-1, the halogen and the halogen in the halo-C₁-C₆alkyl are each independently F, Cl, or Br, such as F.

In a preferred embodiment of the present disclosure, in R^1-1, the C₁-C₆alkyl and the C₁-C₆alkyl in the halo-C₁-C₆alkyl are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

In a preferred embodiment of the present disclosure, in R^1-1, the halo-C₁-C₆alkyl is trifluoromethyl, difluoromethyl, or monofluoromethyl (e.g.

[Image Omitted]

In a preferred embodiment of the present disclosure, R¹and R²together with the N atom to which they are attached form the following groups:

[Image Omitted]

In a preferred embodiment of the present disclosure, R¹and R²together with the N atom to which they are attached form the following groups:

[Image Omitted]

In a preferred embodiment of the present disclosure, in R⁴and R⁵, each halogen is independently F, Cl, or Br, such as F.

In a preferred embodiment of the present disclosure, in R⁴and R⁵, each C₁-C₆alkyl in the aminocarbonyl optionally having 1 or 2 C₁-C₆alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

In a preferred embodiment of the present disclosure, in R⁴and R⁵, each aminocarbonyl optionally having 1 or 2 C₁-C₆alkyl groups is independently

[Image Omitted]

In a preferred embodiment of the present disclosure, the A together with the ring atoms X⁴and X⁵forms a 3- to 11-membered heterocycloalkyl ring, in which the heterocycloalkyl ring is a monocyclic cycloalkyl ring or a spiro bicyclic heterocycloalkyl ring.

In a preferred embodiment of the present disclosure, the A together with the ring atoms X⁴and X⁵forms a 3- to 11-membered heterocycloalkyl ring, in which the number of heteroatoms in the heterocycloalkyl ring is 1, 2, 3, or 4.

In a preferred embodiment of the present disclosure, the A together with the ring atoms X⁴and X⁵forms a 3- to 11-membered heterocycloalkyl ring, in which the 3- to 11-membered heterocycloalkyl ring is a 3- to 7-membered heterocycloalkyl ring.

In a preferred embodiment of the present disclosure, the A together with the ring atoms X⁴and X⁵forms a 3- to 11-membered heterocycloalkyl ring, in which the 3- to 11-membered heterocycloalkyl ring is a monocyclic 3- to 6-membered heterocycloalkyl ring or a spiro bicyclic 7-membered heterocycloalkyl ring, and the heterocycloalkyl ring has 1, 2, or 3 heteroatoms independently being N and/or 0, such as pyrrolidinyl or azaspiro[2.4]heptyl.

In a preferred embodiment of the present disclosure, the A together with the ring atoms X⁴and X⁵forms a 5-membered heteroaromatic ring or 6-membered heteroaromatic ring, in which the number of heteroatoms is 1, 2, 3, or 4.

In a preferred embodiment of the present disclosure, the A together with the ring atoms X⁴and X⁵forms a 5-membered heteroaromatic ring or 6-membered heteroaromatic ring, and the heteroaromatic ring has 1, 2, or 3 heteroatoms being N, such as a pyridine ring, a pyrimidine ring, or a triazole ring.

In a preferred embodiment of the present disclosure, when A is present and the A is further substituted by R^3-1; the number of the R^3-1is 2.

In a preferred embodiment of the present disclosure, in R^3-1, the halogen in the halo-C₁-C₆alkyl is F, Cl, or Br, such as F.

In a preferred embodiment of the present disclosure, in R^3-1, the C₁-C₆alkyl and the C₁-C₆alkyl in the halo-C₁-C₆alkyl and C₁-C₆deuteroalkyl are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl or ethyl.

In a preferred embodiment of the present disclosure, in R^3-1, the halo-C₁-C₆alkyl is

[Image Omitted]

In a preferred embodiment of the present disclosure, in R^3-1, the C₁-C₆deuteroalkyl is —CD₃.

In a preferred embodiment of the present disclosure, in R^3-1, the cycloalkyl in the C₃-C₈cycloalkyl is monocyclic cycloalkyl.

In a preferred embodiment of the present disclosure, in R^3-1, the cycloalkyl in the C₃-C₈cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In a preferred embodiment of the present disclosure,

[Image Omitted]

In a preferred embodiment of the present disclosure, Z¹, Z², and Z³are each independently N, CH, or C.

In a preferred embodiment of the present disclosure, Z⁴and Z⁵are each independently N, NH, CH₂, or CH.

In a preferred embodiment of the present disclosure, R¹and R²together with the N atom to which they are attached form a 3- to 11-membered heterocycloalkyl ring; wherein the 3- to 11-membered heterocycloalkyl ring is further substituted by 0, 1, or more than one R^1-1.

In a preferred embodiment of the present disclosure, R^1-1is halogen, C₁-C₆alkyl, or halo-C₁-C₆alkyl.

In a preferred embodiment of the present disclosure, R⁴and R⁵are independently halogen, cyano, or aminocarbonyl optionally having 1 or 2 C₁-C₆alkyl groups.

In a preferred embodiment of the present disclosure, R^3-1is independently oxo (═O), C₁-C₆alkyl, halo-C₁-C₆alkyl, C₃-C₈cycloalkyl, or C₁-C₆deuteroalkyl.

In a preferred embodiment of the present disclosure, in the heterocyclic compound of formula I:

- Z¹, Z², and Z³are each independently N or C;
- Z⁴and Z⁵are each independently N, NH, CH₂, or CH;
- R¹and R²together with the N atom to which they are attached form a 3- to 11-membered heterocycloalkyl ring; wherein the 3- to 11-membered heterocycloalkyl ring is further substituted by 0, 1, or more than one R^1-1;
- R^1-1is halogen, C₁-C₆alkyl, or halo-C₁-C₆alkyl;
- m and n are 0;
- R³is hydrogen;
- R⁴and R⁵are independently halogen, cyano, or aminocarbonyl optionally having 1 or 2 C₁-C₆alkyl groups;
- R^3-1is independently oxo (═O), C₁-C₆alkyl, halo-C₁-C₆alkyl, C₃-C₅cycloalkyl, or C₁-C₆deuteroalkyl;
- the group moiety

[Image Omitted]

formed by the connection of X⁴and X⁵is as defined above.

It can be understood by those skilled in the art that, according to the conventions used in the art, in the structural formulas of the present disclosure,

[Image Omitted]

or are used to depict a chemical bond, wherein the chemical bond is a point at which a moiety or a substituent is attached to a core structure or a backbone structure.