15-PGDH inhibitors and their use

Abstract

A 15-PGDH inhibitor and its use are disclosed. The 15-PGDH inhibitor is a heterocyclic compound represented by formula I, a solvate thereof, a pharma- ceutically acceptable salt thereof, a solvate of the pharma-ceutically acceptable salt thereof, or a prodrug thereof. The compound has excellent 15-PGDH inhibitory activity.

Description

[Technical Field]

[0001] This application claims priority to Chinese patent application 202111372073X, filed on November 18, 2021; priority to Chinese patent application 2022108370158, filed on July 15, 2022; and priority to Chinese patent application 2022114082124, filed on November 10, 2022. This application incorporates the full text of the above Chinese patent applications.

[0002] This invention belongs to the pharmaceutical field, and more specifically, it relates to a 15-PGDH inhibitor and its use. [Background technology]

[0003] The 15-hydroxyprostaglandin hydrogenase (15-PGDH) gene is located on chromosome 4q34-q35, spanning approximately 31kb, with a total of 7 exons and a molecular weight of 29kD. 15-PGDH consists of 266 amino acids and belongs to the short-chain dehydrogenase (SDR) family. It forms a dimer with two identical subunits, although some argue that it only exhibits enzymatic activity when present as a monomer. 15-PGDH is an important enzyme in the degradation and inactivation of prostaglandins (PGs) and related eicosane bioactive substances. It is widely present in normal tissues of humans and mammals, including the lungs, kidneys, gastrointestinal tract, thyroid, prostate, and placenta. On the one hand, it can catalyze the oxidation of active 15-hydroxyprostaglandins to 15-ketoprostaglandins, which have significantly reduced activity. On the other hand, it can catalyze the oxidation of NAD + In the presence of coenzyme factors, certain other non-prostaglandin polycyclic aromatic hydrocarbons can be broken down, and through oxidation reactions, the production of carcinogens and cancer-promoting substances under physiological or pathological conditions can be reduced.

[0004] Currently, drugs with a 15-PGDH inhibitory pathway for treating many symptoms including fibrosis are not commercially available. Therefore, the development of new compounds that can inhibit the activity of 15-PGDH is of positive significance for the treatment of diseases.

Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a 15-PGDH inhibitor and its use to overcome the drawback that there is no drug with a 15-PGDH inhibitory pathway for treating many diseases including fibrosis in the prior art. The compounds of the present invention have excellent inhibitory activity against 15-PGDH.

[0006] The present invention solves the above technical problem through the following technical solutions.

[0007] The object of the present invention is to provide a novel compound used as a 15-PGDH inhibitor.

[0008] In the first aspect of the present invention, there is provided a heterocyclic compound represented by formula I, its solvate, its pharmaceutically acceptable salt, its solvate of the pharmaceutically acceptable salt or its prodrug.

[0009]

Chemical formula

[0010] However, Z 1 、Z 2 、Z 3 、Z 4 and Z 5 each independently represents a ring atom, Z 1 、Z 2 、Z 3 、Z 4 and Z 5 are each independently N, NH, O, S, CH2, CH or C, R 1 and R 2These are, independently, hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, Alternatively, R 1 and R 2 These, together with the N atoms linked to them, form a 3- to 11-membered heterocycloalkyl group, where the 3- to 11-membered heterocycloalkyl group further comprises 0, 1 or more (e.g., 2 or 3) R atoms. 1-1 Substituting with, if there are multiple substituents, the substituents may be the same or different. Each R 1-1 These are, independently, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkoxyC1-C6 alkyl, and C1-C6 alkoxy Xycarbonyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, an aminocarbonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonyl group, an aminosulfonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonylamino group, or an amino having one or two C1-C6 alkyl groups of any choice, R a and R b These are, independently, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, or halo-C1-C6 alkoxy. m and n are independently 0, 1, 2, or 3. X 1 , X 2 , X 3 , X 4 and X 5 Each of these independently represents a ring atom, X 1 , X 2 , X 3 , X 4 and X 5 Each of these is independently N, O, S, CH2, CH, or C. X 4 and X 5 The bond connected between them is either a single bond or a double bond. R 3 These are hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkoxycal Bonyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, an aminocarbonyl group having one or two optionally C1-C6 alkyl groups, a C1-C6 alkylsulfonyl group, an aminosulfonyl group having one or two optionally C1-C6 alkyl groups, a C1-C6 alkylsulfonylamino group, or an amino having one or two optionally C1-C6 alkyl groups. X 4 and X 5 A fragment of the base formed by linking together

[0011] [ka]

[0012] In this case, A does not exist, or A and X 4 , X 5 The ring atoms together form a 3- to 11-membered heterocycloalkyl, a 5-membered heteroaromatic ring, or a 6-membered heteroaromatic ring, and the heteroatoms are independently selected from one or more of N, O, and S. If A does not exist, X 4 and X 5 Each of these is independently R 4 or R5 Replaced by, If A exists, then A further R 3-1 Replaced by, the R 3-1 Substitution by is one or more substitutions, and if there are multiple substituents, the substituents may be the same or different. R 4 and R 3-1 These are, independently, hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkoxy-C1-C6 alkyl , C1-C6 alkoxycarbonyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, an aminocarbonyl group having one or two optionally C1-C6 alkyl groups, a C1-C6 alkylsulfonyl group, an aminosulfonyl group having one or two optionally C1-C6 alkyl groups, a C1-C6 alkylsulfonylamino group, or an amino having one or two optionally C1-C6 alkyl groups, R 5 This includes hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkoxyC1-C6 alkyl, C1-C6 alkoxycarbonylC1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, and one or two R of any choice. 5-1An aminocarbonyl group having substitution by, a C1-C6 alkylsulfonyl group, an aminosulfonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonylamino group, or an amino having one or two C1-C6 alkyl groups of any choice, Each of the above R 5-1 Each of these is independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, C1-C6 alkylsulfonyl group, an aminosulfonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonylamino group, or an amino having one or two C1-C6 alkyl groups of any choice.

[0013] In a second aspect of the present invention, a compound represented by formula I', a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof is provided.

[0014] [ka]

[0015] In equation I', Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of these independently represents a ring atom, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each of these is independently N or C, R 1 and R 2 These are, independently, hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, Alternatively, R 1 and R 2 These, together with the N atoms linked to them, form a 3-11 member heterocycloalkyl group, where the C3-C8 cycloalkyl group or the 3-11 member heterocycloalkyl group is further R 1-1 Replaced by, Each R 1-1 Each of these is independently a halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, an aminocarbonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonyl group, an aminosulfonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonylamino group, or an amino having one or two C1-C6 alkyl groups of any choice. R a and R b These are, independently, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, or halo-C1-C6 alkoxy. m and n are independently 0, 1, 2, or 3. X 1 , X 2 , X 3 , X 4 and X 5 Each of these independently represents a ring atom, X 1 , X 2 , X 3 , X 4 and X 5 Each of these is independently N or C, Each R 3 These are, independently, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, or halo-C1-C6 alkoxy. X 4 and X 5 A fragment of the base formed by linking together

[0016] [ka]

[0017] In this case, A does not exist, or A and X 4 , X 5 The ring atoms together form a 3- to 11-membered heterocycloalkyl, a 5-membered heteroaromatic ring, or a 6-membered heteroaromatic ring, and the heteroatoms are selected from one or more of N, O, and S. If A does not exist, X 4 and X 5 Each of these is independently R 4 or R 5 Replaced by, If A exists, then A further R 3-1 Replaced by, the R 3-1 Substitution by is one or more substitutions, and if there are multiple substituents, the substituents may be the same or different. R 4 , R 5 and R 3-1These are, independently, hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkoxy-C1-C6 alkyl, and C1-C6 alkoxy The group is a xycarbonyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, an aminocarbonyl group having one or two optionally C1-C6 alkyl groups, a C1-C6 alkylsulfonyl group, an aminosulfonyl group having one or two optionally C1-C6 alkyl groups, a C1-C6 alkylsulfonylamino group, or an amino having one or two optionally C1-C6 alkyl groups.

[0018] In the present invention, the definitions of specific substituents of the heterocyclic compound represented by formula I are as described below, and the definitions of substituents not mentioned are as described in the optional scheme above.

[0019] In a preferred embodiment of the present invention, the heteroatoms in the 3- to 11-membered heterocycloalkyl, 5-membered heteroaromatic ring, and 6-membered heteroaromatic ring are one or more N, O, or S atoms, and their number is 1, 2, 3, or 4.

[0020] In a preferred embodiment of the present invention,

[0021] [ka]

[0022] This is phenyl or "a six-membered heteroaromatic ring having one, two, or three heteroatoms, where the heteroatoms are selected from one or more N, O, and S."

[0023] In a preferred embodiment of the present invention,

[0024] [ka]

[0025] This is phenyl or "a six-membered heteroaromatic ring having one, two, or three heteroatoms, where the heteroatoms are selected from one or more N, O, and S," for example, a pyridine ring.

[0026] In a preferred embodiment of the present invention,

[0027] [ka]

[0028] This is defined as "a six-membered heteroalkyl ring substituted with cyclopropane, having one heteroatom, and the heteroatom being selected from N and O."

[0029] In a preferred embodiment of the present invention,

[0030] [ka]

[0031] This is defined as "a six-membered heteroalkyl ring substituted with cyclopropane, having one heteroatom, and the heteroatom being selected from N and O," or "a six-membered heteroalkyl ring substituted with cyclopropane, having one heteroatom, and the heteroatom being selected from N," for example, a pyridine ring.

[0032] In a preferred embodiment of the present invention,

[0033] [ka]

[0034] That is the case.

[0035] In a preferred embodiment of the present invention,

[0036]

Chemical formula

[0037] the ring in which [it] is located is linked to

[0038]

Chemical formula

[0039] form.

[0040] In a preferred embodiment of the present invention, the heterocyclic ring system compound represented by the formula I has a structure represented by the formula I-1 or a structure represented by the formula I-2.

[0041]

Chemical formula

[0042] In a preferred embodiment of the present invention, the solvate is a hydrate.

[0043] In a preferred embodiment of the present invention, the R 1 and R 2 the heterocycloalkyl in the 3- to 11-membered heterocycloalkyl formed together with the N atom to which they are linked is monocyclic heterocycloalkyl, bicyclic heterocycloalkyl of a bridged ring or bicyclic heterocycloalkyl of a spiro ring.

[0044] In a preferred embodiment of the present invention, the heteroatom in the 3- to 11-membered heterocycloalkyl formed together with the N atom to which the R 1 and R 2 are linked is one or more of N, O or S, and the number is 1, 2, 3 or 4.

[0045] In a preferred embodiment of the present invention, the R 1 and R 2 together with the N atom to which they are attached form a 3- to 11-membered heterocycloalkyl which is further substituted by one or more R 1-1 .

[0046] In a preferred embodiment of the present invention, the R 1 and R 2 together with the N atom to which they are attached form a 3- to 8-membered heterocycloalkyl.

[0047] Preferably, the 3- to 8-membered heterocycloalkyl is a monocyclic 3- to 8-membered heterocycloalkyl, a fused bicyclic 3- to 8-membered heterocycloalkyl, or a bicyclic 3- to 8-membered heterocycloalkyl optionally containing a bridged ring or a spiro ring.

[0048] Preferably, the 3- to 8-membered heterocycloalkyl further has 1 to 3 heteroatoms selected from one or more of N, O and S.

[0049] Preferably, the 3- to 8-membered heterocycloalkyl is further substituted by halogen or halo C1-C6 alkyl, or the 3- to 8-membered heterocycloalkyl is further substituted by halogen and / or halo C1-C6 alkyl.

[0050] More preferably, the 3- to 8-membered heterocycloalkyl is a monocyclic 3- to 6-membered heterocycloalkyl, a bicyclic 6- to 8-membered heterocycloalkyl with a bridged ring or a bicyclic 8-membered heterocycloalkyl with a spiro ring, the heteroatoms are N and / or O, the number is one or two, for example, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolidinyl-fused-cyclopropyl, oxaazaspiro[2.5]octyl, azaspiro[2.5]octyl or octahydrocyclopenta[c]pyrrolidinyl.

[0051] In a preferred embodiment of the present invention, the 3- to 8-membered heterocycloalkyl group is further substituted with C1- to C6 alkyl groups. Preferably, the substitutions are 0, 1, 2, or 3.

[0052] In a preferred embodiment of the present invention, R 1-1 In this context, the halogen and the halo in the halogen and the halo C1-C6 alkyl are each independently F, Cl, or Br, for example, F.

[0053] In a preferred embodiment of the present invention, R 1-1 Among these, the C1-C6 alkyl in the C1-C6 alkyl and the halo-C1-C6 alkyl are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl.

[0054] In a preferred embodiment of the present invention, R 1-1 Among these, the halo C1-C6 alkyl is trifluoromethyl, difluoromethyl, or monofluoromethyl (for example,

[0055] [ka]

[0056] )

[0057] In a preferred embodiment of the present invention, R 1 and R 2 These, together with the N atoms linked to them, form the following groups.

[0058] [ka]

[0059] In a preferred embodiment of the present invention, R 1 and R 2 These, together with the N atoms linked to them, form the following groups.

[0060] [ka]

[0061] In a preferred embodiment of the present invention, R 4 and R 5 Among these, the halogens are independently F, Cl, or Br, for example, F.

[0062] In a preferred embodiment of the present invention, R 4 and R 5 In the aminocarbonyl group having one or two optionally selected C1-C6 alkyl groups, the C1-C6 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl.

[0063] In a preferred embodiment of the present invention, R 4 and R 5 Among these, the aminocarbonyl groups having one or two C1-C6 alkyl groups of any choice are each independently

[0064] [ka]

[0065] That is the case.

[0066] In a preferred embodiment of the present invention, A and X 4 , X 5 In 3- to 11-membered heterocycloalkyl groups formed by ring atoms, the heterocycloalkyl group is either a monocyclic cycloalkyl group or a bicyclic heterocycloalkyl group with a spiro ring.

[0067] In a preferred embodiment of the present invention, A and X 4 , X 5In a 3- to 11-membered heterocycloalkyl group formed by the ring atoms, the number of heteroatoms in the heterocycloalkyl group is 1, 2, 3, or 4.

[0068] In a preferred embodiment of the present invention, A and X 4 , X 5 In 3- to 11-membered heterocycloalkyl groups formed by the ring atoms together, the 3- to 11-membered heterocycloalkyl group is a 3- to 7-membered heterocycloalkyl group.

[0069] In a preferred embodiment of the present invention, A and X 4 , X 5 In 3- to 11-membered heterocycloalkyls formed by the ring atoms together, the 3- to 11-membered heterocycloalkyls are monocyclic 3- to 6-membered heterocycloalkyls or bicyclic 7-membered heterocycloalkyls of a spiro ring, where the heteroatoms are independently N and / or O, and their number is 1, 2, or 3, e.g., pyrrolidinyl or azaspiro[2.4]heptyl.

[0070] In a preferred embodiment of the present invention, A and X 4 , X 5 The number of heteroatoms in a 5-membered heteroaromatic ring or a 6-membered heteroaromatic ring formed by ring atoms together is 1, 2, 3, or 4.

[0071] In a preferred embodiment of the present invention, A and X 4 , X 5 In a five-membered heteroaromatic ring or a six-membered heteroaromatic ring formed by ring atoms, the heteroatoms are nitrogen atoms, and their number is one, two, or three, such as a pyridine ring, a pyrimidine ring, or a triazole ring.

[0072] In a preferred embodiment of the present invention, if A is present, then A further R 3-1 Replaced by, the R 3-1 The number is 2.

[0073] In a preferred embodiment of the present invention, R 3-1In this context, the halo in the halo C1-C6 alkyl group is F, Cl, or Br, for example, F.

[0074] In a preferred embodiment of the present invention, R 3-1 In the above, the C1-C6 alkyl in the C1-C6 alkyl, the halo-C1-C6 alkyl, and the C1-C6 deuterated alkyl are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl.

[0075] In a preferred embodiment of the present invention, R 3-1 Among them, the halo C1-C6 alkyl is

[0076] [ka]

[0077] That is the case.

[0078] In a preferred embodiment of the present invention, R 3-1 Among these, the C1-C6 deuterated alkyl group is -CD3.

[0079] In a preferred embodiment of the present invention, R 3-1 In this context, the cycloalkyl group in the C3-C8 cycloalkyl group is a monocyclic cycloalkyl group.

[0080] In a preferred embodiment of the present invention, R 3-1 In the C3-C8 cycloalkyl group, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0081] In a preferred embodiment of the present invention,

[0082] [ka]

[0083] In a preferred embodiment of the present invention, Z 1 , Z 2 and Z 3 These are N, CH, or C, respectively, independently.

[0084] In a preferred embodiment of the present invention, Z 4 and Z 5 These are, independently, N, NH, CH2, or CH.

[0085] In a preferred embodiment of the present invention, R 1 and R 2 These, together with the N atoms linked to them, form a 3- to 11-membered heterocycloalkyl group, where the 3- to 11-membered heterocycloalkyl group further comprises 0, 1 or more R atoms. 1-1 It is replaced by.

[0086] In a preferred embodiment of the present invention, R 1-1 These are halogens, C1-C6 alkyls, or halo-C1-C6 alkyls.

[0087] In a preferred embodiment of the present invention, in the heterocyclic compound represented by formula I, Z 1 , Z 2 and Z 3 Each of these is independently N or C, Z 4 and Z 5 These are independently N, NH, CH2, or CH, R 1 and R 2 These, together with the N atoms linked to them, form a 3- to 11-membered heterocycloalkyl group, where the 3- to 11-membered heterocycloalkyl group further comprises 0, 1 or more R atoms. 1-1 Replaced by, R 1-1 These are halogens, C1-C6 alkyls, or halo-C1-C6 alkyls. m and n are 0, R 3 It is hydrogen, R4 and R 5 is independently a halogen, cyano or an aminocarbonyl group optionally having one or two C1-C6 alkyl groups, R 3-1 is independently oxo(=O), C1-C6 alkyl, halo C1-C6 alkyl, C3-C8 cycloalkyl or C1-C6 deuterated alkyl, X 4 and X 5 a fragment of the group formed by linking

[0088]

Chemical formula

[0089] The definitions of all are as described above.

[0090] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formulas of the present application,

[0091]

Chemical formula

[0092] is used to depict a chemical bond, and it can be understood that the chemical bond is where a moiety or substituent is linked to the core structure or skeletal structure.

[0093] In a preferred embodiment of the present invention, the heterocyclic compound represented by the formula I is selected from the following structures.

[0094]

Chemical formula

[0095] Here, X 4 and X 5 each independently represents a ring atom, X 4 and X 5 are each independently N, CH or C, and A and X4 , X 5 These together form a 3-8 member heterocycloalkyl group, and the 3-8 member heterocycloalkyl group is further R 3-1 Replaced by, the R 3-1 Substitution by is one or more substitutions, and if there are multiple substituents, the substituents may be the same or different, each R 3-1 These are, independently, hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkoxy-C1-C6 alkyl , C1-C6 alkoxycarbonyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, an aminocarbonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonyl group, an aminosulfonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonylamino group, or an amino having one or two C1-C6 alkyl groups of any choice, Z 1 , Z 2 , Z 3 , X 1 , X 2 and X 3 The definition of is as described in one aspect of the present invention, R 1 , R 2 , R 3 , R a , R b The definitions of m and n are as described in one aspect of this invention.

[0096] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0097] [ka]

[0098] Here, X 4 and X 5 Each of these independently represents a ring atom, X 4 and X 5 These are independently N or C, and A and X 4 , X 5 These together form a 3-8 member heterocycloalkyl group, and the 3-8 member heterocycloalkyl group is further R 3-1 Replaced by, the R 3-1 Substitution by is one or more substitutions, and if there are multiple substituents, the substituents may be the same or different, each R 3-1 These are, independently, hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkoxy-C1-C6 alkyl, and C1-C6 alkoxy Xycarbonyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, an aminocarbonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonyl group, an aminosulfonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonylamino group, or an amino having one or two C1-C6 alkyl groups of any choice, Z 1 , Z 2 , Z 3 , X 1 , X 2 and X 3 The definition of is as described in one aspect of the present invention, R 1 , R 2 , R 3 , R a , R b The definitions of m and n are as described in one aspect of this invention.

[0099] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0100] [ka]

[0101] Here, R 3 , R 4 and R 5 These are, independently, hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkoxy-C1-C6 alkyl, and C1-C6 alkoxy Xycarbonyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, an aminocarbonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonyl group, an aminosulfonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonylamino group, or an amino having one or two C1-C6 alkyl groups of any choice, Z 1 , Z 2 , Z 3 , X 1 , X 2 and X 3 The definition of is as described in one aspect of the present invention, R 1 , R 2 , R a , R b The definitions of m and n are as described in one aspect of this invention.

[0102] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0103] [ka]

[0104] Here, R 3 These are halogens, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy, and R 4 and R 5 These are, independently, hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkoxy-C1-C6 alkyl , C1-C6 alkoxycarbonyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, an aminocarbonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonyl group, an aminosulfonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonylamino group, or an amino having one or two C1-C6 alkyl groups of any choice, Z 1 , Z 2 , Z 3 , X 1 , X 2 and X 3 The definition of is as described in one aspect of the present invention, R 1 , R 2 , R a , R b The definitions of m and n are as described in one aspect of this invention.

[0105] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0106] [Chemical formula]

[0107] Here, R 3 is H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo C1-C6 alkoxy,

[0108] R 4 and R 5 are each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxycarbonyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, an aminocarbonyl group optionally having one or two C1-C6 alkyl groups, a C1-C6 alkylsulfonyl group, an aminosulfonyl group optionally having one or two C1-C6 alkyl groups, a C1-C6 alkylsulfonylamino group or an amino optionally having one or two C1-C6 alkyl groups,

[0109] Z 1 Z 2 Z 3 X 1 X 2 X 3 R 1 R 2 R a R b The definitions of Z, Z, Z, X, X, X, R, R, R, R, m and n are as described in the first aspect of the present invention.

[0110] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0111] [ka]

[0112] Here, Z 1 , Z 2 , Z 3 , X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 3-1 , R a , R b The definitions of m and n are as described in one aspect of this invention.

[0113] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0114] [ka]

[0115] Here, Z 1 , Z 2 , Z 3 , X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 3-1 , R a , R b The definitions of m and n are as described in one aspect of this invention.

[0116] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0117] [ka]

[0118] Here, Z 1 , Z 2 , Z 3 , X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 3-1 , R a , R b The definitions of m and n are as described in one aspect of this invention.

[0119] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0120] [ka]

[0121] Here, Z 1 , Z 2 , Z 3 , X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 3-1 , R a , R b The definitions of m and n are as described in one aspect of this invention.

[0122] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0123] [ka]

[0124] Here, Z 1 , Z 2 , Z 3 , X1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 3-1 , R a , R b The definitions of m and n are as described in one aspect of this invention.

[0125] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0126] [ka]

[0127] Here, Z 1 , Z 2 , Z 3 , X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 3-1 , R a , R b The definitions of m and n are as described in one aspect of this invention.

[0128] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0129] [ka]

[0130] Here, Z 1 , Z 2 , Z 3 , X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 3-1 , R a , R bThe definitions of m and n are as described in one aspect of this invention.

[0131] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0132] [ka]

[0133] Here, Z 1 , Z 2 , Z 3 , X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 3-1 , R a , R b The definitions of m and n are as described in one aspect of this invention.

[0134] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0135] [ka]

[0136] Here, Z 1 , Z 2 , Z 3 , X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 3-1 , R a , R b The definitions of m and n are as described in one aspect of this invention.

[0137] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0138] [ka]

[0139] Here, R 5-1 These are hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkoxycal Bonyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, an aminocarbonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonyl group, an aminosulfonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonylamino group, or an amino having one or two C1-C6 alkyl groups of any choice, Z 1 , Z 2 , Z 3 , X 1 , X 2 and X 3 The definition of is as described in one aspect of the present invention, R 1 , R 2 , R 3 , R a , R b The definitions of m and n are as described in one aspect of this invention.

[0140] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0141] [ka]

[0142] Here, R 5-1This is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, an aminocarbonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonyl group, a C1-C6 alkylsulfonylamino group, or an amino having one or two C1-C6 alkyl groups of any choice, Z 1 , Z 2 , Z 3 , X 1 , X 2 and X 3 The definition of is as described in one aspect of the present invention, R 1 , R 2 , R 3 , R a , R b The definitions of m and n are as described in one aspect of this invention.

[0143] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0144] [ka]

[0145] Here, R 5-1These are hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkoxycal Bonyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, an aminocarbonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonyl group, an aminosulfonyl group having one or two C1-C6 alkyl groups of any choice, a C1-C6 alkylsulfonylamino group, or an amino having one or two C1-C6 alkyl groups of any choice, Z 1 , Z 2 , Z 3 , X 1 , X 2 and X 3 The definition of is as described in one aspect of the present invention, R 1 , R 2 , R 3 , R a , R b The definitions of m and n are as described in one aspect of the present invention, and R 4 It does not exist.

[0146] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from the following structures.

[0147] [ka]

[0148] Here, R 5-1is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxycarbonyl-C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 cycloalkoxy, C1-C6 alkylsulfonyl group, aminosulfonyl group having one or two C1-C6 alkyl groups of any choice, C1-C6 alkylsulfonylamino group, or amino having one or two C1-C6 alkyl groups of any choice, Z 1 , Z 2 , Z 3 , X 1 , X 2 and X 3 The definition of is as described in one aspect of the present invention, R 1 , R 2 , R 3 , R a , R b The definitions of m and n are as described in one aspect of the present invention, and R 4 It does not exist.

[0149] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from any one of the following compounds.

[0150] [ka]

[0151] [ka]

[0152] [ka]

[0153] [ka]

[0154] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from any one of the following compounds.

[0155] [ka]

[0156] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from any one of the following compounds.

[0157] The retention time is 0.743 min under the following SFC conditions.

[0158] [ka]

[0159] Chromatography column: Chiralpak AD-3 50×4.6 mm ID, 3 μm; Mobile phase: Mobile phase A: CO2; Mobile phase B: Solution of isopropanol and acetonitrile containing 0.05 volume percent diethylamine;

[0160] Isocratic elution: 50 volume solution of isopropanol and acetonitrile containing 0.05 volume percentage diethylamine in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; column pressure: 100 Bar;

[0161] The retention time is 1.670 min under the following SFC conditions.

[0162] [ka]

[0163] Chromatography column: Chiralpak AD-3 50×4.6 mm ID, 3 μm; Mobile phase: Mobile phase A: CO2; Mobile phase B: Solution of isopropanol and acetonitrile containing 0.05 volume percent diethylamine;

[0164] Isocratic elution: 50 volume solution of isopropanol and acetonitrile containing 0.05 volume percentage diethylamine in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; column pressure: 100 Bar;

[0165] The retention time is 0.816 min under the following SFC conditions.

[0166] [ka]

[0167] Chromatography column: Chiralpak AS-3 50×4.6mm ID, 3μm; Mobile phase: Mobile phase A: CO2, Mobile phase B: Solution of isopropanol and acetonitrile with 0.05 vol% diethylamine; Isocratic elution: 40 vol% solution of isopropanol and acetonitrile with 0.05 vol% diethylamine in CO2, flow rate: 3 mL / min; Detector: PDA, Column temperature: 35℃; Column pressure: 100 Bar;

[0168] The retention time is 1.477 min under the following SFC conditions.

[0169] [ka]

[0170] Chromatography column: Chiralpak AS-3 50×4.6mm ID, 3μm; Mobile phase: Mobile phase A: CO2, Mobile phase B: Solution of isopropanol and acetonitrile with 0.05 vol% diethylamine; Isocratic elution: 40 vol% solution of isopropanol and acetonitrile with 0.05 vol% diethylamine in CO2, flow rate: 3 mL / min; Detector: PDA, Column temperature: 35℃; Column pressure: 100 Bar;

[0171] The retention time is 0.764 min under the following SFC conditions.

[0172] [ka]

[0173] Chromatography column: Chiralpak AD-3 50×4.6mm ID, 3μm; Mobile phase: Mobile phase A: CO2, Mobile phase B: Solution of isopropanol and acetonitrile with 0.05 vol% diethylamine; Isocratic elution: 50 vol% solution of isopropanol and acetonitrile with 0.05 vol% diethylamine in CO2; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35℃; Column pressure: 100 Bar;

[0174] Furthermore, the retention time is 1.702 min under the following SFC conditions.

[0175] [ka]

[0176] Chromatography column: Chiralpak AD-3 50×4.6mm ID, 3μm; Mobile phase: Mobile phase A: CO2, Mobile phase B: Solution of isopropanol and acetonitrile with 0.05 vol% diethylamine; Isocratic elution: 50 vol% solution of isopropanol and acetonitrile with 0.05 vol% diethylamine in CO2; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35℃; Column pressure: 100 Bar.

[0177] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from any one of the following compounds.

[0178] IC under the test conditions of Example 1 50 The mass is 12.16 nM.

[0179] [ka]

[0180] IC under the test conditions of Example 1 50 The value is 3.58 nM.

[0181] [ka]

[0182] IC under the test conditions of Example 1 50 The value is 1.52 nM.

[0183] [ka]

[0184] Furthermore, under the test conditions of Example 1, IC 50 The mass is 7.42 nM.

[0185] [ka]

[0186] IC under the test conditions of Example 1 50 The value is 15.8 nM.

[0187] [ka]

[0188] Furthermore, under the test conditions of Example 1, IC 50 The value is 3.78 nM.

[0189] [ka]

[0190] In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from any one of the following compounds.

[0191] Under the test conditions of Example 2, the increase factor is 0.9.

[0192] [ka]

[0193] Under the test conditions of Example 2, the increase factor is 4.8.

[0194] [ka]

[0195] Under the test conditions of Example 2, the increase factor is 0.9.

[0196] [ka]

[0197] Furthermore, the increase factor is 4.4 under the test conditions of Example 2.

[0198] [ka]

[0199] In a preferred embodiment of the present invention,

[0200] [ka]

[0201] Under the test conditions of Example 3, the total pulmonary fibrosis score was 3.34.

[0202] [ka]

[0203] That is the case.

[0204] In a preferred embodiment of the present invention,

[0205] [ka]

[0206] Under the test conditions of Example 5, C max The value is 4480 ng / mL.

[0207] [ka]

[0208] That is the case.

[0209] In a preferred embodiment of the present invention,

[0210] [ka]

[0211] The AUC under the test conditions of Example 5 is (0-t)The value is 33173 h·ng / mL.

[0212] [ka]

[0213] That is the case.

[0214] A third aspect of the present invention provides a pharmaceutical composition comprising a compound represented by formula I as described in the first aspect of the present invention, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier.

[0215] A fourth aspect of the present invention provides the use of a compound represented by formula I as described in the first aspect of the present invention, its solvate, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof, or the use of a pharmaceutical composition as described in the third aspect of the present invention, the use of which includes use in the manufacture of a pharmaceutically, pharmaceutical composition, or formulation for inhibiting 15-PGDH and / or preventing and / or treating 15-PGDH-related diseases and / or as a 15-PGDH inhibitor and / or for the prevention and / or treatment of 15-PGDH-related diseases.

[0216] Preferably, the 15-PGDH-related diseases include, but are not limited to, one, two, or more of the following: fibrous diseases, inflammatory diseases, cardiovascular diseases, trauma, autoimmune diseases, graft-versus-host diseases, hair growth disorders, osteoporosis, ear disorders, eye disorders, neutropenia, diabetes mellitus, underactive bladder, transplantation promotion in stem cell or bone marrow transplantation or organ transplantation, neurogenesis and neuronal cell death, hematopoietic recombination, tissue injury, cervical diseases, and kidney diseases.

[0217] Preferably, the 15-PGDH-related diseases include, but are not limited to, one, two, or more of the following: fibrous diseases, inflammatory diseases, cardiovascular diseases, trauma, autoimmune diseases, graft-versus-host diseases, hair growth, osteoporosis, ear diseases, eye diseases, neutropenia, diabetes, underactive bladder, transplantation promotion in stem cell or bone marrow transplantation or organ transplantation, neurogenesis and neuronal cell death, hematopoietic remodeling, tissue injury, cervical diseases and kidney diseases. Preferably, the 15-PGDH-related diseases include, but are not limited to, fibrous diseases (e.g., pulmonary fibrosis including idiopathic pulmonary fibrosis, hepatic fibrosis, renal fibrosis, myocardial fibrosis, scleroderma and myelofibrosis), inflammatory diseases (e.g., chronic obstructive pulmonary disease (COPD), acute lung injury, sepsis, asthma and exacerbations of lung diseases, inflammatory bowel disease (IBD) (e.g., ulcerative colitis and Crohn's disease), peptic ulcers (e.g., NSAID-induced ulcers), autoinflammatory diseases (e.g., Behçet's disease), vasculitis syndromes, acute liver injury, acute kidney injury, non-alcoholic fatty liver disease (NASH), atopic dermatitis, psoriasis, interstitial cystitis, prostatitis syndromes (e.g., chronic prostatitis / chronic pelvic pain syndrome), cardiovascular diseases (e.g., pulmonary hypertension, angina pectoris, myocardial infarction, heart failure, ischemic heart disease, stroke and peripheral circulatory disorders), kidney diseases (e.g., chronic kidney disease and renal failure), trauma (e.g., diabetic ulcers, burns, pressure ulcers, schews). This includes, but is not limited to, one, two, or more of the following: acute mucosal injury including Glenn's syndrome; mucosal injury (e.g., mucositis or stomatitis); injury related to anticancer chemotherapy agents (primarily alkylating agents, DNA synthesis inhibitors, DNA gyrase inhibitors) or antimetabolites; cell or humoral immunotherapy or radiation-related injury); autoimmune diseases (e.g., multiple sclerosis or rheumatoid arthritis); graft-versus-host disease (GVHD); hair growth; osteoporosis; ear diseases (e.g., hearing loss, tinnitus, dizziness, and balance disorders); eye diseases (e.g., glaucoma and dry eye); neutropenia; diabetes mellitus; hypoactive bladder; transplantation promotion in stem cell or bone marrow transplantation or organ transplantation; neurogenesis and neuronal cell death (e.g., neuropsychiatric disorders, neuropathic disorders, neurotoxic diseases, neuropathic pain, and neurodegenerative diseases); liver regeneration; muscle regeneration (e.g., muscle atrophy, muscular dystrophy, and muscle injury); and cervical diseases.

[0218] Preferably, the tissue damage is liver damage and / or muscle damage (e.g., muscle atrophy and muscular dystrophy).

[0219] Preferably, the 15-PGDH-related diseases include, but are not limited to, idiopathic pulmonary fibrosis (IPF).

[0220] Preferably, the prevention and / or treatment of the 15-PGDH-related disease includes, but is not limited to, liver regeneration.

[0221] Preferably, the 15-PGDH-related diseases include, but are not limited to, liver injury.

[0222] Preferably, the 15-PGDH-related diseases include, but are not limited to, IBD.

[0223] In a fifth aspect of the present invention, the use of a compound represented by formula I, its solvate, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof, the use of which is used in the manufacture of a medicament for the prevention or treatment of the following diseases; the disease being one or more of fibrotic diseases, inflammatory diseases, or tissue injuries.

[0224] The aforementioned fibrous disease, inflammatory disease, and tissue injury are all as described above.

[0225] A sixth aspect of the present invention provides a method for inhibiting 15-PGDH or preventing and / or treating 15-PGDH-related diseases, comprising the step of administering to a subject in need of a compound represented by formula I as described in the first aspect of the present invention, its solvate, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0226] The diseases in the aforementioned 15-PGDH-related disorders are as described above.

[0227] A seventh aspect of the present invention provides a method for preventing or treating a disease, comprising the step of administering to a subject in need of a compound represented by formula I as described in the first aspect of the present invention, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein the disease is one or more of fibrous diseases, inflammatory diseases, or tissue injuries.

[0228] The aforementioned fibrous diseases and inflammatory diseases are as described above.

[0229] Additional aspects and advantages of the present invention are given in part in the following description, and in part may become apparent from the following description or may be understood through the implementation of the present invention. [Terms and Definitions]

[0230] Unless otherwise specified, the definitions of groups and terms described in the specification and claims of this application, including definitions in examples, illustrative definitions, preferred definitions, definitions listed in tables, and definitions of specific compounds in examples, may be combined and linked to each other in any way. The definitions of groups and the structures of compounds resulting from such combinations and linkages should fall within the scope described in the specification of this application.

[0231] 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 category of claims belongs. Unless otherwise noted, all patents, patent applications, and published materials cited herein are incorporated herein by whole or in whole by reference. If there are multiple definitions of a term herein, the definition in this chapter shall prevail.

[0232] Please understand that the above brief description and the following detailed description 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 stated by 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, "or" and "or" as used mean "and / or". Furthermore, the term "includes" and other forms such as "contains," "includes," and "contains" as used are not limiting.

[0233] 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, the manufacture, formulation and delivery of pharmaceuticals, and the 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 techniques and methods described above 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, base groups and their substituents may be selected by those skilled in the art to provide stable structural parts and compounds.

[0234] When substituents are described by the usual chemical formula written from left to right, those substituents also include chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to CH2. As used herein,

[0235] [ka]

[0236] The symbols indicate the binding site of the group. As used herein, "R1", "R1", and "R 1 The symbols " and " have the same meaning and can be used interchangeably. The same definitions apply to other symbols such as R2, and they have the same meaning.

[0237] 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.

[0238] In addition to the above, as used in the specification and claims of this application, unless otherwise specified, the following terms have the meanings set forth below.

[0239] With respect to numerical ranges described in the specification and claims of this application, if a numerical range is understood as "integers," it 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 all integers 0, 1, 2, 3, 4, 5, and 6. If a numerical range is understood as "numbers," it should be understood to include the two endpoints of the range, each integer within that range, and all decimal points within that range. For example, "numbers from 1 to 10" should be understood not only to include all integers 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also to include the sum of at least all integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9 respectively, so for example, 1 to 3 should be understood as 1, 2, and 3.

[0240] In this application, the term "halogen," either alone or as part of another substituent, refers to fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

[0241] As used herein, the term "alkyl" means a linear or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturated bonds, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by single bonds. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. 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.

[0242] 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, either alone or as part of another substituent. 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 groups have 1, 2, or 3 carbon atoms (“C1-C3 alkyl”), such as methyl, ethyl, n-propyl, or isopropyl.

[0243] The term "cycloalkyl" refers to a cyclic alkyl group, either alone or as part of another substituent. The term "m-n member cycloalkyl" or "C" refers to an alkyl group. m ~C n "Cycloalkyl" should be understood to represent a 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. "3 to 10-membered cycloalkyl" contains 3 to 10 carbon atoms. It may include monocyclic, bicyclic, tricyclic, spirocyclic, or bridging rings. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as decalin rings. The term "cycloalkyl" can be used interchangeably with the term "carbocyclic."

[0244] When used alone or as part of other substituents, the term "heterocycloalkyl" refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are substituted by heteroatoms, the heteroatoms being, for example, N, O, S, and P. The term "m-n member heterocycloalkyl" or "C m ~C n"Hypercycloalkyl" should be understood to represent a saturated ring having m to n atoms, where the heterocyclo atoms are selected from N, O, S, and P, preferably from N, O, or S. For example, the terms "4-8 membered heterocycloalkyl" or "C4-C8 heterocycloalkyl" should be understood to represent a saturated ring having 4 to 8 ring atoms, where 1, 2, 3, or 4 ring atoms are selected from N, O, S, and P, preferably from N, O, or S. "4-10 membered heterocyclyl" means a saturated ring having 4 to 10 ring atoms. When prefixes such as 4-8 membered or 4-10 membered are used to represent heterocycloalkyl, the number of carbons means that heteroatoms are also included. This includes monocyclic, bicyclic, tricyclic, spirocyclic, or bridging rings. Examples of heterocycloalkyls include pyrrolidinyl, tetrahydrofuranil, tetrahydropyranil, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanil, diazepanil, and oxazepanil. The term "heterocycloalkyl" can be used interchangeably with the term "heteroalkyl ring".

[0245] On its own or as part of another substituent, the term “alkenyl” refers to a linear or branched monovalent hydrocarbon having 2 to 40 carbon atoms with at least one carbon-carbon sp2 double bond (e.g., C2-C6 alkenyls, or, for example, C2-C4 alkenyls), and also includes groups having “cis” and “trans” orientation or “E” and “Z” orientation. Examples of alkenyls include, but are not limited to, vinyl and allyl.

[0246] The term "alkynyl," either alone or as part of another substituent, refers to a linear or branched monovalent hydrocarbon having 2 to 40 carbon atoms in at least one carbon-carbon sp triple bond (e.g., C2-C6 alkynyls, or, for example, C2-C4 alkynyls). Examples of alkynyls include, but are not limited to, ethynyl and propynyl.

[0247] The term "alkoxy," either alone or as part of another substituent, means -OR X It refers to the base, and here, R X This is the "alkyl" defined above.

[0248] On its own or as part of another substituent, the term "oxo" refers to the substitution of two hydrogen atoms on a methylene group with oxygen, i.e., the substitution of a methylene group with a carbonyl group.

[0249] On its own or as part of another substituent, the term “aryl” refers to a monocyclic or polycyclic carbocyclic ring having 6 to 20 carbon atoms, where at least one is an aromatic ring. Where one of the rings is a non-aromatic ring, its group may be linked via the aromatic ring or via the non-aromatic ring. Examples of aryls include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthracenyl, and acenaphthyl.

[0250] On its own or as part of other substituents, the term “heteroaromatic ring” refers to a monocyclic or polycyclic carbocyclic ring, where at least one ring atom is a heteroatom independently selected from oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon, of which at least one is an aromatic ring. The group may be a carbon group or a heteroatom group (i.e., C-linked or N-linked, wherever possible). Where one ring is a non-aromatic ring, the group may be linked via an aromatic ring or via a non-aromatic ring. Examples of heteroaryls include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridadinyl, pyridyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl, and tetrahydroquinolyl. The term "heteroaromatic ring" can be used interchangeably with the terms "heteroaromatic ring," "heteroaryl," or "heteroaromatic ring group."

[0251] On its own or as part of another substituent, the term "heteroalkenyl ring" refers to a monocyclic group having heteroatoms (the monocyclic group having a double bond but not aromatic), preferably a monocyclic ring of one, two, or three independently selected ring heteroatoms from N, O, and S. Examples of heterocycloalkenyls include: dihydrofuranyl, dihydrothienyl, dihydropyrrolyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridyl, 3,4-dihydro-2H-pyran, pyranyl, thiopyranyl, dihydropyridyl, dihydropyradinyl, dihydropyrimidinyl, oxazinyl, dihydrotetrazolyl, etc. The term "heteroalkenyl ring" can be used interchangeably with the term "heterocycloalkenyl."

[0252] On its own or as part of another substituent, the term “spiro ring” refers to a polycyclic group that shares one carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more double bonds but have no rings with a fully conjugated π-electron system. Based on the number of shared spiro atoms between the rings, spirocycloalkyls can be classified as monospirocycloalkyls, bisspirocycloalkyls, or polyspirocycloalkyls, preferably monospirocycloalkyls and bisspirocycloalkyls. Non-limiting examples of spirocycloalkyls are:

[0253] [ka]

[0254] Includes.

[0255] Furthermore, this also includes spirocycloalkyls in which monospirocycloalkyls and heterocyclocycloalkyls share a spiro atom, and non-limiting examples include:

[0256] [ka]

[0257] Includes.

[0258] The term "bridged ring" refers to a cyclic hydrocarbon in which any two rings in a compound share two carbon atoms that are not directly bonded. Depending on the number of rings, these can be classified into bicyclic, tricyclic, tetracyclic, etc. Non-restrictive examples include:

[0259] [ka]

[0260] Includes.

[0261] On its own or as part of other substituents, “haloalkyl” refers to a branched and linear saturated aliphatic hydrocarbon group (e.g., ~CvFw, where v=1~3 and w=1~(2v+1)) substituted with one or more halogens, containing a specific number of carbon atoms. Examples of haloalkyls include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0262] The term “deuterated alkyl” refers to an alkyl group substituted with one or more deuterium atoms, where alkyl is as defined above, either alone or as part of another substituent.

[0263] In this application, "optional" or "optionally" means that the event or situation described thereafter may or may not occur, and the description includes both occurrence and non-occurrence of that event or situation. For example, "optionally substituted aryl" means that the aryl is substituted or not substituted, and the description includes both substituted and non-substituted aryls.

[0264] 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 salt” applies to those compounds, materials, compositions and / or dosage forms that are within the bounds of reliable medical judgment, suitable for contact with human and animal tissues, have little toxicity, irritation, allergic reaction or other problem or complication, and meet a reasonable benefit / risk ratio.

[0265] "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 in the production of other pharmaceutically acceptable salts, or they may be used in the identification, characterization, or purification of the compound of this invention.

[0266] 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.

[0267] The term "pharmaceutically acceptable salt solvate" refers to a substance formed after a compound is combined with a pharmaceutically acceptable acid or base and a solvent (including, but not limited to, water, methanol, and ethanol). Here, the amount of solvent may be stoichiometric or non-stoichiometric. Pharmaceutically acceptable salt solvates include, but are not limited to, hydrochloride monohydrates.

[0268] The term "prodrug" refers to the compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present invention is produced by modifying a functional group in the compound, and such 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 mammal, the prodrug separates to form free hydroxyl and free amino groups, respectively.

[0269] 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 exert biological activity.

[0270] 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 human or animal products.

[0271] The term "excipient" refers to a medicinal, 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, by increasing their fluidity and / or tackiness, they can make the formulations more suitable for direct compression.

[0272] The term "treatment" refers to therapeutic therapy. With respect to a particular disease, treatment means (1) alleviating one or more biological expressions of the disease or symptoms; (2) (a) interfering with one or more points in the biological cascade that leads to or causes the disease or (b) interfering with one or more biological expressions of the disease; (3) improving one or more symptoms, effects or side effects associated with the disease, or one or more symptoms, effects or side effects associated with the disease or its treatment; or (4) reducing the disease or one or more biological expressions of the disease.

[0273] The term "prevention" refers to reducing the risk of acquiring or developing a disease or disability.

[0274] The term "patient" refers to any animal that is scheduled to be administered the compound or composition in accordance with the embodiments of the present invention, or has already been administered, and is preferably a mammal. The term "mammal" includes any mammal. Mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, and are preferably humans.

[0275] The term "therapeutic dose" refers to the amount of compound sufficient to effectively treat the disease or symptoms described in this application when administered to a patient. The "therapeutic dose" is subject to change depending on the compound, the disease and its severity, and the age of the patient being treated, but can be adjusted as needed by those skilled in the art.

[0276] The term "inflammatory bowel disease" (IBD) refers to a disorder characterized by chronic inflammation of the gastrointestinal tract. The main types include ulcerative colitis and Crohn's disease. Ulcerative colitis causes inflammation and ulcers in the surface layer of the large intestine (colon) and rectum. Crohn's disease is characterized by inflammation of the inner layer of the gastrointestinal tract, often affecting the deeper layers.

[0277] 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 completion of each step of the reaction, 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. If it does not affect the next reaction, the target compound can be proceeded to the next reaction without separation or purification.

[0278] The aforementioned preferred conditions can be combined in any way, as long as they do not violate the ordinary knowledge of the art, to obtain each preferred embodiment of the present invention.

[0279] Positive Progressive Effects of the Invention: As a result of extensive and meticulous research, the inventors have developed unexpected heterocyclic compounds or pharmaceutically acceptable salts thereof, as well as methods for producing and using them. The compounds represented by Formula I of the present invention have at least one of the following beneficial effects:

[0280] (1) The present invention provides a compound represented by formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein the compound represented by formula I has a significant inhibitory effect on 15-PGDH.

[0281] (2) Between 2.5 nM and 2500 nM, PGE2 production can be significantly increased in a dose-dependent manner, resulting in a significant effect on IPF and liver regeneration.

[0282] (3) When combined with pharmacokinetic data in mice, the compounds of the present invention exhibit excellent pharmacokinetic properties in mice, demonstrating high safety and good drug discovery potential.

[0283] (4) The present invention provides a method for producing a compound represented by formula I, its solvate, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof, and intermediates thereof, the method being easy to operate, having high yield and purity, and usable for industrial production of pharmaceuticals.

[0284] The above and / or additional aspects and advantages of the present invention will become apparent and readily apparent from the description of the embodiments with reference to the following drawings. [Brief explanation of the drawing]

[0285] [Figure 1] This graph shows the pulmonary fibrosis scores of animals in each group during the efficacy experiment of the IPF prevention model in Test Example 3 of the present invention. Here, one-way ANOVA was used: "***" indicates p<0.001 vs. sham surgery group, and "#" indicates p<0.05 vs. G2 model group. [Figure 2]This graph shows the pulmonary fibrosis scores of animals in each group in the IPF treatment model efficacy experiment of Test Example 4 of the present invention. Here, "***" indicates p<0.001 vs. G1-Sham, T-test: "#" indicates p<0.05 vs. model group, and "##" indicates p<0.01 vs. model group. [Figure 3] This graph shows the DAI scores for each group in Test Example 7 of the present invention. Here, "***" indicates p<0.001 vs. the G2 model control group. [Figure 4] This graph shows the intestinal weight / intestinal length / body weight index for each group in Test Example 7 of the present invention. Here, one-way ANOVA was used: "***" indicates p<0.001 vs. G2 model control group. [Figure 5] This graph shows the colon injury scores for each group in Test Example 7 of the present invention. Here, "***" indicates p<0.001 vs. G2 model control group, and "**" indicates p<0.01 vs. G2 model control group. [Figure 6] This graph shows the colon inflammatory cell infiltration scores for each group in Test Example 7 of the present invention. Here, "***" indicates p<0.001 vs. G2 model control group, and "*" indicates p<0.05 vs. G2 model control group. [Modes for carrying out the invention]

[0286] The present invention will be further described below with reference to the embodiments described, but this does not limit the present invention to the scope of the embodiments described.

[0287] 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 as limiting the scope of protection of the present invention. Based on a thorough understanding of the present invention, in the following examples, experimental methods for which specific conditions are not indicated may, in which those skilled in the art may make non-essential modifications to the technical solutions of the present invention, usually following 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.

[0288] This application has the following definitions: Symbol or unit: I C 50 : This refers to the median inhibitory concentration, the concentration at which half of the maximum inhibitory effect is achieved. M stands for mol / L. For example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution) represents an n-hexane solution of n-butyllithium with a molar concentration of 2.5 mol / L. N represents the equivalent concentration; for example, 2N hydrochloric acid represents a 2 mol / L hydrochloric acid solution. reagent: NBS: N-bromosuccinimide DMF: N,N-dimethylformamide IPA: Isopropyl alcohol DEA: Diethylamine

[0289] Preparation of intermediate A1: 6'-bromo-2'-methylspiro[cyclopropan-1,1'-isoindoline]-3'-one

[0290] The synthesis route for intermediate A1 is as follows:

[0291] [ka]

[0292] Step 1: Synthesis of 5-bromo-2-methylisoindorin-1-one (A1-2)

[0293] [ka]

[0294] In a sealed tube, 1 g (3.26 mmol) of methyl 4-bromo-2-(bromomethyl)benzoate was added to a mixture of 2 M methylamine (1.95 ml, 3.9 mmol) and triethylamine (0.9 ml, 6.52 mmol) of tetrahydrofuran, and the mixture was heated at 100°C for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was pulverized with hexane to obtain 5-bromo-2-methylisoindorin-1-one (500 mg, yield: 68%).

[0295] LC-MS, M / Z (ESI): 225.9 [M+H] + .

[0296] Step 2: Synthesis of 6'-bromo-2'-methylspiro[cyclopropan-1,1'-isoindoline]-3'-one (A1)

[0297] [ka]

[0298] 5-Bromo-2-methylisoindorin-1-one (500 mg, 2.21 mmol) was dissolved in DMF (20 ml), and 1,2-dibromoethane (499 mg, 2.65 mmol) and cesium carbonate (1.44 g, 4.42 mmol) were added. The mixture was heated at 100°C for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1 to 6:1) to obtain 6'-bromo-2'-methylspiro[cyclopropane-1,1'-isoindorin]-3'-one (250 mg, yield: 44.8%).

[0299] LC-MS, M / Z (ESI): 251.9 [M+H] + .

[0300] Preparation of intermediate A2: 6'-bromo-2'-(deuteromethyl)-spiro[cyclopropane-1,1'-isoindolin]-3'-one

[0301] [ka]

[0302] The synthesis of intermediate A2 followed the procedure for intermediate A1, with methylamine being replaced by deuterated methylamine. LC-MS, M / Z (ESI): 255.1 [M+H] + .

[0303] Preparation of intermediate A3: 3'-bromo-6'-methylspiro[cyclopropane-1,5'-pyrrolo[3,4-b]pyridine]-7'(6'H)-one

[0304] The synthesis route for intermediate A3 is as follows:

[0305] [ka]

[0306] Step 1: Synthesis of 5-bromo-3-(bromomethyl)pyridine-2-carboxylate methyl (A3-2)

[0307] [ka]

[0308] 5-Bromo-3-methylpyridine-2-carboxylate methyl (A3-1) (5 g, 21.73 mmol) was dissolved in carbon tetrachloride (50 mL), and azobisisobutyronitrile (0.71 g, 4.35 mmol) and NBS (4.64 g, 26.1 mmol) were added. The mixture was reacted at 80°C for 5 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V / V) = 5:1 to 1:1) to obtain compound 5-bromo-3-(bromomethyl)pyridine-2-carboxylate methyl (A3-2) (4.5 g, yield: 67%).

[0309] LC-MS, M / Z (ESI): 307.8 [M+H] + .

[0310] Step 2: Synthesis of 3-bromo-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one (A3-3)

[0311] [ka]

[0312] In a sealed tube, methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (1 g, 3.24 mmol) was added to a mixture of 2 M methylamine (1.95 ml, 3.9 mmol) and triethylamine (0.9 ml, 6.52 mmol) of tetrahydrofuran, and the mixture was heated at 100°C for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was pulverized with hexane to obtain 3-bromo-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one (500 mg, yield: 68%).

[0313] LC-MS, M / Z (ESI): 226.9 [M+H] + .

[0314] Step 3: Synthesis of 3'-bromo-6'-methylspiro[cyclopropane-1,5'-pyrrolo[3,4-b]pyridine]-7'(6'H)-one (A3)

[0315] [ka]

[0316] 3-Bromo-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one (500 mg, 2.20 mmol) was dissolved in DMF (20 ml), and 1,2-dibromoethane (496 mg, 2.64 mmol) and cesium carbonate (1.43 g, 4.40 mmol) were added. The mixture was heated at 100°C for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 10:1 to 3:1) to obtain 3'-bromo-6'-methylspiro[cyclopropane-1,5'-pyrrolo[3,4-b]pyridine]-7'(6'H)-one (250 mg, yield 44.9%).

[0317] LC-MS, M / Z (ESI): 253.0 [M+H] + .

[0318] Example 1: Preparation of 5-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropane[c][1,8]naphthyrizin-3-yl)-2-methylisoindoline-1-one (I-1)

[0319] The synthesis route for target compound I-1 is as follows:

[0320] [ka]

[0321] Step 1: Synthesis of 6-bromo-1-(4-methoxybenzyl)-1,8-naphthyridine-2(1H)-one (B1-2)

[0322] [ka]

[0323] Dissolve 6-bromo-1,8-naphthyrizine-2(1H)-one (500 mg, 2.22 mmol) in tetrahydrofuran (5 ml), add sodium hydrogen (133 mg, 3.33 mmol, 60% content) under nitrogen gas protection at 0-5°C, and react for 1 hour at 0-5°C after addition is complete. At 0-10°C, add 1-(chloromethyl)-4-methoxybenzene (522 mg, 3.33 mmol) to the reaction system, and react for 5 hours at 25°C after addition is complete to form the reaction solution. Under the protection of nitrogen gas, the mixture was quenched in saturated ammonium chloride (50 ml) at 0-10°C. After quenching, it was extracted with ethyl acetate (50 ml x 2), the organic phases were combined, washed with saturated saline solution (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 6-bromo-1-(4-methoxybenzyl)-1,8-naphthyrizine-2(1H)-one (B1-2) (700 mg, yellow crude product), which was used directly in the next step.

[0324] LC-MS, M / Z (ESI): 345.0 [M+H] + .

[0325] Step 2: Synthesis of 6-bromo-3-(4-methoxybenzyl)-1,1a,3,7b-tetrahydro-2H-cyclopropa[c][1,8]naphthyrizin-2-one (B1-3)

[0326] [ka]

[0327] Under the protection of nitrogen gas, sodium hydrogen (118 mg, 2.95 mmol, purity: 60%) is dispersed in tetrahydrofuran (5 ml), and trimethylsulfoxonium iodide (574 mg, 2.61 mmol) is added in batches at 0-10°C. After addition is complete, the mixture is reacted at 0-10°C for 1 hour. Under the protection of nitrogen gas, 6-bromo-1-(4-methoxybenzyl)-1,8-naphthyrizine-2(1H)-one (600 mg, 1.74 mmol) is added in batches at 25°C, and after addition is complete, the mixture is reacted at 90°C for 2 hours. The reaction solution is then sterilized under the protection of nitrogen gas at 0-10°C using saturated anhydrous chloride. Monium (30 ml) was added to quench the mixture, then it was extracted with ethyl acetate (50 ml x 2), the organic phases were combined, washed with saturated saline solution (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 20:1 to 6:1) to obtain compound 6-bromo-3-(4-methoxybenzyl)-1,1a,3,7b-tetrahydro-2H-cyclopropa[c][1,8]naphthyrizin-2-one (B1-3) (yellow solid, 350 mg, yield: 56.1%).

[0328] LC-MS, M / Z (ESI): 359.0 [M+H] + .

[0329] Step 3: Synthesis of 6-bromo-3-(4-methoxybenzyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine (B1-4)

[0330] [ka]

[0331] Under the protection of nitrogen gas, 6-bromo-3-(4-methoxybenzyl)-1,1a,3,7b-tetrahydro-2H-cyclopropa[c][1,8]naphthyrizin-2-one (500 mg, 1.39 mmol) is added to tetrahydrofuran (4 ml), and boranedimethyl sulfide solution (10 M, 1.39 ml, 13.9 mmol) is added dropwise at 0-10°C. After the addition is complete, the mixture is stirred at 60°C for 1 hour to allow it to react. The reaction solution is then quenched by adding water (10 ml) at 0-5°C under the protection of nitrogen gas, and then, Extraction was performed with dichloromethane (50 ml x 2), the organic phase was combined, washed with saturated saline solution (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 200:1 to 20:1) to obtain the colorless liquid compound 6-bromo-3-(4-methoxybenzyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine (B1-4) (400 mg, yield: 69.4%).

[0332] LC-MS, M / Z (ESI): 345.0 [M+H] + .

[0333] Step 4: Synthesis of 3-(4-methoxybenzyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylate methyl (B1-5)

[0334] [ka]

[0335] At 25°C, under the protection of nitrogen gas, 6-bromo-3-(4-methoxybenzyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyrizine (400 mg, 1.16 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (169 mg, 232 μmol), triethylamine (352 mg, 3.48 mmol), and methanol (10 ml) were added to an autoclave, purged with nitrogen gas, and then... CO was passed through the mixture, and the reaction was carried out with stirring at 120°C and a pressure of 4 MPa for 48 hours. The reaction solution was filtered and concentrated to obtain the crude product, which was then purified by silica gel chromatography (petroleum ether:ethyl acetate (V / V) = 200:1 to 20:1) to obtain the white solid compound 3-(4-methoxybenzyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyrizine-6-carboxylate methyl (B1-5) (350 mg, yield: 93.1%).

[0336] LC-MS, M / Z (ESI): 325.1 [M+H] + .

[0337] Step 5: Synthesis of 3-(4-methoxybenzyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylic acid (B1-6)

[0338] [ka]

[0339] Under the protection of nitrogen gas, 3-(4-methoxybenzyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyrizine-6-carboxylate methyl (340 mg, 1.05 mmol) and lithium hydroxide monohydrate (176 mg, 4.19 mmol) are added to tetrahydrofuran (3 ml) and water (1 ml), and the mixture is reacted at 60°C for 1 hour. Water (10 ml) is then added to the reaction solution, and 0-1 At 0°C, the pH was adjusted to 3-4 with 1M dilute hydrochloric acid, extracted with dichloromethane (50 ml x 2), combined the organic phases, washed with saturated saline solution (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3-(4-methoxybenzyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyrizine-6-carboxylic acid (B1-6) (320 mg, yellow solid crude product).

[0340] LC-MS, M / Z (ESI): 310.9 [M+H] + .

[0341] Step 6: Synthesis of (4,4-difluoropiperidine-1-yl)(3-(4-methoxybenzyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)methanone (B1-7)

[0342] [ka]

[0343] Under the protection of nitrogen gas, 3-(4-methoxybenzyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyrizine-6-carboxylic acid (320 mg, 1.03 mmol), 4,4-difluoropiperidine (249 mg, 2.06 mmol), N,N-diisopropylethylamine (399 mg, 3.09 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (784 mg, 2.06 mmol) were added to N,N-dimethylformamide (4 ml). After addition, the mixture was stirred at 25°C for 16 hours and then reconstituted. The reaction solution was then mixed with water (30 ml), extracted with ethyl acetate (50 ml x 2), combined with the organic phase, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 50:1~6:1) to obtain the white solid compound (4,4-difluoropiperidine-1-yl)(3-(4-methoxybenzyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthirizine-6-yl)methanone (B1-7) (350 mg, 2-step yield: 82.1%).

[0344] LC-MS, M / Z (ESI): 414.3 [M+H] + .

[0345] Step 7: Synthesis of (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)methanone (B1-8)

[0346] [ka]

[0347] Under the protection of nitrogen gas, (4,4-difluoropiperidine-1-yl)(3-(4-methoxybenzyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthirizin-6-yl)methanone (50 mg, 121 μmol) was added to trifluoroacetic acid (0.2 ml). After the addition was complete, the mixture was stirred at 60°C for 4 hours to allow the reaction to proceed. The reaction solution was concentrated under reduced pressure to obtain the crude product of (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthirizin-6-yl)methanone, a yellow solid (B1-8) (35.0 mg).

[0348] LC-MS, M / Z (ESI): 294.2 [M+H] + .

[0349] Step 8: 5-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methylisoindorin-1-one(I-1)

[0350] [ka]

[0351] Under the protection of nitrogen gas, (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)methanone (35.0 mg, 119 μmol), cesium carbonate (155 mg, 477 μmol), 2-methyl-5-bromoisoindorin-1-one (40.4 mg, 179 μmol), bis(dibenzylideneacetone)palladium (6.86 mg, 11.9 μmol), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (69.0 mg, 119 μmol) were added to dioxane (1 ml), and the mixture was stirred at 100 °C for 12 hours to react. The reaction solution was concentrated to obtain the crude product. The crude product was then separated and subjected to preparative high-performance liquid chromatography (column: Phenomenex Synergi C). 18The target compound 5-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methylisoindorin-1-one(I-1) (13.0 mg, yield: 23.5%) was obtained by (150 × 25 mm × 5 μm; solvent: A = water + 0.1 volume percent trifluoroformic acid (99%), B = acetonitrile; gradient: B from 23% to 53%, 9 min).

[0352] 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, 1H), 7.80 (d, 1H), 7.65 (d, 1H), 7.26 (s, 1H), 7.25 (s, 1H), 4.34 (d, 2H), 3.84-3.92 (m, 2H), 3.74 (br, 4H), 3.18 (s, 3H), 2.00-2.06 (m, 6H), 1.24-1.26 (m, 1H), 1.07-1.10 (m, 1H).

[0353] LC-MS, M / Z (ESI): 439.3[M+H] + .

[0354] Example 2: Preparation of 3-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-6-methyl-5,6-dihydro-7H-pyrrolo[3,4b]pyridine-7-one (I-2)

[0355] The synthesis route for target compound I-2 is as follows:

[0356] [ka]

[0357] Under the protection of nitrogen gas, (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)methanone (35.0 mg, 119 μmol), cesium carbonate (155 mg, 477 μmol), 3-bromo-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one (40.6 mg, 179 μmol), bis(dibenzylideneacetone)palladium (6.86 mg, 11.9 μmol), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (69.0 mg, 119 μmol) were added to dioxane (1 ml), and the mixture was stirred at 100°C for 12 hours to react. The reaction solution was then concentrated to obtain the crude product. Next, the crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1 to 1:1) to obtain the target compound 3-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-6-methyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridine-7-one (I-2) (15.0 mg, yield: 28.6%).

[0358] 1 H NMR (400 MHz, DMSO) δ 8.60 (d, 1H), 7.93 (d, 1H), 7.84 (d, 1H), 7.80 (d, 1H), 4.45 (s, 2H), 3.87 (s, 2H), 3.60 (br, 4H), 3.10 (s, 3H), 2.18-2.50 (m, 1H), 2.00-2.09 (m, 3H), 1.22-1.23 (m, 2H), 1.06-1.08 (m, 1H), 0.83-0.86 (m, 1H).

[0359] LC-MS, M / Z (ESI): 440.2 [M+H] + .

[0360] Example 3: Preparation of 7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methyl-[1,2,4]triazolyl[4,3a]pyridine-3(2H)-one(I-3)

[0361] The synthesis route for target compound I-3 is as follows:

[0362] [ka]

[0363] Step 1: 4-Bromo-2-Hydrazinopyridine (B3-2)

[0364] [ka]

[0365] 17 ml of 80% hydrazine hydrate solution was added to a 50 ml ethanol solution of 4-bromo-2-fluoropyridine (5 g, 28.4 mmol). The reaction mixture was stirred at room temperature for 12 hours, concentrated, diluted with water (50 ml), extracted with ethyl acetate (50 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 4-bromo-2-hydrazinopyridine (3.7 g, yield: 69.3%).

[0366] LC-MS, M / Z (ESI): 187.9 [M+H] + .

[0367] Step 2: 7-Bromo-[1,2,4]Triazolo[4,3-a]Pyridine-3(2H)-one(B3-3)

[0368] [ka]

[0369] 4-bromo-2-hydrazinopyridine (3.2 g, 17.02 mmol) was dissolved in tetrahydrofuran (30 ml), carbonyldiimidazole (5.52 g, 34.0 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with water (50 ml), extracted with ethyl acetate (50 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried, and slurryed with ethyl acetate (10 ml) to obtain 7-bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (2.2 g, yield: 60.4%).

[0370] LC-MS, M / Z (ESI): 213.9 [M+H] + .

[0371] Step 3: 7-Bromo-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(B3-4)

[0372] [ka]

[0373] At room temperature, iodomethane (995 mg, 7.01 mmol) was added dropwise to a mixture of 7-bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (500 mg, 2.33 mmol) and cesium carbonate (1.14 g, 3.50 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 3 hours, diluted with water (20 ml), extracted with ethyl acetate (20 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1 to 1:1) to obtain 7-bromo-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (400 mg, yield: 75%).

[0374] LC-MS, M / Z (ESI): 227.9 [M+H] + .

[0375] Step 4: 7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2-methyl-[1,2,4]triazolo[4,3a]pyridine-3(2H)-one(I-3)

[0376] [ka]

[0377] Under the protection of nitrogen gas, (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)methanone (35.0 mg, 119 μmol), cesium carbonate (155 mg, 477 μmol), 7-bromo-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (40.8 mg, 179 μmol), bis(dibenzylideneacetone)palladium (6.86 mg, 11.9 μmol), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (69.0 mg, 119 μmol) were added to dioxane (1 ml), and the mixture was stirred at 100 °C for 12 hours to react. The reaction solution was concentrated to obtain the crude product. Next, the crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1 to 1:1) to obtain the target compound 7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(I-3) (20.0 mg, yield: 38.1%).

[0378] The product was separated by SFC (chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: mobile phase A: CO2, mobile phase B: IPA + ACN (DEA at 0.05 volume percent);

[0379] Isocratic elution: 50% IPA + ACN (0.05% DEA) in CO2, flow rate: 3 mL / min; detector: PDA, column temperature: 35°C; column pressure: 100 Bar). Isomers (I-3A) (RT=0.743 min) and (I-3B) (RT=1.670 min) were obtained.

[0380] [ka]

[0381] 1 H NMR (400 MHz, DMSO) δ 8.04 (d, 1H), 7.81 (d, 1H), 7.61 (d, 1H), 6.68 (d, 1H), 6.58 (dd, 2.0 Hz, 1H), 3.90 (d, 1H), 3.70 -3.52 (m, 5H), 3.48 (s, 3H), 2.18 (dt, 1H), 2.13-1.93 (m, 5H), 1.06 (dd, 2H).

[0382] LC-MS, M / Z (ESI): 441.1 [M+H] + .

[0383] Example 4: Preparation of 2-Cyclopropyl-7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(I-4)

[0384] The synthesis route for target compound I-4 is as follows:

[0385] [ka]

[0386] Step 1: 7-Bromo-2-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(B4-1)

[0387] [ka]

[0388] Cyclopropyl bromide (848 mg, 7.01 mmol) was added dropwise to a mixture of 7-bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (500 mg, 2.33 mmol) and cesium carbonate (1.14 g, 3.50 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 3 hours, diluted with water (20 ml), extracted with ethyl acetate (20 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1 to 1:1) to obtain 7-bromo-2-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (B4-1) (200 mg, yield: 37.5%).

[0389] LC-MS, M / Z (ESI): 253.9 [M+H] + .

[0390] Step 2: 2-Cyclopropyl-7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-[1,2,4]triazolo[4,3a]pyridine-3(2H)-one(I-4)

[0391] [ka]

[0392] Under the protection of nitrogen gas, (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)methanone (35.0 mg, 119 μmol), cesium carbonate (155 mg, 477 μmol), 7-bromo-2-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (45.5 mg, 179 μmol), bis(dibenzylideneacetone)palladium (6.86 mg, 11.9 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (69.0 mg, 119 μmol) were added to dioxane (1 ml), and the mixture was stirred at 100 °C for 12 hours to react. The reaction solution was concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1 to 1:1) to obtain the target compound 2-cyclopropyl-7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(I-4) (20.0 mg, yield: 55.7%).

[0393] LC-MS, M / Z (ESI): 467.1 [M+H] + .

[0394] Example 5: Preparation of 6'-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (I-5)

[0395] The synthesis route for target compound I-5 is as follows:

[0396] [ka]

[0397] Under the protection of nitrogen gas, (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)methanone (35.0 mg, 119 μmol), cesium carbonate (155 mg, 477 μmol), 6'-bromo-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (45.1 mg, 179 μmol), bis(dibenzylideneacetone)palladium (6.86 mg, 11.9 μmol), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (69.0 mg, 119 μmol) were added to dioxane (1 ml), and the mixture was stirred at 100 °C for 12 hours to react. The reaction solution was concentrated to obtain the crude product. Next, the crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1 to 1:1) to obtain the target compound 6'-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (I-5) (25.0 mg, yield: 45.1%).

[0398] LC-MS, M / Z (ESI): 465.2 [M+H] + .

[0399] Example 6: Preparation of 6'-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2'-(deuterated methyl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (I-6)

[0400] The synthesis route for target compound I-6 is as follows:

[0401] [ka]

[0402] Under the protection of nitrogen gas, (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)methanone (35.0 mg, 119 μmol), cesium carbonate (155 mg, 477 μmol), 6'-bromo-2'-deuterated methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (45.7 mg, 179 μmol), bis(dibenzylideneacetone)palladium (6.86 mg, 11.9 μmol), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (69.0 mg, 119 μmol) were added to dioxane (1 ml), and the mixture was stirred at 100 °C for 12 hours to react. The reaction solution was concentrated to obtain the crude product. Next, the crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1 to 1:1) to obtain the target compound 6'-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2'-(deuterated methyl)spiro[cyclopropane-1,1'-isoindoline]-3'-one (I-6) (26.0 mg, yield: 46.6%).

[0403] LC-MS, M / Z (ESI): 468.2 [M+H] + .

[0404] Example 7: Preparation of 7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(I-7)

[0405] The synthesis route for target compound I-7 is as follows:

[0406] [ka]

[0407] Under the protection of nitrogen gas, (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyrizin-6-yl)methanone (50.0 mg, 170 μmol), cesium carbonate (166 mg, 510 μmol), 7-bromo-2-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (For the synthesis of B7-1, see WO2020145250A1) (60.6 mg, 205 μmol), bis(dibenzylideneacetone)palladium (9.8 mg, 1.70 μmol), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (98.6 mg, 1.70 μmol) were added to dioxane (1 ml), and the reaction was carried out with stirring at 100°C for 12 hours. The reaction solution was concentrated to obtain the crude product. Next, the crude product was separated and subjected to preparative high-performance liquid chromatography (column: Phenomenex Synergi C 18 The target compound 7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(I-7) (18.8 mg, yield: 21.6%) was obtained by (150 × 25 mm × 5 μm; solvent: A = water + 0.1 volume percent trifluoroformic acid (99%), B = acetonitrile; gradient: 25% to 56% B, 8 min).

[0408] LC-MS, M / Z (ESI): 509.2 [M+H] + .

[0409] Example 8: Preparation of 7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)quinazoline-4(3H)-one(I-8)

[0410] The synthesis route for target compound I-8 is as follows:

[0411] [ka]

[0412] Under the protection of nitrogen gas, (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)methanone (50.0 mg, 170 μmol), cesium carbonate (166 mg, 510 μmol), 7-bromoquinazoline-4(3H)-one (46.0 mg, 205 μmol), bis(dibenzylideneacetone)palladium (9.8 mg, 1.70 μmol), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (98.6 mg, 1.70 μmol) were added to dioxane (1 ml), and the mixture was stirred at 100 °C for 12 hours to react. The reaction solution was concentrated to obtain the crude product. Next, the crude product was separated and subjected to preparative high-performance liquid chromatography (column: Phenomenex Synergi C). 18 The target compound 7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)quinazoline-4(3H)-one(I-8) (25.0 mg, yield: 33.0%) was obtained by (150 × 25 mm × 5 μm; solvent: A = water + 0.1 volume percent trifluoroformic acid (99%), B = acetonitrile; gradient: 29% to 60% B, 7 min).

[0413] LC-MS, M / Z (ESI): 438.2 [M+H] + .

[0414] Example 9: Preparation of 4-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2-fluoro-N-methylbenzamide (I-9)

[0415] The synthesis route for target compound I-9 is as follows:

[0416] [ka]

[0417] Under the protection of nitrogen gas, (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)methanone (50.0 mg, 170 μmol), cesium carbonate (166 mg, 510 μmol), 4-bromo-2-fluoro-N-methylbenzamide (47.5 mg, 205 μmol), bis(dibenzylideneacetone)palladium (9.8 mg, 1.70 μmol), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (98.6 mg, 1.70 μmol) were added to dioxane (1 ml), and the mixture was stirred at 100 °C for 12 hours to react. The reaction solution was concentrated to obtain the crude product. Next, the crude product was separated and subjected to preparative high-performance liquid chromatography (column: Phenomenex Synergi C). 18 The target compound 4-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2-fluoro-N-methylbenzamide (I-9) (30.5 mg, yield: 40.3%) was obtained by (150 × 25 mm × 5 μm; solvent: A = water + 0.1 volume percent trifluoroformic acid (99%), B = acetonitrile; gradient: B from 20% to 70%, 9 min).

[0418] LC-MS, M / Z (ESI): 445.2 [M+H] + .

[0419] Example 10: Preparation of 5-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-N-methylpicolinamide (I-10)

[0420] The synthesis route for target compound I-10 is as follows:

[0421] [ka]

[0422] Under the protection of nitrogen gas, (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)methanone (50.0 mg, 170 μmol), cesium carbonate (166 mg, 510 μmol), 5-bromo-N-methylpicolinamide (44.0 mg, 205 μmol), bis(dibenzylideneacetone)palladium (9.8 mg, 1.70 μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (98.6 mg, 1.70 μmol) were added to dioxane (1 ml), and the mixture was stirred at 100 °C for 12 hours to react. The reaction solution was concentrated to obtain the crude product. Next, the crude product was separated and subjected to preparative high-performance liquid chromatography (column: Phenomenex Synergi C). 18 The target compound 5-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-N-methylpicolinamide (I-10) (26.5 mg, yield: 36.4%) was obtained by (150 × 25 mm × 5 μm; solvent: A = water + 0.1 volume percent trifluoroformic acid (99%), B = acetonitrile; gradient: 18% to 75% B, 10 min).

[0423] LC-MS, M / Z (ESI): 428.2 [M+H] + .

[0424] Example 11: Preparation of 4-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)benzonitrile (I-11)

[0425] The synthesis route for target compound I-11 is as follows:

[0426] [ka]

[0427] Under the protection of nitrogen gas, (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)methanone (50.0 mg, 170 μmol), cesium carbonate (166 mg, 510 μmol), 4-bromo-benzonitrile (37.2 mg, 205 μmol), bis(dibenzylideneacetone)palladium (9.8 mg, 1.70 μmol), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (98.6 mg, 1.70 μmol) were added to dioxane (1 ml), and the mixture was stirred at 100 °C for 12 hours to react. The reaction solution was concentrated to obtain the crude product. Next, the crude product was separated and subjected to preparative high-performance liquid chromatography (column: Phenomenex Synergi C). 18 The target compound 4-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthirizine-3-yl)benzonitrile (28.8 mg, yield: 42.8%) was obtained by (150 × 25 mm × 5 μm; solvent: A = water + 0.1 volume percent trifluoroformic acid (99%), B = acetonitrile; gradient: 30% to 80% B, 12 min).

[0428] 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, 1H), 7.68 (d, 1H), 7.61 (s, 1H), 7.59 (s, 1H), 7.29 (s, 1H), 7.26 (s, 1H), 3.94 (d, 1H), 3.85-3.63 (m, 5H), 2.04 (ddd, 6H), 1.18 (q, 1H), 1.11 (td, 1H).

[0429] LC-MS, M / Z (ESI): 395.2 [M+H] + .

[0430] Example 12: Preparation of 6-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methylisoquinoline-1(2H)-one(I-12)

[0431] The synthetic route for target compound I-12 is as follows:

[0432] [ka]

[0433] Under the protection of nitrogen gas, (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)methanone (50.0 mg, 170 μmol), cesium carbonate (166 mg, 510 μmol), 6-bromo-2-methylisoquinoline-1(2H)-one (48.7 mg, 205 μmol), bis(dibenzylideneacetone)palladium (9.8 mg, 1.70 μmol), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (98.6 mg, 1.70 μmol) were added to dioxane (1 mL), and the mixture was stirred at 100 °C for 12 hours to react. The reaction solution was concentrated to obtain the crude product. Next, the crude product was separated and subjected to preparative high-performance liquid chromatography (column: Phenomenex Synergi C). 18 The target compound 6-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2-methylisoquinoline-1(2H)-one(I-12) (21.1 mg, yield: 27.5%) was obtained by (150 × 25 mm × 5 μm; solvent: A = water + 0.1 volume percent trifluoroformic acid (99%), B = acetonitrile; gradient: 30% to 70% B, 10 min).

[0434] The obtained product was separated by SFC (chromatographic column: Chiralpak AS-3 50×4.6 mm ID, 3 μm; mobile phase: mobile phase A: CO2, mobile phase B: IPA + ACN (DEA at 0.05 vol.%); isocratic elution: IPA at 40 vol.%) (DEA at 0.05 vol.%) in CO2; flow rate: 3 mL / min; detector: PDA, column temperature: 35°C; column pressure: 100 Bar). Isomer I-12A (RT=0.816 min) and isomer I-12B (RT=1.477 min) were obtained.

[0435] [ka]

[0436] 1 H NMR (400 MHz,CDCl3) δ 8.33 (d, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.35 (d, 1H), 7.20 (s, 1H), 7.03 (d, 1H), 6.40 (d, 1H), 3.91 (dd, 2H), 3.81-3.62 (m, 4H), 3.58 (s, 3H), 2.09-1.95 (m, 6H), 1.25 (s, 1H), 1.09 (s, 1H).

[0437] LC-MS, M / Z (ESI): 451.2 [M+H] + .

[0438] Example 13: Preparation of 6-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c]quinoline-3-yl)-2-methylphthalazine-1(2H)-one(I-13)

[0439] The synthesis route for target compound I-13 is as follows:

[0440] [ka]

[0441] The synthesis of compound I-13 followed the example of compound I-1, with intermediate B13-1 replacing A1-2. The synthesis of intermediate B13-1 followed the example of patent WO2021016333.

[0442] 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.35 (d, 1H), 7.20 (s, 1H), 7.03 (d, 1H), 6.40 (d, 1H), 3.91 (dd, 2H), 3.81-3.62 (m, 4H), 3.58 (s, 3H), 2.09-1.95 (m, 6H), 1.25 (s, 1H), 1.09 (s, 1H).

[0443] LC-MS, M / Z (ESI): 451.2[M+H] + .

[0444] Example 14: Preparation of 3-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c]quinoline-3-yl)-7-methylpyrido[2,3-d]pyridazine-8(7H)-one(I-14)

[0445] The synthesis route for target compound I-14 is as follows:

[0446] [ka]

[0447] The synthesis of compound I-14 followed the example of compound I-1, with intermediate B14-1 replacing A1-2. The synthesis of intermediate B14-1 followed the example of patent WO2021016333.

[0448] 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 3.75-4.04 (m, 9H), 2.03-2.13 (m, 5H), 1.18-1.25 (m, 3H).

[0449] LC-MS, M / Z (ESI): 452.2[M+H] + .

[0450] Example 15: Preparation of 7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c]quinoline-3-yl)-3-methylpyrido[3,2-d]pyrimidine-4(3H)-one(I-15)

[0451] The synthesis route for target compound I-15 is as follows:

[0452] [ka]

[0453] The synthesis of compound I-15 followed the example of compound I-1, with intermediate B15-1 replacing A1-2. The synthesis of intermediate B15-1 followed the example of patent WO2021016333.

[0454] 1 H NMR (400 MHz, CDCl3) δ 8.89 (d, 1H), 8.08 (s, 1H), 7.99 (d, 1H), 7.73 (d, 1H), 7.61 (d, 1H), 4.02 (d, 1H), 3.66-3.85 (m, 8H), 2.03-2.13 (m, 5H), 1.25-1.31 (m, 3H).

[0455] LC-MS, M / Z (ESI): 452.2[M+H] + .

[0456] Example 16: Preparation of (3-([1,2,4]triazolo[1,5-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)(4,4-difluoropiperidine-1-yl)methanone (I-16)

[0457] The synthetic route for target compound I-16 is as follows:

[0458] [ka]

[0459] The synthesis of compound I-16 followed the procedure for compound I-1, with intermediate B16-1 replacing A1-2.

[0460] 1 H NMR (400 MHz, CDCl3) δ 8.37 (d, 1H), 8.24 (s, 1H), 8.05 (d, 1H), 7.72 (d, 1H), 7.28 (d, 1H), 7.07 (dd, 1H), 4.03 (d, 1H), 3.82 (d, 2H), 3.75 (s, 3H), 2.10 (dd, 2H), 2.02 (s, 4H), 1.22 (dd, 1H), 1.15 (td, 1H).

[0461] LC-MS, M / Z (ESI): 411.2[M+H] + .

[0462] Example 17: Preparation of (3-([1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)(4,4-difluoropiperidine-1-yl)methanone (I-17)

[0463] The synthesis route for target compound I-17 is as follows:

[0464] [ka]

[0465] The synthesis of compound I-17 followed the procedure for compound I-1, with intermediate B17-1 replacing A1-2.

[0466] 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.05 (d, 1H), 7.91 (d, 1H), 7.70 (d, 1H), 7.24 (s, 1H), 6.94 (d, 1H), 4.03 (d, 1H), 3.81 (d, 2H), 3.75 (s, 3H), 2.11 (dd, 2H), 2.02 (s, 4H), 1.18 (ddd, 2H).

[0467] LC-MS, M / Z (ESI): 411.2[M+H] + .

[0468] Example 18: Preparation of 6-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridine-3-one (I-18)

[0469] The synthesis route for target compound I-18 is as follows:

[0470] [ka]

[0471] Step 1: Synthesis of 6-chloro-4-formylnicotinic acid (B18-2)

[0472] [ka]

[0473] To a tetrahydrofuran solution of 2,2,6,6-tetramethylpiperidine (50 ml), n-butyllithium (40.6 ml, 102 mmol) was added dropwise at -78°C. After the addition was complete, stirring was continued at -78°C for 30 minutes, and then at -50°C for another 30 minutes. Subsequently, a tetrahydrofuran solution of 6-chloronicotinic acid (4 g, 25.4 mmol) (25 ml) was added dropwise at -78°C. After the addition was complete, stirring was continued at -78°C for 30 minutes, and then at -50°C for another 30 minutes. Finally, N,N-dimethylformamide (12 ml, 155.2 mmol) was added dropwise at -78°C, and the mixture was slowly raised to room temperature and stirred overnight. The reaction system was quenched by adding 2N HCl at 0°C, the pH was adjusted to 7, and most of the tetrahydrofuran solvent was removed by vacuum distillation. Further, the pH was adjusted to 3 with 2N HCl, a large amount of solid was precipitated, filtered, the cake was washed with water (40 ml), the cake was drained and dried to obtain 1.61 g of the pale gray solid compound 6-chloro-4-formylnicotinic acid (B18-2) (1.61 g, yield: 34.2%).

[0474] LC-MS, M / Z (ESI): 183.8[MH] - .

[0475] Step 2: Synthesis of 6-chloro-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridine-3-one (B18-3)

[0476] [ka]

[0477] Using nitrogen gas, a suspension of 6-chloro-4-formylnicotinic acid (520 mg, 2.8 mmol) in glacial acetic acid (1.12 ml, 19.6 mmol) was mixed with 40% aqueous methylamine solution (0.36 ml, 3.22 mmol), a 4M dioxane solution of hydrogen chloride (0.77 ml, 3.08 mmol), and sodium triacetoxyborohydride (891 mg, 4.2 mmol). The mixture was stirred at room temperature for 18 hours, then stirred at 60°C for 5 hours. Further, 40% aqueous methylamine solution (0.25 ml, 2.24 mmol) and sodium triacetoxyborohydride (475 mg, 2.24 mmol) were added at room temperature, and the reaction was continued at room temperature for 18 hours. Ethyl acetate (30 ml) was added, washed with 1 M sodium carbonate solution (30 ml), washed with water (30 ml), washed with saturated saline solution (30 ml), dried over anhydrous sodium sulfate, and concentrated to obtain compound 6-chloro-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridine-3-one (B18-3) (pale yellow solid, 312.2 mg, yield: 61%).

[0478] LC-MS, M / Z (ESI): 183.0[M+H] + .

[0479] Step 3: Synthesis of 6-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridine-3-one (I-18)

[0480] [ka]

[0481] The synthesis of compound I-18 followed the procedure for compound I-1, with intermediate B18-3 replacing A1-2.

[0482] 1H NMR (400 MHz, DMSO) δ 8.58 (d, 1H), 8.12 (d, 1H), 7.90 (d, 1H), 7.58 (s, 1H), 4.88 (d, 1H), 4.41 (dd, 2H), 3.63 (s, 4H), 3.34 (s, 1H), 3.01 (s, 3H), 2.19 (td, 1H), 2.15-1.99 (m, 5H), 1.09-1.01 (m, 1H), 0.90 (d, 1H).

[0483] LC-MS, M / Z (ESI): 440.2[M+H] + .

[0484] Example 19: Preparation of 3'-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-6'-methylspiro[cyclopropane-1,5'-pyrrolo[3,4-b]pyridine]-7'(6'H)-one (I-19)

[0485] The synthetic route for target compound I-19 is as follows:

[0486] [ka]

[0487] The synthesis of compound I-19 followed the procedure for compound I-1, with intermediate A3 replacing A1-2.

[0488] 1 H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.98 (d, 1H), 7.72 (s, 1H), 7.22 (s, 1H), 3.94-3.91 (m, 2H), 3.81-3.76 (m, 2H), 3.25 (s, 3H), 2.07-2.04 (m, 3H), 1.73-1.62 (m, 6H), 1.37 (s, 1H), 1.28-1.23 (m, 3H), 1.19-1.17(m, 1H).

[0489] LC-MS, M / Z (ESI): 466.2[M+H] + .

[0490] Example 20: Preparation of 7-(6-(3-fluoro-3-methylazetidine-1-carbonyl)-1a,2-dihydro-1H-cyclopropa[c][1,8]naphthyridine-3(7bH)-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-20)

[0491] The synthetic route for target compound I-20 is as follows:

[0492] [ka]

[0493] Step 1: 1a,2,3,7b-Tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylate methyl (B20-1)

[0494] [ka]

[0495] 35 g, 108 mmol of 3-(4-methoxybenzyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthirizine-6-carboxylate methyl ester (108 mmol) was placed in a 500 ml flask, trifluoroacetic acid (83 ml) was added, and the mixture was stirred at 60°C for 4 hours to allow it to react. After the reaction was complete, trifluoroacetic acid was removed by spin distillation, and the residue was slowly added to 500 ml of water. The pH was adjusted to 1 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (300 ml x 3). The aqueous phase was further adjusted to 9 with sodium carbonate powder, and extracted with dichloromethane (500 ml x 3). The organic phases were combined, anhydrous sodium sulfate was added, and the mixture was dried. The mixture was filtered and concentrated to obtain 1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthirizine-6-carboxylate methyl ester (20.3 g, yield: 92%).

[0496] LC-MS, M / Z (ESI): 205.1 [M+H] + .

[0497] Step 2: 3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylate methyl(B20-2)

[0498] [ka]

[0499] Under the protection of nitrogen gas, 1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylate methyl (19.4 g, 95 mmol), cesium carbonate (77 g, 237 mmol), 7-bromo-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (23.83 g, 104 mmol), bis(dibenzylideneacetone)palladium (8.7 g, 9.5 mmol), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (5.5 g, 19.5 mmol) were added to dioxane (200 ml), and the reaction was stirred at 85°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. Ethyl acetate (90 ml) and petroleum ether (180 ml) were added to the crude product, and the mixture was stirred for 2 hours to form a slurry. The mixture was then filtered to obtain 3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylate methyl (44 g, crude product).

[0500] LC-MS, M / Z (ESI): 352.1 [M+H] + .

[0501] Step 3: 3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylic acid (B20-3)

[0502] [ka]

[0503] The crude product 3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylate methyl (41.3 g, 118 mmol) was dissolved in a mixed solution of tetrahydrofuran (300 ml), methanol (60 ml), and water (60 ml), and lithium hydroxide monohydrate (24.66 g, 588 mmol) was added. The mixture was stirred at room temperature for 12 hours. The mixture was stirred, and after the reaction was complete, it was concentrated to obtain the residue. The residue was dissolved in water (300 ml), extracted with ethyl acetate (300 ml x 3), concentrated hydrochloric acid was added dropwise to the aqueous phase under stirring conditions to adjust the pH to 1, and filtered to obtain 3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylic acid (27 g, 2-step yield: 87%).

[0504] LC-MS, M / Z (ESI): 338.1 [M+H] + .

[0505] Step 4: 7-(6-(3-fluoro-3-methylazetidine-1-carbonyl)-1a,2-dihydro-1H-cyclopropa[c][1,8]naphthyridine-3(7bH)-yl)-2-methyl-[1,2,4]triazolo[4,3a]pyridine-3(2H)-one(I-20)

[0506] [ka]

[0507] Under the protection of nitrogen gas, 3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylic acid (280 mg, 830 μmol), 3-fluoro-3-methylazetidine hydrochloride (148 mg, 1.18 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (316 mg, 830 μmol), and N,N-diisopropylethylamine (107 mg, 830 μmol) were added to N,N-dimethylformamide (5 ml) and reacted at 25°C for 8 hours under the protection of nitrogen gas. After the reaction was complete, water (50 ml) was added to the reaction solution, then extracted with ethyl acetate (60 ml x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by high-performance liquid chromatography (LAC: Phenomenex Synergi C). 18 The sample size was 150 × 50 mm × 10 μm; solvent: A = water + 0.1 volume percent ammonium bicarbonate (99%), B = acetonitrile; gradient: 16% to 46%, 10 min. The target compound 7-(6-(3-fluoro-3-methylazetidine-1-carbonyl)-1a,2-dihydro-1H-cyclopropa[c][1,8]naphthyridine-3(7bH)-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(I-20) (218 mg, yield: 62.9%).

[0508] 1H NMR (400 MHz, CDCl3) δ 8.23 ​​(d, J = 2.0 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 6.52-6.54 (m, 2H), 4.39-4.46 (m, 1.11-1.16 (m, 2H).

[0509] LC-MS, M / Z (ESI): 409.1 [M+H] + .

[0510] Example 21: Preparation of 7-(6-(3,3-difluoropyrrolidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-21)

[0511] The synthesis route for target compound I-21 is as follows:

[0512] [ka]

[0513] 3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylic acid (200 mg, 0.6 mmol), 3,3-difluoropyrrolidine (62 mg, 0.7 mmol), and N,N-diisopropylethylamine (155 mg, 1.2 mmol) were dissolved in N,N-dimethylformamide (10 ml), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (270 mg, 0.7 mmol) was added. The reaction solution was allowed to react at 25°C for 1 hour. After the reaction was complete, the solution was diluted with water (20 ml), extracted three times with ethyl acetate (90 ml), the organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by reverse-phase high-performance liquid chromatography (COL: Phenomenex C). 18 The sample was 75 × 30 mm × 3 μm; solvent: A = water + 1 volume percent formic acid (99%) + water, B = acetonitrile; gradient: 28% to 58%, 7 min), and 7-(6-(3,3-difluoropyrrolidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-21) (170 mg, yield: 50.4%) was obtained.

[0514] 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, 1H), 7.91 (s, 1H), 7.62 (d, 1H), 6.70 (s, 1H), 6.57 (d, 1H), 3.88-3.91 (m, 3H), 3.65-3.68 (m, 3H), 3.48 (s, 3H), 2.40-2.45(m, 2H), 2.20-2.23(m, 1H), 2.06-2.08(m, 1H), 1.04-1.09(m, 2H).

[0515] LC-MS, M / Z (ESI): 427.2 [M+H]+ .

[0516] Example 22: Preparation of 2-methyl-7-(6-(morpholine-4-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-22)

[0517] The synthetic route for target compound I-22 is as follows:

[0518] [ka]

[0519] 3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cycloproa[c][1,8]naphthyrizine-6-carboxylic acid (200 mg, 0.6 mmol), morpholine (62 mg, 0.7 mmol), and N,N-diisopropylethylamine (155 mg, 1.2 mmol) were dissolved in N,N-dimethylformamide (10 ml), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (270 mg, 0.7 mmol) was added. The reaction solution was allowed to react at 25°C for 1 hour. After the reaction was complete, the solution was diluted with water (20 mL), extracted three times with ethyl acetate (90 mL), combined the organic phases, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by reverse-phase high-performance liquid chromatography (COL: Phenomenex C). 18The sample was 75 × 30 mm × 3 μm; solvent: A = water + 1 volume percent formic acid (99%) + water, B = acetonitrile; gradient: 28%~58%, 7 min), and was freeze-dried to obtain 2-methyl-7-(6-(morpholine-4-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(I-22) (170 mg, yield: 50.4%).

[0520] 1 H NMR (400 MHz, CDCl3) δ 8.08 (d, 1H), 7.71 (d, 1H), 7.58 (dd, 1H), 6.55-6.50 (d, 2H), 3.95 (d, 1H), 3.71-3.63 (m, 12H), 2.01-2.06 (m, 2H), 1.18-1.13 (m, 2H).

[0521] LC-MS, M / Z (ESI): 407.2 [M+H] + .

[0522] Example 23: Preparation of 7-(6-(3-(difluoromethyl)piperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-23)

[0523] The synthesis route for target compound I-23 is as follows:

[0524] [ka]

[0525] 3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylic acid (200 mg, 0.6 mmol), 3-(difluoromethyl)piperidine (96 mg, 0.7 mmol), and N,N-diisopropylethylamine (155 mg, 1.2 mmol) were dissolved in N,N-dimethylformamide (10 ml), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (270 mg, 0.7 mmol) was added. The reaction solution was allowed to react at 25°C for 1 hour. After the reaction was complete, the solution was diluted with water (20 mL), extracted three times with ethyl acetate (90 mL), combined the organic phases, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by reverse-phase high-performance liquid chromatography (COL: Phenomenex C). 18 The sample was 75 × 30 mm × 3 μm; solvent: A = water + 1 volume percent formic acid (99%) + water, B = acetonitrile; gradient: 28% to 58%, 7 min), and 7-(6-(3-(difluoromethyl)piperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-23) (144 mg, yield: 53.5%) was obtained.

[0526] 1 H NMR (400 MHz, CDCl3) δ 8.07 (t, 1H), 7.69 (t, 1H), 7.58 (d, 1H), 6.55-6.50 (m, 2H), 5.69 (t, 1H), 3.95 (d, 1H), 3.70 (d, 1H), 3.63 (s, 3H), 3.01 (b, 2H), 2.09-2.01 (m, 4H), 1.60 (b, 1H), 1.58-1.49 (m, 4H), 1.18 -1.12 (m, 2H).

[0527] LC-MS, M / Z (ESI): 455.2 [M+H] + .

[0528] Example 24: Preparation of 7-(6-(3,3-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2-methyl-[1,2,4]triazolo[4,3a]pyridine-3(2H)-one (I-24)

[0529] The synthetic route for target compound I-24 is as follows:

[0530] [ka]

[0531] 3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylic acid (200 mg, 593 μmol), 3,3-difluoropiperidine (108 mg, 889 μmol), and N,N-diisopropylethylamine (153 mg, 1.18 mmol) were dissolved in N,N-dimethylformamide (10 ml), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (271 mg, 711 μmol) was added. The reaction solution was allowed to react at 25°C for 1 hour. After the reaction was complete, the solution was diluted with water (20 mL), extracted three times with ethyl acetate (10 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was analyzed by column chromatography (DCM / MeOH(v / v)=15 / 1) to obtain the target compound 7-(6-(3,3-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(I-24) (120 mg, yield: 46%).

[0532] 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 6.55 (dd, J = 7.6, 2.0 Hz, 1H), 6.51 (d, J = 1.5 Hz, 1H), 3.94 (d, J = 11.1 Hz, 1H), 3.79 (d, J = 9.2 Hz, 2H), 3.70 (dd, J = 10.9, 1.4 Hz, 2H), 3.63 (s, 4H), 2.14-2.04 (m, 4H), 1.89-1.81 (m, 2H), 1.19-1.10 (m, 2H).

[0533] LC-MS, M / Z (ESI): 441.1 [M+H] + .

[0534] Example 25: Preparation of 7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2-(methyl-d3)-[1,2,4]triazolo[4,3a]pyridine-3(2H)-one(I-25)

[0535] The synthetic route for target compound I-25 is as follows:

[0536] [ka]

[0537] The synthesis of compound I-25 followed the procedure for compound I-3, with iodomethane replaced by deuterated iodomethane. LC-MS, M / Z (ESI): 444.2[M+H] + .

[0538] 1H NMR (400 MHz, DMSO) δ 8.03 (d, 1H), 7.80 (s, 1H), 7.61 (d, 1H), 6.68 (d, 1H), 6.58 (dd, 1H), 3.90 (d, 1H), 3.66-3.59(m, 5H), 2.18-2.16(m, 1H), 2.08-1.99(m, 5H), 1.06 (t, 2H)

[0539] Product I-25 was separated by SFC (chromatographic column: Chiralpak AD-3 50×4.6 mm ID, 3 μm; mobile phase: mobile phase A: CO2, mobile phase B: IPA + ACN (DEA at 0.05 vol.%); isocratic elution: IPA + ACN (DEA at 0.05 vol.%) (in CO2); flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; column pressure: 100 Bar). Isomers (I-25A) (RT=0.764 min) and (I-25B) (RT=1.702 min) were obtained.

[0540] [ka]

[0541] Example 26: Preparation of 2-methyl-7-(6-(3-(trifluoromethyl)piperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-26)

[0542] The synthetic route for target compound I-26 is as follows:

[0543] [ka]

[0544] 3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylic acid (200 mg, 593 μmol), 3-trifluoromethylpiperidine (136 mg, 889 μmol), and N,N-diisopropylethylamine (153 mg, 1.18 mmol) were dissolved in N,N-dimethylformamide (10 ml), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (271 mg, 711 μmol) was added. The reaction solution was allowed to react at 25°C for 1 hour. After the reaction was complete, the solution was diluted with water (20 ml), extracted three times with ethyl acetate (10 ml), the organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was analyzed by column chromatography (DCM / MeOH(v / v)=15 / 1) to obtain the target compound (I-26) (130 mg, yield: 50%).

[0545] 1 H NMR (400 MHz, CDCl3) δ 8.06 (t, J = 2.0 Hz, 1H), 7.68 (t, J = 1.9 Hz, 1H), 7.58 (dd, J = 7.6, 0.5 Hz, 1H), 6.54 (dd, J = 7.6, 2.0 Hz, 1H), 6.51 (d, J = 1.4 Hz, 1H), 3.94 (d, J = 11.0 Hz, 1H), 3.70 (d, J = 10.4 Hz, 1H), 3.63 (s, 3H), 2.98 (s, 2H), 2.32 (s, 1H), 2.09 (ddd, J = 11.7, 10.3, 7.3Hz, 3H), 1.84 (s, 1H), 1.68 (d, J = 10.3 Hz, 1H), 1.66-1.45 (m, 3H), 1.19-1.10 (m, 2H).

[0546] LC-MS, M / Z (ESI): 473.1 [M+H] + .

[0547] Example 27: Preparation of 7-(6-(3-fluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-27)

[0548] The synthesis route for target compound I-27 is as follows:

[0549] [ka]

[0550] Add 3-(2-methyl-3-oxy-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyrizine-6-carboxylic acid (200 mg, 0.59 mmol) and 3-fluoropiperidine hydrochloride (83 mg, 0.59 mmol), N,N-diisopropylethylamine (307 mg, 2.37 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (271 mg, 0.71 mmol) to N,N-dimethylformamide (6 ml) and heat at room temperature for 2 The reaction was carried out, the reaction solution was added to water (30 ml), then extracted with dichloromethane (50 ml x 2), the organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was purified by silica gel column chromatography (ethyl acetate:methanol (V / V) = 20:1) to obtain compound 7-(6-(3-fluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-27) (196 mg, yield: 78.4%).

[0551] 1H NMR (400 MHz, DMSO) δ 7.96 (d, 1H), 7.75 (d, 1H), 7.62 (d, 1H), 6.68 (d, 1H), 6.59 (ddd, 1H), 4.77 (d, 1H), 3.91 (d, 2H), 3.65 (dd, 1H), 3.49 (s, 5H), 3.15 (s, 1H), 2.19 (dt, 1H), 2.08 (dd, 1H), 1.90 (d, 2H), 1.77-1.66 (m, 1H), 1.54 (s, 1H), 1.12-1.03 (m, 2H).

[0552] LC-MS, M / Z (ESI): 423.3 [M+H] + .

[0553] Example 28: Preparation of 7-(6-(6-azaspiro[2.5]octane-6-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-28)

[0554] The synthetic route for target compound I-28 is as follows:

[0555] [ka]

[0556] Add 3-(2-methyl-3-oxy-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyrizine-6-carboxylic acid (120 mg, 0.36 mmol), 6-azaspiro[2.5]octane (40 mg, 0.36 mmol), N,N-diisopropylethylamine (184 mg, 1.42 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (162 mg, 0.43 mmol) to N,N-dimethylformamide (5 ml) and incubate at room temperature for 2 hours. The reaction solution was added to water (30 ml), then extracted with dichloromethane (50 ml x 2), the organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 30:1) to obtain compound 7-(6-(6-azaspiro[2.5]octane-6-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(I-28) (82 mg, yield: 53.6%).

[0557] 1 H NMR (400 MHz, DMSO) δ 7.98 (d, 1H), 7.77 (d, 1H), 7.61 (d, 1H), 6.67 (d, 1H), 6.59 (dd, 1H), 3.90 (d, 1H), 3.64 (dd, 2H), 3.48 (s, 5H), 2.19 (dd, 1H), 2.07 (dd, 1H), 1.35 (s, 4H), 1.25 (dd, 1H), 1.06 (t, 2H), 0.34 (s, 4H).

[0558] LC-MS, M / Z (ESI): 431.2 [M+H] + .

[0559] Example 29: Preparation of 7-(6-(3-azabicyclo[3.1.0]hexane-3-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-29)

[0560] The synthetic route for target compound I-29 is as follows:

[0561] [ka]

[0562] 3-(2-methyl-3-oxy-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyrizine-6-carboxylic acid (200 mg, 0.59 mmol), 3-azabicyclo[3.1.0]hexane (49 mg, 0.59 mmol), N,N-diisopropylethylamine (307 mg, 2.37 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added to N,N-dimethylformamide (5 ml), and the mixture was reacted at room temperature for 2 hours to obtain the reaction solution. The mixture was added to water (30 ml), then extracted with dichloromethane (50 ml x 2), the organic phases were combined, washed with saturated saline solution (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was purified by silica gel column chromatography (ethyl acetate:methanol (V / V) = 25:1) to obtain compound 7-(6-(3-azabicyclo[3.1.0]hexane-3-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-29) (158 mg, yield: 66.1%).

[0563] 1H NMR (400 MHz, DMSO) δ 8.06 (d, 1H), 7.82 (d, 1H), 7.61 (d, 1H), 6.68 (d, 1H), 6.57 (dd, 1H), 3.93 (dd, 2H), 3.80-3.61 (m, 2H), 3.48 (s, 3H), 3.43 (d, 2H), 2.18 (dd, 1H), 2.11-2.03 (m, 1H), 1.54 (d, 2H), 1.11-0.99 (m, 2H), 0.64 (dd, 1H), 0.07 (s, 1H).

[0564] LC-MS, M / Z (ESI): 403.2 [M+H] +

[0565] Example 30: Preparation of 7-(6-((R)-3-(fluoromethyl)piperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-30)

[0566] The synthesis route for target compound I-30 is as follows:

[0567] [ka]

[0568] 3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylic acid (200 mg, 0.6 mmol), (R)-3-(fluoromethyl)piperidine (70 mg, 0.6 mmol), and N,N-diisopropylethylamine (155 mg, 1.2 mmol) were dissolved in N,N-dimethylformamide (10 ml), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (270 mg, 0.7 mmol) was added. The reaction solution was allowed to react at 25°C for 1 hour. After the reaction was complete, the solution was diluted with water (20 mL), extracted three times with ethyl acetate (90 mL), combined the organic phases, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by reverse-phase high-performance liquid chromatography (COL: Phenomenex C). 18 The sample was 75 × 30 mm × 3 μm; solvent: A = water + 1 volume percent formic acid (99%) + water, B = acetonitrile; gradient: 28% to 58%, 7 min), and 7-(6-((R)-3-(fluoromethyl)piperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(I-30) (183 mg, yield: 70.7%).

[0569] 1 H NMR (400 MHz, CDCl3) δ 8.07 (t, 1H), 7.69 (s, 1H), 7.58 (d, 1H), 6.56-6.54 (m, 1H), 6.45 (t, 1H), 4.36 (d, 3H), 3.95 (d, 1H), 3.69 (d, 1H), 3.63 (s, 3H), 3.01 (b, 2H), 2.09-1.78 (m, 6H), 1.60 (b, 1H), 1.40 (b, 1H), 1.19 -1.10 (m, 2H).

[0570] LC-MS, M / Z (ESI): 437.2 [M+H] + .

[0571] Example 31: Preparation of 7-(6-((S)-3-(fluoromethyl)piperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-31)

[0572] [ka]

[0573] 3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-carboxylic acid (200 mg, 0.6 mmol), (S)-3-(fluoromethyl)piperidine (70 mg, 0.6 mmol), and N,N-diisopropylethylamine (155 mg, 1.2 mmol) were dissolved in N,N-dimethylformamide (10 ml), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (270 mg, 0.7 mmol) was added. The reaction solution was allowed to react at 25°C for 1 hour. After the reaction was complete, the solution was diluted with water (20 ml), extracted three times with ethyl acetate (90 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by reverse-phase high-performance liquid chromatography (COL: Phenomenex C). 18The sample was 75 × 30 mm × 3 μm; solvent: A = water + 1 volume percent formic acid (99%) + water, B = acetonitrile; gradient: 28% to 58%, 7 min), and 7-(6-((S)-3-(fluoromethyl)piperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(I-31) (white solid, 206 mg, yield: 79.6%).

[0574] 1 H NMR (400 MHz, CDCl3) δ 8.07 (t, 1H), 7.69 (s, 1H), 7.58 (d, 1H), 6.56-6.54 (m, 1H), 6.45 (t, 1H), 4.36 (d, 3H), 3.95 (d, 1H), 3.69 (d, 1H), 3.63 (s, 3H), 3.01 (b, 2H), 2.09-1.78 (m, 6H), 1.60 (b, 1H), 1.40 (b, 1H), 1.19-1.10 (m, 2H).

[0575] LC-MS, M / Z (ESI): 437.2 [M+H] + .

[0576] Example 32: Preparation of 7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyrizin-3-yl)-2-ethyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (I-32)

[0577] The synthetic route for target compound I-32 is as follows:

[0578] [ka]

[0579] Step 1: Synthesis of 7-bromo-2-ethyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (B32-1)

[0580] [ka]

[0581] 7-Bromo-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (B3-3) (100 mg, 467 ml) was dissolved in N,N-dimethylformamide (5 ml), cesium carbonate (457 mg, 1.40 mmol) was added, and ethyl iodide (219 mg, 1.40 mmol) was added under the protection of nitrogen gas at 0-10°C. After the addition was complete, the reaction was carried out at 25°C for 2 hours, the reaction solution was poured into water (10 ml), extracted with ethyl acetate (20 ml x 3), the organic phases were combined, washed with saturated saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 7-bromo-2-ethyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (B32-1) (113 mg, yield: 99.4%).

[0582] LC-MS, M / Z (ESI): 242.1 [M+H] + .

[0583] Step 2: Synthesis of 7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2-ethyl-[1,2,4]triazolo[4,3a]pyridine-3(2H)-one(I-32)

[0584] [ka]

[0585] Under the protection of nitrogen gas, (4,4-difluoropiperidine-1-yl)(1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)methanone (145 mg, 493 umol), cesium carbonate (201 mg, 477 umol), 7-bromo-2-ethyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (60.0 mg, 247 umol), bis(dibenzylideneacetone)palladium (22.6 mg, 24.7 umol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28.5 mg, 49.3 umol) were added to 1,4-dioxane (10 ml) and reacted with stirring at 100°C for 2 hours. After the reaction was complete, the reaction solution was poured into water (10 ml), extracted with ethyl acetate (10 ml x 3), combined the organic phases, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Next, the crude product was separated and analyzed using preparative high-performance liquid chromatography (column: Phenomenex Synergi C). 18 Compound 7-(6-(4,4-difluoropiperidine-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropa[c][1,8]naphthyridine-3-yl)-2-ethyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one(I-32) (80.0 mg, yield: 71.2%) was obtained by (150 × 25 mm × 5 μm; solvent: A = water + 0.1 volume percent formic acid (99%), B = acetonitrile; gradient: 30% to 60% B, 7 min).

[0586] 1 H NMR (400 MHz, DMSO d6) δ = 8.04 (d, 1H), 7.82 (d, 1H), 7.63 (d, 1H), 6.72 (s, 1H), 6.57-6.60 (m, 1H), 3.87-3.93 (m, 3H), 3.61-3.67 (m, 5H), 2.15-2.18 (m, 1H), 2.01-2.09 (m, 5H), 1.28 (t, 3H), 1.06-1.09 (m, 2H).

[0587] Test Example 1: 15-PGDH enzyme inhibition test using a compound 15-PGDH (R&D Systems, catalog number: 5660-DH-010) was prepared to twice its final concentration, i.e., 30 nM, using Assay Buffer (50 mM Tris-HCl, pH: 7.5, Tween20 at 0.01 volume). Next, 8 μl / well was added to a 384 white plate (Cisbio Bioassays, catalog number: 66PL384025). A negative control well was prepared and only Assay Buffer was added without the enzyme. Next, the compound was diluted 3-fold to 10 concentrations, starting at 4 times its final concentration, i.e., 4000 nM, using Assay Buffer. 4 μl / well was added to the above white plate, mixed uniformly, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 10 minutes. Simultaneously, a positive control well (15-PGDH only added) and a negative control well (no 15-PGDH added) were prepared. Furthermore, using Assay Buffer, NAD + A mixed solution of (Select, catalog number: S2518) and PGE2 (R&D Systems, catalog number: 2296 / 10) was prepared. Using ssay buffer, each was converted to NAD + PGE2 was prepared at four times its final concentration, i.e., 2 mM and 0.12 mM. Next, 4 μl / well was added to the above white plate, mixed uniformly, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 30 minutes to allow the reaction to occur. Detection was performed using a TECAN SPARK 20M instrument at excitation wavelength 340 nm and emission wavelength 485 nm. The data was fitted with four parameters using GraphPad Prism 8.0 and IC was performed. 50 The value was calculated.

[0588] [Table 1]

[0589] The experimental results showed that the compound of the present invention has a significant inhibitory effect on 15-PGDH.

[0590] Test Example 2: Effect of Compounds on PGE2 Levels in A549 Cell Supernatant A549 cells (Procell, Wuhan) were cultured in F12K + 10% FBS. Logarithmic phase cells with good cell condition were selected for the experiment, digested and counted, and seeded at 8000 cells / well in a 24-well plate. The cells were cultured overnight in a 37°C, 5% CO2 incubator. After the cells adhered to the cell walls, the medium was changed to one containing 0.5% FBS and treated for approximately 10 hours. IL-1β (final concentration: 20 ng / mL, 1 mL / well) was added to each well, and a control group (without IL-1β) was simultaneously established. After stimulation with IL-1β for approximately 24 hours, the cell culture medium was aspirated and removed from each well. Each well was gently washed with fresh medium containing 0.5% FBS, and then 400 μL of medium containing the respective concentrations of the compound (20 nM and 2500 nM) was added to each well and treated for approximately 12 hours. The supernatant was collected, and PGE2 was detected using an ELISA kit (R&D Systems, catalog number: KGE004B).

[0591] [Table 2]

[0592] The experimental results show that the compound of the present invention can significantly increase the production of PGE2.

[0593] Example 3: Drug efficacy experiment in a mouse IPF prevention model Male mice were adaptively reared for 1-2 weeks until they reached standard body weight (25g), after which a predetermined amount of bleomycin was administered to induce an IPF model (idiopathic pulmonary fibrosis model). On the day of modeling, the animals were randomly divided into a model group and a treatment group according to their body weight. The treatment group was administered nintedanib (60mg / kg, once daily (qd) and compound I-3B of the present invention (2.5mg / kg, twice daily (bid))), with daily oral intragastric administration initiated. The solvent control group was administered a blank solvent, and administration continued for 21 days. Body weight was measured every 3 days during the administration period. At the end of the last day of administration, the animals were euthanized, the lungs were removed from the thyroid cartilage (perfusion was not necessary), and 10% formalin was slowly perfused into the lungs until both lungs were filled. After ligating the main trachea, the lungs were fixed with 10% formalin at 5-10 times the tissue volume. The left lung was then paraffinized, stained with HE, and Masson. Trichrome staining was performed, and panoramic scans of the sections were carried out for pathological analysis using a Hamamatsu NanoZoomer Digital Pathology (S210) slide scanner.

[0594] [Table 3]

[0595] [Table 4]

[0596] The experimental results show that the compound of the present invention can significantly reduce the degree of fibrosis in a mouse IPF prevention model.

[0597] Example 4: Drug efficacy experiment in a mouse IPF treatment model Male mice were adaptively reared for 1-2 weeks until they reached a standard body weight (25g), after which a predetermined amount of bleomycin was administered to induce an IPF model (idiopathic pulmonary fibrosis model). On the day of modeling, the animals were randomly divided into a model group and a treatment group according to their body weight. The treatment group received nintedanib (60mg / kg, qd), a low dose of the present invention's compound I-3B (1mg / kg, bid), and a high dose of the present invention's compound I-3B (2.5mg / kg, bid), with daily oral intragastric administration starting from Day 7. The solvent control group received a blank solvent, and administration continued for 14 consecutive days. Body weight was measured twice a week during the administration period. At the end of the final day of administration, the animals were euthanized, the lungs were removed from the thyroid cartilage (perfusion was not necessary), and 10% formalin was slowly perfused into the lungs until both lungs were full. The main trachea was then ligated, and the lungs were fixed with 10% formalin at 5-10 times their tissue volume. The left lung was subjected to paraffin tissue sectioning, HE staining, and Masson Trichrome staining, and a panoramic scan of the section was performed for pathological analysis using a Hamamatsu NanoZoomer Digital Pathology (S210) slide scanner.

[0598] [Table 5]

[0599] [Table 6]

[0600] The experimental results show that the compound of the present invention can significantly reduce the degree of fibrosis in a mouse IPF treatment model.

[0601] Experiment Example 5: Experiment on the regenerative effect after liver resection in mice Eight-week-old male C57BL / 6J mice (20-24g) were anesthetized, their abdomens were fixed in an upward position, the surgical site was shaved, and disinfected with iodine. A transverse abdominal incision of approximately 1.5-2 cm was made, and both abdominal wall arteries were clamped with hemostatic clips. After opening the abdominal cavity, each liver lobe was separated, and the hepatic hilum of the liver lobe to be resected was tied off with surgical wire. Once the color had darkened, the left outer and middle lobes of the liver were resected. Postoperatively, residual blood in the abdominal cavity was washed away, and the muscular and cortical layers were sutured layer by layer, with careful postoperative care. Administration was started on the day of modeling, and eight animals were euthanized on day 1 and day 3. Intact liver tissue was removed, weighed, and compared with the model group to evaluate the effect of the drug on promoting liver regeneration.

[0602] The experimental results indicate that the compound of the present invention can significantly promote liver regeneration.

[0603] Study Example 6: Pharmacokinetics in Mice The pharmacokinetic properties of the compound of the present invention were measured in mice by referring to the experimental method described below.

[0604] Three male CD-1 mice were used and administered intragastricly at a dose of 10 mg / kg. The solvent was 5% DMSO + 10% Solutol + 85% Saline. The mice were fasted overnight, and blood samples were collected before administration and at 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours post-administration. 6800 g of blood samples were centrifuged at 2–8°C for 6 minutes to collect plasma, which was then stored at -80°C. 10 μL of plasma was taken at each time point, 200 μL of methanol containing a 100 ng / mL internal standard was added, and the mixture was vortexed to ensure homogeneity. The samples were then centrifuged at 18000 rpm at 2–8°C for 7 minutes. 200 μL was taken and transferred to a 96-well sample plate for LC-MS / MS quantitative analysis. Key pharmacokinetic parameters were analyzed using a non-compartment model with WinNonlin 7.0 software.

[0605] [Table 7]

[0606] The experimental results show that the compound of the present invention exhibits favorable pharmacokinetic properties in mice.

[0607] Test Example 7: Pharmacological efficacy against IBD in mice Female C57BL / 6 mice aged 6-8 weeks were divided into five groups: G1-G5 were the normal control group, model control group, positive control group, low-dose compound I-3B group, and high-dose compound I-3B group, respectively. Mice in groups G2-G6 were given a 2% DSS aqueous solution from days 0-6, normal water from days 0-10, and administered the solvent / positive substance / test substance from days 0-9. On day 10, they were euthanized and necropped, and intestinal weight (CW) and intestinal length (CL) were measured, and intestinal tissue (BW) was subjected to histopathological examination. The test results showed that, compared to the G2 model group, the G3-positive control group (cyclosporine CsA 25 mg / kg-qd) animals had a significantly increased body weight, a significantly decreased DAI in the model animals, a significantly increased CL, and a significantly decreased CW, CL / CW / BW, and CL / CW. Histopathological examination of the colon tissue of the model animals showed a decrease in inflammatory cell infiltration and tissue damage scores, but the difference was not statistically significant. The G4-compound I-3B (2.5 mg / kg-bid) and G5-compound I-3B (5 mg / kg-bid) groups both showed an increase in body weight, with the G5 animals showing a significantly increased increase. The animals' DAI decreased significantly in all groups, CL increased significantly in all groups, and CW, CL / CW / BW, and CL / CW all decreased significantly. Histopathological examination of the colon tissue showed a significant decrease in inflammatory cell infiltration and tissue damage scores.

[0608] [Table 8]

[0609] The experimental results show that compound I-3B (2.5 mg / kg and 5 mg / kg) significantly improved IBD symptoms and tissue damage in mice, demonstrating a therapeutic effect greater than or equal to that of the positive group.

[0610] Although embodiments of the present invention have been shown and described above, these embodiments are illustrative and should not be construed as limiting the present invention. It should be understood that changes, modifications, substitutions, and variations of the above embodiments can be made by those skilled in the art within the scope of the present invention.

Claims

1. A heterocyclic compound represented by formula I, its solvate, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (however, Z １ Z ２ Z ３ Z ４ and Z ５ Each of these independently represents a ring atom, Z １ and Z ４ Each of these is independently N, Z ２ and Z ３ are each independently C or CH, Z ５ CH ２ or CH, R １ and R ２ These are hydrogen and C, respectively, independently. １ ~C ６ Alkyl or C ３ ~C ８ It is a cycloalkyl, Or, R １ and R ２ These, together with the N atoms linked to them, form a 3- to 8-membered heterocycloalkyl ring, where the heteroatoms contained in the 3- to 8-membered heterocycloalkyl ring are selected from N, O, or S, and the number of heteroatoms is 1, 2, 3, or 4, and further, 0, 1, or more R atoms. １－１ Substituting with, if there are multiple substituents, the substituents may be the same or different. Each R １－１ These are, independently, halogen, hydroxyl, amino, nitro, cyano, and C. １ ~C ６ Alkyl, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, Halo C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, or one or two C atoms of any choice １ ~C ６ It is an amino acid having an alkyl group, R ａ and R ｂ These are, independently, halogen, hydroxyl, amino, nitro, cyano, and C. １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy or Halo C １ ~C ６ It is an alkoxy, m and n are independently 0, 1, 2, or 3. X １ , X ２ , X ３ , X ４ and X ５ Each of these independently represents a ring atom, X ４ and X ５ These are N and CH, respectively, independently. ２ , CH or C, X1, X2, and X3 are each independently N, CH, or C. X ４ and X ５ The bond connected between them is either a single bond or a double bond. R ３ is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C １ -C ６ alkyl, C １ -C ６ deuterated alkyl, C ２ -C ６ alkynyl, halo C １ -C ６ alkyl, hydroxy C １ -C ６ alkyl, C １ -C ６ alkylcarbonyl, C １ -C ６ alkoxy, halo C １ -C ６ alkoxy, C １ -C ６ alkoxycarbonyl, C １ -C ６ alkoxy C １ -C ６ alkyl, C １ -C ６ alkoxycarbonyl C １ -C ６ alkyl, C ３ -C ８ cycloalkyl, C ３ -C ８ cycloalkylcarbonyl, C ３ -C ８ cycloalkoxy, optionally having one or two C １ -C ６ alkyl groups of an aminocarbonyl group, C １ -C ６ alkylsulfonyl group, optionally having one or two C １ -C ６ alkyl groups of an aminosulfonyl group, C １ -C ６ alkylsulfonylamino group or optionally having one or two C １ -C ６ alkyl groups of an amino and, X ４ and X ５ A base fragment formed by linking these fragments 【Chemistry 2】 In this case, A does not exist, or A and X ４ , X ５ The ring atoms together form a 3- to 7-membered heterocycloalkyl ring, a 5-membered heteroaromatic ring, or a 6-membered heteroaromatic ring, and the heteroatoms are independently selected from one or more of N, O, and S. If A does not exist, X ４ and X ５ Each of them is R independently ４ or R ５ Replaced by, If A exists, then A further R ３－１ Replaced by, the R ３－１ Substitution by is one or more substitutions, and if there are multiple substituents, the substituents may be the same or different. R ４ and R ３－１ These are, independently, hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, and C. １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkoxy, Halo C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxycarbonyl, C １ ~C ６ Alkylcarbonyloxy, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ６ Alkoxycarbonyl C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Cycloalkylcarbonyl, C ３ ~C ８ Cycloalkoxy, one or two C as optional １ ~C ６ an aminocarbonyl group having an alkyl group, C １ ~C ６ Alkyl sulfonyl group, optionally one or two C １ ~C ６ aminosulfonyl group having an alkyl group, C １ ~C ６ Alkylsulfonylamino group or one or two C groups of any choice １ ~C ６ It is an amino acid having an alkyl group, R ５ These are hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkoxy, Halo C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxycarbonyl, C １ ~C ６ Alkylcarbonyloxy, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ６ Alkoxycarbonyl C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Cycloalkylcarbonyl, C ３ ~C ８ Cycloalkoxy, one or two R's of your choice ５－１ an aminocarbonyl group having substitution by C １ ~C ６ Alkyl sulfonyl group, optionally one or two C １ ~C ６ aminosulfonyl group having an alkyl group, C １ ~C ６ Alkylsulfonylamino group or one or two C groups of any choice １ ~C ６ It is an amino acid having an alkyl group, Each of the aforementioned R ５－１ These are hydrogen and C, respectively, independently. １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, Halo C １ ~C ６ Alkoxy, or C １ ~C ６ Alkoxy C １ ~C ６ It is alkyl.

2. The heterocyclic compound represented by formula I is characterized by satisfying one or more of the following conditions: the heterocyclic compound represented by formula I according to claim 1, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof. ((1) The above R １ and R ２ However, in the 3- to 8-membered heterocycloalkyl rings formed together with the N atoms linked to them, the heterocycloalkyl ring is a monocyclic heterocycloalkyl ring, a bicyclic heterocycloalkyl ring with a bridged ring, or a bicyclic heterocycloalkyl ring with a spiro ring. (2) R １－１ In this, the halogen and the halo C １ ~C ６ In alkyl groups, the halogen and halo are independently F, Cl, or Br. (3) Caution １－１ In the case of C １ ~C ６ Alkyl and the halo C １ ~C ６ In alkyl groups, C １ ~C ６ The alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. (4) R ４ and R ５ In this, the halogens are independently F, Cl, or Br. (5) Caution ４ and R ５ In this case, one or two C of the above optional selection １ ~C ６ In an aminocarbonyl group having an alkyl group, C １ ~C ６ The alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. (6) A and X ４ , X ５ In a 3- to 7-membered heterocycloalkyl ring formed by ring atoms together, the heterocycloalkyl ring is either a monocyclic heterocycloalkyl ring or a bicyclic heterocycloalkyl ring of a spiro ring. (7) A and X ４ , X ５ In a 3- to 7-membered heterocycloalkyl ring formed by ring atoms, the number of heteroatoms in the heterocycloalkyl ring is 1, 2, 3, or 4. (8) A and X ４ , X ５ In a five-membered heteroaromatic ring or a six-membered heteroaromatic ring formed by ring atoms together, the number of heteroatoms is 1, 2, 3, or 4. (9) A exists, and the A further R ３－１ When replaced by, the R ３－１ The number is 2, (10) R ３－１ In the above-mentioned Hal C １ ~C ６ In alkyl groups, the halo is F, Cl, or Br. (11) R ３－１ In the case of C １ ~C ６ Alkyl, the aforementioned halo C １ ~C ６ Alkyl and the C １ ~C ６ In alkyl deuterated products, C １ ~C ６ The alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. (12) R ３－１ In the case of C ３ ~C ８ The cycloalkyl in cycloalkyl refers to a monocyclic cycloalkyl. (13) R ３－１ In the case of C ３ ~C ８ The cycloalkyl in cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. （１４） 【Transformation 3】 (This refers to phenyl or "a six-membered heteroaromatic ring having one, two, or three heteroatoms, where the heteroatoms are selected from one or more N, O, and S atoms.")

3. The heterocyclic compound represented by formula I is characterized by satisfying one or more of the following conditions: the heterocyclic compound represented by formula I according to claim 2, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof. ((1) Note １－１ In this, the halogen and the halo C １ ~C ６ In alkyl groups, halogens and halos are each independently represented by F. (2) R １－１ In the case of C １ ~C ６ Alkyl and the halo C １ ~C ６ In alkyl groups, C １ ~C ６ Each alkyl group is independently methyl. (3) Caution ４ and R ５ In this, each of the halogens is independently F, (4) R ４ and R ５ In this case, one or two C of the above optional selection １ ~C ６ In an aminocarbonyl group having an alkyl group, C １ ~C ６ Each alkyl group is independently methyl. (5) Caution ３－１ In the above-mentioned Hal C １ ~C ６ In alkyl groups, the halo is F. (6) R ３－１ In the case of C １ ~C ６ Alkyl, the aforementioned halo C １ ~C ６ Alkyl and the C １ ~C ６ In alkyl deuterated products, C １ ~C ６ Alkyl atoms are independently either methyl or ethyl. (7) The phenyl is 【Chemistry 4】 And, (8) "A six-membered heteroaromatic ring having one, two, or three heteroatoms, where the heteroatoms are selected from one or more N, O, and S" is, 【Transformation 5】 (That is the case.)

4. The heterocyclic compound represented by formula I is characterized by satisfying one or more of the following conditions: the heterocyclic compound represented by formula I according to claim 2, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof. (1) The 3- to 8-membered heterocycloalkyl ring is a monocyclic 3- to 6-membered heterocycloalkyl ring, a bicyclic 6- to 8-membered heterocycloalkyl ring of a bridged ring, or a bicyclic 8-membered heterocycloalkyl ring of a spiro ring, and the heteroatoms are N and / or O, and the number is one or two. (2) The 3-8 member heterocycloalkyl ring may further be a halogen and / or halo C １ ~C ６ Substituted with alkyl, (3) Caution １－１ In the above-mentioned Hal C １ ~C ６ Alkyl is trifluoromethyl, difluoromethyl, or monofluoromethyl. (4) R ４ and R ５ In this case, one or two C of the above optional selection １ ~C ６ Each aminocarbonyl group having an alkyl group is independently 【Transformation 6】 And, (5) A and X ４ , X ５ In a 3- to 7-membered heterocycloalkyl ring formed by ring atoms together, the 3- to 7-membered heterocycloalkyl ring is either a monocyclic 3- to 6-membered heterocycloalkyl ring or a bicyclic 7-membered heterocycloalkyl ring of a spiro ring, and the heteroatoms are independently N and / or O, and their number is 1, 2, or 3. (6) A and X ４ , X ５ In a five-membered heteroaromatic ring or a six-membered heteroaromatic ring formed by ring atoms, the heteroatoms are nitrogen (N), and their number is 1, 2, or 3. (7) R ３－１ In the above-mentioned Hal C １ ~C ６ Alkyl is, 【Transformation 7】 And, (8) R ３－１ In the case of C １ ~C ６ Alkyl deuterated is -CD ３ And, （９） 【Transformation 8】 The rings in which it is located are connected 【Chemistry 9】 (To form.)

5. The heterocyclic compound represented by formula I is characterized by satisfying one or more of the following conditions: the heterocyclic compound represented by formula I according to claim 4, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof. (1) The 3- to 8-membered heterocycloalkyl ring is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolidinyl-condensed-cyclopropyl, oxazaspiro[2.5]octyl, azaspiro[2.5]octyl, or octahydrocyclopenta[c]pyrrolidinyl, (2) A and X ４ , X ５ The ring atoms together form a 3- to 7-membered heterocycloalkyl ring, and this 3- to 7-membered heterocycloalkyl ring is pyrrolidinyl or azaspiro[2.4]heptyl. (3) A and X ４ , X ５ The ring atoms together form a five-membered heteroaromatic ring or a six-membered heteroaromatic ring, which is a pyridine ring, a pyrimidine ring, or a triazole ring.

6. The heterocyclic compound represented by formula I is characterized by satisfying (1) and / or (2), as described in claim 1, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof. ((1) Note １ and R ２ Together with the N atoms linked to them, they form the following groups: 【Chemistry 10】 （２） 【Chemistry 11】 teeth, 【Chemistry 12】 (That is the case.)

7. The heterocyclic compound represented by formula I is characterized by satisfying one or more of the following conditions: the heterocyclic compound represented by formula I according to claim 1, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof. ((1) Note １ and R ２ These, together with the N atoms linked to them, form a 3- to 8-membered heterocycloalkyl ring, where the 3- to 8-membered heterocycloalkyl ring further comprises 0, 1 or more R atoms. １－１ Replaced by, (2) R １－１ is halogen, C １ ~C ６ Alkyl or Halo C １ ~C ６ It is alkyl, (3) Caution ４ and R ５ It independently contains one or two C atoms of halogen, cyano, or of any choice. １ ~C ６ It is an aminocarbonyl group having an alkyl group, (4) R ３－１ These are independently oxo and C １ ~C ６ Alkyl, Halo C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl or C １ ~C ６ It is an alkyl deuterated, (5) The solvate of the pharmaceutically acceptable salt of the heterocyclic compound represented by formula I is a hydrate, (6) The heterocyclic compound represented by formula I has the structure represented by formula I-1 or the structure represented by formula I-2. 【Chemistry 13】 ）

8. The heterocyclic compound represented by formula I according to any one of claims 1 to 7, characterized in that the heterocyclic compound represented by formula I is one of the following schemes, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof. Scheme 1: The heterocyclic compound represented by formula I is the compound represented by formula I', 【Chemistry 14】 In equation I', Z １ Z ２ Z ３ Z ４ and Z ５ Each of these independently represents a ring atom, Z １ and Z ４ Each of these is independently N, Z ２ and Z ３ Each of them is independently either C or CH, Z ５ CH ２ or CH, R １ and R ２ These are hydrogen and C, respectively, independently. １ ~C ６ Alkyl or C ３ ~C ８ It is a cycloalkyl, R １ and R ２ These, together with the N atoms linked to them, form a 3-8 membered heterocycloalkyl ring, where the 3-8 membered heterocycloalkyl ring is further R １－１ Replaced by, Each R １－１ These are, independently, halogen, hydroxyl, amino, nitro, cyano, and C. １ ~C ６ Alkyl, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, Halo C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, or one or two C atoms of any choice １ ~C ６ It is an amino acid having an alkyl group, R ａ and R ｂ These are, independently, halogen, hydroxyl, amino, nitro, cyano, and C. １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy or Halo C １ ~C ６ It is an alkoxy, m and n are independently 0, 1, 2, or 3. X １ , X ２ , X ３ , X ４ and X ５ Each of these independently represents a ring atom, X １ , X ２ , X ３ , X ４ and X ５ Each of these is independently N or C, R ３ These are halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkoxy or Halo C １ ~C ６ It is an alkoxy, X ４ and X ５ A fragment of the base formed by linking together 【Chemistry 15】 In this case, A does not exist, or A and X ４ , X ５ The ring atoms together form a 3- to 7-membered heterocycloalkyl ring, a 5-membered heteroaromatic ring, or a 6-membered heteroaromatic ring, and the heteroatoms are selected from one or more of N, O, and S. If A does not exist, X ４ and X ５ Each of them is R independently ４ or R ５ Replaced by, A exists, and the aforementioned A is further R ３－１ When replaced by, the R ３－１ Substitution by is one or more substitutions, and if there are multiple substituents, the substituents may be the same or different. R ４ , R ５ and R ３－１ These are, independently, hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, and C. １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkoxy, Halo C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxycarbonyl, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ６ Alkoxycarbonyl C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Cycloalkylcarbonyl, C ３ ~C ８ Cycloalkoxy, one or two C as optional １ ~C ６ an aminocarbonyl group having an alkyl group, C １ ~C ６ Alkyl sulfonyl group, optionally one or two C １ ~C ６ aminosulfonyl group having an alkyl group, C １ ~C ６ Alkylsulfonylamino group or one or two C groups of any choice １ ~C ６ It is an amino acid having an alkyl group, Scheme 2: In the heterocyclic compound represented by the above formula I, Z １ is N, Z ２ and Z ３ is C, Z ４ is N, Z ５ CH ２ or CH, R １ and R ２ These, together with the N atoms linked to them, form a 3- to 8-membered heterocycloalkyl ring, where the 3- to 8-membered heterocycloalkyl ring further comprises 0, 1 or more R atoms. １－１ Replaced by, R １－１ is halogen, C １ ~C ６ Alkyl or Halo C １ ~C ６ It is alkyl, m and n are 0, R ３ It is hydrogen, R ４ and R ５ It independently contains one or two C atoms of halogen, cyano, or of any choice. １ ~C ６ aminocarbonyl group having an alkyl group; R ３－１ These are independently oxo and C １ ~C ６ Alkyl, Halo C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl or C １ ~C ６ It is an alkyl deuterated, X ４ and X ５ A fragment of the base formed by linking together 【Chemistry 16】 The definition is as described in claim 1, Scheme 3: The heterocyclic compound represented by formula I has the structure shown in formula II-1 below, 【Chemistry 17】 The definitions of each group in Equation II-1 are as follows: X ４ and X ５ Each of these independently represents a ring atom, X ４ and X ５ Each of these is independently C, and A and X ４ , X ５ Together, they form a 3-7 membered heterocycloalkyl ring, and the 3-7 membered heterocycloalkyl ring is further R ３－１ Replaced by, the R ３－１ Substitution by is one or more substitutions, and if there are multiple substituents, the substituents may be the same or different. Each R ３－１ These are, independently, hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, and C. １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkoxy, Halo C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxycarbonyl, C １ ~C ６ Alkylcarbonyloxy, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ６ Alkoxycarbonyl C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Cycloalkylcarbonyl, C ３ ~C ８ Cycloalkoxy, one or two C as optional １ ~C ６ aminocarbonyl group having an alkyl group , C １ ~C ６ Alkyl sulfonyl group, optionally one or two C １ ~C ６ aminosulfonyl group having an alkyl group, C １ ~C ６ Alkylsulfonylamino group or one or two C groups of any choice １ ~C ６ It is an amino acid having an alkyl group, Z １ Z ２ Z ３ , R １ , R ２ , R ３ , R ａ , R ｂ The definitions of m and n are as described in claim 1, X1 and X2 are independently N or CH, X 3 is C, Scheme 4: The heterocyclic compound represented by formula I has the structure shown in formula II-2 below, [Chemistry 18] The definitions of each group in Equation II-2 are as follows: R ３ , R ４ and R ５ These are, independently, hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, and C. １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkoxy, Halo C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxycarbonyl, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ６ Alkoxycarbonyl C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Cycloalkylcarbonyl, C ３ ~C ８ Cycloalkoxy, one or two C as optional １ ~C ６ an aminocarbonyl group having an alkyl group, C １ ~C ６ Alkyl sulfonyl group, optionally one or two C １ ~C ６ aminosulfonyl group having an alkyl group, C １ ~C ６ Alkylsulfonylamino group and optionally one or two C groups １ ~C ６ Selected from amino acids having alkyl groups, Z １ Z ２ Z ３ , R １ , R ２ , R ａ , R ｂ The definitions of m and n are as described in claim 1, X1 and X2 are independently N or CH, X 3 is C, Scheme 5: The heterocyclic compound represented by formula I has the structure represented by the following formulas III-1, III-2, III-3, III-4, III-5, III-6, III-7, and III-8. 【Chemistry 19】 【Chemistry 20】 Here, Z １ Z ２ Z ３ , R １ , R ２ , R ３ , R ３－１ , R ａ , R ｂ The definitions of m and n are as described in claim 1, X1 and X2 are independently N or CH, X 3 is C, Scheme 6: The heterocyclic compound represented by formula I has the structure shown in formula IV-1 below, 【Chemistry 21】 The definitions of each group in formula IV-1 are as follows: R ５－１ is hydrogen, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkoxy, Halo C １ ~C ６ Alkoxy, or C １ ~C ６ Alkoxy C １ ~C ６ It is alkyl, Z １ Z ２ Z ３ , R １ , R ２ , R ３ , R ａ , R ｂ The definitions of m and n are as described in claim 1, X1 and X2 are independently N or CH, X 3 is C, Scheme 7: The heterocyclic compound represented by formula I has the structure shown in formula IV-2 below, 【Chemistry 22】 The definitions of each group in formula IV-2 are as follows: R ５－１ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkoxy, Halo C １ ~C ６ Alkoxy, or C １ ~C ６ Alkoxy C １ ~C ６ It is alkyl, Z １ Z ２ Z ３ , R １ , R ２ , R ３ , R ａ , R ｂ The definitions of m and n are as described in claim 1, and R ４ It does not exist, X1 and X2 are independently N or CH, X 3 is C.

9. A heterocyclic compound represented by formula I as described in claim 8, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, In Equation II-1, X ４ and X ５ Each of these independently represents a ring atom, X ４ and X ５ Each of these is independently C, and A and X ４ , X ５ Together, they form a 3-7 membered heterocycloalkyl ring, and the 3-7 membered heterocycloalkyl ring is further R ３－１ Replaced by, the R ３－１ Substitution by is one or more substitutions, and if there are multiple substituents, the substituents may be the same or different. Each R ３－１ These are, independently, hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, and C. １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkoxy, Halo C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxycarbonyl, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ６ Alkoxycarbonyl C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Cycloalkylcarbonyl, C ３ ~C ８ Cycloalkoxy, one or two C as optional １ ~C ６ an aminocarbonyl group having an alkyl group, C １ ~C ６ Alkyl sulfonyl group, optionally one or two C １ ~C ６ aminosulfonyl group having an alkyl group, C １ ~C ６ Alkylsulfonylamino group or one or two C groups of any choice １ ~C ６ It is an amino acid having an alkyl group, In Equation II-2, R ３ These are hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkoxy or Halo C １ ~C ６ It is an alkoxy, R ４ and R ５ These are, independently, hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, and C. １ ~C ６ Alkyl, C １ ~C ６ Alkyl deuterated, C ２ ~C ６ Alkinil, Halo C １ ~C ６ Alkyl, hydroxy C １ ~C ６ Alkyl, C １ ~C ６ Alkylcarbonyl, C １ ~C ６ Alkoxy, Halo C １ ~C ６ Alkoxy, C １ ~C ６ Alkoxycarbonyl, C １ ~C ６ Alkylcarbonyloxy, C １ ~C ６ Alkoxy C １ ~C ６ Alkyl, C １ ~C ６ Alkoxycarbonyl C １ ~C ６ Alkyl, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Cycloalkylcarbonyl, C ３ ~C ８ Cycloalkoxy, one or two C as optional １ ~C ６ an aminocarbonyl group having an alkyl group, C １ ~C ６ Alkyl sulfonyl group, optionally one or two C １ ~C ６ aminosulfonyl group having an alkyl group, C １ ~C ６ Alkylsulfonylamino group or one or two C groups of any choice １ ~C ６ It is an amino acid having an alkyl group.

10. The heterocyclic compound represented by formula I is selected from any one of the following compounds, as described in claim 1: the heterocyclic compound represented by formula I, its solvate, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof. 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】

11. The heterocyclic compound represented by formula I is selected from one of the following compounds: 【Chemistry 26】 Alternatively, the heterocyclic compound represented by formula I may be selected from any one of the following compounds: The hold time is 0.743 min under the following SFC conditions: 【Chemistry 27】 Chromatography column: Chiralpak AD-3 50 × 4.6 mm I.D., 3 μm, Mobile phase: Mobile phase A: CO ２ Mobile phase B: A solution of isopropanol and acetonitrile containing 0.05 volume percent diethylamine. Isocratic elution: CO ２ A 50-volume solution of isopropanol and acetonitrile containing 0.05 volume diethylamine, flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; column pressure: 100 Bar; Under the following SFC conditions, the hold time is 1.670 min: 【Chemistry 28】 Chromatography column: Chiralpak AD-3 50 × 4.6 mm I.D., 3 μm, Mobile phase: Mobile phase A: CO ２ Mobile phase B: A solution of isopropanol and acetonitrile containing 0.05 volume percent diethylamine. Isocratic elution: CO ２ A 50-volume solution of isopropanol and acetonitrile containing 0.05 volume diethylamine, flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; column pressure: 100 Bar; The hold time is 0.816 min under the following SFC conditions: 【Chemistry 29】 Chromatography column: Chiralpak AS-3 50 × 4.6 mm I.D., 3 μm; Mobile phase: Mobile phase A: CO ２ Mobile phase B: Solution of isopropanol and acetonitrile containing 0.05 volume percent diethylamine; Isocratic elution: CO ２ A 40-volume solution of isopropanol and acetonitrile containing 0.05-volume diethylamine; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; column pressure: 100 Bar; Under the following SFC conditions, the hold time is 1.477 min: 【Transformation 30】 Chromatography column: Chiralpak AS-3 50 × 4.6 mm I.D., 3 μm; Mobile phase: Mobile phase A: CO ２ Mobile phase B: Solution of isopropanol and acetonitrile containing 0.05 volume percent diethylamine; Isocratic elution: CO ２ A 40-volume solution of isopropanol and acetonitrile containing 0.05-volume diethylamine; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; column pressure: 100 Bar; The hold time is 0.764 min under the following SFC conditions: 【Chemistry 31】 Chromatography column: Chiralpak AD-3 50 × 4.6 mm I.D., 3 μm, Mobile phase: Mobile phase A: CO ２ Mobile phase B: Solution of isopropanol and acetonitrile containing 0.05 volume percent diethylamine; Isocratic elution: CO ２ A 50-volume solution of isopropanol and acetonitrile containing 0.05 volume diethylamine, flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; column pressure: 100 Bar; Furthermore, the retention time is 1.702 min under the following SFC conditions: 【Chemistry 32】 Chromatography column: Chiralpak AD-3 50 × 4.6 mm I.D., 3 μm, Mobile phase: Mobile phase A: CO ２ Mobile phase B: Solution of isopropanol and acetonitrile containing 0.05 volume percent diethylamine; Isocratic elution: CO ２ A 50-volume solution of isopropanol and acetonitrile containing 0.05 volume diethylamine, flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; column pressure: 100 Bar; A heterocyclic compound represented by formula I according to claim 10, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that...

12. A pharmaceutical composition comprising a heterocyclic compound represented by formula I as described in any one of claims 1 to 11, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. Use of a substance, wherein the substance is a heterocyclic compound represented by formula I as described in any one of claims 1 to 11, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof. The use of the substance is characterized by being the manufacture of a 15-PGDH inhibitor or the manufacture of a pharmaceutical product for the prevention and / or treatment of a 15-PGDH-related disease.

14. The use according to claim 13, characterized in that the 15-PGDH-related disease is one, two or more of the following: fibrous disease, inflammatory disease, cardiovascular disease, trauma, autoimmune disease, graft-versus-host disease, hair growth, osteoporosis, ear disease, eye disease, neutropenia, diabetes, underactive bladder, transplantation promotion in stem cell or bone marrow transplantation or organ transplantation, neurogenesis and neuronal cell death, hematopoietic remodeling, tissue injury, cervical disease or kidney disease.

15. The aforementioned fibrous disease is one or more of the following: pulmonary fibrosis, hepatic fibrosis, renal fibrosis, myocardial fibrosis, scleroderma, or myelofibrosis. and / or, the inflammatory disease is one or more of the following: chronic obstructive pulmonary disease, acute lung injury, sepsis, exacerbation of asthma and lung disease, inflammatory bowel disease, peptic ulcer, autoinflammatory disease, vasculitis syndrome, acute liver injury, acute kidney injury, non-alcoholic fatty liver disease, atopic dermatitis, psoriasis, interstitial cystitis, or prostatitis syndrome. and / or, the cardiovascular disease is one or more of pulmonary hypertension, angina pectoris, myocardial infarction, heart failure, ischemic heart disease, stroke, or peripheral circulatory disorder. and / or the trauma includes diabetic ulcers, burns, pressure ulcers, acute mucosal injuries including Sjögren's syndrome, mucosal injuries, injuries related to anticancer chemotherapy agents, antimetabolites, cellular or humoral immunity One or more of the following are therapy-related or radiation-related injuries: And / or, the autoimmune disease is multiple sclerosis and / or rheumatoid arthritis. and / or, the ear disorder is one or more of hearing loss, tinnitus, dizziness, or a balance disorder. And / or, the eye disease is glaucoma and / or dry eye. and / or, the neurogenesis and neuronal cell death are one or more of the following: psychiatric neurological disorders, neurological disorders, neurotoxic diseases, neuropathic pain, or neurodegenerative diseases. and / or the tissue injury is liver injury and / or muscle injury, The use according to claim 14, characterized in that the kidney disease is chronic kidney disease and / or renal failure.

16. The aforementioned pulmonary fibrosis is idiopathic pulmonary fibrosis. And / or, the inflammatory bowel disease is ulcerative colitis and / or Crohn's disease. and / or, the peptic ulcer is an NSAID-induced ulcer, and / or, the autoinflammatory disease is Behçet's disease, And / or, the aforementioned prostatitis syndrome is chronic prostatitis and / or chronic pelvic pain syndrome. and / or, the anticancer chemotherapy agent is one or more alkylating agents, DNA synthesis inhibitors, or DNA gyrase inhibitors. and / or the muscle injury is muscle atrophy and / or muscular dystrophy. The use according to claim 15, characterized in that it is a use according to claim 15.

17. The use according to claim 13, characterized in that the prevention and / or treatment of the 15-PGDH-related disease is the prevention and / or treatment of liver regeneration.

18. Use of a heterocyclic compound represented by formula I, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product for preventing or treating one or more of the following diseases: fibrous diseases, inflammatory diseases, or tissue injuries, as described in any one of claims 1 to 11.

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