Hydroxamic acid derivative and application thereof

Abstract

The invention relates to a hydroxamic acid derivative and application thereof, in particular to a compound shown in the formula I and a pharmaceutically acceptable salt or prodrug thereof, and the compound shown in the formula I has good inhibitory activity on acid sphingomyelinase and has better pharmacokinetic property compared with a parent drug. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly relates to a hydroxamic acid derivative and its use. Background Art

[0002] Ceramide is an important second messenger, which plays an important role in signal transduction and is involved in various cellular functions, such as regulating cell growth, proliferation, mutation, inducing apoptosis, regulating protein secretion, participating in immune processes and inflammatory responses, etc. (Progress in Lipid Research, 2016, 61: 51-62).

[0003] Hydrolysis of sphingomyelin by acid sphingomyelinase is the fastest and most direct way to generate ceramide in vivo. So far, a variety of endogenous and exogenous factors have been found, including tumor necrosis factor-α (TNF-α), interleukin-β (IL-β), interferon-γ, etc., as well as oxidative stress, ionizing radiation, ultraviolet irradiation, heat shock, trauma, bacterial infection, and chemical reagents, etc., which can activate acid sphingomyelinase, resulting in a large amount of generation and aggregation of ceramide. After the ceramide level increases, on the one hand, it can participate in in vivo signal transduction as a lipid signal molecule itself, and on the other hand, it aggregates in the cell membrane to form a lipid signal platform, participating in signal transport and material transfer inside and outside the cell (FEBS Lett, 2010, 84(9): 1728-1740).

[0004] A large number of studies have shown that the acid sphingomyelinase-ceramide pathway is involved in in vivo processes such as inflammation, apoptosis, and oxidative stress, and is closely related to the occurrence and development of various diseases (Progress in Lipid Research, 2016, 61: 51-62; Apoptosis, 2015, 20: 607-620). Currently, the diseases in which acid sphingomyelinase is involved have been found to include atherosclerosis (AS), diabetes, emphysema, pulmonary edema, pulmonary fibrosis and cystic fibrosis (CF), non-alcoholic fatty liver, Alzheimer's disease (AD), multiple sclerosis (MS), depression, etc. (The FASEB Journal, 2008, 22: 3419-3431; Biol.Chem. 2015, 396: 707-736).

[0005] By inhibiting acid sphingomyelinase to restore the normal level of ceramide, the symptoms of related diseases can be effectively alleviated. However, the only reported direct inhibitors of acid sphingomyelinase are substrate analogs, diphosphate esters, 3,5-diphosphoinositides, and a few natural product classes. The reported inhibitors have defects such as poor selectivity, poor drug-likeness, poor phosphatase stability, and poor membrane permeability, and cannot be applied to the drug development of related diseases (Cell Physiol. Biochem. 2010, 26:01-08).

[0006] Therefore, acid sphingomyelinase is a potential therapeutic target, and there is an urgent need to develop new inhibitors with higher metabolic stability and bioavailability for the development of candidate drugs for treating related diseases. Summary of the Invention

[0007] In a first aspect, the present invention provides a compound of formula I, a pharmaceutically acceptable salt or prodrug thereof,

[0008]

[0009] wherein n is 0, 1, 2 or 3;

[0010] R 1 is C 1-10 alkyl, 3-7-membered cycloalkyl, 3-7-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl or -C 1-6 alkylene-6-10-membered aryl, and the 3-7-membered cycloalkyl, 3-7-membered heterocycloalkyl, 6-10-membered aryl and 5-10-membered heteroaryl are optionally substituted by one or more substituents selected from the following: halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-4 haloalkyl;

[0011] R 2 is hydrogen, halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-4 haloalkyl;

[0012] Each R 3 is independently halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-4 haloalkyl;

[0013] m is 0, 1, 2, 4 or 5;

[0014] R 4 is hydrogen or C 1-6 alkyl;

[0015] R 5 is hydrogen, C 1-6 alkyl, -C(=O)-R 5a or -C(=O)NR 5b R 5c , an amino acid residue, a dipeptide residue, a polypeptide residue or -R 5d OR 5e ;

[0016] R 5a is C 1-20 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heteroalkyl, where the 3- to 7-membered cycloalkyl and 3- to 7-membered heteroalkyl are optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-4 haloalkyl;

[0017] R 5b and R 5c are each independently hydrogen, C 1-6 alkyl, -C 1-6 alkylene-6- to 10-membered aryl, where the 6- to 10-membered aryl is optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-4 haloalkyl;

[0018] R 5d is an amino acid residue;

[0019] R 5e is an amino acid residue.

[0020] In some embodiments, n is 0.

[0021] In some embodiments, R 1 is 6- to 10-membered aryl or 5- to 10-membered heteroaryl, where the 6- to 10-membered aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-4 haloalkyl.

[0022] In some embodiments, R 1 is 6- to 10-membered aryl, where the 6- to 10-membered aryl is optionally substituted with one or more substituents selected from: halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-4 haloalkyl.

[0023] In some embodiments, R 1 is phenyl, and the phenyl is optionally substituted with one or more substituents selected from the following: halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, or C 1-4 haloalkyl.

[0024] In some embodiments, R 1 is phenyl, and the phenyl is optionally substituted with one or more halogens (e.g., fluorine, chlorine, or bromine).

[0025] In some embodiments, R 2 is hydrogen.

[0026] In some embodiments, R 3 is halogen (e.g., fluorine, chlorine, or bromine).

[0027] In some embodiments, m is 1.

[0028] In some embodiments, R 4 is hydrogen or C 1-4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0029] In some embodiments, R 4 is hydrogen, methyl, ethyl, n-propyl, or isopropyl.

[0030] In some embodiments, R 4 is C 1-6 alkyl.

[0031] In some embodiments, R 4 is C 1-4 alkyl.

[0032] In some embodiments, R 4 is methyl, ethyl, n-propyl, or isopropyl.

[0033] In some embodiments, R 5 is hydrogen, C 1-6 alkyl, -C(=O)-R 5a , -C(=O)NR 5b R 5c , an amino acid residue, or -R 5d OR 5e .

[0034] In some embodiments, R 5 is hydrogen, -C(=O)-R 5a , an amino acid residue, or -R 5d OR 5e, R 5a is C 1-20 alkyl.

[0035] In some embodiments, R 5 wherein the C 1-6 alkyl is C 1-4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl). In some embodiments, R 5 wherein the C 1-6 alkyl is ethyl or isopropyl.

[0036] In some embodiments, R 5 wherein the amino acid residue is an aliphatic amino acid residue. In some embodiments, R 5 wherein the amino acid residue is In some embodiments, R 5 wherein the amino acid residue is

[0037] In some embodiments, R 5a is C 1-20 alkyl or 3-7 membered heteroalkyl.

[0038] In some embodiments, R 5a is C 1-20 alkyl.

[0039] In some embodiments, R 5a wherein the C 1-20 alkyl is a straight-chain C 1-20 alkyl (such as C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 or C 20 straight-chain alkyl) or C 3-20 alkyl (such as C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 or C 20(branched alkyl). In some embodiments, R 5a wherein the C 1-20 alkyl is methyl, n-propyl or C 15 linear alkyl.

[0040] In some embodiments, R 5a wherein the 3- to 7-membered heterocycloalkyl is a 3- to 7-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 5a wherein the 3- to 7-membered heterocycloalkyl is a 5- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms selected from N and O. In some embodiments, R 5a wherein the 3- to 7-membered heterocycloalkyl is morpholinyl or piperazinyl.

[0041] In some embodiments, R 5b and R 5c wherein the C 1-6 alkyls are each independently C 1-4 alkyls (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl). In some embodiments, R 5b and R 5c wherein the C 1-6 alkyls are each independently methyl or ethyl.

[0042] In some embodiments, R 5b and R 5c wherein the C 1-6 alkylene groups are each independently C 1-4 alkylene groups (such as methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene or tert-butylene). In some embodiments, R 5b and R 5c wherein the C 1-6 alkylene groups are each independently methylene.

[0043] In some embodiments, R 5b and R 5c wherein the 6- to 10-membered aryl is phenyl.

[0044] In some embodiments, R 5d wherein the amino acid residue is an aliphatic amino acid residue. In some embodiments, R 5d wherein the amino acid residue is In some embodiments, R 5d wherein the amino acid residue is

[0045] In some embodiments, R 5ewherein the amino acid residue is an aliphatic amino acid residue. In some embodiments, R 5e wherein the amino acid residue is In some embodiments, R 5d wherein the amino acid residue is

[0046] In some embodiments, R 5e wherein the amino acid residue is In some embodiments, R 5d wherein the amino acid residue is

[0047] In some embodiments, the compound of formula I is any of the following structures:

[0048]

[0049] In a second aspect, the present disclosure provides a pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0050] In a third aspect, the present disclosure provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the preparation of a drug as an acid sphingomyelinase inhibitor.

[0051] The present disclosure provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the preparation of a drug for treating acid sphingomyelinase-related diseases.

[0052] The present disclosure further provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the preparation of a drug for treating diseases.

[0053] In some embodiments, the diseases are preferably selected from metabolic diseases, respiratory diseases, and central nervous system diseases.

[0054] In some embodiments, the metabolic diseases include but are not limited to atherosclerosis, diabetes, fatty liver, and liver fibrosis.

[0055] In some embodiments, the respiratory diseases include but are not limited to emphysema, pulmonary edema, pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, pulmonary hypertension, and acute lung injury.

[0056] In some embodiments, the central nervous system diseases include but are not limited to multiple sclerosis, stroke, Alzheimer's disease, anxiety disorder, bipolar disorder, and depression.

[0057] Fourth aspect, the present disclosure also provides a method for preparing the above-mentioned compound represented by formula I, its pharmaceutically acceptable salt or prodrug, which includes the step of preparing the compound represented by formula I from the compound represented by formula II through one or more steps,

[0058]

[0059] wherein, R 1 , R 2 , R 3 , R 4 , R 5 , m and n are defined as in any one of the above-mentioned compounds represented by formula I.

[0060] Terminology Definition

[0061] In the case where no specific configuration is defined in the present disclosure, the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereoisomers, (D)- isomers, (L)- isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereoisomer-enriched mixtures, all of these mixtures are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included within the scope of the present disclosure.

[0062] In addition, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. An example of the lactam-lactim equilibrium is between A and B shown below.

[0063]

[0064] All compounds in the present disclosure can be drawn in the form of A or B. All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomer.

[0065] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers are included, such as enantiomers and diastereoisomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. The optically pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0066] Optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and optionally in combination with chemical derivatization (such as formation of a carbamate from an amine).

[0067] The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight-chain or branched-chain group containing 1 to 30 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and their various branched isomers, etc. More preferably, it is an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.

[0068] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; polycyclic cycloalkyl includes spiro, fused-ring, and bridged-ring cycloalkyl.

[0069] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, C(=O) or S(=O) m (where m is an integer from 0 to 2), but does not include the ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocycloalkyl includes spiro, fused and bridged heterocycloalkyl. Non-limiting examples of "heterocycloalkyl" include:

[0070]

[0071] The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, where the ring connected to the parent structure is a heterocycloalkyl ring, and non-limiting examples thereof include:

[0072]

[0073] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6 to 12 members, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:

[0074]

[0075] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 members, more preferably 5 or 6 members. For example. Non-limiting examples thereof include: imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, etc.

[0076] The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0077]

[0078]

[0079] The term "spiro" refers to a compound in which two rings share a single atom.

[0080] The term "spiroalkyl" refers to a polycyclic group in which a 5- to 20-membered monocyclic ring shares a single carbon atom (referred to as a spiro atom) between rings, which may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. According to the number of spiro atoms shared between rings, spiroalkyl is classified into monospiroalkyl, bisspiroalkyl or polyspiroalkyl, preferably monospiroalkyl and bisspiroalkyl. More preferably, it is 4 / 4, 4 / 5, 4 / 6, 5 / 5 or 5 / 6 monospiroalkyl. "Spirocarbocycle" refers to the ring system in spiroalkyl. Non-limiting examples of spiroalkyl include:

[0081]

[0082] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which a 5- to 20-membered monocyclic ring shares a single atom (referred to as a spiro atom) between rings, and one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. According to the number of spiro atoms shared between rings, spiroheterocyclic group is classified into monospiroheterocyclic group, bisspiroheterocyclic group or polyspiroheterocyclic group, preferably monospiroheterocyclic group and bisspiroheterocyclic group. More preferably, it is 4 / 4, 4 / 5, 4 / 6, 5 / 5 or 5 / 6 monospiroheterocyclic group. "Spiroheterocycle" refers to the ring system in spiroheterocyclic group. Non-limiting examples of spiroheterocyclic group include:

[0083]

[0084] The term "fused ring" refers to a compound formed by fusing two or more rings through sharing two adjacent atoms.

[0085] The term "fused cycloalkyl" refers to a fully carbon polycyclic group with 5 to 20 members, where each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, and one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5 / 5 or 5 / 6 bicyclic alkyl. Non-limiting examples of fused cycloalkyl include:

[0086]

[0087] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group having 5 to 20 members, wherein each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system, and one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. "Fused heterocycle" refers to the ring system in the fused heterocyclic group. Non-limiting examples of the fused heterocyclic group include:

[0088]

[0089] The term "fused heteroaryl" may be an unsaturated aromatic fused ring structure containing 5 - 14 ring atoms (wherein at least one heteroatom is contained), formed by connecting two or more cyclic structures sharing two adjacent atoms with each other, and at the same time including the cases where carbon atoms, nitrogen atoms and sulfur atoms can be oxo-substituted. Preferably, it is "5 - 12 membered fused heteroaryl", "7 - 12 membered fused heteroaryl", "9 - 12 membered fused heteroaryl", etc. For example, benzofuranyl, benzisofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2 - quinolinone, 4 - quinolinone, 1 - isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, phenazinyl, phenothiazinyl, etc. "Fused heteroaromatic ring" refers to the ring system in the fused heteroaryl.

[0090] The term "bridged ring" refers to a structure formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other.

[0091] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group having 5 to 20 members, wherein any two rings share two non-directly connected carbon atoms, and it may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of the bridged cycloalkyl include:

[0092]

[0093] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group having 5 to 14 members, in which any two rings share two non-adjacent atoms, which may contain one or more double bonds, but no ring has a completely conjugated π-electron system, and one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of the bridged heterocyclic group include:

[0094]

[0095] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as above.

[0096] The term "hydroxy" refers to -OH.

[0097] The term "mercapto" refers to -SH.

[0098] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0099] The term "haloalkyl" refers to an alkyl group substituted by halogen, where alkyl is defined as above.

[0100] The term "cyano" refers to -CN.

[0101] The term "nitro" refers to -NO2.

[0102] The term "amino" refers to -NH2.

[0103] The term "carboxyl" refers to -C(O)OH.

[0104] The term "substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine the possible or impossible substitutions without much effort (through experiments or theories).

[0105] "Substituted by one or more..." means that it can be substituted by a single or multiple substituents. When substituted by multiple substituents, it can be a plurality of the same substituents or a combination of one or a plurality of different substituents.

[0106] The term "linked", when indicating the connection between two molecules, means that the two molecules are connected by a covalent bond or the two molecules are associated via a non-covalent bond (e.g., hydrogen bond or ionic bond), including direct connection and indirect connection.

[0107] The term "directly connected" means that a first compound or group is connected to a second compound or group without any intervening atom or atomic group. The term "indirectly connected" means that a first compound or group is connected to a second compound or group through an intermediate group, compound, or molecule (e.g., a linking group).

[0108] In the chemical structure of the compounds described in the present disclosure, a bond represents an unspecified configuration, i.e., if there are chiral isomers in the chemical structure, the bond can be or can contain both configurations. Although all of the above structural formulas are drawn in certain isomeric forms for simplicity, the present disclosure can include all isomers, such as tautomers, rotamers, geometric isomers, diastereomers, racemates, and enantiomers. In the chemical structure of the compounds described in the present disclosure, the bond does not specify a configuration, i.e., the configuration of the bond can be the E-form or the Z-form, or can contain both the E and Z configurations.

[0109] Unless otherwise indicated, the symbol used herein means that it can be connected to one or more any groups according to the scope of the disclosure described herein.

[0110] In the present disclosure, the terms "comprising" and "including" can be replaced with "consisting of".

[0111] The term "composition" refers to a mixture of a drug containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or precursors and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of the composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and thereby exert biological activity.

[0112] The term "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that has been approved by the US Food and Drug Administration for use in humans or domestic animals.

[0113] Unless otherwise specified, the "compounds" of the present disclosure can independently exist in the form of salts, mixed salts, or non-salts (e.g., free acids or free bases). When in the form of salts or mixed salts, they can be pharmaceutically acceptable salts or medicinally acceptable salts.

[0114] The terms "pharmaceutically acceptable salt" and "medicinally acceptable salt" can be used interchangeably and refer to pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0115] "Pharmaceutically acceptable acid addition salts" refers to salts formed with inorganic or organic acids that can retain the biological effectiveness of the free base without other side effects and can be prepared by methods known in the art.

[0116] "Pharmaceutically acceptable base addition salts" refers to salts formed with inorganic or organic bases that can maintain the biological effectiveness of the free acid without other side effects and these salts can be prepared by methods known in the art.

[0117] "Effective amount", "effective dose", "effective therapeutic amount" or "therapeutically effective amount" refers to the amount of a drug, compound or pharmaceutical composition necessary to obtain any one or more beneficial or desired therapeutic results. For prophylactic use, beneficial or desired results include eliminating or reducing the risk, alleviating the severity or delaying the onset of a disease, including the biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presented during the development of the disease.

[0118] As used herein, "subject", "patient", "test subject" or "individual" are used interchangeably and include human or non-human animals, such as mammals, such as humans or monkeys. Specific embodiments

[0119] The present disclosure is further described below in conjunction with examples, but these examples do not limit the scope of the present disclosure. The experimental methods without specific conditions noted in the examples of the present disclosure are generally carried out under conventional conditions or according to the conditions recommended by the raw material or commodity manufacturer. For reagents without specific sources noted, the reagents can be obtained from any supplier of molecular biology reagents in the quality / purity for molecular biology applications.

[0120] Unless otherwise specified, the reagents used in the following examples are all commercially available products.

[0121] Example 1

[0122] 5-(4-Bromophenyl)-1-(4-chlorophenyl)-N-((methylcarbamoyl)oxy)-1H-pyrazole-3-carboxamide

[0123]

[0124] First step

[0125] Ethyl 4-(4-bromophenyl)-2,4-dioxobutyrate 1c

[0126] At room temperature, weigh metallic sodium (346.5 mg, 15.07 mmol) into a 100 mL eggplant-shaped flask, add 10 mL of absolute ethanol and stir until there is no solid and the solution temperature drops to room temperature. Weigh 4-bromoacetophenone 1a (1 g, 5.02 mmol) and mix it evenly with 5 mL of ethanol, then drop it into the ethanol solution of sodium ethoxide. After stirring at room temperature for 30 minutes, dilute diethyl oxalate 1b (1.19 g, 10.05 mmol) with 5 mL of absolute ethanol and drop it into the reaction mixture. The reaction is stirred at room temperature for 3 hours. Add dilute hydrochloric acid to adjust the pH of the reaction mixture to 1 - 2. Concentrate under reduced pressure to remove most of the ethanol. Add 20 ml of water for dilution, and extract with 150 ml of ethyl acetate three times. Separate and combine the organic layers, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and dry in a vacuum drying oven to obtain compound 1c (1.27 g, yield 84.7%).

[0127] 1 1H-NMR (300 MHz, CDCl3) δ 15.08 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 6.92 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).

[0128] The second step

[0129] Ethyl 5-(4-bromophenyl)-1-(4-chlorophenyl)-1H-pyrazole-3-carboxylate 1e

[0130] Weigh ethyl 4-(4-bromophenyl)-2,4-dioxobutyrate 1c (1.27 g, 4.24 mmol) into a 100 mL eggplant-shaped flask, add 10 mL of absolute ethanol and mix evenly. Add p-chlorophenylhydrazine hydrochloride 1d (911.5 mg, 5.09 mmol), and dropwise add 1 mL of glacial acetic acid. After stirring the reaction at 80 °C for 3 hours, stop heating and let it cool naturally to room temperature. Dropwise add saturated sodium bicarbonate solution to adjust the pH of the reaction mixture to 7. Concentrate under reduced pressure to remove most of the ethanol. Add 20 ml of water for dilution, and extract with 150 ml of ethyl acetate three times. Separate and combine the organic layers, dry over anhydrous sodium sulfate, concentrate under reduced pressure, purify by column chromatography (petroleum ether:ethyl acetate = 16:1, silica gel 200 - 300 mesh), and dry in a vacuum drying oven to obtain compound 1e (1.56 g, yield 90.7%).

[0131] 1H-NMR (300 MHz, CDCl3) δ 7.57 - 7.44 (m, 2H), 7.42 - 7.33 (m, 2H), 7.31 - 7.28 (m, 2H), 7.14 - 7.07 (m, 2H), 7.05 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H).

[0132] The third step

[0133] 5-(4-Bromophenyl)-1-(4-chlorophenyl)-N-hydroxy-1H-pyrazole-3-carboxamide 1f

[0134] At room temperature, weigh intermediate ethyl 5-(4-bromophenyl)-1-(4-chlorophenyl)-1H-pyrazole-3-carboxylate 1e (1.56 g, 3.85 mmol) into a 100 mL two-necked flask. After adding 9 mL of anhydrous methanol and mixing evenly, add 10 mL of 1.54 mol / L hydroxylamine solution. The reaction is stirred at room temperature for 12 hours. Dilute hydrochloric acid is added dropwise at 0 °C to adjust the pH of the reaction mixture to 3. Most of the methanol is removed by concentration under reduced pressure to obtain a yellow solid. Recrystallize with ethyl acetate (5 ml) and petroleum ether (20 ml), filter by suction. The filter cake is washed 3 times with 15 ml of petroleum ether and dried in a vacuum drying oven to obtain compound 1f (1.32 g, yield 87.4%).

[0135] 1 H-NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.10 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.04 (s, 1H).

[0136] The fourth step

[0137] 5-(4-Bromophenyl)-1-(4-chlorophenyl)-N-((methylcarbamoyl)oxy)-1H-pyrazole-3-carboxamide I-1

[0138] At room temperature, 5-(4-bromophenyl)-1-(4-chlorophenyl)-N-hydroxy-1H-pyrazole-3-carboxamide 1f (200 mg, 509.38 μmol) was weighed and placed in a 50 ml eggplant-shaped flask. 2 ml of acetonitrile was added and mixed evenly. N,N'-carbonyldiimidazole (90.86 mg, 560.31 μmol) was weighed and added. After the reaction was stirred at room temperature for 45 min, methylamine (17.4 mg, 560.31 μmol) was weighed and added. After the reaction was stirred at room temperature for 12 h, 5 ml of dilute hydrochloric acid was added, and the mixture was extracted three times with 45 ml of ethyl acetate. The organic layers were separated and combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 6:1 - 4:1, silica gel 200 - 300 mesh) to obtain compound I-1 (176 mg, yield 74.5%).

[0139] 1 H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.44 (s, 3H), 7.07 (s, 7H), 2.84 (s, 3H).

[0140] Example 2, Example 3, and Example 4 used the methods and general preparation procedures described in Example 1, but the corresponding amines were used in the fourth step.

[0141] Example 2

[0142] 5-(4-bromophenyl)-1-(4-chlorophenyl)-N-((ethylcarbamoyl)oxy)-1H-pyrazole-3-carboxamide

[0143]

[0144] 1 H NMR (300 MHz, DMSO) δ 12.08 (s, 1H), 7.77 (t, J = 5.6 Hz, 1H), 7.65–7.53 (m, 4H), 7.43–7.35 (m, 2H), 7.27–7.20 (m, 2H), 7.11 (s, 1H), 3.08 (p, J = 7.2 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H).

[0145] Example 3

[0146] N-((benzylcarbamoyl)oxy)-5-(4-bromophenyl)-1-(4-chlorophenyl)-1H-pyrazole-3-carboxamide

[0147]

[0148] 11H NMR (300 MHz, DMSO) δ 12.11 (s, 1H), 8.35 (t, J = 6.2 Hz, 1H), 7.64–7.54 (m, 4H), 7.42–7.37 (m, 2H), 7.36–7.28 (m, 5H), 7.26–7.22 (m, 2H), 7.12 (s, 1H), 4.27 (d, J = 6.1 Hz, 2H).

[0149] Example 4

[0150] 5-(4-Bromophenyl)-1-(4-chlorophenyl)-N-((morpholine-4-carbonyl)oxy)-1H-pyrazole-3-carboxamide

[0151]

[0152] 1 1H NMR (300 MHz, DMSO) δ 9.47 (s, 1H), 7.64–7.57 (m, 2H), 7.51–7.45 (m, 2H), 7.29–7.17 (m, 4H), 6.80 (s, 1H), 3.59 (t, J = 4.7 Hz, 4H), 3.44 (t, J = 4.7 Hz, 4H).

[0153] Example 5

[0154] 5-(4-Bromophenyl)-1-(4-chlorophenyl)-N-ethoxy-N-ethyl-1H-pyrazole-3-carboxamide

[0155]

[0156] At room temperature, weigh 5-(4-bromophenyl)-1-(4-chlorophenyl)-N-hydroxy-1H-pyrazole-3-carboxamide 1f (200 mg, 509.38 μmol) into a 50 ml eggplant-shaped flask, add 3 ml of anhydrous N,N-dimethylformamide and mix well. Weigh and add cesium carbonate (414.91 mg, 1.27 mmol). After stirring the reaction at room temperature for 1 h, weigh and add iodoethane (79.45 mg, 509.38 μmol). After stirring the reaction at room temperature for 6 h, add 5 ml of dilute hydrochloric acid, and extract with 45 ml of ethyl acetate three times. Separate and combine the organic layers, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (petroleum ether:ethyl acetate = 6:1 - 4:1, silica gel 200 - 300 mesh) to obtain a white solid, namely compound I-5 (150 mg, yield 65.6%).

[0157] 11H NMR (300 MHz, DMSO) δ 7.66–7.51 (m, 4H), 7.40–7.33 (m, 2H), 7.27–7.20 (m, 2H), 7.04 (s, 1H), 4.04 (q, J = 7.0 Hz, 2H), 3.92–3.76 (m, 2H), 1.23–1.14 (m, 6H).

[0158] Example 6 The method and general preparation procedure described in Example 5 were used, and the corresponding haloalkane was replaced.

[0159] Example 6

[0160] 5-(4-Bromophenyl)-1-(4-chlorophenyl)-N-isopropoxy-N-isopropyl-1H-pyrazole-3-carboxamide

[0161]

[0162] 1 1H NMR (300 MHz, DMSO) δ 7.65–7.47 (m, 4H), 7.41–7.30 (m, 2H), 7.28–7.17 (m, 2H), 7.02 (s, 1H), 4.80–4.62 (m, 1H), 4.23 (hept, J = 6.3 Hz, 1H), 1.24 (d, J = 6.5 Hz, 6H), 1.17 (d, J = 6.2 Hz, 6H).

[0163] Examples 7 and 8 The method and general preparation procedure described in Example 5 were used, and the equivalent amount of the corresponding haloalkane was halved when selected.

[0164] Example 7

[0165] 5-(4-Bromophenyl)-1-(4-chlorophenyl)-N-ethoxy-1H-pyrazole-3-carboxamide

[0166]

[0167] 1 1H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 7.67–7.51 (m, 4H), 7.43–7.33 (m, 2H), 7.26–7.19 (m, 2H), 7.07 (s, 1H), 3.92 (q, J = 7.0 Hz, 2H), 1.20 (t, J = 7.0 Hz, 3H).

[0168] Example 8

[0169] 5-(4-Bromophenyl)-1-(4-chlorophenyl)-N-isopropoxy-1H-pyrazole-3-carboxamide

[0170]

[0171] 1 H NMR (300 MHz, DMSO) δ 11.49 (s, 1H), 7.66–7.51 (m, 4H), 7.43–7.36 (m, 2H), 7.26–7.21 (m, 2H), 7.06 (s, 1H), 4.13 (p, J = 6.2 Hz, 1H), 1.20 (d, J = 6.2 Hz, 6H).

[0172] Example 9

[0173] 5-(4-Bromophenyl)-1-(4-chlorophenyl)-N-((piperazine-1-carbonyl)oxy)-1H-pyrazole-3-carboxamide

[0174]

[0175] At room temperature, trichloromethyl chloroformate (151.15 mg, 509.38 μmol) was weighed and placed in a 50 ml eggplant-shaped flask. 3 ml of toluene was added and mixed evenly. 1-tert-Butoxycarbonylpiperazine (142.31 mg, 764.06 μmol) and triethylamine (154.64 mg, 1.53 mmol) were weighed and added. After the reaction was stirred at room temperature for 2 h, 1 ml of pyridine was added. 5-(4-Bromophenyl)-1-(4-chlorophenyl)-N-hydroxy-1H-pyrazole-3-carboxamide 1f (200 mg, 509.38 μmol) was weighed and added. After the reaction was stirred at room temperature for 12 h, 20 ml of water was added, and the mixture was extracted three times with 45 ml of ethyl acetate. The organic layers were separated and combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1 - 2:1, silica gel 200 - 300 mesh) to obtain compound 6a (297 mg, yield 96.4%). It was placed in a 50 ml eggplant-shaped flask, 2 ml of ethyl acetate was added and mixed evenly. 2 ml of a 4 mol / l hydrochloric acid ethyl acetate solution was added. After the reaction was stirred at room temperature for 1 h, ethyl acetate was removed by concentration under reduced pressure to obtain compound I-9 (236 mg, yield 95.2%, overall yield 91.8%).

[0176] 1 H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 7.64–7.55 (m, 4H), 7.45–7.37 (m, 2H), 7.28–7.23 (m, 2H), 7.13 (s, 1H), 3.69 (s, 4H), 3.13 (t, J = 5.3 Hz, 4H), 3.02 (s, 2H).

[0177] Example 10

[0178] N-((D-Valyl)oxy)-5-(4-bromophenyl)-1-(4-chlorophenyl)-1H-pyrazole-3-carboxamide

[0179]

[0180] At room temperature, weigh N-Boc-L-valine (276.67 mg, 1.27 mmol) into a 50 ml eggplant-shaped flask. At 0 °C, add 3 ml of anhydrous N,N-dimethylformamide and mix well. Weigh and add HATU (724.36 mg, 1.91 mmol) and N,N-diisopropylethylamine (328.27 mg, 2.54 mmol). After stirring the reaction at 0 °C for 30 minutes, weigh and add 5-(4-bromophenyl)-1-(4-chlorophenyl)-N-hydroxy-1H-pyrazole-3-carboxamide 1f (500 mg, 1.27 mmol). After stirring the reaction at 0 °C for 1 hour, add 10 ml of water. A white solid precipitates. Filter by suction. Wash the filter cake three times with 15 ml of water and dry it in a vacuum drying oven. Purify by column chromatography (dichloromethane:methanol = 450:1, silica gel 200 - 300 mesh) to obtain compound 7a (470 mg, yield 62.4%). Place it in a 50 ml eggplant-shaped flask, add 2 ml of ethyl acetate and mix well. Add 2 ml of a 4 mol / l hydrochloric acid ethyl acetate solution. After stirring the reaction at room temperature for 1 h, concentrate under reduced pressure to remove ethyl acetate to obtain compound I-10 (402 mg, yield 95.8%, total yield 59.8%).

[0181] 1 H NMR (400 MHz, DMSO) δ 12.96 (s, 1H), 9.02–8.47 (m, 3H), 7.66–7.56 (m, 4H), 7.46–7.40 (m, 2H), 7.27–7.23 (m, 2H), 7.20 (s, 1H), 4.31–4.26 (m, 1H), 2.38–2.27 (m, 1H), 1.11 (dd, J = 17.4, 6.9 Hz, 6H).

[0182] Example 11

[0183] N-((((D-Valyl)oxy)-D-valyl)oxy)-5-(4-bromophenyl)-1-(4-chlorophenyl)-1H-pyrazole-3-carboxamide

[0184]

[0185] At room temperature, weigh N-Boc-L-valine (132.54 mg, 610.04 μmol) into a 50 ml eggplant-shaped flask. At 0 °C, add 3 ml of anhydrous N,N-dimethylformamide and mix well. Weigh and add HATU (231.96 mg, 610.04 μmol) and N,N-diisopropylethylamine (210.26 mg, 1.63 mmol). After stirring the reaction at 0 °C for 30 minutes, weigh and add N-((((D-valinyl)oxy)-D-valinyl)oxy)-5-(4-bromophenyl)-1-(4-chlorophenyl)-1H-pyrazole-3-carboxamide I-10 (200 mg, 406.69 μmol). After stirring the reaction at 0 °C for 1 hour, add 10 ml of water. A white solid precipitates. Filter by suction. Wash the filter cake three times with 15 ml of water and dry it in a vacuum drying oven. Purify by column chromatography (dichloromethane:methanol = 400:1, silica gel 200 - 300 mesh) to obtain compound 8a (246 mg, yield 87.5%). Place it in a 50 ml eggplant-shaped flask, add 2 ml of ethyl acetate and mix well. Add 2 ml of a 4 mol / l hydrochloric acid ethyl acetate solution. After stirring the reaction at room temperature for 1 h, concentrate under reduced pressure to remove ethyl acetate to obtain compound I-11 (202 mg, yield 90.4%, overall yield 79.2%).

[0186] 1 H NMR (300 MHz, DMSO) δ 12.62 (s, 1H), 8.83 (d, J = 8.0 Hz, 1H), 8.24 (s, 3H), 7.65–7.55 (m, 4H), 7.44–7.38 (m, 2H), 7.28–7.22 (m, 2H), 7.15 (s, 1H), 4.52 (dd, J = 7.9, 5.7 Hz, 1H), 3.79 (s, 1H), 2.33–2.18 (m, 1H), 2.12 (q, J = 6.6 Hz, 1H), 1.07 (dd, J = 6.9, 2.4 Hz, 6H), 0.97 (dd, J = 6.9, 2.0 Hz, 6H).

[0187] Example 12 Use the method and general preparation procedure described in Example 11 and replace with the corresponding N-Boc amino acid.

[0188] Example 12

[0189] N-((((D-glutamyl)oxy)-D-valinyl)oxy)-5-(4-bromophenyl)-1-(4-chlorophenyl)-1H-pyrazole-3-carboxamide

[0190]

[0191] 11H NMR (300 MHz, DMSO) δ 12.65 (s, 1H), 8.92 (d, J = 8.6 Hz, 1H), 8.17 (s, 3H), 7.60 (dd, J = 14.3, 8.6 Hz, 4H), 7.41 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 7.15 (s, 1H), 4.60 (dd, J = 8.6, 5.6 Hz, 1H), 3.68 (d, J = 5.7 Hz, 2H), 2.32–2.13 (m, 1H), 1.02 (dd, J = 6.8, 2.5 Hz, 6H).

[0192] Example 13

[0193] N-Acetoxy-5-(4-bromophenyl)-1-(4-chlorophenyl)-1H-pyrazole-3-carboxamide

[0194]

[0195] At room temperature, 5-(4-bromophenyl)-1-(4-chlorophenyl)-N-hydroxy-1H-pyrazole-3-carboxamide 1f (100 mg, 254.69 μmol) was weighed into a 50 ml eggplant-shaped flask, 2 ml of dichloromethane was added and mixed evenly, 5 drops of 2 mol / L aqueous NaOH solution were added and mixed evenly, acetic anhydride (17.33 mg, 169.79 μmol) was weighed and added. After the reaction was stirred at room temperature for 15 min, 20 ml of water was added, and the mixture was extracted three times with 45 ml of dichloromethane. The organic layers were separated and combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 4:1 - 2:1, 200 - 300 mesh silica gel) to obtain compound I-13 (98 mg, yield 88.2%).

[0196] 1 1H NMR (300 MHz, DMSO) δ 12.37 (s, 1H), 7.66–7.53 (m, 4H), 7.47–7.37 (m, 2H), 7.29–7.20 (m, 2H), 7.14 (s, 1H), 2.22 (s, 3H).

[0197] Examples 14 and 15 used the methods and general preparation procedures described in Example 13 and replaced with the corresponding acid anhydrides.

[0198] Example 14

[0199] N-Butyryloxy-5-(4-bromophenyl)-1-(4-chlorophenyl)-1H-pyrazole-3-carboxamide

[0200]

[0201] 1 1H NMR (300 MHz, DMSO) δ 12.36 (s, 1H), 7.66–7.54 (m, 4H), 7.45–7.37 (m, 2H), 7.29–7.22 (m, 2H), 7.13 (s, 1H), 2.47 (s, 2H), 1.64 (h, J = 7.3 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H).

[0202] Example 15

[0203] N-Palmitoyloxy-5-(4-bromophenyl)-1-(4-chlorophenyl)-1H-pyrazole-3-carboxamide

[0204]

[0205] 1 1H NMR (300 MHz, DMSO) δ 12.35 (s, 1H), 7.67–7.51 (m, 4H), 7.48–7.36 (m, 2H), 7.31–7.20 (m, 2H), 7.13 (s, 1H), 2.47 (s, 2H), 1.59 (q, J = 7.3 Hz, 2H), 1.25 (d, J = 5.1 Hz, 24H), 0.87 (d, J = 6.2 Hz, 3H).

[0206] Example 16

[0207] N-Acetoxy-5-(4-bromophenyl)-1-(4-chlorophenyl)-N-ethyl-1H-pyrazole-3-carboxamide

[0208]

[0209] At room temperature, weigh N-acetoxy-5-(4-bromophenyl)-1-(4-chlorophenyl)-1H-pyrazole-3-carboxamide I-13 (500 mg, 1.15 mmol) into a 25 ml two-necked flask, add 3 ml of anhydrous N,N-dimethylformamide and mix well. Weigh and add cesium carbonate (936.96 mg, 2.88 mmol). After the reaction is stirred at 45 °C for 1 h, weigh and add iodoethane (269.11 mg, 1.73 mmol). After the reaction is stirred at 45 °C for 12 h, cool to room temperature, add 10 ml of ethyl acetate, filter by suction. The obtained filtrate is added with 15 ml of saturated sodium chloride solution and extracted three times with 45 ml of ethyl acetate. The organic layers are separated and combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (methylene chloride:methanol = 600:1, silica gel 200 - 300 mesh) to obtain compound I-16 (264 mg, yield 49.6%).

[0210] 11H NMR (300 MHz, DMSO) δ 7.64–7.53 (m, 4H), 7.35 (d, J = 8.7 Hz, 2H), 7.28–7.21 (m, 2H), 7.12 (s, 1H), 3.97 (s, 2H), 2.18 (s, 3H), 1.20 (d, J = 7.0 Hz, 3H).

[0211] Example 17

[0212] 5-(4-Bromophenyl)-1-(4-chlorophenyl)-N-ethyl-N-hydroxy-1H-pyrazole-3-carboxamide

[0213]

[0214] At room temperature, weigh N-acetoxy-5-(4-bromophenyl)-1-(4-chlorophenyl)-N-ethyl-1H-pyrazole-3-carboxamide I-16 into a 25 ml eggplant-shaped flask, add 2 ml of methanol and mix well. Add 3 drops of 2 mol / L NaOH aqueous solution and mix well. After stirring at room temperature for 5 min, concentrate under reduced pressure to remove methanol. Add 10 ml of dilute hydrochloric acid, and extract three times with 45 ml of ethyl acetate. Separate and combine the organic layers, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by preparative thin layer chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound I-17.

[0215] 1 1H NMR (300 MHz, DMSO) δ 10.50 (s, 1H), 7.56 (dd, J = 23.1, 8.3 Hz, 4H), 7.33 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 6.84 (s, 1H), 4.34 (q, J = 7.0 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H).

[0216] Test Example 1: Pharmacokinetics Test of Compounds in Mice

[0217] Prepare solutions of compound 1f and compounds I-1 to I-17 with concentrations of 10 mg / ml and 1 mg / ml respectively. The required reagent ratios are V DMSO :V 吐温80 :V PEG400 :V 生理盐水 = 10:15:15:60 and V DMSO :V 吐温80 :V PEG400 :V 生理盐水= 10:5:15:70. Taking Compound 1f as an example, a total of 12 mice required for the experiment were divided into two groups and numbered respectively. Group one was administered by intravenous injection at a dose of 1 mg / kg, and Group two was administered by gavage at a dose of 10 mg / kg. Mice numbered 1, 2, and 3 in each group were bled by orbital blood collection at 5 min, 15 min, and 30 min and the blood samples were placed in centrifuge tubes. Mice numbered 4, 5, and 6 in each group were bled by orbital blood collection at 60 min, 120 min, and 360 min and the blood samples were placed in centrifuge tubes. The obtained blood samples were centrifuged at 12000 r / min for 10 min, and the upper serum was taken. The concentration of Compound 1f in each sample was determined by LC-MS / MS method. The experimental protocol for Compounds I-1 to I-17 was the same as above, and the concentrations of Compounds I-1 to I-17 and Compound 1f in the obtained serum were determined by LC-MS / MS method.

[0218] The results of the pharmacokinetics test of Compound 1f in mice showed that after intravenous administration, T 1 / 2 = 0.904 h, AUC 0-inf_obs = 1636.626 ng / ml*h, C max = 2359.677 ng / ml. After gavage administration, T 1 / 2 = 1.048 h, AUC 0-inf_obs = 2006.257 ng / ml*h, C max = 2453.888 ng / ml.

[0219] The results of the pharmacokinetics test of Compounds I-1 to I-17 in mice showed that the exposure levels of Compounds I-1, I-2, I-3, I-6, I-7, I-8, and I-9 were very low after both intravenous and gavage administrations, compared with Compound 1f. For Compounds I-5 and I-6, the original compounds were detected in plasma after both intravenous and gavage administrations, but the exposure levels of the parent drugs were very low, indicating that they could not be cleaved and release the parent drugs.

[0220] The pharmacokinetics test of Compound I-10 in mice showed that after intravenous administration, the AUC 0-inf_obs of the parent drug released by Compound I-10 increased to 2387.421 ng / ml*h, and T 1 / 2 extended to 8.264 h. After gavage administration, the AUC 0-inf_obs of the parent drug released by Compound I-10 increased to 2968.193 ng / ml*h, and T 1 / 2 extended to 2.498 h.

[0221] Pharmacokinetic tests of Compound I-11 in mice showed that after intravenous administration, the exposure levels of both the parent drug were very low. However, after intragastric administration, the AUC of the parent drug released from Compound I-11 0-inf_obs increased to 10209.38 ng / ml*h, and the T 1 / 2 extended to 44.468 h.

[0222] Pharmacokinetic tests of Compound I-14 in mice showed that after intravenous administration, the exposure levels of both the parent drug were very low. However, after intragastric administration, the AUC of the parent drug released from Compound I-14 0-inf_obs increased to 7588.023 ng / ml*h, and the T 1 / 2 extended to 1.875 h, and the C max increased to 4784.923 ng / ml.

[0223] Pharmacokinetic tests of Compound I-15 in mice showed that after intravenous administration, the AUC of the parent drug released from Compound I-15 0-inf_obs increased to 5110.724 ng / ml*h, and the T 1 / 2 extended to 1.177 h, and the C max increased to 13465.317 ng / ml. After intragastric administration, the AUC of the parent drug released from Compound I-15 0-inf_obs increased to 2245.404 ng / ml*h, and the T 1 / 2 extended to 5.465 h.

[0224] Pharmacokinetic tests of Compound I-16 in mice showed that after intravenous administration, the AUC of the parent drug released from Compound I-16 0-inf_obs increased to 3136.943 ng / ml*h, and the T 1 / 2 extended to 4.011 h. After intragastric administration, the AUC of the parent drug released from Compound I-16 0-inf_obs increased to 11191.609 ng / ml*h, and the T 1 / 2 extended to 2.880 h, and the C max increased to 3103.922 ng / ml.

[0225] Pharmacokinetic tests of Compound I-17 in mice showed that after intravenous administration, the AUC of the parent drug released from Compound I-17 0-inf_obs increased to 1898.078 ng / ml*h, and the T 1 / 2 extended to 1.608 h. After intragastric administration, the AUC of the parent drug released from Compound I-17 0-inf_obs increased to 10759.510 ng / ml*h, and the T 1 / 2Extended to 4.439 h, but its C max Dropped to 2025.332 ng / ml.

Claims

1. A compound represented by formula I, a pharmaceutically acceptable salt or prodrug thereof, Among them, n is 0, 1, 2 or 3; R 1 is C 1-10 alkyl, 3-7 membered cycloalkyl, 3-7 membered hetero cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or -C 1-6 alkylene-6-10 membered aryl, wherein the 3-7 membered cycloalkyl, 3-7 membered hetero cycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl are optionally substituted by one or more substituents selected from: halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-4 haloalkyl; R 2 is hydrogen, halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-4 haloalkyl; Each R 3 is independently a halogen, a hydroxyl group, a cyano group, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group or a C 1-4 haloalkyl group; m is 0, 1, 2, 4 or 5; R 4 is hydrogen or C 1-6 alkyl; R 5 is hydrogen, C 1-6 alkyl, -C(=O)-R 5a or -C(=O)NR 5b R 5c , an amino acid residue, a dipeptide residue, a polypeptide residue or -R 5d OR 5e ; R 5a is C 1-20 alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heteroalkyl, wherein the 3- to 7-membered cycloalkyl and 3- to 7-membered heteroalkyl are optionally substituted with one or more substituents selected from the following: halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-4 haloalkyl; R 5b and R 5c each independently is hydrogen, C 1-6 alkyl, -C 1-6 alkylene-6-10-membered aryl, the 6-10-membered aryl optionally substituted by one or more substituents selected from: halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-4 haloalkyl; R 5d is an amino acid residue; R 5e is an amino acid residue.

2. The compound of formula I as defined in claim 1, a pharmaceutically acceptable salt or prodrug thereof, wherein R 1 is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl, preferably 6- to 10-membered aryl, and the 6- to 10-membered aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more substituents selected from the following: halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or C 1-4 haloalkyl; more preferably R 1 is phenyl, and the phenyl is optionally substituted by one or more halogens (such as fluorine, chlorine or bromine).

3. The compound of formula I, its pharmaceutically acceptable salt or prodrug according to claim 1 or 2, wherein R 2 is hydrogen; and / or, R 3 is a halogen; and / or, n is 0.

4. The compound of formula I, its pharmaceutically acceptable salt or prodrug according to any one of claims 1-3, wherein R 4 is hydrogen or C 1-4 alkyl, preferably hydrogen, methyl, ethyl, n-propyl or isopropyl; Alternatively, R 4 is C 1-6 alkyl, preferably C 1-4 alkyl, more preferably methyl, ethyl, n-propyl or isopropyl.

5. The compound of formula I, its pharmaceutically acceptable salt or prodrug according to any one of claims 1-4, wherein R 5 is hydrogen, C 1-6 alkyl, -C(=O)-R 5a , -C(=O)NR 5b R 5c , an amino acid residue or -R 5d OR 5e ; Preferably, R 5 is hydrogen, -C(=O)-R 5a , an amino acid residue or -R 5d OR 5e , R 5a is C 1-20 alkyl.

6. The compound of formula I, its pharmaceutically acceptable salt or prodrug according to any one of claims 1-5, wherein R 5 wherein the amino acid residue is an aliphatic amino acid residue, preferably more preferably 7. The compound of formula I, its pharmaceutically acceptable salt or prodrug according to any one of claims 1-6, wherein R 5a is C 1-20 alkyl or 3-7 membered heterocycloalkyl, preferably C 1-20 alkyl; and / or, R 5d wherein the amino acid residue is an aliphatic amino acid residue, preferably more preferably and / or, R 5e wherein the amino acid residue is an aliphatic amino acid residue, preferably more preferably 8. The compound represented by formula I, a pharmaceutically acceptable salt or prodrug thereof according to any one of claims 1-7, wherein the compound represented by formula I is any of the following structures:

9. A pharmaceutical composition comprising the compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 and a pharmaceutically acceptable excipient.

10. Use of the compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, or the pharmaceutical composition according to claim 9 in the preparation of a drug as an acid sphingomyelinase inhibitor.

11. Use of the compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, or the pharmaceutical composition according to claim 9 in the preparation of a drug for the treatment of diseases related to acid sphingomyelinase; Preferably, the diseases are preferably selected from metabolic diseases, respiratory diseases and central nervous system diseases; More preferably, the metabolic diseases are selected from atherosclerosis, diabetes, fatty liver, liver fibrosis, the respiratory diseases are selected from emphysema, pulmonary edema, pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, pulmonary hypertension, acute lung injury, and the central nervous system diseases are selected from multiple sclerosis, stroke, Alzheimer's disease, anxiety disorder, bipolar disorder and depression.

12. Use of the compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, or the pharmaceutical composition according to claim 9 in the preparation of a drug for the treatment of diseases, the diseases are preferably selected from metabolic diseases, respiratory diseases and central nervous system diseases; Preferably, the metabolic diseases are selected from atherosclerosis, diabetes, fatty liver, liver fibrosis, the respiratory diseases are selected from emphysema, pulmonary edema, pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, pulmonary hypertension, acute lung injury, and the central nervous system diseases are selected from multiple sclerosis, stroke, Alzheimer's disease, anxiety disorder, bipolar disorder and depression.

13. A method for preparing the compound represented by formula I, a pharmaceutically acceptable salt or prodrug thereof according to any one of claims 1-8, which comprises the step of preparing the compound represented by formula I from the compound represented by formula II through one or more steps of reaction, Among them, R 1 、R 2 、R 3 、R 4 、R 5 、m and n are as defined in any one of claims 1 - 7.

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