CN119019333A - Indazole-pyrazole skeleton compound and use thereof - Google Patents

Abstract

The present disclosure relates to indazole-pyrazole backbone compounds and uses thereof. In particular, the present disclosure provides a compound as shown in formula I or a pharmaceutically acceptable salt thereof. The compound disclosed by the disclosure has good inhibition effect on PDE4 and good treatment effect on acute lung injury.

Description

Indazole-pyrazole skeleton compound and application thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to an indazole-pyrazole skeleton compound and application thereof.

Background

Phosphodiesterase 4 (phosphodiesterase, pde 4) belongs to the family of phosphodiesterases and is responsible for degrading cyclic adenosine monophosphate (cyclic adenosine monophosphate, cAMP) in vivo, and is the earliest and most member protein in the family of phosphodiesterases, and together with nucleotide cyclases, regulates intracellular cAMP levels, playing a key role in cAMP signal homeostasis. PDE4 comprises four subtypes A, B, C and D, of which the distribution of expression in the C subtype is less, the predominant subtype present being A, B, D, and the subtypes have significant differences in expression in different tissues and organs, with more subtypes currently being studied being B and D. Each subtype gene is subjected to different splicing to form various splice variants, and can be classified into long forms, short forms, ultrashort forms and dead short forms according to the difference of upstream conserved sequences (upstream conserved regions, UCRs). Wherein the long PDE4 comprises UCR1 and UCR2, the short form comprises UCR2 only, the ultra-short form comprises truncated UCR2, and each PDE4 subtype and splice variant may have unique functions.

CAMP is an important signaling molecule that regulates important physiological and pathological processes such as inflammatory response, fibrotic processes, body injury processes, central nervous system functions, etc., and can affect the development of inflammation, the formation of fibrosis, post-injury inflammatory and repair processes, neurogenesis, establishment of neuronal circuits, apoptosis, neuroplasticity, sleep, sensorimotor gating, mood stabilization, memory and other cognitive functions. PDE4 has been attracting attention in recent years as one of the important members for regulating cAMP signaling in the treatment of diseases such as inflammation, fibrosis, injury and central nervous system, and related diseases including chronic obstructive pulmonary disease, asthma, dermatitis, hepatitis, nonalcoholic fatty liver, psoriasis, rhinitis, behcet's syndrome, arthritis, eczema, vitiligo and ulcerative colitis; fibrotic diseases such as pulmonary fibrosis, liver fibrosis and cystic fibrosis, injury related diseases such as lung injury, liver injury, kidney injury, edema and traumatic brain injury, and central nervous diseases such as Alzheimer's disease, antidepressant, anxiolytic, multiple sclerosis, cerebral apoplexy and cognitive improvement.

PDE4 is involved in a variety of physiological functions and is closely associated with a variety of diseases by regulating cAMP levels in the body. The major pathways involved in PDE4 include the cAMP/PKA/CREB signaling pathway and the MAPK/ERK/CREB pathway. By inhibiting PDE4 activity, cAMP hydrolysis is blocked, cellular levels are elevated, which in turn activates cAMP-dependent Protein Kinase A (PKA), activates cAMP/PKA/CREB and/or MAPK/ERK/CREB signaling pathways, and thereby modulates expression of various target genes including BDNF, bax, PEPCK, IL-2 and the like, thereby participating in various physiological and pathological processes related to inflammation, fibrosis, injury, memory, learning and the like.

Numerous clinical and preclinical studies have shown that inhibitors regulate PDE4 activity, regulate cAMP levels, and can play a role in the treatment of a variety of diseases. There are a number of PDE4 inhibitors currently on the market, including roflumilast, apremilast, crow, and the like. Because of the problems of gastrointestinal side effects, central nervous system side effects and the like of medicines on the market, PDE4 inhibitors are still hot spots for research at present, improvement of therapeutic indexes is a main research target, the main direction of research is to change the administration route, high-activity subtype selective inhibitors and double-target inhibitors are found, and inhibitors and indication research of difficult blood brain barrier penetration are found.

The research shows that PDE4 is a drug-induced target with great potential, has great therapeutic potential in the fields of inflammatory diseases, fibrosis related diseases, injury related diseases, central nervous system related diseases and the like, and is urgently needed to develop novel PDE4 inhibitors for developing candidate drugs of related diseases.

Disclosure of Invention

A compound shown as a formula I or pharmaceutically acceptable salt thereof,

Wherein Z is

X is O or NR ⁵;

R ¹ and R ⁵ are each independently hydrogen, C _1-6 alkyl, unsubstituted or substituted with R ^1-1;

R ² is hydrogen, C _1-6 alkyl which is unsubstituted or substituted by R ^2-1, 3-6 membered cycloalkyl which is unsubstituted or substituted by R ^2-2, 3-6 membered heterocycloalkyl which is unsubstituted or substituted by R ^2-3;

R ³ and R ⁴ are each independently hydrogen, halogen, hydroxy, mercapto, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R ^1-1 and R ^2-1 are each independently halogen, hydroxy, mercapto, amino, nitro, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy;

R ^2-2 and R ^2-3 are each independently halogen, hydroxy, mercapto, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 carboxyl;

R ⁵ and R ⁶ are each independently halogen, hydroxy, mercapto, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

n1 is 0,1, 2 or 3;

n2 is 0,1, 2,3 or 4.

In some embodiments, in a compound of formula I or a pharmaceutically acceptable salt thereof, X is O;

R ¹ is hydrogen, C _1-6 alkyl which is unsubstituted or substituted by R ^1-1;

r ² is hydrogen, C _1-6 alkyl which is unsubstituted or substituted by R ^2-1;

R ³ and R ⁴ are each independently hydrogen, halogen, hydroxy, mercapto, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy;

r ^1-1 and R ^2-1 are each independently halogen, hydroxy, amino, nitro, cyano;

R ^2-2 and R ^2-3 are each independently halogen, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy.

In some embodiments, X is O.

In some embodiments, R ¹ is hydrogen, C _1-6 alkyl, unsubstituted or substituted with R ^1-1.

In some embodiments, R ¹ is C _1-6 alkyl, unsubstituted or substituted with R ^1-1.

In some embodiments, R ¹ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

In some embodiments, R ¹ is hydrogen, methyl, ethyl, n-propyl, isopropyl.

In some embodiments, R ¹ is ethyl.

In some embodiments, R ² is hydrogen, C _1-6 alkyl, unsubstituted or substituted with R ^2-1.

In some embodiments, R ² is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

In some embodiments, R ² is hydrogen, methyl, ethyl, n-propyl, isopropyl.

In some embodiments, R ² is hydrogen.

In some embodiments, R ³ and R ⁴ are each independently hydrogen, halogen, hydroxy, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy.

In some embodiments, R ³ and R ⁴ are each independently hydrogen, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy.

In some embodiments, R ³ and R ⁴ are hydrogen.

In some embodiments, R ^1-1 and R ^2-1 are each independently halogen, hydroxy, amino, nitro, cyano.

In some embodiments, R ^2-2 and R ^2-3 are each independently halogen, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy.

In some embodiments, n1 is 0.

In some embodiments, n2 is 0.

In some embodiments, in R ¹、R² and R ⁵, the C _1-6 alkyl groups are each independently a C _1-4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

In some embodiments, in R ², each of the 3-6 membered cycloalkyl groups is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, in R ², the 3-6 membered heterocycloalkyl is each independently a "3-6 membered heterocycloalkyl having 1,2, or 3 heteroatoms" selected from one or more of N, O and S.

In some embodiments, in R ³、R⁴、R^1-1、R^2-1、R^2-2、R^2-3、R⁵ and R ⁶, the halogen is each independently fluorine, chlorine or bromine.

In some embodiments, in R ³、R⁴、R^2-2、R^2-3、R⁵ and R ⁶, the C _1-4 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

In some embodiments, in R ³、R⁴、R^1-1、R^2-1、R^2-2、R^2-3、R⁵ and R ⁶, the alkyl groups in the C _1-4 haloalkyl are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

In some embodiments, in R ³、R⁴、R^1-1、R^2-1、R^2-2、R^2-3、R⁵ and R ⁶, the halogen in the C _1-4 haloalkyl is each independently fluorine, chlorine or bromine. In some embodiments, in R ³、R⁴、R^1-1、R^2-1、R^2-2 and R ^2-3, the halogen in the C _1-4 haloalkyl is each independently fluorine.

In some embodiments, in R ³、R⁴、R^1-1、R^2-1、R^2-2、R^2-3、R⁵ and R ⁶, the alkyl groups in the C _1-4 haloalkyl groups are each independently-CF ₃、-CHF₂ or-CH ₂ F.

In some embodiments, in R ³、R⁴、R^1-1、R^2-1、R^2-2、R^2-3、R⁵ and R ⁶, the C _1-4 alkoxy groups are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

In some embodiments, in R ³、R⁴、R^1-1、R^2-1、R^2-2、R^2-3、R⁵ and R ⁶, the alkoxy groups in the C _1-4 haloalkoxy groups are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

In some embodiments, in R ³、R⁴、R^1-1、R^2-1、R^2-2、R^2-3、R⁵ and R ⁶, the halogen in the C _1-4 haloalkoxy is each independently fluorine, chlorine or bromine.

In some embodiments, the compound of formula I in the compound of formula I or a pharmaceutically acceptable salt thereof is of any one of the structures,

The present disclosure provides a pharmaceutical composition comprising a compound as shown in formula I above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

The disclosure also provides an application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing medicines serving as PDE4 inhibitors. In some embodiments, the PDE4 inhibitor is a PDE4B and/or PDE4D inhibitor.

The disclosure also provides application of the compound shown in the formula I or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparation of medicines for preventing and/or treating diseases related to PDE 4. In some embodiments, the PDE4 is PDE4B and/or PDE4D. In some embodiments, the PDE 4-related disease is an inflammatory disease, a fibrotic disease, an injury disease, and a central nervous disease. In some embodiments, the inflammatory disease comprises chronic obstructive pulmonary disease, asthma, dermatitis, hepatitis, nonalcoholic fatty liver, psoriasis, rhinitis, behcet's syndrome, arthritis, eczema, vitiligo, and ulcerative colitis. In some embodiments, the fibrotic disease includes pulmonary fibrosis, liver fibrosis, and cystic fibrosis. In some embodiments, the traumatic disease includes lung injury, liver injury, kidney injury, edema, and traumatic brain injury. In some embodiments, the central nervous disease comprises alzheimer's disease, antidepressant, anxiolytic, multiple sclerosis, stroke, and a cognitive disorder related disorder. In some embodiments, the PDE 4-related disease is acute lung injury.

The present disclosure also provides an application of the compound shown in the formula I or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing a medicament for preventing and/or treating diseases, such as inflammatory diseases, fibrosis diseases, injury diseases and central nervous diseases. In some embodiments, the inflammatory disease comprises chronic obstructive pulmonary disease, asthma, dermatitis, hepatitis, nonalcoholic fatty liver, psoriasis, rhinitis, behcet's syndrome, arthritis, eczema, vitiligo, and ulcerative colitis. In some embodiments, the fibrotic disease includes pulmonary fibrosis, liver fibrosis, and cystic fibrosis. In some embodiments, the traumatic disease includes lung injury, liver injury, kidney injury, edema, and traumatic brain injury. In some embodiments, the central nervous disorder includes alzheimer's disease, antidepressant, anxiolytic, multiple sclerosis, cerebral apoplexy, and improving cognition. In some embodiments, the disease is acute lung injury.

The present disclosure also provides a compound of formula II or a pharmaceutically acceptable salt thereof,

Wherein Y is nitro or amino; z, R ⁵ and n1 are as defined for any one of the schemes for the compounds of formula I.

In some embodiments, the compound of formula II is any of the following structures:

The disclosure also provides a preparation method of the compound shown in the formula I, which comprises the following steps:

(1) Reacting a compound shown in a formula IV with a compound shown in a formula V to obtain a compound shown in a formula II-1;

(2) The compound shown in the formula II-1 is subjected to reduction reaction to obtain a compound shown in the formula II-2;

(3) Reacting a compound shown in a formula II-2 with a compound shown in a formula III to obtain a compound shown in a formula I;

Wherein a ₁ and a ₂ are each independently halogen; z, R ²、R⁵、R⁶, n1 and n2 are as defined for any of the schemes for the compounds of formula I.

Definition of terms

Where the present disclosure does not define a particular configuration, the compounds of the present disclosure may exist in a particular geometric or stereoisomeric form. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present disclosure.

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 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 tautomers via proton transfer, such as keto-enol and imine-enamine, lactam-lactam isomerization. Examples of lactam-lactam balances are between a and B as shown below.

All compounds in the present disclosure may be drawn as form a or form B. All tautomeric forms are within the scope of the disclosure. The naming of the compounds does not exclude any tautomers.

The compounds of the present disclosure may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The asymmetric carbon atom containing compounds of the present disclosure may be isolated in optically active pure or racemic forms. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

Optically active (R) -and (S) -isomers and 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 may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Or when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), forms a diastereomeric salt with an appropriate optically active acid or base, and then undergoes diastereomeric resolution by conventional methods well known in the art, followed by recovery of the pure enantiomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 30 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 10 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms, and even more preferably an alkyl group containing from 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 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-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are alkyl groups 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-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like.

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

The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, C (=o) or S (=o) _m (where m is an integer from 0 to 2), but excluding the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:

etc.

The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocycloalkyl group, non-limiting examples of which include:

Etc.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above.

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

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

The term "haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂.

The term "amino" refers to-NH ₂.

The term "carboxy" refers to-C (O) OH.

The term "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort.

"Substituted with one or more … …" means that it may be substituted with single or multiple substituents. When substituted with multiple substituents, there may be multiple identical substituents, or there may be one or a combination of multiple different substituents.

The term "linked," when referring to a connection between two molecules, refers to the connection of the two molecules by covalent bonds or the association of the two molecules via non-covalent bonds (e.g., hydrogen or ionic bonds), including direct and indirect connections.

The term "directly linked" means that a first compound or group is linked to a second compound or group without any intervening atoms or groups of atoms. The term "indirectly attached" refers to a first compound or group being attached to a second compound or group through an intervening group, compound or molecule (e.g., a linking group).

In the chemical structure of the compounds of the present disclosure, the bondIndicating unspecified configuration, i.e. bonds if chiral isomers are present in the chemical structureMay beOr at the same time containTwo configurations. Although all of the above structural formulae are drawn as certain isomeric forms for simplicity, the present disclosure may include all isomers, such as tautomers, rotamers, geometric isomers, diastereomers, racemates and enantiomers. In the chemical structure of the compounds of the present disclosure, the bondNot specifying configuration, i.e. keysThe configuration of (a) may be E-type or Z-type, or both E and Z configurations may be included.

Unless otherwise indicated, the symbols used hereinMeaning that it may be attached to one or more of any of the groups according to the scope of the disclosure described herein.

In this disclosure, the terms "comprising," including, "and" comprising "are interchangeable with" consisting of … ….

The term "composition" means a mixture of a drug containing one or more of the compounds described herein, or a physiologically acceptable salt or precursor thereof, with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The composition aims at promoting the administration to organisms, facilitating the absorption of active ingredients and further exerting biological activity.

The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable excipient" includes, but is not limited to, any auxiliary agent, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that has been approved by the U.S. food and drug administration for use in humans or livestock animals.

Unless otherwise indicated, the "compounds" of the present disclosure may each independently exist in the form of a salt, a mixed salt, or a non-salt (e.g., free acid or free base). When present in salt or mixed salt form, it may be a pharmaceutically acceptable salt or a pharmaceutically acceptable salt.

The terms "pharmaceutically acceptable salt" and "pharmaceutically acceptable salt" are used interchangeably and are meant to include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid capable of retaining the biological effectiveness of the free base without other side effects, and can be prepared by methods known in the art.

By "pharmaceutically acceptable base addition salt" is meant salts with inorganic or organic bases capable of maintaining the bioavailability of the free acid without other side effects, which salts can be prepared by methods known in the art.

An "effective amount", "effective dose", "effective therapeutic amount" or "therapeutically effective amount" refers to the amount of a drug, compound or pharmaceutical composition necessary to achieve any one or more beneficial or desired therapeutic results. For prophylactic use, beneficial or desired results include elimination or reduction of risk, lessening the severity, or delaying the onset of a disorder, including biochemical, histological and/or behavioral symptoms of the disorder, its complications, and intermediate pathological phenotypes that are exhibited during the development of the disorder.

As used herein, "subject," "patient," "subject," or "individual" are used interchangeably and include a human or non-human animal, such as a mammal, e.g., a human or monkey.

Drawings

FIG. 1 shows the results of anti-inflammatory activity at the cellular level of compounds in vitro.

FIG. 2 shows results of lung tissue sections of compound acute lung injury pharmacodynamic tests.

FIG. 3 shows the test results of the drug effect index of the compound acute lung injury drug effect test, wherein (a) the result of the lung dry weight ratio is shown; (b) lavage fluid neutrophil count results; (c) MPO measurement; (d) NO assay; (e) TNF- α content measurement in lavage fluid; (f) results of measurement of IL-1. Beta. Content in lavage fluid; (g) results of measurement of IL-6 content in lavage fluid.

Detailed description of the preferred embodiments

The present disclosure is further described below in connection with the examples, which are not intended to limit the scope of the present disclosure. Experimental methods for which specific conditions are not noted in the examples of the present disclosure are generally performed under conventional conditions or under conditions suggested by the manufacturer of the raw materials or goods. Reagents of particular origin are not noted, but are available from any supplier of molecular biological reagents in quality/purity for molecular biological applications.

Unless otherwise indicated, the reagents used in the examples below are all commercially available.

Example 1

Step 1.3-bromo-1- (2, 2-difluoroethyl) -5-nitro-1H-indazole

The starting 3-bromo-5-nitroindazole (3.00 g,12.40mmol,1.00 eq) was placed in a 100mL round bottom flask, anhydrous acetonitrile (10 mL) was used as solvent, and 1, 1-difluoro-2-iodoethane (1637. Mu.l, 18.60mmol,1.50 eq), potassium carbonate (571 mg,4.14mmol,2.00 eq) were added in sequence, followed by heating reflux at 85℃for 12h. After the completion of the TLC detection reaction, the reaction solution was cooled to room temperature, filtered through celite, the organic phase was dried by distillation under reduced pressure, ethyl acetate was redissolved, and extracted three times (20 ml×3) with ethyl acetate after adding water, the organic phase was collected and washed twice with saturated brine, dried over anhydrous sodium sulfate for 0.5h, distilled off under reduced pressure, and then the solvent was purified by wet column chromatography (petroleum ether: dichloromethane=8:1) to give 2.99g as a pale yellow solid powder product with a yield of 79%.

¹HNMR(300MHz,DMSO-d₆)δ8.50(d,J＝1.6Hz,1H),8.37(dd,J＝9.3,2.2Hz,1H),8.02(d,J＝9.7Hz,1H),6.49(tt,J＝54.3,3.3Hz,1H),5.09(td,J＝15.5,3.3Hz,2H)ppm.

Step 2 preparation of 1- (2, 2-difluoroethyl) -3- (1-ethyl-1H-pyrazol-5-yl) -5-nitro-1H-indazole

Intermediate (380 mg,1.25mmol,1.00 eq) and 1-ethylpyrazole-5-boronic acid (806 mg,3.26mmol,2.00 eq) were placed in a 50mL two-necked flask, dissolved in a mixed solvent of toluene (8 mL) and methanol (4 mL), then added with an aqueous solution of sodium carbonate (284 mg,5.02mmol,4.00 eq) in 2mL, evacuated for 5min, then added with catalyst [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (92 mg,0.13 eq), evacuated for 10min and heated to reflux under nitrogen for 14h at 100 ℃. After the TLC detection reaction was completed, the reaction solution was cooled to room temperature, suction filtration was performed using celite, the organic solvent was distilled off under reduced pressure, and after adding a proper amount of water, extraction was performed three times using ethyl acetate (30 ml×3), the combined organic phases were collected, washed twice with saturated saline, dried over anhydrous sodium sulfate for 0.5h, concentrated under reduced pressure, and then sand was made, and purified by column chromatography (petroleum ether: ethyl acetate=32:1), to give 210mg of a pale yellow solid powdery product in 40% yield.

¹HNMR(300MHz,DMSO-d₆)δ8.74(d,J＝1.5Hz,1H),8.38(dd,J＝9.3,2.1Hz,1H),8.06(d,J＝9.3Hz,1H),7.68(d,J＝2.0Hz,1H),7.05(d,J＝2.0Hz,1H),6.56(tt,J＝54.3,3.2Hz,1H),5.17(td,J＝15.6,3.2Hz,2H),4.52(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H)ppm.

Step 3 preparation of 1- (2, 2-difluoroethyl) -3- (1-ethyl-1H-pyrazol-5-yl) -1H-indazol-5-amine

The intermediate (270 mg,0.79mmol,1.00 eq) was placed in a 50mL single-necked flask, and a mixed solvent of ethanol (12 mL) and water (6 mL) was dissolved, followed by addition of iron powder (177 mg,3.17mmol,4.00 eq), ammonium chloride (423 mg,7.92mmol,10.00 eq) and heating reflux reaction at 80℃for 4h. After the completion of the TLC detection reaction, the mixture was filtered while it was still hot, and the filtrate was extracted three times with methylene chloride (30 mL. Times.3), the organic phases were combined and washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate for 0.5h, and concentrated under reduced pressure to give 170mg of a reddish-brown flaky solid product in 89% yield.

¹HNMR(300MHz,DMSO-d₆)δ7.59(d,J＝1.9Hz,1H),7.52(d,J＝9.5Hz,1H),7.00–6.86(m,2H),6.66(d,J＝1.9Hz,1H),6.44(tt,J＝54.8,3.6Hz,1H),5.29(s,2H),4.89(td,J＝15.2,3.6Hz,2H),4.50(q,J＝7.1Hz,2H),1.33(t,J＝7.1Hz,3H)ppm.

Step 4 preparation of ethyl (4- ((1- (2, 2-difluoroethyl) -3- (1-ethyl-1H-pyrazol-5-yl) -1H-imidazol-5-yl) amino) phenyl) acetate (Compound 2)

The intermediate (210 mg,0.68mmol,1.00 eq) and methyl p-bromophenylacetate (118. Mu.l, 0.75mmol,1.10 eq) were placed in a 25mL two-necked flask, dissolved in anhydrous toluene (6 mL) as a solvent, cesium carbonate (440 mg,1.35mmol,2.00 eq), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (84 mg,0.135mmol,0.20 eq) were added sequentially, and after evacuation for 5min, palladium acetate (15 mg,0.068mmol,0.10 eq) was added, evacuation was continued for 10min, and reflux reaction was continued at 100℃under nitrogen protection. After the completion of the TLC detection reaction, the reaction solution was cooled to room temperature, suction filtration was performed using celite, the organic solvent was distilled off under reduced pressure, and after adding a proper amount of water, extraction was performed three times using ethyl acetate (30 mL. Times.3), the combined organic phases were collected, washed twice with saturated brine, dried over anhydrous sodium sulfate for 0.5h, concentrated under reduced pressure, and then sand was produced, and purified by column chromatography (petroleum ether: ethyl acetate=16:1) to give 85mg of a yellow solid powdery product in 49% yield.

M.P.150-153℃.¹HNMR(300MHz,DMSO-d₆)δ8.19(s,1H),7.74(d,J＝9.0

Hz,1H),7.60(d,J＝1.9Hz,1H),7.43(d,J＝1.9Hz,1H),7.31(dd,J＝9.0,2.0Hz,1H),7.11(d,J＝8.5Hz,2H),7.01(d,J＝8.6Hz,2H),6.69(d,J＝1.9Hz,1H),6.68–6.30(m,1H),4.98(td,J＝15.3,3.5Hz,2H),4.50(q,J＝7.1Hz,2H),3.60(s,3H),3.56(s,2H),1.35(t,J＝7.1Hz,3H)ppm.¹³C NMR(101MHz,CDCl₃)δ172.51,143.35,138.75,137.89,137.82,135.97,133.45,130.35,125.89,123.74,122.94,116.61,116.30,113.87,111.44,110.12,109.04,106.37,52.07,51.33(t,J＝28.3Hz),45.99,40.40,15.72ppm.HRMS(ESI⁺):m/z[M+H]⁺calculated for C₂₃H₂₃F₂N₅O₂,440.1898;found440.1891.HPLC purity＝95.02％,t_R＝14.44min.

Step 5. Preparation of 2- (4- ((1- (2, 2-difluoroethyl) -3- (1-ethyl-1H-pyrazol-5-yl) -1H-imidazol-5-yl) aminophenyl) acetic acid (Compound 1)

Compound 2 (95 mg,0.21mmol,1.00 eq) was dissolved in 3mL of methanol, and an aqueous solution of KOH (33 mg,0.83mmol,4.00 eq) was added thereto for 2mL and the mixture was heated at 80℃under reflux for 4h. After the completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, and after adding a proper amount of water, the pH was adjusted to 1-2 with a dilute hydrochloric acid (1 mol/L) solution, followed by extraction three times with ethyl acetate (20 mL. Times.3), the combined organic phases were collected, dried over anhydrous sodium sulfate for 0.5h, concentrated under reduced pressure, and then sand was made, and purified by column chromatography (dichloromethane: methanol=80:1) to give 22mg of a pale yellow powdery solid product in 54% yield.

M.P.139-140℃.¹H NMR(300MHz,DMSO-d₆)δ11.70(s,1H),8.16(d,J＝5.9

Hz,1H),7.73(d,J＝9.0Hz,1H),7.59(s,1H),7.43(s,1H),7.30(d,J＝9.1Hz,1H),7.20–7.05(m,2H),7.01(d,J＝8.3Hz,2H),6.68(d,J＝6.6Hz,1H),6.49(tt,J＝54.6,3.6Hz,1H),4.98(td,J＝15.2,3.4Hz,2H),4.50(q,J＝7.1Hz,2H),3.45(s,2H),1.35(t,J＝7.0Hz,3H)ppm.¹³C NMR(101MHz,DMSO)δ173.68,143.30,139.04,138.91,137.53,134.65,133.70,130.66,126.28,123.06,122.03,117.65,117.29,116.35,114.89,112.49,111.74,106.14,105.30,50.71(t,J＝25.3Hz),45.75,16.11ppm.HRMS(ESI⁺):m/z[M+H]⁺calculated for C₂₂H₂₁F₂N₅O₂,426.17416;found 426.17300.HPLC purity＝98.07％,t_R＝8.31min.

Test example 1: PDE4 inhibition Activity assay

The specific test method is as follows:

compound solution preparation:

By calculation, 0.005mmol of each test compound was precisely weighed, dissolved in 0.5mL of DMSO, blown up multiple times, and mixed uniformly to prepare 10mM of compound mother liquor, and then the mother liquor was diluted stepwise to ten concentrations of 1mM, 100. Mu.M, 10. Mu.M, 1. Mu.M, 100nM, 10nM, 1nM, 0.1nM, 0.01 nM.

Preparing a mixed solution:

(1) PDE4B1 stock (10 nM): 10 μg (M.W. =109 kDa, purity 70%) of enzyme was taken, dissolved in 6.419mL of buffer (25 mM Tris-HCl, pH 8.0, 100mM sodium chloride, 0.05% Tween-20, 50% glycerol and 3mM DTT), gently swished, mixed well and split into 10 tubes, 641.9 μl/tube. Re-dissolving in ice bath for 5min before use, re-dissolving at room temperature for 3min, slowly blowing, mixing, and slowly blowing for 3 times before sampling.

(2) Buffer solution: 60mL of an aqueous solution containing 61mM Tris-HCl,12mM MgCl2, 61mM KCl,6.1mM TCEP, 0.48mM PEP, 0.012mM NADH, 0.048mM ATP, pH 8.0 was prepared.

(3) Myokinase solution: taking enzyme suspension preserved at 2-8deg.C, standing at room temperature for 5min, slowly beating to mix uniformly, precisely measuring 65 μl of enzyme suspension, adding 335 μl LBuffer, making 335 μl solution, and slowly beating to mix uniformly (preserving on ice).

(4) Pyruvate kinase solution: taking enzyme solid powder stored at-80deg.C, precisely weighing 0.3mg, dissolving in 200 mu LBuffer, and slowly blowing to mix well (stored on ice).

(5) Lactate dehydrogenase solution: taking enzyme solid powder stored at-80deg.C, precisely weighing 0.9mg, dissolving in 200 mu LBuffer, and slowly blowing to mix well (stored on ice).

(6) PDE4B1 solution: taking the subpackaged solution stored at-80deg.C, re-dissolving in ice for 5min, re-dissolving at room temperature for 5min, and mixing.

(7) CAMP solution (0.032 mM): a solution of 2mL of 0.032mM was prepared from appropriate amount of cAMP using Buffer.

The operation flow is as follows:

(1) Preparing a mixed solution in a 96-well plate, adding 145 mu L of Buffer, sequentially adding 6 mu L of myokinase, 3.2 mu L of pyruvate kinase, 2 mu L of lactate dehydrogenase and 10 mu L of LPDE4B1 solution, blowing slowly for 3 times after each solution addition, and uniformly mixing.

(2) Sequentially adding 10 mu L of compound solution with corresponding concentration, slowly blowing, uniformly mixing, replacing blank group (without compound) with equal volume of DMSO, and incubating for 5-10 minutes at room temperature.

(3) 25 Μl of cAMP solution was added before measurement, and the mixture was blown 3 times, mixed well, and no cAMP well was replaced with an equal volume Buffer.

(4) Excitation wavelength 355nM, emission wavelength 460nM, and measurement is continued for 10 min, and measurement is stopped after the platform appears.

And (3) data processing: and selecting Microsoft Excel2010 electronic form software for data processing, wherein the calculation formula is as follows:

Inhibition％＝(Signal-Min)/(Max-Min)*100％

Signal: inhibitor well NADH fluorescence intensity; max: NADH fluorescence intensity without cAMP well; min: NADH fluorescence intensity in the compound-free wells.

The results are shown in Table 1:

enzyme inhibitory Activity of Compounds of Table 1 against PDE4B

Conclusion: the inhibition activity of the compound 1 on PDE4B1 is 20nM, which is 450 times of that of the positive drug rolipram, 10 times of that of the self-grinding positive compound, and has excellent in vitro enzyme activity.

Test example 2: in vitro cellular level anti-inflammatory Activity test of Compounds

The specific test method comprises the following steps: the effect of PDE4B inhibitors on the production of the cellular inflammatory factor TNF-alpha was examined by ELISA. The cell density was adjusted to 2X 10 ⁵ cells/mL, 100. Mu.L of each well was inoculated into a 96-well plate, and incubated in an incubator at 37℃and 5% CO ₂ saturated humidity for 12 hours until the cells adhered to the wall. The experiments were divided into blank and LPS control groups and test groups; test groups were incubated in an incubator for 1h with different concentrations of the test compounds (10. Mu.M, 25. Mu.M, and 50. Mu.M) added to each well; except for the blank, LPS solution (200 ng/mL) was added to each group, culturing was continued for 24 hours, the culture solution in each well was aspirated into a centrifuge tube, and centrifuged at 3500rpm at 4℃for 10 minutes, and the supernatant was taken for measuring the level of TNF- α.

As shown in FIG. 1, RAW 264.7 cells were induced with LPS, and the inflammatory response of the cells was inhibited in a dose-dependent manner at 1. Mu.M, 2. Mu.M, and 4. Mu.M by detecting the inflammatory factor TNF-. Alpha.Compound 1, showing good anti-inflammatory activity.

Test example 3: compound acute lung injury pharmacodynamic test lung tissue section results

The specific test method comprises the following steps: first, an acute lung injury model of mice is established by using LPS. After the mice are anesthetized (1.25% avermectin, 0.2mL/kg, intraperitoneal injection), the trachea is exposed, 60 mu L of lipopolysaccharide solution is instilled by using a 1mL syringe trachea, after the injection is finished, the mice are erected and rotated for 30 circles, then are vertically placed for 2-3min, the neck is sutured, placed in an environment with proper temperature for awakening, placed back into a mouse cage for continuous feeding, and the model is established successfully. Lung tissue was isolated, preserved in formalin solution, HE stained, microscopic observation of lung tissue sections and reporting of the results.

The results are shown in figure 2, where the model group had severe congestion compared to the blank group, and more red blood cells were seen, most alveolar spaces were filled with pink fluid (edema fluid) and a small number of red blood cells, and a small number of gas vacuoles were seen. The positive drug group and compound 1 low dose group were significantly less hyperemic, less red blood cells and concentrated only in a partial area, with long and narrow gas vacuoles. The high-dose group of the compound 1 has the advantages of less congestion of cells, less red blood cells, unobvious red blood cell aggregation area and smaller gas vacuoles.

Test example 4: test result of drug effect index of compound acute lung injury drug effect test

The specific test method comprises the following steps: LPS-induced acute lung injury in mice was modeled as in test example 3. Bronchoalveolar lavage fluid (BALF) was collected as follows. Mice were sacrificed after blood collection from the eyeballs, fixed on the console, right lung ligated after dissection, tracheal intubation and fixation were performed using a venous indwelling needle, and then left lung bronchi were alveolar lavage with 0.3mLPBS (1×) solution, and the procedure was repeated three times. Mixing the recovered bronchoalveolar lavage fluid, centrifuging at 4deg.C for 10min, collecting supernatant, and storing at-80deg.C. The ELISA detection kit is used for measuring the contents of inflammatory factors TNF-alpha, IL-1 beta and IL-6 in BALF. The mice were dissected, lung tissue was taken, homogenized, and the viability of the lung tissue MPO and NO was tested according to the kit instructions.

The results are shown in figure 3, both low and high doses of compound 1 are superior to the positive drug dexamethasone in inhibiting neutrophil and restoring MPO viability and NO levels; in terms of inhibiting inflammatory factors TNF-alpha, IL-1 beta and IL-6, the low dosage of WPBL-II-06 is basically the same as that of the positive medicine, and the high dosage is better than that of the positive medicine. And all indices exhibit a clear dose dependence from a finishing point of view, it is reasonable to believe that compound 1 has great potential in the treatment of pulmonary inflammation, in particular acute lung injury or acute respiratory distress syndrome.

Claims (10)

1. A compound shown as a formula I or pharmaceutically acceptable salt thereof,

Wherein Z is

X is O or NR ⁵;

R ¹ and R ⁵ are each independently hydrogen, C _1-6 alkyl, unsubstituted or substituted with R ^1-1;

R ² is hydrogen, C _1-6 alkyl which is unsubstituted or substituted by R ^2-1, 3-6 membered cycloalkyl which is unsubstituted or substituted by R ^2-2, 3-6 membered heterocycloalkyl which is unsubstituted or substituted by R ^2-3;

R ³ and R ⁴ are each independently hydrogen, halogen, hydroxy, mercapto, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

R ^1-1 and R ^2-1 are each independently halogen, hydroxy, mercapto, amino, nitro, cyano, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 carboxy, -C (=o) -C _1-4 alkyl, -NHC (=o) -C _1-4 alkyl or-C (=o) NH-C _1-4 alkyl;

R ^2-2 and R ^2-3 are each independently halogen, hydroxy, mercapto, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 carboxyl;

R ⁵ and R ⁶ are each independently halogen, hydroxy, mercapto, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy;

n1 is 0,1, 2 or 3;

n2 is 0,1, 2,3 or 4.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein, in the compound of formula I or a pharmaceutically acceptable salt thereof, X is O;

R ¹ is hydrogen, C _1-6 alkyl which is unsubstituted or substituted by R ^1-1;

r ² is hydrogen, C _1-6 alkyl which is unsubstituted or substituted by R ^2-1;

R ³ and R ⁴ are each independently hydrogen, halogen, hydroxy, mercapto, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy;

r ^1-1 and R ^2-1 are each independently halogen, hydroxy, amino, nitro, cyano;

R ^2-2 and R ^2-3 are each independently halogen, hydroxy, amino, nitro, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein,

In R ¹、R² and R ⁵, the C _1-6 alkyl groups are each independently a C _1-4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or, in R ², each of the 3-6 membered cycloalkyl groups is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or, in R ², the 3-6 membered heterocycloalkyl groups are each independently "a 3-6 membered heterocycloalkyl group having 1,2 or 3 heteroatoms selected from one or more of N, O and S";

And/or, in R ³、R⁴、R^1-1、R^2-1、R^2-2、R^2-3、R⁵ and R ⁶, each of the halogens is independently fluorine, chlorine or bromine;

And/or, in R ³、R⁴、R^2-2、R^2-3、R⁵ and R ⁶, the C _1-4 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or, in R ³、R⁴、R^1-1、R^2-1、R^2-2、R^2-3、R⁵ and R ⁶, the alkyl groups in the C _1-4 haloalkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or, in R ³、R⁴、R^1-1、R^2-1、R^2-2、R^2-3、R⁵ and R ⁶, the halogen in the C _1-4 haloalkyl is each independently fluorine, chlorine or bromine;

And/or, in R ³、R⁴、R^1-1、R^2-1、R^2-2、R^2-3、R⁵ and R ⁶, the C _1-4 alkoxy groups are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

And/or, in R ³、R⁴、R^1-1、R^2-1、R^2-2、R^2-3、R⁵ and R ⁶, the alkoxy groups in the C _1-4 haloalkoxy groups are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

and/or, in R ³、R⁴、R^1-1、R^2-1、R^2-2、R^2-3、R⁵ and R ⁶, the halogen in the C _1-4 haloalkoxy group is each independently fluorine, chlorine or bromine.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claim 1 to 3, wherein the compound of formula I has any one of the following structures,

5. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-4, and a pharmaceutically acceptable excipient.

6. Use of a compound of formula I as defined in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 5 for the manufacture of a medicament as a PDE4 inhibitor.

7. Use of a compound of formula I as defined in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 5 for the manufacture of a medicament for the prophylaxis and/or treatment of a PDE 4-related disease, preferably acute lung injury.

8. Use of a compound of formula I as defined in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 5 for the manufacture of a medicament for the prophylaxis and/or treatment of inflammatory diseases, fibrotic diseases, damaging diseases and central nervous diseases, preferably acute lung injury.

9. A compound shown as a formula II or pharmaceutically acceptable salt thereof,

Wherein Y is nitro or amino; z, R ⁵ and n1 are as defined in any one of claims 1 to 4.

10. A process for the preparation of a compound of formula I comprising the steps of:

(1) Reacting a compound shown in a formula IV with a compound shown in a formula V to obtain a compound shown in a formula II-1;

(2) The compound shown in the formula II-1 is subjected to reduction reaction to obtain a compound shown in the formula II-2;

(3) Reacting a compound shown in a formula II-2 with a compound shown in a formula III to obtain a compound shown in a formula I;

Wherein a ₁ and a ₂ are each independently halogen; z, R ²、R⁵、R⁶, n1 and n2 are as defined in any one of claims 1 to 4.