Indazole-pyrazole scaffold compound and use thereof

Abstract

The present disclosure relates to an indazole-pyrazole scaffold compound and a use thereof. Specifically, the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof. The compound of the present disclosure has good inhibition effects on PDE4 and good therapeutic effects on acute lung injury.

Description

An indazole-pyrazole skeleton compound and use thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicinal chemistry, in particular to an indazole-pyrazole skeleton compound and use thereof. BACKGROUND

[0002] Phosphodiesterase 4 (PDE4) belongs to the phosphodiesterase family, which is responsible for the degradation of cyclic adenosine monophosphate (cAMP) in vivo, is the earliest discovered and the most members of the phosphodiesterase family, and regulates the level of intracellular cAMP together with nucleotide cyclase, and plays a key role in the cAMP signal homeostasis. PDE4 includes four subtypes A, B, C and D, among which the C subtype is less expressed and distributed in vivo, and the main existing subtypes are A, B and D, each subtype has significant expression difference in different tissues and organs, and the currently studied subtypes are B and D. Each subtype gene forms a variety of splice variants after different splicing, which can be divided into long, short, ultra-short and dead short types according to the different upstream conserved regions (UCRs). Among them, the long type PDE4 contains UCR1 and UCR2, the short type contains only UCR2, and the ultra-short type contains a truncated UCR2. Each PDE4 subtype and splice variant may have its own unique function.

[0003] cAMP is an important signal molecule that regulates important physiological and pathological processes such as inflammatory response, fibrosis process, body injury process, central nervous system function, and can affect the occurrence and development of inflammation, the formation of fibrosis, the inflammation and repair process after injury, neurogenesis, the establishment of neuronal circuit, apoptosis, neural plasticity, sleep, sensory motor gating, emotional stability, memory and other cognitive functions. As one of the important members of cAMP signal regulation, PDE4 has attracted much attention in the field of treating inflammation, fibrosis, injury and central nervous system diseases in recent years, and the related diseases include chronic obstructive pulmonary disease, asthma, dermatitis, hepatitis, non-alcoholic fatty liver, psoriasis, rhinitis, Behcet's syndrome, arthritis, eczema, vitiligo and ulcerative colitis, etc. inflammatory diseases; pulmonary fibrosis, liver fibrosis and cystic fibrosis, etc. fibrosis diseases, lung injury, liver injury, kidney injury, edema and traumatic brain injury, etc. injury-related diseases, Alzheimer's disease, antidepressant, anxiolytic, multiple sclerosis, stroke and cognitive improvement, etc. central nervous diseases.

[0004] PDE4 participates in various physiological functions and is closely related to a variety of diseases by regulating cAMP levels in the body. The main pathways in which PDE4 is involved include the cAMP / PKA / CREB signaling pathway and the MAPK / ERK / CREB pathway. By inhibiting PDE4 activity, cAMP hydrolysis is blocked, and the cellular level increases, which in turn activates cAMP-dependent protein kinase A (PKA), activating the cAMP / PKA / CREB and / or MAPK / ERK / CREB signaling pathways. This, in turn, regulates the expression of multiple target genes, including BDNF, Bax, PEPCK, and IL-2, thereby participating in a variety of physiological and pathological processes related to inflammation, fibrosis, injury, memory, and learning.

[0005] Numerous clinical and preclinical studies have demonstrated that regulating PDE4 activity and cAMP levels through inhibitors can treat a variety of diseases. Several PDE4 inhibitors are currently on the market, including roflumilast, apremilast, and claborone. Due to gastrointestinal and central nervous system side effects of marketed drugs, PDE4 inhibitors remain a hot research topic. Improving the therapeutic index is the primary research goal, with key research directions including altering the route of administration, discovering highly active subtype-selective inhibitors, dual-target inhibitors, discovering inhibitors that have difficulty crossing the blood-brain barrier, and investigating indications.

[0006] The above studies indicate that PDE4 is a promising druggable target with great therapeutic potential in inflammatory diseases, fibrosis-related diseases, injury-related diseases, and central nervous system-related diseases. There is an urgent need to develop novel PDE4 inhibitors for the development of candidate drugs for these diseases. Summary of the Invention

[0007] A compound as shown in Formula I, or a pharmaceutically acceptable salt thereof.

[0008] Where Z is

[0009] X is O or NR 5 ;

[0010] R 1 and R 5 Each is independently hydrogen, unsubstituted, or R-substituted. 1-1 Replacement C 1-6 alkyl;

[0011] R 2 Hydrogen, unsubstituted or R 2-1 Replacement C 1-6 Alkyl, unsubstituted or R 2-2 Substituted 3-6 membered cycloalkyl, unsubstituted or R2-3 Substituted 3-6 membered heterocyclic alkyl groups;

[0012] R 3 and R 4 Each can be independently represented by hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, or C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0013] R 1-1 and R 2-1 Each can be independently a halogen, hydroxyl, mercapto, amino, nitro, cyano, or C group. 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0014] R 2-2 and R 2-3 Each can be independently a halogen, hydroxyl, mercapto, amino, nitro, cyano, or C group. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 carboxyl;

[0015] R 5 and R 6 Each can be independently a halogen, hydroxyl, mercapto, amino, nitro, cyano, or C group. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0016] n1 is 0, 1, 2 or 3;

[0017] n2 can be 0, 1, 2, 3 or 4.

[0018] In some embodiments, X is O in the compound of Formula I or a pharmaceutically acceptable salt thereof;

[0019] R 1 Hydrogen, unsubstituted or R 1-1 Replacement C 1-6 alkyl;

[0020] R 2 Hydrogen, unsubstituted or R 2-1 Replacement C 1-6 alkyl;

[0021] R 3 and R 4 Each can be independently represented by hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, or C.1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy;

[0022] R 1-1 and R 2-1 Each can be independently halogenated, hydroxyl, amino, nitro, or cyano.

[0023] R 2-2 and R 2-3 Each is independently a halogen, hydroxyl, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyl group.

[0024] In some implementations, X is O.

[0025] In some implementation schemes, R 1 Hydrogen, unsubstituted or R 1-1 Replacement C 1-6 alkyl.

[0026] In some implementation schemes, R 1 For not replaced or by R 1-1 Replacement C 1-6 alkyl.

[0027] In some implementation schemes, R 1 It can be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0028] In some implementation schemes, R 1 It can be hydrogen, methyl, ethyl, n-propyl, or isopropyl.

[0029] In some implementation schemes, R 1 It is an ethyl group.

[0030] In some implementation schemes, R 2 Hydrogen, unsubstituted or R 2-1 Replacement C 1-6 alkyl.

[0031] In some implementation schemes, R 2 It can be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0032] In some implementation schemes, R 2 It can be hydrogen, methyl, ethyl, n-propyl, or isopropyl.

[0033] In some implementation schemes, R 2 It is hydrogen.

[0034] In some embodiments, R 3 and R 4 are each independently hydrogen, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy.

[0035] 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.

[0036] In some embodiments, R 3 and R 4 are hydrogen.

[0037] In some embodiments, R 1-1 and R 2-1 are each independently halogen, hydroxyl, amino, nitro, cyano.

[0038] In some embodiments, R 2-2 and R 2-3 are each independently halogen, hydroxyl, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy.

[0039] In some embodiments, n1 is 0.

[0040] In some embodiments, n2 is 0.

[0041] In some embodiments, R 1 , R 2 , and R 5 , the C 1-6 alkyl is each independently C 1-4 alkyl, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl.

[0042] In some embodiments, R 2 , the 3-6 membered cycloalkyl is each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0043] In some embodiments, R 2 , the 3-6 membered heterocycloalkyl is each independently a “3-6 membered heterocycloalkyl wherein the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.”

[0044] In some embodiments, R 3R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In this context, each of the halogens is independently fluorine, chlorine, or bromine.

[0045] In some implementation schemes, R 3 R 4 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 Each alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0046] In some implementation schemes, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 The alkyl group in the haloalkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0047] In some implementation schemes, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6 In, the C 1-4 The halogen in the haloalkyl group is independently fluorine, chlorine, or bromine. In some embodiments, R 3 R 4 R 1-1 R 2-1 R 2-2 and R 2-3 In, the C 1-4 The halogens in haloalkyl groups are each independently fluorine.

[0048] In some implementation schemes, R 3 R 4 R 1-1 R 2-1 R 2-2 R 2-3 R 5 and R 6In some embodiments, R 1-4 each alkyl in haloalkyl is independently -CF3, -CHF2, or -CH2F.

[0049] In some embodiments, R 3 , R 4 , R 1-1 , R 2-1 , R 2-2 , R 2-3 , R 5 , and R 6 each C 1-4 each alkoxy is independently methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy.

[0050] In some embodiments, R 3 , R 4 , R 1-1 , R 2-1 , R 2-2 , R 2-3 , R 5 , and R 6 each C 1-4 each alkoxy in haloalkoxy is independently methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy.

[0051] In some embodiments, R 3 , R 4 , R 1-1 , R 2-1 , R 2-2 , R 2-3 , R 5 , and R 6 each C 1-4 each halo in haloalkoxy is independently fluorine, chlorine, or bromine.

[0052] In some embodiments, the compound of Formula I or pharmaceutically acceptable salt thereof in the compound of Formula I is any one of the following structures,

[0053] The present disclosure provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0054] The present disclosure also provides use of a compound of Formula I or a pharmaceutically acceptable salt thereof as described above, or a pharmaceutical composition as described above, in the preparation of a medicament as a PDE4 inhibitor. In some embodiments, the PDE4 inhibitor is a PDE4B and / or PDE4D inhibitor.

[0055] The present disclosure also provides a use of the compound of Formula I or a pharmaceutically acceptable salt thereof or the pharmaceutical composition described above in the preparation of a medicament for preventing and / or treating a disease associated with PDE4. In some embodiments, the PDE4 is PDE4B and / or PDE4D. In some embodiments, the disease associated with PDE4 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, non-alcoholic fatty liver, psoriasis, rhinitis, Behcet's syndrome, arthritis, eczema, vitiligo, and ulcerative colitis. In some embodiments, the fibrotic disease comprises pulmonary fibrosis, liver fibrosis, and cystic fibrosis. In some embodiments, the injury disease comprises lung injury, liver injury, kidney injury, edema, and traumatic brain injury. In some embodiments, the central nervous disease comprises Alzheimer's disease, anti-depression, anti-anxiety, multiple sclerosis, stroke, and cognitive impairment. In some embodiments, the disease associated with PDE4 is acute lung injury.

[0056] The present disclosure also provides a use of the compound of Formula I or a pharmaceutically acceptable salt thereof or the pharmaceutical composition described above in the preparation of a medicament for preventing and / or treating a disease associated with PDE4. In some embodiments, the PDE4 is PDE4B and / or PDE4D. In some embodiments, the disease associated with PDE4 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, non-alcoholic fatty liver, psoriasis, rhinitis, Behcet's syndrome, arthritis, eczema, vitiligo, and ulcerative colitis. In some embodiments, the fibrotic disease comprises pulmonary fibrosis, liver fibrosis, and cystic fibrosis. In some embodiments, the injury disease comprises lung injury, liver injury, kidney injury, edema, and traumatic brain injury. In some embodiments, the central nervous disease comprises Alzheimer's disease, anti-depression, anti-anxiety, multiple sclerosis, stroke, and cognitive impairment. In some embodiments, the disease associated with PDE4 is acute lung injury.

[0057] The present disclosure also provides a compound of Formula II or a pharmaceutically acceptable salt thereof,

[0058] wherein Y is nitro or amino; Z, R 5 and n1 are defined as any of the embodiments of Formula I.

[0059] In some embodiments, the compound of Formula II is any of the following structures:

[0060] The present disclosure also provides a method for preparing a compound of Formula I, comprising the following steps:

[0061] (1) reacting a compound of Formula IV with a compound of Formula V to give a compound of Formula II-1;

[0062] (2) reducing a compound of Formula II-1 to give a compound of Formula II-2;

[0063] (3) reacting a compound of Formula II-2 with a compound of Formula III to give a compound of Formula I;

[0064] wherein A1and A2are each independently halogen; Z, R 2 , R 5 , R 6 , n1and n2are defined as in any of the embodiments of the compound of Formula I.

[0065] Definitions

[0066] Where the disclosure does not specify particular configurations, compounds of the disclosure can exist in particular geometric or stereoisomeric forms. The disclosure contemplates all such compounds, including cis- and trans-forms, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as racemic mixtures and other mixtures thereof, e.g., mixtures of enantiomers or diastereomers, all of which are intended to be within the scope of the disclosure. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers, as well as mixtures thereof, are included within the scope of the disclosure.

[0067] Compounds and intermediates of the disclosure can also exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure. The term “tautomer” or “tautomeric forms” refers to different energy structures that are interconvertible via a low energy barrier. For example, prototropic 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 a lactam-lactim equilibrium is between A and B as shown below.

[0068] All compounds in the disclosure can be drawn in either the A or B form. All tautomeric forms are within the scope of the disclosure. The naming of the compounds does not exclude any tautomers.

[0069] The compounds of the present disclosure can be asymmetric, e.g., having one or more stereocenters. Unless otherwise stated, all stereoisomers are included, e.g., enantiomers and diastereomers. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active form or as racemic mixtures. The optically active forms can be obtained from racemic mixtures by resolution of the racemic forms or by synthesis using chiral reagents or chiral starting materials.

[0070] 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 can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group) is present in the molecule, diastereomeric salts are formed with an appropriate optically active acid or base, and the diastereomeric salt is separated by conventional means, and the pure enantiomer recovered by treating with base or acid, respectively. In addition, separation of the enantiomers and diastereomers is often accomplished by using chromatography with a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamates from amines).

[0071] The term "alkyl" refers to saturated aliphatic hydrocarbon groups that are straight-chain or branched groups, preferably alkyl groups containing 1 to 30 carbon atoms, more preferably 1 to 12 carbon atoms, more preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, further preferably 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-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 various branched isomers thereof, and the like. More preferred are alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-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, and the like.

[0072] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused ring, and bridged ring cycloalkyl groups.

[0073] The term "heterocycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents containing from 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, C(=O) or S(=O) m ring members are carbon. Preferred are 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferred are 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 spirocyclic, fused, and bridged heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" groups include:

[0074]

[0075] The heterocycloalkyl ring can be fused to an aryl or heteroaryl ring, where the ring that is attached to the parent structure is a heterocycloalkyl group, non-limiting examples of which include:

[0076]

[0077] The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined above.

[0078] The term "hydroxy" refers to -OH.

[0079] The term "mercapto" refers to -SH.

[0080] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0081] The term "haloalkyl" refers to an alkyl group substituted with a halogen, where alkyl is as defined above.

[0082] The term "cyano" refers to -CN.

[0083] The term "nitro" refers to -NO2.

[0084] The term "amino" refers to -NH2.

[0085] The term "carboxyl" refers to -C(O)OH.

[0086] The term "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of each other replaced with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can or cannot be possible, can be determined by a person skilled in the art without undue effort (experimentally or theoretically).​​

[0087] "Being replaced by one or more..." means that it can be replaced by a single or multiple substituents. When replaced by multiple substituents, it can be a plurality of identical substituents or a combination of one or a plurality of different substituents.

[0088] The term "connection," when referring to the link between two molecules, means that the two molecules are connected by a covalent bond or by a non-covalent bond (e.g., a hydrogen bond or an ionic bond), including direct and indirect connections.

[0089] The term "direct link" refers to the connection between a first compound or group and a second compound or group without any intercalating atoms or groups. The term "indirect link" refers to the connection between a first compound or group and a second compound or group via an intermediate group, compound, or molecule (e.g., a linking group).

[0090] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. Although all the above structural formulas are shown in certain isomer forms for simplicity, this disclosure can include all isomers, such as tautomers, rotatimers, geometric isomers, diastereomers, racemates, and enantiomers. In the chemical structure of the compounds described in this disclosure, the bonds... No configuration was specified, i.e., key The configuration can be E-type or Z-type, or it can contain both E-type and Z-type configurations.

[0091] Unless otherwise specified, the symbols used in this article are as follows: This indicates that it can be connected with one or more groups according to the scope of disclosure described herein.

[0092] In this disclosure, the terms “comprising” or “including” may be replaced with “consisting of”.

[0093] 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 prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of the composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0094] The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" includes any adjuvant, carrier, flow regulator, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surface-active agent, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsor that is useful in preparing pharmaceutical compositions, which are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable with respect to safety, toxicity and the like.

[0095] Unless otherwise specified, the "compounds" of the present disclosure can exist independently as a salt, a mixed salt, or a non-salt (e.g., a free acid or a free base). When existing as a salt or a mixed salt, it can be a pharmaceutically acceptable salt or a pharmaceutically acceptable salt.

[0096] The terms "pharmaceutically acceptable salt" and "pharmaceutically acceptable salt" are used interchangeably and refer to both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0097] A "pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and non-toxicity of the free bases, and which are, in addition, useful in preparing pharmaceutical compositions. Such salts can be made by methods known in the art.

[0098] A "pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and non-toxicity of the free acids, and which are, in addition, useful in preparing pharmaceutical compositions. Such salts can be made by methods known in the art.

[0099] An "effective amount", "effective dose", "effective therapeutic amount", or "therapeutically effective amount" refers to the amount of a drug, compound, or pharmaceutical composition that is necessary to result in one or more beneficial or desired therapeutic results. For prophylactic use, beneficial or desired results include eliminating or reducing the risk, lessening the severity, or delaying the onset of a disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease.

[0100] 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 a monkey. BRIEF DESCRIPTION OF DRAWINGS

[0101] Figure 1 is the result of in vitro cell level anti-inflammatory activity of the compounds.

[0102] Figure 2 is the result of lung tissue section of acute lung injury pharmacodynamic test of the compounds.

[0103] Figure 3 shows the results of the pharmacodynamic index detection of the compound acute lung injury pharmacodynamic test, wherein (a) is the lung dry / wet weight ratio result; (b) is the lavage fluid neutrophil count result; (c) is the MPO determination result; (d) is the NO determination result; (e) is the TNF-α content determination result in the lavage fluid; (f) is the IL-1β content determination result in the lavage fluid; (g) is the IL-6 content determination result in the lavage fluid. Specific embodiments

[0104] The present disclosure will be further described with reference to the following examples, but the examples are not intended to limit the scope of the present disclosure. The experimental methods in the examples of the present disclosure, unless otherwise specified, are generally performed according to the conventional conditions or according to the conditions recommended by the manufacturers of the raw materials or commercial products. The reagents, unless otherwise specified, are obtained from any supplier of molecular biology reagents in a quality / purity suitable for molecular biology applications.

[0105] Unless otherwise specified, the reagents used in the following examples are commercially available.

[0106] Example 1

[0107] Step 1. 3-bromo-1-(2,2-difluoroethyl)-5-nitro-1H-indazole

[0108] The raw material 3-bromo-5-nitroindazole (3.00 g, 12.40 mmol, 1.00 eq) was placed in a 100 mL round-bottom flask with anhydrous acetonitrile (10 mL) as the solvent, and then 1,1-difluoro-2-iodoethane (1637 μl, 18.60 mmol, 1.50 eq), potassium carbonate (571 mg, 4.14 mmol, 2.00 eq) were added in sequence, and heated to reflux at 85°C for 12 h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature, filtered through diatomite, the organic phase was rotary evaporated under reduced pressure, redissolved in ethyl acetate, and then extracted with ethyl acetate three times (20 ml x 3) after adding water. The organic phase was collected and washed with saturated brine twice, dried over anhydrous sodium sulfate for 0.5 h, and then the solvent was removed under reduced pressure. The product was obtained as a light yellow solid powder by column chromatography (petroleum ether: dichloromethane = 8:1) after wet column chromatography purification.

[0109] 1 H NMR (300 MHz, DMSO-d6) δ 8.50 (d, J = 1.6 Hz, 1H), 8.37 (dd, J = 9.3, 2.2 Hz, 1H), 8.02 (d, J = 9.7 Hz, 1H), 6.49 (tt, J = 54.3, 3.3 Hz, 1H), 5.09 (td, J = 15.5, 3.3 Hz, 2H) ppm.

[0110] Step 2. Preparation of 1-(2,2-difluoroethyl)-3-(1-ethyl-1H-pyrazol-5-yl)-5-nitro-1H- indazole

[0111] Intermediate (380 mg, 1.25 mmol, 1.00 eq) and 1-ethylpyrazole-5-boronic acid (456 mg, 3.26 mmol, 2.00 eq) were placed in a 50 mL two-necked flask, dissolved in a mixed solvent of toluene (8 mL) and methanol (4 mL), and then 2 mL of an aqueous solution of sodium carbonate (532 mg, 5.02 mmol, 4.00 eq) was added. After vacuum suction for 5 min, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (92 mg, 0.13 mmol, 0.1 eq) was added, vacuum suction was continued for 10 min, and then the reaction was heated to reflux at 100°C under nitrogen protection for 14 h. After the reaction was completed by TLC detection, the reaction solution was cooled to room temperature, filtered with diatomite, and then the organic solvent was removed by evaporation under reduced pressure. The product was extracted with ethyl acetate three times (30 mL x 3) after the addition of an appropriate amount of water, and then the combined organic phase was washed with saturated brine twice, dried over anhydrous sodium sulfate for 0.5 h, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 32: 1) to obtain 210 mg of the product in the form of a light yellow solid powder, with a yield of 40%.

[0112] 1 H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J = 1.5 Hz, 1H), 8.38 (dd, J = 9.3, 2.1 Hz, 1H), 8.06 (d, J = 9.3 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.56 (tt, J = 54.3, 3.2 Hz, 1H), 5.17 (td, J = 15.6, 3.2 Hz, 2H), 4.52 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H) ppm.

[0113] Step 3. Preparation of 1-(2,2-difluoroethyl)-3-(1-ethyl-1H-pyrazol-5-yl)-1H-indazole-5- amine

[0114] Intermediate (270 mg, 0.79 mmol, 1.00 eq) was placed in a 50 mL single neck flask, dissolved in a mixed solvent of ethanol (12 mL) and water (6 mL), and then iron powder (177 mg, 3.17 mmol, 4.00 eq), ammonium chloride (423 mg, 7.92 mmol, 10.00 eq) were added successively, and the reaction was heated to reflux at 80 °C for 4 h. After the reaction was completed by TLC detection, it was filtered while hot, and then water was added to the filtrate, which was extracted with dichloromethane three times (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution twice, dried over anhydrous sodium sulfate for 0.5 h, and concentrated under reduced pressure to obtain 170 mg of red-brown flaky solid product with a yield of 89%.

[0115] 1 H NMR (300 MHz, DMSO-d6) δ 7.59 (d, J = 1.9 Hz, 1H), 7.52 (d, J = 9.5 Hz, 1H), 7.00 - 6.86 (m, 2H), 6.66 (d, J = 1.9 Hz, 1H), 6.44 (tt, J = 54.8, 3.6 Hz, 1H), 5.29 (s, 2H), 4.89 (td, J = 15.2, 3.6 Hz, 2H), 4.50 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H) ppm.

[0116] 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)

[0117] Intermediate (210 mg, 0.68 mmol, 1.00 eq) and methyl p-bromophenylacetate (118 μl, 0.75 mmol, 1.10 eq) were placed in a 25 mL two-neck flask, dissolved in anhydrous toluene (6 mL), and then cesium carbonate (440 mg, 1.35 mmol, 2.00 eq), 1,1'-binaphthalene-2,2'-diphenylphosphine (84 mg, 0.135 mmol, 0.20 eq) were added successively, vacuumed for 5 min, and then palladium acetate (15 mg, 0.068 mmol, 0.10 eq) was added. The reaction was heated to reflux at 100 °C for 20 h under nitrogen protection. After the reaction was completed by TLC detection, the reaction liquid was cooled to room temperature, and then filtered with celite. The organic solvent was removed by evaporation under reduced pressure, and then extracted with ethyl acetate three times (30 mL x 3) after adding an appropriate amount of water. The combined organic phase was washed with saturated brine twice, dried over anhydrous sodium sulfate for 0.5 h, and concentrated under reduced pressure to obtain 85 mg of yellow solid powder product with a yield of 49%.

[0118] M.P. 150-153 °C. 1 H NMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 9.0, 2.0 Hz, 1H), 7.11 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 1.9 Hz, 1H), 6.68 - 6.30 (m, 1H), 4.98 (td, J = 15.3, 3.5 Hz, 2H), 4.50 (q, J = 7.1 Hz, 2H), 3.60 (s, 3H), 3.56 (s, 2H), 1.35 (t, J = 7.1 Hz, 3H) ppm. 13 C NMR (101 MHz, CDC13) δ 172.51, 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 = 28.3 Hz), 45.99, 40.40, 15.72 ppm. HRMS (ESI + ): m / z [M+H] + calculated for C 23 H 23 F2N5O2, 440.1898; found 440.1891. HPLC purity = 95.02%, t R = 14.44 min.

[0119] Step 5. Preparation of 2-(4-((l-(2,2-difluoroethyl)-3-(l-ethyl-lH-pyrazol-5-yl)-lH- imidazol-5-yl)aminophenyl)acetic acid (Compound 1)

[0120] Compound 2 (95 mg, 0.21 mmol, 1.00 eq) was dissolved in 3 mL of methanol, and then 2 mL of aqueous KOH (33 mg, 0.83 mmol, 4.00 eq) was added. The reaction was heated to reflux at 80 °C for 4 h. After the reaction was completed by TLC detection, the solvent was removed by distillation under reduced pressure, and then the pH was adjusted to 1-2 with a dilute hydrochloric acid (1 mol / L) solution after adding an appropriate amount of water. Then the organic phase was extracted with ethyl acetate three times (20 mL x 3), dried over anhydrous sodium sulfate for 0.5 h, and concentrated under reduced pressure to obtain a yellow powder. The product was purified by column chromatography (dichloromethane:methanol = 80:1) to obtain 22 mg of a yellow powder solid product with a yield of 54%.

[0121] M.P. 139-140 °C. 1 H NMR (300 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.16 (d, J = 5.9 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.30 (d, J = 9.1 Hz, 1H), 7.20 - 7.05 (m, 2H), 7.01 (d, J = 8.3 Hz, 2H), 6.68 (d, J = 6.6 Hz, 1H), 6.49 (tt, J = 54.6, 3.6 Hz, 1H), 4.98 (td, J = 15.2, 3.4 Hz, 2H), 4.50 (q, J = 7.1 Hz, 2H), 3.45 (s, 2H), 1.35 (t, J = 7.0 Hz, 3H) ppm. 13 C NMR (101 MHz, DMSO) δ 173.68, 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 = 25.3 Hz), 45.75, 16.11 ppm. HRMS (ESI + ): m / z [M+H] + calculated for C 22 H 21 F2N5O2, 426.17416; found 426.17300. HPLC purity = 98.07%, t R = 8.31 min.

[0122] Test Example 1: PDE4 inhibitory activity test

[0123] The specific test method is as follows:

[0124] Compound solution preparation:

[0125] By calculation, 0.005 mmol of each test compound was accurately weighed and dissolved in 0.5 mL of DMSO, mixed well by blowing several times, and prepared into a 10 mM compound stock solution. The stock solution was then diluted to 1 mM, 100 μΜ, 10 μΜ, 1 μΜ, 100 nM, 10 nM, 1 nM, 0.1 nM, 0.01 nM, and 10 concentrations.

[0126] Mixed solution preparation:

[0127] (1) PDE4B1 stock solution (10 nM): 10 μg of enzyme (M.W. = 109 kDa, purity 70%) was dissolved in 6.419 mL of buffer (25 mM Tris-HCl, pH 8.0, 100 mM sodium chloride, 0.05% Tween-20, 50% glycerol, and 3 mM DTT), slowly blown and mixed well, divided into 10 tubes, 641.9 μL / tube. Before use, it was reconstituted in an ice bath for 5 min, and then reconstituted at room temperature for 3 min, slowly blown and mixed well, and blown 3 times before sampling.

[0128] (2) Buffer solution: 61 mM Tris-HCl, 12 mM MgCl2, 61 mM KCl, 6.1 mM TCEP, 0.48 mM PEP, 0.012 mM NADH, 0.048 mM ATP aqueous solution, pH 8.0, prepared 60 mL.

[0129] (3) Myokinase solution: enzyme suspension stored at 2-8°C was placed at room temperature for 5 min, and mixed well by slow beating. 65 μL of enzyme suspension was accurately measured and added to 335 μL of Buffer to prepare 335 μL of solution, which was mixed well by slow blowing (stored on ice).

[0130] (4) Pyruvate kinase solution: 0.3 mg of enzyme solid powder stored at -80°C was accurately weighed and dissolved in 200 μL of Buffer, and mixed well by slow blowing (stored on ice).

[0131] (5) Lactate dehydrogenase solution: 0.9 mg of enzyme solid powder stored at -80°C was accurately weighed and dissolved in 200 μL of Buffer, and mixed well by slow blowing (stored on ice).

[0132] (6) PDE4B1 solution: the aliquoted solution stored at -80°C was reconstituted on ice for 5 min and at room temperature for 5 min, and mixed well by slow blowing before use.

[0133] (7) cAMP solution (0.032 mM): Take cAMP, and prepare 2 mL of 0.032 mM solution with Buffer.

[0134] Operation flow:

[0135] (1) Prepare mixed solution in 96-well plate, first add Buffer 145 μL, then successively add 6 μL of myokinase, 3.2 μL of pyruvate kinase, 2 μL of lactate dehydrogenase, and 10 μL of PDE4B1 solution, and blow gently 3 times after each addition of solution, and mix well.

[0136] (2) Successively add 10 μL of compound solution of corresponding concentration, and mix well after slow blowing, and replace with equal volume of DMSO for blank group (without compound), and incubate at room temperature for 5-10 minutes.

[0137] (3) Add 25 μL of cAMP solution before determination, and blow 3 times, and mix well, and replace with equal volume of Buffer for no cAMP well.

[0138] (4) Excitation wavelength 355 nM, emission wavelength 460 nM, and continuously determine for 10 minutes, and stop determination after platform appears.

[0139] Data processing: Microsoft Excel 2010 spreadsheet software is selected for data processing, and calculation formula is:

[0140] Inhibition % = (Signal - Min) / (Max - Min) * 100%

[0141] Signal: NADH fluorescence intensity of inhibitor well; Max: NADH fluorescence intensity of no cAMP well; Min: NADH fluorescence intensity of no compound well.

[0142] Results are shown in Table 1:

[0143] Table 1: Enzyme inhibition activity of compound on PDE4B

[0144] Conclusion: Inhibition activity of compound 1 on PDE4B1 is 20 nM, which is 450 times of positive drug rolipram, and 10 times of self-research positive compound, and has excellent in-vitro enzyme activity.

[0145] Test example 2: In-vitro cell level anti-inflammatory activity test of compound

[0146] Specific test method: Influence of PDE4B inhibitor on cell inflammatory factor TNF-α production is detected by ELISA method. Cell density is adjusted to 2 x 10 5The cells were inoculated in 96-well plates at 1×105cells / mL, 100 μL per well, and incubated at 37°C in a 5% CO2saturated humidity incubator for 12 h until the cells adhered to the wall. The experiment was divided into a blank group, an LPS control group, and a test group; the test group was added with different concentrations of the test compound (10 μM, 25 μM, and 50 μM) in each well, and incubated in the incubator for 1 h; LPS solution (200 ng / mL) was added to each group except the blank group, and incubated for 24 h; the culture solution in each well was aspirated into a centrifuge tube, centrifuged at 3500 rpm for 10 min at 4°C, and the supernatant was used to determine the level of TNF-α.

[0147] The results are shown in Figure 1. The LPS-induced RAW 264.7 cells were detected for the inflammatory factor TNF-α, and Compound 1 showed good anti-inflammatory activity in a dose-dependent manner at 1 μM, 2 μM, and 4 μM.

[0148] Test Example 3: Results of the acute lung injury pharmacodynamic test of lung tissue sections

[0149] Specific test method: First, an acute lung injury model of mice was established using LPS. After the mice were anesthetized (1.25% alverine, 0.2 mL / kg, intraperitoneal injection), the trachea was exposed, and 60 μL of lipopolysaccharide solution was dropped into the trachea using a 1 mL syringe. After the injection was completed, the mice were straightened and rotated for 30 turns, and then straightened and placed for 2-3 min. The neck was sutured, and the mice were placed in a suitable temperature environment to wake up, and then returned to the cage for further feeding. The lung tissue was separated and preserved in a formaldehyde solution, stained with HE, and the lung tissue sections were observed under a microscope and the results were reported.

[0150] The results are shown in Figure 2. The model group had severe congestion, and many red blood cells were visible. Most of the alveolar cavities were filled with pink liquid (edema fluid) and a small amount of red blood cells, and a small amount of gas vacuoles were visible. The positive drug group and the low-dose Compound 1 group had significantly less congestion, and red blood cells were less visible and only concentrated in some areas, and the gas vacuoles were narrow and long. The high-dose Compound 1 group had few cells with congestion, and red blood cells were rare, and the red blood cell aggregation area was not obvious, and the gas vacuoles were small.

[0151] Test Example 4: Results of the detection of pharmacodynamic indicators in the acute lung injury pharmacodynamic test of the compound

[0152] Specific test method: the LPS-induced acute lung injury model in mice was established as in Test Example 3. The collection method of bronchoalveolar lavage fluid (BALF) is as follows. After the mice were sacrificed by enucleation and blood collection, they were fixed on the operating table, and after dissection, the right lung was ligated, the trachea was intubated using an intravenous indwelling needle and fixed, and then the left bronchial alveoli were lavaged with 0.3 mL of PBS (1x) solution, and the operation was repeated three times. The recovered bronchoalveolar lavage fluid was mixed and centrifuged at 4°C for 10 min, and the supernatant was stored at -80°C. The content of inflammatory factors TNF-α, IL-1β and IL-6 in BALF was determined using an ELISA kit. The mice were dissected, and the lung tissue was taken and homogenized. The lung tissue MPO and NO activity were tested according to the kit instructions.

[0153] The results are shown in Figure 3. Compound 1 low dose and high dose were better than the positive drug dexamethasone in inhibiting neutrophils and restoring MPO activity and NO levels; in terms of inhibiting inflammatory factors TNF-α, IL-1β and IL-6, WPBL-II-06 low dose was basically the same as the positive drug, while high dose was better than the positive drug. And from the overall, all indicators showed a clear dose-dependent, so it is reasonable to believe that compound 1 has great potential in the treatment of lung inflammation, especially acute lung injury or acute respiratory distress syndrome.

Claims

1. A compound of formula I ###0001### or a pharmaceutically acceptable salt thereof. wherein, Z is X is O or NR 5 ; R 1 and R 5 Each is independently hydrogen, unsubstituted, or R-substituted. 1-1 Replacement C 1-6 alkyl; R 2 Hydrogen, unsubstituted or R 2-1 Replacement C 1-6 Alkyl, unsubstituted or R 2-2 Substituted 3-6 membered cycloalkyl, unsubstituted or R 2-3 Substituted 3-6 membered heterocyclic alkyl groups; R 3 and R 4 each independently is hydrogen, halogen, hydroxyl, thiol, 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 each independently halogen, hydroxy, thio, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, 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 each independently halogen, hydroxy, thio, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 carboxy; R 5 and R 6 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 claim 1, or a pharmaceutically acceptable salt thereof, wherein X is O in the compound of formula I or a pharmaceutically acceptable salt thereof; R 1 is hydrogen, unsubstituted or substituted by R 1-1 substituted C 1-6 alkyl; R 2 is hydrogen, unsubstituted or substituted by R 2-1 is hydrogen, unsubstituted or substituted by R 1-6 alkyl; R 3 and R 4 each independently is hydrogen, halogen, hydroxyl, thiol, amino, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy; R 1-1 and R 2-1 each independently halogen, hydroxy, amino, nitro, cyano; R 2-2 and R 2-3 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 R 1 R 2 and R 5 In, the C 1-6 Each alkyl group is independently C10. 1-4 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; and / or, R 2 In some embodiments, each of the 3-6 membered cycloalkyl groups is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. and / or, R 2 In the above, each of the 3-6 membered heterocycloalkyl groups is independently a 3-6 membered heterocycloalkyl group wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. and / or, R 3 , R 4 , R 1-1 , R 2-1 , R 2-2 , R 2-3 , R 5 and R 6 each independently is fluorine, chlorine or bromine; and / or, R 3 , R 4 , R 2-2 , R 2-3 , R 5 , and R 6 , the C 1-4 each alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl; and / or, R 3 , R 4 , R 1-1 , R 2-1 , R 2-2 , R 2-3 , R 5 and R 6 , each of the C 1-4 alkyl groups in the haloalkyl groups is independently a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; and / or, R 3 , R 4 , R 1-1 , R 2-1 , R 2-2 , R 2-3 , R 5 and R 6 , wherein the C 1-4 haloalkyl groups are each independently fluorinated, chlorinated or brominated; and / or, R 3 , R 4 , R 1-1 , R 2-1 , R 2-2 , R 2-3 , R 5 and R 6 , each of said C 1-4 alkoxy is methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy or t-butoxy; and / or, R 3 , R 4 , R 1-1 , R 2-1 , R 2-2 , R 2-3 , R 5 and R 6 , each of the C 1-4 haloalkoxy groups is independently a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, or a t-butoxy group; and / or, R 3 , R 4 , R 1-1 , R 2-1 , R 2-2 , R 2-3 , R 5 and R 6 , R 1-4 each of the halogens in the haloalkyl and haloalkoxy groups is independently fluorine, chlorine or bromine.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein, The compound as shown in Formula I is any one of the following structures, 5. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, and a pharmaceutically acceptable excipient.

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

7. Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 for the preparation of a medicament for the prevention and / or treatment of a PDE4 associated disease, preferably acute lung injury.

8. Use of a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 for the preparation of a medicament for the prevention and / or treatment of a disease, preferably acute lung injury, selected from the group consisting of inflammatory diseases, fibrotic diseases, injury diseases and central nervous diseases.

9. A compound of Formula II ###0007### or a pharmaceutically acceptable salt thereof. wherein Y is nitro or amino; Z, R 5 and n1 is as defined in any one of claims 1 to 4.

10. A process for preparing a compound of formula I, comprising the following steps: (1) reacting a compound of formula IV with a compound of formula V to obtain a compound of formula II-1; (2) reducing a compound of formula II-1 to obtain a compound of formula II-2; (3) reacting a compound of Formula II-2 with a compound of Formula III to give a compound of Formula I; wherein A1and A2are each independently halogen; Z, R 2 , R 5 , R 6 , n1and n2are as defined in any one of claims 1-4.

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