Compound targeting phosphodiesterase subtype PDE4b and use thereof

Abstract

Provided in the present invention are a compound targeting phosphodiesterase subtype PDE4B or a pharmaceutically acceptable salt thereof, and a preparation method therefor. The structure of the compound is shown as formula I. Also provided are a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, and the use thereof in the treatment of phosphodiesterase subtype PDE4B mediated diseases.

Description

Compounds targeting phosphodiesterase subtype PDE4B and uses thereof TECHNICAL FIELD

[0001] The present invention is in the field of chemical drugs, in particular to a compound selectively targeting phosphodiesterase subtype PDE4B and pharmaceutically acceptable salts thereof, and a preparation method thereof. Further, the present invention relates to a pharmaceutical composition comprising a compound selectively targeting phosphodiesterase subtype PDE4B or a pharmaceutically acceptable salt thereof, and uses thereof in treating patients in need thereof. BACKGROUND

[0002] Cyclic nucleotides are ubiquitous signaling molecules and are considered as canonical second messengers. Both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling systems are fundamental to key pathways necessary for brain development and function. cAMP is a key intracellular messenger, which is usually generated by adenylyl cyclase. Adenylyl cyclase is activated by a variety of signaling molecules, such as the Gαs subunit of G protein-coupled receptors (GPCRs). In the cAMP signaling pathway, cAMP-dependent protein kinase (PKA) is a core molecule. When the intracellular cAMP concentration is elevated, cAMP binds to the regulatory subunit of PKA, leading to the release and activation of the catalytic subunit of PKA. Activated PKA is able to phosphorylate a variety of substrates, such as transcription factors, ion channels, cytoskeletal proteins, etc., and thus regulates a variety of cellular processes. The regulation of cAMP in cells is maintained by the action of a superfamily of enzymes called 3’5’-cyclic nucleotide phosphodiesterases (PDEs). PDEs are the only known enzymes that can degrade cyclic nucleotides, and they reduce the intracellular cAMP concentration by hydrolyzing cAMP to 5'-AMP, thus converting cAMP. Therefore, by inhibiting PDE, the hydrolysis of cAMP can be prevented to increase the intracellular cAMP level (Francis et al., Physiol Rev, 2011, 91:651-690).

[0003] The PDE superfamily has 11 members (PDE 1-11) that are the products of alternative splicing of 21 genes. Different structural PDEs have different substrate specificities, and the cAMP-specific PDE4 family is divided into four subfamilies (A, B, C, and D). The amino acid sequences among PDE4 subtypes are highly similar, especially all have a highly conserved catalytic domain, which brings great challenges to the development of selective PDE4 subtype inhibitors. On the other hand, PDE4 subtypes differ in regulatory domains. Each subtype contains two regulatory domains (UPSTREAM Conserved Regions, UCR1 and UCR2). The amino acid sequences and lengths between UCR1 and UCR2 differ among different subtypes, which also provides a clue for the development of selective PDE4 subtype inhibitors.

[0004] The role of PDE4B in signal transduction is not limited to the cAMP pathway, it can also interact with other signaling pathways, such as protein kinase C (PKC). PKC is a class of serine / threonine kinases involved in various biological processes, which can regulate the activity of PDE4B by phosphorylation. In addition, the activation of PKC also affects the cAMP signaling pathway, thereby regulating the function of PDE4B. Changes in intracellular calcium ion concentration are involved in multiple signaling processes. PDE4B is regulated by calcium / calmodulin-dependent protein kinase (CaMK) and other calcium-related signaling pathways. At the same time, there is also interaction between the cAMP signaling pathway and the calcium signaling pathway, so that PDE4B can affect the activity of the calcium ion channel by regulating the cAMP signaling pathway. The mitogen-activated protein kinase (MAPK) signaling pathway plays a key role in cell growth, differentiation, and apoptosis. PDE4B interacts with the MAPK signaling pathway, such as the ERK (extracellular signal-regulated kinase) family members of MAPK can regulate the activity of PDE4B. In addition, there is also interaction between cAMP and the MAPK signaling pathway. The phosphatidylinositol 3-kinase (PI3K) / protein kinase B (Akt) signaling pathway is essential for cell growth, proliferation, and metabolism. PDE4B may affect the activity of the PI3K / Akt signaling pathway by regulating the cAMP signaling pathway and PKA activity. At the same time, the PI3K / Akt signaling pathway may also feedback regulate the activity and function of PDE4B. GPCR is a class of transmembrane receptors involved in various signaling processes. GPCR activation can regulate the activity of adenylyl cyclase, thereby affecting the cAMP signaling pathway. Therefore, PDE4B is closely related to the GPCR signaling pathway, and it realizes this connection by regulating the cAMP signaling pathway. These interactions can have synergistic or antagonistic effects on cell signaling. For example, in the inflammatory response, PDE4B can affect the activation and release of inflammatory mediators in inflammatory cells (such as macrophages, T cells, and B cells) by regulating cAMP levels and PKA activity; in immune regulation, PDE4B also affects the proliferation, differentiation, and function of immune cells by affecting the cAMP and PKA signaling pathways; in smooth muscle contraction and cardiovascular function regulation, PDE4B can regulate the contraction and relaxation of vascular smooth muscle cells and cardiomyocytes, thereby affecting vascular tone and cardiac function. In addition, PDE4B is also involved in neural signal transduction processes, regulating neuronal excitability and neurotransmitter release. Through these regulatory effects, PDE4B plays a crucial role in maintaining the normal physiological functions of living organisms.

[0005] The currently marketed PDE4 inhibitors, such as Roflumilast and Apremilast, target multiple isoforms of the PDE4 family. The main drawback of pan-PDE4 inhibitors is their non-selectivity, which leads to the ubiquitous adverse effects of these drugs, such as gastrointestinal side effects. Different PDE4 isoforms and isoforms are expressed in a tissue- and cell-specific manner, and increasing the selectivity of the inhibitors can reduce adverse reactions while maintaining efficacy. PDE4 isoform-selective inhibitors have higher target specificity, which can more accurately target PDE4 isoforms associated with diseases, thereby improving therapeutic efficacy and safety.

[0006] Analysis of mRNA levels shows that PDE4B is the most abundant subfamily in the human, monkey and rat brain, which is involved in the regulation of many biological processes, such as inflammatory response, immune regulation, neural signal transduction, smooth muscle contraction and cardiovascular function regulation, and plays a key role in the occurrence and development of various reported diseases such as chronic obstructive pulmonary disease, psoriasis, atopic dermatitis, lung injury and cancer, which makes PDE4B a potential target for disease treatment. However, there is currently no selective inhibitor for PDE4B isoforms approved for marketing. Therefore, there is still a need in the art to develop a compound with high selectivity targeting PDE4B, which has fewer adverse reactions and better drugability. SUMMARY

[0007] The main purpose of the present application is to provide a compound targeting (especially selectively targeting) phosphodiesterase subtype PDE4B and its pharmaceutically acceptable salt, as well as a preparation method and use thereof. The present application further relates to a pharmaceutical composition comprising a compound targeting (especially selectively targeting) phosphodiesterase subtype PDE4B or a pharmaceutically acceptable salt thereof. The present application also relates to the use of the compound in the treatment of patients in need thereof.

[0008] According to a first aspect of the present application, a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof is provided,

[0009] wherein L is selected from a single bond or C1-C3 alkylene optionally substituted with one or more substituents selected from -D, halogen, C1-C3 alkyl or C1-C3 alkoxy;

[0010] R1is selected from -D, -H, halogen (e.g. F, Cl, Br or I), -OH, -CN, -CHO, -OR5, -OC(O)R5, -COOR5, -NR6R7, -CONR6R7, -SR5, -SOR5, -SO2NR6R7, -CH=NOR8or

[0011] R5 is independently selected from -D, -H, C1-C. 15 Alkyl or benzo[a]heterocyclic group, wherein C1-C 15 Alkyl or benzo[a]heterocyclic group may be optionally surrounded by one or more groups selected from -D, halogen, -OH, -NH2, C1-C5 alkyl, Substituents of C1-C5 alkoxy groups;

[0012] R6 and R7 are each independently selected from -D, -H, -OH, -CN, C1-C5 alkyl or C1-C5 alkoxy or 3-6 membered cycloalkyl or -SO2-C1-C5 alkyl, wherein the C1-C5 alkyl or C1-C5 alkoxy or 3-6 membered cycloalkyl or -SO2-C1-C5 alkyl is optionally substituted by one or more substituents selected from -D, halogen, -OH, -NH2, C1-C5 alkoxy.

[0013] Alternatively, R6 and R7, together with the N atom to which they are attached, form a 3-10 membered heterocyclic alkyl group, wherein the 3-10 membered heterocyclic alkyl group is optionally substituted by one or more substituents selected from -D, halogen, -OH, -NH2, -CN, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, or hydroxyl-substituted C1-C6 alkyl groups.

[0014] R8 is selected from -D, -H, or -COR5.

[0015] R2 is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, or 5-10-membered heteroaryl, wherein the 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, C6-C 10 The aryl group, or 5-10 heteroaryl group, is optionally substituted by one or more substituents selected from -D, halogen, -OH, -NH2, -CN, oxo, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxy, hydroxy-substituted C1-C5 alkyl, C1-C3 alkyl-O-C1-C3 alkyl, -CO-C1-C5 alkyl, -CONR6R7, C1-C5 haloalkyl, C2-C5 haloalkenyl, C1-C5 haloalkoxy, hydroxy-substituted C1-C5 haloalkyl, C1-C3 haloalkyl-O-C1-C3 haloalkyl or -CO-C1-C5 haloalkyl;

[0016] R3 and R4 are independently selected from -D, -H, halogen, -OH, or C1-C6 alkyl groups.

[0017] X is selected from -O-, -S-, -SO-, -SO2- or -CO-, Y is selected from -CH2- or -NR6-, and n is 0 or 1.

[0018] In the context of this invention, when a substituent represented by the same symbol is mentioned in different groups, it does not mean that the different groups are related to each other. Rather, the substituent represented by the same symbol in the different groups can be independently selected from the same or different groups. For example, in the case of R1, both groups -OR5 and -OC(O)R5 contain a substituent represented by the symbol R5. The R5 in groups -OR5 and -OC(O)R5 can be the same or different, and each can be independently selected from the same group of groups.

[0019] In some embodiments, L is selected from a single bond. In some embodiments, L is selected from methylene or ethylene, optionally substituted with one or more substituents selected from -D, halogen, C1-C3 alkyl, or C1-C3 alkoxy. In some embodiments, L is selected from methylene or ethylene, optionally substituted with one or more substituents selected from -D, -F, -Cl, methyl, ethyl, methoxy, or ethoxy. In some embodiments, L is selected from methylene, ethylene, -CH(CH3)-, -CH(CH2CH3)-, -C(CH3)2-, -CH2CH(CH3)-, -CH(CH3)CH2-, -CH2C(CH3)2-, -CH2CH(CH2CH3)-, -CF2CH2-, or -CH(OCH3)CH2-.

[0020] In some embodiments, R5 is selected from -D, -H, or optionally selected from one or more of -D, halogen, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, Substituents of C1-C 11 Alkyl, such as C1-C3 alkyl. In some embodiments, R5 is selected from H. In some embodiments, R5 is selected from optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, -C7H. 15 -C 11 H 23 -C2H4OCH3

[0021] In some embodiments, R5 is a substituted (e.g., substituted by one or more substituents selected from -D, halogen, -OH, -CN, C1-C3 alkyl, oxo (=O)) or unsubstituted benzo[5] heterocyclic group, including but not limited to substituted or unsubstituted groups. In some implementations, R5 is selected from the alternatives.

[0022] In some embodiments, R6 is selected from -D, -H, -OH or C1-C5 alkyl groups.

[0023] In some embodiments, R7is selected from -D, -H, -CN, or C1-C5alkyl or C1-C5alkoxy optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, C1-C5alkoxy, or 3-6 membered cycloalkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, methoxy, or ethoxy substituted methoxy.

[0024] In some embodiments, R6and R7are both H, C1-C5alkyl, or C1-C5alkoxy. In some embodiments, R6and R7are both C1-C5alkyl. In some embodiments, R6and R7are both C1-C5alkoxy.

[0025] In some embodiments, R6is H, and R7is selected from -OH, -CN, optionally substituted C1-C5alkyl (for example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or t-butyl), optionally substituted C1-C5alkoxy (for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or t-butoxy), optionally substituted 3-6 membered cycloalkyl (for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), or optionally substituted -SO2-C1-C5alkyl (for example -SO2CH3, -SO2CH2CH3, -SO2(CH2)2CH3, -SO2(CH2)3CH3, -SO2(CH2)4CH3).

[0026] In some embodiments, R6is -OH, and R7is selected from optionally substituted C1-C5alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or t-butyl. In some embodiments, R6is selected from optionally substituted C1-C5alkyl, and R7is selected from optionally substituted C1-C5alkoxy. In some embodiments, R6is selected from methyl, ethyl, or propyl, and R7is selected from methoxy, ethoxy, or propoxy.

[0027] In some embodiments, R6and R7, together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl, for example, and the 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from -D, halogen, -OH, -CN, C1-C6alkyl, C1-C6alkoxy, or hydroxy substituted C1-C6alkyl.

[0028] In some embodiments, R8is -D, -H, -COH, or -COC1-C 15alkyl. In some embodiments, R8is -COC1-C5alkyl. In some embodiments, R8is -COC1-C3alkyl. In some embodiments, R8is -COCH3. 10 alkyl. In some embodiments, R8is -COC1-C5alkyl. In some embodiments, R8is -COC1-C3alkyl. In some embodiments, R8is -COCH3.

[0029] In some embodiments, -L-R1is selected from any one of the following groups: -COOH, -CH2COOH, -CH2COOCH2CH3, -CH2CONHOH, -CH2CONHCH3, -CH2CONH2, -CH2CONHCH2CH3, -CH2COOCH3, -CH2COOCH(CH3)2, -CH2CN, -CH2CH2OH, -CH2CHO, -CH2CONHCH2CH2CH3, -CH2COOCH2CH(CH3)2, -CH2CHF2, -CH2CON(CH3)2, -CH2CONHSO2CH3, -CH2CONHCN, -CH2CONHCH2CH2OH, -CH2CONHCH2CH2NH2, -CH2CONHOCH3, -CH2CON(CH3)OCH3, -CH2SO2NHCH3, -CH2SO2NHCH2CH3, -CH2SO2NH2, -CH2CON(CH3)OH, -CH2OH, -CH2CH(CH3)OH, -CH2C(CH3)2OH, -CH2CH(OH)CH2CH3, -CH(CH3)OH, -CH(OH)CH2CH3, -CONHCH3, -CH=NOH, -CH(CH3)CH3OH, -C(CH3)2OH, -CH=NOOCCH3, -CF2CH2OH, -CHO, -CH(OCH3)CH2OH, -CH(CH3)CHO, -C(CH3)2CHO, -CH2CH2OCH3, -CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OCH(CH3)2, -CH2OCH2CH2OCH3, -CH2COOC(CH3)3, -CH2CH2OCH2CH2OCH3,

[0030] In some embodiments, R2is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10aryl, or 5-10 membered heteroaryl optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, -CN, oxo, -CHO, -COOH, C1-C3 alkyl, C2-C3 alkenyl, C1-C3 alkoxy, hydroxy substituted C1-C3 alkyl, C1-C3 alkyl-O-C1-C3 alkyl, -CO-C1-C5 alkyl, -CONR6R7, C1-C3 haloalkyl, C2-C3 haloalkenyl, C1-C3 haloalkoxy, hydroxy substituted C1-C3 haloalkyl, C1-C3 haloalkyl-O-C1-C3 haloalkyl, or -CO-C1-C3 haloalkyl, wherein R6and R7are each independently selected from -D, -H, -OH, -CN, C1-C5 alkyl, or C1-C5 alkoxy, or 3-6 membered cycloalkyl, said C1-C5 alkyl or C1-C5 alkoxy, or 3-6 membered cycloalkyl optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, C1-C5 alkoxy.

[0031] In some embodiments, the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl optionally substituted with one or more substituents selected from -D, -F, -Cl, -Br, -OH, -NH2, methyl, methoxy, hydroxy substituted methyl, ethyl, ethoxy, hydroxy substituted ethyl, ethenyl, propenyl, allyl, -CH2OCH3, -COCH3, -COCH2CH3, -COCH2CH2CH3, or -CONHCH3, -CONHCH2CH3, -CONHCH2CH2CH3, or -CON(CH3)2.

[0032] In some embodiments, R2is selected from substituted or unsubstituted 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl. In some embodiments, R2is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In some embodiments, R2is selected from substituted or unsubstituted oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, piperazinyl, hexahydropyrazinyl, morpholinyl, piperidinyl, or dithianyl. In some embodiments, R2is selected from substituted or unsubstituted phenyl, naphthyl, or anthracenyl. In some embodiments, R2is selected from substituted or unsubstituted thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzotriazolyl, or benzothiazolyl.

[0033] In some embodiments, R2is selected from substituted or unsubstituted phenyl,

[0034] In some embodiments, R2is selected from C6-C 10 aryl or 5-10 membered heteroaryl, optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, -CN, -CHO, -COOH, C1-C3alkyl, C2-C3alkenyl, C1-C3alkoxy, hydroxyl substituted C1-C3alkyl, C1-C3alkyl-O-C1-C3alkyl, -CO-C1-C5alkyl, -CONR6R7, wherein R6and R7are each independently selected from -H, -OH, -CN, C1-C5alkyl or C1-C5alkoxy or 3-6 membered cycloalkyl, said C1-C5alkyl or C1-C5alkoxy or 3-6 membered cycloalkyl optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, C1-C5alkoxy.

[0035] In some embodiments, R2is selected from 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, optionally substituted with one or more substituents selected from -D, -OH, -NH2, -CN, oxo, -CHO, -COOH, C1-C3alkyl, C1-C3alkoxy.

[0036] In some embodiments, R3and R4are each independently selected from -D, -H, halogen or C1-C6alkyl. In some embodiments, R3and R4are each independently selected from -D, -H, -F, -Cl, -Br.

[0037] In some embodiments, n is 0, and X is selected from -O-, -S-, -SO-, -SO2- or -CO-, Y is selected from -CH2-. In some embodiments, n is 1, and X is selected from -S-, -SO-, -SO2-, Y is selected from -CH2-. In some embodiments, n is 1, and X is selected from -CO-, Y is selected from -NH- or -N(CH3)-.

[0038] In further embodiments, R2in formula I is specifically (including ),

[0039] In further embodiments, R2in formula I is specifically (including ),

[0040] According to a second aspect of the application, there is provided a compound of formula II, or a pharmaceutically acceptable salt thereof,

[0041] wherein L, R1, R3and R4, and X, Y and n are as defined above for the corresponding substituents in formula I;

[0042] R 10 , R 11 , R 12 , R 13 are each independently selected from -D, -H, halogen, C1-C5alkyl, C1-C5haloalkyl, hydroxyl substituted C1-C5alkyl;

[0043] R9is selected from -D, -H, halogen, -OH, -NH2, -CN, C1-C5alkyl, C2-C5alkenyl, C1-C5alkoxy, hydroxyl substituted C1-C5alkyl, C1-C3alkyl-O-C1-C3alkyl, -CO-C1-C5alkyl, -CONR6R7, C1-C5haloalkyl, C2-C5haloalkenyl, C1-C5haloalkoxy, hydroxyl substituted C1-C5haloalkyl, C1-C3haloalkyl-O-C1-C3haloalkyl, or -CO-C1-C5haloalkyl, wherein R6and R7are each independently selected from -D, -H, -OH, -CN, C1-C5alkyl, or C1-C5alkoxy or 3-6 membered cycloalkyl or -SO2-C1-C5alkyl, said C1-C5alkyl or C1-C5alkoxy or 3-6 membered cycloalkyl or -SO2-C1-C5alkyl optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, C1-C5alkoxy.

[0044] In some embodiments, R 10 , R 11 , R 12 , R 13 are all the same. In some embodiments, R 10 , R 11 , R 12 , R 13 are all different. In some embodiments, R 10 and R 12 are the same. In some embodiments, R 11 and R 13 are the same. In some embodiments, at least one of R 10 , R 11 , R 12 , R 13 is -D or -H, for example at least 1, at least 2, or at least 3. In some embodiments, R 10 , R 11 , R12 at least one of R 13 is selected from halogen, e.g. at least 1, at least 2, or at least 3 independently of each other selected from halogen, preferably -F, -Cl, -Br.

[0045] In some embodiments, at least one of R 10 and R 12 is selected from (e.g. at least 1 or at least 2 independently of each other selected from) halogen (preferably -F, -Cl, -Br), C1-C5 alkyl, C1-C5 haloalkyl (especially perfluoro-substituted C1-C5 alkyl), hydroxy-substituted C1-C5 alkyl, or hydroxy-substituted C1-C5 haloalkyl (especially hydroxy-substituted perfluoro-substituted C1-C5 alkyl, i.e. one or more fluorines in a perfluoro-substituted C1-C5 alkyl are replaced by hydroxy). 10 and R 12 is selected from (e.g. at least 1 or at least 2 independently of each other selected from) halogen (preferably -F, -Cl, -Br), C1-C3 alkyl, C1-C3 haloalkyl (especially perfluoro-substituted C1-C3 alkyl), hydroxy-substituted C1-C3 alkyl, or hydroxy-substituted C1-C3 haloalkyl (especially hydroxy-substituted perfluoro-substituted C1-C3 alkyl).

[0046] In some embodiments, at least one of R 11 and R 13 is independently of each other selected from -D or -H.

[0047] In some embodiments, R 11 , R 12 , R 13 are each -D or -H, and R 10 is selected from halogen, C1-C5 alkyl, C1-C5 haloalkyl (especially perfluoro-substituted C1-C5 alkyl), hydroxy-substituted C1-C5 alkyl, or hydroxy-substituted C1-C5 haloalkyl (especially hydroxy-substituted perfluoro-substituted C1-C5 alkyl).

[0048] In some embodiments, R 10 , R 11 , R 12 , R 13 are each independently selected from -D, -H, -F, -Cl, -Br, C1-C3 alkyl, C1-C3 haloalkyl, hydroxy-substituted C1-C3 alkyl. In some embodiments, R 10 , R 11 , R 12 , R 13 are each independently selected from -D, -H, -F, -Cl, -CF3, -CH3, -CH2OH. In some embodiments, R10 R 11 R 12 R 13 are each -D or -H.

[0049] In some embodiments, R9is selected from -D, -H, halogen, -OH, -NH2, -CN, C1-C3alkyl, C2-C3alkenyl, C1-C3alkoxy, hydroxyl substituted C1-C3alkyl, C1-C3alkyl-O-C1-C3alkyl, -CO-C1-C3alkyl, -CONR6R7, C1-C3haloalkyl, C2-C3haloalkenyl, C1-C3haloalkoxy, hydroxyl substituted C1-C3haloalkyl, C1-C3haloalkyl-O-C1-C3haloalkyl, or -CO-C1-C3haloalkyl.

[0050] In some embodiments, R9is selected from -CONR6R7, wherein R6is selected from -D, -H, -OH, or C1-C5alkyl; and / or R7is selected from -D, -H, -CN, or C1-C5alkyl or C1-C5alkoxy optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, C1-C5alkoxy, or 3-6 membered cycloalkyl, preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, methoxy, or ethoxy substituted methoxy. In some embodiments, R9is selected from -CONR6R7, wherein R6is H and R7is selected from -OH, -CN, optionally substituted C1-C5alkyl, optionally substituted C1-C5alkoxy, optionally substituted 3-6 membered cycloalkyl, or optionally substituted -SO2-C1-C5alkyl, or R6is -OH and R7is selected from optionally substituted C1-C5alkyl; or R6is selected from optionally substituted C1-C5alkyl and R7is selected from optionally substituted C1-C5alkoxy; or R6is selected from methyl, ethyl, or propyl and R7is selected from methoxy, ethoxy, or propoxy.

[0051] In some embodiments, R9is selected from -D, -H, -F, -Cl, -Br, -OH, -NH2, methyl, methoxy, hydroxyl substituted methyl, ethyl, ethoxy, hydroxyl substituted ethyl, ethenyl, propenyl, allyl, -CH2OCH3, -COCH3, -COCH2CH3, -COCH2CH2CH3, or -CONHCH3, -CONHCH2CH3, -CONHCH2CH2CH3, or -CON(CH3)2.

[0052] In some embodiments, is selected from

[0053] In further embodiments, R1in formula II is In particular, R1in formula II is (including ), or

[0054] In other embodiments, R1in formula II is In particular, R1in formula II is (including ),

[0055] In some particular embodiments, the present application provides a compound of Table 1.

[0056] Table 1 : Exemplary compounds of the present application

[0057] According to a third aspect of the present application, there is provided a pharmaceutical composition comprising a compound according to the first or second aspect of the present application, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0058] According to a fourth aspect of the present application, there is provided the use of a compound according to the first or second aspect of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the present application, in the manufacture of a medicament for the prevention or treatment of a PDE4 or, in particular, PDE4B mediated disease or disorder.

[0059] In some embodiments, the disease or condition includes, but is not limited to, an autoimmune disease, acquired immune deficiency syndrome, acute kidney injury, airway obstruction, alcoholic neuropathy, alcohol addiction, panic disorder, alopecia areata, Alzheimer’s disease, allergy, arthritis such as experimental arthritis, juvenile arthritis, psoriatic arthritis, or rheumatoid arthritis, pain, fever, ankylosing spondylitis, asthma such as exercise-induced asthma, atherosclerosis, Behcet’s syndrome, bone metabolism disease, bronchial disease such as bronchospasm, bronchiolitis, chronic bronchitis, cancerous lesion, cancer such as hepatocellular carcinoma or renal cell carcinoma, cardiac disease such as heart failure, myocardial infarction, myocardial ischemia-reperfusion injury, myocardial fibrosis, cardiac dilatation, or restrictive cardiomyopathy, carotid artery disease, carotid artery thrombosis, central nervous system disease, nervous system disease, neuralgia, neurodegenerative disease, brain disease such as cognitive impairment, memory disorder, amnesia, depression, and neurodegenerative disease, ataxia, brain edema, brain injury such as traumatic brain injury, cerebral ischemia, brain tumor, cerebral infarction, cerebrovascular disease, cholera, colitis, ulcerative colitis, colorectal tumor, coronary artery disease, respiratory disease such as cough, SARS, COVID-19, skin disease such as dermatitis such as allergic contact dermatitis, atopic dermatitis, or phototoxic dermatitis, diabetes such as type 1 diabetes and type 2 diabetes, diabetic nephropathy, encephalomyelitis such as experimental autoimmune encephalomyelitis, endotoxemia, hypertension, inflammatory bowel disease, stroke such as ischemic stroke, leukemia such as chronic lymphocytic leukemia, pediatric acute lymphoblastic leukemia, inflammatory lung disease, obstructive lung disease such as chronic obstructive pulmonary disease, pulmonary fibrosis such as idiopathic pulmonary fibrosis, organ fibrosis, lung injury such as acute lung injury, pulmonary arterial hypertension, pulmonary edema, lung tumor, glioblastoma, glioma, follicular adenocarcinoma, adenoma, prostatic adenoma, malignant bladder cancer, cystitis, gastric tumor, abdominal aortic aneurysm, Behcet’s syndrome, lymphoma such as B-cell lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, medulloblastoma, neuroblastoma, melanoma, osteosarcoma, Parkinson’s disease, pityriasis, pneumonia, psoriasis, multiple sclerosis, cirrhosis, obesity, fatty liver, osteonecrosis, myopia, spinal cord injury, tuberculosis.

[0060] In some embodiments, the medicament is for treating one or more diseases or conditions selected from the group consisting of:

[0061] Arthritis, such as experimental arthritis, juvenile arthritis, psoriatic arthritis, rheumatoid arthritis; pain, fever, ankylosing spondylitis, acute kidney injury, bronchial diseases such as bronchospasm, bronchiolitis, chronic bronchitis, asthma, obstructive pulmonary disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, lung injury, acute lung injury, pulmonary hypertension, pulmonary edema, SARS, COVID-19, Alzheimer's disease, cognitive impairment, depression, memory impairment, amnesia, neurodegenerative disease, ataxia, alcohol addiction, panic disorder, skin diseases such as dermatitis, psoriasis, heart failure, cardiomegaly, myocardial fibrosis, restrictive cardiomyopathy, carotid artery disease, coronary artery disease, atherosclerosis, hypertension, myocardial ischemia-reperfusion injury, myocardial infarction, stroke, colorectal tumor, malignant bladder cancer, cystitis, adenoma, lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, leukemia, childhood acute lymphoblastic leukemia, gastric tumor, abdominal aortic aneurysm, Behcet's syndrome, colitis, ulcerative colitis, endotoxemia, diabetes such as type 1 diabetes and type 2 diabetes, multiple sclerosis, liver cirrhosis, obesity, fatty liver, bone necrosis, or myopia.

[0062] According to a fifth aspect of the present application, there is also provided a method of treating a PDE4, in particular PDE4B mediated disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to the first or second aspect of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the present application. Advantages

[0063] The compounds of the present application have good inhibitory effect on the activity of phosphodiesterase (PDEs), in particular PDE4B, can inhibit LPS-induced TNF-a expression, and can be used for treating PDE4B related diseases or disorders, and as an anti-inflammatory drug for the treatment of related diseases or disorders. DETAILED DESCRIPTION

[0064] In order to make the objects, technical solutions and advantages of the present application clearer, the following further describes the present application in conjunction with embodiments. The specific embodiments described herein are only used to explain the present application and do not constitute any limitation on the present application. In addition, in the following description, the description of well-known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present disclosure. Such structures and technologies are also described in many publications.

[0065] Definitions

[0066] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will include the plural and vice versa.

[0067] The term "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group having the indicated number of carbon atoms. Alkyl groups used in the present application (including where it is used by itself or as part of another substituent) can contain from 1 to 20 carbon atoms, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms, preferably from 1 to 15 carbon atoms, more preferably from 1 to 10 carbon atoms, and further preferably from 1 to 5 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, and various branched isomers thereof.

[0068] The term "alkylene" refers to a divalent straight-chain or branched-chain saturated hydrocarbon group, which is obtained by further losing one H atom from an alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene, etc.

[0069] The term "cycloalkyl" refers to a cyclic alkyl group including saturated monocyclic, bicyclic, or polycyclic rings, for example, 3-10 membered cycloalkyl groups, for example, monocyclic, bicyclic, or polycyclic rings having 3, 4, 5, 6, 7, 8, 9, 10 carbon ring atoms. Cycloalkyl groups can also include cycloalkyl groups having structures of spiro, bridged, annelated, etc., for example, 5-10 membered fused bicyclic rings, 5-10 membered spiro bicyclic rings, etc. Cycloalkyl groups suitable for use in the present application include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Examples of 5-10 membered fused bicyclic rings include, but are not limited to, Examples of 5-10 membered spiro bicyclic rings include, but are not limited to, Examples of 5-10 membered spiro bicyclic rings include, but are not limited to,

[0070] The terms "heterocyclic alkyl" or "heterocyclic group" are used interchangeably in this disclosure and refer to substituted or unsubstituted non-aromatic, partially unsaturated or fully saturated heterocyclic groups. Heterocyclic groups may contain 1 to 3 heteroatoms selected from N, O, or S as ring members, and may include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spirocyclic heterocycles, etc. Heterocyclic groups suitable for this invention may contain 3 to 12 ring atoms (3-12 membered heterocycles), for example 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, preferably 3-12, more preferably 3-10, and more preferably 3-8 ring atoms. Heterocyclic groups may be attached to heteroatoms or carbon atoms. The N and S in the heterocyclic ring may be oxidized to various oxidation states. Non-limiting examples of heterocyclic groups include oxoheterobutyl, azaheterobutyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, dioxaneyl, piperazineyl, hexahydropyrazineyl, morpholinyl, piperidinyl, dithiaalkyl, etc.

[0071] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic ring system (preferably a 6-10 membered aromatic ring) having a total of 5 to 15 ring members (or ring atoms), wherein all rings in the system are aromatic and each ring in the system contains 3 to 7 ring members; when not all rings in the system are aromatic, it is considered a cycloalkyl or heterocyclic alkyl group. In some embodiments of the invention, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, indenyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl, and anthraceneyl. Fused aryl groups may be attached to another group at a suitable position on a cycloalkyl or aromatic ring.

[0072] The term "heteroaromatic ring" or "heteroaryl" refers to a heterocycle that is aromatic. Non-limiting examples of heteroaryl include thiophene, furanyl, pyrrole, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, inzolyl, benzofuranyl, benzothiophene, benzoxazolyl, benzotriazolyl, or benzothiazolyl.

[0073] The term "alkoxy" or "alkyloxy" refers to -O-alkyl, such as -O-C1-C. 10 Alkyl groups, preferably -O-C1-C5 alkyl groups, more preferably -O-C1-C3 alkyl groups. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

[0074] The term "halogen" refers to F, Cl, Br, I, or their isotopes.

[0075] The term "halo" or "halogen substituted" means that a hydrogen atom is replaced by one or more halogen atoms selected from F, CI, Br, I, or their isotopes, the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that the group being substituted can be replaced with, and in the absence of a specific limitation, the number of halogen substituents is any integer between 1 and the upper limit, and when the number of halogen substituents is greater than 1, the halogen substituents can be the same or different.

[0076] The term "deuterated" or "deuterated" as used herein means that a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, etc. group is replaced by at least one isotope of deuterium, the upper limit of the number of deuterium is equal to the sum of the number of hydrogens that the group being substituted can be replaced with. In the absence of a specific limitation, the number of deuterium is any integer between 1 and the upper limit, preferably 1-10 deuterium atoms are replaced, more preferably 1-6 deuterium atoms are replaced, and further preferably 1-3 deuterium atoms are replaced. In the absence of a specific limitation, the compounds of the present application encompass instances in which one or more hydrogen atoms are replaced by the isotope of deuterium.

[0077] The term "alkenyl" means a straight or branched, non-cyclic, unsaturated hydrocarbon group having the specified number of carbon atoms, in which at least two carbon atoms are bonded to each other by an unsaturated double bond. Alkenyl groups suitable for use in the present application can have 2-10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 2-5 carbon atoms. Examples of C2-5alkenyl groups include, but are not limited to, ethenyl, 1 -propen-1 -yl, 1 -propen-2-yl, 2-propen-1 -yl, 2-methyl-1 -propen-1 -yl, 2-methyl-2-propen-1 -yl, 1 -buten-1 -yl, 1 -buten-2-yl, 2-buten-1 -yl, 2-buten-2-yl, 3-buten-1 -yl, 3-buten-2-yl, 1,3-buta- dien-1 -yl, 1,3-buta-dien-2-yl, 1 -penten-1 -yl, 2-penten-1 -yl, 2-penten-2-yl, 3-penten-1 -yl, 3-penten-3-yl, 4-penten-1 -yl, 4-penten-4-yl, and the like. The alkenyl group preferably has one double bond. It is also preferred that the double bond in the alkenyl group is directly bonded to the remainder of the compound containing the alkenyl group, e.g., 1 -propen-1 -yl is preferred over 2-propen-1 -yl.

[0078] In the present application, "oxo" means a double-bonded oxygen (=0).

[0079] A line drawn from a ring system indicates that one end of the bond can be attached to any suitable ring atom in the ring system through which the bond is drawn, through one ring, indicating attachment at any optional position on that ring, through multiple rings, indicating attachment at any optional position on the multiple rings. For example, the structure of includes any one of the following structures:

[0080] The term "pharmaceutical composition" means a mixture of one or more compounds described herein or a pharmaceutically acceptable salt thereof, with other ingredients customary in pharmaceutical practice.

[0081] The term "pharmaceutically acceptable salt" refers to salts of acidic functional groups (e.g., -COOH) present in the compounds provided herein with appropriate inorganic or organic cations (bases), and includes, but is not limited to, alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic base salts, such as ammonium salts; organic base salts, such as tertiary octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenethylamine salts, piperazine salts, tetramethylamine salts, tris(hydroxymethyl)aminomethane salts, and to salts of basic functional groups (e.g., -NH2) present in the compounds provided herein with appropriate inorganic or organic anions (acids), and includes, but is not limited to, hydrogen halide salts, such as hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, etc.; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkylsulfonic acid salts, such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, etc.; arylsulfonic acid salts, such as benzenesulfonates, p-toluenesulfonates, etc.; organic acid salts, such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, maleates, etc.; amino acid salts, such as glycine salts, trimethylglycine salts, arginine salts, ornithine salts, glutamic acid salts, aspartic acid salts, etc. See, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002).

[0082] The pharmaceutical composition according to the present application can contain pharmaceutically acceptable adjuvants, including, but not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, lanolin, and the like.

[0083] The pharmaceutical compositions of the present application can be prepared according to different administration routes in various forms. For example, the pharmaceutical compositions can be administered in any of the following ways: orally, spray inhalation, rectally, nasally, buccally, vaginally, topically, parenterally, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or by means of an implanted reservoir. Oral or intravenous administration is preferred.

[0084] The compounds of the present application can optionally also be used in combination with other active ingredients, each of which can be adjusted in amount and ratio by those skilled in the art depending on the specific condition and patient and clinical needs, etc. The combination does not mean that the therapies or therapeutic agents must be administered and / or formulated for delivery together, although these methods of delivery are within the scope of the present application. The therapeutic agents used in combination can be administered simultaneously, before, or after one or more of the other additional therapies or therapeutic agents. The therapeutic agents or therapeutic regimens can be administered in any order.

[0085] The term "subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some embodiments, the subject is a human.

[0086] The term "effective amount" refers to the amount of a compound or pharmaceutical composition of the present disclosure that will elicit the desired effect in a subject, environment, or object.

[0087] In some embodiments, a "therapeutically effective amount" refers to an amount of a compound disclosed herein that, when administered, will relieve, to some extent, one or more of the symptoms of the disease or condition being treated. In some embodiments, the result is reduction and / or alleviation of a sign, symptom, or cause of disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound disclosed herein that is sufficient to provide a clinically significant decrease in disease symptoms.

[0088] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0089] The application is further described in conjunction with the following specific examples, which are not to be construed as limiting the scope of the application as claimed.

[0090] Example

[0091] Synthesis of intermediate 2-(1-Boc-2,3-dihydro-1H-indol-5-yl)acetic acid

[0092] In a round bottom flask, 80 mesh zinc powder (Zn, 1.1 eq.) was added, vacuumed and replaced with nitrogen, THF and TMSCl (0.05 eq.) were added, and the reaction was stirred at room temperature for 1 hour. Compound 1 (1 eq.) was slowly added, and after initiation of the reaction (if not initiated, it can be heated carefully), the reaction was carried out at 80°C for 1 hour. A light yellow filter cake was obtained after filtration, which was compound 2 (yield 68%).

[0093] In a round bottom flask, compound 3 (1 eq.) was added and dissolved with HOAc. NaCNBH3 (1 eq.) was slowly added at 0°C, and the reaction was stirred at room temperature for 5 hours and detected by thin layer chromatography. After the reaction was completed, the HOAc was removed by rotary evaporation, the residue was dissolved with EtOAc, the pH was adjusted to 9-10 with NaOH (6N) aqueous solution, the organic phase was separated, the aqueous phase was extracted with EtOAc, and the combined organic phase was dried over Na2SO4 and rotary evaporated. Compound 4 was obtained by column chromatography with a yield of 76%.

[0094] Compound 4 (1 eq.) was added to a round bottom flask, THF:H2O=1:1 solution was added, and after dissolution, NaHCO3 solid was added, and Boc anhydride (1.1 eq.) was added dropwise. The reaction was carried out at room temperature for 2 hours, detected by thin layer chromatography, and after filtration, the solid was extracted with EtOAc, washed with PE, and dried to obtain compound 5 with a yield of 65%.

[0095] Compound 5 (1 eq.) was added to a single-neck round bottom flask. Vacuum and replace with nitrogen, dissolve with THF, add LiHMDS (1.1 eq.), and react at room temperature for 0.5 hours. Compound 2 (3 eq.), catalyst Pd2(dba)3 (0.03 eq.), and ligand X-phos (0.03 eq.) were added to another two-neck round bottom flask, dissolved with THF under nitrogen protection, and the THF solution in the single-neck flask was transferred to the two-neck flask under nitrogen protection. The reaction was carried out at 80°C for 2 hours. After filtration and rotary evaporation, compound 6 was obtained by column chromatography with a yield of 62%.

[0096] Compound 6 (1 eq.) was added to a round bottom flask, 2M hydrochloric acid ethanol solution was added, and the reaction was carried out at 80°C for 1-2 hours. After the EtOH was removed, it was dissolved with EtOAc, washed with saturated sodium bicarbonate solution, extracted, rotary evaporated, and compound 7 was obtained by column chromatography with a yield of 65%.

[0097] In a round bottom flask, compound 7 (1 eq.) was dissolved in THF:H20 = 1 : 1 followed by addition of NaHC03 solid, dropwise addition of Boc anhydride (1.1 eq.) and reaction at room temperature for 2 hours. TLC was used to check the completion of the reaction, addition of potassium carbonate and reaction at room temperature for 1 hour. TLC was used to check the completion of the reaction, filtration followed by extraction with EtOAc and washing of the solid with PE. Drying followed by evaporation gave compound A in 65% yield.

[0098] In the above reaction scheme, starting material 3 was replaced with (CAS: 434960-42-6) and compound (i.e. entry 19 in Table 2, reactant A) was produced by the same route.

[0099] Alternatively, starting material 3 was replaced with compound 9 as shown in the above reaction scheme and 11 was produced by the same synthetic route. Further, compound 11 was dissolved in MeCN and NBS was added dropwise at 0 °C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. After the completion of the reaction, as checked by TLC, the reaction mixture was evaporated and purified by column chromatography to give compound 12 in 62% yield. Using compound 12 in place of compound 5 as the starting material, reactant A in entries 7, 18 and 24 in Table 2 below was produced by the same synthetic route.

[0100] Table 2: Different starting reactants A and B to produce intermediates C by the above synthetic route

[0101] Example 2: Synthesis of amide intermediate CI from compound A

[0102] Compound A (1 eq.) was weighed into a reaction flask, EDCI (2 eq.), DMAP (0.2 eq.), TEA (3 eq.) and B (1 eq.) were added and dissolved in dry DCM. The reaction mixture was sealed and stirred at room temperature overnight. After the completion of the reaction, the mixture was extracted with DCM / water, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Compound 8 was isolated by semi-preparative liquid chromatography (water / methanol) in 35% yield.

[0103] Compound 8 (1 eq.) was added to a round bottom flask and dissolved in DCM per mmol of compound. TFA (18 eq.) was added dropwise and the reaction was allowed to proceed for 6 hours. Saturated sodium bicarbonate solution was added until no more bubbles were formed. The mixture was extracted with DCM, evaporated and purified by column chromatography to give intermediate CI in 57% yield.

[0104] Example 3 Synthesis of ester intermediate C2 from compound 6

[0105] Compound 6 (1 eq.) was added to a round bottom flask, and a solution of hydrochloric acid in solvent B was added. The reaction was allowed to proceed at 80 °C for 1-2 h. Solvent B was removed by rotary evaporation, and EtOAc was added to dissolve the residue. The solution was washed with saturated sodium bicarbonate solution, extracted, and dried by rotary evaporation. Compound 7 was obtained by column chromatography in 65% yield.

[0106] Example 4 Synthesis of intermediate 2-(2,3-dihydro-lH-indol-5-yl)acetonitrile

[0107] The starting materials 1 (1 eq.) and 2 (1.5 eq.) were added to a two-neck flask, followed by KF (1 eq.). The solution was degassed by ultrasonication for 5 min after the addition of H2O:DMSO = 1:2. PdCl2dppf (0.03 eq.) was added, and the solution was degassed again by ultrasonication. The reaction was allowed to proceed at 130 °C for 16 h. After filtration, 5 volumes of EA were added to the organic phase, which was washed with saturated sodium chloride solution. Compound 3 was obtained by column chromatography in 25% yield.

[0108] Compound 5 was added to a round bottom flask, and TFA (15 eq.) was added to dissolve the solution at 0 °C. The reaction was allowed to proceed at room temperature for 4 h. After washing with saturated sodium bicarbonate solution, compound 4 was obtained by column chromatography in 54% yield.

[0109] Example 5

[0110] Compound 1 was dissolved in THF in a dry round bottom flask under ice bath. LiAlH4was added slowly, and the reaction was allowed to proceed for 45 min. TLC was used to monitor the reaction. After the reaction was completed, MeOH was added dropwise to quench the reaction. The reaction solution was filtered through celite, and the filter cake was washed with MeOH until no target product was detected. The filtrate was dried by rotary evaporation, and compound 2 was obtained by column chromatography in 79% yield.

[0111] Compound 2 was added to a round bottom flask and dissolved in a mixture of TFA (20 eq.) and DCM (2:1) under ice bath. The reaction was allowed to proceed for 0.5-1 h. Saturated sodium bicarbonate solution was added until no bubbles were observed. The solution was extracted with DCM, dried by rotary evaporation, and purified by column chromatography to obtain intermediate 3 in 37% yield.

[0112] Compound 2 was dissolved in DCM in a dry round bottom flask. PPh3and CBr4were added slowly under ice bath, and the reaction was allowed to proceed at room temperature for 3-4 h. TLC was used to monitor the reaction. After the reaction was completed, the solution was dried by rotary evaporation, and compound 4 was obtained by column chromatography.

[0113] Compound 4 (1 eq.) was weighed into a reaction flask, sodium thiomethoxide (5 eq.) was added, followed by solvent ethanol, sealed, and reacted at room temperature for 24 hours. After the reaction was completed, it was concentrated under vacuum, and compound 5 was isolated using a silica gel column, with a yield of 85%.

[0114] Compound 5 (1 eq.) was added to a round-bottom flask, and TFA (18 eq.) was added dropwise per mmol of compound dissolved in DCM at an ice bath. After 6 hours, saturated sodium bicarbonate solution was added until no bubbles were produced, and DCM was added for extraction. After spin-drying, column chromatography and purification, intermediate 6 was obtained with a yield of 57%.

[0115] Alternatively, compound 5 above was dissolved in DCM in a round-bottom flask, and 0.8 eq. or 2.5 eq. of m-CPBA was added, respectively. After stirring at room temperature for 0.25 hours, compound 7 and 9 were obtained with a yield of 45% to 70% after spin-drying, column chromatography and purification.

[0116] Under the same reaction conditions as for the generation of intermediate 6, intermediate 8 and 10 were obtained from compounds 7 and 9, respectively.

[0117] Compound 11 was dissolved in THF in a round-bottom flask, and DMAP was added. After dropwise addition of Boc anhydride at room temperature, the reaction was allowed to proceed for 8 to 10 hours, and thin-layer chromatography was used for detection. After the reaction was completed, spin-drying was performed, and column chromatography and purification were used to obtain compound 12.

[0118] Compound 12 was dissolved in PhMe in a dry round-bottom flask, and was cooled to -78°C. After addition of DIBAL-H under nitrogen protection, the reaction was allowed to proceed for 2 hours, and thin-layer chromatography was used for detection. After the starting material was consumed, MeOH was added at -78°C until no gas was produced. After warming to room temperature, water and EtOAc were added, and the organic phase was separated after shaking and partitioning. The aqueous phase was further extracted with EtOAc until no target residue was left in the water. After all the organic phases were combined, Na2SO4 was added for drying, and spin-drying was performed. Column chromatography was used to isolate compound 13.

[0119] Compound 13 was dissolved in DCM in a dry round-bottom flask, and PPh3 and CBr4 were slowly added at an ice bath, respectively. After reaction at room temperature for 3 to 4 hours, thin-layer chromatography was used for detection. After the reaction was completed, spin-drying was performed, and column chromatography and purification were used to obtain compound 14. Compound 14 (1 eq.) was weighed into a reaction flask, sodium thiomethoxide (5 eq.) was added, solvent ethanol was added, and the reaction was sealed and reacted at room temperature for 24 hours. After the reaction was completed, it was concentrated under vacuum, and compound 15 was isolated using a silica gel column, with a yield of 85%.

[0120] Compound 15 was dissolved in water and methanol (1:4) in a dry round bottom flask, potassium carbonate (2.5 eq.) was added and the reaction was heated to 86°C for 3-4 hours, TLC was used to monitor the reaction. After the reaction was completed, it was evaporated and purified by column chromatography to obtain compound 16.

[0121] Compound 16 was dissolved in HOAc in a round bottom flask, NaCNBH3 (1 eq.) was added slowly at 0°C, the reaction was allowed to warm to room temperature and stirred for 5 hours, TLC was used to monitor the reaction. After the reaction was completed, the HOAc was evaporated, the residue was dissolved in EtOAc and the pH was adjusted to 9-10 using NaOH (6N) aqueous solution. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, evaporated and purified by column chromatography to obtain compound 17 in 76% yield.

[0122] Compound 17 was dissolved in THF in a round bottom flask, DMAP was added and Boc anhydride was added dropwise at room temperature. The reaction was stirred for 8-10 hours and TLC was used to monitor the reaction. After the reaction was completed, it was evaporated and purified by column chromatography to obtain compound 18.

[0123] Compounds 18 was used in place of compound 5 to obtain intermediates 20 and 22 by the same procedure as for intermediates 8 and 10.

[0124] Table 3 shows the desired reaction intermediates obtained by different reactants based on this route.

[0125] Table 3:

[0126] Synthesis of intermediate C2 in example 6

[0127] Solvent B was added in a round bottom flask, NaH (1 eq.) was added at 0°C and the reaction was stirred for 30 minutes. Then A was added and the reaction was stirred until completion. The reaction was quenched with water, extracted with EA, evaporated and purified by column chromatography to obtain compound 1 in 58% yield.

[0128] Compound 1 was added to a round bottom flask, dissolved in DCM and TFA (15 eq.) was added at 0°C. The reaction was allowed to warm to room temperature and stirred for 4 hours. Saturated sodium bicarbonate was added, evaporated and purified by column chromatography to obtain intermediate C2 in 54% yield. Different reaction intermediates C2 were obtained by different reactants A and B by this route (Table 4).

[0129] Table 4: Reaction intermediates C2 obtained by different reactants A and B by this route

[0130] Synthesis of intermediate C3 in Example 7

[0131] Compound 1, DCM and MsCl were added into a single-neck flask, cooled to -20 °C, then triethylamine (TEA) was added, stirred for 8 h at the temperature, then purified by column chromatography, and then the above product was added into a single-neck flask, dissolved in THF, cooled to 0 °C, NaH was added again, stirred for 12 h at room temperature after the addition was completed, then rotary evaporation and purified by column chromatography to obtain compound B with a yield of 90%.

[0132] A, B, NaOtBu, Pd(OAc)2, X-PHOS were added into a single-neck flask, replaced with N2, then toluene was added, heated to 110 °C for 16 h, filtered, rotary evaporation and purified by column chromatography to obtain the target product compound 2 with a yield of 40%.

[0133] Compound 2 was added into a single-neck flask, dissolved in DCM, cooled to 0 °C, then boron trifluoride ether was added, heated to room temperature for 4 h, then saturated sodium bicarbonate was added for washing, rotary evaporation and purified by column chromatography to obtain the target product compound C3 with a yield of 45%-50%. Table 5 shows different reaction intermediates C3 obtained by the reaction route of different starting reactants A and B.

[0134] Table 5: Different reaction intermediates C3 obtained by the reaction route of different starting reactants A and B

[0135] Synthesis of intermediate C4 in Example 8

[0136] Compound 1 was dissolved in acetone in a round-bottom flask, potassium carbonate and CD3I were added, the reaction was complete, filtered, rotary evaporation and purified by column chromatography to obtain A with a yield of 58%.

[0137] A was added into a dry round-bottom flask, dissolved in MeOH, the reaction liquid was cooled to an ice bath, AcCl was slowly added after 10 min, the reaction liquid was heated to room temperature, TLC was used for detection, and the reaction was complete after 24 h, then the reaction liquid was directly rotary evaporated to obtain a yellow solid, which was purified by slurry in EtOAc to obtain compound 2 with a yield of 66%.

[0138] Compound 2 was added into a dry sealed tube, and a self-made saturated solution of NH3 in MeOH was added. The reaction was complete after 17-24 h under airtight condition, the reaction liquid was rotary evaporated to obtain a light yellow solid, which was purified by slurry in EtOAc to obtain intermediate C4 with a yield of 92%. Table 6 shows different reaction intermediates C4 obtained by the reaction route of reactant A.

[0139] Table 6: Different reaction intermediates C4 obtained from reactant A through this reaction route

[0140] Example 9: Synthesis of compounds of formula I

[0141] Compound 1 and starting material B were dissolved in THF in a sealed tube, DIPEA was added, and the reaction was stirred at 115°C for 6-8 hours. After rotary evaporation, the product compound 2 was obtained by column chromatography with a yield of 45%-72%.

[0142] A and 2, XPhosPb-G3 were added to a two-necked round-bottom flask, and after nitrogen replacement, THF solution was added under nitrogen protection, followed by the addition of 0.5M potassium phosphate aqueous solution. The reaction was stirred at room temperature or 60°C for 20min to 1.5h. After quenching with water, EA extraction, rotary evaporation, and column chromatography purification, the product compound 3 was obtained with a yield of 35%-67%.

[0143] In the above reaction, the amount of phenylboronic acid and catalyst was strictly controlled not to exceed the amount required for the reaction, and the temperature and time were controlled. The reaction time was determined by monitoring the reaction with nuclear magnetic resonance.

[0144] Compound 3 was dissolved in DCM in a round-bottom flask, 0.8eq. of m-CPBA was added, and the reaction was stirred at room temperature for 0.25h. After rotary evaporation, the product compound 4 was obtained by column chromatography purification with a yield of 45%-70%.

[0145] Compound 4 was dissolved in DCM in a round-bottom flask, 1.2eq. of m-CPBA was added, and the reaction was stirred at room temperature for 0.25h. After rotary evaporation, the product compound 5 was obtained by column chromatography purification with a yield of 45%-70%.

[0146] When the product is an ester compound, the corresponding carboxylic acid can be obtained through the following reaction conditions:

[0147] Compound 6 was dissolved in THF in a round-bottom flask, 1.0M sodium hydroxide aqueous solution was added, and the reaction was stirred at 60°C for 2h. After cooling to room temperature, 2M hydrochloric acid was added to adjust the pH to acidic. After EA extraction, rotary evaporation, and column chromatography purification, the product compound 7 was obtained with a yield of 45%-70%.

[0148] When the product contains a cyano group, the corresponding tetrazole can be obtained through the following reaction:

[0149] Compound 8, NaN3, and triethylamine hydrochloride were added to a round-bottom flask, and toluene was added at 110°C for 24h. After filtration, the filter cake was slurried with DCM to obtain the product compound 9 with a yield of 70%.

[0150] When the product contains a PMB protecting group, it can be removed by the reaction condition as above:

[0151] Compound 11 was obtained by adding starting material compound 10 into a round bottom flask, dissolving in DCM and adding TFA, and reacting at room temperature for 24 h. After washing with saturated sodium bicarbonate and spin-drying, compound 11 was purified by column chromatography.

[0152] Compound 13 (Example Compound I-106) was obtained by the following reaction:

[0153] Compound 13 was obtained by adding starting material compound 12 into a round bottom flask, dissolving in ethylenediamine and heating to 60 °C for 1 h. After dilution with water, extraction with EtOAc, washing and spin-drying, compound 13 was purified by column chromatography. Table 7 summarizes the synthesis scheme and results characterization of Example Compounds I-1 to I-109.

[0154] Table 7: Overview of synthesis scheme of Example Compounds I-1 to I-109

[0155] The fluorine-containing intermediates required for the synthesis of compound I-109 in the above table can be synthesized by the following route

[0156] In a dry round bottom flask, compound 14 was dissolved in THF and cooled to -78°C under N2protection, then LDA was added dropwise slowly, and the reaction was kept at -78°C for 30 min. NFSI was dissolved in super dry THF and added dropwise slowly to the above reaction solution. TLC was used to monitor the reaction, and after 12 h, the starting material was consumed. The reaction was quenched by adding saturated ammonium chloride solution at -78°C. The reaction solution was extracted with EtOAc, and the organic phases were combined, dried over Na2S04, and concentrated. Compound 15 was obtained by column chromatography with a yield of 67%.

[0157] In a dry round bottom flask, compound 15 was dissolved in DCM and cooled to 0°C. BF3.Et20 was added dropwise slowly, and the reaction was kept at 0°C for 24 h. TLC was used to monitor the reaction, and after the starting material was consumed, water was added to quench the reaction. The aqueous phase was extracted with DCM, and the organic phases were combined, dried over Na2S04, and concentrated. Compound 16 was obtained by column chromatography with a yield of 86%.

[0158] Compound 27 was dissolved in methanol in a dry round bottom flask, and the reaction solution was cooled to 0°C. NaBH4was added dropwise slowly, and the reaction was completed after 2 h. Water was added to quench the reaction, and the aqueous phase was extracted with DCM. The organic phases were combined, dried over Na2S04, and concentrated. Compound 17 was obtained by column chromatography with a yield of 43%.

[0159] Example 10

[0160] Similar to the synthetic route in Example 9, the reaction condition of compound 2 to compound 3 was replaced by: compound 2 and starting material A were dissolved in THF in a sealed tube, DIPEA was added, and the reaction was stirred at 115°C for 6-8 h. Compound 3 was obtained by concentration and column chromatography purification with a yield of 45%-72%. Table 8 summarizes the synthetic scheme and results of Example compounds I-110 to I-117.

[0161] Table 8: Overview of the synthetic scheme of Example compounds I-110 to I-117

[0162] Example 11

[0163] Compound 1 (1 eq.) was weighed into a reaction flask, Dess-Martin periodinane (2.5 eq.), pyridine (2.5 eq.) were added, DCM was added as solvent, and the reaction was allowed to proceed at room temperature for 2.5 h. After the reaction was completed, the solid was washed with 50% acetonitrile / water, and dried to give compound 2 in 85% yield. Compound 4 was obtained from compound 3 by the same reaction condition. Compounds 2 and 4 were used as reactant A in the next step.

[0164] In a round bottom flask, A was added, and N2 was bubbled through. A THF solution of B was added at 0 °C, and the reaction was allowed to proceed for 1 h. The reaction was quenched with saturated NH4Cl, extracted with EA, and dried. The compound was purified by column chromatography to give a yield of 62%.

[0165] The reaction conditions involving m-CPBA in the examples based on this synthetic route were the same as those in Example 9. Table 9 summarizes the synthetic scheme and characterization results of the example compounds I-118 to I-135.

[0166] Table 9: Overview of the synthetic scheme of the example compounds I-118 to I-135

[0167] Example 12:

[0168] In a round bottom flask, A was added, and N2 was bubbled through. A THF solution of MeMgBr was added at 0 °C, and the reaction was allowed to proceed for 1 h. The reaction was quenched with saturated NH4Cl, extracted with EA, and dried. Compound 3 was purified by column chromatography to give a yield of 62%.

[0169] The reaction conditions involving m-CPBA in the examples based on this synthetic route were the same as those in Example 9. Table 10 summarizes the synthetic scheme and characterization results of the example compounds I-136 to I-139.

[0170] Table 10: Overview of the synthetic scheme of the example compounds I-136 to I-139

[0171] Example 13:

[0172] Compound 1 was placed in a single-neck flask, N2 was bubbled through, THF was added, and LiHMDS was slowly added dropwise at -78 °C. After stirring for 10 min, A was added, and the reaction was allowed to proceed at -78 °C for 7 h. After the reaction was completed, the reaction was quenched with saturated NH4Cl, extracted with EA, and dried. Compound 2 was purified by column chromatography to give a yield of 60%.

[0173] Compound 2 was placed in a single neck flask, N2 was purged, toluene was added, DIBAL-H (3.0 eq) was slowly added at -78 °C, the reaction was allowed to react for 1 h at -78 °C, the reaction was complete, saturated NaK tartrate was used to quench the reaction, celite was used to filter, the filtrate was spin dried and purified by column chromatography to obtain compound 3 with a yield of 47%. Compound 4 was obtained when DIBAL-H (1.0 eq) was added.

[0174] The reaction conditions involving m-CPBA in the examples based on this synthetic route were the same as in the synthetic route of Example 9. Table 11 summarizes the synthetic scheme and the results characterization of example compounds I-140 to I-148.

[0175] Table 11: Overview of the synthetic scheme of example compounds I-140 to I-148

[0176] Example 14:

[0177] A was dissolved in DCM in a round bottom flask, B was added, MgS04, NaHC03 were added in sequence, the reaction was allowed to react for 8 h at room temperature, insoluble solids were filtered out, the filtrate was spin dried. The filtrate was dissolved in THF, NaBH3CN, HC1 were slowly added, the reaction was allowed to react for 1 h at room temperature, saturated NaHC03 was used to quench, EA was used to extract, spin dried and purified by column chromatography to obtain the product with a yield of 43%.

[0178] A was dissolved in DCM in a round bottom flask, DAST was added, the reaction was allowed to react for 30 min at room temperature, spin dried and purified by column chromatography to obtain the product with a yield of 43%. Table 12 summarizes the synthetic scheme and the results characterization of example compounds I-149 to I-152.

[0179] Table 12: Overview of the synthetic scheme of example compounds I-149 to I-152

[0180] Example 15:

[0181] MeONa (5.58 g, 103.24 mmol, 1.2 eq.) was dissolved in MeOH (100 mL), 2- methylthioacetic acid methyl ester (9.13 g, 86.03 mmol, 7.85 mL, 1 eq.) was added, and the reaction was allowed to proceed at room temperature for 30 min. Methyl 4- chlorobutanoate (14.1 g, 103.24 mmol, 12.53 mL, 1.2 eq.) and KI (142.81 mg, 860.32 μmol, 45.77 μL, 0.01 eq.) were added, and the reaction was allowed to proceed at 65° for 18 h. After the reaction was completed, the reaction was cooled to room temperature. Filtration was performed, and vacuum concentration was performed. 100 mL of water was added, extraction was performed with DCM, the organic phases were combined, anhydrous sodium sulfate was added for drying, filtration was performed, and vacuum concentration was performed to obtain the crude compound 1 (19.5 g, 94.54 mmol, yield 109%), which was directly subjected to the next step.

[0182] Compound 2 (19 g, 92.12 mmol, 1 eq.) was dissolved in toluene (230 mL), MeONa (5.47 g, 101.33 mmol, 1.1 eq.) was added at room temperature, and the reaction was allowed to proceed at 105° for 3 h. After the reaction was completed, the reaction was cooled to room temperature, and the reaction liquid was poured into ice water. 17 mL of concentrated hydrochloric acid was added, stirring was performed for 5 min, extraction was performed with EA, the organic phases were combined, anhydrous sodium sulfate was added for drying, filtration was performed, and vacuum concentration was performed to obtain the crude compound 3 (11 g, 63.14 mmol, yield 68%), which was directly subjected to the next step.

[0183] KOH (14.17 g, 252.56 mmol, 6.93 mL, 4 eq.) was dissolved in MeOH, and compound 3 (11 g, 63.14 mmol, 1 eq.) and 2-methylisothiourea (8.54 g, 94.71 mmol, 1.5 eq.) were sequentially added. The reaction was allowed to proceed at room temperature for 4 h. After the reaction was completed, the reaction liquid was poured into ice water, acetic acid was added, and stirring was performed until a solid was precipitated. The solid was collected by filtration, and drying was performed to obtain the crude compound 4 (12 g, 55.99 mmol, yield 88%)

[0184] Compound 4 (12 g, 55.99 mmol, 1 eq.) was placed in a reaction flask, POCl3 (54.08 g, 352.72 mmol, 32.88 mL, 6.3 eq.) and N,N-dimethylaniline (678.54 mg, 5.60 mmol, 4.3 mL, 0.1 eq.) were added, and the reaction was allowed to proceed at 90° for 2 h. After the reaction was completed, the reaction was cooled to room temperature, and the reaction liquid was poured into ice water. Ethyl acetate was added for dilution, sodium bicarbonate was added to adjust the pH to 9-10, or until no gas bubbles were generated. Extraction was performed with EA, the organic phases were combined, anhydrous sodium sulfate was added for drying, vacuum concentration was performed, and compound 5 (6.4 g, 27.50 mmol, yield 49%) was separated by silica gel column chromatography.

[0185] Similar to the synthetic route in Example 9, wherein the reaction condition of compound 6 to 7 is:

[0186] Compound 6 (1 eq.), A (3 eq.), tetrakis(triphenylphosphine)palladium(0) (0.03 eq.), copper(I) thiophene-2-carboxylate (3 eq.) were added into a microwave reaction tube in sequence, dry THF was added, and the reaction was carried out at 80 °C for 3 h. After the reaction was completed, it was concentrated under vacuum, and compound 7 was separated by semi-preparative chromatography (water / methanol) with a yield of 27%. Table 13 summarizes the synthetic scheme and results of the example compounds I-153 to I-169.

[0187] Table 13: Overview of the synthetic scheme of example compounds I-153 to I-169

[0188] Example 16:

[0189] Compound 1 (1 eq.) was weighed into a reaction flask, 4-methoxybenzaldehyde (1.1 eq.) and TEA (1.5 eq.) were added, MeOH was added as solvent, and the reaction was stirred at room temperature for 1 h. The reaction was cooled to 0 °C, NaBH4 (2 eq.) was added, and the reaction was allowed to warm to room temperature and react for 1 h. After the reaction was completed, water was added at 0 °C to quench the reaction, and the filtrate was obtained by filtration. Most of the methanol was removed under vacuum, and the product was extracted with DCM / water. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain crude compound 2, which was used directly in the next step.

[0190] Compound 2 (1 eq.) was weighed into a reaction flask, DCM was added as solvent, and ethyl 3-chloro-3-oxopropanoate (1.1 eq.) was added dropwise at 0 °C. The reaction was allowed to warm to room temperature and react for 1.5 h. After the reaction was completed, the reaction was adjusted to weakly acidic by dropwise addition of dilute hydrochloric acid. The product was extracted with DCM / water. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain crude compound 3, which was used directly in the next step.

[0191] Compound 3 (1 eq.) was weighed into a reaction flask, toluene was added as solvent, and a 25 wt% sodium methoxide solution in methanol (3 eq.) was added dropwise. The reaction was refluxed at 100 °C for 2 h. After the reaction was completed, the reaction was adjusted to weakly acidic by dropwise addition of concentrated hydrochloric acid in an ice-water bath. Most of the toluene was removed under vacuum, and the product was extracted with DCM / water. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain crude compound 4, which was used directly in the next step.

[0192] Compound 4 (1 eq.) was weighed into a reaction flask, compound A (1.2 eq.) was added, DBU (3 eq.), solvent toluene was added, sealed, reacted at 130 °C for 2 h, after the reaction was completed, concentrated under vacuum to obtain crude compound 12, which was directly subjected to the next step.

[0193] Compound 5 was weighed into a reaction flask, POCl3was added dropwise, reacted at 100 °C for 1.5 h, after the reaction was completed, diluted with dilute NaOH in an ice water bath to quench, the reaction solution was adjusted to weak alkaline, extracted with DCM / water, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography to obtain compound 6.

[0194] Compound 6 (1.2 eq.) was weighed into a microwave tube, 2-(indolin-5-yl)ethan-1-ol (1 eq.) was added, DIPEA (10 eq.), solvent THF was added, placed in a microwave reactor and reacted at 120 °C for 1 h, after the reaction was completed, concentrated under vacuum, dissolved in methanol / DMSO, and separated by semi-preparative liquid chromatography (water / methanol) to obtain compound 7 with a yield of 70%.

[0195] Compound 7 was weighed into a microwave tube, TFA was added, placed in a microwave reactor and reacted at 110 °C for 3 h, after the reaction was completed, concentrated under vacuum, dissolved in THF, 1M NaOH solution was added dropwise, stirred at room temperature for 30 min, concentrated under vacuum to remove THF, extracted with DCM / water, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, dissolved in methanol / DMSO, and separated by semi-preparative liquid chromatography (water / methanol) to obtain compound 8 with a yield of 50%.

[0196] According to this route, compounds I-170 to I-249 can be synthesized using different starting materials B. Table 14 summarizes the synthesis scheme and results characterization of example compounds I-170 to I-249.

[0197] Table 14: Overview of the synthesis scheme of example compounds I-170 to I-249

[0198] Example 17: Enzymatic activity inhibition assay of compounds

[0199] PDE4 enzymatic reaction buffer consists of 50 mM Tris pH 7.5, 100 mM NaCl, 10 mM MgCl2, 0.01% Triton X-100 and 0.5 mM DTT. Enzymatic reactions were performed in 384-well plates in a total volume of 20 μΐ / well.

[0200] Compounds were dissolved in DMSO, and the compounds were prepared as 4X compound concentration solutions with reaction buffer; PDE4B and PDE4D proteins were diluted to 100 pM PDE4B protein solution and 160 pM PDE4D protein solution with reaction buffer; 2.5 μΐ^of 4X compound concentration solution was mixed with 5 μΐ^of PDE4B protein or PDE4D protein, and incubated for 10 minutes; then 2.5 μΐ^of substrate solution containing 20 μΜ cAMP and 40 U / mL alkaline phosphatase was added to initiate the reaction. The final concentrations of reaction components were as follows: 50 pM PDE4B protein or 80 pM PDE4D protein, 5 μΜ cAMP, 10 U / mL alkaline phosphatase, 1% DMSO. After incubation for 90 minutes, 10 μΐ^of 2 μΜ Phosphate Sensor (Invitrogen, PV4407) was added, and the mixture was mixed well and then the fluorescence signal (excitation wavelength 430 nm and emission wavelength 450 nm) was detected on a multifunctional microplate reader Synergy Neo2 (BioTek). IC50values were determined using a 3-fold serial dilution of compound, and each concentration was measured in triplicate. The positive control contained protein reaction solution, DMSO and cAMP, and the negative control contained only protein reaction solution and DMSO; the data were expressed as inhibition rate.

[0201] The inhibition rate was calculated according to the following formula, and the results are shown in Table 15:

[0202] Inhibition rate (%) = (positive control average - sample average) / (positive control average - negative control average) * 100

[0203] Table 15: Results of activity inhibition test of compounds

[0204] The symbols in the table represent the corresponding IC50 values: "++++": <10nM; "+++": 10nM-100nM; "++": 100nM-1uM; "+": 1μM-10μM; "-": >10μM.

[0205] Example 18: Inhibition of LPS-induced TNF-α expression by the compounds of the present invention

[0206] Mouse macrophages RAW264.7 were passaged in DMEM medium containing 100 U / ml penicillin, 100 μg / ml streptomycin, and 10% fetal bovine serum at 37°C and 5% CO2. Cells were initially seeded in 96-well plates at 5 × 10⁶ wells. 4 Cells were cultured overnight at a concentration of 100 ng / ml per well to allow cell adhesion. The experiment included a blank control group, an LPS group (LPS final concentration 100 ng / ml), and an LPS + compound group (LPS final concentration 100 ng / ml, compound concentrations of 10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.0001 μM, 0.00001 μM), with two replicates per group. After 18 hours of incubation in a cell culture incubator, the cell supernatant was aspirated, and TNF-α levels were detected by ELISA. The detection method followed the reagent instructions (Invitrogen, 88-7324-88): The day before the experiment, 100 μl of the capture antibody was added to each well of a high-binding-surface 96-well plate, and the plate was incubated overnight at 4°C. On the second day, wash the plate and discard any remaining liquid. Add 200 μl of ELISA / ELISPOT Diluent to each well and incubate at room temperature for 1 hour. Then wash the plate again and discard any remaining liquid. Add 100 μl of diluted cell supernatant (1:100 dilution) and serially diluted standards to each well and incubate at room temperature with shaking for 2 hours. Wash the plate again and discard any remaining liquid. Add 100 μl of detection antibody to each well and incubate at room temperature with shaking for 1 hour. Then wash the plate again and discard any remaining liquid. Add 100 μl of streptavidin-HRP to each well and incubate at room temperature with shaking for 30 minutes. After the reaction, add 100 μl of TMB solution to each well and incubate at room temperature with shaking for color development. After 15 minutes, add 100 μl of ELISA stop solution to each well and read the absorbance at 450 nm and 570 nm using a Synergy Neo2 microplate reader. Finally, construct a standard curve based on the standard concentrations and corresponding OD values, and calculate the TNF-α content in the cell supernatant. The inhibition rate of the compounds was calculated by comparing them with the LPS group, and the IC50 of the compounds was calculated by a three-factor nonlinear fitting using GraphPad Prism 8.0. The results of the inhibitory assays of the compounds on LPS-induced TNF-α expression are shown in Table 16.

[0207] Table 16: Results of the inhibition assay of compounds on LPS-induced TNF-α expression

[0208] The symbols in the table represent the corresponding IC50values: "++++": < 10 nM; "+++": 10 nM - 100 nM; "++": 100 nM - 1 μM; "+": 1 μM - 10 μM.

[0209] The preferred embodiments of the present application only are described above and not intended to limit the present application, and any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein L is selected from a single bond or C1-C3 alkylene optionally substituted with one or more substituents selected from -D, halogen, C1-C3 alkyl or C1-C3 alkoxy; R1is selected from -D, -H, halogen, -OH, -CN, -CHO, -OR5, -OC(O)R5, -COOR5, -NR6R7, -CONR6R7, -SR5, -SOR5, -SO2NR6R7, -CH=NOR8, or wherein each R5is independently selected from -D, -H, C1-C 15 alkyl or benzo-heterocyclyl, said C1-C 15 alkyl or benzo-heterocyclyl, said C1-C C1-C5 alkoxy; and / or R7 is selected from -D, -H, -CN or C1-C5 alkyl or C1-C5 alkoxy or 3-6 membered cycloalkyl optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, C1-C5 alkoxy, preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methoxy or ethoxy substituted methoxy; R6 and R7 are each independently selected from -D, -H, -OH, -CN, C1-C5 alkyl or C1-C5 alkoxy or 3-6 membered cycloalkyl or -SO2-C1-C5 alkyl, said C1-C5 alkyl or C1-C5 alkoxy or 3-6 membered cycloalkyl or -SO2-C1-C5 alkyl optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, C1-C5 alkoxy, or R6 and R7 together with the N atom to which they are attached join to form a 3-10 membered heterocycloalkyl, and said 3-10 membered heterocycloalkyl is optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, -CN, oxo (=0), C1-C6 alkyl, C1-C6 alkoxy or hydroxy substituted C1-C6 alkyl, R8 is selected from -D, -H or -COR5, R2is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, -CN, oxo, C1-C5alkyl, C2-C5alkenyl, C1-C5alkoxy, hydroxy-substituted C1-C5alkyl, C1-C3alkyl-O-C1-C3alkyl, -CO-C1-C5alkyl, -CONR6R7, C1-C5halogenated alkyl, C2-C5halogenated alkenyl, C1-C5halogenated alkoxy, hydroxy-substituted C1-C5halogenated alkyl, C1-C3halogenated alkyl-O-C1-C3halogenated alkyl, or -CO-C1-C5halogenated alkyl; R3 and R4 are each independently selected from -D, -H, halogen, -OH or C1-C6 alkyl, X is selected from -0-, -S-, -SO-, -SO2- or -CO-, Y is selected from -CH2-, or -NR6-, and n is 0 or 1.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is selected from a single bond, or L is selected from methylene, ethylene optionally substituted with one or more substituents selected from -D, halogen, C1-C3 alkyl or C1-C3 alkoxy; Preferably, L is selected from methylene or ethylene optionally substituted with one or more substituents selected from -D, -F, -Cl, methyl, ethyl, methoxy, ethoxy; More preferably, L is selected from methylene, ethylene, -CH(CH3)-, -CH(CH2CH3)-, -C(CH3)2-, -CH2CH(CH3)-, -CH(CH3)CH2-, -CH2C(CH3)2-, -CH2CH(CH2CH3)-, -CF2CH2-, or -CH(OCH3)CH2-.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from -D, -H, or C1-C3 alkyl optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkyl; and each R6 is independently selected from -D, -H, or C1-C3 alkyl optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, 11 C1-C3 alkyl; and each R6 is independently selected from -D, -H, or C1-C3 alkyl optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2 Preferably, R5is selected from optionally substituted methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, -C7H 15 , -C 11 H 23 , -C2H4OCH3, 4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from the group consisting of optionally substituted with one or more substituents selected from -D, halogen, -OH, -CN, C1-C3 alkyl, oxo Preferably, each R5is independently selected from the group consisting of optionally substituted with one or more substituents selected from -D, halogen, -OH, -CN, C1-C3alkyl, oxo 5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R6 is selected from -D, -H, -OH or C1-C5 alkyl; and / or R7 is selected from -D, -H, -CN or C1-C5 alkyl or C1-C5 alkoxy or 3-6 membered cycloalkyl optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, C1-C5 alkoxy, preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methoxy or ethoxy substituted methoxy; Preferably, R6 and R7 are both H, C1-C5 alkyl or C1-C5 alkoxy. ​ 6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R6 is H and R7 is selected from -OH, -CN, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkoxy, optionally substituted 3-6 membered cycloalkyl, or optionally substituted -SO2-C1-C5 alkyl; or R6 is -OH and R7 is selected from optionally substituted C1-C5 alkyl; or R6 is selected from optionally substituted C1-C5 alkyl and R7 is selected from optionally substituted C1-C5 alkoxy; or R6 is selected from methyl, ethyl, or propyl and R7 is selected from methoxy, ethoxy, or propoxy.

7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R6 and R7, together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl, and the 3-8 membered heterocycloalkyl is optionally substituted with one or more substituents selected from -D, halogen, -OH, -CN, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy substituted C1-C6 alkyl.

8. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R8 is -D, -H, -COH, or -COCi-C5 alkyl. 15 alkyl, preferably R8 is -COCi-C5 alkyl, more preferably R8 is -COCi-C3 alkyl, further preferably R8 is -COCH3. 10 alkyl, preferably R8 is -COCi-C5 alkyl, more preferably R8 is -COCi-C3 alkyl, further preferably R8 is -COCH3.

9. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein -L-R1 is selected from any one of the following groups: -COOH, -CH2COOH, -CH2COOCH2CH3, -CH2CONHOH, -CH2CONHCH3, -CH2CONH2, -CH2CONHCH2CH3, -CH2COOCH3, -CH2COOCH(CH3)2, -CH2CN, -CH2CH2OH, -CH2CHO, -CH2CONHCH2CH2CH3, -CH2COOCH2CH(CH3)2, -CH2CHF2, -CH2CON(CH3)2, -CH2CONHSO2CH3, -CH2CONHCN, -CH2CONHCH2CH2OH, -CH2CONHCH2CH2NH2, -CH2CONHOCH3, -CH2CON(CH3)OCH3, -CH2SO2NHCH3, -CH2SO2NHCH2CH3, -CH2SO2NH2, -CH2CON(CH3)OH, -CH2OH, -CH2CH(CH3)OH, -CH2C(CH3)2OH, -CH2CH(OH)CH2CH3, -CH(CH3)OH, -CH(OH)CH2CH3, -CONHCH3, -CH=NOH, -CH(CH3)CH3OH, -C(CH3)2OH, -CH=NOOCCH3, -CF2CH2OH, -CHO, -CH(OCH3)CH2OH, -CH(CH3)CHO, -C(CH3)2CHO, -CH2CH2OCH3, -CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OCH(CH3)2, -CH2OCH2CH2OCH3, -CH2COOC(CH3)3, -CH2CH2OCH2CH2OCH3, 10. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, -CN, oxo, -CHO, -COOH, C1-C3 alkyl, C2-C3 alkenyl, C1-C3 alkoxy, hydroxy-substituted C1-C3 alkyl, C1-C3 alkyl-O-C1-C3 alkyl, -CO-C1-C5 alkyl, -CONR6R7, C1-C3 haloalkyl, C2-C3 haloalkenyl, C1-C3 haloalkoxy, hydroxy-substituted C1-C3 haloalkyl, C1-C3 haloalkyl-O-C1-C3 haloalkyl, or -CO-C1-C3 haloalkyl, wherein R6 and R7 are each independently selected from -D, -H, -OH, -CN, C1-C5 alkyl, or C1-C5 alkoxy, or 3-6 membered cycloalkyl, said C1-C5 alkyl or C1-C5 alkoxy, or 3-6 membered cycloalkyl is optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, C1-C5 alkoxy.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C6-Ci0 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from -D, -F, -Cl, -Br, -OH, -NH2, methyl, methoxy, hydroxyl-substituted methyl, ethyl, ethoxy, hydroxyl-substituted ethyl, ethenyl, propenyl, allyl, -CH2OCH3, -COCH3, -COCH2CH3, -COCH2CH2CH3, or -CONHCH3, -CONHCH2CH3, -CONHCH2CH2CH3, or -CON(CH3)2. 10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from -D, -F, -Cl, -Br, -OH, -NH2, methyl, methoxy, hydroxyl-substituted methyl, ethyl, ethoxy, hydroxyl-substituted ethyl, ethenyl, propenyl, allyl, -CH2OCH3, -COCH3, -COCH2CH3, -COCH2CH2CH3, or -CONHCH3, -CONHCH2CH3, -CONHCH2CH2CH3, or -CON(CH3)2.

12. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from substituted or unsubstituted 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C6-Ci0 aryl, or 5-10 membered heteroaryl. 10 R2 is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or R2 is selected from substituted or unsubstituted oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, piperazinyl, hexahydropyrazinyl, morpholinyl, piperidinyl, or dithianyl, or R2 is selected from substituted or unsubstituted phenyl, naphthyl, or anthracenyl, or R2 is selected from substituted or unsubstituted thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzotriazolyl, or benzothiazolyl.

13. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from substituted or unsubstituted phenyl, 14. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 0 and X is selected from -O-, -S-, -SO-, -SO2-, or -CO-, Y is selected from -CH2-.

15. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 1 and X is selected from -S-, -SO-, -SO2-, Y is selected from -CH2-.

16. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 1 and X is selected from -CO-, Y is selected from -NH- or -N(CH3)-.

17. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is selected from Preferably, wherein selected from the group consisting of and / or and / or selected from the group consisting of and / or 18. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the structure of R2 is according to Formula IA: wherein, R9 is selected from -D, -H, halogen, -OH, -NH2, -CN, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxy, hydroxy substituted C1-C5 alkyl, C1-C3 alkyl-O-C1-C3 alkyl, -CO-C1-C5 alkyl, -CONR6R7, C1-C5 haloalkyl, C2-C5 haloalkenyl, C1-C5 haloalkoxy, hydroxy substituted C1-C5 haloalkyl, C1-C3 haloalkyl-O-C1-C3 haloalkyl, or -CO-C1-C5 haloalkyl; R 10 , R 11 , R 12 , R 13 each independently is selected from -D, -H, halogen, C1-C5alkyl, C1-C5haloalkyl, hydroxy-substituted C1-C5alkyl, hydroxy-substituted C1-C5haloalkyl.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R 10 , R 11 , R 12 , R 13 are the same or each different; and / or R 10 , R 11 , R 12 , R 13 is -D or -H or halogen; and / or R 10 and at least one of R 12 is selected from halogen, C1-C5alkyl, C1-C5haloalkyl, hydroxy-substituted C1-C5alkyl, or hydroxy-substituted C1-C5haloalkyl; and / or R 11 and R 13 are each independently selected from -D or -H; and / or R 11 , R 12 , R 13 are each -D or -H, and R 10 is selected from halogen, C1-C5alkyl, C1-C5haloalkyl, hydroxy- substituted C1-C5alkyl, or hydroxy-substituted C1-C5haloalkyl.

20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R 10 , R 11 , R 12 , R 13 are each independently selected from the group consisting of -D, -H, -F, -Cl, -Br, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl substituted C1-C3 alkyl, hydroxyl substituted C1-C3 haloalkyl; preferably, R 10 , R 11 , R 12 , R 13 are each independently selected from the group consisting of -D, -H, -F, -Cl, -CF3, -CH3, -CH2OH; more preferably, R 10 , R 11 , R 12 , R 13 are each -D or -H.

21. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R9 is selected from -D, -H, halogen, -OH, -NH2, -CN, C1-C3 alkyl, C2-C3 alkenyl, C1-C3 alkoxy, hydroxyl substituted C1-C3 alkyl, C1-C3 alkyl-O-C1-C3 alkyl, -CO-C1-C3 alkyl, -CONR6R7, C1-C3 haloalkyl, C2-C3 haloalkenyl, C1-C3 haloalkoxy, hydroxyl substituted C1-C3 haloalkyl, C1-C3 haloalkyl-O-C1-C3 haloalkyl, or -CO-C1-C3 haloalkyl, wherein R6 is selected from -D, -H, -OH, or C1-C5 alkyl; and / or R7 is selected from -D, -H, -CN, or C1-C5 alkyl or C1-C5 alkoxy optionally substituted with one or more substituents selected from -D, halogen, -OH, -NH2, C1-C5 alkoxy, or 3-6 membered cycloalkyl, preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, methoxy, or ethoxy substituted methoxy.

22. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R9 is selected from -CONR6R7, wherein R6 is H, and R7 is selected from -OH, -CN, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkoxy, optionally substituted 3-6 membered cycloalkyl, or optionally substituted -SO2-C1-C5 alkyl, or R6 is -OH, and R7 is selected from optionally substituted C1-C5 alkyl; or R6 is selected from optionally substituted C1-C5 alkyl, and R7 is selected from optionally substituted C1-C5 alkoxy; or R6 is selected from methyl, ethyl, or propyl, and R7 is selected from methoxy, ethoxy, or propoxy.

23. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R9 is selected from -D, -H, -F, -Cl, -Br, -OH, -NH2, methyl, methoxy, hydroxyl substituted methyl, ethyl, ethoxy, hydroxyl substituted ethyl, ethenyl, propenyl, allyl, -CH2OCH3, -COCH3, -COCH2CH3, -COCH2CH2CH3, -CONHCH3, -CONHCH2CH3, -CONHCH2CH2CH3, or -CON(CH3)2.

26. A pharmaceutical composition comprising a compound according to any one of claims 1-25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

27. Use of a compound according to any one of claims 1-25, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a PDE4, especially PDE4B, mediated disease or disorder. ​ 24. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from 25. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: ​ ​ 28. The use of claim 27, wherein the disease or disorder is selected from the group consisting of: an autoimmune disease, acquired immune deficiency syndrome, acute kidney injury, airway obstruction, alcoholic neuropathy, alcohol addiction, panic disorder, alopecia areata, Alzheimer’s disease, allergy, arthritis such as experimental arthritis, juvenile arthritis, psoriatic arthritis or rheumatoid arthritis, pain, fever, ankylosing spondylitis, asthma such as exercise-induced asthma, atherosclerosis, Behcet’s syndrome, bone metabolism disease, bronchial disease such as bronchospasm, bronchiolitis, chronic bronchitis, cancerous lesions, cancer such as hepatocellular carcinoma or renal cell carcinoma, cardiac disease such as heart failure, myocardial infarction, myocardial ischemia-reperfusion injury, myocardial fibrosis, cardiac dilatation or restrictive cardiomyopathy, carotid artery disease, carotid artery thrombosis, central nervous system disease, nervous system disease, neuralgia, neurodegenerative disease, brain disease such as cognitive deficiency, memory disorder, amnesia, depression, and neurodegenerative disease, ataxia, brain edema, brain injury such as traumatic brain injury, brain ischemia, brain tumor, cerebral infarction, cerebrovascular disease, cholera, colitis, ulcerative colitis, colorectal tumor, coronary artery disease, respiratory disease such as cough, SARS, COVID-19, skin disease such as dermatitis such as allergic contact dermatitis, atopic dermatitis, or phototoxic dermatitis, diabetes such as type 1 diabetes and type 2 diabetes, diabetic nephropathy, encephalomyelitis such as experimental autoimmune encephalomyelitis, endotoxemia, hypertension, inflammatory bowel disease, stroke such as ischemic stroke, leukemia such as chronic lymphocytic leukemia, pediatric acute lymphoblastic leukemia, inflammatory lung disease, obstructive lung disease such as chronic obstructive pulmonary disease, pulmonary fibrosis such as idiopathic pulmonary fibrosis, organ fibrosis, lung injury such as acute lung injury, pulmonary arterial hypertension, pulmonary edema, lung tumor, glioblastoma, glioma, follicular adenocarcinoma, adenoma, prostatic adenoma, malignant bladder cancer, cystitis, gastric tumor, abdominal aortic aneurysm, Behcet’s syndrome, lymphoma such as B-cell lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, medulloblastoma, neuroblastoma, melanoma, osteosarcoma, Parkinson’s disease, pityriasis, pneumonia, psoriasis, multiple sclerosis, cirrhosis, obesity, fatty liver, osteonecrosis, myopia, spinal cord injury, tuberculosis.

Images