CN116194451A

CN116194451A - Aryl or heteroaryl substituted five-membered aromatic heterocyclic compounds and uses thereof

Info

Publication number: CN116194451A
Application number: CN202180062290.0A
Authority: CN
Inventors: 王中利; 郝欣; 刘桑
Original assignee: Ruishi Biomedical Co ltd
Current assignee: Ruishi Biomedical Co ltd
Priority date: 2020-11-27
Filing date: 2021-11-26
Publication date: 2023-05-30
Also published as: TW202227424A; WO2022111605A1

Abstract

The present disclosure relates to aryl or heteroaryl substituted five-membered aromatic heterocyclic compounds and uses thereof. Specifically, a compound shown as a formula I or pharmaceutically acceptable salt thereof is provided, wherein R ¹ 、R ² 、Y ¹ Ring a and ring B are as defined herein.

Description

Aryl or heteroaryl substituted five-membered aromatic heterocyclic compounds and uses thereof

Technical Field

The present disclosure belongs to the field of medicine, and relates to an aryl or heteroaryl substituted five-membered aromatic heterocyclic compound and application thereof.

Background

Phosphodiesterases (PDEs) are a class of intracellular enzymes that cleave phosphodiester bonds on the second messenger molecules 3',5' -cyclic adenosine monophosphate (cAMP) and 3',5' -cyclic guanosine monophosphate (cGMP). The cyclic nucleotides cAMP and cGMP act as second messengers in various cellular pathways. Among them, PDE4 is highly specific for cAMP, with 4 subtypes: PDE4A, PDE4B, PDE4C and PDE4D. PDE4 is involved in promoting monocyte and macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, vasodilation, myocardial contraction, and other relevant physiological and pathological processes, and has effects on central nervous system function, cardiovascular function, inflammation/immune system, cell adhesion, etc. PDE4 plays a major regulatory role in the expression of pro-inflammatory and anti-inflammatory mediators, and PDE4 inhibitors can inhibit the release of deleterious mediators from inflammatory cells.

In recent years, many PDE4 inhibitors have been discovered. For example, roflumilast is approved for use in severe Chronic Obstructive Pulmonary Disease (COPD) to reduce the number of episodes or prevent exacerbation of COPD symptoms, and aplastic is approved for use in treating adults with active psoriatic arthritis. Although PDE4 inhibitors exhibit good pharmacological activity, these PDE inhibitors may exhibit side effects such as induction of gastrointestinal symptoms such as emesis and diarrhea, and there remains a need to develop selective PDE4 inhibitors, particularly selective PDE4 inhibitors having affinity for PDE4B and PDE 4D.

In addition, various heterocyclic structures such as oxazole compounds have been reported, such as WO03/072102, WO98/15274, WO2007058338, etc., however, the heterocyclic compounds of the present disclosure are not disclosed in any document.

Disclosure of Invention

The disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof

Wherein R is ¹ Selected from aryl or heteroaryl optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy, and/or the aryl or heteroaryl is fused to cycloalkyl or heterocycloalkyl, optionally with one or more R ^A1 Substituted;

R ^A1 selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino;

R ² selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, hydroxyAlkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S (O) ₂ R ', -NR ' (R "), -COR ', -COOR ', or-CONR ' (R '), said alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, or cycloalkenyloxy being optionally substituted with one or more R ' s ^A2 Substituted;

R ^A2 selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, C _6-10 Aryl or 5-to 6-membered heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, C _6-10 Aryl or 5-to 6-membered heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino;

ring A is selected from 5 membered heteroaromatic rings optionally substituted with one or more R ^A3 Substituted and R is ¹ In meta position on ring a with ring B;

R ^A3 selected from halogen, deuterium, hydroxy, nitro, cyano, amino, and C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group or a 3-to 6-membered heterocycloalkoxy group, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy optionally being substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino;

ring B is selected from 3-to 6-membered carbocycle or heterocycle, said ring B optionally being substituted with oneOr a plurality of R ^A4 Substituted;

R ^A4 selected from halogen, deuterium, hydroxy, nitro, cyano, amino, and C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group or a 3-to 6-membered heterocycloalkoxy group, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy optionally being substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino;

Y ¹ selected from the group consisting of bond, -C (=O) -, -C (=O) N (R) ³ )-、-N(R ⁴ )C(＝O)-、-S(O) _n -、-S(O) _m N(R ³ ) -or-N (R) ⁴ )S(O) _m -，R ³ Or R is ⁴ Independently selected from hydrogen, deuterium or C _1-6 Alkyl, n and m are each independently selected from integers from 0 to 2;

r 'or R' is independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, or amino.

In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof ¹ Selected from C _6-10 Aryl or 5-to 10-membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 3-to 6-membered heterocycloalkoxy or C _3-6 Substituted by cycloalkenyloxy, and/or the aryl or heteroaryl is fused to a 3-to 10-membered cycloalkyl or 3-to 10-membered heterocycloalkyl, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring Optionally one or more R ^A1 Substituted, R ^A1 As defined previously.

In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof ¹ Selected from C _6-10 Aryl optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl or C _3-6 Substituted by cycloalkenyloxy and/or the aryl is fused to a 3-to 10-membered cycloalkyl, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or the fused ring being optionally substituted by one or more R ^A1 Substituted, R ^A1 As defined previously.

In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof ¹ Selected from C _6-10 Aryl optionally substituted with one or more substituents selected from C _1-6 Alkoxy, C _3-6 Substituted with a cycloalkoxy or a 3-to 6-membered heterocycloalkoxy and/or the aryl is fused with a 3-to 10-membered heterocycloalkyl, the alkoxy, cycloalkoxy or fused ring optionally being substituted with one or more R ^A1 Substituted, R ^A1 As defined previously.

In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof ¹ Selected from C _6-10 Aryl optionally substituted with one or more groups selected from deuterium, halogen, hydroxy or amino.

In another aspect, some embodiments provide that the compound of formula I is

Wherein R is ⁶ 、R ⁷ 、R ⁸ 、R ⁹ Or R is ¹⁰ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, and C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 3-to 6-membered heterocycloalkoxy or C _3-6 Substituted with cycloalkenyloxy, said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl, heterocycloalkoxy or heterocycloalkylyl being optionally substituted with one or more R ^A1 Substituted or R ⁶ 、R ⁷ Forms a 5-to 10-membered carbocyclic ring or a 5-to 10-membered heterocyclic ring with adjacent carbon atoms, said carbocyclic ring or heterocyclic ring optionally being substituted with one or more R ^A1 Substituted, R ^A1 As defined previously.

In some embodiments, R in a compound represented by formula IIA or a pharmaceutically acceptable salt thereof ⁸ Selected from hydrogen, deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined previously.

In some embodiments, R in a compound represented by formula IIA or a pharmaceutically acceptable salt thereof ⁸ Selected from C _1-6 Alkoxy, said alkoxy optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined previously.

In some embodiments, R in a compound represented by formula IIA or a pharmaceutically acceptable salt thereof ⁸ Selected from C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 3-to 6-membered heterocycloalkoxy or C _3-6 Cycloalkenyloxy, said alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl, heterocycloalkoxy or heterocycloalkyl being optionally substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined previously.

In other embodiments, R in a compound of formula IIA or a pharmaceutically acceptable salt thereof ⁶ Selected from hydrogen, deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined previously. In some embodiments, R ⁶ Selected from hydrogen or deuterium. In some embodiments, R ⁶ Selected from hydrogen.

In other embodiments, R in a compound of formula IIA or a pharmaceutically acceptable salt thereof ¹⁰ Selected from hydrogen, deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined previously. In some embodiments, R ¹⁰ Selected from hydrogen or deuterium. In some embodiments, R ¹⁰ Selected from hydrogen.

On the other hand, in some embodiments, R in the compound of formula II or a pharmaceutically acceptable salt thereof ⁷ Selected from hydrogen, deuterium, halogen, hydroxy, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined previously.

In some embodiments, R in a compound of formula II or a pharmaceutically acceptable salt thereof ⁷ Selected from C _1-6 Alkoxy, said alkoxy optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined previously.

In some embodiments, R in a compound of formula II or a pharmaceutically acceptable salt thereof ⁷ Selected from C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 3-to 6-membered heterocycloalkoxy or C _3-6 Cycloalkenyloxy, said alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl, heterocycloalkoxy or heterocycloalkyl being optionally substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined previously.

In other embodiments, R in a compound of formula II or a pharmaceutically acceptable salt thereof ⁷ Selected from the group consisting of3 to 6 heterocycloalkoxy, preferably heterocycloalkoxy containing at least one heteroatom selected from N, O or S, said heterocycloalkoxy optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined previously. In some embodiments, the heterocycloalkoxy group includes, but is not limited to

In other embodiments, R in a compound of formula II or a pharmaceutically acceptable salt thereof ⁶ 、R ⁹ Or R is ¹⁰ Selected from hydrogen or deuterium. In some embodiments, R in a compound of formula II or a pharmaceutically acceptable salt thereof ⁸ Selected from C _1-6 Alkoxy, said alkoxy optionally being substituted with 1 to 3R ^A1 Substituted; r is R ⁷ Selected from C _1-6 Alkoxy, said alkoxy optionally being substituted with 1 to 3R ^A1 Substituted.

In some embodiments, R in a compound of formula II or a pharmaceutically acceptable salt thereof ⁸ Selected from C _1-6 Alkoxy, said alkoxy optionally being substituted with 1 to 3R ^A1 Substituted; r is R ⁷ Selected from C _1-6 Alkoxy, said alkoxy optionally being substituted with 1 to 3R ^A1 Substituted; r is R ⁶ 、R ⁹ And R is ¹⁰ Selected from hydrogen or deuterium.

In some embodiments, R in a compound of formula II or a pharmaceutically acceptable salt thereof ⁷ Selected from the group consisting of heterocycloalkoxy containing at least one heteroatom selected from N, O or S, said heterocycloalkoxy optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As previously defined; r is R ⁸ Selected from C _1-6 Alkoxy, said alkoxy optionally being substituted with 1 to 3R ^A1 Substituted; r is R ⁶ 、R ⁹ Or R is ¹⁰ Selected from hydrogen or deuterium.

In other embodiments, R in a compound of formula II or a pharmaceutically acceptable salt thereof is provided ⁶ 、R ⁷ Forming a 5-to 10-membered heterocyclic ring with adjacent carbon atoms, said heterocyclic ring optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined previously.

In some embodiments, R in a compound of formula II or a pharmaceutically acceptable salt thereof ⁶ 、R ⁷ Forming a 5-to 10-membered heterocyclic ring with adjacent carbon atoms, said heterocyclic ring optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined in claim 1; r is R ⁸ Selected from hydrogen, deuterium, halogen, hydroxy, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined previously.

In some embodiments, R in a compound of formula II or a pharmaceutically acceptable salt thereof ⁶ 、R ⁷ Forming a 5-to 10-membered heterocyclic ring with adjacent carbon atoms, said heterocyclic ring optionally being substituted with 1 to 3R ^A1 Substituted;

R ⁸ selected from hydrogen, deuterium, halogen, hydroxy, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with 1 to 3R ^A1 Substituted;

R ⁹ or R is ¹⁰ Selected from hydrogen;

R ^A1 as defined previously.

In other embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof ¹ Selected from 5 to 10 membered heteroaryl, optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 3-to 6-membered heterocycloalkoxy or C _3-6 Substituted by cycloalkenyloxy, andor the aryl is fused to a 3 to 10 membered cycloalkyl or 3 to 10 membered heterocycloalkyl, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring being optionally substituted with one or more R ^A1 Substituted, R ^A1 As defined previously.

In some embodiments, R in a compound of formula I or a pharmaceutically acceptable salt thereof ¹ Selected from 5 to 10 membered heteroaryl, optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with one or more R ^A1 Substituted, R ^A1 As defined previously.

In another aspect, the present disclosure provides a compound of formula I

Wherein R is ¹¹ 、R ¹² 、R ¹³ 、R ¹⁴ Or R is ¹⁵ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, and C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with one or more R ^A1 Substituted, R ^A1 As defined previously.

In some embodiments, Y in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ¹ Selected from-C (=O) N (R) ³ ) -or-N (R) ⁴ )C(＝O)-，R ³ Or R is ⁴ Independently selected from hydrogen, deuterium or C _1-6 An alkyl group.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² -Y ¹ -the following: r is R ² -C(＝O)N(R ³ )-，R ³ Independently selected from hydrogen, deuterium or C _1-6 An alkyl group.

In some embodiments of the present invention, in some embodiments,r in the compound shown in the formula I or the formula II or pharmaceutically acceptable salt thereof ² -Y ¹ -the following: r is R ² -C(＝O)N(R ³ )-，R ³ Independently selected from hydrogen.

Some embodiments provide that the compound of formula I is

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² -Y ¹ -the following: r is R ² -N(R ⁴ )C(＝O)-，R ⁴ Independently selected from hydrogen, deuterium or C _1-6 An alkyl group.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² -Y ¹ -the following: r is R ² -N(R ⁴ )C(＝O)-，R ⁴ Independently selected from hydrogen.

In some embodiments, Y in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ¹ Selected from the group consisting of bond, -C (=o) -.

In some embodiments, Y in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ¹ Selected from-S (O) _n -、-S(O) _m N(R ³ ) -or-N (R) ⁴ )S(O) _m -, n and m are each independently selected from integers from 0 to 2, R ³ Or R is ⁴ Independently selected from hydrogen, deuterium or C _1-6 An alkyl group.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² Selected from C _6-10 Aryl or 5-to 9-membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3 to 6 heterocycleAlkoxy, C _3-8 Cycloalkenyloxy, -SR', -S (O) ₂ R ', -NR' (R '), -COR', -COOR 'or-CONR' (R '), said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy being optionally substituted with one or more R' s ^A2 Substituted, R' and R ^A2 As defined previously.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² Selected from C _6-10 Aryl optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-6 heterocycloalkoxy, C _3-8 Cycloalkenyloxy, -SR', -S (O) ₂ R ', -NR' (R '), -COR', -COOR 'or-CONR' (R '), said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy being optionally substituted with 1 to 3R' s ^A2 Substituted, R' and R ^A2 As defined previously.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² Selected from C _6-10 Aryl optionally substituted with 1 to 3 groups selected from deuterium, halogen, hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy or C _3-6 Substituted with cycloalkoxy, said alkyl, alkoxy or cycloalkoxy optionally being 1 to 3R ^A2 Substituted, R ^A2 As defined previously.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² Selected from C _6-10 Aryl, optionally substituted with C _1-6 Substituted with alkoxy optionally substituted with 1 to 3R' s ^A2 Substituted, R ^A2 As defined previously.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² Selected from C _6-10 Aryl, optionally substituted with 1 to 3 groups selected from-SR', -S (O) ₂ R ', -NR ' (R '), -COR ', -COOR ' or-CONR ' (R ') are substituted, R ' and R ' are as defined previously.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² Selected from C _6-10 Aryl, optionally substituted with 1 to 3 groups selected from C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, 3-6 heterocycloalkoxy or C _3-8 Substituted by cycloalkenyloxy, said alkenyloxy, alkynyloxy or cycloalkenyloxy being optionally substituted by 1 to 3R ^A2 Substituted, R ^A2 As defined previously.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² Selected from phenyl groups, said phenyl groups being substituted with 1 to 3 groups selected from deuterium, halogen, hydroxy, C _1-6 Alkyl or C _1-6 Alkoxy optionally substituted, said alkyl or alkoxy being optionally substituted with 1 to 3R ^A2 Substituted, R ^A2 As defined previously.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² Selected from phenyl groups, said phenyl groups being substituted with 1 to 3 groups selected from C _1-6 Alkoxy groups are substituted, for example methoxy, ethoxy or propoxy.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² Selected from 5 to 9 membered heteroaryl groups optionally substituted with 1 to 3 groups selected from deuterium, halogen, hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy or C _3-6 Substituted with cycloalkoxy, said alkyl, cycloalkyl, alkoxy or cycloalkoxy optionally being substituted with 1 to 3R ^A2 Substituted, R ^A2 As defined previously.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² Selected from the group consisting of

Further said R ² Optionally 1 to 3 groups selected from deuterium, halogen, hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy or C _3-6 Substituted with cycloalkoxy.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² Selected from:

in some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ² Selected from C _3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl, optionally substituted with 1 to 3 groups selected from deuterium, halogen, hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy or C _3-6 Substituted with cycloalkoxy, said alkyl, cycloalkyl, alkoxy or cycloalkoxy optionally being substituted with 1 to 3R ^A2 Substituted, R ^A2 As defined previously.

In another aspect, ring A of a compound of formula I or formula II or a pharmaceutically acceptable salt thereof is selected from the group consisting of

Further, the ring A ring is optionally substituted with one or more R ^A3 Substituted, R ^A3 As defined previously.

In some embodiments, ring A of a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, is selected from

In some embodiments, the compound of formula I

The method comprises the following steps:

in some embodiments, the compound of formula I

The method comprises the following steps:

some embodiments provide compounds of formula I or formula II as

On the other hand, in some embodiments, ring B in the compounds of formula I or formula II is selected from 3 to 6 membered carbocycles, said ring B optionally being substituted with one or more R ^A4 Substituted.

In some embodiments, ring B in the compound of formula I or formula II is selected from

Further said ring B is optionally substituted with one or more R ^A4 Substituted.

The compound shown in the formula I or the formula II is

Wherein p=an integer between 0 and 3. In some embodiments, p=0, 1 or 2 in the compound of formula VA or a pharmaceutically acceptable salt thereof. In some embodiments, p=0 in the compound of formula VA or a pharmaceutically acceptable salt thereof.

In other embodiments, ring B of the compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, is selected from a 4-to 6-membered nitrogen atom-containing heterocycle or an oxygen atom-containing heterocycle, said ring B optionally being substituted with one or more R ^A4 Substituted.

In some embodiments, ring B of a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, is selected from

On the other hand, in some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ^A1 Selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ^A1 Selected from hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ^A1 Selected from phenyl or 5-to 6-membered heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ^A2 Selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ^A2 Selected from hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ^A3 Selected from halogen, deuterium, nitro or cyanoHalogen, such as fluorine, is preferred.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ^A3 Selected from hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ^A4 Selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.

In some embodiments, R in a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof ^A4 Selected from hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.

In some embodiments, R 'or R' in a compound of formula I or formula II or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, C _1-6 Alkyl or C _1-6 Alkoxy group, the C _1-6 Alkyl or C _1-6 The alkoxy groups are optionally substituted with one or more groups selected from halogen or deuterium.

Further, the present disclosure provides compounds of formula I or formula II or pharmaceutically acceptable salts thereof wherein R ² Selected from 5-to 6-membered heteroaromatic rings. In some embodiments, R ² Selected from thiazolyl, imidazolyl, pyridinyl, oxazolyl, pyrimidinyl or pyrazolyl, further said R ² Optionally by one or more groups selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with one or more R ^A2 Substituted, R ^A2 As described aboveAnd (5) defining.

In other embodiments, R ² Selected from thiazolyl groups optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with one or more R ^A2 Substituted, R ^A2 As defined above.

In other embodiments, R ² Selected from imidazolyl optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with one or more R ^A2 Substituted, R ^A2 As defined above.

Other embodiments provide that the compound of formula I is

Wherein R is ¹⁶ Or R is ¹⁷ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, and C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with one or more R ^A1 Substituted, R ^A1 As defined previously.

In some embodiments, the compound of formula I is

In some embodiments, R in a compound of formula IIIC or a pharmaceutically acceptable salt thereof ¹⁶ Or R is ¹⁷ Each independently selected from hydrogen, deuterium or C _1-6 An alkoxy group.

In some embodiments, R in a compound of formula IIIC or a pharmaceutically acceptable salt thereof ¹⁶ Or R is ¹⁷ Each independently selectFrom hydrogen, halogen, amino, hydroxy or C _1-6 An alkoxy group.

In some embodiments, R in a compound of formula IIIC or a pharmaceutically acceptable salt thereof ¹⁶ Or R is ¹⁷ Each independently selected from C _1-6 Alkyl or C _1-6 An alkoxy group.

In another aspect, further embodiments provide compounds of formula I or formula II or a pharmaceutically acceptable salt thereof wherein R ² Selected from pyridyl or oxazolyl optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with one or more R ^A2 Substituted, R ^A2 As defined above.

Other embodiments provide that the compound of formula I is

Wherein R is ¹⁸ Or R is ¹⁹ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, and C _1-6 Alkyl or C _1-6 Alkoxy, R ²⁰ Selected from hydrogen, deuterium or C _1-6 Alkyl, said alkyl or alkoxy optionally being substituted with one or more R ^A6 Substituted, R ^A6 Selected from halogen, deuterium, hydroxy, nitro, cyano, amino, and C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group or a 3-to 6-membered heterocycloalkoxy group, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.

In some embodiments, the compound of formula I is

In some embodiments, R in a compound of formula III or a pharmaceutically acceptable salt thereof ¹⁸ Or R is ¹⁹ Each independently selected from hydrogen, halogen, amino, hydroxy or C _1-6 Alkoxy, R ²⁰ Selected from hydrogen, deuterium or C _1-6 An alkyl group.

In some embodiments, R in a compound of formula III or a pharmaceutically acceptable salt thereof ¹⁸ Or R is ¹⁹ Each independently selected from hydrogen, C _1-6 Alkyl or C _1-6 Alkoxy, R ²⁰ Selected from hydrogen, deuterium or C _1-6 An alkyl group.

Other embodiments provide that the compound of formula I is

Other embodiments provide that the compound of formula I is

Other embodiments provide that the compound of formula I is

Other embodiments provide that the compound of formula I is

Typical compounds of formula I or pharmaceutically acceptable salts thereof include, but are not limited to:

in another aspect, the present disclosure also provides a process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising the following reaction schemes,

in some embodiments, a method of preparing a compound of formula IIIA or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of formula ZA with a compound of formula ZB to form a compound of formula IIIA,

another aspect of the present disclosure also provides a compound of formula ZB or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula ZB or a pharmaceutically acceptable salt thereof is used in the synthesis or preparation of the compound of formula IIIA or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula ZB or a pharmaceutically acceptable salt thereof is

The present disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, or a compound prepared by the method, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition is in a unit dose of 0.001mg to 1000mg.

In certain embodiments, the pharmaceutical composition comprises 0.01 to 99.99% of the foregoing compound, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1-99.9% of the foregoing compound or pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the foregoing compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical compositions comprise 1% to 99% of the foregoing compounds, or pharmaceutically acceptable salts thereof. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of the foregoing compound or a pharmaceutically acceptable salt thereof.

In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient.

The present disclosure also provides a method of preventing and/or treating a patient suffering from a PDE-related disorder by administering to the patient a therapeutically effective amount of a compound of formula I or formula II as described above, or a pharmaceutically acceptable salt thereof, or a compound obtainable by the method described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described above.

In some embodiments, the PDE-related disorder is preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatism.

The present disclosure also provides a method for preventing and/or treating a patient suffering from asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatism comprising administering to the patient a therapeutically effective amount of a compound as shown in formula I or formula II, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a compound prepared by the foregoing method, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the foregoing pharmaceutical composition, to the patient.

The present disclosure also provides the use of a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof, as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention and/or treatment of a PDE-related disorder. In some embodiments, the PDE-related disorder is preferably asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatism.

The present disclosure also provides the use of a compound represented by the foregoing formula I or formula II, or a pharmaceutically acceptable salt thereof, or the foregoing pharmaceutical composition in the preparation of a medicament for preventing and/or treating asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatism.

In another aspect, pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic salts or organic salts.

The compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present disclosure. The asymmetric carbon atom containing compounds of the present disclosure may be isolated in optically active pure or racemic forms. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).

In the chemical structure of the compounds of the present disclosure, the bond

Indicating unspecified configuration, i.e. bonds if chiral isomers are present in the chemical structure

May be

Or at the same time contain

Two configurations.

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

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

The present disclosure also includes some isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the replacement of one or more atoms by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, respectively ² H、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹³ N、 ¹⁵ N、 ¹⁵ O、 ¹⁷ O、 ¹⁸ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F、 ¹²³ I、 ¹²⁵ I and ³⁶ cl, and the like.

Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium (i.e., at least 10% deuterium incorporation) having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). The natural abundance of a compound in an example can be at least 1000 times greater than the abundance of deuterium, at least 2000 times greater than the abundance of deuterium, at least 3000 times greater than the abundance of deuterium, at least 4000 times greater than the abundance of deuterium, at least 5000 times greater than the abundance of deuterium, at least 6000 times greater than the abundance of deuterium, or higher than the abundance of deuterium. The present disclosure also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds of formula (I). Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound of formula (I) or they may be synthesized using conventional techniques with deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

"optionally" or "optionally" is intended to mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example "C optionally substituted by halogen or cyano _1-6 Alkyl "means that halogen or cyano may be, but need not be, present, and this description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

Term interpretation:

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

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

An "effective amount" or "therapeutically effective amount" as used in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount is also meant to be an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the route of administration and the dosage and severity of the side effects. An effective amount may be the maximum dose or regimen that avoids significant side effects or toxic effects.

"alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, and various branched isomers thereof, and the like. The alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.

"alkenyl" includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. For example "C _2-6 Alkenyl "means havingAlkenyl groups having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. Alkenyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino

"alkynyl" includes branched and straight chain alkynyl groups having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups, or if specified, means that particular number of carbon atoms. Such as ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl. Alkynyl groups may be substituted or unsubstituted and when substituted, substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl, said C _1-6 Alkyl group,C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.

The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.

The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyanoRadicals, amino radicals, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.

The term "cycloalkenyl" refers to partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl. The cycloalkenyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.

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

etc.

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

etc.

The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy radicalRadical, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S (O) ₂ R ', -NR ' (R "), -COR ', -COOR ', or-CONR ' (R"), R ' or R ' are independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, or amino.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 6 to 12 membered, more preferably 5 or 6 membered. For example. Non-limiting examples of which include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine,

etc.

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

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S (O) ₂ R ', -NR ' (R "), -COR ', -COOR ', or-CONR ' (R"), R ' or R ' are independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, or amino.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 An alkenyloxy group,C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl is optionally substituted by one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino. Similarly, "alkynyloxy", "alkenyloxy", "cycloalkoxy", "heterocycloalkoxy", "cycloalkenyloxy" are defined as above for "alkoxy".

The term "heterocycloalkoxy" refers to-O- (heterocycloalkyl) wherein heterocycloalkyl is as defined above.

The term "hydroxy" refers to an-OH group.

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

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

The term "oxo" refers to an =o substituent.

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

Drawings

Fig. 1: inhibition of ear swelling for each group in the model.

Fig. 2: the ear thickness of each group in the model is increased.

Detailed Description

The present disclosure is further described below in connection with examples, which are not intended to limit the scope of the disclosure.

Experimental methods for which specific conditions are not noted in the examples in this disclosure are generally in accordance with conventional conditions, or in accordance with conditions recommended by the manufacturer of the raw materials or goods. The reagents of specific origin are not noted and are commercially available conventional reagents.

The structure of the compound is obtained by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS)And (3) determining. NMR shift (. Delta.) of 10 ^-6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated Methanol (Methanol-d) ₄ ) The internal standard is Tetramethylsilane (TMS).

HPLC was determined using an Agilent1100 high pressure liquid chromatograph, GAS15B DAD ultraviolet detector, water Vbridge C18 150 x 4.6mm 5um column.

The mass of the sample is measured by an Agilent6120 triple quadrupole mass spectrometer, a G1315D DAD detector, a Waters Xbridge C18.6 x 50mm, a 5um chromatographic column, and the sample is scanned in a positive/negative ion mode, and the mass scanning range is 80-1200.

The thin layer chromatography silica gel plate is a smoke table yellow sea HSGF254 silica gel plate, the Thin Layer Chromatography (TLC) adopts a silica gel plate with the specification of 0.2mm plus or minus 0.03mm, and the thin layer chromatography separation and purification product adopts a specification of 0.4mm-0.5mm.

Flash column purification systems used Combiflash Rf150 (teldyne ISCO) or isolaraone (Biotage).

The forward column chromatography generally uses the yellow sea silica gel of the smoke table with 200-300 meshes or 300-400 meshes as a carrier, or uses the Santai prefill of Changzhou to prefill the ultra-pure phase silica gel column (40-63 mu m,60g,24g,40g,120g or other specifications).

Known starting materials in the present disclosure may be synthesized using or following methods known in the art, or may be purchased from Shanghai taitant technology, ABCR GmbH & Co.KG, acros Organics, aldrich Chemical Company, shaoshan chemical technology (Accela ChemBio Inc), pichia medicine, and the like.

The examples are not particularly described, and the reactions can all be carried out under nitrogen atmosphere.

The nitrogen atmosphere is defined as the reaction flask being connected to a nitrogen balloon of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The hydrogen is prepared by a QPH-1L type hydrogen generator of Shanghai full-pump scientific instrument company.

The nitrogen atmosphere or the hydrogenation atmosphere is usually vacuumized, filled with nitrogen or hydrogen, and repeatedly operated for 3 times.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The reaction progress in the examples was monitored by Thin Layer Chromatography (TLC), a developing agent used in the reaction, a system of column chromatography eluent used for purifying the compound and a developing agent system of thin layer chromatography, and the volume ratio of the solvent was adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine and acetic acid.

Example 1

Step 1: synthesis of Compound 1b

To a 250 ml single-necked flask, compound 1a (10.0 g,55.5 mmol) was added, and N, N-dimethylformamide (40 ml) was added and stirred until dissolved, isopropyl bromide (8.50 g,69.1 mmol) and potassium carbonate (9.55 g,69.2 mmol) were added. The reaction solution was warmed to 80 ℃ and stirred for 2 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (200 ml. Times.2), and washed with saturated brine (100 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 1b (12 g crude). LCMS: M/z 231.1 (M+H) ⁺ 。

Step 2: synthesis of Compound 1c

To a 250 ml single-necked flask, compound 1b (12.0 g,52.2 mmol) was added under ice-water bath, and ethyl acetate (80 ml) was added and stirred until dissolved, followed by sulfamic acid (5.68 g,58.5 mmol) and water (10 ml). The reaction temperature was controlled below 20℃and 25% aqueous sodium chlorite (21.2 g,58.5 mmol) was added dropwise until the TLC was complete. Subsequently, 25% aqueous sodium hydroxide (10 ml) and 10% aqueous sodium sulfite (80.4 g,63.8 mmol) were added in this order, stirring was continued for 15 minutes, concentrated hydrochloric acid (2 ml) was added to the reaction system, and the organic phase was separated and concentrated under reduced pressure. Methanol (40 ml), water (80 ml) and 25% aqueous sodium hydroxide solution were added to the concentrated residue, and the mixture was dissolved by stirring, and concentrated hydrochloric acid was added dropwise thereto and stirred for 1 hour. Filtration and vacuum drying of the resulting filter cake gave compound 1c (6.4 g).

LCMS:m/z 245.0(M-H) ^- 。

Step 3: synthesis of Compound 1d

To a 250 ml single vial was added compound 3c (6.4 g,26 mmol) at room temperature, and acetonitrile (80 ml) was added and stirred until dissolved, followed by carbonyldiimidazole (5.1 g,31.2 mmol). The reaction mixture was stirred at room temperature for 3 hours, followed by addition of 28% aqueous ammonia, a large amount of white precipitate was formed. The mixture was filtered and the filter cake was washed to give compound 1d (6.2 g). LCMS: M/z 246.1 (M+H) ⁺ 。

Step 4: synthesis of Compound 1e

To a 100 mL single-necked flask, 1d (5.5 g,22.41 mmol), 1, 3-dichloroacetone (5.46 g,44.81 mmol) and toluene (55 ml) were added at room temperature. The reaction was warmed to 130 ℃ and stirring was continued until TLC monitored to complete the reaction. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to give Compound 1e (4.5 g), LCMS: M/z 317.9 (M+H) ⁺ 。

Step 5: synthesis of Compound 1f

To a 250 mL single vial was added compound 1e (4.5 g,14.19 mmol), potassium acetate (1.66 g,17.03 mmol) and N, N-dimethylformamide (50 mL) at room temperature. The reaction was warmed to 100 ℃ and the reaction was monitored by TLC to completion. The reaction solution was cooled to room temperature, then diluted with water (500 ml) and extracted with dichloromethane (200 ml X3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to give crude compound 1f (5.8 g).

LCMS:m/z 342.0(M+H) ⁺ 。

Step 6: synthesis of Compound 1g

To a 100 ml single-necked flask, compound 1f (5.8 g,17.0 mmol) was added at room temperature, and methanol (20 ml) and 25% aqueous sodium hydroxide solution (50 ml) were added. The reaction body fluid was heated to 100℃and stirring was continued for 3-8 hours. The reaction solution was then cooled to room temperature and filtered. The filtrate was concentrated, and the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether) to give 1g (2.55 g) of the compound. LCMS: M/z 300.0 (M+H) ⁺ 。

Step 7: synthesis of Compound 1h

To a 250 ml single-necked flask, 1g (1.5 g,5.0 mmol) of the compound was added, and tetrahydrofuran (15 ml) was added and stirred until dissolved, followed by addition of active manganese dioxide (4.3 mg,50.0 mmol). The reaction was warmed to 70 ℃ and stirring was continued until the reaction was complete as monitored by TLC. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to give compound 1H (1.36 g), CMS: M/z 298.0 (M+H) ⁺ 。

Step 8: synthesis of Compound 1i

To a 100 mL single-necked flask was added compound 1h (1.55 g,5.22 mmol), hydroxylamine hydrochloride (268 mg,5.22 mmol), sodium acetate (428 mg,5.22 mmol) and ethanol (35 ml) at room temperature, and the mixture was stirred until dissolved. The reaction solution was warmed to 85℃and stirred for 2-10 hours. Cooled to room temperature, the reaction mixture was concentrated, and the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether) to give Compound 1i (825 mg), LCMS: M/z 313.0 (M+H) ⁺ 。

Step 9: synthesis of Compound 1j

To a 100 ml single-port flask, compound 1i (823mg, 2.64 mmol) and acetic anhydride (5 ml) were added at room temperature. The reaction was warmed to 120 ℃ and stirred until LCMS monitored reaction was complete. The reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate (10 ml) was added, and extracted with dichloromethane (10 ml X3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated and the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether) to give Compound 1j (720 mg), LCMS: M/z 342.0 (M+H) ⁺ 。

Step 10: synthesis of Compound 1k

To a 25 ml three-necked flask, compound 1j (100 mg,0.34 mmol), diethyl ether (3 ml) and toluene (3 ml) were added at room temperature. The reaction solution was cooled to-78℃and tetraisopropyl titanate (0.13 ml,0.41 mmol) and ethyl magnesium bromide (0.27 ml,0.82 mmol) were added in this order, and reacted at-78℃for 10-40 minutes. Rapidly heating to room temperature. Boron trifluoride diethyl etherate (0.07 ml,0.09 mmol) was then added and the reaction stirred at room temperature until LCMS monitored to be complete. To the reaction solution was added 1 mol of diluted hydrochloric acid, followed by 1 mol of aqueous sodium hydroxide solution, extraction was performed with ethyl acetate (10 ml X3), and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated and the resulting residue was purified by column chromatography (methanol/dichloromethane) to give compound 1k (75 mg), LCMS: M/z 325.1 (M+H) ⁺ 。

Step 11: synthesis of Compound 1

To a 25 mL three-necked flask was added compound 1k (75 mg,0.23 mmol), 2-ethoxybenzoic acid (38 mg,0.23 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (132 mg,0.35 mmol), N, N-diisopropylethylamine (60 mg,0.46 mmol) and N, N-dimethylformamide (3 ml) at room temperature. The reaction was stirred at room temperature until LCMS monitored to be complete. The reaction mixture was concentrated, and the residue was subjected to high performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system) to give compound 1 (25 mg).

LCMS:m/z 473.5(M+H) ⁺

¹ H NMR(400MHz,CD ₃ OD)δ7.80-7.78(m,2H),7.67(d,J＝1.8Hz,1H),7.56(dd,J＝8.4,1.8Hz,1H),7.50–7.43(m,1H),7.23(d,J＝8.4Hz,1H),7.11(d,J＝8.4Hz,1H),7.03(t,J＝7.5Hz,1H),6.80(t,J＝74.9Hz,1H),4.77–4.66(m,1H),4.25-4.2(m,2H),1.55–1.46(m,5H),1.37(d,J＝6.0Hz,6H),1.30-1.27(m,4H).

Compound 2 was prepared according to the procedure described in example 1.

LCMS:m/z 430.1(M+H) ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.69(s,1H),8.57(d,J＝4.1Hz,1H),8.21(d,J＝7.8Hz,1H),7.89-7.87(m,1H),7.59–7.50(m,3H),7.48-7.45(m,1H),7.18(d,J＝8.3Hz,1H),6.60(t,J＝75.2Hz,1H),473-4.65(m,1H),1.59–1.55(m,2H),1.39(d,J＝6.1Hz,6H),1.35-1.32(m,2H).

Compound 3 was prepared according to the procedure described in example 1.

LCMS:m/z 444.1(M+H) ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.80(s,1H),8.40(d,J＝4.6Hz,1H),7.68–7.46(m,4H),7.34(dd,J＝7.8,4.6Hz,1H),7.18(d,J＝8.3Hz,1H),6.60(t,J＝75.3Hz,1H),4.71-4.65(m,1H),2.74(s,3H),1.57–1.52(m,2H),1.39(d,J＝6.1Hz,6H),1.33-1.29(m,2H).

Compound 4 was prepared according to the procedure described in example 1.

LCMS:m/z 431.0(M+H) ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.90(d,J＝4.9Hz,2H),8.66(s,1H),7.62(s,1H),7.58-7.53(m,2H),,7.48-7.46(m,1H),7.18(d,J＝8.3Hz,1H),6.60(t,J＝75.2Hz,1H),4.72-4.68(m,1H),1.61–1.58(m,2H),1.39(d,J＝6.1Hz,6H),1.37–1.33(m,2H).

Compound 5 was prepared according to the procedure described in example 1.

LCMS:m/z 474.1(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) delta 8.37 (s, 1H), 8.18 (d, j=8.0 hz, 1H), 7.93-7.89 (m, 2H), 7.67 (d, j=2.0 hz, 1H), 7.57 (dd, j=8.0, 2.0hz, 1H), 7.24 (d, j=8.0 hz, 1H), 6.80 (t, j=76.0 hz, 1H), 4.75-4.69 (m, 1H), 4.43 (q, j=8.0 hz, 2H), 1.58-1.54 (m, 4H), 1.38 (d, j=2.0 hz, 6H), 1.32-1.29 (m, 3H).

Compound 6 was prepared according to the procedure described in example 1.

LCMS:m/z 420.2(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) delta 8.61-8.44 (m, 2H), 7.74-7.64 (m, 2H), 7.56 (d, j=8.2 hz, 1H), 7.22 (d, j=8.3 hz, 1H), 6.79 (t, j=74.9 hz, 1H), 4.73-4.68 (m, 1H), 1.53-1.48 (m, 2H), 1.33 (d, j=6.0 hz, 6H), 1.32-1.28 (m, 2H).

Compound 7 was prepared according to the procedure described in example 1.

LCMS:m/z 433.1(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.80(s,1H),8.14(s,1H),7.87-7.86(m,2H),7.55–7.50(m,2H),7.33–6.96(m,2H),4.75-4.69(m,1H),3.85(s,3H),1.34-1.30(m,8H),1.15-1.12(m,2H).

Compound 8 was prepared according to the procedure described in example 1.

LCMS:m/z 420.1(M+H) ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.82(s,1H),7.72(s,1H),7.59-7.52(m,3H),7.24(s,1H),7.19(d,J＝8.0Hz,1H),6.61(t,J＝76.0Hz,1H),4.72-4.65(m,1H),1.57–1.55(m,2H),1.40(d,J＝8.0Hz,6H),1.36-1.33(m,2H).

Compound 9 was prepared according to the procedure described in example 1.

LCMS:m/z 448.1(M+H) ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.51(s,1H),8.39(d,J＝8.0Hz,1H),7.61(s,1H),7.59–7.43(m,4H),7.18(d,J＝8.0Hz,1H),6.60(t,J＝76.0Hz,1H),4.71-4.65(m,1H),1.56-1.53(m,2H),1.39(d,J＝8.0Hz,6H),1.35-1.32(m,2H).

Compound 10 was prepared according to the procedure described in example 1.

LCMS:m/z 477.1(M+H) ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.76(s,1H),7.58(d,J＝2.0Hz,1H),7.54(dd,J＝8.0,2.0Hz,1H),7.35-7.29(m,1H),7.19(d,J＝8.0Hz,1H),6.80-6.42(m,4H),4.70-4.67(m,1H),3.90(s,3H),1.62–1.58(m,2H),1.40(d,J＝6.1Hz,6H),1.35-1.32(m,2H).

Compound 11 was prepared according to the procedure described in example 1.

LCMS:m/z 460.1(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) delta 8.37-8.18 (m, 1H), 7.82 (s, 1H), 7.70-7.68 (m, 4H), 7.24 (d, j=8.0 hz, 1H), 6.80 (t, j=76.0 hz, 1H), 4.75-4.69 (m, 1H), 3.98 (s, 3H), 1.54-1.48 (m, 2H), 1.38 (d, j=4.0 hz, 6H), 1.33-1.29 (m, 2H).

Compound 12 was prepared according to the procedure described in example 1.

LCMS:m/z 477.1(M+H) ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.29(s,1H),8.22(dd,J＝8.8,7.2Hz,1H),7.58–7.53(m,3H),7.18(d,J＝8.4Hz,1H),6.81–6.76(m,1H),6.73-6.69(m,1H),6.60(d,J＝75.2Hz,1H),4.71-4.65(m,1H),3.99(s,3H),1.55-1.53(m,2H),1.39(d,J＝6.4Hz,6H),1.29–1.26(m,2H).

Compound 13 was prepared according to the procedure described in example 1.

LCMS:m/z 464.1(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) delta 8.58 (s, 1H), 8.05 (d, j=8.4 hz, 1H), 7.90 (s, 1H), 7.69 (d, j=2.0 hz, 1H), 7.58 (dd, j=8.4, 2.0hz, 2H), 7.24 (d, j=8.4 hz, 1H), 6.79 (t, j=74.8 hz, 1H), 4.76-4.70 (m, 1H), 1.55-1.52 (m, 2H), 1.38 (d, j=6.0 hz, 6H), 1.36-1.33 (m, 2H).

Compound 14 was prepared according to the procedure described in example 1.

LCMS:m/z 466.1(M+H) ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ8.34(s,1H),8.30(d,J＝2.0Hz,1H),7.60(s,1H),7.57(d,J＝1.6Hz,1H),7.53(d,J＝8.4,2.0Hz,1H),7.37–7.31(m,1H),7.19(d,J＝8.4Hz,1H),6.60(t,J＝75.2Hz,2H),4.71-4.65(m,1H),1.54-1.53(m,2H),1.43(d,J＝6.0Hz,6H),1.34–1.30(m,2H).

Compound 15 was prepared according to the procedure described in example 1.

LCMS:m/z 433.0(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ9.07(s,1H),7.92(s,1H),7.55(d,J＝1.8Hz,1H),7.51(dd,J＝8.4,1.8Hz,1H),7.36(s,1H),7.30(d,J＝8.0Hz,1H),7.14(t,J＝74.0Hz,1H),6.99(d,J＝1.2Hz,1H),4.76–4.70(m,1H),3.93(s,3H),1.34-1.28(m,8H),1.24–1.21(m,2H).

Compound 16 was prepared according to the procedure described in example 1.

LCMS:m/z 436.1(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ9.19(d,J＝2.0Hz,1H),9.16(s,1H),8.35(d,J＝2.0Hz,1H),7.90(s,1H),7.55(d,J＝2.0Hz,1H),7.51(dd,J＝8.4,2.0Hz,1H),7.30(d,J＝8.4Hz,1H),7.14(t,J＝74.0Hz,1H),4.76–4.70(m,1H),1.37-1.34(m,2H),1.31(d,J＝6.0Hz,6H),1.26-1.23(m,2H).

Compound 17 was prepared according to the procedure described in example 1.

LCMS:m/z 450.1(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.99(s,1H),8.92(s,1H),7.89(s,1H),7.58(s,1H),7.53–7.47(m,1H),7.35–6.88(m,2H),4.82–4.59(m,1H),2.74(s,3H),1.35-1.30(m,8H),1.23-1.21(m,2H).

Step 1: synthesis of intermediate 18b

To a 500mL single-necked flask, 18a (20 g,99.8 mmol) and N, N-dimethylformamide (300 mL) were added and stirred at room temperature until dissolved. N-bromosuccinimide (19.6 g,110.1 mmol) was added in portions to the reaction solution. The reaction solution was stirred at room temperature for 3 hours. LCMS monitored, reaction was complete. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL. Times.3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by flash column chromatography (ethyl acetate/petroleum ether) to give the objective compound 18b (25.5 g).

¹ H NMR(400MHz,CDCl ₃ )δ7.42-7.38(m,6H),7.06(d,J＝2.2Hz,1H),7.01(dd,J＝8.4,2.2Hz,1H),6.82(d,J＝8.4Hz,1H),5.07(s,2H).

Step 2: synthesis of intermediate 18c

18b (25.5 g,91.3 mmol), diethyl bromodifluoromethylphosphonate (48.8 g,182.7 mmol) and acetonitrile (300 mL) were added sequentially to a 500mL single vial at room temperature and stirred until dissolved. To the reaction solution was slowly added dropwise a solution of potassium hydroxide (25.7 g,458.1 mmol) in water (100 mL). The reaction solution was stirred at room temperature for 18 hours. TLC monitoring, reaction was complete. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL. Times.3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether) to give 18c (14.5 g).

¹ H NMR(400MHz,CDCl ₃ )δ7.46–7.30(m,6H),7.16(d,J＝1.8Hz,1H),7.08–7.01(m,1H),6.53(t,J＝74.8Hz,1H),5.10(s,2H).

Step 3: synthesis of intermediate 18d

18c (14.5 g,44.0 mmol), 4, 5-tetramethyl-2- (tetramethyl-1, 3, 2-dioxaborane-2-yl) -1,3, 2-dioxaborane (16.8 g,66.1 mmol) and dioxane (250 mL) were added sequentially to a 500mL single-necked flask at room temperature and stirred until dissolved. To the reaction solution were added potassium acetate (8.7 g,88.6 mmol) and bis [5- (diphenylphosphino) cyclopent-1, 3-dien-1-yl ] iron palladium dichloride (1 g,1.3 mmol). The reaction solution was stirred for 18 hours at 90℃under nitrogen. LCMS monitored, reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (150 mL. Times.3), and the organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to give the objective compound 18d (14.1 g).

LCMS:m/z 375.2(M-H) ⁺ 。

Step 4: synthesis of intermediate 18e

To a 50mL single-necked flask, 18d (13.5 g,35.8 mmol) and dioxane (240 mL) and water (80 mL) were added and stirred at room temperature until dissolved. To the reaction solution were added ethyl 2-chloro-1, 3-oxazole-4-carboxylate (6 g,34.1 mmol), bis [5- (diphenylphosphino) cyclopent-1, 3-dien-1-yl ] iron palladium dichloride (1.3 g,1.7 mmol) and potassium phosphate (16.6 g,72.086 mmol) in this order. The reaction solution was reacted at 70℃for 18 hours under nitrogen protection. LCMS monitored, reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (80 mL), extracted with ethyl acetate (100 mL. Times.3), and the organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to give the objective compound 18e (8.2 g).

¹ H NMR(400MHz,CDCl ₃ )δ8.26(s,1H),7.84(d,J＝2.0Hz,1H),7.70-7.68(m,1H),7.47-7.33(m,5H),7.41(d,J＝7.6Hz,1H),6.64(t,J＝74.8Hz,1H),5.21(s,2H),4.43(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H).

Step 5: synthesis of intermediate 18f

To a 50mL single-necked flask, 18e (8 g,20.5 mmol) and methanol (80 mL) were added and stirred at room temperature until dissolved. To the reaction solution was added 7M methanolic ammonia (80 mL,560 mmol). The reaction solution was stirred at 60℃for 18 hours. LCMS monitored, reaction was complete. The reaction solution was filtered and concentrated. The target compound 17q (6.9 g) was obtained.

LCMS:m/z 361.3(M+1) ⁺ 。

Step 6: synthesis of intermediate 18g

To a 50mL single-necked flask, 18f (6.9 g,19.1 mmol) and methylene chloride (50 mL) were added and stirred at room temperature until dissolved. To the reaction solution was added a Buerger reagent (9.1 g,38.2 mmol). The reaction solution was stirred at room temperature for 18 hours. LCMS monitored, reaction was complete. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (50 mL. Times.3), and the organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to give 18g (4.9 g) of the objective compound.

LCMS:m/z 343.2(M+H) ⁺ 。

Step 7: synthesis of intermediate 18h

To a 50mL three-necked flask, 18g (500 mg,1.4 mmol) of a mixed solvent of toluene (10 mL) and diethyl ether (10 mL) was added at room temperature, and the mixture was stirred until dissolved. The reaction solution was cooled to-78℃and titanium tetraisopropoxide (0.5 mL,1.7 mmol) and 3M ethyl magnesium bromide (1.2 mL,3.6 mmoL) were added to the reaction solution. The reaction mixture was stirred at-78℃for 30 minutes, then warmed to room temperature, and stirred for 1 hour. To the reaction solution was added boron trifluoride diethyl etherate (0.01 mL,0.07 mmol). The reaction solution was stirred for 2 hours. LCMS monitored, reaction was complete. To the system was added 1M hydrochloric acid (10 mL) for dilution, and the pH was adjusted to 10 with 1M sodium hydroxide solution, and the mixture was extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (methanol/dichloromethane) to give the objective compound 18h (458 mg).

LCMS:m/z 373.1(M+H) ⁺ 。

Step 8: synthesis of intermediate 18i

To a 50mL single-necked flask was successively added 18H (600 mg,1.61 mmol), 1-methyl-1H-imidazole-2-carboxylic acid (203 mg,1.61 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.23 g,3.23 mmol), N, N-diisopropylethylamine (416 mg,3.23 mmol) and N, N-dimethylformamide (10 mL) at room temperature, followed by stirring until dissolved. The reaction solution was stirred at room temperature and reacted for 6 hours. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (20 mL. Times.3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate/petroleum ether) to give 18i (499 mg).

LCMS m/z 480.6(M+H) ⁺ 。

Step 9: synthesis of intermediate 18j

To a 25 mL three-necked flask, 18i (499 mg,1.04 mmol) and absolute methanol (10.0 mL) were added and stirred at room temperature until completely dissolved. To the reaction solution was added 10% palladium on carbon (40 mg). The reaction solution was stirred at room temperature under a hydrogen balloon for 16 hours. LCMS monitored, reaction was complete. The reaction solution was filtered, and the filtrate was concentrated to give the objective compound 18j (368 mg).

LCMS:m/z 391.1(M+H) ⁺ 。

Step 10: synthesis of Compound 18

18j (100 mg,0.26 mmol), (S) -tetrahydrofuran-3-ol (22.56 mg,0.26 mmol), triphenylphosphine (100.79 mg,0.38 mmol) and tetrahydrofuran (5 mL) were added sequentially to a 25 mL three-necked flask at room temperature and stirred until dissolved. Diisopropyl azodicarboxylate (93.57 mg,0.41 mmol) was added to the reaction solution. The reaction solution was stirred at room temperature for 16 hours. LCMS monitored, reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to give the objective compound 18 (8.45 mg).

LCMS:m/z 461.1(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) delta 7.82 (s, 1H), 7.59 (d, j=1.6 hz, 1H), 7.59 (d, j=8.4 hz, 1H), 7.40 (s, 1H), 7.25 (d, j=8.4 hz, 1H), 7.24 (s, 1H), 6.80 (t, j=74.8 hz, 1H), 5.17-5.15 (m, 1H), 4.03 (s, 3H), 4.02-3.96 (m, 3H), 3.93-3.88 (m, 1H), 2.35-2.25 (m, 1H), 2.20-2.14 (m, 1H), 1.52-1.48 (m, 2H), 1.35-1.31 (m, 2H).

Compound 19 was prepared according to the methods described in example 18.

LCMS:m/z 461.1(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) delta 7.84 (s, 1H), 7.65 (s, 1H), 7.61 (d, j=8.4 hz, 1H), 7.44 (s, 1H), 7.27 (d, j=8.4 hz, 2H), 6.80 (t, j=74.8 hz, 1H), 5.17-5.16 (m, 1H), 4.05 (s, 3H), 4.02-3.96 (m, 3H), 3.93-3.88 (m, 1H), 2.35-2.29 (m, 1H), 2.20-2.14 (m, 1H), 1.52-1.49 (m, 2H), 1.35-1.32 (m, 2H).

Compound 20 was prepared according to the methods described in example 18.

LCMS:m/z 447.1(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) delta 7.78 (s, 1H), 7.62 (dd, J=8.4, 1.8Hz, 1H), 7.30-7.28 (m, 2H), 7.24 (s, 1H), 7.07-6.70 (m, 2H), 5.48-5.36 (m, 1H), 5.06 (t, J=6.8 Hz, 2H), 4.77-4.74 (m, 2H), 4.00 (s, 3H), 1.50-1.47 (m, 2H), 1.32-1.29 (m, 2H).

Step 1: synthesis of intermediate 21a

To a 25mL single vial was added 18h (620 mg,1.67 mmol), thiazole-4-carboxylic acid (215 mg,1.67 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (760 mg,2.00 mmol), N, N-diisopropylethylamine (431 mg,3.34 mmol) and N, N-dimethylformamide (10 mL) in sequence at room temperature. The reaction solution was stirred at 20℃for 6 hours. LCMS monitored, reaction was complete. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (20 mL. Times.3). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was subjected to column chromatography (petroleum ether/ethyl acetate) to give 21a (483 mg).

LCMS:m/z:484.0(M+H) ⁺ 。

Step 2: synthesis of intermediate 21b

21b (200 mg,0.41 mmol), trimethyliodosilane (331 mg,1.65 mmol) and acetonitrile (4 mL) were added sequentially to a 25mL single-necked flask at room temperature and stirred until dissolved. The reaction solution was stirred at 60℃for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (50 mL), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and the residue was purified by prep plate chromatography to give 21c (86 mg).

LCMS:m/z 394.0(M+H) ⁺ 。

Step 3: synthesis of Compound 21

21c (40 mg,0.11 mmol), (S) -tetrahydrofuran-3-ol (35.2 mg,0.41 mmol), triphenylphosphine (107 mg,0.41 mmol) and tetrahydrofuran (5 mL) were added sequentially to a 25mL three-necked flask at room temperature and stirred until dissolved. Diisopropyl azodicarboxylate (82.2 mg,0.408 mmol) was added to the reaction solution. The reaction solution was stirred at room temperature for 16 hours. LCMS monitored, reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to give the objective compound 21 (9.37 mg).

LCMS:m/z 464.2(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) delta 9.02 (d, j=2.0 hz, 1H), 8.29 (d, j=2.0 hz, 1H), 7.74 (s, 1H), 7.66 (d, j=2.0 hz, 1H), 7.60 (dd, j=8.4, 2.0hz, 1H), 7.26 (d, j=8.4 hz, 1H), 6.80 (t, j=74.4 hz, 1H), 5.18-5.16 (m, 1H), 4.02-3.88 (m, 4H), 2.32-2.26 (m, 1H), 2.18-2.16 (m, 1H), 1.53-1.50 (m, 2H), 1.35-1.32 (m, 2H).

Compound 22 was prepared according to the procedure described in example 21.

LCMS:m/z 464.0(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) delta 9.02 (d, j=2.0 hz, 1H), 8.29 (d, j=2.0 hz, 1H), 7.74 (s, 1H), 7.66 (d, j=2.0 hz, 1H), 7.60 (dd, j=8.4, 2.0hz, 1H), 7.26 (d, j=8.4 hz, 1H), 6.80 (t, j=74.4 hz, 1H), 5.18-5.17 (m, 1H), 4.03-3.88 (m, 4H), 2.35-2.26 (m, 1H), 2.19-2.14 (m, 1H), 1.53-1.50 (m, 2H), 1.34-1.32 (m, 2H).

Compound 23 was prepared according to the procedure described in example 21.

LCMS:m/z 450.0(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) delta 9.02 (d, j=1.6 hz, 1H), 8.29 (d, j=2.0 hz, 1H), 7.73 (s, 1H), 7.62 (dd, j=8.4, 1.6hz, 1H), 7.29-7.28 (m, 2H), 6.88 (t, j=74.0 hz, 1H), 5.42-5.38 (m, 1H), 5.05 (t, j=6.8 hz, 2H), 4.76-4.73 (m, 2H), 1.51-1.49 (m, 2H), 1.34-1.32 (m, 2H).

Compound 24 was prepared according to the methods described in example 21.

LCMS:m/z:501.2(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) delta 7.80-7.78 (m, 2H), 7.65 (s, 1H), 7.61 (dd, j=8.4, 2.0hz, 1H), 7.48-7.45 (m, 1H), 7.27 (d, j=8.0 hz, 1H), 7.12 (d, j=8.4 hz, 1H), 7.04 (t, j=7.6 hz, 1H), 6.80 (t, j=74.8 hz, 1H), 5.18-5.17(m,1H),4.23(q,J＝7.0Hz,2H),4.08-3.95(m,3H),3.91-3.88(m,1H),2.33-2.28(m,1H),2.19-2.15(m,1H),1.53-1.50(m,5H),1.30-1.28(m,2H).

Compound 25 was prepared according to the procedure described in example 21.

LCMS:m/z 472.1(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) delta 9.06 (s, 1H), 7.76 (d, j=7.6 hz, 1H), 7.66 (s, 1H), 7.53 (d, j=8.4 hz, 1H), 7.47 (t, j=8.4 hz, 1H), 7.24 (d, j=8.4 hz, 1H), 7.11 (d, j=8.4 hz, 1H), 7.07 (s, 1H), 7.04 (t, j=7.6 hz, 1H), 6.79 (t, j=74.8 hz, 1H), 4.73-4.67 (m, 1H), 4.21 (q, j=7.2 hz, 2H), 1.54-1.51 (m, 2H), 1.48 (t, j=8.0 hz, 3H), 1.42-1.39 (m, 2H), 1.37 (d, j=7.6 hz, 1H)

Compound 26 was prepared according to the methods described in example 21.

LCMS:m/z 432.1(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) delta 7.66 (d, j=2.0 hz, 1H), 7.53 (dd, j=8.0, 1.6hz, 1H), 7.27 (s, 1H), 7.23 (d, j=8.4 hz, 1H), 7.06-7.05 (m, 2H), 6.80 (t, j=74.8 hz, 1H), 4.72-4.70 (m, 1H), 4.00 (s, 3H), 1.53-1.49 (m, 2H), 1.43-1.39 (m, 2H), 1.37 (d, j=6.4 hz, 6H).

Compound 27 was prepared according to the methods described in example 21.

LCMS:m/z 435.1(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) δ9.02 (d, j=2.0 hz, 1H), 8.31 (d, j=2.0 hz, 1H), 7.65 (d, j=2.0 hz, 1H), 7.52 (dd, j=8.4, 2.0hz, 1H), 7.23 (d, j=8.4 hz, 1H), 7.03 (s, 1H), 6.79 (t, j=74.8 hz, 1H), 4.74-4.68 (m, 1H), 1.54-1.51 (m, 2H), 1.45-1.41 (m, 2H), 1.37 (d, j=6.0 hz, 6H).

Compound 28 was prepared according to the procedure described in example 1.

LCMS:m/z:459.1(M+H) ⁺ 。

¹ H NMR (400 MHz, deuterated methanol-d 4) δ9.03 (s, 1H), 7.79-7.78 (m, 2H), 7.67 (d, j=2.0 hz, 1H), 7.57 (dd, j=8.0, 2.0hz, 1H), 7.49-7.45 (m, 1H), 7.23 (d, j=8.0 hz, 1H), 7.12 (d, j=8.0 hz, 1H), 7.04 (t, j=8.0 hz, 1H), 6.82 (t, j=76.0 hz, 1H), 4.26-4.16 (m, 4H), 1.53-1.44 (m, 8H), 1.30-1.27 (m, 2H).

Biological evaluation

The following further description explains the present disclosure in connection with test examples, which are not meant to limit the scope of the present disclosure.

The structure of the compound A is as follows:

compound a was prepared using the procedure disclosed in patent application "CN104603116a, page 25, example 1".

Test example 1: in vitro PDE4B enzyme Activity assay

1. Experimental materials

Name of the name	Branding	Goods number/model
PDE4B1	BPS	60041
Trequinsin	T℃RIS	2337/10
IMAP FP IPP Explorer Kit	Molecular Device	R8124
FAM-cAMP	Molecular Device	R7506
OptiPlate ^TM -384 F black assay plate	PerkinElmer	6007279
384 well Echo plate	Labcyte	PP-0200

2. Experimental procedure

For compound testing, stock solutions of compound at a concentration of 10mM were first prepared in test tubes in 90% DMSO (10% water) and used to prepare serial dilutions with a dilution gradient of 1:5, starting at a final concentration of 100uM,as low as 0.05nM. For enzyme assays, 0.2ul of compound solution was transferred to 384 well reaction plates, and both negative and positive controls were transferred to 0.2ul of 100% dmso. 10ul of 2-fold concentration PDE4B1 enzyme solution (final concentration 0.04 nM) was then added to the wells, and for the no enzyme activity control wells, 10ul of 1-fold reaction buffer was used in place of the enzyme solution. Centrifuge at 1000rpm for 1min and incubate at room temperature for 15 min. Next, 10ul of a 2-fold FAM-cAMP substrate solution (substrate final concentration of 0.1. Mu.M) was added to each well of 384-well reaction plate, centrifuged at 1000rpm for 1min, and reacted at 25℃for 30 minutes. After the reaction, 60ul of reaction stop solution was added to each well of 384-well reaction plate to stop the reaction, and the reaction was incubated at room temperature for 60 minutes under shaking at 600rpm in the dark. After incubation, RLU data are read and inhibition rate is calculated, and IC is calculated according to concentration and inhibition rate fitting curve ₅₀ Values, where maximum refers to the read of DMSO control and minimum refers to the read of no enzyme activity control.

Examples of the disclosure inhibition of PDE4B1 enzyme activity in vitro was determined by the above assay, IC measured ₅₀ The values are shown in Table 1.

Numbering device

PDE4B1/IC ₅₀ (nM)

Numbering device

PDE4B1/IC ₅₀ (nM)

Compound 1	29	Compound 2	139
Compound 3	67	Compound 4	NA
Compound 5	NA	Compound 6	138
Compound 7	NA	Compound 8	NA
Compound 9	194	Compound 10	NA
Compound 11	NA	Compound 12	NA
Compound 13	NA	Compound 14	NA
Compound 15	19.5	Compound 16	16.5
Compound 17	43	Compound 18	17
Compound 19	115.3	Compound 20	40
Compound 21	21	Compound 22	153
Compound 23	103	Compound 24	30
Compound 25	60.36	Compound 26	71
Compound 27	64	Compound 28	96
Compound A	31.78

Note that: N/A undetected

Test example 2: inhibition of release of Peripheral Blood Mononuclear Cell (PBMC) pro-inflammatory cytokines by compounds

Thawing frozen PBMC and trypan blue staining to detect cell viability and number. The thawed PBMC were washed with RPMI1640 complete medium (RPMI 1640+10% FBS+1% PS), centrifuged and the supernatant was discarded. PBMC were resuspended in RPMI1640 complete medium to adjust cell density to 2X 10 ⁶ cells/mL. Spread 2X 10 ⁵ PBMC cells are added with compounds to be tested in different concentrations into a 96-well cell culture plate, and 9-concentration gradient dilutions are performed according to the ratio of 1:5 from the maximum concentration of the compounds to 100 mu M, so that double-well detection is performed. LPS was added at a final concentration of 0.1ng/mL in a total volume of 200. Mu.L. Negative and positive controls were set, LPS alone and DMSO at final concentration were added to the negative control wells, and 1. Mu.g/mL dexamethasone was added as a positive control in addition to cells and LPS to the positive control wells. Cells were incubated in a 37 degree incubator for 24 hours. After completion of incubation, 100. Mu.L of cell culture supernatant was collected and the levels of TNF-. Alpha.were detected by ELISA. To the remaining cells per well, 100. Mu.L CellTiter-Glo was added and the level of cell viability was measured. Calculation of compounds for inhibition of TNF-alpha Release ₅₀ Values.

Examples of the disclosure inhibition of PBMC pro-inflammatory cytokine release in vitro was determined by the above assay, IC measured ₅₀ The values are shown in Table 2.

TABLE 2

Numbering device	PBMC/IC ₅₀ (nM)	Numbering device	PBMC/IC ₅₀ (nM)
Compound 1	164	Compound 15	173.48
Compound 16	161.66	Compound 18	98.87
Compound 21	12.01	Compound 24	76.47

Compound A

213

Test example 3Allergic dermatitis inhibition experiment

An appropriate amount of compound 21 was taken and formulated into an ointment of the following composition: 1% of compound 21, 10% of glyceryl triacetate, 62.5% of white vaseline, 20% of liquid paraffin, 3% of paraffin and 3.5% of white beeswax, and mechanically stirring to obtain ointment

Molding and drug administration:

after the fixed position of the left ear of the experimental mouse is measured to be thick (MDC-1"SB,Mitutoyo Corporation) on the day of the experiment, 20 mu L (12-) phorbol myristate (-13-) acetate (PMA, P1585, sigma) and acetone solution (2 ug/ear) are coated on the left ear for the first 2 hours and 15 minutes, 10mg of a test object or a positive medicine or a blank preparation, namely 20 mg/ear, are respectively coated on the inner side and the outer side of the left ear. Ear thickness was measured 6 hours after PMA application. The experiment was performed in a normal control group, a model control group, a low, medium and high dose group and a reference compound group.

Evaluation index: changes in ear thickness after PMA induced ear swelling for 6 hours ([ IC-IT ]/IC X100%, IC and IT are the increase in ear thickness (mm) of mice in control and treatment groups, respectively) as an inflammation index; changes in body weight after 24 hours of PMA induction are used as indicators of systemic toxic and side effects.

Experimental results: compound 21 can inhibit PMA-induced ear swelling in mice in a dose-dependent manner, and the inhibition rate of the three low, medium and high dose groups is significantly higher than that of the model group, and the ear swelling inhibition rates are 36.7±14.5%,81.0% ±18.5% and 93.9±5.9% (mean±sd) respectively. The low and high doses of reference compound a also inhibited ear swelling in PMA-induced mice, with low and high dose group ear swelling inhibition rates of 12.7% ± 16.2% and 45.3% ± 23.0% (mean ± SD), respectively.

The above results demonstrate that compound 21 has better therapeutic effects on PMA-induced skin inflammation models than the reference compound a.

Claims

Compounds of formula I or pharmaceutically acceptable salts thereof

Wherein R is ¹ Selected from aryl or heteroaryl groups, saidAryl or heteroaryl is optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, nitro, cyano, amino, alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy, and/or the aryl or heteroaryl is fused to cycloalkyl or heterocycloalkyl, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring being optionally substituted with one or more R ^A1 Substituted;

R ^A1 Selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, aryl or 5-to 6-membered heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino;

R ² selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, cycloalkenyloxy, -SR', -S (O) ₂ R ', -NR ' (R "), -COR ', -COOR ', or-CONR ' (R '), said alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy, or cycloalkenyloxy being optionally substituted with one or more R ' s ^A2 Substituted;

R ^A2 selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl, C _3-6 Cycloalkyl group,3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, C _6-10 Aryl or 5-to 6-membered heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, C _6-10 Aryl or 5-to 6-membered heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino;

ring A is selected from 5 membered heteroaromatic rings optionally substituted with one or more R ^A3 Substituted and R is ¹ In meta position on ring a with ring B;

R ^A3 selected from halogen, deuterium, hydroxy, nitro, cyano, amino, and C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group or a 3-to 6-membered heterocycloalkoxy group, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy optionally being substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino;

ring B is selected from 3-to 6-membered carbocycle or heterocycle, said ring B optionally being substituted with one or more R ^A4 Substituted;

R ^A4 selected from halogen, deuterium, hydroxy, nitro, cyano, amino, and C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group or a 3-to 6-membered heterocycloalkoxy group, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy optionally being substituted by one or more groups selected from halogen, deuterium, hydroxyOxo, nitro, cyano, amino;

Y ¹ selected from the group consisting of bond, -C (=O) -, -C (=O) N (R) ³ )-、-N(R ⁴ )C(＝O)-、-S(O) _n -、-S(O) _m N(R ³ ) -or-N (R) ⁴ )S(O) _m -，R ³ Or R is ⁴ Independently selected from hydrogen, deuterium or C _1-6 Alkyl, n and m are each independently selected from integers from 0 to 2;

r 'or R' is independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, or amino.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from C _6-10 Aryl or 5-to 10-membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 3-to 6-membered heterocycloalkoxy or C _3-6 Substituted by cycloalkenyloxy, and/or the aryl or heteroaryl is fused to a 3-to 10-membered cycloalkyl or 3-to 10-membered heterocycloalkyl, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring being optionally substituted by one or more R ^A1 Substituted, R ^A1 As defined in claim 1.
A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from C _6-10 Aryl optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 3-to 6-membered heterocycloalkoxy or C _3-6 Substituted by cycloalkenyloxy, and/or the aryl is fused to a 3 to 10 membered cycloalkyl or 3 to 10 membered heterocycloalkyl, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring being optionally substituted by one or more R ^A1 Substituted, R ^A1 As defined in claim 1.
A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from C _6-10 Aryl optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl or C _3-6 Substituted by cycloalkenyloxy and/or the aryl is fused to a 3-to 10-membered cycloalkyl, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or the fused ring being optionally substituted by one or more R ^A1 Substituted, R ^A1 As defined in claim 1.
A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from C _6-10 Aryl optionally substituted with one or more substituents selected from C _1-6 Alkoxy, C _3-6 Substituted with a cycloalkoxy or a 3-to 6-membered heterocycloalkoxy and/or the aryl is fused with a 3-to 10-membered heterocycloalkyl, the alkoxy, cycloalkoxy or fused ring optionally being substituted with one or more R ^A1 Substituted, R ^A1 As defined in claim 1.
A compound or pharmaceutically acceptable salt thereof according to any one of claim 1 to 3,wherein R is ¹ Selected from C _6-10 Aryl optionally substituted with one or more groups selected from deuterium, halogen, hydroxy or amino.
A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from

Wherein R is ⁶ 、R ⁷ 、R ⁸ 、R ⁹ Or R is ¹⁰ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, and C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 3-to 6-membered heterocycloalkoxy or C _3-6 Substituted with cycloalkenyloxy, said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl, heterocycloalkoxy or heterocycloalkylyl being optionally substituted with one or more R ^A1 Substituted or R ⁶ 、R ⁷ Forms a 5-to 10-membered carbocyclic ring or a 5-to 10-membered heterocyclic ring with adjacent carbon atoms, said carbocyclic ring or heterocyclic ring optionally being substituted with one or more R ^A1 Substituted, R ^A1 As defined in claim 1.
The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R ⁸ Selected from hydrogen, deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined in claim 1.
The process of claim 7 or 8A compound or pharmaceutically acceptable salt thereof, wherein R ⁸ Selected from C _1-6 Alkoxy, said alkoxy optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined in claim 1.
The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R ⁸ Selected from C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 3-to 6-membered heterocycloalkoxy or C _3-6 Cycloalkenyloxy, said alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl, heterocycloalkoxy or heterocycloalkyl being optionally substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined in claim 1.
The compound of any one of claims 7-10, or a pharmaceutically acceptable salt thereof, wherein R ⁶ Selected from hydrogen, deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 R is as defined in claim 1 ⁶ Hydrogen or deuterium is preferred.
The compound of any one of claims 7-11, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ Selected from hydrogen, deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 R is as defined in claim 1 ¹⁰ Hydrogen or deuterium is preferred.
The compound of any one of claims 7-12, or a pharmaceutically acceptable salt thereof, wherein R ⁷ Selected from hydrogen, deuterium, halogen, hydroxy, C _1-6 Alkyl or C _1-6 Alkoxy groupThe alkyl or alkoxy is optionally substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined in claim 1.
The compound of any one of claims 7-13, or a pharmaceutically acceptable salt thereof, wherein R ⁷ Selected from C _1-6 Alkoxy, said alkoxy optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined in claim 1.
The compound of any one of claims 7-12, or a pharmaceutically acceptable salt thereof, wherein R ⁷ Selected from C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 3-to 6-membered heterocycloalkoxy or C _3-6 Cycloalkenyloxy, said alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkyl, heterocycloalkoxy or heterocycloalkyl being optionally substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined in claim 1.
The compound of any one of claims 7-12, or a pharmaceutically acceptable salt thereof, wherein R ⁷ Selected from 3 to 6 heterocycloalkoxy groups, preferably containing at least one heteroatom selected from N, O or S, said heterocycloalkoxy group optionally being substituted with 1 to 3R ^A1 Substituted, R ^A1 As defined in claim 1.
The compound of any one of claims 7-16, or a pharmaceutically acceptable salt thereof, wherein R ⁶ 、R ⁹ Or R is ¹⁰ Selected from hydrogen or deuterium.
The compound of any one of claims 7-17, or a pharmaceutically acceptable salt thereof, wherein R ⁶ 、R ⁷ Forming a 5-to 10-membered heterocyclic ring with adjacent carbon atoms, said heterocyclic ring optionally being substituted1 to 3R ^A1 Substituted, R ^A1 As defined in claim 1.
A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from 5 to 10 membered heteroaryl, optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy radicals C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, 3-to 6-membered heterocycloalkoxy or C _3-6 Substituted by cycloalkenyloxy, and/or the aryl is fused to a 3 to 10 membered cycloalkyl or 3 to 10 membered heterocycloalkyl, the alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy or fused ring being optionally substituted by one or more R ^A1 Substituted, R ^A1 As defined in claim 1.
The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein Y ¹ Selected from-C (=O) N (R) ³ ) -or-N (R) ⁴ )C(＝O)-，R ³ Or R is ⁴ Independently selected from hydrogen, deuterium or C _1-6 An alkyl group.
The compound of claim 1 or 20, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from
The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R ² Selected from C _6-10 Aryl or 5-to 9-membered heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen,Hydroxy, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-6 heterocycloalkoxy, C _3-8 Cycloalkenyloxy, -SR', -S (O) ₂ R ', -NR' (R '), -COR', -COOR 'or-CONR' (R '), said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy being optionally substituted with one or more R' s ^A2 Substituted, R' and R ^A2 As defined in claim 1.
The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R ² Selected from C _6-10 Aryl optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-6 heterocycloalkoxy, C _3-8 Cycloalkenyloxy, -SR', -S (O) ₂ R ', -NR' (R '), -COR', -COOR 'or-CONR' (R '), said alkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, heterocycloalkoxy or cycloalkenyloxy being optionally substituted with 1 to 3R' s ^A2 Substituted, R' and R ^A2 As defined in claim 1.
The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein R ² Selected from C _6-10 Aryl optionally substituted with 1 to 3 groups selected from deuterium, halogen, hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy or C _3-6 Substituted with cycloalkoxy, said alkyl, alkoxy or cycloalkoxy optionally being 1 to 3R ^A2 Substituted, R ^A2 As defined in claim 1; further, R ² Preferably from phenyl groups, said phenyl groups being substituted with 1 to 3 groups selected from deuterium,Halogen, hydroxy, C _1-6 Alkyl or C _1-6 Alkoxy optionally substituted, said alkyl or alkoxy being optionally substituted with 1 to 3R ^A2 Substituted, R ^A2 As defined in claim 1.
The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein R ² Selected from 5 to 9 membered heteroaryl groups optionally substituted with 1 to 3 groups selected from deuterium, halogen, hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy or C _3-6 Substituted with cycloalkoxy, said alkyl, cycloalkyl, alkoxy or cycloalkoxy optionally being substituted with 1 to 3R ^A2 Substituted, R ^A2 As defined in claim 1.
The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R ² Selected from:

further said R ² Optionally 1 to 3 groups selected from deuterium, halogen, hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl, C _1-6 Alkoxy or C _3-6 Substituted with cycloalkoxy.
The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from

Preferably
Further, the ring A ring is optionally substituted with one or more R ^A3 Substituted, R ^A3 As defined in claim 1.
The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from
A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 3 to 6 membered carbocycles, preferably
The ring B being optionally substituted with one or more R ^A4 Substituted.
The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from

Where p=an integer between 0 and 3, preferably p=0, 1 or 2, more preferably p=0.
The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R ^A1 Selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereofR in (B) ^A1 Selected from hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R ^A1 Selected from phenyl or 5-to 6-membered heteroaryl optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R ^A2 Selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R ^A2 Selected from hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R ^A3 Selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R ^A3 Selected from hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein R ^A4 Selected from halogen, deuterium, nitro or cyano, preferably halogen, such as fluorine.
The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein R ^A4 Selected from hydroxy, C _1-6 Alkyl, C _3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R ² Selected from 5-to 6-membered heteroaromatic rings, preferably from thiazolyl, imidazolyl, pyridinyl, oxazolyl, pyrimidinyl or pyrazolyl, further said R ² Optionally by one or more groups selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with one or more R ^A2 Substituted, R ^A2 As defined in claim 1.
A compound according to claim 40, or a pharmaceutically acceptable salt thereof, wherein R ² Selected from thiazolyl groups optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with one or more R ^A2 Substituted, R ^A2 As in claim 1Defined as follows.
A compound according to claim 40, or a pharmaceutically acceptable salt thereof, wherein R ² Selected from imidazolyl optionally substituted with one or more groups selected from deuterium, halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with one or more R ^A2 Substituted, R ^A2 As defined in claim 1.
The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from

Wherein R is ¹⁶ Or R is ¹⁷ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, and C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy optionally being substituted with one or more R ^A5 Substituted, R ^A5 Selected from halogen, deuterium, hydroxy, nitro, cyano, amino, and C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group or a 3-to 6-membered heterocycloalkoxy group, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
The compound of claim 43, wherein the compound of formula I is selected from the group consisting of
The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from

Wherein R is ¹⁸ Or R is ¹⁹ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, and C _1-6 Alkyl or C _1-6 Alkoxy, R ²⁰ Selected from hydrogen, deuterium or C _1-6 Alkyl, said alkyl or alkoxy optionally being substituted with one or more R ^A6 Substituted, R ^A6 Selected from halogen, deuterium, hydroxy, nitro, cyano, amino, and C _1-6 Alkyl, C _3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _1-6 Alkoxy, C _3-6 A cycloalkoxy group or a 3-to 6-membered heterocycloalkoxy group, said C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 The cycloalkoxy or 3-to 6-membered heterocycloalkoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, amino.
The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from
Compounds of formula I or pharmaceutically acceptable salts thereof

Preferably:
a pharmaceutical composition comprising at least one therapeutically effective amount of a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A method of preventing and/or treating a patient suffering from a PDE-related disorder by administering to the patient a therapeutically effective amount of a compound as defined in any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 48.
A method of preventing and/or treating a patient suffering from asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative enteritis, or rheumatism by administering to the patient a therapeutically effective amount of a compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 48.
Use of a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, in the manufacture of a medicament for the prophylaxis and/or treatment of a PDE-related condition.
Use of a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, in the manufacture of a medicament for the prophylaxis and/or treatment of asthma, obstructive pulmonary disease, sepsis, nephritis, diabetes, allergic rhinitis, allergic conjunctivitis, ulcerative colitis, or rheumatism.