CN109836428A

CN109836428A - Pyrazoles [4,3-d] pyrimidine derivatives and purposes with immunosuppressive activity

Info

Publication number: CN109836428A
Application number: CN201910144641.7A
Authority: CN
Inventors: 吕伟; 颜幸佳; 张秋萌; 左建平
Original assignee: East China Normal University
Current assignee: East China Normal University
Priority date: 2019-02-27
Filing date: 2019-02-27
Publication date: 2019-06-04

Abstract

The invention discloses a kind of pyrazoles [4,3-d] pyrimidine derivatives and purposes with immunosuppressive activity, the derivative have structure shown in Formulas I A or IB；Pharmacological Results show that the compounds of this invention has bone-marrow-derived lymphocyte and T lymphocyte inhibitory activity, can be used for preparing treatment or control rheumatoid arthritis, the drug of the disease of immune system such as systemic loupus erythematosus and diseases associated with inflammation.

Description

Pyrazoles [4,3-d] pyrimidine derivatives and purposes with immunosuppressive activity

Technical field

The present invention relates to field of medicinal chemistry, and in particular to pyrazole [4,3-d] pyrimidine derivatives and its immunization.

Background technique

Autoimmune disease is autoreactivity T, B cell overactivity, and autoantibody generates, and causes respective organization organ even A kind of disease of systemic injury.There are higher morbidity and mortality, patient is mostly young man, especially women, is caused Social and economic effect it is huge.Many studies have shown that bone-marrow-derived lymphocyte and T lymphocyte are in diseases associated with inflammation, autoimmune It is played an important role in disease or immune-mediated disease.For example, the bone-marrow-derived lymphocyte that imbalance occurs can induce for abnormal signal increases It grows and breaks up, so as to cause the lymthoma of multiple types, including various acute or chronic lymphatic leukemias；And it can lead to itself The formation of antibody, so as to cause diseases associated with inflammation, autoimmune disease or immune-mediated disease.

Autoimmunity disease is often divided into organ specificity (organ-specific) generally according to the distribution of antigenic component With systemic (systemic) two major classes.The pathological lesion and dysfunction of the former histoorgan are only limitted to antibody or sensitization lymph The targeted a certain organ of cell, extent of disease Chang Yange is limited in the organ and its range in one's power, such as chronic lymphatic first Shape adenositis, myasthenia gravis etc..The targeting antigen and lesion of the latter is often in whole body distribution, and lesion can cause whole body multiple organ to damage example Such as systemic loupus erythematosus (systemic lupus erythematosus).

For many years, treatment autoimmune disease relies primarily on non-selective immunosuppressor and cell toxicity medicament, sugared cortex Hormone medicine can only play of short duration effect in palindromia or deterioration.The nineties, the introducing of Biotherapy method opened The frontier for the treatment of autoimmune diseases produces significant impact to the course of disease and quality of life of patient.But traditional medicine Object has inevitable toxic side effect, and biological agent is then expensive, and common patient can't afford.It would therefore be highly desirable to develop Can the potential activation for inhibiting immunocyte, to inhibit and cure the small of various difficult disease of immune system and diseases associated with inflammation Molecular compound.

Summary of the invention

The object of the present invention is to provide a kind of noval chemical compound that can inhibit immunologic cellular activity and acceptable there is pharmacology Active isomer or its salt.

Another object of the present invention is related to a kind of pharmaceutical composition, and described pharmaceutical composition includes one or more present invention Formulas I A, IB compound or its stereoisomer, tautomer, solvated compounds or its pharmaceutically acceptable salt, and Pharmaceutically acceptable auxiliary material.

Pharmaceutical composition of the present invention can also include one or more drugs selected from the following: immunosuppressor, Glucocorticoid, non-steroidal anti-inflammatory drugs, TNF-α binding protein, interferon and interleukins.

Realizing the specific technical solution of the object of the invention is:

A kind of pyrazoles [4,3-d] pyrimidine derivatives with immunosuppressive activity, with structure shown in Formulas I A or IB:

In structure above IA or IB,

R¹For hydrogen or C_1-6Alkyl；

R²For hydrogen or C_1-6Alkyl；

R³For hydrogen, halogen, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Halogenated alkoxy, hydroxyl, cyano or nitre Base；

R⁴For hydrogen, halogen, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Halogenated alkoxy, hydroxyl, cyano or Nitro；

R⁵For hydrogen atom, halogen atom, hydroxyl, nitro, cyano, C_6-12Aryl, 5-10 unit's heteroaryl, phenoxy group, heterocycle C_1-6Alkyl or C_1-6Alkyl oxy C_1-6Alkyl；

X is NH or O；

A and B is each independently hydrogen, halogen or dimethylamino；

Wherein:

The C_6-12Aryl refers to 6 to 12 atoms and the aromatic radical that is made of 1 or 2 ring；

The heterocycle C_1-6Alkyl is

The C_1-6Alkyl oxy C_1-6Alkyl is

A kind of pharmaceutical composition contains compound IA, IB or its pharmaceutically acceptable salt and pharmaceutically acceptable load Body.

The pharmaceutically acceptable carrier is nanoparticle ball or liposome.

The pharmaceutically acceptable salt is hydrochloride, sulfate, phosphate, the maleate, richness of compound IA or IB Horse hydrochlorate, citrate, mesylate, tosilate or tartrate.

A kind of compound described above is in preparation for preventing or treating diseases associated with inflammation, autoimmune disease or immune Purposes in the drug of mediated disease.

Bone-marrow-derived lymphocyte, the T of the diseases associated with inflammation, autoimmune disease or immune-mediated disease by abnormal activation Both lymphocytes mediate.

The diseases associated with inflammation, autoimmune disease or immune-mediated disease be arthritis, rheumatoid arthritis, Joint of vertebral column inflammation, urarthritis, other arthrtic conditions, lupus, systemic loupus erythematosus, psoriasis, eczema or skin It is scorching.

The preferred structure of pyrazoles [4,3-d] pyrimidine derivatives IA or IB of the present invention are as follows:

Compared with prior art, the invention has the advantages that

(a) the present invention provides a kind of novel pyrazoles [4,3-d] pyrimidine structure, design has synthesized a series of new chemical combination Object.

(b) the compound of the present invention, isomer and its pharmaceutically acceptable salt can inhibit bone-marrow-derived lymphocyte simultaneously And T lymphocyte.

Detailed description of the invention

Fig. 1 is inhibiting effect result figure of the compounds of this invention to leukocyte infiltration degree after immunostimulation.

Specific embodiment

Work as R²The compound of the present invention IA can be prepared with following method when for hydrogen:

Embodiment 1

The preparation of 1.1 compound 8A-1

Known compound 7A-1 300mg (1.48mmol, 1eq) is thrown in 25mL bottle with two necks, 206mg 3- nitro is added 2h is stirred at room temperature in phenol (1.48mmol, 1eq), 963mg cesium carbonate (2.96mmol, 2eq) and 5mL DMF, and raw material reacts completely, System is added in 50mL water, yellow solid is precipitated, and filters, washing, dry 430mg product, yield 95%.

¹H NMR(400MHz,DMSO-d₆) δ 8.41 (s, 1H), 8.35 (s, 1H), 8.26 (d, J=7.5Hz, 1H), 7.97 (d, J=7.1Hz, 1H), 7.86 (t, J=7.8Hz, 1H), 4.34 (s, 3H).

The preparation of 1.2 compound 9A-1

The fluoro- 4- morpholine aniline 225mg of compound 8A-1 350mg (1.14mmol 1eq), 3- (1.14mmol 1eq), Pd₂ (dba)₃100mg (0.11mmol, 0.1eq), Xantphos 127mg (0.22mmol, 0.2eq), potassium carbonate 316mg (2.29mmol, 2eq) and 8mL Isosorbide-5-Nitrae-dioxane are thrown in 25mL bottle with two necks, nitrogen protection, are warming up to 90 DEG C, stirred Night, raw material react completely, and filtering, filtrate is washed with water after EA is added, and are washed with saturated common salt, and anhydrous sodium sulfate is dry, column chromatography Separate the yellow solid 320mg of (DCM:MeOH=20:1), yield 60%.

¹H NMR(400MHz,CDCl₃) δ 8.29-8.23 (m, 1H), 8.22 (d, J=2.1Hz, 1H), 8.05 (d, J= 8.5Hz, 1H), 7.87 (s, 1H), 7.70-7.65 (m, 2H), 7.19 (s, 1H), 6.48 (d, J=2.1Hz, 1H), 6.36 (d, J =8.8Hz, 1H), 4.31 (s, 3H), 3.88-3.85 (m, 4H), 3.83 (s, 3H), 3.11-3.05 (m, 4H).

The preparation of 1.3 compound 10A-1

9A-1 120mg to be thrown, 12mL methanol is added in 50mL bottle with two necks, 12mg Raney Ni changes hydrogen, is stirred at room temperature, Raw material reacts completely after four hours, filters, the yellow solid 100mg that filtrate is spin-dried for.

¹H NMR(400MHz,DMSO-d₆) δ 7.94 (d, J=8.7Hz, 1H), 7.89 (s, 1H), 7.34 (s, 1H), 7.12 (t, J=8.3Hz, 1H), 6.61 (d, J=1.8Hz, 1H), 6.54 (s, 1H), 6.52 (s, 1H), 6.48 (d, J=8.6Hz, 1H), 6.41 (d, J=8.7Hz, 1H), 5.36 (s, 2H), 4.19 (s, 3H), 3.80 (s, 3H), 3.77-3.71 (m, 4H), 3.06 (d, J=4.2Hz, 4H).

The preparation of 1.4 compound IA-1

10A-1 70mg (0.16mmol, 1eq) is thrown, 5mLTHF and sodium bicarbonate 27mg is added in 25mL single port bottle (0.32mmol, 2eq) is cooled to 0 DEG C.13 μ L acryloyl chlorides are added dropwise again, are warmed to room temperature after adding, stir 30min, raw material DCM to Quan Rong is added in reaction completely, system, and organic phase is washed with water, and saturated common salt washing, anhydrous sodium sulfate dries, filters, and revolves Dry, it is white solid 30mg, purity 99.2% that crude product, which obtains target product by column chromatography for separation,.

¹H NMR(400MHz,DMSO-d₆) δ 10.73 (s, 1H), 7.90 (s, 1H), 7.79 (d, J=7.7Hz, 2H), 7.60 (d, J=8.1Hz, 1H), 7.38 (s, 1H), 7.12 (d, J=8.0Hz, 1H), 6.58 (d, J=1.7Hz, 1H), 6.49-6.41 (m, 1H), 6.29 (td, J=16.6Hz, 5.1Hz 2H), 5,82-5,75 (m, 1H), 4.22 (s, 3H), 3.77 (s, 3H), 3.75-3.70(m,4H),3.05-3.00(m,4H)。

Embodiment 2

2.2 the preparation of compound 9A-2

Using compound 8A-1 and corresponding aryl moieties as raw material, compound 9A-2 is synthesized by method 1.2.

¹H NMR(400MHz,DMSO-d₆) δ 8.96 (s, 1H), 8.37 (s, 1H), 8.25 (d, J=8.0Hz, 1H), 8.06- 7.90 (m, 2H), 7.83 (t, J=8.1Hz, 1H), 7.46 (d, J=7.8Hz, 2H), 6.75 (d, J=8.5Hz, 2H), 4.23 (s,3H),3.72(s,4H),2.97(s,4H)。

The preparation of 2.3 compound 10A-2

Using compound 9A-2 as raw material, compound 10A-2 is synthesized by method 1.3.¹H NMR(400MHz,DMSO-d₆)δ 8.95(s,1H),7.88(s,1H),7.57(s,2H),7.11(s,1H),6.79(s,2H),6.53(s,3H),5.33(s,2H), 4.18(s,3H),3.72(s,4H),2.98(s,4H)。

The preparation of 2.4 compound IA-2

Using compound 10A-2 as raw material, compound IA-2 is synthesized by method 1.4.¹H NMR(400MHz,DMSO-d₆)δ 10.37 (s, 1H), 8.97 (s, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.63 (d, J=7.5Hz, 1H), 7.48 (d, J= 7.3Hz, 3H), 7.13 (d, J=7.3Hz, 1H), 6.75 (d, J=5.8Hz, 2H), 6.45 (dd, J=16.6,10.2Hz, 1H), 6.28 (d, J=16.7Hz, 1H), 5.81-5.74 (m, 1H), 4.22 (s, 3H), 3.72 (s, 4H), 2.97 (s, 4H).

Embodiment 3

The preparation of 3.2 compound 9A-3

Using compound 8A-1 and corresponding aryl moieties as raw material, compound 9A-3 is synthesized by method 1.2.¹H NMR (400MHz,DMSO-d₆) δ 9.28 (s, 1H), 8.40 (s, 1H), 8.26 (d, J=8.2Hz, 1H), 8.00 (s, 1H), 7.97 (d, J=9.2Hz, 1H), 7.55 (d, J=15.3Hz, 1H), 7.23 (d, J=8.3Hz, 1H), 6.85 (t, J=9.4Hz, 1H), 4.25(s,3H),3.71(s,4H),2.88(s,4H)。

The preparation of 3.3 compound 10A-3

Using compound 9A-3 as raw material, compound 10A-3 is synthesized by method 1.3.¹H NMR(400MHz,DMSO-d₆)δ 9.25 (s, 1H), 7.96 (s, 1H), 7.69 (d, J=16.5Hz, 1H), 7.39 (d, J=8.4Hz, 1H), 7.12 (t, J= 7.9Hz, 1H), 6.88 (t, J=9.3Hz, 1H), 6.53 (s, 1H), 6.50 (d, J=12.9Hz, 2H), 5.33 (s, 2H), 4.20 (s,3H),3.72(s,4H),2.90(s,4H)。

The preparation of 3.4 compound IA-3

Using compound 10A-3 as raw material, compound IA-3 is synthesized by method 1.4.¹H NMR(400MHz,DMSO-d₆)δ 10.36 (s, 1H), 9.26 (s, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 7.60 (d, J=9.0Hz, 2H), 7.48 (t, J= 8.1Hz, 1H), 7.31 (d, J=8.4Hz, 1H), 7.14 (d, J=9.0Hz, 1H), 6.84 (t, J=9.4Hz, 1H), 6.45 (dd, J=16.9,10.1Hz, 1H), 6.27 (d, J=15.7Hz, 1H), 5.78 (d, J=11.4Hz, 1H), 4.24 (s, 3H), 3.71 (d, J=4.2Hz, 4H), 2.88 (s, 4H).

Embodiment 4

The preparation of 4.1 compound 8A-4

In N₂Under protection, known compound 7A-1 610mg (3mmol, 1eq.), 3- nitroaniline is added in dry DMF In 456mg (3.3mmol, 1.1eq.) and DIPEA 1ml (6mmol, 2eq.) mixed system.It is warming up to 60 DEG C of reaction 12h.Toward body It is added suitable quantity of water in system, system is muddy, and solid is precipitated, and filters, dry compound 8A-4 yellow solid 830mg, yield 68%.

¹H NMR(400MHz,DMSO-d₆) δ 9.51 (s, 1H), 8.64 (s, 1H), 8.17 (d, J=8.0Hz, 1H), 8.11 (s, 1H), 8.02 (d, J=8.1Hz, 1H), 7.71 (t, J=8.2Hz, 1H), 4.39 (s, 3H).

The preparation of 4.2 compound 9A-4

Using compound 8A-4 and corresponding aryl moieties as raw material, compound 9A-4 is synthesized by method 1.2.¹H NMR (400MHz,DMSO-d₆)δ9.08(s,1H),8.56(s,1H),8.24(s,1H),7.95(s,2H),7.78(s,1H),7.61 (s,1H),7.45(s,1H),6.62(s,1H),6.41(s,1H),4.29(s,3H),3.79(s,3H),3.74(s,4H),3.06 (s,4H)。

The preparation of 4.3 compound 10A-4

Using compound 9A-4 as raw material, compound 10A-4 is synthesized by method 1.3.It directly throws in next step.

The preparation of 4.4 compound IA-4

Using compound 10A-4 as raw material, compound IA-4 is synthesized by method 1.4.¹H NMR(400MHz,DMSO-d₆)δ 10.19 (s, 1H), 8.75 (s, 1H), 8.16 (s, 1H), 8.09 (d, J=8.7Hz, 1H), 7.76 (s, 1H), 7.45 (d, J= 6.2Hz, 1H), 7.34 (s, 2H), 7.26 (s, 1H), 6.62 (s, 1H), 6.47 (dd, J=16.9,10.1Hz, 1H), 6.39 (d, J=8.8Hz, 1H), 6.28 (d, J=17.0Hz, 1H), 5.77 (d, J=10.3Hz, 1H), 4.28 (s, 3H), 3.82 (s, 3H), 3.74(s,4H),3.04(s,4H)。

Embodiment 5

The preparation of 5.2 compound 9A-5

Using compound 8A-4 and corresponding aryl moieties as raw material, compound 9A-5 is synthesized by method 1.2.¹H NMR (400MHz,DMSO-d₆) δ 9.16 (s, 1H), 9.11 (s, 1H), 8.50 (s, 1H), 8.33 (d, J=7.8Hz, 1H), 8.00 (d, J=7.9Hz, 1H), 7.87 (s, 1H), 7.78 (d, J=15.6Hz, 1H), 7.68 (t, J=8.0Hz, 1H), 7.68 (t, J= 8.0Hz, 1H), 7.68 (t, J=8.0Hz, 1H), 7.32 (d, J=8.2Hz, 1H), 6.90 (t, J=9.3Hz, 1H), 4.32 (s, 3H),3.73(s,4H),2.90(s,4H).The preparation of 5.3 compound 10A-5

Using compound 9A-5 as raw material, compound 10A-5 is synthesized by method 1.3, is directly thrown in next step.

The preparation of 5.4 compound IA-5

Using compound 10A-5 as raw material, compound IA-5 is synthesized by method 1.4.¹H NMR(400MHz,DMSO-d₆)δ 10.18 (s, 1H), 8.94 (s, 1H), 8.82 (s, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.75 (d, J=15.5Hz, 1H), 7.51 (d, J=7.8Hz, 1H), 7.46 (d, J=7.7Hz, 1H), 7.36 (dd, J=15.5,7.7Hz, 2H), 6.86 (t, J= 9.3Hz, 1H), 6.47 (dd, J=16.9,10.1Hz, 1H), 6.27 (d, J=16.9Hz, 1H), 5.77 (d, J=10.1Hz, 1H),4.30(s,3H),3.72(s,4H),2.89(s,4H)。

Work as R²It can be prepared with following method for C1-6 alkyl the compound of the present invention IA:

Embodiment 6

The preparation of 6.1 compound 21A-6

Using corresponding parent segment as raw material, compound 21A-6 is synthesized by method 1.1.¹H NMR(400MHz,CDCl₃)δ 8.28-8.22 (m, 1H), 8.19 (t, J=2.0Hz, 1H), 7.70 (dd, J=3.8,1.8Hz, 2H), 4.32 (s, 3H), 2.61 (s,3H)。

The preparation of 6.2 compound 22A-6

Using 21A-6 and corresponding aryl moieties as raw material, compound 22A-6 is synthesized by method 1.2.¹H NMR(400MHz, CDCl₃) δ 8.22 (dd, J=6.6,4.5Hz, 1H), 8.19 (d, J=1.7Hz, 1H), 8.07 (d, J=8.4Hz, 1H), 7.74- 7.59 (m, 2H), 7.23 (s, 1H), 6.49 (d, J=2.4Hz, 1H), 6.35 (dd, J=8.8,2.0Hz, 1H), 4.22 (s, 3H),3.81(s,3H),3.17–3.09(m,4H),2.63–2.58(m,4H),2.54(s,3H),2.36(s,3H)。

The preparation of 6.3 compound 23A-6

Using 22A-6 as raw material, compound 23A-6 is synthesized by method 1.3.¹H NMR(400MHz,CDCl₃) δ 8.23 (d, J= 8.7Hz, 1H), 7.35 (s, 1H), 7.24 (dd, J=13.2,5.2Hz, 1H), 6.68-6.62 (m, 2H), 6.61 (t, J= 2.1Hz, 1H), 6.51 (d, J=2.5Hz, 1H), 6.43 (dd, J=8.8,2.4Hz, 1H), 4.20 (s, 4H), 3.83 (s, 3H), 3.82–3.79(m,2H),3.16–3.11(m,4H),2.61–2.57(m,4H),2.54(s,3H),2.36(s,3H)。

The preparation of 6.4 compound IA-6

Using compound 23A-6 as raw material, compound IA-6 is synthesized by method 1.4.¹H NMR(400MHz,CDCl₃)δ8.10 (d, J=8.7Hz, 1H), 7.89 (s, 1H), 7.58 (d, J=8.8Hz, 2H), 7.40 (t, J=8.0Hz, 1H), 7.31 (s, 1H), 7.06-6.96 (m, 1H), 6.46 (d, J=2.3Hz, 1H), 6.42 (d, J=16.8Hz, 1H), 6.36 (dd, J=8.8, 2.1Hz, 1H), 6.23 (dd, J=16.8,10.2Hz, 1H), 5.73 (d, J=11.0Hz, 1H), 4.19 (s, 3H), 3.77 (s, 3H),3.23–2.96(m,4H),2.63–2.54(m,4H),2.52(s,3H),2.34(s,3H)。

Embodiment 7

The preparation of 7.2 compound 22A-7

Using 21A-6 and corresponding aryl moieties as raw material, compound 22A-7 is synthesized by method 1.2.¹H NMR(400MHz, CDCl₃) δ 8.21 (d, J=3.1Hz, 1H), 8.19 (s, 1H), 7.64 (d, J=5.4Hz, 2H), 7.35 (d, J=8.9Hz, 2H), 6.77 (dd, J=6.0,2.8Hz, 3H), 4.23 (s, 3H), 4.12-4.02 (m, 2H), 3.79-3.66 (m, 2H), 3.45 (s,3H),2.53(s,3H)。

The preparation of 7.3 compound 23A-7

Using compound 22A-7 as raw material, compound 23A-7 is synthesized by method 1.3.¹H NMR(400MHz,CDCl₃)δ7.43 (d, J=6.9Hz, 2H), 6.82 (s, 3H), 6.71-6.52 (m, 3H), 4.22 (s, 3H), 4.08 (s, 2H), 3.81 (s, 2H), 3.74(s,2H),3.46(s,3H),2.53(s,3H)。

The preparation of 7.4 compound IA-8

Using compound 23A-7 as raw material, compound IA-7 is synthesized by method 1.4.¹H NMR(400MHz,CDCl₃)δ7.89 (s, 1H), 7.67 (s, 1H), 7.38 (d, J=6.6Hz, 2H), 7.34 (d, J=8.3Hz, 2H), 6.99 (s, 2H), 6.74 (d, J =8.4Hz, 2H), 6.43 (d, J=16.9Hz, 1H), 6.25 (dd, J=16.7,10.3Hz, 1H), 5.75 (d, J=10.1Hz, 1H),4.18(s,3H),4.06(s,2H),3.73(s,2H),3.44(s,3H),2.51(s,3H)。

Embodiment 8

The preparation of 8.2 compound 22A-8

Using 21A-6 and corresponding aryl moieties as raw material, compound 22A-8 is synthesized by method 1.2.¹H NMR(400MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.37 (t, J=2.0Hz, 1H), 8.25 (dd, J=8.2,1.2Hz, 1H), 7.93 (dd, J= 8.1,1.2Hz, 1H), 7.82 (t, J=8.2Hz, 1H), 7.41 (d, J=15.7Hz, 2H), 7.16 (d, J=7.9Hz, 1H), 6.78 (t, J=9.4Hz, 1H), 4.15 (s, 3H), 2.85 (s, 4H), 2.53-2.45 (m, 3H), 2.41 (s, 4H), 2.19 (s, 3H)。

The preparation of 8.3 compound 23A-8

Using compound 22A-8 as raw material, compound 23A-8 is synthesized by method 1.3.¹H NMR(400MHz,CDCl₃)δ7.52 (dd, J=14.9,2.1Hz, 1H), 7.21 (dd, J=17.0,9.0Hz, 2H), 7.03-6.95 (m, 1H), 6.82 (t, J= 9.1Hz, 1H), 6.62 (d, J=8.0Hz, 2H), 6.56 (s, 1H), 4.20 (s, 3H), 3.85 (s, 2H), 3.03 (s, 4H), 2.59(s,4H),2.52(s,3H),2.34(s,3H).

The preparation of 8.4 compound IA-8

Using compound 23A-8 as raw material, compound IA-8 is synthesized by method 1.4.¹H NMR(400MHz,CDCl₃)δ7.74 (d, J=9.0Hz, 2H), 7.46 (dd, J=15.0,2.0Hz, 1H), 7.41-7.33 (m, 2H), 7.06 (s, 1H), 7.00 (d, J =7.2Hz, 1H), 6.94 (d, J=8.7Hz, 1H), 6.79 (t, J=9.1Hz, 1H), 6.43 (d, J=16.8Hz, 1H), 6.26 (dd, J=16.8,10.2Hz, 1H), 5.77 (d, J=10.3Hz, 1H), 4.19 (s, 3H), 3.02 (s, 4H), 2.60 (s, 4H), 2.52(s,3H),2.35(s,3H)。

Embodiment 9

The preparation of 9.2 compound 22A-9

Using 21A-6 and corresponding aryl moieties as raw material, compound 22A-9 is synthesized by method 1.2.¹H NMR(400MHz, CDCl₃) δ 8.20 (d, J=1.9Hz, 1H), 7.66-7.61 (m, 2H), 7.42 (d, J=2.3Hz, 1H), 7.37 (d, J= 8.9Hz, 2H), 6.78 (d, J=9.0Hz, 2H), 6.73 (s, 1H), 4.24 (s, 3H), 3.96-3.72 (m, 4H), 3.18-2.96 (m,4H),2.54(s,3H)。

The preparation of 9.3 compound 23A-9

Using compound 22A-9 as raw material, compound 23A-9 is synthesized by method 1.3.¹H NMR(400MHz,DMSO-d₆)δ 9.01 (s, 1H), 7.56 (d, J=8.5Hz, 2H), 7.12 (t, J=7.9Hz, 1H), 6.76 (d, J=8.7Hz, 2H), 6.52 (d, J=11.6Hz, 2H), 6.47 (d, J=8.0Hz, 1H), 5.34 (s, 2H), 4.11 (s, 3H), 3.72 (s, 4H), 2.98 (s, 4H),2.40(s,3H)。

The preparation of 9.4 compound IA-9

Using compound 23A-9 as raw material, compound IA-9 is synthesized by method 1.4.¹H NMR(400MHz,DMSO-d₆)δ 10.38 (s, 1H), 9.04 (s, 1H), 7.75 (s, 1H), 7.64 (d, J=8.5Hz, 1H), 7.47 (t, J=8.1Hz, 3H), 7.11 (d, J=8.0Hz, 1H), 6.70 (d, J=8.8Hz, 2H), 6.45 (dd, J=16.9,10.0Hz, 1H), 6.27 (d, J= 16.7Hz, 1H), 5.79 (d, J=9.9Hz, 1H), 4.15 (s, 3H), 3.72 (d, J=4.1Hz, 4H), 2.95 (s, 4H), 2.41 (s,3H)。

Embodiment 10

The preparation of 10.2 compound 22A-10

Using 21A-6 and corresponding aryl moieties as raw material, compound 22A-10 is synthesized by method 1.2.¹H NMR (400MHz,CDCl₃) δ 8.23-8.13 (m, 2H), 7.68-7.60 (m, 2H), 7.45 (d, J=8.9Hz, 2H), 7.30 (t, J= 7.9Hz, 2H), 7.05 (t, J=7.4Hz, 1H), 6.95 (d, J=8.2Hz, 3H), 6.87 (d, J=8.9Hz, 2H), 4.24 (s, 3H),2.53(s,3H)。

The preparation of 10.3 compound 23A-10

Using compound 22A-10 as raw material, compound 23A-10 is synthesized by method 1.3.¹H NMR(400MHz,DMSO-d₆)δ 9.32 (s, 1H), 7.70 (d, J=8.5Hz, 2H), 7.34 (t, J=7.5Hz, 2H), 7.12 (t, J=7.9Hz, 1H), 7.05 (t, J=7.2Hz, 1H), 6.91 (d, J=7.9Hz, 2H), 6.85 (d, J=8.6Hz, 2H), 6.53 (d, J=7.5Hz, 2H), 6.48 (d, J=7.6Hz, 1H), 5.34 (s, 2H), 4.14 (s, 3H), 2.42 (s, 3H).

The preparation of 10.4 compound IA-10

Using compound 23A-10 as raw material, compound IA-10 is synthesized by method 1.4.¹H NMR(400MHz,CDCl₃)δ 7.79 (s, 1H), 7.57 (s, 1H), 7.48 (d, J=8.8Hz, 2H), 7.36 (dd, J=15.6,8.1Hz, 2H), 7.29 (t, J =7.9Hz, 2H), 7.04 (t, J=7.4Hz, 2H), 6.94 (d, J=7.8Hz, 2H), 6.87 (d, J=8.8Hz, 2H), 6.43 (d, J=16.7Hz, 1H), 6.23 (dd, J=16.8,10.2Hz, 1H), 5.77 (d, J=10.3Hz, 1H), 4.21 (s, 3H), 2.53(s,3H)。

Embodiment 11

The preparation of 11.2 compound 22A-11

Using 21A-6 and corresponding aryl moieties as raw material, compound 22A-11 is synthesized by method 1.2.¹H NMR (400MHz,DMSO-d₆) δ 9.00 (s, 1H), 8.36 (s, 1H), 8.25 (d, J=7.8Hz, 1H), 7.94 (d, J=7.7Hz, 1H), 7.83 (t, J=8.1Hz, 1H), 7.40 (d, J=7.2Hz, 2H), 6.69 (d, J=8.4Hz, 2H), 4.15 (s, 3H), 2.99(s,4H),2.44(s,4H),2.41(s,3H),2.22(s,3H)。

The preparation of 11.3 compound 23A-11

Using compound 22A-11 as raw material, compound 23A-11 is synthesized by method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.45 (d, J=8.9Hz, 2H), 7.23 (d, J=8.0Hz, 1H), 6.85 (d, J=9.0Hz, 2H), 6.81 (s, 1H), 6.67- 6.62 (m, 2H), 6.60 (t, J=2.1Hz, 1H), 4.21 (s, 3H), 3.17-3.05 (m, 4H), 2.61-2.55 (m, 4H), 2.52(s,3H),2.35(s,3H)。

The preparation of 11.4 chemical combination IA-11

Using compound 23A-11 as raw material, compound IA-11 is synthesized by method 1.4.¹H NMR(400MHz,CDCl₃)δ 7.64 (s, 1H), 7.57-7.46 (m, 2H), 7.40 (dd, J=13.3,8.4Hz, 3H), 7.02 (t, J=8.5Hz, 1H), 6.85 (d, J=6.7Hz, 1H), 6.80 (d, J=8.7Hz, 2H), 6.45 (d, J=16.8Hz, 1H), 6.25 (dd, J=16.8, 10.2Hz, 1H), 5.78 (d, J=10.2Hz, 1H), 4.20 (s, 3H), 3.11 (s, 4H), 2.66-2.56 (m, 4H), 2.52 (s, 3H),2.36(s,3H)。

Embodiment 12

The preparation of 12.2 compound 22A-12

Using 21A-6 and corresponding aryl moieties as raw material, compound 22A-12 is synthesized by method 1.2.¹H NMR (400MHz,DMSO-d₆) δ 8.32 (s, 1H), 8.23 (d, J=8.2Hz, 1H), 7.92 (d, J=8.1Hz, 1H), 7.81 (t, J =8.2Hz, 1H), 7.67 (d, J=7.8Hz, 1H), 7.50 (s, 1H), 6.55 (t, J=4.4Hz, 1H), 6.26 (d, J= 8.7Hz,1H),4.16(s,3H),3.81–3.65(m,7H),3.08–2.94(m,4H),2.40(s,3H)。

The preparation of 12.3 compound 23A-12

Using compound 22A-12 as raw material, compound 23A-12 is synthesized by method 1.3.¹H NMR(400MHz,CDCl₃)δ 8.25 (d, J=8.7Hz, 1H), 7.37 (s, 1H), 7.23 (d, J=8.0Hz, 1H), 6.65 (t, J=8.8Hz, 2H), 6.61 (s, 1H), 6.48 (d, J=2.2Hz, 1H), 6.41 (dd, J=8.8,2.1Hz, 1H), 4.20 (s, 3H), 3.89-3.85 (m, 4H),3.83(s,4H),3.12–2.99(m,4H),2.54(s,3H)。

The preparation of 12.4 compound IA-12

Using compound 23A-12 as raw material, compound IA-12 is synthesized by method 1.4.¹H NMR(400MHz,CDCl₃)δ 8.14 (d, J=8.6Hz, 1H), 7.61 (d, J=7.9Hz, 1H), 7.56 (s, 1H), 7.42 (t, J=8.1Hz, 1H), 7.34 (s, 1H), 7.04 (d, J=8.0Hz, 1H), 6.43 (d, J=16.6Hz, 2H), 6.36 (d, J=8.0Hz, 1H), 6.23 (dd, J =16.8,10.2Hz, 1H), 5.75 (d, J=10.2Hz, 1H), 4.20 (s, 3H), 3.90-3.82 (m, 4H), 3.78 (s, 3H), 3.05(s,4H),2.53(s,3H)。

Embodiment 13

The preparation of 13.1 compound 21A-13

Using corresponding parent segment as raw material, compound 21A-13 is synthesized by method 4.1.¹H NMR(400MHz,DMSO- d₆) δ 9.44 (s, 1H), 8.61 (s, 1H), 8.14 (d, J=6.3Hz, 1H), 7.98 (d, J=6.0Hz, 1H), 7.67 (s, 1H), 4.28(s,3H),2.37(s,3H)。

The preparation of 13.2 compound 22A-13

Compound 21A-13 1g (3.1mmol, 1eq.) and the fluoro- 4- of 3- (4- morpholinyl)-aniline 668mg (3.4mmol, It 1.1eq.) is dissolved in isopropanol, N₂Protection is lower to instill TFA 0.23ml (3.1mmol, 1eq.).It is warming up to reflux for 24 hours.It is added full With NaHCO3 aqueous solution tune pH to 8.Methylene chloride, organic phase washing is added, saturated sodium-chloride is washed, and anhydrous sodium sulfate is dry.It is dense Compound 22B-3 red brown solid 1.2g, yield 76% are recrystallized to obtain after contracting.

¹H NMR(400MHz,CDCl₃) δ 8.53 (t, J=2.1Hz, 1H), 8.01 (ddd, J=15.1,8.1,1.8Hz, 2H), 7.66 (dd, J=14.8,2.4Hz, 1H), 7.55 (t, J=8.2Hz, 1H), 7.10 (dd, J=8.6,1.8Hz, 1H), 7.02 (s, 1H), 6.88 (dd, J=19.3,10.1Hz, 2H), 4.29 (s, 3H), 3.90-3.86 (m, 4H), 3.08-2.99 (m, 4H),2.50(s,3H)。

The preparation of 13.3 compound 23A-13

Using compound 22A-13 as raw material, compound 23A-13 is synthesized by method 1.3.¹H NMR(400MHz,CDCl₃)δ 8.31 (d, J=9.4Hz, 1H), 7.21 (s, 1H), 7.12 (t, J=8.0Hz, 1H), 6.77-6.67 (m, 2H), 6.57 (dd, J =6.3,2.5Hz, 2H), 6.46 (dd, J=8.0,1.5Hz, 1H), 4.18 (s, 3H), 3.87 (s, 3H), 3.21-3.09 (m, 4H),2.68–2.59(m,4H),2.49(s,3H),2.37(s,3H)。

The preparation of 13.4 compound IA-13

Using compound 23A-13 as raw material, compound IA-13 is synthesized by method 1.4.¹H NMR(400MHz,CDCl₃)δ 8.22 (s, 1H), 8.04 (s, 1H), 7.69 (dd, J=15.0,1.9Hz, 1H), 7.32 (d, 1H), 7.14 (d, J=7.5Hz, 1H), 6.93 (s, 1H), 6.86 (t, J=9.1Hz, 1H), 6.49 (d, J=16.7Hz, 1H), 6.31 (dd, J=16.8, 10.1Hz, 1H), 5.80 (d, J=10.6Hz, 1H), 4.16 (s, 3H), 3.97-3.83 (m, 4H), 3.05 (s, 4H), 2.48 (s, 3H)。

Embodiment 14

The preparation of 14.2 compound 22A-14

Using compound 21A-13 and corresponding aryl moieties as raw material, compound 22A-14 is synthesized by method 13.2.¹H NMR(400MHz,DMSO-d₆)δ9.08(s,1H),8.55(s,1H),8.21(s,1H),7.93(s,2H),7.60(s,1H), 7.41(s,1H),6.62(s,1H),6.39(s,1H),4.21(s,3H),3.80(s,3H),3.08(s,4H),2.47(s,4H), 2.35(s,3H),2.23(s,3H)。

The preparation of 14.3 compound 23A-14

Using compound 22A-14 as raw material, compound 23A-14 is synthesized by method 1.3.¹H NMR(400MHz,CDCl₃)δ 8.31 (d, J=9.4Hz, 1H), 7.21 (s, 1H), 7.12 (t, J=8.0Hz, 1H), 6.73 (dd, J=8.0,1.3Hz, 1H), 6.70 (s, 1H), 6.57 (dd, J=6.3,2.5Hz, 2H), 6.46 (dd, J=8.0,1.5Hz, 1H), 4.18 (s, 3H), 3.87 (s,3H),3.20–3.12(m,4H),2.64–2.55(m,4H),2.49(s,3H),2.37(s,3H)。

The preparation of 14.4 compound IA-14

Using compound 23A-14 as raw material, compound IA-14 is synthesized by method 1.4.¹H NMR(400MHz,CDCl₃)δ 8.26 (d, J=8.7Hz, 1H), 8.03 (s, 1H), 7.66 (s, 1H), 7.44 (s, 1H), 7.29 (s, 1H), 7.25 (s, 1H), 6.87 (s, 1H), 6.53 (s, 1H), 6.49 (d, J=8.8Hz, 1H), 6.44 (dd, J=16.8,1.1Hz, 1H), 6.27 (dd, J =16.8,10.1Hz, 1H), 5.76 (dd, J=10.2,1.1Hz, 1H), 4.18 (s, 3H), 3.85 (s, 3H), 3.15 (s, 4H), 2.65–2.53(m,4H),2.47(s,3H),2.36(s,3H)。

Embodiment 15

The preparation of 15.2 compound 22A-15

Using compound 21A-13 and corresponding aryl moieties as raw material, compound 22A-15 is synthesized by method 13.2.¹H NMR(400MHz,CDCl₃) δ 8.57 (s, 1H), 8.35 (d, J=8.6Hz, 1H), 8.00 (td, J=8.2,2.0Hz, 2H), 7.53 (t, J=8.2Hz, 1H), 7.31 (s, 1H), 6.91 (s, 1H), 6.54 (d, J=2.4Hz, 1H), 6.50 (d, J= 8.7Hz, 1H), 4.27 (s, 3H), 3.89 (d, J=7.4Hz, 7H), 3.15-3.02 (m, 4H), 2.50 (s, 3H).

The preparation of 15.3 compound 23A-15

Using compound 22A-15 as raw material, compound 23A-15 is synthesized by method 1.3.¹H NMR(400MHz,DMSO-d₆)δ 8.44 (s, 1H), 8.23 (d, J=8.8Hz, 1H), 7.20 (s, 1H), 7.00 (t, J=7.9Hz, 1H), 6.93 (s, 1H), 6.76 (d, J=7.9Hz, 1H), 6.63 (d, J=2.3Hz, 1H), 6.45 (dd, J=8.8,2.3Hz, 1H), 6.36 (dd, J=7.9, 1.1Hz,1H),5.08(s,2H),4.15(s,3H),3.84(s,3H),3.78–3.70(m,4H),3.09–3.00(m,4H), 2.34(s,3H)。

The preparation of 15.4 compound IA-15

Using compound 23A-15 as raw material, compound IA-15 is synthesized by method 1.4.¹H NMR(400MHz,CDCl₃)δ 8.30 (s, 1H), 8.02 (s, 1H), 7.65 (s, 1H), 7.45 (d, J=6.0Hz, 1H), 7.29 (s, 1H), 7.26 (s, 1H), 6.86 (s, 1H), 6.51 (s, 1H), 6.44 (d, J=16.8Hz, 2H), 6.26 (dd, J=16.8,10.2Hz, 1H), 5.76 (d, J=10.3Hz, 1H), 4.18 (s, 3H), 3.90-3.80 (m, 7H), 3.09 (s, 4H), 2.47 (s, 3H).

Embodiment 16

The preparation of 16.2 compound 22A-16

Using compound 21A-13 and corresponding aryl moieties as raw material, compound 22A-16 is synthesized by method 13.2.¹H NMR(400MHz,CDCl₃) δ 8.50 (s, 1H), 8.15-7.90 (m, 2H), 7.64 (dd, J=14.8,2.3Hz, 1H), 7.56 (t, J=8.2Hz, 1H), 7.11 (dd, J=8.6,1.7Hz, 1H), 6.98 (s, 1H), 6.90 (t, J=9.1Hz, 2H), 4.29 (s,3H),3.09(s,4H),2.64(s,4H),2.51(s,3H),2.37(s,3H)。

The preparation of 16.3 compound 23A-16

Using compound 22A-16 as raw material, compound 23A-16 is synthesized by method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.63 (d, J=14.8Hz, 1H), 7.21-7.06 (m, 3H), 6.96-6.90 (m, 1H), 6.89 (d, J=9.2Hz, 1H), 6.79 (d, J=7.9Hz, 1H), 6.73 (s, 1H), 6.50 (d, J=7.8Hz, 1H), 4.20 (s, 3H), 3.07 (s, 4H), 2.61 (s, 4H),2.48(s,3H),2.36(s,3H)。

The preparation of 16.4 compound IA-16

Using compound 23A-16 as raw material, compound IA-16 is synthesized by method 1.4.¹H NMR(400MHz,DMSO-d₆)δ 10.20 (s, 1H), 8.97 (s, 1H), 8.81 (s, 1H), 7.97 (s, 1H), 7.68 (d, J=16.1Hz, 1H), 7.51 (d, J= 7.7Hz, 1H), 7.40 (s, 2H), 7.34 (t, J=8.0Hz, 1H), 6.82 (t, J=9.4Hz, 1H), 6.46 (dd, J=17.0, 10.1Hz, 1H), 6.26 (dd, J=17.0,1.9Hz, 1H), 5.75 (dd, J=10.1,1.9Hz, 1H), 4.19 (s, 3H), 2.90(s,4H),2.51–2.50(m,7H),2.36(s,3H),2.25(s,3H)。

Embodiment 17

The preparation of 17.2 compound 22A-17

Using compound 21A-13 and corresponding aryl moieties as raw material, compound 22A-17 is synthesized by method 13.2.¹H NMR(400MHz,CDCl₃) δ 8.49 (d, J=2.0Hz, 1H), 8.00 (td, J=8.3,1.7Hz, 2H), 7.51 (t, J= 8.4Hz, 3H), 6.88 (d, J=8.9Hz, 2H), 4.28 (s, 3H), 3.93-3.86 (m, 4H), 3.13-3.06 (m, 4H), 2.49 (s,3H)。

The preparation of 17.3 compound 23A-17

Using compound 22A-17 as raw material, compound 23A-17 is synthesized by method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.47 (d, J=8.9Hz, 2H), 7.19 (s, 1H), 7.18 (s, 1H), 7.05 (t, J=8.0Hz, 1H), 6.84 (d, J= 8.9Hz, 2H), 6.66 (d, J=8.3Hz, 2H), 6.39 (dd, J=7.9,1.7Hz, 1H), 4.14 (s, 3H), 3.83-3.76 (m,4H),3.09–2.99(m,4H),2.41(s,3H)。

The preparation of 17.4 compound IA-17

Using compound 23A-17 as raw material, compound IA-17 is synthesized by method 1.4.¹H NMR(400MHz,DMSO-d₆)δ 10.19 (s, 1H), 8.73 (d, J=24.4Hz, 2H), 7.96 (s, 1H), 7.60 (d, J=8.0Hz, 2H), 7.52 (d, J= 7.8Hz, 1H), 7.42 (d, J=7.7Hz, 1H), 7.33 (t, J=7.9Hz, 1H), 6.75 (d, J=8.1Hz, 2H), 6.47 (dd, J=16.9,10.1Hz, 1H), 6.27 (d, J=16.9Hz, 1H), 5.77 (d, J=9.3Hz, 1H), 4.18 (s, 3H), 3.71(s,4H),3.34(s,3H),2.96(s,4H),2.35(s,3H)。

Embodiment 18

The preparation of 18.2 compound 22A-18

Using compound 21A-13 and corresponding aryl moieties as raw material, compound 22A-18 is synthesized by method 13.2.¹H NMR(400MHz,CDCl₃) δ 8.49 (t, J=2.1Hz, 1H), 8.04 (dd, J=8.1,1.4Hz, 1H), 7.99 (dd, J= 8.2,1.4Hz, 1H), 7.66-7.58 (m, 2H), 7.52 (t, J=8.2Hz, 1H), 7.37-7.28 (m, 2H), 7.07 (t, J= 7.4Hz, 1H), 7.01 (d, J=1.0Hz, 1H), 7.00-6.95 (m, 4H), 6.93 (s, 1H), 4.29 (s, 3H), 2.50 (s, 3H)。

The preparation of 18.3 compound 23A-18

Using compound 22A-18 as raw material, compound 23A-18 is synthesized by method 1.3.¹H NMR(400MHz,DMSO-d₆)δ 8.98 (s, 1H), 8.50 (s, 1H), 7.83 (d, J=8.4Hz, 2H), 7.33 (t, J=7.6Hz, 2H), 7.09-6.98 (m, 2H), 6.95 (d, J=13.4Hz, 2H), 6.87 (d, J=3.4Hz, 2H), 6.82 (d, J=7.8Hz, 1H), 6.37 (d, J= 7.4Hz,1H),5.10(s,2H),4.21(s,1H),4.17(s,3H),2.35(s,3H)。

The preparation of 18.4 compound IA-18

Using compound 23A-18 as raw material, compound IA-18 is synthesized by method 1.4.¹H NMR(400MHz,DMSO-d₆)δ 9.33 (s, 1H), 8.39 (t, J=2.0Hz, 1H), 8.27 (dd, J=8.2,1.2Hz, 1H), 7.95 (dd, J=8.1,1.2Hz, 1H), 7.84 (t, J=8.2Hz, 1H), 7.41 (dd, J=17.2,10.1Hz, 2H), 7.18 (d, J=7.9Hz, 1H), 6.79 (t, J=9.4Hz, 1H), 4.17 (s, 3H), 2.86 (s, 4H), 2.43 (s, 4H), 2.21 (s, 3H).

Embodiment 19

The preparation of 19.2 compound 22A-19

Using compound 21A-13 and corresponding aryl moieties as raw material, compound 22A-19 is synthesized by method 13.2.¹H NMR(400MHz,CDCl₃) δ 8.44 (s, 1H), 8.04 (d, J=7.6Hz, 1H), 7.98 (dd, J=8.0,1.8Hz, 1H), 7.50 (t, J=8.2Hz, 3H), 6.96 (d, J=13.0Hz, 2H), 6.90-6.83 (m, 2H), 4.27 (s, 3H), 4.12 (dd, J =5.5,4.0Hz, 2H), 3.77 (dd, J=5.5,4.0Hz, 2H), 3.47 (s, 3H), 2.49 (s, 3H).

The preparation of 19.3 compound 23A-19

Using compound 22A-19 as raw material, compound 23A-19 is synthesized by method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.50 (d, J=8.5Hz, 2H), 7.10 (t, J=7.9Hz, 1H), 6.89 (d, J=8.5Hz, 3H), 6.70 (d, J=8.4Hz, 2H), 6.44 (d, J=7.6Hz, 1H), 4.17 (s, 3H), 4.13-3.99 (m, 2H), 3.75 (d, J=4.2Hz, 2H), 3.45 (s,3H),2.46(s,3H)。

The preparation of 19.4 compound IA-19

Using compound 23A-19 as raw material, compound 23A-19 is synthesized by method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.71 (s, 1H), 7.47 (d, J=8.0Hz, 1H), 7.43-7.37 (m, 1H), 7.36 (t, J=8.4Hz, 2H), 7.01 (d, J= 8.2Hz, 1H), 6.78 (d, J=8.8Hz, 2H), 6.44 (d, J=16.8Hz, 1H), 6.28 (dd, J=16.8,10.2Hz, 1H), 5.77 (d, J=10.2Hz, 1H), 4.20 (s, 3H), 3.13 (s, 2H), 2.67 (s, 2H), 2.52 (s, 3H), 2.40 (s, 3H)。

Work as R²The compound of the present invention (IB) can be prepared with following method when for hydrogen:

Embodiment 20

The synthesis of 20.1 compound 8B-1

Using corresponding parent segment as raw material, compound 8B-1 is synthesized by method 1.1.¹H NMR(400MHz,DMSO-d₆)δ 8.74 (s, 1H), 8.35 (s, 1H), 8.24 (d, J=7.9Hz, 1H), 7.92 (d, J=7.8Hz, 1H), 7.83 (t, J= 8.1Hz,1H),4.29(s,3H)。

The synthesis of 20.2 compound 9B-1

Using compound 8B-1 and corresponding arylamine segment as raw material, compound 9B-1 is synthesized by method 1.2.¹H NMR (400MHz,DMSO-d₆) δ 9.17 (s, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 8.24 (d, J=8.2Hz, 1H), 7.91 (d, J=8.1Hz, 1H), 7.82 (t, J=8.2Hz, 1H), 7.65 (d, J=15.5Hz, 1H), 7.30 (d, J=8.2Hz, 1H), 6.87 (t, J=9.4Hz, 1H), 4.18 (s, 3H), 3.72 (s, 4H), 2.89 (s, 4H).

The synthesis of 20.3 compound 10B-1

Using compound 9B-1 as raw material, compound 10B-1 is synthesized by method 1.3.It directly throws in next step.

The synthesis of 20.4 compound IB-1

Using compound 10B-1 as raw material, compound IB-1 is synthesized by method 1.4.¹H NMR(400MHz,DMSO-d₆)δ 10.35 (s, 1H), 9.15 (s, 1H), 8.27 (s, 1H), 7.69 (d, J=10.4Hz, 2H), 7.61 (d, J=8.2Hz, 1H), 7.46 (t, J=8.1Hz, 1H), 7.36 (s, 1H), 7.08 (dd, J=8.0,1.5Hz, 1H), 6.87 (t, J=9.4Hz, 1H), 6.44 (dd, J=16.9,10.1Hz, 1H), 6.27 (dd, J=17.0,1.7Hz, 1H), 5.78 (dd, J=10.1,1.7Hz, 1H),4.17(s,3H),3.74–3.69(m,4H),2.92–2.87(m,4H)。

Embodiment 21

The synthesis of 21.1 compound 8B-2

Using corresponding parent segment as raw material, compound 8B-2 is synthesized by method 4.1.¹H NMR(400MHz,DMSO-d₆)δ 11.03 (s, 1H), 9.07 (s, 1H), 8.48 (s, 1H), 8.36 (d, J=7.9Hz, 1H), 7.94 (d, J=7.7Hz, 1H), 7.66 (t, J=8.1Hz, 1H), 4.23 (s, 3H).

The synthesis of 21.2 compound 9B-2

Using compound 8B-2 and corresponding arylamine segment as raw material, 9B-2 is obtained according to step 1.2 in embodiment.¹H NMR (400MHz,DMSO-d₆)δ10.49(s,1H),9.07(s,1H),8.84(s,1H),8.80(s,1H),8.15(s,1H),7.93 (t, J=11.6Hz, 2H), 7.65 (t, J=7.1Hz, 1H), 7.44 (d, J=7.2Hz, 1H), 6.97 (t, J=8.5Hz, 1H), 4.17(s,3H),3.75(s,4H),2.95(s,4H)。

The synthesis of 21.3 compound 10B-2:

Compound 9B-2 is raw material, obtains 10B-2 according to step 1.3 in example, is directly thrown in next step.21.4 compounds The synthesis of IB-2:

Compound 10B-2 is raw material, obtains IB-2 according to step 1.4 in embodiment.

¹H NMR(300MHz,DMSO-d₆)δ10.15–10.06(m,1H),10.02–9.96(m,1H),8.82–8.77(m, 1H),8.26–8.18(m,1H),8.09(s,1H),7.98–7.87(m,1H),7.83–7.74(m,1H),7.58–7.48(m, 1H),7.47–7.39(m,1H),7.35–7.23(m,1H),6.99–6.89(m,1H),6.55–6.42(m,1H),6.33–6.22 (m,1H),5.81–5.72(m,1H),4.13(s,3H),3.74(s,4H),2.93(s,4H)。

Work as R²It can be prepared with following method for C1-6 alkyl the compound of the present invention (IB):

Embodiment 22

The preparation of 22.1 compound 21B-3

Using corresponding parent segment as raw material, compound 21B-3 is synthesized by method 4.1.¹H NMR(400MHz,CDCl₃)δ 8.70 (s, 1H), 8.35 (d, J=8.2Hz, 1H), 8.05-7.90 (m, 2H), 7.59 (t, J=8.2Hz, 1H), 4.11 (s, 3H),2.62(s,3H)。

The preparation of 3.2 compound 22B-3

Using 21B-3 and corresponding aryl moieties as raw material, compound 22B-3 is synthesized by method 13.2.¹H NMR (400MHz,CDCl₃) δ 8.85 (s, 1H), 8.06 (d, J=7.9Hz, 1H), 7.96 (d, J=7.7Hz, 1H), 7.89-7.75 (m, 2H), 7.53 (t, J=8.1Hz, 1H), 7.21 (d, J=7.5Hz, 1H), 6.92 (dd, J=16.1,6.8Hz, 2H), 4.05 (s,3H),3.94–3.80(m,4H),3.18–3.00(m,4H),2.57(s,3H)。

The preparation of 22.3 compound 23B-3

Using compound 22B-3 as raw material, compound 23B-3 is synthesized by method 1.3.¹H NMR(400MHz,CDCl₃)δ7.81 (dd, J=14.9,1.9Hz, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 7.23-7.07 (m, 3H), 7.00 (d, J=7.7Hz, 1H), 6.91 (t, J=9.0Hz, 1H), 6.46 (d, J=7.7Hz, 1H), 4.02 (s, 3H), 3.94-3.60 (m, 6H), 3.10- 2.97(m,4H),2.54(s,3H)。

The preparation of 22.4 compound IB-3

Using compound 23B-3 as raw material, compound IB-3 is synthesized by method 1.4.¹H NMR(400MHz,CDCl₃)δ8.36 (s, 1H), 7.91-7.54 (m, 3H), 7.44-7.25 (m, 4H), 7.14 (d, J=8.4Hz, 1H), 6.85 (t, J=9.1Hz, 1H), 6.45 (d, J=16.8Hz, 1H), 6.28 (dd, J=16.7,10.1Hz, 1H), 5.74 (d, J=10.1Hz, 1H), 3.89 (dd, J=22.4,18.3Hz, 7H), 3.02 (d, J=3.8Hz, 4H), 2.49 (s, 3H).

Embodiment 23

The preparation of 23.2 compound 22B-4

Using 21B-3 and corresponding aryl moieties as raw material, compound 22B-4 is synthesized according to method 13.2.¹H NMR (400MHz,CDCl₃) δ 8.73 (s, 1H), 8.07 (d, J=8.0Hz, 1H), 7.90 (d, J=8.0Hz, 1H), 7.77 (s, 1H), 7.62 (d, J=8.8Hz, 2H), 7.45 (t, J=8.2Hz, 1H), 6.92 (d, J=8.8Hz, 3H), 4.19-4.07 (m, 2H), 4.01(s,3H),3.81–3.69(m,2H),3.47(s,3H),2.53(s,3H)。

The preparation of 23.3 compound 23B-4

Using compound 22B-4 as raw material, compound 23B-4 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.63-7.53 (m, 2H), 7.53-7.42 (m, 2H), 7.10 (t, J=7.9Hz, 1H), 7.01-6.86 (m, 3H), 6.79 (s, 1H), 6.42 (d, J=7.8Hz, 1H), 4.12 (s, 2H), 4.01 (s, 3H), 3.79-3.72 (m, 2H), 3.72-3.64 (m, 2H),3.46(s,3H),2.52(s,3H)。

The preparation of 23.4 compound IB-4

Using compound 23B-4 as raw material, compound IB-4 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 8.32 (s, 1H), 7.62 (s, 1H), 7.60-7.45 (m, 4H), 7.26-7.20 (m, 2H), 7.08 (s, 1H), 6.89 (d, J= 8.9Hz, 2H), 6.44 (d, J=16.7Hz, 1H), 6.25 (dd, J=16.8,10.2Hz, 1H), 5.75 (d, J=10.2, 1.2Hz,1H),4.13–4.03(m,2H),3.97(s,3H),3.77–3.68(m,2H),3.45(s,3H),2.48(s,3H)。

Embodiment 24

The preparation of 24.2 compound 22B-5

Using 21B-3 and corresponding aryl moieties as raw material, compound 22B-5 is synthesized according to method 13.2.¹H NMR (400MHz,CDCl₃) δ 8.80 (s, 1H), 8.07 (d, J=8.1Hz, 1H), 8.03-7.90 (m, 2H), 7.81 (dd, J= 14.9,1.9Hz, 1H), 7.50 (t, J=8.2Hz, 1H), 7.21 (d, J=8.4Hz, 1H), 7.03-6.88 (m, 2H), 4.04 (s,3H),3.21–2.99(m,4H),2.75–2.50(m,7H),2.37(s,3H)。

The preparation of 24.3 compound 23B-5

Using compound 22B-5 as raw material, compound 23B-5 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.77 (d, J=14.9Hz, 1H), 7.50 (s, 1H), 7.40 (s, 1H), 7.23-7.08 (m, 2H), 7.05-6.84 (m, 3H), 6.45 (d, J=6.3Hz, 1H), 4.02 (s, 3H), 3.74 (s, 2H), 3.20-2.99 (m, 4H), 2.72-2.48 (m, 7H), 2.37(s,3H)。

The preparation of 24.4 compound IB-5

Using compound 23B-5 as raw material, compound IB-5 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 8.38(s,1H),7.87–7.64(m,2H),7.62–7.42(m,1H),7.41–7.26(m,3H),7.20–7.09(m,2H), 6.89 (t, J=9.1Hz, 1H), 6.46 (d, J=16.8Hz, 1H), 6.29 (dd, J=16.7,10.1Hz, 1H), 5.76 (d, J =10.1Hz, 1H), 3.98 (s, 3H), 3.14-2.96 (m, 4H), 2.67-2.54 (m, 4H), 2.51 (s, 3H), 2.36 (s, 3H)。

Embodiment 25

The preparation of 25.2 compound 22B-6

Using 21B-3 and corresponding aryl moieties as raw material, compound 22B-6 is synthesized according to method 13.2.¹H NMR (400MHz,CDCl₃) δ 8.78 (s, 1H), 8.08 (d, J=8.1Hz, 1H), 7.92 (d, J=8.1Hz, 1H), 7.81 (s, 1H), 7.73 (d, J=8.9Hz, 2H), 7.48 (t, J=8.1Hz, 1H), 7.36-7.28 (m, 2H), 7.11-6.95 (m, 6H), 4.03 (s,3H),2.55(s,3H)。

The preparation of 25.3 compound 23B-6

Using compound 22B-6 as raw material, compound 23B-6 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.71 (d, J=8.8Hz, 2H), 7.45 (s, 1H), 7.44-7.42 (m, 1H), 7.34-7.28 (m, 2H), 7.13 (t, J= 8.0Hz,1H),7.09–6.95(m,6H),6.91(s,1H),6.47–6.39(m,1H),4.03(s,3H),3.70(s,2H), 2.54(s,3H)。

The preparation of 25.4 compound IB-6

Using compound 23B-6 as raw material, compound IB-6 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 8.37 (s, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.65 (d, J=8.8Hz, 2H), 7.53 (s, 1H), 7.42 (d, J= 7.3Hz, 1H), 7.36-7.27 (m, 2H), 7.23-7.14 (m, 1H), 7.04 (t, J=7.4Hz, 1H), 7.00-6.91 (m, 4H), 6.42 (d, J=16.7Hz, 1H), 6.28 (dd, J=16.8,10.1Hz, 1H), 5.69 (d, J=10.2Hz, 1H), 3.93 (s,3H),2.46(s,3H)。

Embodiment 26

The preparation of 26.2 compound 22B-7

Using 21B-3 and corresponding aryl moieties as raw material, compound 22B-7 is synthesized according to method 13.2.¹H NMR (400MHz,CDCl₃) δ 8.79-8.73 (m, 1H), 8.10 (dd, J=8.1,1.6Hz, 1H), 7.91 (dd, J=8.1,1.7Hz, 1H), 7.79 (s, 1H), 7.62 (d, J=8.9Hz, 2H), 7.47 (t, J=8.2Hz, 1H), 6.95 (d, J=8.9Hz, 2H), 6.85(s,1H),4.02(s,3H),3.25–3.11(m,4H),2.66–2.49(m,7H),2.37(s,3H)。

The preparation of 26.3 compound 23B-7

Using compound 22B-7 as raw material, compound 23B-7 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.57 (d, J=8.8Hz, 2H), 7.51 (s, 1H), 7.46 (s, 1H), 7.10 (t, J=8.0Hz, 1H), 6.96 (d, J= 8.9Hz, 2H), 6.89 (d, J=7.9Hz, 1H), 6.78 (s, 1H), 6.41 (d, J=7.8Hz, 1H), 4.01 (s, 3H), 3.67 (s,2H),3.22–3.13(m,4H),2.64–2.57(m,4H),2.52(s,3H),2.36(s,3H)。

The preparation of 26.4 compound IB-7

Using compound 23B-7 as raw material, compound IB-7 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 8.38 (s, 1H), 7.63 (s, 1H), 7.56 (t, J=9.7Hz, 4H), 7.26 (d, J=3.9Hz, 2H), 7.14 (s, 1H), 6.91 (d, J=8.9Hz, 2H), 6.49-6.41 (m, 1H), 6.30 (dd, J=16.8,10.1Hz, 1H), 5.81-5.70 (m, 1H), 3.98 (s, 3H), 3.22-3.07 (m, 4H), 2.60 (d, J=4.7Hz, 4H), 2.50 (s, 4H), 2.36 (s, 3H).

Embodiment 27

27.2 the preparation of compound 22B-8

Using 21B-3 and corresponding aryl moieties as raw material, compound 22B-8 is synthesized according to method 13.2.¹H NMR (400MHz,CDCl₃) δ 8.79 (s, 1H), 8.06 (d, J=8.1Hz, 1H), 7.92 (d, J=8.1Hz, 1H), 7.74 (s, 1H), 7.64 (d, J=8.1Hz, 2H), 7.47 (t, J=8.1Hz, 1H), 6.93 (d, J=8.2Hz, 2H), 6.89 (s, 1H), 4.03 (s,3H),3.94–3.85(m,4H),3.18–3.08(m,4H),2.54(s,3H)。

27.3 the preparation of compound 23B-8

Using compound 22B-8 as raw material, compound 23B-8 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.61 (d, J=8.9Hz, 2H), 7.51-7.48 (m, 1H), 7.47 (s, 1H), 7.11 (t, J=8.0Hz, 1H), 6.97-6.90 (m,3H),6.77(s,1H),6.45–6.40(m,1H),4.02(s,3H),3.91–3.83(m,4H),3.67(s,2H),3.16– 3.06(m,4H),2.53(s,3H)。

The preparation of 27.4 compound IB-8

Using compound 23B-8 as raw material, compound IB-8 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 8.39 (s, 1H), 7.67-7.55 (m, 3H), 7.51 (d, J=5.8Hz, 1H), 7.37 (s, 1H), 7.34-7.27 (m, 2H), 7.12 (s, 1H), 6.91 (s, 2H), 6.47 (d, J=16.7Hz, 1H), 6.29 (dd, J=16.7,10.2Hz, 1H), 5.78 (d, J=10.2Hz, 1H), 4.00 (s, 3H), 3.90-3.79 (m, 4H), 3.26-2.95 (m, 4H), 2.51 (s, 3H).

Embodiment 28

28.2 the preparation of compound 22B-9

Using 21B-3 and corresponding aryl moieties as raw material, compound 22B-9 is synthesized according to method 13.2.¹H NMR (400MHz,CDCl₃) δ 8.91 (s, 1H), 8.54 (d, J=8.6Hz, 1H), 8.10 (dd, J=8.2,1.4Hz, 1H), 7.97- 7.90 (m, 1H), 7.77 (s, 1H), 7.51 (t, J=8.2Hz, 1H), 7.36 (s, 1H), 6.61-6.52 (m, 2H), 4.03 (s, 3H),3.93(s,3H),3.91–3.82(m,4H),3.18–3.07(m,4H),2.56(s,3H)。

The preparation of 28.3 compound 23B-9

Using compound 22B-9 as raw material, compound 23B-9 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 8.44 (d, J=7.7Hz, 1H), 7.56-7.44 (m, 2H), 7.13 (t, J=7.9Hz, 1H), 6.97 (d, J=7.9Hz, 1H), 6.62-6.51 (m, 2H), 6.43 (d, J=7.8Hz, 1H), 4.01 (s, 3H), 3.96-3.82 (m, 7H), 3.70 (s, 2H), 3.22–3.03(m,4H),2.54(s,3H)。

The preparation of 28.4 compound IB-9

Using compound 23B-9 as raw material, compound IB-9 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 8.36 (d, J=8.6Hz, 1H), 8.13 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.53 (d, J=6.7Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 7.35-7.25 (m, 2H), 6.59-6.50 (m, 2H), 6.43 (d, J=16.8Hz, 1H), 6.26 (dd, J=16.8,10.1Hz, 1H), 5.72 (d, J=10.1Hz, 1H), 3.93 (s, 3H), 3.86 (d, J=7.1Hz, 7H), 3.11 (d, J=4.5Hz, 4H), 2.46 (s, 3H).

Embodiment 29

29.2 the preparation of compound 22B-10

Using 21B-3 and corresponding aryl moieties as raw material, compound 22B-10 is synthesized according to method 13.2.¹H NMR (400MHz,CDCl₃) δ 8.87 (s, 1H), 8.51 (d, J=9.4Hz, 1H), 8.12 (d, J=9.3Hz, 1H), 7.92 (d, J= 9.6Hz,1H),7.77(s,1H),7.54–7.45(m,1H),7.34(s,1H),6.65–6.53(m,2H),4.02(s,3H), 3.92(s,3H),3.25–3.12(m,4H),2.68–2.51(m,7H),2.37(s,3H)。

The preparation of 29.3 compound 23B-10

Using compound 22B-10 as raw material, compound 23B-10 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 8.40 (d, J=8.6Hz, 1H), 7.53 (d, J=6.5Hz, 2H), 7.17 (s, 1H), 7.15-7.07 (m, 1H), 6.96 (d, J= 7.9Hz,1H),6.64–6.54(m,2H),6.45–6.39(m,1H),3.99(s,3H),3.87(s,3H),3.72(s,2H), 3.22–3.12(m,4H),2.66–2.57(m,4H),2.52(s,3H),2.36(s,3H)。

The preparation of 29.4 compound IB-10

Using compound 23B-10 as raw material, compound IB-10 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 8.35 (d, J=8.5Hz, 1H), 8.22 (s, 1H), 7.65 (s, 1H), 7.60-7.48 (m, 2H), 7.39 (d, J=8.7Hz, 1H), 7.35-7.26 (m, 3H), 6.62-6.53 (m, 2H), 6.45 (d, J=16.8Hz, 1H), 6.28 (dd, J=16.8, 10.1Hz, 1H), 5.76 (d, J=10.1Hz, 1H), 3.98 (s, 3H), 3.88 (s, 3H), 3.26-3.11 (m, 4H), 2.66- 2.55(m,4H),2.50(s,3H),2.37(s,3H)。

Embodiment 30

The preparation of 30.1 compound 21B-11

Using corresponding parent segment as raw material, compound IB-10 is synthesized according to method 1.1.¹H NMR(400MHz,CDCl₃) δ8.27–8.16(m,2H),7.73–7.62(m,2H),4.21(s,3H),2.68(s,3H)。

The preparation of 30.2 compound 22B-11

Using compound 21B-11 and corresponding aryl moieties as raw material, compound 22B-11 is synthesized according to method 1.2.¹H NMR(400MHz,CDCl₃) δ 8.33 (d, J=8.4Hz, 1H), 8.24 (t, J=2.1Hz, 1H), 8.21-8.16 (m, 1H), 7.72-7.56 (m, 2H), 7.17 (s, 1H), 6.51 (d, J=2.4Hz, 1H), 6.49-6.42 (m, 1H), 4.12 (s, 3H), 3.83(s,3H),3.24–3.07(m,4H),2.73–2.50(m,7H),2.34(s,3H)。

The preparation of 30.3 compound 23B-11

Using compound 22B-11 as raw material, compound 23B-11 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.86-7.76 (m, 1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.23-7.06 (m, 3H), 7.00 (d, J=7.7Hz, 1H), 6.91 (t, J=9.0Hz, 1H), 6.46 (d, J=7.7Hz, 1H), 4.02 (s, 3H), 3.93-3.59 (m, 6H), 3.10-2.97 (m,4H),2.54(s,3H)。

The preparation of 30.4 compound IB-11

Using compound 23B-11 as raw material, compound IB-11 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 8.30 (d, J=8.8Hz), 7.84-7.50 (m), 7.50-7.35 (m), 7.24 (s), 7.07 (d, J=8.0Hz), 6.55-6.34 (m), 6.24 (dd, J=16.8,10.2Hz), 5.74 (d, J=10.2Hz), 4.09 (s), 3.78 (s), 3.22-3.03 (m), 2.70–2.50(m),2.37(s)。

Embodiment 31

31.2 the preparation of compound 22B-12

Using compound 21B-11 and corresponding aryl moieties as raw material, compound 22B-12 is synthesized according to method 1.2.¹H NMR(400MHz,CDCl₃) δ 8.22 (t, J=2.1Hz, 1H), 8.20-8.14 (m, 1H), 7.70-7.58 (m, 2H), 7.52- 7.41(m,2H),6.88–6.76(m,2H),6.67(s,1H),4.12(s,3H),4.10–4.06(m,2H),3.77–3.70(m, 2H),3.45(s,3H),2.59(s,3H)。

The preparation of 31.3 compound 23B-12

Using compound 22B-12 as raw material, compound 23B-12 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.53 (d, J=8.2Hz, 2H), 7.21 (t, J=8.0Hz, 1H), 6.84 (d, J=8.3Hz, 2H), 6.75 (s, 1H), 6.69 (d, J=8.0Hz, 1H), 6.65-6.58 (m, 2H), 4.16-4.03 (m, 5H), 3.81-3.69 (m, 4H), 3.45 (s, 3H), 2.58(s,3H)。

The preparation of 31.4 compound IB-12

Using compound 23B-12 as raw material, compound IB-12 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 7.98 (s, 1H), 7.64-7.55 (m, 1H), 7.51 (s, 1H), 7.42 (d, J=8.4Hz, 2H), 7.32 (t, J=8.1Hz, 1H), 7.00 (d, J=7.9Hz, 1H), 6.87 (s, 1H), 6.76 (d, J=8.4Hz, 2H), 6.39 (d, J=16.8Hz, 1H), 6.24 (dd, J=16.8,10.2Hz, 1H), 5.70 (d, J=10.1Hz, 1H), 4.06 (s, 5H), 3.78-3.66 (m, 2H), 3.43(s,3H),2.53(s,3H)。

Embodiment 32

32.2 the preparation of compound 22B-13

Using compound 21B-11 and corresponding aryl moieties as raw material, compound 22B-13 is synthesized according to method 1.2.¹H NMR(400MHz,CDCl₃) δ 8.23 (s, 1H), 8.18 (d, J=7.8Hz, 1H), 7.69-7.60 (m, 2H), 7.49 (d, J= 8.5Hz, 2H), 6.83 (d, J=8.5Hz, 2H), 6.66 (s, 1H), 4.13 (s, 3H), 3.93-3.81 (m, 4H), 3.15-3.02 (m,4H),2.60(s,3H)。

The preparation of 32.3 compound 23B-13

Using compound 22B-13 as raw material, compound 23B-13 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.55 (d, J=8.5Hz, 2H), 7.21 (t, J=7.8Hz, 1H), 6.85 (d, J=8.5Hz, 2H), 6.78 (s, 1H), 6.69 (d, J=8.0Hz, 1H), 6.66-6.57 (m, 2H), 4.10 (s, 3H), 3.90-3.83 (m, 4H), 3.78 (s, 2H), 3.13- 3.04(m,4H),2.57(s,3H)。

The preparation of 32.4 compound IB-13

Using compound 23B-13 as raw material, compound IB-13 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 7.66 (d, J=7.1Hz, 1H), 7.61-7.42 (m, 4H), 7.39 (t, J=8.1Hz, 1H), 7.05 (d, J=8.1Hz, 1H), 6.81 (s, 3H), 6.43 (d, J=16.8Hz, 1H), 6.24 (dd, J=16.8,10.1Hz, 1H), 5.76 (d, J=10.1Hz, 1H),4.09(s,3H),3.95–3.77(m,4H),3.34–2.83(m,4H),2.57(s,3H)。

Embodiment 33

The preparation of 33.2 compound 22B-14

Using compound 21B-11 and corresponding aryl moieties as raw material, compound 22B-14 is synthesized according to method 1.2.¹H NMR(400MHz,CDCl₃) δ 8.24 (s, 1H), 8.18 (d, J=7.8Hz, 1H), 7.70-7.54 (m, 4H), 7.35-7.28 (m, 2H), 7.06 (t, J=7.4Hz, 1H), 7.01-6.89 (m, 4H), 6.75 (s, 1H), 4.14 (s, 3H), 2.61 (s, 3H).

The preparation of 33.3 compound 23B-14

Using compound 22B-14 as raw material, compound 23B-14 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.61 (d, J=8.6Hz, 2H), 7.34-7.27 (m, 2H), 7.22 (t, J=8.0Hz, 1H), 7.04 (t, J=7.2Hz, 1H), 7.01-6.90 (m, 4H), 6.85 (s, 1H), 6.69 (d, J=8.0Hz, 1H), 6.65-6.56 (m, 2H), 4.11 (s, 3H), 3.77(s,2H),2.58(s,3H)。

The preparation of 33.4 compound IB-14

Using compound 23B-14 as raw material, compound IB-14 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 7.64-7.56 (m, 3H), 7.53 (d, J=7.5Hz, 1H), 7.43-7.35 (m, 2H), 7.33-7.27 (m, 2H), 7.09-7.01 (m, 2H), 7.00-6.86 (m, 5H), 6.43 (d, J=16.9Hz, 1H), 6.23 (dd, J=16.8,10.3Hz, 1H), 5.77 (d, J=10.2Hz, 1H), 4.11 (s, 3H), 2.58 (s, 3H).

Embodiment 34

The preparation of 34.2 compound 22B-15

Using compound 21B-11 and corresponding aryl moieties as raw material, compound 22B-15 is synthesized according to method 1.2.¹H NMR(400MHz,CDCl₃) δ 7.64-7.56 (m, 3H), 7.53 (d, J=7.5Hz, 1H), 7.43-7.35 (m, 2H), 7.33- 7.27 (m, 2H), 7.09-7.01 (m, 2H), 7.00-6.86 (m, 5H), 6.43 (d, J=16.9Hz, 1H), 6.23 (dd, J= 16.8,10.3Hz, 1H), 5.77 (d, J=10.2Hz, 1H), 4.11 (s, 3H), 2.58 (s, 3H).

The preparation of 34.3 compound 23B-15

Using compound 22B-15 as raw material, compound 23B-15 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.53 (d, J=8.4Hz, 2H), 7.21 (t, J=7.9Hz, 1H), 6.87 (d, J=8.3Hz, 2H), 6.74 (s, 1H), 6.69 (d, J=7.9Hz, 1H), 6.66-6.57 (m, 2H), 4.10 (s, 3H), 3.83-3.71 (m, 2H), 3.20-3.07 (m, 4H), 2.65–2.52(m,7H),2.35(s,3H)。

The preparation of 34.4 compound IB-15

Using compound 23B-15 as raw material, compound IB-15 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 7.72-7.61 (m, 2H), 7.57 (s, 1H), 7.46 (d, J=8.6Hz, 2H), 7.39 (t, J=8.1Hz, 1H), 7.05 (d, J= 7.6Hz, 1H), 6.87 (s, 1H), 6.82 (d, J=8.6Hz, 2H), 6.43 (d, J=16.8Hz, 1H), 6.29 (dd, J= 16.8,10.1Hz, 1H), 5.76 (d, J=10.1Hz, 1H), 4.10 (s, 3H), 3.24-3.09 (m, 4H), 2.75-2.61 (m, 4H),2.57(s,3H),2.42(s,3H)。

Embodiment 35

The preparation of 35.2 compound 22B-16

Using compound 21B-11 and corresponding aryl moieties as raw material, compound 22B-16 is synthesized according to method 1.2.¹H NMR(400MHz,CDCl₃) δ 8.34 (d, J=8.6Hz, 1H), 8.25 (s, 1H), 8.19 (d, J=8.0Hz, 1H), 7.73- 7.57 (m, 2H), 7.18 (s, 1H), 6.49 (d, J=2.1Hz, 1H), 6.44 (d, J=8.8Hz, 1H), 4.12 (s, 3H), 3.97–3.78(m,7H),3.22–3.02(m,4H),2.61(s,3H)。

35.3 the preparation of compound 23B-16

Using compound 22B-16 as raw material, compound 23B-16 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 8.44 (d, J=7.0Hz, 1H), 7.22 (t, J=7.9Hz, 2H), 6.72 (d, J=7.8Hz, 1H), 6.68-6.58 (m, 2H), 6.53–6.39(m,2H),4.10(s,3H),3.93–3.67(m,9H),3.18–3.00(m,4H),2.58(s,3H)。

The preparation of 35.4 compound IB-16

Using compound 23B-16 as raw material, compound IB-16 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 8.30 (d, J=7.9Hz, 1H), 8.08-7.85 (m, 1H), 7.77 (d, J=7.4Hz, 1H), 7.46-7.33 (m, 2H), 7.05 (d, J=5.7Hz, 1H), 6.52-6.34 (m, 3H), 6.22 (dd, J=16.7,10.2Hz, 1H), 5.72 (d, J=10.1Hz, 1H),4.08(s,3H),3.93–3.81(m,4H),3.75(s,3H),3.13–2.98(m,4H),2.56(s,3H)。

Embodiment 36

The preparation of 36.2 compound 22B-17

Using compound 21B-11 and corresponding aryl moieties as raw material, compound 22B-17 is synthesized according to method 1.2.¹H NMR(400MHz,CDCl₃) δ 8.36-8.13 (m, 2H), 7.73-7.56 (m, 3H), 7.01 (d, J=8.7Hz, 1H), 6.94- 6.68(m,2H),4.14(s,3H),3.96–3.80(m,4H),3.10–2.92(m,4H),2.61(s,3H)。

The preparation of 36.3 compound 23B-17

Using compound 22B-17 as raw material, compound 23B-17 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.68 (d, J=15.0Hz, 1H), 7.22-7.11 (m, 2H), 7.00 (d, J=8.6Hz, 1H), 6.78 (t, J=9.1Hz, 1H), 6.63 (d, J=8.1Hz, 1H), 6.58-6.50 (m, 2H), 4.06 (s, 3H), 3.95-3.63 (m, 6H), 3.03-2.91 (m, 4H),2.54(s,3H)。

The preparation of 36.4 compound IB-17

Using compound 23B-17 as raw material, compound IB-17 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 7.90 (s, 1H), 7.70-7.60 (m, 1H), 7.60-7.48 (m, 2H), 7.33 (t, J=8.1Hz, 1H), 7.08-6.95 (m, 3H), 6.78 (t, J=9.1Hz, 1H), 6.39 (d, J=16.8Hz, 1H), 6.23 (dd, J=16.8,10.2Hz, 1H), 5.71 (d, J=10.2Hz, 1H), 4.09 (s, 3H), 3.92-3.77 (m, 4H), 3.05-2.90 (m, 4H), 2.56 (s, 3H).

Embodiment 37

The preparation of 37.2 compound 22B-18

Using compound 21B-11 and corresponding aryl moieties as raw material, compound 22B-18 is synthesized according to method 1.2.¹H NMR(400MHz,CDCl₃) δ 8.21 (s, 1H), 8.18 (d, J=7.2Hz, 1H), 7.74-7.53 (m, 3H), 7.01 (d, J= 8.6Hz,1H),6.91–6.73(m,2H),4.12(s,3H),3.16–2.95(m,4H),2.78–2.45(m,7H),2.35(s, 3H)。

The preparation of 37.3 compound 23B-18

Using compound 22B-18 as raw material, compound 23B-18 is synthesized according to method 1.3.¹H NMR(400MHz,CDCl₃)δ 7.71-7.63 (m, 1H), 7.24-7.15 (m, 1H), 7.12-6.97 (m, 2H), 6.84 (t, J=9.1Hz, 1H), 6.73-6.55 (m,3H),4.09(s,3H),3.83(s,2H),3.15–3.01(m,4H),2.74–2.64(m,4H),2.57(s,3H),2.41 (s,3H)。

The preparation of 37.3 compound IB-18

Using compound 23B-18 as raw material, compound IB-18 is synthesized according to method 1.4.¹H NMR(400MHz,CDCl₃)δ 8.10-7.92 (m, 1H), 7.70-7.57 (m, 2H), 7.54 (d, J=7.9Hz, 1H), 7.35 (t, J=8.1Hz, 1H), 7.07 (s, 1H), 7.04-6.96 (m, 2H), 6.81 (t, J=9.1Hz, 1H), 6.40 (d, J=16.9Hz, 1H), 6.26 (dd, J= 16.8,10.1Hz, 1H), 5.72 (d, J=10.0Hz, 1H), 4.09 (s, 3H), 3.10-2.94 (m, 4H), 2.70-2.45 (m, 7H),2.34(s,3H)。

Embodiment 38

The non-specific toxicity of mouse lymphocyte acts on and breeder reaction experiment

Sterile to take its spleen and prepare individual cells suspension after mouse is put to death, erythrocyte cracked liquid removes red blood cell, adjusts Cell concentration.

Mouse spleen lymphocyte suspension 1 × 10⁶/ hole is inoculated in 96 orifice plates, while various concentration compound is added, and separately sets Corresponding Vehicle controls and culture solution Background control, total volume are 200 μ l.37 DEG C, 5%CO₂48h is cultivated in incubator.Terminate 20 μ l CCK-8 solution are added in 6h before cultivating.Terminate to culture, OD value is measured at microplate reader 450nM (reference 650nM).

Mouse spleen lymphocyte suspension 5 × 10⁵/ hole is inoculated in 96 orifice plates, and ConA (5 μ g/ml of final concentration) or LPS is added (10 μ g/ml of final concentration), various concentration compound, and set accordingly without ConA, LPS control wells and without drug control wells.37 DEG C, 5%CO₂48h is cultivated in incubator.Culture terminates preceding 8h, and 25 μ l are added in every hole³H- thymidylic acid (10 μ Ci/ ml).It continues to culture until the end of the experiment.Cell is collected with cell collector to glass fibre membrane, be added scintillation solution after in Incorporation cell DNA is read in Beta numeration instrument (MicroBeta Trilux, PerkinElmer)³H-TdR amount, with the representative of cpm value The case where cell Proliferation.

Result evaluation:

Compound to the effect of the non-specific toxicity of spleen cell using sample to be tested OD value divided by cell control well OD value, Labeled as cell survival rate (%).The breeder reaction of lymphocyte subtracts tested sample cpm using positive control sample cpm value Then value removes positive control sample cpm value, be labeled as proliferation inhibition rate (%).CC₅₀And IC₅₀Value uses GraphPad Prism The fitting of 5 softwares.Wherein A ' means CC₅₀≤ 1000nmol, B ' mean CC₅₀Mean CC for 1000-5000nmol, C '₅₀It is 5000- 10000nmol, and D ' means CC₅₀≥10000nmol.Wherein A means IC₅₀≤ 500nmol, B mean IC₅₀For 500- 1000nmol, C mean IC₅₀It is 1000-10000nmol, D means IC₅₀≥10000nmol.According to compound SI value, SI > 5 are recognized There is immunosuppressive activity for compound；Think that compound does not have immunosuppressive activity in SI < 2；Think compound in 2 < SI < 5 Immunosuppressive activity may be due to caused by its cytotoxicity.

1 part test-compound immunosuppressive activity the selection result of table

Pharmacological evaluation proves that the compound of the present invention IA-14, IB-3 has mouse T, B lymphocyte proliferation stronger Inhibitory activity, and without obvious cytotoxic effect, especially IA-14.IA-02, IA-03, IA-06, IB-13 drench mouse T, B Bar cell Proliferation has certain inhibitory activity.IA-13, IB-01, IB-03, IB-07, IB-06, IB-16 increase T lymphocyte Grow without obvious inhibitory activity or activity it is weaker, to mouse B lymphocyte proliferation have certain inhibitory activity, especially IA-13, IB-09.Remaining compound is weaker without obvious inhibitory activity or activity to mouse T, B lymphocyte proliferation.

From these facts it may be concluded that part of compounds of the invention, lives since it effectively inhibits immunocyte Property, so that the prevention or treatment to immunological diseases are effective.

Embodiment 39

The oral administration biaavailability of compound IA-12 is studied

Compound IA-12 shows good immune cell propagation inhibitory activity, as immunosuppressor into one Before step is studied on animal model, its oral administration biaavailability is studied, as a result as shown in table 2 and table 3.

PK (2mg/kg) is administered in 2 single injection of table

PK (10mg/kg) is administered in 3 single oral of table

After IA-12 gastric infusion, whole blood exposed amount AUC is larger, Relative oral bioavailability 44.59%, druggability Preferably.

Embodiment 40

Compound IA-12 back of mice air bag inflammatory reaction result

Compound IA-12 ion vitro immunization activity is good, has good oral administration biaavailability, therefore lure by carrageenan The vivo immunization inhibitory activity of compound is further investigated in the back of mice air bag inflammatory reaction experiment led.Mouse subcutaneously repeatedly Air is injected, after a few days, air bag inner wall can form structure and function and the quite similar inner membrance of articular cavity synovial membrane.By carrageenan After injecting in air bag, inflammatory reaction can be caused, be mainly shown as leukocyte infiltration and inflammatory factor release.With methotrexate (MTX) (MTX, 2mg/kg) is positive compound, and resulting experimental result is as shown in Figure 1.

It is pg/mL that Fig. 1 ordinate, which is tumor necrosis factor emission levels its unit, and abscissa is blank group, contrast groups, first Tri- kinds of different dosing concentration of aminopterin positive controls and compound IA-12.

Fig. 1 shows compounds to the inhibiting effect of leukocyte infiltration degree after immunostimulation, the results show that compound IA- 12 have centainly leukocyte infiltration caused by immunostimulation under tri- administration concentrations of 10mg/kg, 30mg/kg and 100mg/kg Inhibiting effect, wherein inhibiting effect is significant under 30mg/kg and 100mg/kg administration concentration.Fig. 1 shows compounds to immune thorn The inhibiting effect of tumor necrosis factor after swashing, the results show that compound IA-12 is under 30mg/kg and 100mg/kg administration concentration It is significant to tumor necrosis factor release inhibiting effect, inhibiting effect is discharged without tumor necrosis factor under 10mg/kg administration concentration. The experimental results showed that, compound IA-12 is significant to neoplasm necrosis release inhibiting effect in vivo above.

Claims

1. pyrazoles [4,3-d] pyrimidine derivatives that one kind has immunosuppressive activity, which is characterized in that the analog derivative has formula Structure shown in IA or IB:

In Formulas I A or IB,

R¹For hydrogen or C_1-6Alkyl；

R²For hydrogen or C_1-6Alkyl；

R³For hydrogen, halogen, C_1-6Alkyl, C_1-6Halogenated alkyl, C_1-6Alkoxy, C_1-6Halogenated alkoxy, hydroxyl, cyano or nitro；

R⁵For hydrogen atom, halogen atom, hydroxyl, nitro, cyano, C_6-12Aryl, 5-10 unit's heteroaryl, phenoxy group, heterocycle C_1-6 Alkyl or C_1-6Alkyl oxy C_1-6Alkyl；

X is NH or O；

A and B is each independently hydrogen, halogen or dimethylamino；

Wherein:

The heterocycle C_1-6Alkyl is

The C_1-6Alkyl oxy C_1-6Alkyl is

2. a kind of pharmaceutical composition, which is characterized in that containing compound IA, IB or its pharmaceutically acceptable salt and pharmaceutically may be used The carrier of receiving；

The pharmaceutically acceptable carrier is nanoparticle ball or liposome；

The pharmaceutically acceptable salt is hydrochloride, sulfate, phosphate, maleate, the fumaric acid of compound IA or IB Salt, citrate, mesylate, tosilate or tartrate.

3. compound described in a kind of claim 1 preparation for prevent or treat diseases associated with inflammation, autoimmune disease or Purposes in the drug of immune-mediated disease.

4. purposes according to claim 3, which is characterized in that the diseases associated with inflammation, autoimmune disease or immune Mediated disease is mediated by both the bone-marrow-derived lymphocyte of abnormal activation, T lymphocyte.

5. purposes according to claim 3, which is characterized in that the diseases associated with inflammation, autoimmune disease or immune Mediated disease is arthritis, rheumatoid arthritis, joint of vertebral column inflammation, urarthritis, other arthrtic conditions, wolf Sore, systemic loupus erythematosus, psoriasis, eczema or dermatitis.