Cnoline compounds as prolyl hydroxylase inhibitors

Abstract

The invention relates to the field of organic synthesis, and particularly discloses a cinnoline compound as shown in a formula I. The cinnoline compound can be used as a prolyl hydroxylase inhibitor. The compound has prolyl hydroxylase inhibitory activity and can be used for treating diseases mediated by prolyl hydroxylase activity, such as renal anemia and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a cinnoline compound having prolyl hydroxylase inhibitory effect and a drug combination thereof, and further relates to a preparation method and pharmaceutical use thereof. Background Art

[0002] In cases of anemia, trauma, tissue necrosis and defect, tissues or cells are often in a state of hypoxia. Hypoxia leads to the expression of a series of transcription induction factors, which are involved in angiogenesis, iron and sugar metabolism, and cell growth and proliferation. Among them, hypoxia inducible factor (HIF) is a transcription factor activated by somatic cells under hypoxia, which responds to cellular hypoxia by mediating a series of gene regulation in biological cells. HIF is a heterodimer containing an oxygen-regulated α-subunit (HIFα) and a constitutively expressed β-subunit (HIFβ / ARNT). In oxygenated (normal oxygen content) cells, the HIF a subunit is rapidly degraded through the mechanism of ubiquitination by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. Under hypoxic conditions, HIFα is not degraded and the active HIFα / β complex accumulates in the nucleus and activates the expression of various genes, including glycolytic enzymes, glucose transporters, erythropoietin (EPO) and vascular endothelial growth factor (VEGF).

[0003] Erythropoietin (EPO) is a naturally occurring hormone produced with HIFα that stimulates the production of red fat (erythrocytes) that carry oxygen throughout the body. EPO is usually secreted by the kidneys, and endogenous EPO increases under conditions of reduced oxygen (hypoxia). All types of anemia are characterized by a reduced ability of the blood to carry oxygen, and are therefore accompanied by similar signs and symptoms, including pale skin and mucous membranes, weakness, dizziness, fatigue and lethargy, leading to a decrease in quality of life. Anemia is usually associated with conditions in which there is a lack of blood in red blood cells or in hemoglobin. Common causes of anemia include iron, vitamin B12 and folic acid deficiencies, and are also complicated by chronic diseases, such as inflammatory diseases, including diseases with secondary bone marrow inflammatory suppression, etc. Anemia is also associated with renal dysfunction, and most renal failure patients who are often dialyzed suffer from chronic anemia.

[0004] Prolyl hydroxylase domain (PHD) is a key factor in regulating HIF. Under normoxic conditions, PHD can hydroxylate two key proline residues Pro402 and Pro564 of HIFα, increase its affinity with pVHL, and accelerate the degradation process. Under hypoxia and other pathological conditions, the HIF reaction catalyzed by PHD is blocked, the degradation rate of protease is slowed down, causing HIFα to accumulate in cells, and then causing a series of adaptive responses of cells to hypoxia. Inhibiting PHD through PHD inhibitors, prolonging the action of HIF, and then increasing the expression of genes such as EPO, can effectively treat and prevent HIF-related and / or EPO-related diseases, such as anemia, local ischemia and hypoxia.

[0005] Although prior art such as WO2004108681A1 discloses isoquinoline compounds for regulating HIF and / or EPO, its therapeutic effect is still not very satisfactory, which greatly limits its extensive use in clinical applications. CN101394843A discloses a cinnoline compound of the general formula and explains that the compound of the general formula can be used as a medicament for stabilizing HIFα, but does not provide the relevant reagent implementation effect. Therefore, there is still a need for new effective compounds for treating the following diseases with HIF as the target: erythropoietin-related conditions, such as anemia, including anemia related to diabetes, anemia, ulcers, renal failure, cancer, infection, dialysis, surgery and chemotherapy, and conditions involving ischemia and hypoxia, such as arterial occlusive disease, angina pectoris, intestinal infarction, pulmonary infarction, cerebral ischemia and myocardial infarction. It is also necessary to effectively prevent the tissue damage caused by ischemia, which occurs due to pulmonary diseases such as atherosclerosis, diabetes and pulmonary embolism and similar diseases. In summary, there is a need in the art for methods and compounds that modulate HIF and / or endogenous erythropoietin and that are useful in treating and preventing HIF-related and EPO-related disorders, including conditions involving anemia, ischemia, and hypoxia. Summary of the invention

[0006] The present invention relates to a cinnoline compound as a HIF-PHD inhibitor and a pharmaceutical composition thereof, which can be used to treat various HIF-related or EPO-related diseases, such as anemia, etc. Specifically, the present invention relates to a compound having a structure of formula (I) and a pharmaceutical composition thereof, wherein the compound or pharmaceutical composition can effectively inhibit prolyl hydroxylase.

[0007]

[0008] In one aspect, the present invention relates to a compound, which is a cinnoline compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof:

[0009]

[0010] in,

[0011] R 1 , R 2 , R 3 , R 4 Each is independently a unit selected from the following atoms or groups:

[0012] 1) Hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, halogen, cyano; or,

[0013] 2) aryloxy, heteroaryloxy, which are optionally substituted with one or more, identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; or two adjacent carbon atoms in the aromatic ring thereof can form a heterocyclic structure; or,

[0014] 3) aryl, heteroaryl, optionally substituted with one or more, identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; or two adjacent carbon atoms in the aromatic ring thereof can form a heterocyclic structure; or,

[0015] 4) Wherein, L is selected from -CH2-, -CH2O-; n is 0 or 1; R 5 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, substituted phenyl, 5-6 membered aromatic heterocycle containing oxygen or nitrogen, R 5 Optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen;

[0016] The heterocyclic structure has the following structure:

[0017]

[0018] which are optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6haloalkyl, halogen, cyano, phenyl; wherein n is an integer of 1, 2, 3 or 4, A 1 and A 2 Each is independently selected from oxygen, carbon or nitrogen atoms.

[0019] Furthermore, R 1 , R 2 , R 3 , R 4 Each is independently a unit selected from the following atoms or groups:

[0020] 1) Deuterium, C 1-6 haloalkyl; or,

[0021] 2) aryloxy, heteroaryloxy, which are optionally substituted with one or more, identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; or two adjacent carbon atoms in the aromatic ring thereof can form a heterocyclic structure; or,

[0022] 3) aryl, heteroaryl, optionally substituted with one or more, identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; or two adjacent carbon atoms in the aromatic ring thereof can form a heterocyclic structure; or,

[0023] 4) Wherein, L is selected from -CH2-, -CH2O-; n is 0 or 1; R 5 Selected from C 3-6 Cycloalkyl, phenyl (n is not 0), substituted phenyl, 5-6 membered aromatic heterocycle containing oxygen or nitrogen, R 5 Optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen;

[0024] The heterocyclic structure has the following structure:

[0025]

[0026] which are optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, halogen, cyano, phenyl; wherein n is an integer of 1, 2, 3 or 4, A 1 and A2 Each is independently selected from oxygen, carbon or nitrogen atoms.

[0027] Furthermore, the compound has the structure of the following formula (Ia), (Ib), (Ic):

[0028]

[0029] in,

[0030] 1) In formula (Ia) and (Ib), Ar is an aryl group or a heteroaryl group, which is optionally substituted with one or more identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; or optionally, two adjacent carbon atoms in the aromatic ring form a heterocyclic structure:

[0031] The heterocyclic structure has the following structure:

[0032]

[0033] which are optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, halogen, cyano, phenyl; wherein n is an integer of 1, 2, 3 or 4, A 1 and A 2 are each independently selected from oxygen, carbon or nitrogen atoms;

[0034] 2) In formula (Ic), L is selected from -CH2-, -CH2O-; n is 0 or 1; R 5 Selected from C 3-6 Cycloalkyl, phenyl (n is not 0), substituted phenyl, 5-6 membered aromatic heterocycle containing oxygen or nitrogen, R 5 Optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or a 5-6 membered aromatic heterocycle containing oxygen or nitrogen.

[0035] Furthermore, the C 1-6 The alkyl group is selected from C 1-4 Alkyl; the C 1-6 Alkoxy is selected from C 1-4 Alkoxy; the C 1-6 The haloalkyl group is selected from C 1-4 Halogenated alkyl.

[0036] Furthermore, the C 1-4 The alkyl group is selected from C1-2 Alkyl, C 1-4 Alkoxy is selected from C 1-2 Alkoxy, C 1-4 The haloalkyl group is selected from C 1-2 Halogenated alkyl.

[0037] Furthermore, the halogen is any one of F, Cl, I and Br.

[0038] Furthermore, the aryloxy group is a phenoxy group.

[0039] Furthermore, the aryl group is any one of phenyl and naphthyl.

[0040] Furthermore, the heteroaryl group is any one of pyridyl, pyrimidinyl and quinolyl.

[0041] Furthermore, the C 3-6 The cyclic group is any of a cyclopropyl group and a cyclohexyl group.

[0042] Furthermore, in the heterocyclic structure, n is an integer of 2, A 1 and A 2 are each independently selected from oxygen atoms.

[0043] Furthermore, the heterocyclic structure is further optionally substituted with one or two, identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, halogen, cyano, phenyl; preferably substituted with one or two, identical or different C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, halogen, cyano, phenyl. Further, the compound is selected from:

[0044] 1)

[0045] 2)

[0046] 3)

[0047] 4)

[0048] 5)

[0049] 6)

[0050] 7)

[0051] 8)

[0052] 9)

[0053] 10)

[0054] 11)

[0055] 12)

[0056] 13)

[0057] 14)

[0058] 15)

[0059] 16)

[0060] 17)

[0061] 18)

[0062] 19)

[0063] 20)

[0064] twenty one)

[0065] twenty two)

[0066] twenty three)

[0067] twenty four)

[0068] 25)

[0069] 26)

[0070] 27)

[0071] 28) Furthermore, the compound is selected from:

[0072] 6)

[0073] 7)

[0074] 8)

[0075] 9)

[0076] 10)

[0077] 11)

[0078] twenty three)

[0079] twenty four)

[0080] 25)

[0081] 28)

[0082] On the other hand, the present invention provides a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.

[0083] Furthermore, use of the compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug in the preparation of drugs.

[0084] Further, the medicament is used for treating, preventing or pre-treating a disease which is at least partially mediated by hypoxia inducible factor (HIF) and / or erythropoietin (EPO).

[0085] Further, the disease is selected from the group consisting of at least one of anemic disorders, renal anemia, neurological disorders and / or injuries, peripheral vascular disorders, ulcers, burns, chronic wounds, and ischemia-reperfusion injury.

[0086] Furthermore, the disease may be selected from at least one of ischemia, such as myocardial infarction, pulmonary embolism, intestinal infarction, chronic renal failure, ischemic stroke, cardiosclerosis, transient ischemic attack, macular degeneration, peripheral arterial disease and congestive heart failure.

[0087] In another aspect, the present invention provides a use of the compound or pharmaceutical composition described above in the present invention in the preparation of a medicament for inhibiting the activity of prolyl hydroxylase.

[0088] Furthermore, the mode of action of the use is that the prolyl hydroxylase is contacted with the compound described herein or a pharmaceutically acceptable salt, stereoisomer, tautomer, or solvate thereof.

[0089] In another aspect, the present invention provides a method for preparing the cinnoline compound represented by formula (I);

[0090]

[0091] When R 1 , R 2 , R 3 , R 4 Each is independently a unit selected from the following atoms or groups:

[0092] 1) Hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, halogen, cyano; or,

[0093] 2) aryloxy, heteroaryloxy, which are optionally substituted with one or more, identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; or two adjacent carbon atoms in the aromatic ring thereof can form a heterocyclic structure; or,

[0094] 3) aryl, heteroaryl, optionally substituted with one or more, identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; or two adjacent carbon atoms in the aromatic ring thereof can form a heterocyclic structure; or,

[0095] 4) Wherein, L is selected from -CH2-, -CH2O-; n is 0 or 1; R 5 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, substituted phenyl, 5-6 membered aromatic heterocycle containing oxygen or nitrogen, R 5 Optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen;

[0096] The heterocyclic structure has the following structure:

[0097]

[0098] which are optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, halogen, cyano, phenyl; wherein n is an integer of 1, 2, 3 or 4, A 1 and A 2 Each is independently selected from oxygen, carbon or nitrogen atoms.

[0099] Furthermore, R 1 , R 2 , R 3 , R 4 Each is independently a unit selected from the following atoms or groups:

[0100] 1) Deuterium, C 1-6 haloalkyl; or,

[0101] 2) aryloxy, heteroaryloxy, which are optionally substituted with one or more, identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; or two adjacent carbon atoms in the aromatic ring thereof may form a heterocyclic structure;

[0102] The heterocyclic structure has the following structure:

[0103]

[0104] which are optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, halogen, cyano, phenyl; wherein n is an integer of 1, 2, 3 or 4, A 1 and A 2 are each independently selected from oxygen, carbon or nitrogen atoms;

[0105] The synthetic route is as follows:

[0106]

[0107] R 6 is any one of methyl, tert-butyl and benzyl;

[0108] The following steps are involved:

[0109] Step 1: reacting compound 1 with sodium nitrite and 2-cyanoacetamide to obtain compound 2;

[0110] Step 2: reacting compound 2 with aluminum chloride to obtain compound 3;

[0111] Step 3: reacting compound 3 with potassium hydroxide to obtain compound 4;

[0112] Step 4: reacting compound 4 with thionyl chloride to obtain compound 5;

[0113] Step 5: reacting compound 5 with a glycine ester compound to obtain compound 6;

[0114] Step 6: reacting compound 6 with lithium hydroxide to obtain a compound of formula (I);

[0115] Step 7: reacting compound 4 with a glycine ester compound to obtain compound 7;

[0116] Step eight: react compound 7 with lithium hydroxide to obtain a compound of formula (I).

[0117] Further, preferably the following steps are performed:

[0118] Step 1: reacting compound 1 with a mixture of sodium nitrite and hydrochloric acid at low temperature, then adding a mixture of 2-cyanoacetamide and sodium acetate, and reacting at room temperature to obtain compound 2;

[0119] Step 2: Compound 2 reacts with aluminum chloride under heating conditions to obtain compound 3;

[0120] Step 3: Compound 3 reacts with potassium hydroxide under heating conditions to obtain compound 4;

[0121] Step 4: Compound 4 reacts with thionyl chloride or phosphorus oxychloride under heating conditions to obtain compound 5;

[0122] Step 5: Compound 5 reacts with a glycine ester compound to obtain compound 6, wherein the glycine ester compound can be selected from any one of glycine methyl ester, glycine tert-butyl ester and glycine benzyl ester;

[0123] Step 6: Compound 6 reacts with a base to obtain a compound of formula (I), wherein the base can be selected from any one of sodium hydroxide, potassium hydroxide and lithium hydroxide;

[0124] Step 7: Compound 4 reacts with a glycine ester compound in the presence of a catalyst to obtain compound 7, wherein the glycine ester compound can be selected from any one of glycine methyl ester, glycine tert-butyl ester and glycine benzyl ester, and the catalyst can be selected from a combination of PyBOP or EDCI and HOBt;

[0125] Step eight: Compound 7 reacts with a base to obtain a compound of formula (I), wherein the base can be selected from any one of sodium hydroxide, potassium hydroxide and lithium hydroxide.

[0126] Furthermore, the present application also provides a method for preparing the compound represented by formula (Ia), and the synthetic route is as follows:

[0127]

[0128] R 6 is any one of methyl, tert-butyl and benzyl;

[0129] Step 1: Compound 1a is reacted with sodium nitrite and 2-cyanoacetamide to obtain compound 2a;

[0130] Step 2: reacting compound 2a with aluminum chloride to obtain compound 3a;

[0131] Step 3: reacting compound 3a with potassium hydroxide to obtain compound 4a;

[0132] Step 4: reacting compound 4a with thionyl chloride to obtain compound 5a;

[0133] Step 5: reacting compound 5a with a glycine ester compound to obtain compound 6a;

[0134] Step 6: reacting compound 6a with lithium hydroxide to obtain a compound of formula (Ia);

[0135] Step 7: reacting compound 4a with a glycine ester compound to obtain compound 7a;

[0136] Step eight: react compound 7a with lithium hydroxide to obtain a compound of formula (Ia).

[0137] Further, the following steps are included:

[0138] Step 1: reacting compound 1a with a mixture of sodium nitrite and hydrochloric acid at low temperature, then adding a mixture of 2-cyanoacetamide and sodium acetate, and reacting at room temperature to obtain compound 2a;

[0139] Step 2: Compound 2a reacts with aluminum chloride under heating conditions to obtain compound 3a;

[0140] Step 3: Compound 3a reacts with potassium hydroxide under heating conditions to obtain compound 4a;

[0141] Step 4: Compound 4a reacts with thionyl chloride or phosphorus oxychloride under heating conditions to obtain compound 5a;

[0142] Step 5: Compound 5a reacts with a glycine ester compound to obtain compound 6a, wherein the glycine ester compound is selected from any one of glycine methyl ester, glycine tert-butyl ester and glycine benzyl ester;

[0143] Step 6: Compound 6a reacts with a base to obtain a compound of formula (Ia), wherein the base is selected from any one of sodium hydroxide, potassium hydroxide and lithium hydroxide;

[0144] Step 7: Compound 4a reacts with a glycine ester compound in the presence of a catalyst to obtain compound 7a, wherein the glycine ester compound is selected from any one of glycine methyl ester, glycine tert-butyl ester and glycine benzyl ester, and the catalyst is selected from a combination of PyBOP or EDCI and HOBt;

[0145] Step eight: Compound 7a reacts with a base to obtain a compound of formula (Ia), wherein the base can be selected from any one of sodium hydroxide, potassium hydroxide and lithium hydroxide.

[0146] Furthermore, the present application also provides a method for preparing the compound represented by formula (Ib), and the synthetic route is as follows:

[0147]

[0148] R 6 is any one of methyl, tert-butyl and benzyl;

[0149] The following steps are involved:

[0150] Step 1: Compound 1b is reacted with sodium nitrite and 2-cyanoacetamide to obtain compound 2b;

[0151] Step 2: reacting compound 2b with aluminum chloride to obtain compound 3b;

[0152] Step 3: reacting compound 3b with potassium hydroxide to obtain compound 4b;

[0153] Step 4: reacting compound 4b with thionyl chloride to obtain compound 5b;

[0154] Step 5: reacting compound 5b with thionyl chloride or phosphorus oxychloride to obtain compound 6b;

[0155] Step 6: reacting compound 6b with arylboronic acid to obtain compound 8b;

[0156] Step 7: react compound 8b with lithium hydroxide to obtain a compound of formula (Ib).

[0157] Further, the following steps are included:

[0158] Step 1: reacting compound 1b with a mixture of sodium nitrite and hydrochloric acid at low temperature, then adding a mixture of 2-cyanoacetamide and sodium acetate, and reacting at room temperature to obtain compound 2b;

[0159] Step 2: Compound 2b reacts with aluminum chloride under heating conditions to obtain compound 3b;

[0160] Step 3: Compound 3b reacts with potassium hydroxide under heating conditions to obtain compound 4b;

[0161] Step 4: Compound 4b reacts with thionyl chloride or phosphorus oxychloride under heating conditions to obtain compound 5b;

[0162] Step 5: Compound 5b reacts with a glycine ester compound to obtain compound 6b, wherein the glycine ester compound can be selected from any one of glycine methyl ester, glycine tert-butyl ester and glycine benzyl ester;

[0163] Step 6: Compound 6 reacts with an arylboronic acid compound under the conditions of a catalyst, a ligand, and a base to obtain a compound of formula 8b, wherein the catalyst is a palladium catalyst, and the palladium catalyst can be selected from any one of Pd(PPh3)4 and Pd(dppf)2Cl; the base can be selected from any one of cesium carbonate, potassium phosphate, potassium carbonate and sodium carbonate;

[0164] Step 7: Compound 8 reacts with a base to obtain a compound of formula (I), wherein the base can be selected from any one of sodium hydroxide, potassium hydroxide and lithium hydroxide.

[0165] Furthermore, the present application also provides a method for preparing the compound represented by formula (Ic), and the synthetic route is as follows:

[0166]

[0167] R 6 is any one of methyl, tert-butyl and benzyl;

[0168] The following steps are involved:

[0169] Step 1: Compound 1c is reacted with sodium nitrite and 2-cyanoacetamide to obtain compound 2c;

[0170] Step 2: reacting compound 2c with aluminum chloride to obtain compound 3c;

[0171] Step 3: reacting compound 3c with potassium hydroxide to obtain compound 4c;

[0172] Step 4: reacting compound 4c with thionyl chloride to obtain compound 5c;

[0173] Step 5: reacting compound 5c with a glycine ester compound to obtain compound 6c;

[0174] Step 6: reacting compound 6c with an alkynyl compound to obtain compound 8c;

[0175] Step 7: react compound 8c with lithium hydroxide to obtain a compound of formula (Ic).

[0176] Further, the following steps are included:

[0177] Step 1: reacting compound 1c with a mixture of sodium nitrite and hydrochloric acid at low temperature, then adding a mixture of 2-cyanoacetamide and sodium acetate, and reacting at room temperature to obtain compound 2c;

[0178] Step 2: Compound 2c reacts with aluminum chloride under heating conditions to obtain compound 3c;

[0179] Step 3: Compound 3c reacts with potassium hydroxide under heating conditions to obtain compound 4c;

[0180] Step 4: Compound 4c reacts with thionyl chloride or phosphorus oxychloride under heating conditions to obtain compound 5c;

[0181] Step 5: Compound 5c reacts with a glycine ester compound to obtain compound 6c, wherein the glycine ester compound can be selected from any one of glycine methyl ester, glycine tert-butyl ester and glycine benzyl ester;

[0182] Step 6: Compound 6c reacts with an alkynyl compound under the conditions of a catalyst, a ligand, and a base to obtain a compound of formula 8c, wherein the catalyst is a combination of a palladium catalyst and a copper catalyst, and the palladium catalyst can be selected from any one of Pd(PPh3)2Cl2, Pd(PhCN)2Cl2 and Pd(MeCN)2Cl2; the copper catalyst can be selected from any one of cuprous iodide and copper acetate; the ligand can be selected from NN-dimethylglycine and its hydrochloride, 1,10-phenanthroline, tri-tert-butylphosphine, 2-pyridinecarboxylic acid; the base can be selected from any one of triethylamine and diisopropylethylamine;

[0183] Step 7: Compound 8c reacts with a base to obtain a compound of formula (Ic), wherein the base can be selected from any one of sodium hydroxide, potassium hydroxide and lithium hydroxide.

[0184] The term "pharmaceutically acceptable salt" as used herein is intended to mean a salt of a free acid or base of a compound represented by formula (I) which is non-toxic, biologically tolerable, or in other words biologically suitable for administration to a subject. Generally, see GS Paulekuhn, et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based Analysis of the Orange Book Database", J. Med. Chem., 2007, 50: 6665-72, SM Berge, et al., "Pharmaceutical Salts", JP harm Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahland Wermuth, Eds., Wiley-VC Hand VHCA, Zurich, 2002 (GS Paulekuhn et al., "Trends in the selection of active pharmaceutical ingredient salts based on analysis of the Orange Book database", Journal of Medicinal Chemistry, 2007, Vol. 50, pp. 6665-6672; SM Berge et al., "Pharmaceutically acceptable salts", Journal of Pharmaceutical Sciences, 1977, Vol. 66, pp. 1-19; and Pharmaceutical Salts: Properties, Selection and Application, Stahl and Wermuth, eds., Wiley-VCH and VHCA, Zurich, 2002). Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation or allergic response. The compounds of formula (I) may have sufficiently acidic groups, sufficiently basic groups, or both types of functional groups to react with a variety of inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts.

[0185] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, thiocyanates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioate, hexyne-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, alkylbenzoates, oxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, tea-2-sulfonates, and mandelates.

[0186] The compounds of formula (I) contain basic nitrogen, and the desired pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, nitric acid, boric acid, phosphoric acid, etc., or by treating the free base with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid , lauric acid, arsenic acid (such as glucuronic acid or galacturonic acid), α-hydrocarbon acid (such as mandelic acid, citric acid or tartaric acid), amino acid (such as aspartic acid, glutaric acid or glutamic acid), aromatic acid (such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid), sulfonic acid (such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), any compatible mixture of acids such as those given as examples herein, and any other acids and mixtures thereof that are considered to be equivalents or acceptable substitutes according to the ordinary skill level in the art.

[0187] The compounds of formula (I) also contain carboxylic acids, and the desired pharmaceutically acceptable salts may be prepared by any suitable method, for example by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, an alkaline earth metal hydroxide, any compatible mixtures of bases such as those given as examples herein, and any other bases and mixtures thereof which are considered to be equivalent or acceptable substitutes according to the ordinary skill in the art. Illustrative examples of suitable salts include organic salts derived from amino acids (e.g., N-methyl-D-glucamine, lysine, choline, glycine and arginine), ammonia, carbonates, bicarbonates, primary, secondary, tertiary amines and cyclic amines (e.g., tromethamine, benzylamine, pyrrolidine, piperidine, morpholine and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0188] Prodrugs described herein may include compounds having an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues covalently attached to a carboxylic acid group of formula (I) via an amide bond or an ester bond. Examples of amino acid residues include the twenty naturally occurring amino acids commonly identified by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline homocysteine, homoserine, ornithine, and methionine sulfone.

[0189] Other types of prodrugs can be prepared by derivatizing the free carboxylic acid of the structure of formula (I) to an amide or alkyl ester. Examples of amides include those derived from ammonia, C 16 Alkyl primary amine and di(C 1-6 Secondary amines include 5-membered or 6-membered heterocycloalkyl or heteroaryl ring moieties. Examples of acid amines include those derived from amino. 1-3 Alkyl primary amine and di(C 1-2 Examples of lipids of the present invention include C 1-7 Alkyl ester, C 5-7 Cycloalkyl esters, phenyl esters and (C 1-6Preferably, lipids include methyl esters. Prodrugs can also be prepared by derivatizing free hydroxyl groups with groups including hemisuccinate, phosphate, dimethylaminoacetate, and phosphoryloxymethoxycarbonyl according to methods such as those described in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130. Hydroxyl and amino carbamate derivatives can also produce prodrugs. Hydroxyl carbonate derivatives, sulfonic acid esters and sulfates can also provide prodrugs. Hydroxyl derivatization is to (acyloxy) methyl esters and (acyloxy) ethyl esters, wherein the acyl group can be an alkyl ester optionally substituted with one or more ether, amine or hydroxyl functional groups, or wherein the acyl group is an amino acid ester as described above, which can also be used to produce prodrugs. Prodrugs of this type can be prepared as described in Robinsone et al., J Med Chem. 1996, 39 (1), 10-18. Free amines can also be derivatized to form phthalamides, sulfonamides or phosphophthalamides. All of these prodrug moieties can incorporate groups including ether, amine and carboxylic acid functional groups.

[0190] The inhibitory activity of some compounds of the present invention on PHD2 enzyme is shown in Table 1. The inhibitory effect of compound 2 on PHD2 enzyme reaches a level comparable to that of the marketed drug roxadustat (FG-4592), indicating that the cinnoline compounds of the present invention exhibit good biological activity on prolyl hydroxylase and can be used to prepare drugs for inhibiting the activity of prolyl hydroxylase.

[0191] The following examples may further describe the present invention, and the skilled person will recognize that, in order to obtain the various compounds herein, the starting materials may be appropriately selected so that the ultimately desired substituents may be carried throughout the reaction scheme with or without protection as required to obtain the desired product. Alternatively, it may be necessary or desirable to replace the ultimately desired substituent with a suitable group, which may be run through the reaction scheme and then substituted with the desired substituent where appropriate. Unless otherwise indicated, the various variables are as defined above for formula (I). The reaction may be carried out between the melting point and the reflux temperature of the solvent, preferably between 0°C and the reflux temperature of the solvent. The reaction may also be carried out in a closed pressure vessel above the normal reflux temperature of the solvent. However, these examples should not be taken as limiting the scope of the present invention; Example

[0192] Example 1

[0193] 2-(4-Hydroxy-cinnoline-3-carboxamido)acetic acid

[0194]

[0195] Step 1) 2-((2-phenyl)hydrazine)-2-cyanoacetamide

[0196] In reaction flask A, add 3-phenoxyaniline (13.7 g, 147.6 mmol) to a mixed solution of acetic acid (60 mL) / hydrochloric acid (30 mL) / water (36 mL), then cool to -10 ° C and stir, then slowly add sodium nitrite aqueous solution (8.8 g / 36 mL) to reaction flask A, control the internal temperature not to exceed 0 ° C, and continue to stir for 0.5 hours. In reaction flask B, add ethanol (270 mL), tap water (720 mL), 2-cyanoacetamide (12.2 g, 145.1 mmol), sodium acetate (15.2 g, 184.5 mmol) in sequence, cool to -10 ° C and stir for 10 minutes, then add the mixed solution in reaction flask A to reaction flask B and stir for two hours at the same temperature, filter, and dry the filter cake to obtain 15.0 g of yellow solid.

[0197] MS m / z (ESI): 189.06

[0198] Step 2) 4-aminocinnoline-3-carboxamide

[0199] 2-((2-phenyl)hydrazine-2-cyanoacetamide (15.0 g, 79.7 mmol) was placed in a reaction bottle and toluene (120 mL) was added, followed by AlCl3 (47.8 g, 358.5 mmol), nitrogen was replaced three times and the reaction bottle was sealed. Using microwave irradiation, the reaction mixture was heated to 150°C and maintained for half an hour. After the reaction solution was cooled to room temperature, 4N HCl solution was added to the reaction solution to form a solid. The generated solid was filtered and the filter cake was dried to obtain 17.7 g of the product.

[0200] MS m / z (ESI): 189.10

[0201] Step 3) 4-Hydroxycinnoline-3-carboxylic acid

[0202] 4-aminocinnoline-3-carboxamide (17.0 g, 48.5 mmol) was placed in a reaction flask and 1,4-dioxane (170 mL) was added. Then, 25% KOH aqueous solution (1.0 L) was added and the temperature was raised to 110°C and refluxed for 16 hours. After the reaction solution was cooled to room temperature, 3N HCl was used to adjust the pH to between 1 and 2, and an off-white solid appeared. The off-white solid was filtered and the filter cake was dried to obtain 10.0 g of the product.

[0203] MS m / z (ESI): 190.09

[0204] Step 4) N-[(4-chloro-3-cinnoline)carbonyl]glycine methyl ester

[0205] 4-Hydroxycinnoline-3-carboxylic acid (9.0g, 46.5mml) was placed in a reaction flask and thionyl chloride (140mL) was added, and then 2 drops of N,N-dimethylformamide were added at room temperature, followed by heating and reflux, and stirring overnight. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove thionyl chloride, and co-rotated with dichloromethane solution three times to obtain a yellow solid. Dichloromethane (150mL) was added to the reaction flask, and then N,N-diisopropylacetamide (25.0mL, 142.6mmol) and glycine methyl hydrochloride (7.2g, 57.1mmol) were added in sequence and stirred at room temperature for 1 hour. Water was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phases were combined, concentrated under reduced pressure, and separated by column chromatography to obtain 3.0g of the product.

[0206] MS m / z (ESI): 279.98

[0207] Step 4) N-[(4-chloro-3-cinnoline)carbonyl]glycine

[0208] N-[(4-chloro-3-cinnoline)carbonyl]glycine methyl ester (270 mg, 0.96 mmol) was dissolved in a mixed solution of tetrahydrofuran and water in a volume ratio of 4:1 (5.0 mL), and then lithium hydroxide (90.0 mg, 3.84 mmol) was added and stirred at room temperature for 2 hours. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, and then the pH was adjusted to between 1 and 2 with 4N HCl. Solids appeared, and the solids were filtered and the filter cake was dried to obtain 100 mg of the product.

[0209] MS m / z (ESI): 248.02

[0210] Example 2

[0211] 2-(4-Hydroxy-7-iodo-cinnoline-3-carboxamido)acetic acid

[0212]

[0213] Step 1) 2-((2-m-iodophenyl)hydrazine)-2-cyanoacetamide

[0214] In reaction flask A, add m-iodoaniline (12.7 g, 58.0 mmol) to a mixed solution of acetic acid (30 mL) / hydrochloric acid (15 mL) / water (18 mL), then cool to -10 ° C and stir, then slowly add sodium nitrite aqueous solution (4.4 g / 18 mL) to reaction flask A, control the internal temperature not to exceed 0 ° C, and continue stirring for 0.5 hours. In reaction flask B, add ethanol (135 mL), tap water (360 mL), 2-cyanoacetamide (6.1 g, 73.0 mmol), sodium acetate (7.6 g, 93.0 mmol) in sequence, cool to -10 ° C and stir for 10 minutes, then add the mixed solution in reaction flask A to reaction flask B and stir at the same temperature for two hours, filter, and dry the filter cake to obtain 10.0 g of yellow solid.

[0215] MS m / z (ESI): 314.91

[0216] Step 2) 4-amino-7-iodocinnoline-3-carboxamide

[0217] 2-((2-iodophenyl)hydrazine)-2-cyanoacetamide (5.9 g, 18.7 mmol) was placed in a reaction bottle and toluene (37 mL) was added, followed by AlCl3 (11.2 g, 84.0 mmol), nitrogen was replaced three times and the bottle was sealed. Using microwave radiation, the reaction mixture was heated to 150 ° C and maintained for half an hour. After the reaction solution was cooled to room temperature, 4N HCl solution was added to the reaction solution to form a solid. The generated solid was filtered and the filter cake was dried to obtain 5.5 g of the product.

[0218] Step 3) 4-Hydroxy-7-iodocinnoline-3-carboxylic acid

[0219] 4-Amino-7-iodocinnoline-3-carboxamide (3.5 g, 9.5 mmol) was placed in a reaction flask and 1,4-dioxane (30 mL) was added. Then 25% KOH aqueous solution (180 mL) was added and the temperature was raised to 110°C and refluxed for 16 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to between 1 and 2 with 3N HCl, and an off-white solid appeared. The off-white solid was filtered and the filter cake was dried to obtain 2.4 g of the product.

[0220] MS m / z (ESI): 316.83

[0221] Step 4) N-[(4-chloro-7-iodo-3-cinnoline)carbonyl]glycine methyl ester

[0222] 4-Hydroxy-7-iodocinnoline-3-carboxylic acid (4.1 g, 13.0 mml) was placed in a reaction flask and thionyl chloride (60 mL) was added, followed by 2 drops of N, N-dimethylformamide at room temperature, followed by heating and reflux, and stirring overnight. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove thionyl chloride, and co-rotated with a dichloromethane solution three times to obtain a black solid. Dichloromethane (30 mL) was added to the reaction flask, followed by N, N-diisopropylacetamide (5.0 mL, 39.6 mmol), glycine methyl hydrochloride (2.0 g, 16.0 mmol) and stirred at room temperature for 1 hour. Water was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phases were combined, concentrated under reduced pressure, and separated by column chromatography to obtain 2.5 g of the product.

[0223] MS m / z (ESI): 405.98

[0224] Step 5) N-[(4-chloro-7-iodo-3-cinnoline)carbonyl]glycine

[0225] N-[(4-chloro-7-iodo-3-cinnoline)carbonyl]glycine methyl ester (320 mg, 0.79 mmol) was dissolved in a mixed solution of tetrahydrofuran and water in a volume ratio of 4:1 (6.0 mL), and then lithium hydroxide (76.0 mg, 3.84 mmol) was added and stirred at room temperature for 2 hours. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, and then the pH was adjusted to between 1 and 2 with 4N HCl. Solids appeared, and the solids were filtered and the filter cake was dried to obtain 170 mg of the product.

[0226] MS m / z (ESI): 374.03

[0227] Example 3

[0228] 2-(4-Hydroxy-7-chlorocinnoline-3-carboxamido)acetic acid

[0229]

[0230] Step 1) 2-((2-m-chlorophenyl)hydrazine)-2-cyanoacetamide

[0231] In reaction flask A, add m-chloroaniline (10.0 g, 78.4 mmol) to a mixed solution of acetic acid (30 mL) / hydrochloric acid (15 mL) / water (15 mL), then cool to -10 ° C and stir, then slowly add sodium nitrite aqueous solution (5.4 g / 15 mL) to reaction flask A, control the internal temperature not to exceed 0 ° C, and continue stirring for 0.5 hours. In reaction flask B, add ethanol (110 mL), tap water (300 mL), 2-cyanoacetamide (6.6 g, 78.4 mmol), sodium acetate (8.4 g, 101.9 mmol) in sequence, cool to -10 ° C and stir for 10 minutes, then add the mixed solution in reaction flask A to reaction flask B and stir at the same temperature for two hours, filter, and dry the filter cake to obtain 15.0 g of yellow solid.

[0232] Step 2) 4-amino-7-chlorocinnoline-3-carboxamide

[0233] 2-((2-chlorophenyl)hydrazine)-2-cyanoacetamide (15.0 g, 68.1 mmol) was placed in a reaction bottle and toluene (120 mL) was added, followed by AlCl3 (40.5 g, 84.0 mmol), nitrogen was replaced three times and the bottle was sealed. Using microwave radiation, the reaction mixture was heated to 150 ° C and maintained for half an hour. After the reaction solution was cooled to room temperature, 4N HCl solution was added to the reaction solution to form a solid. The generated solid was filtered and the filter cake was dried to obtain 15.0 g of the product.

[0234] Step 3) 4-Hydroxy-7-chlorocinnoline-3-carboxylic acid

[0235] 4-Amino-7-chlorocinnoline-3-carboxamide (15.0 g, 68.1 mmol) was placed in a reaction flask and 1,4-dioxane (127 mL) was added. Then 25% KOH aqueous solution (1.0 L) was added and the temperature was raised to 110°C and refluxed for 16 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to between 1 and 2 with 3N HCl, and an off-white solid appeared. The off-white solid was filtered and the filter cake was dried to obtain 9.2 g of the product.

[0236] Step 4) N-[(4-hydroxy-7-chloro-3-cinnoline)carbonyl]glycine methyl ester

[0237] 4-Hydroxy-7-chlorocinnoline-3-carboxylic acid (1.0 g, 3.54 mmol) was placed in a reaction flask and N, N-dimethylformamide (15 mL) was added, followed by PyBOP (2.76 g, 5.31 mmol) at room temperature and continued to stir for half an hour. Half an hour later, glycine methyl ester hydrochloride (1.25 g, 9.91 mmol) was added and stirred overnight. After TLC monitoring, the reaction was complete, water was added to quench the reaction, and a brown solid was precipitated, which was filtered to obtain 400 mg of the product.

[0238] Step 5) N-[(4-hydroxy-7-chloro-3-cinnoline)carbonyl]glycine

[0239] N-[(4-Hydroxy-7-chloro-3-cinnoline)carbonyl]glycine methyl ester (350 mg, 1.18 mmol) was dissolved in a mixed solution of tetrahydrofuran and water in a volume ratio of 4:1 (6.0 mL), and then lithium hydroxide (113.4 mg, 4.73 mmol) was added and stirred at room temperature for 2 hours. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, and then the pH was adjusted to between 1 and 2 with 4N HCl. Solids appeared, and the solids were filtered and the filter cake was dried to obtain 220 mg of the product.

[0240] MS m / z (ESI): 281.97

[0241] 1 HNMR (400MHz, d-DMSO) δ (ppm): 14.16 (brs, 1H), 12.90 (brs, 1H), 9.89 (t, J = 5.6Hz, 1H), 8.21 (d , J=8.8Hz, 1H), 7.77 (d, J=2.0Hz, 1H), 7.60 (dd, J=8.8Hz, J=2.0Hz, 1H), 4.08 (d, J=5.6Hz, 2H).

[0242] Example 4

[0243] 2-(4-Hydroxy-7-bromocinnoline-3-carboxamido)acetic acid

[0244]

[0245] Step 1) 2-((2-m-bromophenyl)hydrazine)-2-cyanoacetamide

[0246] In reaction flask A, m-bromoaniline (20.0 g) was added to a mixed solution of acetic acid (60 mL) / hydrochloric acid (30 mL) / water (36 mL), then cooled to -10°C and stirred, then sodium nitrite aqueous solution (8.8 g / 36 mL) was slowly added to reaction flask A, the internal temperature was controlled not to exceed 0°C, and stirring was continued for 0.5 hours. In reaction flask B, ethanol (270 mL), tap water (720 mL), 2-cyanoacetamide (12.2 g), sodium acetate (15.2 g) were added in sequence, cooled to -10°C and stirred for 10 minutes, then the mixed solution in reaction flask A was added to reaction flask B and stirred at the same temperature for two hours, filtered, and the filter cake was dried to obtain 10.0 g of yellow solid.

[0247] MS m / z (ESI): 268.92

[0248] Step 2) 4-amino-7-bromocinnoline-3-carboxamide

[0249] 2-((2-bromophenyl)hydrazine)-2-cyanoacetamide (20.0 g, 74.9 mml) was placed in a reaction bottle and toluene (160 mL) was added, followed by AlCl3 (44.9 g, 337 mmol), nitrogen was replaced three times and the bottle was sealed. Using microwave radiation, the reaction mixture was heated to 150 ° C and maintained for half an hour. After the reaction solution was cooled to room temperature, 4N HCl solution was added to the reaction solution to form a solid. The generated solid was filtered and the filter cake was dried to obtain 11.1 g of the product.

[0250] MS m / z (ESI): 268.96

[0251] Step 3) 4-Hydroxy-7-bromocinnoline-3-carboxylic acid

[0252] 4-Amino-7-bromocinnoline-3-carboxamide (5.0 g, 13.1 mmol) was placed in a reaction flask and 1,4-dioxane (25 mL) was added. Then, 25% KOH aqueous solution (180 mL) was added and the temperature was raised to 110°C and refluxed for 16 hours. After the reaction solution was cooled to room temperature, 3N HCl was used to adjust the pH to between 1 and 2, and an off-white solid appeared. The off-white solid was filtered and the filter cake was dried to obtain 2.4 g of the product.

[0253] MS m / z (ESI): 270.86

[0254] Step 4) N-[(4-hydroxy-7-bromo-3-cinnoline)carbonyl]glycine methyl ester

[0255] 4-Hydroxy-7-bromocinnoline-3-carboxylic acid (2.5g, 9.3mml) was placed in a reaction flask and thionyl chloride (40mL) was added, and then 2 drops of N,N-dimethylformamide were added at room temperature, followed by heating and reflux, and stirring overnight. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove thionyl chloride, and co-rotated with dichloromethane solution three times to obtain a black solid. Dichloromethane (30mL) was added to the reaction flask, and then N,N-diisopropylacetamide (5.0mL) and glycine methyl hydrochloride (1.28g) were added in sequence and stirred at room temperature for 1 hour. Water was added to quench the reaction, and it was extracted three times with dichloromethane, the organic phases were combined, concentrated under reduced pressure, and separated by column chromatography to obtain 810mg of the product.

[0256] Step 5) N-[(4-chloro-7-iodo-3-cinnoline)carbonyl]glycine

[0257] N-[(4-chloro-7-iodo-3-cinnoline)carbonyl]glycine methyl ester (500 mg, 1.39 mmol) was dissolved in a mixed solution of tetrahydrofuran and water in a volume ratio of 4:1 (10 mL), and then lithium hydroxide (135.5 mg, 5.58 mmol) was added and stirred at room temperature for 2 hours. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, and then the pH was adjusted to between 1 and 2 with 4N HCl. A solid appeared, and the solid was filtered and the filter cake was dried to obtain 170 mg of the product.

[0258] MS m / z (ESI): 328.00

[0259] Example 5

[0260] 2-(4-Hydroxy-7-phenoxy-cinnoline-3-carboxamido)acetic acid

[0261]

[0262] Step 1) 2-((2-(3-phenoxy)phenyl)hydrazine)-2-cyanoacetamide

[0263] In reaction bottle A, add 3-phenoxy-aniline (5.0 g, 27.0 mmol) to a mixed solution of acetic acid (10 mE) / hydrochloric acid (5.4 mL) / water (7.5 mL), then cool to -10 ° C and stir, then slowly add sodium nitrite aqueous solution (1.9 g / 7.5 mL) to reaction bottle A, control the internal temperature not to exceed 0 ° C, and continue to stir for 0.5 hours. In reaction bottle B, add ethanol (56 mL), tap water (150 mL), 2-cyanoacetamide (2.3 g, 27.0 mmol), sodium acetate (2.9 g, 35.1 mmol) in sequence, cool to -10 ° C and stir for 10 minutes, then add the mixed solution in reaction bottle A to reaction bottle B and stir at the same temperature for two hours, filter, and dry the filter cake to obtain 3.0 g of yellow solid.

[0264] MS m / z (ESI): 281.13

[0265] Step 2) 4-amino-7-phenoxy-cinnoline-3-carboxamide

[0266] 2-((2-(3-phenoxy)phenyl)hydrazine)-2-cyanoacetamide (3.0 g, 10.7 mml) was placed in a reaction bottle and toluene (24 mL) was added, followed by AlCl3 (6.4 g, 48.2 mmol), nitrogen was replaced three times and the bottle was sealed. Using microwave radiation, the reaction mixture was heated to 150°C and maintained for half an hour. After the reaction solution was cooled to room temperature, 4N HCl solution was added to the reaction solution to form a solid. The generated solid was filtered and the filter cake was dried to obtain 2.5 g of the product.

[0267] Step 3) 4-Hydroxy-7-phenoxy-cinnoline-3-carboxylic acid

[0268] 4-Amino-7-phenoxy-cinnoline-3-carboxamide (3.0 g) was placed in a reaction bottle and 1,4-dioxane (30 mL) was added, followed by 25% KOH aqueous solution (180 mL) and the temperature was raised to 110°C and refluxed for 16 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to between 1 and 2 with 3N HCl, and an off-white solid appeared. The off-white solid was filtered and the filter cake was dried to obtain 2.4 g of the product.

[0269] Step 4) N-[(4-hydroxy-7-phenoxy-3-cinnoline)carbonyl]glycine methyl ester

[0270] 4-Hydroxy-7-phenoxy-cinnoline-3-carboxylic acid (1.0 g) was placed in a reaction bottle and N,N-dimethylformamide (15 mL) was added, and then PyBOP (2.76 g) was added at room temperature and stirred for half an hour, followed by the addition of glycine methyl ester hydrochloride (1.25 g) and stirring overnight. After the reaction was completed, water was added to quench the reaction, and a brown solid appeared, which was filtered to obtain 311 mg of the product.

[0271] Step 5) N-[(4-hydroxy-7-phenoxy-3-cinnoline)carbonyl]glycine

[0272] N-[(4-Hydroxy-7-phenoxy-3-cinnoline)carbonyl]glycine methyl ester (350 mg) was dissolved in a mixed solution of tetrahydrofuran and water in a volume ratio of 4:1 (6.0 mL), and then lithium hydroxide (94.6 mg) was added and stirred at room temperature for 2 hours. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, and then the pH was adjusted to between 1 and 2 with 4N HCl. Solids appeared, and the solids were filtered and the filter cake was dried to obtain 230 mg of the product.

[0273] MS m / z (ESI): 340.16

[0274] 1 H NMR (400MHz, d-DMSO) δ (ppm): 13.96 (brs, 1H), 12.77 (brs, 1H), 10.06 (t, J = 2.4Hz, 1H), 8.23 ​​(d, J = 9.2Hz, 1H), 7.55 (d, J=9.2Hz, 1H), 7.37-7.30 (m, 2H), 7.28 (d, J=8.0Hz, 2H), 6.94 (d, J=2.4Hz, 1H), 4.08 (d, J=5.6Hz, 2H).

[0275] Biological tests

[0276] PHD2 enzyme activity inhibition assay

[0277] Reagents and consumables

[0278] PHD2 enzyme: purchased from Activemotif; α-ketoglutarate sodium salt: purchased from Sigma; FITC-HIF1α: purchased from GL; multiwell plate Nunc TM 384: Purchased from ThermoScientific;

[0279] Test methods

[0280] (1) Prepare 1×Assay buffer detection solution (10 mM HEPES, 150 mM NaCl, 0.05% Tween20, pH 7.4); (2) Preparation of compound concentration gradient: the test compound test concentration is 10 gM starting, 3-fold dilution, 10 concentrations, duplicate testing; dilute to 100 times the final concentration solution in a 384-well plate, and then transfer 100 nL to a 384 reaction plate using Echo550 for use. Add 100nL of 100% DMSO to the negative control well and the positive control well respectively; (3) Prepare an enzyme solution with a concentration of 2 times the final concentration using 1×Assaybuffer; (4) Add 5μL of an enzyme solution with a concentration of 2 times the final concentration to the compound well and the positive control well respectively; (5) Add 5μL of 1×Assaybuffer to the negative control well; (6) Centrifuge at 1000rpm for 30 seconds, shake and mix, and incubate for 15min; (7) Prepare a tracer solution with a concentration of 2 times the final concentration using 1×Assaybuffer. Add 5.0μL of a tracer solution with a concentration of 2 times the final concentration to start the reaction; (8) Centrifuge the 384-well plate at 1000rpm for 30 seconds, shake and mix for 60min, read the mP value from Envision (MultimodePlateReader, PerkinElmer), export the data and process it to obtain the inhibition rate of the test compound. The results are shown in the following table:

[0281] Table 1 Inhibitory activity of some compounds on PHD2 enzyme

[0282] Compound No. <![CDATA[IC 50 (nM)]]> FG-4592 (Roxadustat) 65.6 1 232.2 2 65.2

[0283] It can be seen from the above table that the compounds of the present invention have HIF-prolyl hydroxylase inhibitory activity.

[0284] Although the specific embodiments of this paper have been illustrated and described, it is obvious to those skilled in the art that various other variations and improvements can be made without departing from the spirit and scope of this paper. Therefore, all such variations and improvements within the scope of this paper are intended to be included in the appended claims.

Claims

1. A cinnoline compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof: in, R 1 , R 2 , R 3 , R 4 Each is independently a unit selected from the following atoms or groups: 1) Hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, halogen, cyano; or, 2) aryloxy, heteroaryloxy, which are optionally substituted with one or more, identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; or two adjacent carbon atoms in the aromatic ring thereof can form a heterocyclic structure; or, 3) aryl, heteroaryl, optionally substituted with one or more, identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; or two adjacent carbon atoms in the aromatic ring thereof can form a heterocyclic structure; or, 4) Wherein, L is selected from -CH2-, -CH2O-; n is 0 or 1; R 5 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, substituted phenyl, 5-6 membered aromatic heterocycle containing oxygen or nitrogen, R 5 Optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; The heterocyclic structure has the following structure: which are optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, halogen, cyano, phenyl; wherein n is an integer of 1, 2, 3 or 4, A 1 and A 2 Each is independently selected from oxygen, carbon or nitrogen atoms.

2. The cinnoline compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, characterized in that: The compounds have the following structures: in, 1) In formula (Ia) and (Ib), Ar is an aryl group or a heteroaryl group, which is optionally substituted with one or more identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; or optionally, two adjacent carbon atoms in the aromatic ring form a heterocyclic structure: The heterocyclic structure has the following structure: which are optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, halogen, cyano, phenyl; wherein n is an integer of 1, 2, 3 or 4, A 1 and A 2 are each independently selected from oxygen, carbon or nitrogen atoms; 2) In formula (Ic), L is selected from -CH2-, -CH2O-; n is 0 or 1; R 5 Selected from C 3-6 Cycloalkyl, phenyl (n is not 0), substituted phenyl, 5-6 membered aromatic heterocycle containing oxygen or nitrogen, R 5 Optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or a 5-6 membered aromatic heterocycle containing oxygen or nitrogen.

3. The cinnoline compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, characterized in that: R 1 , R 2 , R 3 , R 4 Each is independently a unit selected from the following atoms or groups: 1) Deuterium, C 1-6 haloalkyl; or, 2) aryloxy, heteroaryloxy, which are optionally substituted with one or more, identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; or two adjacent carbon atoms in the aromatic ring thereof can form a heterocyclic structure; or, 3) aryl, heteroaryl, optionally substituted with one or more, identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; or two adjacent carbon atoms in the aromatic ring thereof can form a heterocyclic structure; or, 4) Wherein, L is selected from -CH2-, -CH2O-; n is 0 or 1; R 5 Selected from C 3-6 Cycloalkyl, phenyl (n is not 0), substituted phenyl, 5-6 membered aromatic heterocycle containing oxygen or nitrogen, R 5 Optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; The heterocyclic structure has the following structure: which are optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, halogen, cyano, phenyl; wherein n is an integer of 1, 2, 3 or 4, A 1 and A 2 Each is independently selected from oxygen, carbon or nitrogen atoms.

4. The cinnoline compound according to claim 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, characterized in that: The compounds have the following structures: in, 1) In formula (Ia) and (Ib), Ar is an aryl group or a heteroaryl group, which is optionally substituted with one or more identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or 5-6 membered aromatic heterocycle containing oxygen or nitrogen; or optionally, two adjacent carbon atoms in the aromatic ring form a heterocyclic structure: The heterocyclic structure has the following structure: which are optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, halogen, cyano, phenyl; wherein n is an integer of 1, 2, 3 or 4, A 1 and A 2 are each independently selected from oxygen, carbon or nitrogen atoms; 2) In formula (Ic), L is selected from -CH2-, -CH2O-; n is 0 or 1; R 5 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, substituted phenyl, 5-6 membered aromatic heterocycle containing oxygen or nitrogen, R 5 Optionally substituted with one or more, identical or different, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, halogen, cyano, phenyl or a 5-6 membered aromatic heterocycle containing oxygen or nitrogen.

5. The cinnoline compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, characterized in that: The C 1-6 The alkyl group is selected from C 1-4 Alkyl, preferably selected from C 1-2 Alkyl; the C 1-6 Alkoxy is selected from C 1-4 Alkoxy, preferably selected from C 1-2 Alkoxy; the C 1-6 The haloalkyl group is selected from C 1-4 Halogenated alkyl, preferably selected from C 1-2 Halogenated alkyl.

6. The cinnoline compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, characterized in that: The halogen is any one of F, Cl, I and Br; the aryloxy is phenoxy; the aryl is any one of phenyl and naphthyl; the heteroaryl is any one of pyridyl, pyrimidinyl and quinolyl; the C 3-6 The cyclic group is any of a cyclopropyl group and a cyclohexyl group.

7. The cinnoline compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, characterized in that: In the heterocyclic structure, n is an integer of 2, A 1 and A 2 are each independently selected from oxygen atoms.

8. The cinnoline compound according to claim 7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, characterized in that: The heterocyclic structure is further optionally substituted with one or two, identical or different C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, halogen, cyano, phenyl; preferably substituted with one or two, identical or different C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, halogen, cyano, phenyl.

9. A cinnoline compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, characterized in that: The compound is selected from: 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 13) 14) 15) 16) 17) 18) 19) 20) 21) 22) 23) 24) 25) 26) 27) 28) 10. The cinnoline compound according to claim 9, characterized in that: The compound is selected from: 6) 7) 8) 9) 10) 11) 23) 24) 25) 28) 11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 and 8 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.

12. Use of a compound according to any one of claims 1 to 4 and 8 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof, in the preparation of a medicament for treating, preventing or pre-treating a disease mediated at least in part by hypoxia inducible factor and / or erythropoietin.

13. The use according to claim 12, characterized in that: The disease is selected from at least one of anemic disorders, renal anemia, neurological disorders and / or injuries, peripheral vascular disorders, ulcers, burns, chronic wounds, and ischemia-reperfusion injury.

14. The use according to claim 12, characterized in that: The disease is selected from at least one of ischemia, such as myocardial infarction, pulmonary embolism, intestinal infarction, chronic renal failure, ischemic stroke, cardiosclerosis, transient ischemic attack, macular degeneration, peripheral arterial disease and congestive heart failure.

15. Use of the compound according to any one of claims 1 to 4 and 8 to 10 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate thereof in the preparation of a medicament for inhibiting the activity of prolyl hydroxylase.

16. The use according to claim 15, characterized in that The prolyl hydroxylase is contacted with a compound according to any one of claims 1 to 4 and 8 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate thereof.

17. A method for preparing the compound according to any one of claims 1 to 4, characterized in that: The synthetic route is as follows: R6 is any one of methyl, tert-butyl and benzyl; The synthesis steps include: Step 1: reacting compound 1 with sodium nitrite and 2-cyanoacetamide to obtain compound 2; Step 2: reacting compound 2 with aluminum chloride to obtain compound 3; Step 3: reacting compound 3 with potassium hydroxide to obtain compound 4; Step 4: reacting compound 4 with thionyl chloride to obtain compound 5; Step 5: reacting compound 5 with a glycine ester compound to obtain compound 6; Step 6: reacting compound 6 with lithium hydroxide to obtain a compound of formula (I); Step 7: reacting compound 4 with a glycine ester compound to obtain compound 7; Step eight: react compound 7 with lithium hydroxide to obtain a compound of formula (I).

18. The preparation method according to claim 17, characterized in that: The synthesis steps include: Step 1: reacting compound 1 with a mixture of sodium nitrite and hydrochloric acid at low temperature, then adding a mixture of 2-cyanoacetamide and sodium acetate, and reacting at room temperature to obtain compound 2; Step 2: Compound 2 reacts with aluminum chloride under heating conditions to obtain compound 3; Step 3: Compound 3 reacts with potassium hydroxide under heating conditions to obtain compound 4; Step 4: Compound 4 reacts with thionyl chloride or phosphorus oxychloride under heating conditions to obtain compound 5; Step 5: Compound 5 reacts with a glycine ester compound to obtain compound 6, wherein the glycine ester compound is selected from any one of glycine methyl ester, glycine tert-butyl ester and glycine benzyl ester; Step 6: Compound 6 reacts with a base to obtain a compound of formula (I), wherein the base is selected from any one of sodium hydroxide, potassium hydroxide and lithium hydroxide; Step 7: Compound 4 reacts with a glycine ester compound in the presence of a catalyst to obtain compound 7, wherein the glycine ester compound is selected from any one of glycine methyl ester, glycine tert-butyl ester and glycine benzyl ester, and the catalyst is selected from a combination of PyBOP or EDCI and HOBt; Step eight: Compound 7 reacts with a base to obtain a compound of formula (I), wherein the base can be selected from any one of sodium hydroxide, potassium hydroxide and lithium hydroxide.

19. The method for preparing the compound according to claim 3 or 4, characterized in that: The synthetic route of the compound of formula (Ib) is as follows: R6 is any one of methyl, tert-butyl and benzyl; The following steps are involved: Step 1: Compound 1b is reacted with sodium nitrite and 2-cyanoacetamide to obtain compound 2b; Step 2: reacting compound 2b with aluminum chloride to obtain compound 3b; Step 3: reacting compound 3b with potassium hydroxide to obtain compound 4b; Step 4: reacting compound 4b with thionyl chloride to obtain compound 5b; Step 5: reacting compound 5b with thionyl chloride or phosphorus oxychloride to obtain compound 6b; Step 6: reacting compound 6b with arylboronic acid to obtain compound 8b; Step 7: react compound 8b with lithium hydroxide to obtain a compound of formula (Ib).

20. The preparation method according to claim 19, characterized in that: The following steps are involved: Step 1: reacting compound 1b with a mixture of sodium nitrite and hydrochloric acid at low temperature, then adding a mixture of 2-cyanoacetamide and sodium acetate, and reacting at room temperature to obtain compound 2b; Step 2: Compound 2b reacts with aluminum chloride under heating conditions to obtain compound 3b; Step 3: Compound 3b reacts with potassium hydroxide under heating conditions to obtain compound 4b; Step 4: Compound 4b reacts with thionyl chloride or phosphorus oxychloride under heating conditions to obtain compound 5b; Step 5: Compound 5b reacts with a glycine ester compound to obtain compound 6b, wherein the glycine ester compound can be selected from any one of glycine methyl ester, glycine tert-butyl ester and glycine benzyl ester; Step 6: Compound 6 reacts with an arylboronic acid compound under the conditions of a catalyst, a ligand, and a base to obtain a compound of formula 8b, wherein the catalyst is a palladium catalyst, and the palladium catalyst can be selected from any one of Pd(PPh3)4 and Pd(dppf)2Cl; the base can be selected from any one of cesium carbonate, potassium phosphate, potassium carbonate and sodium carbonate; Step 7: Compound 8 reacts with a base to obtain a compound of formula (I), wherein the base can be selected from any one of sodium hydroxide, potassium hydroxide and lithium hydroxide.

21. The method for preparing the compound according to claim 3 or 4, characterized in that: The synthetic route of the compound of formula (Ic) is as follows: R 6 is any one of methyl, tert-butyl and benzyl; The following steps are involved: Step 1: Compound 1c is reacted with sodium nitrite and 2-cyanoacetamide to obtain compound 2c; Step 2: reacting compound 2c with aluminum chloride to obtain compound 3c; Step 3: reacting compound 3c with potassium hydroxide to obtain compound 4c; Step 4: reacting compound 4c with thionyl chloride to obtain compound 5c; Step 5: reacting compound 5c with a glycine ester compound to obtain compound 6c; Step 6: reacting compound 6c with an alkynyl compound to obtain compound 8c; Step 7: react compound 8c with lithium hydroxide to obtain a compound of formula (Ic).

22. The preparation method according to claim 21, characterized in that: The following steps are involved: Step 1: reacting compound 1c with a mixture of sodium nitrite and hydrochloric acid at low temperature, then adding a mixture of 2-cyanoacetamide and sodium acetate, and reacting at room temperature to obtain compound 2c; Step 2: Compound 2c reacts with aluminum chloride under heating conditions to obtain compound 3c; Step 3: Compound 3c reacts with potassium hydroxide under heating conditions to obtain compound 4c; Step 4: Compound 4c reacts with thionyl chloride or phosphorus oxychloride under heating conditions to obtain compound 5c; Step 5: Compound 5c reacts with a glycine ester compound to obtain compound 6c, wherein the glycine ester compound can be selected from any one of glycine methyl ester, glycine tert-butyl ester and glycine benzyl ester; Step 6: Compound 6c reacts with an alkynyl compound under the conditions of a catalyst, a ligand, and a base to obtain a compound of formula 8c, wherein the catalyst is a combination of a palladium catalyst and a copper catalyst, and the palladium catalyst can be selected from any one of Pd(PPh3)2Cl2, Pd(PhCN)2Cl2 and Pd(MeCN)2Cl2; the copper catalyst can be selected from any one of cuprous iodide and copper acetate; the ligand can be selected from N,N-dimethylglycine and its hydrochloride, 1,10-phenanthroline, tri-tert-butylphosphine, 2-pyridinecarboxylic acid; the base can be selected from any one of triethylamine and diisopropylethylamine; Step 7: Compound 8c reacts with a base to obtain a compound of formula (Ic), wherein the base can be selected from any one of sodium hydroxide, potassium hydroxide and lithium hydroxide.

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