RU2379291C2 - Nitrogen-containing heteroaryl compounds and use thereof in increasing endogenous erythropoietin - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: novel isoquinoline derivatives are described by general formula

I, where q equals zero; p equals zero or one; R^a is -COOH or WR⁸; under the condition that, if R^a is -COOH, then p equals zero, and if R^a is -WR⁸, then p equals one; W is selected from an oxygen atom and -NR⁹-, where R⁹ is selected from a group consisting of a hydrogen atom, acyl and alkyl; and R⁸ is selected from a group consisting of a hydrogen atom and alkyl; R¹ is selected from a group consisting of a hydrogen atom, alkyl, alkyl substituted with one group selected from alkoxy and dialkylamino, a halogen atom, heteroaryl containing up to six carbon atoms, one of which is nitrogen, aminoacyl, aryl, aryl substituted with alkyl, and -XR⁶, where X is an oxygen atom, -S(O)_n- or -NR⁷, where n equals zero, one or two, R⁶ is selected from a group consisting of alkyl, aryl, aryl substituted with one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamide, heteroaryl, containing up to six carbon atoms, one of which is nitrogen, and R⁷ is a hydrogen atom or aryl; R² and R³ are independently selected from a group consisting of a hydrogen atom, amino, amino substituted with alkoxy-substituted phenylsulfonyl, alkyl, alkyl substituted with up to three times by a halogen atom, aryl, halogen atom -NR⁶C(O)NR⁶R⁶, and -XR⁶, where X is an oxygen atom or -S(O)_n-, where n equals zero, one or two, each of the substitutes R⁶ is independently selected from a group consisting of hydrogen, alkyl, alkyl substituted with aryl, aryl , aryl substituted with one or two groups selected from a halogen atom, alkyl, alkyl substituted with up to three times by a halogen, alkoxy, alkoxy substituted with up to three times by a halogen, aryloxy substituted with a halogen, nitro, alkylsulfonamide, arylsulfonamide and alkyl-substituted arylsulfonamide, cycloalkyl, heteroaryl, containing up to six carbon atoms, one of which is nitrogen, under the condition that if X is -SO₂-, R⁶ cannot be a hydrogen atom; or R² and R³ together with carbon atoms to which they are bonded, are bonded with formation of an aryl group; R⁴ and R⁵ are independently selected from a hydrogen atom or aryl; R is selected from a group which includes a hydrogen atom, deuterium and methyl; R' is selected from a group consisting of a hydrogen atom, deuterium, alkyl or alkyl substituted with one group selected from hydroxyl, amino, carboxyl, aryl, aryl substituted with one hydroxyl and heteroaryl, containing up to five carbon atoms, two of which can be nitrogen; on the other hand, R and R' and the carbon atom to which they are bonded can be bonded with formation of cycloalkyl; R" is formed from a hydrogen atom and alkyl, or R" together with R' and the nitrogen atom to which they are bonded can be bonded with formation of a heterocyclic group containing up to six carbon atoms, one of which is nitrogen; R'" is selected from a group consisting of hydroxyl, alkoxy, alkoxy substituted with aryl, acyloxy, aryl, -S(O)_n-R¹⁰, where R¹⁰ is hydrogen, and n is zero; or its pharmaceutically acceptable salts, esters or amides; under the condition that restrictive conditions given in paragraph 1 of the formula of invention are met. The invention also relates to specific produced and described compounds, a pharmaceutical composition based on compounds with general formula I, a method of treating, preventing and pretreatment using said pharmaceutical composition, a method of inhibiting activity of hydrolase enzyme, based on taking an effective amount of a formula I compound, a composition for preventing and pretreatment, based on formula I compound and erythropoietin.

EFFECT: new isoquinoline derivatives have useful biological properties.

53 cl, 4 tbl, 253 ex

Description

This application is in accordance with Rule 35 U.S.C. § 119 (e) is based on previous US applications No. 60/476811 filed June 6, 2003, No. 60/476420 filed June 6, 2003, No. 60/476633 filed June 6, 2003, and No. 60/476519, filed for consideration on June 6, 2003, which are incorporated in their entirety by reference in this description.

The present invention relates to methods and compounds capable of modulating the stability of the alpha subunits of hypoxia inducing factor (HIF) and increasing endogenous erythropoietin ex vivo and in vivo.

State of the art

An early reaction to tissue hypoxia is the induction of hypoxia inducing factor (HIF), the main transcriptional helix-loop-helix (bHLH) PAS (Per / Arnt / Sim) activator, which mediates a change in gene expression in response to a change in cellular oxygen concentration. HIF is a heterodimer containing an oxygen-regulated alpha subunit (HIFα) and a constitutively expressed beta subunit (HIFβ), also known as an aryl hydrocarbon receptor nuclear transporter (ARNT). In oxygenated (with normal oxygen content) cells, HIFα subunits are easily destroyed by mechanisms that occur universally due to the Hippel-Lindau tumor suppressor ligase (pVHL) E3 complex. Under conditions of hypoxia, HIFα does not degrade and the active HIFα / β complex accumulates in the nuclei and activates the expression of several genes, including glycolytic enzymes, glucose transporter (GLUT) -1, erythropoietin (EPO), and vascular endothelial growth factor (VEGF) (Jiang, et al . (1996) J. Biol. Chem., 271: 17771-17778; Iliopoulus, et al. (1996) Proc. Natl. Acad. Sci. USA, 93: 10595-10599; Maxwell, et al. (1999), Nature, 399: 271-275; Sutter, et al. (2000) Proc. Natl. Acad. Sci. USA, 97: 4748-4753; Cockman, et al. (2000) J. Biol. Chem., 275: 25733 -25741; and Tanimoto, et al. (2000) EMBO. J. 19: 4298-4309).

HIFα protein levels in most cells increase in response to hypoxia, and HIFα is induced in vivo when animals are exposed to anemia or hypoxia. HIFα levels increase within five hours after the development of hypoxia and return to the background value in prolonged hypoxic conditions. HIFs are involved in a variety of cellular and evolutionary processes, including cell proliferation, angiogenesis, and cell cycle arrest. HIFα is also associated with acute myocardial ischemia and early heart attack, pulmonary hypertension and inflammation. Although HIFα is associated with tumor growth and metastasis, there is little evidence that HIFs are directly related to oncogenesis. Hypoxic preconditioning, in which the target organ is subjected to short periods of hypoxia, has been shown to protect both the myocardium and the brain from hypoxic ischemic damage. HIFα stabilization is closely associated with ischemia and is induced by preconditioning (Wang and Semenza (1993) Proc. Natl. Acad. Sci. USA, 90: 4304-4308; Stroka, et al. (2001) FASEB. J., 15: 2445- 2453; Semenza, et al. (1997) Kidney Int., 51: 553-555; Carmeliet, et al. (1998), Nature 394: 485-490; Zhong, et al. (1999) Cancer Res., 59: 5830-5835; Lee, et al. (2000) N. Engl. J. Med., 343: 148-149; Sharp, et al. (2000) J. Cereb. Blood Flow Metab., 20: 1011-1032; Semenza, et al. (2000) Adv. Exp. Med. Biol., 475: 123-130; Thornton, et al , (2000) Biochem. J. 350: 307-312; Deindl and Schaper. (1998) Mol. Cell. Biochem. 186: 43-51; Bergeron, et al. (2000) Ann. Neurol. 48: 285-296).

Some researchers have studied the mechanism of interaction between HIFα and pVHL. Oxygen-dependent domain decomposition (ODD) within HIF-1α from residue 401 to 603 is usually identified as sufficient to confirm oxygen-dependent instability for chimeric protein constructs. A domain containing a portion of the ODD from residue 526 to 652 has been found to be necessary for pVHL-dependent degradation. In addition, the P ₅₆₄ YI mutation to aspartic acids or the K ₅₃₂ mutation to arginine within the region preserved by HIFα homologues (residue 556 to 674 in HIF-1α) makes the full-length protein HIFα stable under normal oxygen conditions and resistant to pVHL -mediated degradation (Huang et al. (1998), Proc. Natl. Acad. Sci. USA, 95: 7987-7992; Tanimoto et al. (2000) EMBO. J., 19: 4298-4309).

HIFα levels increase due to a number of factors that simulate hypoxia, including iron chelates such as desferoxamine (DFO) and divalent metal salts such as CoCl ₂ . HIFα levels increase due to angiotensin II, thrombin and platelet growth factor under normal oxygen conditions using a mechanism involving reactive oxygen species. The articles also suggest that HIFα is regulated by phosphorylation via pathways involving nitric oxide-activated phosphatidylinositol-3'-kinase (PI3K), hepatocyte growth factor, or mitogen-activated protein kinase. The protein kinase, which is the lower target of PI3K, directly phosphorylates the HIFα ODD domain (Richard, et al. (2000) J. Biol. Chem., 275: 26765-26771; Sandau, et al. (2000) Biochem. Biophys. Res Commun. 278: 263-267; Tacchini, et al. (2001) Carcinogenesis, 22: 1363-1371; and Sodhi, et al. (2001) Biochem. Biophys. Res. Commun., 287: 292-300).

Erythropoietin (EPO), a naturally-occurring hormone that is produced in response to HIFα, stimulates the production of red blood cells (red blood cells) that carry oxygen throughout the body. EPO is usually excreted by the kidneys, and endogenous EPO grows in conditions of low oxygen content (hypoxia). All types of anemia are characterized by a reduced ability of the blood to carry oxygen and, therefore, are associated with similar signs and symptoms, including pallor of the skin and mucous membranes, weakness, dizziness, light fatigue and drowsiness, leading to a decrease in the quality of life. Subjects with severe cases of anemia have difficulty breathing and heart problems. Anemia is usually associated with a condition in which blood is deficient in red blood cells or in hemoglobin.

Common cases of anemia include iron, vitamin B _12, and folic acid deficiency. Anemia can also develop in connection with chronic diseases, for example, with inflammatory diseases, including diseases with subsequent inflammatory suppression of bone marrow, etc. Anemia can be caused by blood loss, for example, due to accidents, surgery, or gastrointestinal bleeding caused by medications such as aspirin and ibuprofen. Excessive blood loss can also occur in women with severe menstrual periods and in people with stomach ulcers, hemorrhoids or cancer of the stomach or colon, etc.

Various conditions can cause the decomposition of red blood cells (hemolysis), resulting in anemia. For example, reactions such as allergic reactions to bacterial toxins and various chemical agents such as sulfonamides and benzene can cause hemolysis. Hemolytic anemia is often caused by chemical poisoning, parasites, infection, or sickle cell anemia. In addition, there are unusual situations in which the body produces antibodies against its own red blood cells, which leads to hemolysis. Any disease or injury to the bone marrow can cause anemia, since such tissue is a site of erythropoiesis, that is, the synthesis of red blood cells. Irradiation, disease, or various chemical agents can lead to bone marrow destruction, causing aplastic anemia. Cancer patients undergoing chemotherapy often have aplastic anemia. Anemia is also associated with renal dysfunction, and the severity of anemia is highly dependent on the degree of dysfunction. Most dialysis patients with kidney failure suffer from chronic anemia.

In addition to production in the kidneys, erythropoietin is produced by astrocytes and neurons in the central nervous system (CNS), and EPO and EPO receptors express in the capillaries of the brain-periphery interface. In addition, systemically administered EPO crosses the blood-brain barrier and reduces neuronal cell loss in response to cerebral ischemia and spinal cord ischemia, mechanical trauma, epilepsy, excitotoxins and neuroinflammation (Sakanaka (1998) Proc. Natl. Acad. Sci. USA, 95: 4635 -4640; Celik, et al. (2002) Proc. Natl. Acad. Sci. USA, 99: 2258-2263; Brines, et al. (2000) Proc. Natl. Acad. Sci. USA, 97: 10526-10531 ; Calapai, et al. (2000) Eur. J. Pharmacol., 401: 349-356; and Siren, et al. (2001) Proc. Natl. Acad. Sci. USA, 98: 4044-404).

In the late 1980s. Amgen has introduced a genetically modified EPO to treat anemia in patients with chronic renal failure. EPO is also administered to cancer patients undergoing radiation and / or chemotherapy, which reduces the need for blood transfusion. EPO is used to treat anemia associated with HIV infection or treatment with azidothymidine (AZT). Although the market for EPO treatment is expanding, the high cost of the product negatively affects sales. In addition, treatment with recombinant EPO requires intravenous administration of EPO one to three times a week for up to twelve weeks, that is, a treatment regimen is needed that limits self-administration of the drug and is inconvenient for the patient. In addition, human serum EPO is heterogeneous in size due to extensive and variable glycosylation not reproducible in any recombinant human EPO.

Hypoxia, a condition that induces the production of HIFα, is a condition with a low oxygen content that can occur when the lungs are burdened with a disease or low blood flow. Ischemia, a decrease in blood flow, can cause blockage of an artery or vein due to a blood clot (blood clot), or due to any foreign circulating substance (embolus), or due to a vascular disease such as atherosclerosis. Reduced blood flow may have a sudden development and short duration (acute ischemia) or may have a slow development with a long duration or with frequent relapses (chronic ischemia). Acute ischemia is often associated with regional irreversible tissue necrosis (heart attack), while chronic ischemia is often associated with short-term hypoxic tissue damage. However, if the decrease in perfusion is long and severe, chronic ischemia may be associated with a heart attack. Heart attacks usually occur in the spleen, lungs, brain, and heart, causing diseases such as intestinal infarction, pulmonary infarction, ischemic stroke, and myocardial infarction.

Pathological changes in ischemic diseases depend on the duration and severity of ischemia and on the life expectancy of the patient. Necrosis can occur within a heart attack within the first 24 hours, and an acute inflammatory reaction develops in viable tissues adjacent to the site of the heart attack with leukocyte migration to the site of the dead tissue. In the following days, there is a gradual destruction and removal of cells within a heart attack due to phagocytosis and replacement with a collagen or glial scar.

Hypoperfusion or heart attack in one organ often affects other organs. For example, pulmonary ischemia caused, for example, by pulmonary embolism, affects not only the lung, but also puts the heart and other organs, such as the brain, into a state of hypoxic stress. Myocardial infarction, which often causes blockage of the coronary artery due to thrombosis, vasospasm of the artery walls or a viral infection of the heart, can lead to congestive heart failure and systemic hypotension. Secondary complications, such as global ischemic encephalopathy, can develop if cardiac arrest is delayed with prolonged hypoperfusion. Cerebral ischemia, most often caused by vascular blockage due to atherosclerosis, can range from the severity of the disease from transient cerebrovascular accident (TIA) to cerebral infarction or stroke. Although the symptoms of TIA are temporary and reversible, TIAs tend to recur and are often followed by a stroke.

Diseases associated with arterial obstruction include coronary artery disease, which can lead to myocardial infarction, and peripheral artery disease, which can affect the abdominal aorta, its main branches, and leg arteries. Peripheral artery disease is Buerger's disease, Raynaud's disease, and acrocyanosis. Although peripheral artery disease is usually caused by atherosclerosis, other main causes are, for example, diabetes and others. Complications associated with peripheral artery disease include severe leg cramps, angina pectoris, abnormal heart rhythm, heart failure, heart attack, stroke, and kidney failure.

Coronary and hypoxic diseases are the main cause of morbidity and mortality. Cardiovascular disease results in at least 15 million deaths each year and is responsible for 30% of deaths worldwide. Among various cardiovascular diseases, coronary heart disease and cerebrovascular disease cause approximately 17% of deaths. Annually, 1.3 million fatal cases of acute myocardial infarction are reported, which demonstrates a disease rate of approximately 600 per 100,000 people. In addition, an estimated five million Americans suffer from venous thrombosis each year and approximately 600,000 of these cases result in pulmonary embolism. Approximately one third of cases of pulmonary embolism are fatal, making pulmonary embolism the third most common cause of death in the United States.

Currently, the treatment of ischemic and hypoxic diseases focuses on relieving symptoms and treating causative diseases. For example, treatment for myocardial infarction includes nitroglycerin and analgesics to combat pain and alleviate heart stress. Other medicines, including digoxin, diuretics, amrinone, β-blockers, lipid lowering agents, and angiotensin-converting enzyme inhibitors, are used to stabilize the condition, but none of these treatments are directly aimed at tissue damage caused by ischemia and hypoxia.

Due to the lack of modern treatment and production and use of recombinant EPO, there is still a need for compounds that are effective in treating erythropoietin-related conditions, such as anemia, including anemia associated with diabetes, ulcers, renal failure, cancer, infection, dialysis, surgery and chemotherapy, and conditions involving ischemia and hypoxia, such as blockage in an artery, angina pectoris, intestinal infarction, pulmonary infarction, cerebral ischemia, and myocardial infarction. There is also a need for compounds that are effective in preventing tissue damage caused by ischemia, which occurs, for example, due to atherosclerosis, diabetes and pulmonary diseases such as pulmonary embolism, etc. Thus, in the art there is a need for methods and compounds that modulate HIF and / or endogenous erythropoietin and can be used to treat and prevent diseases associated with HIF and associated with EPO, including conditions including anemia, ischemia and hypoxia.

The present invention relates to new compounds and methods that can modulate hypoxia inducing factor (HIF) and / or endogenous erythropoietin (EPO).

In one aspect of the invention, there are provided compounds represented by Formula I

where q is zero or one;

p is zero or one;

R ^a is —COOH or —WR ⁸ , provided that if R ^a is —COOH, then p is zero, and if R ^a is —WR ⁸ , then p is one;

W is selected from the group consisting of an oxygen atom, -S (O) _n - and -NR ⁹ -, where n is zero, one or two, R ^{9 is} selected from the group consisting of a hydrogen atom, alkyl, substituted alkyl, acyl, aryl , substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, and R ^{8 is} selected from the group consisting of hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, or if W represents -NR ⁹ -, the substituents R ⁸ and R ^9, together with the nitrogen atom to which they are attached, would be formed heterocyclic or substituted heterocyclic group provided that if W is -S (O) _n - and n takes the values one or two, then R ⁸ is not a hydrogen atom;

R ^{1 is} selected from the group consisting of hydrogen atom, alkyl, substituted alkyl, alkoxy group, substituted alkoxy group, amino group, substituted amino group, aminoacyl, aryl, substituted aryl, halogen atom, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle and —XR ⁶ , where X represents an oxygen atom, —S (O) _n - or —NR ⁷ -, where n is zero, one or two, R ^{6 is} selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl , heterocycle and substituted heterocycle, and R ⁷ represents sobo hydrogen, alkyl or aryl or, when X is -NR ^7, the substituents R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, may form a heterocyclic or substituted heterocyclic group;

R ² and R ^{3 are} independently selected from the group consisting of a hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halogen atom, hydroxy group, cyano group, —S (O) _n —N (R ⁶ ) -R ⁶ , where n is 0, 1 or 2, -NR ⁶ C (O) NR ⁶ R ⁶ , -X ⁶ , where X is an oxygen atom, -S (O) _n - and -NR ⁷ - where n is zero, one or two, each of R ^{6 is} independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroar sludge, substituted heteroaryl, heterocycle and substituted heterocycle, provided that if X represents —SO— or —SO ₂ -, then R ^{6 is} not a hydrogen atom and R ^{7 is} selected from the group consisting of hydrogen, alkyl , aryl or R ² , R ³ , together with the carbon atom to which they are attached, form aryl, substituted aryl, heteroaryl or substituted heteroaryl;

R ⁴ and R ^{5 are} independently selected from the group consisting of hydrogen atom, halogen atom, alkyl, substituted alkyl, alkoxy group, substituted alkoxy group, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and —XR ⁶ , where X represents an oxygen atom , -S (O) _n - or -NR ⁷ -, where n is zero, one or two, R ^{6 is} selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle and R ⁷ represents a hydrogen atom, alkyl or aryl, or, if X represents if -NR ⁷ -, then R ⁷ and R ⁸ , together with the nitrogen atom to which they are bonded, can form a heterocyclic or substituted heterocyclic group;

R is selected from the group consisting of hydrogen, deuterium and methyl;

R 'is selected from the group comprising a hydrogen atom, deuterium, alkyl and substituted alkyl; on the other hand, R and R ′ and the carbon atom to which they are attached may form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group;

R "is selected from the group consisting of a hydrogen atom and an alkyl, or R" together with R 'and the nitrogen atom to which they are attached can form a heterocyclic or substituted heterocyclic group;

R "'is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, acyloxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, aryl, -S (O) _n -R ¹⁰ where R ^{10 is} selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, and n is zero, one or two;

and their pharmaceutically acceptable salts, esters and prodrugs,

provided that if the substituents R, R 'and R ”represent a hydrogen atom and q is zero, and the substituent R ^a is either —COOH (p is zero) or —WR ⁸ (p is 1), and W represents an oxygen atom, and R ⁸ represents a hydrogen atom, then at least the following takes place:

1) R ¹ represents fluorine, bromine, iodine, alkyl, substituted alkyl, alkoxy group, aminoacyl, substituted alkoxy group, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle and -XR ⁶ , where X represents an oxygen atom, —S (O) _n - or —NR ⁷ -, where n is zero, one or two, R ^{6 is} selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and R ⁷ represents a hydrogen atom, alkyl or aryl; or

2) R ² represents alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, fluorine, bromine, iodine, cyano, —XR ⁶ , where X represents an oxygen atom, —S (O) _n - or —NR ⁷ -, where n is zero, one or two, R ^{6 is} selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, and R ⁷ represents a hydrogen atom, alkyl or aryl, provided , what:

a) if R ² is substituted alkyl, such a substituent does not include trifluoromethyl;

b) —XR ^{6 is} not an alkoxy group and

c) if —XR ⁶ is a substituted alkoxy group, such a substituent does not include benzyl or benzyl substituted with a substituent selected from the group consisting of (C ₁ -C ₅ ) -alkyl and (C ₁ -C ₅ ) -alkoxy, or does not include fluoroalkoxy substituent of the formula

-O- [CH ₂ ] _x -C _f H _{(2f + 1-g)} F _g ,

where x is zero or one; f takes integer values from 1 to 5 and g takes integer values from 1 to (2f + 1) or

3) R ³ represents substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, bromine, iodine, —XR ⁶ , where X represents an oxygen atom, —S (O) _n - or —NR ⁷ -, where n accepts the values are zero, one or two, R ^{6 is} selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, and R ⁷ represents a hydrogen atom, alkyl or aryl, provided that:

a) if R ³ is substituted alkyl, such a substituent does not include trifluoromethyl;

b) —XR ^{6 is} not an alkoxy group and

c) if —XR ⁶ is a substituted alkoxy group, such a substituent does not include benzyl or benzyl substituted with a substituent selected from the group consisting of (C ₁ -C ₅ ) -alkyl and (C ₁ -C ₅ ) -alkoxy, or does not include fluoroalkoxy substituent of the formula

-O- [CH ₂ ] _x -C _f H _{(2f + 1-g)} F _g ,

where x is zero or one; f takes integer values from 1 to 5 and g takes integer values from 1 to (2f + 1), or

4) R ⁴ represents iodine, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, —XR ⁶ , where X represents an oxygen atom, —S (O) _n - or —NR ⁷ -, where n is zero one or two, R ^{6 is} selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, and R ⁷ represents a hydrogen atom, alkyl or aryl, provided that:

a) if R ⁴ is substituted alkyl, such a substituent does not include trifluoromethyl;

b) —XR ^{6 is} not an alkoxy group and

c) if —XR ⁶ is a substituted alkoxy group, such a substituent does not include a fluoroalkoxy substituent of the formula

-O- [CH ₂ ] _x -C _f H _{(2f + 1-g)} F _g ,

where x is zero or one; f takes integer values from 1 to 5 and g takes integer values from 1 to (2f + 1), or

5) R ⁵ represents iodine, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, —XR ⁶ , where X represents an oxygen atom, —S (O) _n - or —NR ⁷ -, where n is zero one or two, R ^{6 is} selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, and R ⁷ represents a hydrogen atom, alkyl or aryl, provided that:

a) if R ⁵ is substituted alkyl, such a substituent does not include trifluoromethyl;

b) —XR ^{6 is} not an alkoxy group and

c) if —XR ⁶ is a substituted alkoxy group, such a substituent does not include a fluoroalkoxy substituent of the formula

-O- [CH ₂ ] _x -C _f H _{(2f + 1-g)} F _g ,

where x is zero or one; f takes integer values from 1 to 5 and g takes integer values from 1 to (2f + 1);

and under the following additional conditions:

that if the substituents R ¹ , R ³ , R ⁴ and R ⁵ represent a hydrogen atom, then the substituent R ^{2 is} not a bromine atom.

In another embodiment, the compounds of formula I are represented by formula IA

where the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R, R ', R ", R'" and q have the meanings defined above, and

their pharmaceutically acceptable salts, esters and prodrugs.

In yet another embodiment, the compounds of formula I are represented by formula IB

where the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ”, R ″, WR ⁸ and q are as defined above, and

their pharmaceutically acceptable salts, esters and prodrugs.

In yet another embodiment, the invention relates to compounds represented by formula IC

where the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R, R ′, R ″, R ″, WR ⁸ and q are as defined above, and

their pharmaceutically acceptable salts, esters and prodrugs.

In yet another embodiment, the invention relates to compounds represented by formula ID

where the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R, R ', R ", R'" and q have the meanings defined above, and

their pharmaceutically acceptable salts, esters and prodrugs.

In other embodiments, the invention relates to compounds represented by formulas IIA, IIB, IIC, and IID, wherein said formulas are defined below.

Preferred Embodiments

In the compounds of formulas I, IA, IB, IC and ID, the substituent R ^{1 is} preferably selected from the group consisting of hydrogen atom, alkyl, substituted alkyl, halogen, alkoxy group, aryloxy group, substituted aryloxy group, substituted aryl, alkylthio group, aminoacyl, aryl, substituted amino group, heteroaryl, heteroaryloxy, -S (O) _n -aryl, -S (O) _n -substituted aryl, -S (O) _n -heteroaryl and -S (O) _n -substituted heteroaryl, where n is zero, one or two.

More preferably, R ^{1 is} selected from the group consisting of:

(3-methoxyphenyl) sulfanyl;

(4-chlorophenyl) sulfanyl;

(4-methylphenyl) sulfanyl;

2-fluorophenoxy;

2-methoxyphenoxy;

(2-methoxyphenyl) sulfanyl;

3-fluorophenoxy;

3-methoxyphenoxy group;

4- (methylcarbonylamino) phenoxy group;

4- (methylsulfonamido) phenoxy group;

4-fluorophenoxy;

4-methoxyphenoxy;

4-methoxyphenylsulfanyl;

4-methylphenyl;

bromine;

chlorine;

dimethylaminomethyl;

ethoxy group;

ethylsulfanyl;

hydrogen;

isopropyl;

methoxy group;

methoxymethyl;

methyl;

N, N-dimethylaminocarbonyl;

naphth-2-yloxy group;

naphthylsulfanyl;

phenoxy group;

phenyl;

phenylamino group;

phenylsulfinyl;

phenylsulfanyl;

pyridin-2-yloxy group;

pyridin-2-yl and

pyridin-2-ylsulfanyl.

In the compounds of formulas I, IA, IB, IC and ID, the substituent R ^{2 is} preferably selected from the group consisting of a substituted amino group, aryloxy, substituted aryloxy group, alkoxy, substituted alkoxy group, halogen atom, hydrogen atom, alkyl, substituted alkyl, aryl, - S (O) _n -aryl, -S (O) _n -substituted aryl, -S (O) _n -cycloalkyl, where n is zero, one or two, an aminocarbonylamino group, a heteroaryloxy group and a cycloalkyloxy group.

More preferably, R ^{2 is} selected from the group consisting of:

A (4-methoxy) phenylsulfonylamino group;

2,6-dimethylphenoxy group;

3,4-difluorophenoxy group;

3,5-difluorophenoxy group;

3-chloro-4-fluorophenoxy;

3-methoxy-4-fluorophenoxy;

3-methoxy-5-fluorophenoxy;

4- (methylsulfonamido) phenoxy group;

4- (phenylsulfonamido) phenoxy group;

4-CF ₃ -O-phenoxy group;

4-CF ₃ -phenoxy group;

4-chlorophenoxy;

4-fluorophenoxy;

4- (4-fluorophenoxy) phenoxy group;

4-methoxyphenoxy;

4-nitrophenoxy;

benzyloxy group;

bromine;

butoxy group;

CF ₃ ;

chlorine;

cyclohexyloxy group;

cyclohexylsulfanyl;

cyclohexylsulfonyl;

fluorine;

hydrogen;

iodine;

isopropoxy group;

methyl;

phenoxy group;

phenyl;

phenylsulfanyl;

phenylsulfinyl;

phenylsulfonyl;

phenylurea;

pyridin-1-ylsulfanyl;

pyridin-3-yloxy group and

pyridin-4-ylsulfanyl.

In the compounds of formulas I, IA, IB, IC and ID, R ^{3 is} preferably selected from the group consisting of substituted aryloxy, substituted alkoxy, alkoxy, substituted alkyl, alkyl, amino, cycloalkyloxy, hydrogen, halogen, aryl, -S (O) _n -aryl, -S (O) _n -substituted aryl, -S (O) _n -heteroaryl and -S (O) _n -substituted heteroaryl, where n is zero, one or two, aminocarbonylamino and heteroaryloxy .

More preferably, R ^{3 is} selected from the group consisting of

an amino group;

A (4-methyl) phenylsulfonylaminophenoxy group;

3,4-difluorophenoxy group;

3,5-difluorophenoxy group;

3-fluoro-5-methoxyphenoxy group;

3-chloro-4-fluorophenoxy;

4-CF ₃ -O-phenoxy group;

4-CF ₃ -phenoxy group;

4-chlorophenoxy;

4-fluorophenoxy;

4- (4-fluorophenoxy) phenoxy group;

4-methoxyphenoxy;

benzyloxy group;

bromine;

butoxy group;

CF ₃ ;

chlorine;

cyclohexyloxy group;

hydrogen;

iodine;

isopropoxy group;

phenoxy group;

phenyl;

phenylsulfanyl;

phenylsulfonyl;

phenylsulfinyl;

phenylurea;

pyridin-1-ylsulfanyl;

pyridin-3-yloxy group and

pyridin-4-ylsulfanyl.

On the other hand, the substituents R ² and R ³ with the carbon atom to which they are attached form an aryl group. Preferably, the aryl group is phenyl.

In the compounds of formulas I, IA, IB, IC and ID, the substituent R ^{4 is} preferably selected from the group consisting of a substituted arylthio group, a halogen atom, a hydrogen atom, substituted alkyl and aryl.

More preferably, R ^{4 is} selected from the group consisting of

4-chlorophenylsulfanyl;

chlorine;

hydrogen;

methoxymethyl and

phenyl.

In the compounds of formulas I, IA, IB, IC and ID, the substituent R ^{5 is} preferably a hydrogen atom or aryl. More preferably, R ⁵ is a hydrogen atom or phenyl.

In the compounds of formulas I, IA and IC, the substituent R is preferably selected from the group consisting of hydrogen, deuterium, aryl and alkyl. More preferably, R is selected from the group consisting of phenyl, hydrogen, deuterium and methyl.

In the compounds of formulas I, IA and IC, the substituent R ′ is preferably selected from the group consisting of hydrogen, deuterium, alkyl, substituted alkyl and a substituted amino group. More preferably, R ′ is selected from the group consisting of

4-aminobutyl;

4-hydroxybenzyl;

benzyl;

carboxymethyl;

deuterium;

hydroxymethyl;

imidazol-4-ylmethyl;

isopropyl;

methyl and

drank it up.

On the other hand, the substituents R, R 'and the carbon atom to which they are attached form cycloalkyl and more preferably cyclopropyl.

In the compounds of formulas I, IA and IC, the substituent R ″ is preferably a hydrogen atom, an alkyl or substituted alkyl. More preferably, the substituent R ″ represents a hydrogen atom, methyl or carboxymethyl (—CH ₂ C (O) OH). On the other hand, the substituents R ′, R ″ and, respectively, the carbon atom and the nitrogen atom to which they are attached form a heterocyclic group, preferably pyrrolidinyl.

In the compounds of formulas I, IA, IB, IC and ID, the substituent R ″ is preferably selected from the group consisting of a hydrogen atom, a hydroxy, alkoxy group, a substituted alkoxy group, a cycloalkoxy group, a substituted cycloalkoxy group, thiol, an acyloxy group and aryl. Preferably, the substituent R ′ ”is selected from the group consisting of

hydroxy group;

benzyloxy group;

ethoxy group;

thiol;

methoxy group;

methylcarbonyloxy group and

phenyl.

In the compounds of formulas I, IB and IC, the substituent WR ^{8 is} preferably selected from the group consisting of an amino group, a substituted amino group, aminoacyl, hydroxy and alkoxy groups. More preferably, the substituent WR ^{8 is} selected from the group consisting of

an amino group;

dimethylamino group;

hydroxy group;

methoxy group and

methylcarbonylamino group.

Typical compounds of this application are presented in tables A-D, in which the letter designation for the table corresponds to the letter designation of the formulas (that is, examples of compounds of formula IA are in table A).

Table a

No. R ¹ R ² R ³ R R ^' R ^” one Cl N Benzyloxy N Methyl N 2 Cl N N N Hydroxymethyl N 3 Cl N N N Hydroxymethyl N four Cl N Isopropoxy N Hydroxymethyl N 5 Cl N Isopropoxy N Hydroxymethyl N 6 Cl Isopropoxy N N Hydroxymethyl N 7 Cl Isopropoxy N N Hydroxymethyl N 8 Cl N N Methyl Methyl N 9 Cl N Isopropoxy Methyl Methyl N 10 Cl N N N Imidazol-4-ylmethyl N eleven Cl N N N Imidazol-4-ylmethyl N 12 Cl N N N Isopropyl N 13 Cl N N N Isopropyl N fourteen Cl N Isopropoxy N Isopropyl N fifteen Cl N Isopropoxy N Isopropyl N 16 Cl Isopropoxy N N Isopropyl N 17 Cl Isopropoxy N N Isopropyl N eighteen Cl N Benzyloxy N Isopropyl N 19 Cl N N N Benzyl N twenty Cl N N N Benzyl N 21 Cl N Isopropoxy N Benzyl N 22 Cl N Isopropoxy N Benzyl N 23 Cl Isopropoxy N N Benzyl N 24 Cl Isopropoxy N N Benzyl N 25 Cl N N N 4-hydroxybenzyl N 26 Cl N N N 4-hydroxybenzyl N 27 Cl N Isopropoxy N 4-hydroxybenzyl N 28 Cl N Isopropoxy N 4-hydroxybenzyl N 29th Cl Isopropoxy N N 4-hydroxybenzyl N thirty Cl Isopropoxy N N 4-hydroxybenzyl N 31 Cl N Isopropoxy N Propyl N 32 Cl N Isopropoxy N Propyl N 33 Cl N N N R 'and R "carbon atom and nitrogen atom, respectively, to which R" is connected, form pyrrolidinyl - 34 Cl N N N R 'and R "carbon atom and nitrogen atom, respectively, to which R" is connected, form pyrrolidinyl - 35 Cl N Isopropoxy N R 'and R "carbon atom and nitrogen atom, respectively, to which R" is connected, form pyrrolidinyl - 36 Cl N Isopropoxy N R 'and R "carbon atom and nitrogen atom, respectively, to which R" is connected, form pyrrolidinyl - 37 Cl N N N 4-aminobutyl N 38 Cl N N N 4-aminobutyl N 39 Cl N Isopropoxy N 4-aminobutyl N 40 Cl N Isopropoxy N 4-aminobutyl N 41 Cl Isopropoxy N N 4-aminobutyl N 42 Cl Isopropoxy N N 4-aminobutyl N 43 Cl N N N Carboxymethyl N 44 Cl N N N Carboxymethyl N 45 Cl N Isopropoxy N Carboxymethyl N 46 Cl N Isopropoxy N Carboxymethyl N 47 Cl Isopropoxy N N Carboxymethyl N 48 Cl N N N R, R 'together with the carbon atom to which they are attached form cyclopropyl N 49 Cl N Isopropoxy N R, R 'together with the carbon atom to which they are attached form cyclopropyl N fifty Cl N N D D N 51 Cl N Benzyloxy N Methyl N 52 Cl Benzyloxy N N Methyl N 53 Cl Benzyloxy N N Methyl N 54 Cl N N N Methyl N 55 Cl N N N Methyl N 56 Cl N Isopropoxy N Methyl N 57 Cl N Isopropoxy N Methyl N 58 Cl Isopropoxy N N Methyl N 59 Cl Isopropoxy N N Methyl N 60 N 4-chlorophenoxy N N Methyl N 61 N N 4-chlorophenoxy N Methyl N 62 N 3,4-Difluorophenoxy N N Methyl N 63 N Phenylsulfanyl N N Methyl N 64 N Phenylsulfanyl N N Methyl N 65 N Phenoxy N N Methyl N 66 N 4-methoxyphenoxy N N Methyl N 67 N Phenylsulfonyl N N Methyl N 68 Methoxymethyl Phenoxy N N Methyl N 69 Methoxymethyl Phenoxy N N Methyl N 70 N Phenoxy N N Methyl N 71 4-chlorophenylsulfanyl N N N Methyl N 72 4-chlorophenylsulfanyl N N N Methyl N 73 N 3-methoxy-4-fluorophenoxy N N Methyl N 74 N Cyclohexyloxy N N Methyl N 75 Methyl 4-fluorophenoxy N N Methyl N 76 N 4-fluorophenoxy N N Methyl N 77 Methyl Phenoxy N N Methyl N 78 Methyl Phenylsulfanyl N N Methyl N 79 N 4-trifluoromethylphenoxy N N Methyl N

Table B

No. R ² R ³ Wr ⁸ one N N Methoxy 2 Isopropoxy N Amino 3 N Isopropoxy Methoxy four N N Amino 5 N N Hydroxy 6 N Isopropoxy Hydroxy 7 N N Dimethylamino 8 N N Methylcarbonylamino 9 N Isopropoxy Amino 10 N Isopropoxy Dimethylamino eleven Isopropoxy N Methoxy 12 Isopropoxy N Dimethylamino 13 Isopropoxy N Hydroxy

Table C

No. R ² R ³ one Isopropoxy N 2 N Isopropoxy 3 N N

Table D

No. R ¹ R ² R ³ R ⁴ R ⁵ R ^” R ^”' one Br 2,6-Di (CH ₃ ) phenyloxy H H H H OH 2 Br Butoxy H H H H OH 3 Br Phenoxy H H H H OH four Cl Br H H H H OH 5 Br Cl H H H H OH 6 Cl I H H H H OH 7 Cl H I H H H OH 8 Cl Phenoxy H H H H OH 9 Cl Phenylsulfanyl H H H H OH 10 Br -CF ₃ H H H H OH eleven Br H Phenoxy H H H OH 12 Cl H H Phenyl H H OH 13 Cl 2,6-Di (CH ₃ ) phenyloxy H H H H OH fourteen Br H CF ₃ H H H OH fifteen Br Br H H H H OH 16 Br Phenylsulfanyl H H H H OH 17 Cl H Phenylsulfanyl H H H OH eighteen 4-methoxyphenylsulfanyl H H H H H OH 19 Br H H Phenyl H H OH twenty Cl Phenyl H H H H OH 21 Br H H H H H OH 22 Br Methyl H H H H OH 23 Br H Butoxy H H H OH 24 Br H Cl H H H OH 25 Cl H Phenoxy H H H OH 26 Br H Phenoxy H H H OH 27 H I H H H H OH 28 Br Phenyl H H H H OH 29th Br H Phenyl H H H OH thirty Ethylsulfanyl H H H H H OH 31 Phenoxy H H H H H OH 32 H H Phenyl H H H OH 33 Br H H H Phenyl H OH 34 Br F H H H H OH 35 H 2,6-Di (CH ₃ ) phenyloxy H H H H OH 36 Cl H Phenyl H H H OH 37 H Phenoxy H H H H OH 38 H Phenylsulfanyl H H H H OH 39 H Phenyl H H H H OH 40 H H Phenoxy H H H OH 41 H H Phenylsulfanyl H H H OH 42 H H H Phenyl H H OH 43 Cl H H H Phenyl H OH 44 H H H H Phenyl H OH 45 Cl F H H H H OH 46 H F H H H H OH 47 H H Br H H H OH 48 H R ² / R ³ = phenyl - H H H OH 49 Br H Benzyloxy H H Methyl OH fifty Cl H N H H Methyl OH 51 Cl H Isopropoxy H H Methyl OH 52 Cl Isopropoxy N H H Methyl OH 53 Cl H N H H CH ₂ COOH OH 54 Cl H Isopropoxy H H CH ₂ COOH OH 55 Naft-2-yloxy H H H H H OH 56 Pyridin-3-yloxy H H H H H OH 57 4-methoxyphenoxy H H H H H OH 58 3-methoxyphenoxy H H H H H OH 59 3-fluorophenoxy H H H H H OH 60 4-fluorophenoxy H H H H H OH 61 2-fluorophenoxy H H H H H OH 62 2-methoxyphenoxy H H H H H OH 63 4- (Methylcarbonylamino) phenoxy H H H H H OH 64 4- (Methylsulfonamido) phenoxy H H H H H OH 65 Phenylamino H H H H H OH 66 H H Pyridine-3-
iloxy H H H OH 67 H Pyridin-3-yloxy H H H H OH 68 Cl H H H H H Methoxy 69 Cl H H H H H Ethoxy 70 Methoxy H H H H H OH 71 Ethoxy H H H H H OH 72 Phenyl H H H H H Methylcarbonyl-
oxy 73 Phenyl H H H H H OH 74 Ethoxy H H H H H Phenyl 75 Cl H H H H H Phenyl 76 H H H H H H Phenyl 77 Methyl H H H H H OH 78 Methoxymethyl H H H H H OH 79 N, N-Dimethylaminocarbonyl H H H H H OH 80 Methyl H Phenoxy H H H OH 81 Methyl Phenoxy H H H H OH 82 Methyl Phenoxy H H H H Benzyloxy 83 Methyl Phenoxy H H H H Ethoxy 84 N, N-Dimethylaminocarbonyl Phenoxy H H H H OH 85 Methoxymethyl Phenoxy H H H H OH 86 4-methylphenyl H H H H H OH 87 Methyl 4-fluorophenoxy H H H H OH 88 Cl 4-methoxyphenoxy H H H H OH 89 H 4-methoxyphenoxy H H H H OH 90 Cl H 4-methoxyphene
oxy H H H OH 91 H H 4-methoxyphene
oxy H H H OH 92 Cl 4-CF ₃ -phenoxy N H H H OH 93 H 4-CF ₃ -phenoxy N H H H OH 94 Cl H 4-CF ₃ -phenoxy H H H OH 95 H H 4-CF ₃ -phenoxy H H H OH 96 Cl 4-fluorophenoxy N H H H OH 97 H 4-fluorophenoxy N H H H OH 98 Cl N 4-fluorophenoxy H H H OH 99 H N 4-fluorophenoxy H H H OH one hundred H Pyridin-4-ylsulfanyl N H H H OH 101 H N Pyridin-4-ylsulfanyl H H H OH 102 H Phenylsulfinyl N H H H OH 103 H Phenylsulfonyl N H H H OH 104 H N Phenylsulfinyl H H H OH 105 H N Phenylsulfonyl H H H OH 106 H N Amino H H H OH 107 H (4-Methoxy) phenylsulfonylamino N H H H OH 108 H Phenylurea N H H H OH 109 H N Phenylurea H H H OH 110 Phenylsulfanyl N H H H H OH 111 (4-Chlorophenylsulfanyl) N H H H H OH 112 (4-Methylphenylsulfanyl) N H H H H OH 113 Pyridin-2-ylsulfanyl N H H H H OH 114 (3-Methoxyphenylsulfanyl) N H H H H OH 115 2-methoxyphenylsulfanyl N H H H H OH 116 Naphthylsulfanyl N H H H H OH 117 Phenylsulfinyl N H H H H OH 118 Phenylsulfonyl N H H H H OH 119 H Pyridin-2-ylsulfanyl H H H H OH 120 H N Pyridin-2-ylsulfanyl H H H OH 121 Cl Phenoxy Phenoxy H H H OH 122 H Phenoxy Phenoxy H H H OH 123 H N (4-Methyl) phenyl-SO ₂ NH-phenoxy H H H OH 124 H 4-nitrophenoxy H H H H OH 125 H Phenoxy H H H H Thiol 126 H CF ₃ H H H H Thiol 127 H 4- (Phenylsulfonamido) phenoxy H H H H OH 128 H 4- (Methylsulfonamido) phenoxy H H H H OH 129 H 4-chlorophenoxy H H H H OH 130 H N 4-chlorophenoxy H H H OH 131 H N 3-fluoro-5-methoxyphenoxy H H H OH 132 H 3-methoxy-5-fluorophenoxy H H H H OH 133 H 3,4-Difluorophenoxy H H H H OH 134 H N 3,4-Difluorfe-
noxy H H H OH 135 H 4-CF ₃ -O-phenoxy N H H H OH 136 H N 4-CF ₃ -O-phenoxy H H H OH 137 H 3,5-difluorophenoxy N H H H OH 138 H N 3,5-difluorofen
oxy H H H OH 139 H 4- (4-Fluorophenoxy) phenoxy N H H H OH 140 H N 4- (4-Fluorophenoxy)
phenoxy H H H OH 141 H 3-chloro-4-fluorophenoxy N H H H OH 142 N 3-chloro-4-fluorophenoxy H H H OH 143 Methyl 4-chlorophenoxy N H H H OH 144 Methyl N 4-chlorophenoxy H H H OH 145 Methyl 3,5-difluorophenoxy N H H H OH 146 Methyl 4-methoxyphenoxy N H H H OH 147 Methyl N 4-methoxyphene
oxy H H H OH 148 H N Cyclohexyloxy H H H OH 149 H Cyclohexyloxy N H H H OH 150 Methyl Cyclohexyloxy N H H H OH 151 H Cyclohexylsulfanyl H H H H OH 152 H Cyclohexylsulfonyl H H H H OH 153 Isopropyl N H H H H OH 154 Pyridin-2-yl N H H H H OH 155 Ethyl Phenoxy H H H H OH 156 Dimethylaminomethyl Phenylsulfanyl H H H H OH 157 Methyl Phenylsulfanyl H H H H OH 158 Methyl 4-trifluoromethylphenoxy H H H H OH

Compounds within the scope of the present invention are, for example, the compounds shown below:

{[4-hydroxy-1- (naphthalen-2-yloxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-1- (pyridin-3-yloxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-1- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-1- (3-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[1- (3-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[1- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[1- (2-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-1- (2-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[1- (4-acetylaminophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-1- (4-methanesulfonylaminophenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

[(4-hydroxy-1-phenylaminoisoquinoline-3-carbonyl) amino] acetic acid;

{[4-hydroxy-6- (pyridin-3-yloxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-7- (pyridin-3-yloxy) isoquinoline-3-carbonyl] amino} acetic acid;

[(1-chloro-4-methoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1-chloro-4-ethoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-1-methoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1-ethoxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(4-acetoxy-1-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-1-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-ethoxy-4-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-chloro-4-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(4-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-1-methylisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-1-methoxymethylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-dimethylcarbamoyl-4-hydroxyisoquinoline-3-carbonyl) amino]

acetic acid;

[(4-hydroxy-1-methyl-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(4-benzyloxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(4-ethoxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1-dimethylcarbamoyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] vinegar

acid;

[(4-hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-1-p-tolylisoquinoline-3-carbonyl) amino] acetic acid;

{[7- (4-fluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} acetic acid;

{[1-chloro-4-hydroxy-7- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-7- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[1-chloro-4-hydroxy-6- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-6- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[1-chloro-4-hydroxy-7- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-7- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[1-chloro-4-hydroxy-6- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-6- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[1-chloro-7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[1-chloro-6- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[6- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-7- (pyridin-4-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-6- (pyridin-4-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;

[(7-benzenesulfinyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(7-benzenesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(6-benzenesulfinyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(6-benzenesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(6-amino-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

{[4-hydroxy-7- (4-methoxybenzenesulfonylamino) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-7- (3-phenylureido) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-6- (3-phenylureido) isoquinoline-3-carbonyl] amino} acetic acid;

[(4-hydroxy-1-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;

{[1- (4-chlorophenylsulfanyl) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

[(4-hydroxy-1-p-tolyl sulfanilisoquinoline-3-carbonyl) amino] acetic acid;

{[4-hydroxy-1- (pyridin-2-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-1- (3-methoxyphenylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-1- (2-methoxyphenylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-1- (naphthalen-2-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;

[(1-benzenesulfinyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1-benzenesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

{[4-hydroxy-7- (pyridin-2-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-6- (pyridin-2-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;

{[1-chloro-4-hydroxy-6,7-diphenoxyisoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-6,7-diphenoxyisoquinoline-3-carbonyl] amino} acetic acid;

({4-hydroxy-7- [4- (toluene-4-ylsulfonylamino) phenoxy] isoquinoline-3-carbonyl} amino) acetic acid;

{[4-hydroxy-7- (4-nitrophenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

[(4-mercapto-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(4-mercapto-7-trifluoromethylisoquinoline-3-carbonyl) amino] acetic acid;

{[7- (4-benzenesulfonylaminophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-7- (4-methanesulfonylaminophenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[7- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[6- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[6- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[7- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[7- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[6- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-7- (4-trifluoromethoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-6- (4-trifluoromethoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;

2- (S) - {[7- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid;

2- (S) - {[6- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid;

2 - {[7- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid;

2- (S) - [(4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] propionic acid;

2- (R) - [(4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] propionic acid;

2- (R) - [(4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid;

2- (S) - {[4-hydroxy-7- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} propionic acid;

2- (S) - [(7-benzenesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;

(R) -2 - [(4-hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid;

(S) -2 - [(4-hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid;

(S) -2 - [(4-mercapto-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid;

(S) -2 - {[1- (4-chlorophenylsulfanyl) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid;

(R) -2 - {[1- (4-chlorophenylsulfanyl) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid;

[(4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-6-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-chloro-4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-chloro-4-hydroxy-6-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-4-hydroxy-6-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1-chloro-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1-chloro-4-hydroxy-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-4-hydroxy-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;

{[7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[1-chloro-7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[1-bromo-7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

[(1-bromo-7-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-6-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-4-hydroxy-7-trifluoromethylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-4-hydroxy-6-trifluoromethylisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-1-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1,7-dibromo-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(7-bromo-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(6-bromo-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-7-fluoro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(7-fluoro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1-chloro-7-fluoro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1-chloro-4-hydroxybenzo [g] isoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-6-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-7-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-chloro-4-hydroxy-6-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-chloro-4-hydroxy-7-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-4-hydroxy-6-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-4-hydroxy-7-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-5-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-8-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-chloro-4-hydroxy-5-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-chloro-4-hydroxy-8-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-4-hydroxy-5-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-4-hydroxy-8-phenylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-ethylsulfanyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

{[4-hydroxy-1- (4-methoxyphenylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;

[(1-chloro-4-hydroxy-7-iodisoquinoline-3-carbonyl) amino] acetic acid;

[(1-chloro-4-hydroxy-6-iodisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-7-iodisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-4-hydroxy-7-methylisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-7-butoxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(1-bromo-6-butoxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(6-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) methylamino] acetic acid;

[(1-chloro-4-hydroxyisoquinoline-3-carbonyl) methylamino] acetic acid;

[(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) methylamino] acetic acid;

[(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) methylamino] acetic acid;

[carboxymethyl- (1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[carboxymethyl- (1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] acetic acid;

1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (2-aminoethyl) amide (trifluoroacetic acid salt);

1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (2-methoxyethyl) amide;

1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (2-hydroxyethyl) amide;

1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (2-dimethylaminoethyl) amide;

1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (2-acetylaminoethyl) amide;

1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (2-hydroxyethyl) amide;

1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (2-methoxyethyl) amide;

1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (2-aminoethyl) amide (trifluoroacetic acid salt);

1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (2-dimethylaminoethyl) amide;

1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (2-aminoethyl) amide (trifluoroacetic acid salt);

1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (2-methoxyethyl) amide;

1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (2-dimethylaminoethyl) amide;

1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (2-hydroxyethyl) amide;

(S) -2 - [(6-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;

=== (R) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid;

(S) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid;

(R) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid;

(S) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid;

(R) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid;

(S) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid;

2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -2-methylpropionic acid;

2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -2-methylpropionic acid;

(R) -2 - [(1-chloro-4-hydroxyisoquinolin-3-carbonyl) amino] -3- (1H-imidazol-4-yl) propionic acid (trifluoroacetic acid salt);

(S) -2 - [(1-chloro-4-hydroxyisoquinolin-3-carbonyl) amino] -3- (1H-imidazol-4-yl) propionic acid (trifluoroacetic acid salt);

(R) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid;

(S) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid;

(R) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid;

(S) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid;

(R) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid;

(S) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid;

(S) -2 - [(6-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid;

(R) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid;

(S) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid;

(R) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid;

(S) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid;

(R) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid;

(S) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid;

(R) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid;

(S) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid;

(R) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid;

(S) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid;

(R) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid;

(S) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid;

(R) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] pentanoic acid;

(S) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] pentanoic acid;

(R) -1- (1-chloro-4-hydroxyisoquinoline-3-carbonyl) pyrrolidine-2-carboxylic acid;

(S) -1- (1-chloro-4-hydroxyisoquinoline-3-carbonyl) pyrrolidine-2-carboxylic acid;

(R) -1- (1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) pyrrolidine-2-carboxylic acid;

(S) -1- (1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) pyrrolidine-2-carboxylic acid;

(R) -6-amino-2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] hexanoic acid (trifluoroacetic acid salt);

(S) -6-amino-2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] hexanoic acid (trifluoroacetic acid salt);

(R) -6-amino-2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] hexanoic acid (trifluoroacetic acid salt);

(S) -6-amino-2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] hexanoic acid (trifluoroacetic acid salt);

(R) -6-amino-2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] hexanoic acid (trifluoroacetic acid salt);

(S) -6-amino-2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] hexanoic acid (trifluoroacetic acid salt);

(R) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] succinic acid;

(S) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] succinic acid;

(R) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] succinic acid;

(S) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] succinic acid;

(R) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] succinic acid;

1 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] cyclopropanecarboxylic acid;

1 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] cyclopropanecarboxylic acid;

diditero - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

(R) -2 - [(6-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;

(R) -2 - [(7-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;

(R) -2 - [(7-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;

(S) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;

(R) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;

(S) -2 - [(6-isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;

(R) -2 - [(6-isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;

(S) -2 - [(7-isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;

(R) -2 - [(7-isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;

1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (2-hydroxy-1-hydroxymethylethyl) amide;

1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (2-hydroxy-1-hydroxymethylethyl) amide;

(2-hydroxy-1-hydroxymethylethyl) 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid amide;

{[7- (3,5-difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl) amino} acetic acid;

{[6- (3,5-difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl) amino} acetic acid;

({7- [4- (4-fluorophenoxy) phenoxy] -4-hydroxyisoquinoline-3-carbonyl} amino) acetic acid;

({6- [4- (4-fluorophenoxy) phenoxy] -4-hydroxyisoquinoline-3-carbonyl} amino) acetic acid;

{[7- (3-chloro-4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

{[6- (3-chloro-4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;

(S) -2 - {[7- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid;

2- (S) - [(7-cyclohexyloxy-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;

2- (S) - {[7- (4-fluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} propionic acid;

2- (S) - {[7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid;

2- (S) - [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid;

2- (S) - [(4-hydroxy-1-methyl-7-phenylsulfanylisoquinoline-3-carbonyl) amino] propionic acid;

2- (S) - {[4-hydroxy-7- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} propionic acid;

{[7- (4-chlorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} acetic acid;

{[6- (4-chlorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} acetic acid;

{[7- (3,5-difluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-7- (4-methoxyphenoxy) -1-methylisoquinoline-3-carbonyl] amino} acetic acid;

{[4-hydroxy-6- (4-methoxyphenoxy) -1-methylisoquinoline-3-carbonyl] amino} acetic acid;

[(6-cyclohexyloxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(7-cyclohexyloxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(7-cyclohexyloxy-4-hydroxy-1-methylisoquinoline-3-carbonyl) amino] acetic acid;

[(7-cyclohexylsulfanyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(7-cyclohexanesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-1-isobutylisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-1-pyridin-2-yl-isoquinoline-3-carbonyl) amino] acetic acid;

[(1-ethyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl)

amino] acetic acid;

[(1-dimethylaminomethyl-4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;

[(4-hydroxy-1-methyl-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;

{[4-hydroxy-1-methyl-7- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid and

their pharmaceutically acceptable salts, esters and prodrugs.

In yet another embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable excipient or carrier and a pharmaceutically effective amount of a compound of formula I or mixtures of such compounds.

Also provided are methods of treating, preventing or preventing conditions mediated at least in part by HIF and / or EPO. The method comprises administering to a sick mammal a therapeutically effective amount of a compound having the structure of the above formula I, provided that the compound is not selected from the group consisting of:

N - ((1-chloro-4-hydroxy-7- (2-propyloxy) isoquinolin-3-yl) carbonyl) glycine,

N - ((1-chloro-4-hydroxy-6- (2-propyloxy) isoquinolin-3-yl) carbonyl) glycine,

N - ((1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino) acetic acid,

N - ((1-chloro-4-hydroxy-7-methoxyisoquinolin-3-yl) carbonyl) glycine,

N - ((1-chloro-4-hydroxy-6-methoxyisoquinolin-3-yl) carbonyl) glycine,

N - ((7-butyloxy-1-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) glycine,

N - ((6-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino) acetic acid,

N - ((7-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino) acetic acid,

N - ((8-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) glycine,

N - ((7-butoxy-4-hydroxyisoquinoline-3-carbonyl) amino) acetic acid and

((7-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino) acetic acid methyl ester.

In yet another embodiment, the present invention provides a method of inhibiting the activity of a hydroxylase enzyme that modifies the alpha subunit of a hypoxia inducing factor.

The present invention also provides a compound of formula I or a mixture of compounds of formula I in combination with at least one additional therapeutic agent. Preferably, the additional therapeutic agent is erythropoietin.

DETAILED DESCRIPTION OF THE INVENTION

Before describing the compositions and methods under consideration, it should be indicated that the invention is not limited to the specific techniques described, prescriptions, cell lines, evaluation methods and reagents, as they may vary. It should also be understood that the terminology used in the description is intended to describe specific embodiments of the present invention and does not limit the scope of the present invention as set forth in the claims.

It should be noted that the singular forms “a”, “an” and “the” used in the description and in the attached claims include plural references unless otherwise indicated.

Unless otherwise specified, all technical and scientific terms used in the description have the meanings usual for a person skilled in the technical field to which this application belongs. Although any methods and materials similar or equivalent to the described methods and materials can be used in practice and in testing the present invention, the preferred methods, devices and materials are described below. All publications cited in the work are introduced in their entirety as a reference to describe the methods, reagents and tools presented in the publication that could be used in connection with the invention.

Unless otherwise specified, in the practical implementation of this invention will be used usual for a person skilled in the art methods of chemistry, biochemistry, molecular biology, cell biology, genetics, immunology and pharmacology. Such techniques are fully described in the literature (see., E.g., Gennaro, AR, ed. (1990) Remington's Pharmaceutical Sciences, 18 ^{th ed., Mack Publishing Co .;} Colowick, S. et al., Eds., Methods In Enzymology, Academic Press, Inc .; Handbook of Experimental Immunology, Vols. I-IV (DM Weir and CC Blackwell, eds., 1986, Blackwell Scientific Publications); Maniatis, T. et al ., Eds. (1989) Molecular Cloning: A Laboratory Manual, 2 ^nd edition, Vols. I-III, Cold Spring Harbor Laboratory Press; Ausubel, FM et al ., Eds. (1999) Short Protocols in Molecular Biology, 4 ^th edition, John Wiley &Sons; Ream et al . , eds. (1998) Molecular Biology Techniques: An Intensive Laboratory Course, Academic Press); PCR (Introduction to Biotechniques Series), 2nd ed. (Newton & Graham eds., 1997, Springer Verlag)).

The term “anemia” as used herein refers to any abnormality in hemoglobin or red blood cells that results in lower levels of oxygen in the blood. Anemia may be associated with abnormal production, processing, or the action of red blood cells and / or hemoglobin. The term “anemia” refers to a decrease in the number of red blood cells and / or hemoglobin in the blood relative to normal blood levels.

Anemia can occur due to conditions such as acute or chronic kidney disease, infection, inflammation, cancer, radiation, toxins, diabetes, and surgery. Infections can be caused, for example, by a virus, bacteria and / or parasites, etc. Inflammation can be caused by infection, autoimmune diseases such as rheumatoid arthritis, etc. Anemia can also be associated with blood loss, for example, due to a stomach ulcer, duodenal ulcer, hemorrhoids, stomach or colon cancer, trauma, wounds, surgery, etc. Anemia is also associated with radiation therapy, chemotherapy and kidney dialysis. Anemia is also associated with HIV-infected patients being treated with azidothymidine (zidovudine) or other reverse transcriptase inhibitors, and can develop in cancer patients undergoing chemotherapy, for example, with cyclic cisplatin or cisplatin-free chemotherapeutic agents. Aplastic anemia and myelodysplasia syndromes are diseases associated with damage to the bone marrow, which leads to reduced production of red blood cells. In addition, anemia can be the result of defective or abnormal hemoglobin or erythrocytes, as, for example, in diseases including microcytic anemia, hypochromic anemia, etc. Anemia can be the result of disorders in the transfer, processing and absorption of iron, for example, sideroblastic anemia.

The definitions of “violation”, “disease” and “condition” are used together and refer to any condition that deviates from the norm.

The definitions of “anemic conditions” and “anemic disorders” refer to any condition, disease, or disorder associated with anemia. Such diseases include, but are not limited to, the above diseases. Anemic diseases also include, but are not limited to, aplastic anemia, autoimmune hemolytic anemia, bone marrow transplantation, granulomatous allergic angiitis, Diamond-Blackfan anemia, Fanconi syndrome, Felty’s syndrome, graft versus host transplantation, hematopoietic stem cell transplantation - uremic syndrome, myelodysplasia syndrome, nocturnal paroxysmal hemoglobinuria, osteomyelofibrosis, pancytopenia, true erythrocytic aplasia, Scheulein-Genoch disease, seed roblastnuyu anemia, refractory anemia with excess of blasts, rheumatoid arthritis, Shvahmana syndrome (Shwachman), sickle cell disease, thalassemia major, thalassemia minor, thrombocytopenic purpura, etc..

The term “erythropoietin-related conditions” is used inclusively and refers to any condition associated with below normal, abnormal, or inappropriate modulation of erythropoietin. Erythropoietin-related conditions include any condition where an increase in EPO levels will provide therapeutic success. The levels of erythropoietin associated with such conditions can be determined using any measurement accepted and applied by specialists in this field. Erythropoietin-associated conditions include anemic conditions, such as those described above.

Erythropoietin-related conditions also include neurological diseases and / or lesions, including cases of shock, trauma, epilepsy, neurodegenerative diseases, etc., where erythropoietin can create a neuroprotective effect. Neurodegenerative diseases implied by the invention include Alzheimer's disease, Parkinson's disease, Gettington's disease, etc.

The term "erythropoietin" refers to any recombinant or naturally occurring erythropoietin, including, for example, human erythropoietin (GenBank Accession No. AAA52400; Lin et al. (1985) Proc. Nat'l Acad. Sci USA 82: 7580-7584), human recombinant erythropoietin EPOETIN (Amgen, Inc., Thousand Oaks CA), human recombinant erythropoietin ARANESP (Amgen), human recombinant erythropoietin PROCRIT (Ortho Biotech Products, LP, Raritan NJ), etc.

The definition of "HIFα" refers to the alpha subunit of a protein that induces factor hypoxia. HIFα may be a protein of a human or other mammal or its fragment, including human HIF-1α (Genbank Accession No. Q16665), HIF-2α (Genbank Accession No. AAB41495) and HIF-3α (Genbank Accession No. AAD22668); mouse HIF-1α (Genbank Accession No. Q61221), HIF-2α (Genbank Accession No. BAA20130 and AAB41496) and HIF-3α (Genbank Accession No. AAC72734); rat HIF-1α (Genbank Accession No. CAA70701), HIF-2α (Genbank Accession No. CA96612) and HIF-3α (Genbank Accession No. CAB96611) and bovine HIF-1α (Genbank Accession No. BAA78675). HIFα may also be any non-mammalian protein or fragment thereof, including HIF-1α of Xenopus laevis (Genbank Accession No. CAB96628), HIF-1α of Drosophila melanogaster (Genbank Accession No. JC4851) and chicken HIF-1α (Genbank Accession No. BAA34234). The HIFα gene sequence can also be obtained using conventional cloning techniques, for example, using all or part of the HIFα gene sequence described above as a probe for isolating and determining the sequence of HIFα genes in other samples.

A HIFα fragment includes any fragment that retains at least one functional or structural characteristic of HIFα. HIFα fragments include, for example, regions defined by human HIF-1α from amino acids 401 to 603 (Huang et al., Supra), amino acids 531 to 575 (Jiang et al. (1997), J. Biol. Chem., 272 : 19253-19260), amino acids 556 to 575 (Tanimoto et al., Supra), amino acids 557 to 571 (Srinivas et al., (1999) Biochem Biophys Res. Commun 260: 557-561) and amino acids 556 to 575 (Ivan and Kaelin (2001) Science 292: 464-468). In addition, HIFα fragments include any fragment containing at least one case of the LXXLAP motif, for example, which is present in the native sequence of human HIF-1α at L ₃₉₇ TLLAP and L ₅₅₉ EMLAP.

The definitions of "amino acid sequence" or "polypeptide", which are used in the description, for example, with respect to HIFα and its fragments, mean an oligopeptide, peptide or protein sequence, or refer to a fragment of any of them and to naturally occurring or synthetic molecules. "Fragments" may refer to any part of a sequence that retains at least one structural or functional characteristic of a protein. Immunogenic fragments or antigenic fragments are fragments of polypeptides, preferably fragments of approximately five to fifteen amino acids in length, which retain at least one biological or immunological activity. When the "amino acid sequence" is used to refer to the polypeptide sequence of a naturally occurring protein molecule, the "amino acid sequence" and similar terms are not intended to limit the amino acid sequence to the full native sequence associated with the specified protein molecule.

The term “related proteins” used in the description, for example, with respect to proteins related to HIFα prolyl hydroxylase, encompasses other 2-oxoglutarate-dioxygenase enzymes, especially members of those families that likewise require Fe ²⁺ , 2-oxoglutarate and oxygen to maintain hydroxylase activity. Such enzymes include, but are not limited to, for example, procollagen-lysyl hydroxylase, procollagen-prolyl-4-hydroxylase, and HIF inhibitory factor (FIH), asparaginyl hydroxylase, which is responsible for the regulation of HIFα transactivation. (GenBank Accession No. AAL27308; Mahon et al. (2001) Genes Dev 15: 2675-2686; Lando et al. (2002) Science 295: 858-861; and Lando et al. (2002) Genes Dev 16: 1466- 1471. See also Elkins et al. (2002) J. Biol Chem C200644200, etc. )

The definitions of “HIF prolyl hydroxylase” and “HIF PH” refer to any enzyme capable of hydroxylating a proline residue in a HIF protein. Preferably, the HIF hydroxylated proline residue includes proline found within the LXXLAP motif, for example, which occurs in the native sequence at L ₃₉₇ TLLAP and L ₅₅₉ EMLAP of human HIF-1α. HIF PH includes members of the Egl-Nine (EGLN) gene family described by Taylor (2001, Gene 275: 125-132) and characterized by Aravid and Koonin (2001, Genome Biol 2: RESEARCH 0007), Epstein et al. (2001, Cell 107: 43-54) and Bruick and McKnight (2001, Science 294: 1337-1340). Examples of HIF PH enzymes are human SM-20 (EGLN1) (GenBank Accession No. AAG33965; Dupuy et al. (2000) Genomics 69: 348-54), EGLN2 isoform 1 (GenBank Accession No. CAC42510; Taylor, supra), EGLN2 isoform 2 (GenBank Accession No. NP-060025) and EGLN3 (GenBank Accession No. CAC42511; Taylor, supra); mouse EGLN1 (GenBank Accession No. CAC42515), EGLN2 (GenBank Accession No. CAC42511) and EGLN3 (SM-20) (GenBank Accession No. CAC42517) and rat SM-20 (GenBank Accession No. AAA19321). In addition, HIF PH may include EGL-9 Caenorhabditis elegans (GenBank Accession No. AAD56365) and the Drosophila melanogaster CG1114 gene product (GenBank Accession No. AAF52050). HIF PH also includes any fragment of the above full-sized proteins that retains at least one structural or functional characteristic.

The term “agonist” refers to a molecule that increases or prolongs the duration of action of a particular molecule. Agonists may include proteins, nucleic acids, carbohydrates or any other molecules that enhance the effect (s) of the target molecule.

The term “antagonist” refers to a molecule that decreases the degree or duration of the effect of the biological or immunological activity of a particular molecule. Antagonists may include proteins, nucleic acids, carbohydrates, antibodies, or any other molecules that reduce the effect (s) of the target molecule.

The term “micro-community” refers to any arrangement of nucleic acids, amino acids, antibodies, etc. on the substrate. The substrate may be any suitable substrate, for example beads, glass, paper, nitrocellulose, nylon or any suitable membrane, etc. The substrate may be any rigid or semi-rigid substrate, including, but not limited to, membranes, filters, boards, chips, glass slides, fibers, beads, including magnetic or non-magnetic beads, gels, tubes, plates, polymers, microparticles, capillaries etc. The substrate may create a surface for coating and / or may have a number of surface forms, such as walls, rods, recesses, grooves and pores, with which nucleic acids, amino acids, etc. may be related.

The term “excipient” as used herein means an inert or inactive substance used in the manufacture of pharmaceutical products or other tablets, including, but not limited to, any substance used as a binder, disintegrant, coating, compression aid / encapsulation of a cream or lotion, lubricant, parenteral agent, sweetener, or taste and odor corrective substance, a suspending / gelling agent or wet agent granulation. Binders are, for example, carbopol, povidone, xanthan gum and others; coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gelatin based gum, maltodextrin, etc .; pressing / encapsulating additives include, for example, calcium carbonate, dextrose, fructose dc, honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose or microcrystalline cellulose), dc starch, sucrose, etc .; disintegrants include, for example, croscarmellose sodium, gelatin based gum, starch glycolate sodium, and others; creams and lotions include, for example, maltodextrin, carrageenans, etc .; lubricants are, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, and others; chewable tablet materials include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc .; parenteral agents include, for example, mannitol, povidone, etc .; plasticizers are, for example, dibutyl sebacinate, polyvinyl acetate phthalate and others; suspending / gelling agents are, for example, carrageenan, sodium starch glycolate, xanthan gum, etc .; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc., and wet granulation agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

The definition of “loading dose” as used herein refers to a single or multiple dose administered initially to quickly achieve the desired pharmacological level. For example, the loading dose in the case of the methods of the present invention relates to an initial drug regimen that rapidly increases, for example, the plasma concentration of a compound of the present invention to a pharmaceutically active level.

The definition of “inducing dose”, which is used in this case, refers to a repeated dosing concentration, introduced first to quickly achieve the desired physiological response. For example, the inducing dose in the case of the methods of the present invention relates to an initial drug regimen that rapidly increases the level of hematocrit or hemoglobin to the border of the desired interval, which may be at or below normal hematocrit / hemoglobin levels.

The term “maintenance dose” as used herein refers to the level of doses administered after a shock or induction dose to maintain a desired physiological response. For example, a maintenance dose in the case of the methods of the present invention relates to a medication regimen that maintains hematocrit and / or hemoglobin within a desired target range, which may be at or below normal hematocrit / hemoglobin levels.

The definition of "sample" is used in this description in its broadest sense. Samples can be obtained from any source, for example from body fluids, secrets, tissues, cells or cells in culture, including, but not limited to, saliva, blood, urine, serum, plasma, vitreous, synovial fluid, spinal cerebral fluid, amniotic fluid, and organ tissue (e.g., tissue taken for biopsy); from chromosomes, organelles and other membranes isolated from cells; from genomic DNA, cDNA, RNA, mRNA, etc .; and from purified cells or tissues, or from spots or traces of such cells or tissues. Samples can be obtained from any source, such as, for example, a human or non-human mammal, etc. Samples that are derived from any animal model of the disease are also contemplated. Samples can be in solution or, for example, can be fixed on a substrate or associated with the substrate. A sample may refer to any material suitable for testing for the presence of erythropoietin or HIFα or fragments thereof, or suitable for screening molecules that increase endogenous levels of erythropoietin or HIFα or fragments thereof. Methods for obtaining such samples are at the level of knowledge of specialists in this field of technology.

The definition of "object" is used in this description in its broadest sense. Objects can be isolated cells, or prokaryotic or eucaryotic, or tissue grown in culture. In some embodiments, the subject is an animal, especially an animal selected from mammalian species, including rat, rabbit, bovine, sheep, pork, feline, mouse, equine species and primates, especially humans.

As used herein, the term “alkyl” refers to monovalent alkyl groups containing from 1 to 10 carbon atoms, preferably from 1 to 5 carbon atoms, and more preferably from 1 to 3 carbon atoms. Examples of this definition are methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, etc.

The term “substituted alkyl” refers to an alkyl group containing from 1 to 10 carbon atoms, preferably from 1 to 5 carbon atoms, which has from 1 to 5 substituents, preferably from 1 to 3 substituents, independently selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxy, aryloxy aryl, cyano group, halogen atom, hydroxyl, nitro, oxo, thioxo group, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, thiol, alkylthio, substituted alkylthio group, arylthio, substituted arylthio, substituted cycloalkylthio, substituted cycloalkyl substituted heteroarylthio, heterocyclylthio, substituted heterocyclylthio, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, ge erotsikliloksi- substituted heterocyclyloxy, oksikarbonilamino-, oksitiokarbonilaminogruppu, -OS (O) ₂ -alkyl, -OS (O) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, - OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -heterocycle, -OS (O) ₂ -substituted heterocycle, -OSO ₂ -NR ⁴⁰ R ⁴⁰ , where each substituent R ⁴⁰ represents a hydrogen atom or an alkyl, -NR ⁴⁰ S (O) ₂ -alkyl, -NR ⁴⁰ S (O) ₂ -substituted alkyl, -NR ⁴⁰ S (O) ₂ -aryl, -NR ⁴⁰ S (O) _2- substituted aryl, -NR ⁴⁰ S (O) ₂ -heteroaryl, -NR ⁴⁰ S (O) ₂ -substituted heteroaryl, -NR ⁴⁰ S (O) ₂ -heterocycle, -NR ⁴⁰ S- (O) ₂ -substituted heterocycle, -NR ⁴⁰ S (O) ₂ -NR ⁴⁰ - alkyl, -NR ⁴⁰ S (O) ₂ -NR ⁴⁰ -substituted alkyl, -NR ⁴⁰ S (O) ₂ -NR ⁴⁰ -aryl, -NR ⁴⁰ S (O) ₂ -NR ⁴⁰ -substituted aryl, -NR ⁴⁰ S (O) ₂ -NR ⁴⁰ -heteroaryl, -NR ⁴⁰ S (O) ₂ -NR ⁴⁰ -substituted heteroaryl, -NR ⁴⁰ S (O) ₂ -NR ⁴⁰ -heterocycle and -NR ⁴⁰ S (O) ₂ -NR ⁴⁰ -substituted heterocycle where each of the substituents R ⁴⁰ represents a halogen atom or alkyl.

The term “alkoxy” refers to the group “alkyl-O—”, which is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n pentoxy group, etc.

The term “substituted alkoxy” refers to the group “substituted alkyl-O—”.

The term “acyl” refers to the groups H — C (O) -, alkyl-C (O) -, substituted alkyl-C (O) -, alkenyl-C (O) -, substituted alkenyl-C (O) -, alkynyl -C (O) -, substituted alkynyl-C (O) -, cycloalkyl-C (O) -, substituted cycloalkyl-C (O) -, aryl-C (O) -, substituted aryl-C (O) -, heteroaryl-C (O) -, substituted heteroaryl-C (O) -, heterocycle-C (O) - and substituted heterocycle-C (O) -, provided that the nitrogen atom of the heterocyclic or substituted heterocyclic group is not bonded to -C (O) a group wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted ring alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

The term “aminoacyl” or as the prefix “carbamoyl” or “carboxamide” or “substituted carbamoyl” or “substituted carboxamide” refers to the group —C (O) NR ⁴² R ⁴² , where each of the substituents R ^{42 is} independently of one another selected from the group consisting of hydrogen atom, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, and where each of the substituents R ⁴² combined with a nitrogen atom with an image a heterocycle or substituted heterocycle, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle have the meanings defined in the description.

The definition of "acyloxy" refers to the groups alkyl-C (O) O-, substituted alkyl-C (O) O-, alkenyl-C (O) O-, substituted alkenyl-C (O) O-, alkynyl-C (O ) O-, substituted alkynyl-C (O) O-, aryl-C (O) O-, substituted aryl-C (O) O-, cycloalkyl-C (O) O-, substituted cycloalkyl-C (O) O -, heteroaryl-C (O) O-, substituted heteroaryl-C (O) O-, heterocycle-C (O) O- and substituted heterocycle-C (O) O-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl , alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle cells have the meanings defined in the description.

The term “alkenyl” refers to an alkenyl group, preferably containing from 2 to 6 carbon atoms and more preferably from 2 to 4 carbon atoms, and having at least 1 and preferably from 1 to 2 alkenyl unsaturation sites.

The term “substituted alkenyl” refers to alkenyl groups containing from 1 to 3 substituents and preferably from 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy group, cyano group, halogen atom, hydroxyl, nitro group, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle.

The term “alkynyl” refers to an alkynyl group, preferably containing from 2 to 6 carbon atoms and more preferably from 2 to 3 carbon atoms, and having at least 1 and preferably from 1 to 2 sites of alkynyl unsaturation.

The term "substituted alkynyl" refers to alkynyl groups containing from 1 to 3 substituents and preferably containing from 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle.

The term “amino group” refers to the group —NH ₂ .

The term “substituted amino group” refers to the group —NR ⁴¹ R ⁴¹ , wherein each of the substituents R ^{41 is} independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, —SO ₂ -alkyl, —SO ₂ -substituted alkyl,

-SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, —SO ₂ heterocycle, —SO ₂ substituted heterocycle, provided that both R ⁴¹ groups are not a hydrogen atom or R ⁴¹ groups can be combined with a nitrogen atom to form a heterocyclic or substituted heterocyclic ring.

The term “acylamino group” refers to the groups —NR ⁴⁵ C (O) -alkyl, —NR ⁴⁵ C (O) -substituted alkyl, —NR ⁴⁵ C (O) -cycloalkyl, —NR ⁴⁵ C (O) -substituted cycloalkyl, - NR ⁴⁵ C (O) alkenyl, -NR ⁴⁵ C (O) -substituted alkenyl, -NR ⁴⁵ C (O) -alkynyl, -NR ⁴⁵ C (O) -substituted alkynyl, -NR ⁴⁵ C (O) -aryl , -NR ⁴⁵ C (O) -substituted aryl, -NR ⁴⁵ C (O) -heteroaryl, -NR ⁴⁵ C (O) -substituted heteroaryl, -NR ⁴⁵ C (O) -heterocycle and -NR ⁴⁵ C (O) -substituted heterocyclic, wherein the substituent R ⁴⁵ represents hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, ari Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein value.

The term “carbonyloxy amino group” refers to the groups —NR ⁴⁶ C (O) O-alkyl, —NR ⁴⁶ C (O) O-substituted alkyl, —NR ⁴⁶ C (O) O-alkenyl, —NR ⁴⁶ C (O) O- substituted alkenyl, -NR ⁴⁶ C (O) O-alkynyl, -NR ⁴⁶ C (O) O-substituted alkynyl, -NR ⁴⁶ C (O) O-cycloalkyl, -NR ⁴⁶ C (O) O-substituted cycloalkyl, - NR ⁴⁶ C (O) O-aryl, -NR ⁴⁶ C (O) O-substituted aryl, -NR ⁴⁶ C (O) O-heteroaryl, -NR ⁴⁶ C (O) O-substituted heteroaryl, -NR ⁴⁶ C ( O) O-heterocycle and -NR ⁴⁶ C (O) O-substituted heterocycle, where R ⁴⁶ represents a hydrogen atom or alkyl and where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

The term “aminocarbonyloxy group” or as the prefix “carbamoyloxy group” or “substituted carbamoyloxy group” refers to —OC (O) NR ⁴⁷ R ⁴⁷ groups, where each of the substituents R ⁴⁷ independently of one another represents a hydrogen atom, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle or where each of the substituents R ^{47 is} combined with a nitrogen atom to form a heterocycle or a substituted heterocycle, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle have the meanings defined in the description.

The term “aminocarbonylamino group” refers to the group —NR ⁴⁹ C (O) NR ⁴⁹ , wherein R ^{49 is} selected from the group consisting of hydrogen and alkyl.

The term “aryl” or “Ar” refers to a monovalent aromatic carbocyclic group containing from 6 to 14 carbon atoms that has one ring (eg, phenyl) or several fused rings (eg, naphthyl or antryl), and these condensed rings may be aromatic or non-aromatic (for example, 2-benzoxazolinone, 2H-1,4-benzoxazin-3 (4H) -on-7-yl, etc.), provided that the point of attachment is an aryl group. Preferred aryl groups are phenyl and naphthyl.

The term “substituted aryl” refers to aryl groups as defined herein that are substituted with 1-4, preferably 1-3, with substituents selected from the group consisting of hydroxy, acyl, acylamino, carbonylaminothio, acyloxy, alkyl, substituted alkyl, alkoxy -, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, amino, substituted amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl ester, cyclo, thiol, alkylthio, substituted alkylthio, substituted aryl, aryl, aryl, aryl cycloalkylthio group, heterocyclylthio, substituted heterocyclylthio group, cycloalkyl, substituted cycloalkyl, guanidino group, halogen atom, nitro group, heteroaryl, substituted heteroaryl, g heterocycle, substituted heterocycle, hydroxycarbonylamino, oxythiocarbonylamino group, -S (O) ₂ -alkyl, -S (O) ₂ -substituted alkyl, -S (O) ₂ -cycloalkyl, -S (O) ₂ -substituted cycloalkyl, -S (O) ₂ -alkenyl, -S (O) ₂ -substituted alkenyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocycle, - SO ₂ -substituted heterocycle, -OS (O) ₂ -alkyl, -OS (O) ₂ -substituted alkyl, -OS (O) ₂ -aryl, -OS (O) ₂ -substituted aryl, -OS (O) ₂ -heteroaryl, -OS (O) ₂ -substituted heteroaryl, -OS (O) ₂ -heterocycle, -OS (O) ₂ -substituted heterocycle, -ОSO ₂ NR ⁵¹ R ⁵¹ , where each of the substituents R ⁵¹ represents an atom hydrogen or alkyl, -NR ⁵¹ S (O) ₂ -alkyl, -NR ⁵¹ S (O) ₂ -substituted alkyl, -NR ⁵¹ S (O) ₂ -aryl, -NR ⁵¹ S (O) ₂ -substituted aryl, -NR ⁵¹ S (O) ₂ -heteroaryl, -NR ⁵¹ S (O) ₂ -substituted heteroaryl, -NR ⁵¹ S (O) ₂ -heterocycle, -NR ⁵¹ S (O) ₂ -substituted heterocycle,

-NR ⁵¹ S (O) ₂ -NR ⁵¹ -alkyl, -NR ⁵¹ S (O) ₂ -NR ⁵¹ -substituted alkyl, -NR ⁵¹ S (O) ₂ -NR ⁵¹ -aryl, -NR ⁵¹ S (O) ₂ -NR ⁵¹ -substituted aryl, -NR ⁵¹ S (O) ₂ -NR ⁵¹ -heteroaryl, -NR ⁵¹ S (O) ₂ -NR ⁵¹ -substituted heteroaryl, -NR ⁵¹ S (O) ₂ -NR ⁵¹ -heterocycle ,

—NR ⁵¹ S (O) ₂ —NR ⁵¹ —substituted heterocycle where each of the substituents R ⁵¹ represents a hydrogen atom or an alkyl, where each of the definitions has the meaning given in the description.

The term “aryloxy group” refers to an aryl-O— group, which includes, for example, phenoxy, naphthoxy, etc.

The term "substituted aryloxy group" refers to substituted aryl-O-groups.

The term "aryloxyaryl" refers to the groups-aryl-O-aryl.

The term “substituted aryloxyaryl” refers to aryloxyaryl groups substituted with 1 to 3 substituents on either or both aryl rings as defined above for substituted aryl.

The term “carboxyl” refers to the —COOH group or its salts.

The term “carboxyl ester” refers to the groups —C (O) O-alkyl, —C (O) O-substituted alkyl, —C (O) O-aryl, —C (O) O-substituted aryl, where alkyl, substituted alkyl, aryl and substituted aryl are as defined herein.

The term “cycloalkyl” refers to cyclic alkyl groups containing from 3 to 10 carbon atoms, containing one or more rings, including, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, etc.

The term “substituted cycloalkyl” refers to a cycloalkyl group containing from 1 to 5 substituents selected from the group consisting of oxo- (= O), thioxo (= S), alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino group, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy group, cyano group, halogen atom, hydroxyl, nitro group, carboxyl ester, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and

The term “cycloalkoxy” refers to —O-cycloalkyl groups.

The term “substituted cycloalkoxy” refers to —O-substituted cycloalkyl groups.

The definitions of “halogen” or “halogen atom” refer to fluorine, chlorine, bromine and iodine atoms and are preferably a fluorine or chlorine atom.

The term “heteroaryl” refers to an aromatic group containing from 1 to 15 carbon atoms in the ring, preferably from 1 to 10 carbon atoms, and from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. Such heteroaryl groups may include one ring (e.g., pyridinyl or furyl) or several fused rings (e.g., indolisinyl or benzothienyl). Preferred heteroaryl are pyridinyl, pyrrolyl, indolyl, thiophenyl and furyl.

The term “substituted heteroaryl” refers to heteroaryl groups which are substituted with 1-3 substituents selected from the same groups as defined for substituted aryl.

The term “heteroaryloxy group” refers to the —O-heteroaryl group, and “substituted heteroaryloxy group” refers to the —O-substituted heteroaryl group.

The term “heterocycle” or “heterocyclyl” refers to a saturated or unsaturated group containing one ring or several condensed rings containing from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen atoms, where in a condensed system, one or more rings may be aryl or heteroaryl, provided that the point of attachment is in the heterocycle.

The term “substituted heterocycle” refers to heterocyclic groups which are substituted with the same 1-3 substituents as defined for substituted cycloalkyl.

Examples of heterocycles are, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolinezine, tinoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4,4-tetrahydride 6,7-tetrahydrobenzo [b] thiophene, thiazole, thiazolidine, thiophene, Enzo [b] thiophene, morpholinyl, thiomorpholinyl (also referred tiamorfolinilom), piperidinyl, pyrrolidine, tetrahydrofuranyl, etc.

The definition “heterocyclyloxy group” refers to the group —O-heterocycle, and the term “substituted heterocyclyloxy group” refers to the —O-substituted heterocycle.

The term “thiol” or “mercapto” refers to the —SH group.

The definition of “alkylsulfanyl” and “alkylthio group” refers to —S-alkyl groups, where alkyl is as defined above.

The definitions of “substituted alkylthio group” and “substituted alkylsulfanyl” refer to the group —S-substituted alkyl, where alkyl is defined above.

The definitions of “cycloalkylthio group” or “cycloalkylsulfanyl” refer to the group —S-cycloalkyl, where cycloalkyl is as defined above.

The term “substituted cycloalkylthio group” refers to the group —S-substituted cycloalkyl, wherein substituted cycloalkyl is as defined above.

The term “arylthio group” refers to the —S-aryl group, and the term “substituted arylthio group” refers to the —S-substituted aryl group, where aryl and substituted aryl are as defined above.

The term “heteroarylthio” refers to the group —S-heteroaryl, and the term “substituted heteroarylthio” refers to the group —S-substituted heteroaryl, wherein heteroaryl and substituted heteroaryl are as defined above.

The definition “heterocyclylthio group” refers to the —S-heterocycle group, and the term “substituted heterocyclylthio group” refers to the —S-substituted heterocycle group, wherein the heterocycle and substituted heterocycle are as previously defined.

The term “amino acid” refers to any of the naturally occurring amino acids, as well as their synthetic analogs (for example, to the D-stereoisomers of naturally occurring amino acids, such as D-threonine) and their derivatives. α-amino acids contain a carbon atom to which an amino group, a carboxyl group, a hydrogen atom and a distinctive group called the “side chain” are attached. Such side chains of naturally occurring amino acids are well known in the art and represent, for example, a hydrogen atom (e.g., as in glycine), alkyl (e.g., as in alanine, valine, leucine, isoleucine, proline), substituted alkyl (e.g., as in threonine, serine, methionine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine and lysine), arylalkyl (for example, as in phenylalanine and tryptophan), substituted arylalkyl (for example, as in tyrosine) and heteroyl as in histidine). Unnatural amino acids are also known in the art, for example, amino acids presented in Williams (ed.), Synthesis of Optically Active alpha-Amino Acids, Pergamon Press (1989); Evans et al., J. Amer. Chem. Soc., 112: 4011-4030 (1990); Pu et al., J. Amer. Chem. Soc., 56: 1280-1283 (1991); Williams et al., J. Am. Chem. Soc., 113: 9276-9286 (1991), and all references cited therein. The present invention also includes side chains of unnatural amino acids.

The term “pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, and such salts are derived from various organic and inorganic counterions well known in the art and include, for example, sodium, potassium, calcium, magnesium, ammonium, tetralkylammonium ions, etc. ; and when the molecule contains a basic functional group, the salts are salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc.

The term “prodrug” refers to compounds of the present invention that have been modified to introduce a physiologically and biocompatible removable group, and this group is removed in vivo to form the active drug, its pharmaceutically acceptable salt, or its biologically active metabolite. Suitable leaving groups are well known in the art, and ester groups of a carboxylic acid on a glycine substituent are particularly preferred. Preferably, such esters are those derived from alkyl alcohols, substituted alkyl alcohols, hydroxy substituted aryls and heteroaryls, etc. Other preferred leaving groups are amides formed from the carboxylic acid residue on the glycine substituent. Suitable amides are obtained from amines of the formula HNR ²⁰ R ²¹ where the substituents R ²⁰ and R ²¹ independently represent a hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, etc.

It should be understood that in all substituted groups described above, polymers obtained using certain substituents, in turn, with additional substituents (for example, substituted aryl containing a substituted aryl group as a substituent, which in turn is substituted by a substituted aryl group, etc. d.) are not intended to be included in the invention. In such cases, the maximum number of such substituents is three. In other words, each of the above definitions implies a limitation according to which, for example, substituted aryl groups are limited to the group - (substituted aryl) - (substituted aryl) - (substituted aryl).

Similarly, it should be understood that the above definitions do not imply the inclusion of unacceptable substitution options (for example, methyl substituted with 5 fluorine atoms or a hydroxyl group in the alpha position to ethylene or acetylene unsaturation). Such unacceptable substitutional options are well known to those skilled in the art.

The methods of the present invention

The present invention provides methods for modulating HIF and / or EPO by inhibiting the hydroxylation of HIFα, resulting in stabilization of HIF and activation of expression of the HIF-regulated gene. The methods can be used to prevent, pretreat or treat conditions associated with HIF and / or EPO, including anemia, ischemia and hypoxic conditions.

Treating HIF-Related Conditions

Ischemia and hypoxia are two conditions associated with HIF and include, but are not limited to, myocardial infarction, liver ischemia, renal ischemia, and stroke; peripheral vascular diseases, ulcers, burns and chronic wounds; pulmonary embolism; ischemic reperfusion lesions, including, for example, ischemic reperfusion lesions associated with surgery and organ transplantation. In one embodiment, the present invention provides methods for stabilizing HIFα before, during, or immediately after ischemia or hypoxia, especially in connection with myocardial infarction, stroke, or renal ischemic reperfusion injury.

In one aspect, the present invention provides methods for treating various ischemic and hypoxic conditions, in particular using the compounds described in the work. In one embodiment, the methods of the invention provide therapeutic benefit when administered after ischemia or hypoxia. For example, the methods of the present invention provide a sharp reduction in morbidity and mortality after myocardial infarction and significantly improve the condition and function of the heart. In addition, the methods of the present invention improve liver function when administered after hepatic toxic ischemic injury. Hypoxia is an essential component of liver disease, especially in chronic liver disease associated with liver toxic compounds such as ethanol. In addition, gene expression, which is known to be induced by HIFα, for example, nitric oxide synthase or glucose transporter-1, increases with alcoholic liver disease (see, for example, Areel et al . (1997) Hepatology 25: 920- 926; Strubelt (1984) Fundam. Appl. Toxicol. 4: 144-151; Sato (1983) Pharmacol Biochem Behav 18 (Suppl. 1): 443-447; Nanji et al . (1995) Am. J. Pathol. 146 : 329-334; and Morio et al . (2001) Toxicol. Appl. Pharmacol. 172: 44-51).

Thus, the present invention provides a method for treating conditions associated with ischemia and hypoxia, and this method comprises administering to a subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, alone or in combination with a pharmaceutically acceptable excipient. In one embodiment, the compound is administered immediately after the condition causing acute ischemia, for example, after myocardial infarction, pulmonary embolism, intestinal infarction, ischemic stroke, and renal ischemic reperfusion injury. In another embodiment, the compounds are administered to a patient with a diagnosed condition associated with the development of chronic ischemia, for example, cardiac cirrhosis, macular degeneration, pulmonary embolism, acute respiratory failure, neonatal respiratory distress syndrome, and congestive heart failure. In yet another embodiment, the compound is administered immediately after injury or damage.

In yet another aspect, the invention provides methods for treating a patient at risk of developing an ischemic or hypoxic condition, for example, individuals at high risk of atherosclerosis, etc., using the compounds described in the work. Risk factors for atherosclerosis include, for example, hyperlipidemia, smoking, hypertension, diabetes mellitus, hyperinsulinemia and abdominal obesity. Thus, the present invention provides a method for treating ischemic tissue damage, and this method comprises administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, alone or in combination with a pharmaceutically acceptable excipient, to a patient in need. In one embodiment, the compound may be administered based on predisposing conditions, such as, for example, hypertension, diabetes, occlusive arterial disease, chronic venous insufficiency, Raynaud's disease, chronic skin ulcers, cirrhosis, congestive heart failure, and systemic sclerosis.

In one specific embodiment of the invention, these methods are used to increase vascularization and / or granulation of tissue in damaged tissue, wounds and ulcers. For example, the compounds of the present invention have been shown to be effective in stimulating granulation tissue formation during wound healing. Tissue granulation includes newly formed, loosely connected blood vessels and a temporary stroma of plasma proteins such as fibrinogen and plasma fibronectin. The release of growth factors from inflammatory cells, platelets, and activated endothelium stimulates fibroblast and the migration and proliferation of endothelial cells in granulation tissue. Ulceration may occur if vascularization or neural stimulation is impaired. The methods of the present invention are effective in stimulating the formation of granulation tissue. Thus, the present invention provides methods for treating a patient having tissue damage due to, for example, a heart attack, having wounds caused, for example, by injury or bruising, or having chronic wounds or ulcers resulting from a disease, such as diabetes. The method comprises administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, alone or in combination with a pharmaceutically acceptable excipient, to a patient in need thereof.

In another aspect, the present invention provides methods of using the compounds for pre-treating a subject to reduce or prevent the development of tissue damage associated with ischemia or hypoxia. The methods of the present invention provide therapeutic efficacy when administered immediately before the condition causing ischemia or hypoxia. For example, the application of the methods of the present invention before the onset of myocardial infarction shows a statistically significant improvement in the condition and function of the heart. In addition, the methods of the present invention provide a therapeutic effect when administered immediately before or during ischemic reperfusion injury, significantly reducing the diagnostic parameters associated with renal failure.

Thus, the present invention provides a method for pre-treating a subject to reduce or prevent tissue damage associated with ischemia or hypoxia, and this method comprises administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, alone or in combination with a pharmaceutically acceptable excipient, to a patient with a history of ischemic diseases , for example with myocardial infarction, or having symptoms of impending ischemia, such as angina pectoris. In another embodiment, the compounds may be administered based on physical parameters suggesting possible ischemia, for example, individuals under general anesthesia or temporarily working at high altitudes. In yet another embodiment of the invention, the compounds can be used in organ transplants to pretreat donor organs and to preserve organs removed from the body prior to implantation to the recipient.

Preliminary studies have shown that some compounds used in the methods of the present invention are effective inhibitors of procollagen-prolyl-4-hydroxylase. Although it is known that recovery from a primary heart attack or wound requires deposition of connective tissue within the necrotic region, the present invention shows the absence of adverse effects of treatment due to scar formation. Thus, based on the beneficial effects provided by some of the compounds of the present invention in the treatment or prevention of hypoxic tissue damage, the present invention involves a “dual therapy” technique for treating or preventing conditions causing ischemia or hypoxia, including ischemia and hypoxia associated with subsequent reactive fibrosis , for example, with myocardial infarction and congestive heart failure. One compound that inhibits more than one 2-oxoglutarate-dioxygenase enzyme, for example, prolyl hydroxylase and procollagen-prolyl-4-hydroxylase HIF, can be used with either the same specificity or other specificities. Alternatively, a combination of compounds can be used in the method where each compound specifically inhibits only one 2-oxoglutarate-dioxygenase enzyme, for example, one compound specifically inhibits HIF prolyl hydroxylase, and the second compound specifically inhibits procollagen-prolyl 4-hydroxylase.

In one aspect, the compound of the present invention inhibits one or more 2-oxoglutarate dioxygenase enzymes. In one embodiment, the compound inhibits at least two members of the 2-oxoglutarate-dioxygenase family, for example, prolyl hydroxylase HIF and asparagine hydroxylase HIF (FIH-1), either with the same specificity or with other specificities. In one embodiment of the invention, the compound is specific for one 2-oxoglutarate dioxygenase, for example HIF prolyl hydroxylase, and exhibits specificity from slight specificity to its absence in the case of other family members.

The compounds may be administered in combination with various other therapeutic methods. In one embodiment, the compounds are administered with another 2-oxoglutarate dioxygenase inhibitor, where the two compounds have different specificities for individual members of the 2-oxoglutarate dioxygenase family. Two compounds can be introduced simultaneously in the form of a ratio of one relative to the other. Determining the ratio suitable for a given course of treatment or a specific subject is within the knowledge of a person skilled in the art. On the other hand, two compounds can be administered sequentially during the course of treatment, for example, after myocardial infarction. In a preferred embodiment, one compound specifically inhibits the activity of the HIF prolyl hydroxylase enzyme, and the second compound specifically inhibits the activity of the procollagen-prolyl 4-hydroxylase enzyme. In another specific embodiment, one compound specifically inhibits the activity of the HIF prolyl hydroxylase enzyme, and the second compound specifically inhibits the activity of the HIF asparagyl hydroxylase enzyme. In another embodiment, the compound is administered with another therapeutic agent having a different mechanism of action, such as, for example, an ACE inhibitor (ACEI), an angiotensin-II receptor blocker (ARB), statin, diuretic, digoxin, carnitine, etc.

Treatment of conditions associated with EPO

 The present invention provides methods for increasing endogenous erythropoietin (EPO). These methods can be applied in vivo, for example, in blood plasma or in vitro, for example, in a medium conditioning cell culture. The invention also provides methods for increasing endogenous EPO levels to prevent, pretreat or treat EPO related conditions, including, for example, conditions associated with anemia and neurological diseases. Anemia-related conditions include diseases such as acute or chronic kidney disease, diabetes, cancer, ulcers, infection with a virus, such as HIV, bacteria or parasites, inflammation, etc. Anemic conditions may also include conditions associated with procedures or treatment, including, for example, radiation therapy, chemotherapy, dialysis, and surgery. Diseases associated with anemia also include abnormal hemoglobin and / or red blood cells, as is found in diseases such as microcytic anemia, hypochromic anemia, aplastic anemia, etc.

The subject methods can also increase endogenous EPO in a subject undergoing a specific treatment or procedure prophylactically or simultaneously, for example, in an HIV-infected anemic patient being treated with azidothymidine (zidovudine) or other reverse transcriptase inhibitors in an anemic cancer patient, receiving chemotherapeutic agents containing cyclic cisplatin or not containing cisplatin, or from an anemic or non-anemic patient assigned to the surgeon ical operation. Methods for increasing endogenous EPO can also be used to prevent, pretreat or treat EPO-related conditions that are associated with nerve damage and nerve tissue degeneration, including, but not limited to, stroke, trauma, epilepsy, spinal cord injury, and neurodegenerative diseases.

In addition, the methods under consideration can be used to increase the levels of endogenous EPO in anemic or non-anemic patients assigned for surgery, in order to reduce the need for allogeneic blood transfusion or to facilitate the accumulation of blood before surgery. Small decreases in hematocrit, which usually occur after autologous pre-surgical blood injection, do not stimulate an increase in endogenous EPO or compensating erythropoiesis. However, preoperative stimulation of endogenous EPO could effectively increase the mass of red blood cells and the volume of autologous administration while maintaining higher levels of hematocrit, and such methods are specifically implied in this case. In some patients, especially those individuals who have experienced blood loss during surgery of more than 2 liters, the methods of the present invention could be used to reduce exposure to allogeneic blood (Crosby (2002) Amer. J. Therap. 9: 371-376).

The methods of the present invention can also be used to increase athletic performance, increase training ability, and to accelerate or enhance aerobic training. Such methods can be used, for example, by athletes to accelerate training and by soldiers to increase, for example, endurance and endurance.

The methods of the present invention, as shown, increase the levels of endogenous erythropoietin in the medium from culture cells treated in vitro and in the blood plasma of animals treated in vivo. Although the kidney is the main source of erythropoietin in the body, other organs, including the brain, liver and bone marrow, can and do synthesize erythropoietin with appropriate stimulation. When using the methods of the present invention, the expression of endogenous erythropoietin can be increased in various organs, including the brain, kidneys and liver. Indeed, the methods of the present invention even increase endogenous erythropoietin levels in animals that have undergone bilateral nephrectomy.

The methods of the present invention show that erythropoietin levels can be elevated even if renal function is impaired. Although the invention is not limited to the mechanism by which erythropoietin is produced, the decrease in erythropoietin secretion commonly observed in renal failure may be due to hyperoxia in the renal tissue due to the increased amount of leaking fluid / reperfusion (Priyadarshi et al. (2002), Kidney Int. 61 : 542-546).

In addition, the methods of the present invention increase hematocrit and hemoglobin levels in blood in animals treated in vivo. Increases in plasma of EPO, hematocrit and blood hemoglobin in response to the compounds used in the methods of the present invention are dose dependent; however, drug regimens that provide a consistent, controlled level of response to the compounds of the invention can be adopted. In addition, treatment with the compounds of the present invention can eliminate anemia, for example, caused by a toxic compound, such as the chemotherapeutic agent cisplatin, or due to blood loss, for example, trauma, injury, parasites or surgery.

The increase in hematocrit and blood hemoglobin in animals treated with the compounds of the present invention begins by increasing the percentage of circulating immature red blood cells (reticulocytes) in the blood. Essentially, the invention contemplates the use of the compounds of the present invention in methods of increasing blood reticulocyte levels in animals for the production of a cell-free reticulocyte lysate, as described, for example, in Pelham, Jackson. Eur. J. Biochem. 67: 247-256 (1976). Circulating reticulocyte levels increase in animals, for example rabbits, etc., when treated with the compounds of the present invention, alone or in combination with another compound, such as, for example, acetylphenylhydrazine and others. Blood is collected, reticulocytes are pelletized by centrifugation and lysed with distilled water. The extracts may be further processed using any suitable methodology known to those skilled in the art (see, for example, Jackson, Hunt (1983), Methods Enzymol. 96: 50-74).

The compounds of the present invention can be easily prepared from readily available starting materials using the following general methods and techniques. Obviously, when typical or preferred process conditions are given (i.e., reaction temperatures, reaction times, molar ratios of reactants, solvents, pressure, etc.), other process conditions can also be used, unless otherwise stated. Optimum reaction conditions may vary depending on the particular reagents or solvent used, but such conditions can be determined by a person skilled in the art using routine optimization techniques.

In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to protect certain functional groups from undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are also well known in the art. For example, various protecting groups are described in T.W. Greene, G.M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley New York, 1991, as well as the references cited therein.

In addition, the compounds of the present invention typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., individual enantiomers or diastereomers, or as mixtures enriched in a stereoisomer. All such stereoisomers (and enriched mixtures) are included in the scope of the present invention, unless otherwise specified. Pure stereoisomers (or enriched mixtures) can be obtained, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

The compounds of the present invention are preferably prepared using a synthesis scheme combining an amino function and a substituted isoquinolinacetic acid derivative under ordinary coupling conditions, as shown below in Scheme 1.

where R, R ', R ", R'", R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^a have the meanings defined above;

Pg ¹ refers to suitable protecting groups, such as tert-butyl ethers or orthoesters.

DIAGRAM 1

More specifically, in Scheme 1, an appropriately substituted 3- (protected carboxyl) isoquinoline, compound 1, is mixed with at least a stoichiometric amount and preferably with an excess of a suitable amine or its N-alkyl derivative, compound 2. The reaction is carried out under ordinary conditions of coupling well known in the art. In one embodiment, the reaction is carried out in the presence of sodium methoxide in methanol at elevated reaction temperatures and preferably at reflux. The reaction is carried out until it essentially ends, which usually occurs in the range of about 1 to 48 hours. At the end of the reaction, compound 3 can be isolated by conventional methods, such as neutralization, extraction, precipitation, chromatography, filtration, etc., or, on the other hand, the compound is used in the next step without purification and / or isolation.

On the other hand, the combination of substituted 3- (protected carboxyl) isoquinoline, compound 1, with a substituted amine or its N-alkyl derivative, compound 2, can proceed by conventional peptide coupling techniques well known in the art. This coupling reaction is usually carried out using well-known coupling reagents, such as carbodiimides, BOP reagent (benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphonate), etc. Suitable carbodiimides are, for example, dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (DECI), etc. If desired, forms of polymer substrates with carbodiimide coupling reagents can also be used, including, for example, those described in Tetrahedron Letters, 34 (48), 7685 (1993). In addition, well-known coupling promoters such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used to accelerate the coupling reaction.

This coupling reaction is usually carried out by contacting compound 1 (usually in the form of a free acid) with about 1-2 equivalents of the coupling reagent and at least one equivalent, preferably about 1-1.2 equivalents, of compound 2 in an inert diluent such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, etc. Typically, the reaction is carried out at a temperature in the range of from about 0 to 37 ° C for about 12 to 24 hours. At the end of the reaction, compound 3 is recovered by conventional methods, including by neutralization, extraction, precipitation, chromatography, filtration, etc.

Alternatively, the substituted 3- (protected carboxyl) isoquinoline, compound 1, can be converted to an acid halide and the acid halide is combined with compound 2 to give compound 3. The halide of compound 1 can be obtained by contacting compound 1 with an inorganic acid halide such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, or preferably with oxalyl chloride under ordinary conditions. Such a reaction is usually carried out using about 1-5 molar equivalents of an inorganic acid halide or oxalyl chloride, either in a pure form or in an inert solvent such as dichloromethane or carbon tetrachloride, at a temperature in the range of from about 0 to 80 ° C. for about 1 up to 48 hours A catalyst such as DMF may also be used in this reaction.

The acid halide (not shown) is then contacted with at least one equivalent, preferably about 1.1-1.5 equivalents, of compound 2 in an inert diluent such as dichloromethane, at a temperature in the range of about -70 to 40 ° C for approximately 1 to 24 hours. Preferably, such a reaction A. A. A. A. A. A. lead in the presence of a suitable base to absorb acid formed during the reaction. Suitable bases are, for example, tertiary amines such as triethylamine, diisopropylethylamine, N-methylmorpholine, etc. On the other hand, the reaction can be carried out under the conditions of the Schotten-Baumann reaction using aqueous alkali, such as sodium hydroxide, etc. At the end of the reaction, compound 3 is isolated by conventional methods, including neutralization, extraction, precipitation, chromatography, filtration, etc. d.

In one embodiment, the nitrogen atom of the isoquinoline ring system can be oxidized by conventional methods to give the corresponding N-oxide compound, compounds 4 and 5. The oxidation can be carried out using conventional oxidizing agents, such as m-chloroperbenzoic acid or hydrogen peroxide in conventional conditions. As shown in Scheme 1, the formation of N-oxide can be carried out either with substituted 3- (protected carboxyl) isoquinoline, compound 1, or with compound 3.

Starting materials for use in the reactions shown in Scheme 1 are either commercially available or can be prepared using methods well known in the art. For example, glycine and N-alkylglycines, such as sarcosine, N-ethylglycine, etc., are commercially available from Aldrich Chemical Company, Milwaukee, Wisconsin, USA ("Aldrich").

The synthesis of substituted isoquinoline acetic acids is also well known in the art and is described in detail, for example, in US Pat. No. 6,093,730 (Weidmann et al.), Which is incorporated herein by reference in its entirety. One specific way to obtain such derivatives is presented below in scheme 2.

DIAGRAM 2

More specifically, in Scheme 2, commercially available 4-phenylsulfanylphthalonitrile, compound 6, is hydrolyzed to the corresponding diacid, compound 7, under ordinary conditions, such as treatment with a 50% aqueous KOH / methanol mixture, 1: 1. The reaction is continued until it essentially ends, which usually takes about 48 to 96 hours. At the end of the reaction, the resulting diacid, compound 7, is isolated using conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc., or, on the other hand, is used in the next step without purification and / or isolation.

Compound 7 is cyclized in the presence of a stoichiometric equivalent of glycine. The reaction is carried out in the solid phase by first obtaining a homogeneous mixture of reagents, and then the mixture is heated to an elevated temperature to form a molten mass. Preferably, the reaction mixture is heated to a temperature above 200 ° C. And more preferably to a temperature of from about 210 to 220 ° C. The reaction is carried out until it essentially ends, which usually takes from about 48 to 96 hours. At the end of the reaction, the resulting phthalimide, compound 8, can be isolated using conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc., or, on the other hand, can be used in the next step without purification and / or discharge.

The usual esterification of compound 8 leads to compound 9, where the substituent R ⁸ is alkyl. The resulting compound is then subjected to a ring expansion reaction under basic conditions. More specifically, compound 9 is contacted with a stoichiometric excess, preferably 2 equivalents, of sodium or potassium alkoxide, such as sodium butoxide, in a suitable solvent, such as n-butanol, and maintained at an elevated temperature of from about 70 to 120 ° C and preferably from about 95 to 100 ° C. The reaction is carried out until it essentially ends, which usually takes from about 0.5 to 6 hours. Upon completion of the reaction, the obtained isoquinoline isomers, compounds 9 and 10, can be isolated using conventional techniques, such as neutralization, extraction, precipitation, chromatography, filtration, etc., or, on the other hand, can be used in the next step without purification and / or isolation.

The reaction conditions presented above can lead to cross-esterification of ester functionality (if R ^{8 is} not n-butyl). In any case, the alkyl moiety of the ester group serves as an acceptable protecting group for the carboxy functionality of compound 9 and is shown as Pg ¹ in Scheme 1 in compound ¹ .

Obviously, the hydroxyl functionality in position 1 undergoes various conversion schemes, which is well known in the art. Suitable transformations are the formation of products with an alkoxy, substituted alkoxy group, aryloxy, substituted aryloxy group, heteroaryloxy, substituted heteroaryloxy group, heterocyclyloxy, substituted heterocyclyloxy group, halogenation, dehalogenation (to obtain a hydrogen atom in the indicated position, formation) aryl substituted with aryl; heteroaryl substituted with heteroaryl. In addition, the hydroxyl group can be modified using known techniques to give —N (R ⁷ ) R ⁶ derivatives, which can be prepared by reacting a halogen substituent with a suitable amine. Similarly, sulfanyl and oxidized sulfanyl derivatives can be obtained using conventional methods, such as introducing a hydroxyl group into a reaction with phosphorus pentasulfide, Lawesson's reagent or others, followed by optionally reacting the resulting sulfhydryl group with alkylating agents such as ethyl iodide or others, to obtain an alkylsulfanyl derivative. Sulfanyl derivatives can be further oxidized using standard peracid reagents such as m-chloroperbenzoic acid.

In addition, substitution on the phenyl ring of isoquinoline compounds can be achieved by appropriate selection of starting materials. Many of these starting materials are commercially available, for example 4-phenoxyphthalonitrile (Aldrich) and others. On the other hand, compounds such as 4- (2,6-dimethylphenoxy) phthalonitrile can be obtained by methods known in the art.

Alternatively, commercially available substituted phthalic anhydride or phthalic acid can be used instead of compound 7 in Scheme 1. Such anhydrides are, for example, 3-fluorophthalic anhydride (Aldrich), 3-nitrophthalic anhydride (Aldrich), 3-chlorophthalic anhydride ( TCI America, Portland OR 97203 “TCI”) and others. These acids are, for example, 4-fluoromethylphthalic acid (TCI), etc.

TESTS AND INTRODUCTION

Biological tests

The biological activity of the compounds of the present invention can be evaluated using conventional known methods. Suitable evaluation methods are well known in the art. The following evaluation methods are provided as examples only and are not intended to limit the invention. The compounds of the present invention are active in at least one of the following test methods.

Cellular stabilization score of HIFα

Human cells obtained from various tissues are separately plated in 35 mm culture dishes and grown at 37 ° C, 20% O ₂ , 5% CO ₂ in standard culture medium, for example DMEM, 10% FBS. When cell layers reach fusion, the medium is replaced with OPTI-MEM medium (Invitrogen Life Technologies, Carlsbad CA) and the cell layers are incubated for approximately 24 hours in 20% O ₂ , 5% CO ₂ at 37 ° C. Compounds or 0.013% DMSO are then added to the existing medium and incubation is continued overnight.

After incubation, the medium is removed, centrifuged and stored for analysis (see further evaluation methods of VEGF and EPO). Cells were washed twice in cold phosphate-buffered saline (PBS) and then lysed in 1 ml of 10 mM Tris (pH 7.4), 1 mM EDTA, 150 mM NaCl, 0.5% IGEPAL (Sigma-Aldrich, St. Louis MO) and a mixture of protease inhibitors (Roche Molecular Biochemicals) for 15 minutes on ice. Cell lysates are centrifuged at 3000 g for 5 minutes at 4 ° C and the cytosolic fractions (supernatant) are collected. The nuclei (pellets) are resuspended and lysed in 100 μl of 20 mM HEPES (pH 7.2), 400 mM NaCl, 1 mM EDTA, 1 mM dithiothreite and a mixture of proteases (Roche Molecular Biochemicals), centrifuged at 13000 g for 5 minutes at 4 ° C and fractions of nuclear proteins (supernatant) are collected.

Nuclear fractions were analyzed for HIF-1α using a QUANTIKINE immunoassay (R&D Systems, Inc., Minneapolis MN) in accordance with the manufacturer's instructions.

Cellular ELISA Evaluation of VEGF and EPO

Conditioned media collected from cell cultures as described above are analyzed for expression of vascular endothelial growth factor (VEGF) and / or erythropoietin (EPO) using QUANTIKINE immunoassay (R&D Systems) according to the manufacturer's instructions.

Estimated Oxygen Consumption

Oxygen Sensor cell culture plates (BD Biosciences) contain a ruthenium complex that is more fluorescent in the absence of oxygen. Thus, fluorescence reading increases due to the presence of oxygen-consuming cells in the plate, which changes the equilibrium to lower oxygen saturation and higher fluorescence. A compound that stabilizes HIF by inhibiting hydroxylation is expected to lower oxygen consumption by reducing oxygen uptake due to the hydroxylation event itself and / or by shifting cellular metabolism from aerobic to anaerobic energy release.

Human cells obtained from adenovirus-transformed fetal kidney epithelium (293A) or cervical epithelial adenocarcinoma (HeLa) (American Type Culture Collection, Manassas VA) are grown to medium fusion (high-glucose DMEM (Mediatech, Inc., Herndon VA), 1% penicillin / streptomycin (Mediatech) mixtures, 1% serum of the fetus of cattle) at 37 ° С, 10% СО ₂ . Cells are harvested and resuspended in medium at a density of 500,000 cells / ml. A cell suspension was dispensed at a rate of 0.2 ml / well into each well of an Oxygen Biosensor 96-well cell culture plate (BD Biosciences, Bedford MA). The following treatments are added in 10 μl volumes to a triple set of wells: (1) 0.5% DMSO; (2) 200 μM sodium dodecyl sulfate; or (3) 1, 10 or 50 μM compound.

The cultures are incubated at 37 ° C, 10% CO ₂ for 72 hours, and the plates are then read in a FL600 fluorimeter (Biotek Instruments, Inc., Winooski VT) at an excitation wavelength of 485 nm and an emission wavelength of 590 nm. The data are plotted as a function of the rate of change relative to the control with DMSO (O ₂ absorption) or absorbance at a wavelength of 450 nm (WST-1) and a descriptive statistical analysis is performed using EXCEL software (Microsoft Corporation, Bellevue WA).

HIF-PH2 Score (PHD2)

Material

HIF-PH2 (EGLN1) is expressed from Hi5 cells and partially purified through SP ion exchange chromatography column. μ- [1-14C] -Ketoglutaric acid sodium salt is obtained from Perkin-Elmer. Alpha-ketoglutaric acid sodium salt is obtained from SIGMA. Purified HPLC DLD19 peptide (Acetyl-DLDLEMLAPYIPMDDDFQL-CONH ₂ ) was prepared by Synpep.

HIF-PH2 (EGLN1) is expressed from insect Hi5 cells and partially purified through an SP ion-exchange chromatographic column. Enzyme activity is determined by uptake of ¹⁴ CO ₂ using the evaluation method described in Kivirikko, Myllyla (1982, Methods Enzymol. 82: 245-304). Evaluation reactions contain 50 mM HEPES (pH 7.4), 100 μM sodium salt of α-ketoglutaric acid, 0.30 μCi / ml μ- [1-14C] sodium salt of ketoglutaric acid (Perkin-Elmer, Wellesley MA), 40 μM FeSO ₄ , 1 mM ascorbate, 1541.8 U / ml Catalase, with or without 50 μM peptide substrate (Acetyl-DLDLEMLAPYIPMDDDFQL-CONH ₂ ) and various concentrations of the compounds of the present invention. Reactions are initiated by the addition of the HIF-PH2 enzyme.

The peptide-dependent update percentage is calculated by subtracting the update percentage in the absence of the peptide from the update percentage in the presence of the peptide substrate. The percent inhibition and IC _{50 are} calculated using peptide-dependent renewal at a given inhibitor concentration. The calculation of the IC ₅₀ values for each inhibitor is carried out using the GraFit program (Erithacus Software Ltd., Surrey UK).

Pharmaceutical formulations and methods of administration

The compositions of the present invention can be delivered directly or in pharmaceutical compositions together with suitable carriers or excipients, as is well known in the art. Treatment methods contemplated may include administering an effective amount of a compound of the invention to a subject having anemia or at risk of anemia due to, for example, chronic renal failure, diabetes, cancer, AIDS, radiation therapy, chemotherapy, kidney dialysis, or surgery. In a preferred embodiment, the subject is a mammal, and in the most preferred embodiment, the subject is a human.

The effective amount of such agents can be easily determined using routine experiments, as well as the most effective and convenient route of administration and the most suitable formulation. Various formulations and drug delivery systems are available in the art. See, for example, Gennaro AR, ed. (1995), Remington's Pharmaceutical Sciences , supra.

Suitable routes of administration may include, for example, oral, rectal, mucosal, nasal or intestinal administration and parenteral delivery, including intramuscular, subcutaneous, intracerebral injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal or intraocular injections. The agent or its composition can be entered in a local rather than systemic manner. For example, a suitable agent may be delivered via injection or in the target drug delivery system, such as a depot or sustained release formulation.

The pharmaceutical compositions of the present invention can be made by any of the methods well known in the art, such as conventional processes of mixing, dissolving, granulating, grinding, drazhirovany, emulsification, encapsulation, encapsulation (polymer) or lyophilization. As indicated above, the compositions of the present invention may include one or more physiologically acceptable carriers, such as excipients and excipients, which facilitate the processing of active molecules into pharmaceutical preparations.

A suitable formulation is determined by the chosen route of administration. For example, in the case of an injection, the composition may be prepared in the form of aqueous solutions, preferably in physiologically compatible buffers, such as Hanks's solution, Ringer's solution or phosphate-buffered saline. In the case of mucosal administration or nasal administration, penetration agents suitable for the barrier through which it is necessary to pass are used in the formulations. Such penetration promoting agents are generally known in the art. In a preferred embodiment, the compounds of the present invention are formulated for oral administration. In the case of oral administration, the compounds can be easily formulated by mixing the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers provide the possibility of preparing the compounds of the invention in the form of tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions, suspensions, etc., for oral administration by a subject. The compounds can also be obtained in the form of rectal compositions, such as suppositories or retention enemas, containing, for example, conventional suppository bases, such as coconut oil or other glycerides.

Pharmaceutical preparations for oral administration can be obtained in the form of solid excipients, optionally by grinding the resulting mixture and processing the mixture of granules, after adding suitable excipients, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, excipients such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents such as crosslinked polyvinylpyrrolidone, agar or alginic acid or its salts such as sodium alginate can be added. In addition, wetting agents such as sodium dodecyl sulfonate may be included.

Dragee cores are provided with suitable coatings. For these purposes, concentrated sugar solutions may be used, which optionally may contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, glaze solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or dragee coatings for identification or to highlight various combinations of doses of the active compound.

Pharmaceutical preparations for oral administration include stuffed capsules made of gelatin, such as soft, sealed capsules made of gelatin and a plasticizer, such as glycerin or sorbitol. Filled capsules may contain the active ingredients in admixture with an excipient, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally with stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, petroleum jelly, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.

In one embodiment, the compounds of the present invention can be administered transdermally, for example, using a skin patch, or topically. In one aspect, the transdermal or topical formulations of the present invention may further comprise one or more penetration enhancing agents or other effectors, including agents that accelerate the migration of the delivered compound. Transdermal or topical administration may be preferred, for example, in situations in which a specific delivery site is desired.

When administered by inhalation, the compounds for use in accordance with the present invention are conveniently delivered in the form of an aerosol spray from a pressurized package or a nebulizer using a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or any other suitable gas. In the case of compressed aerosol, the appropriate dose can be determined using a valve to release a metered amount. Capsules and cartridges can be prepared, for example, from gelatin for use in an inhaler or insufflator. They usually contain a powdery mixture of the compound and a suitable powdery base, such as lactose or starch.

Compositions prepared for parenteral administration by injection, for example, by injection of a loading dose or by continuous infusion, can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with the addition of a preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain prescription agents, such as suspending, stabilizing and / or dispersing agents. Formulations for parenteral administration include aqueous solutions or other compositions in a water soluble form.

Suspensions of the active compounds can also be prepared as appropriate oily injectable suspensions. Suitable lipophilic solvents or carriers are fatty oils, such as sesame oil, and synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may contain suitable stabilizers or agents that increase the solubility of the compound to provide highly concentrated solutions. Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable vehicle, for example, sterile pyrogen-free water.

As mentioned above, the compositions of the present invention can also be prepared as a depot preparation. Such sustained active formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the subject compounds can be prepared with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or with ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

Suitable carriers for the hydrophobic molecules of the present invention are well known in the art and include cosolvent systems containing, for example, benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be a VPD co-solvent system. VPD is a solution of 3% w / v. benzyl alcohol, 8% wt./about. non-polar surfactant polysorbate 80 and 65% wt./about. polyethylene glycol 300, brought to volume in absolute ethanol. The VPD co-solvent system (VPD: 5W) consists of VPD diluted (1: 1) with a 5% dextrose solution in water. Such a co-solvent system is effective in the dissolution of hydrophobic compounds and has low toxicity with systemic administration. Typically, the proportions of the co-solvent system can vary significantly without violating the characteristics of its solvent capacity and toxicity. In addition, the distinctive feature of the components of cosolvents may vary. For example, other low toxic non-polar surfactants can be used instead of polysorbate 80, the fractional size of polyethylene glycol can change, other biocompatible polymers can replace polyethylene glycol, for example polyvinylpyrrolidone, and other sugars or polysaccharides can replace dextrose.

Alternatively, other hydrophobic molecule delivery systems may be used. Liposomes and emulsions are well known examples of delivery solvents or carriers for hydrophobic drugs. Liposome delivery systems are discussed above in the context of gene delivery systems. Some organic solvents, such as dimethyl sulfoxide, can also be used, although usually at the cost of higher toxicity. In addition, the compounds can be delivered using sustained release systems, such as semipermeable matrices of solid hydrophobic polymers containing an effective amount of the composition to be administered. Various sustained release materials are known and are available to those skilled in the art. Slow-release capsules may, depending on their chemical nature, release the compound over a period of several weeks to over 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies can be used to stabilize proteins.

In the case of any composition used in the considered methods of treatment, the therapeutically effective dose can be estimated using methods well known in the art. For example, when evaluating cell culture, a dose can be obtained in animal models to achieve a range of circulating concentration that includes the IC ₅₀ concentration determined in the cell culture. Dosage ranges suitable for humans can be determined, for example, using data from cell culture assays and other animal studies.

A therapeutically effective dose of an agent refers to the amount of agent that results in amelioration of symptoms or prolongation of the life of the subject. The toxicity and therapeutic efficacy of such molecules can be determined using standard pharmaceutical techniques in cell cultures or experimental animals, for example, by determining LD ₅₀ (lethal dose for 50% of the population) and ED ₅₀ (dose therapeutically effective for 50% of the population). The dose ratio of the toxic effect and the therapeutic effect is the therapeutic index, which can be expressed as the ratio LD ₅₀ / ED ₅₀ . Preferred are agents that exhibit high therapeutic indices.

Doses preferably fall within the range of circulating concentrations that include the ED ₅₀ with little or no toxicity. Doses can vary over a wide range depending on the dosage form used and the route of administration used. The exact formulation, route of administration and dose should be selected by methods known in the art, taking into account the characteristics of the subject.

The dosage amount and dose range can be individually adjusted to provide plasma levels of the active residue that are sufficient to modulate the desired plasma levels of endogenous erythropoietin, i.e., the minimum effective concentration (MEK, MEC). IEC will vary for each compound, but can be estimated, for example, based on in vitro data. Doses required to achieve IEC will depend on the individual characteristics and route of administration. Agents or compositions thereof should be administered using a regimen that maintains a plasma level above the MEK for approximately 10-90% of the treatment duration, preferably about 30-90% of the treatment duration, and most preferably from 50 to 90%. In the case of topical application or selective absorption, the effective local concentration of the drug may not correlate with the concentration in plasma. On the other hand, stimulation of endogenous erythropoietin can be achieved by 1) administering a saturation dose, followed by a maintenance dose, 2) administering an inducing dose to quickly achieve erythropoietin levels within a given interval, followed by a lower maintenance dose to maintain hematocrit in within the desired target interval, or 3) by repeated intermittent dosing.

The amount of agent or composition administered, of course, will depend on a number of factors, including the sex, age and weight of the subject being treated, the severity of the physical condition, route of administration and medical opinion.

If necessary, the compositions in question can be presented in packages or dispensers containing one or more unit dosage forms containing the active ingredient. Such a package or such device may, for example, consist of a metal or plastic foil, such as a blister pack. The packaging or dispenser may be provided with instructions for use. Compositions containing a compound of the present invention prepared in a compatible pharmaceutical carrier can also be prepared, packaged in an appropriate container and labeled for treating the condition. Suitable conditions indicated on the label may include the treatment of conditions, diseases and disorders in which anemia is the main indication.

These and other embodiments of the present invention can be easily performed by a person of ordinary skill in the art, taking into account the above description, and are specifically provided.

EXAMPLES

The invention is further illustrated by the following examples, which are intended to serve only as an example of the invention. The present invention is not limited in scope by the exemplary embodiments of the invention, which are intended to illustrate only certain aspects of the invention. Any methods that are functionally equivalent are within the scope of the present invention. Various modifications of the invention, in addition to those described, will be apparent to those skilled in the art from the description below and the accompanying drawings. Such modifications fall within the scope of the attached claims.

Unless otherwise specified, all temperatures are in degrees Celsius. In addition, in all examples and in other cases, the abbreviations have the following meanings:

μl = microliter Amu = atomic mass unit Atm = Atmosphere ear.s. = widened singlet ClCO ₂ i-Bu = isobutyl chloroformate Clconme ₂ = dimethylcarbamic acid chloride conc. = concentrated d. = doublet Dabco = diazobicyclo [2.2.2] octane dd = doublet of doublets DMF = dimethylformamide DMSO = dimethyl sulfoxide Et ₂ SO ₄ = ethyl sulfate Eti = ethyl iodide EtOAc = ethyl acetate EtOH = ethanol g = gram hour = hour Hatu = N-dimethylamino-1H-1,2,3-triazolo [4,5-b] pyridin-1-ylmethylene-N-methylmethanammonium hexafluorophosphate N-oxide HBTU = 1H-benzotriazolium Hz = hertz M = molar M = multiplet Me ₂ SO ₄ = methyl sulfate Me ₃ OBF ₄ = trimethylboroxine Mei = methyl iodide MeOCH ₂ I = iodomethoxymethane Meon = methanol Meona = sodium methoxide mg = milligram MHz = megahertz min = minute ml = milliliter Mmol = millimole n = normal NaOMe = sodium methoxide n-BuLi = n-butyllithium n-BuOH = n-butanol NEt ₃ = triethylamine PhCH ₂ Br = bromomethylbenzene sq = quartet quint = quintet ct = room temperature R _f = retention coefficient second = secondary t = triplet TFUK = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography % wt. = mass percentage

Example A-1

(S) -2 - [(6-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid

but. (S) -2 - [(6-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid methyl ester

6-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (can be obtained in accordance with US patent No. 6093730, 10/1998, Weidmann et al.) (0.33 g), 0.5 ml of triethylamine, 0.38 g of HATU and 0.151 g of commercial L-alanine methyl ester hydrochloride are stirred in 15 ml of CH ₂ Cl ₂ at room temperature for 18 hours, after chromatography on silica gel (eluent: hexane: EtOAc, 4: 1), 0.220 g of methyl ester ( S) -2 - [(6-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid as a white solid. MS - (+) - ion: M + 1 = 415.8 aem.

b. (S) -2 - [(6-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid

At room temperature, for 20 hours, 0.200 g of the (S) -methyl ester described in Example A-1 a) and 15 ml of a 1.5 M solution of NaOH in methanol were stirred and concentrated. The residue was dissolved in water and extracted with EtOAc. The aqueous layer was acidified to pH ~ 1 with hydrochloric acid and the resulting precipitate was filtered off, washed with water, dried in a vacuum oven (70 ° C), and 0.174 g of (S) -2 - [(6-benzyloxy-1-chloro-4-hydroxyisoquinoline- 3-carbonyl) amino] propionic acid as an almost white solid. MS - (+) - ion: M + 1 = 401.0 am.

Example A-2

(R) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid

but. (1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid butyl ester

A mixture of 160 ml of butanol, 20.0 g of (1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid (94.6 mmol) and 2.0 ml of concentrated sulfuric acid is refluxed with stirring for 24 hours . Then 5 g of sodium bicarbonate are added in portions, stirring is continued at rt. 5 min and the solvent was evaporated in vacuo. The residue was partitioned between 100 ml of water and 100 ml of ethyl acetate. The organic phase is washed with 100 ml of brine, dried over sodium sulfate and evaporated in vacuo to give a yellowish oil, which later solidifies. 24.02 g of the title compound are obtained. MS - (+) - ion: M + 1 = 261.9 am.

b. 1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

4.41 g of sodium (190 mmol) are dissolved in 250 ml of n-butanol with stirring. After complete dissolution of sodium, the solution was allowed to cool to ambient temperature and a solution of 24.0 g (91.9 mmol) of butyl ether (1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid in 150 ml of butanol was added with stirring . The solution is heated to 100 ° C for 30 minutes and stirred at this temperature for 1 hour. Then the mixture is allowed to cool to ambient temperature and maintained at this temperature for 18 hours. Then the pH of the mixture was adjusted to a value of 2 to 3 by adding 2N with stirring. aqueous hydrochloric acid. Stirring is continued for 30 minutes before separation of the solid components by suction filtration. The filter cake was washed thoroughly with water and dried in vacuo at 50 ° C to give a white solid. 17.75 g of the title compound are obtained. MS - (+) - ion. M + 1 = 262.1 aem.

from. 1-Chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 17.3 g (66.2 mmol) of butyl ester of 1,4-dihydroxyisoquinoline-3-carboxylic acid and 100 ml of phosphorus oxychloride is stirred at room temperature for 1 hour and then heated slowly under stirring for 2 hours to the boiling temperature under reflux . The mixture is gently boiled with stirring for 30 minutes. After cooling to room temperature, the excess phosphorus oxychloride was evaporated in vacuo and the residue was dissolved in 100 ml of ethyl acetate. The solution was poured with stirring into 300 ml of a saturated aqueous solution of sodium bicarbonate. The precipitate formed is removed by vacuum filtration. The organic phase is separated and the aqueous phase is extracted with ethyl acetate (3 x 100 ml). The combined aqueous phases are dried over sodium sulfate, filtered through a plug of silica gel and evaporated in vacuo to give a brown oil, which later solidifies. 11.37 g of the title compound are obtained. ¹ H NMR (CDCl ₃ ): δ = 11.91 (s, 1H), 8.41 (m, 1H), 8.29 (m, 1H), 7.83 (m, 2H), 4.49 ( t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).

d. 1-Chloro-4-hydroxyisoquinoline-3-carboxylic acid

A mixture of 9.23 g of 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ether (33 mol), 90 ml of 2.5N. an aqueous solution of sodium hydroxide, water (20 ml) and ethanol (110 ml) is refluxed with stirring for 2 hours. Then the pH of the mixture was adjusted to 2 by adding concentrated aqueous hydrochloric acid. During the addition, the temperature of the mixture was maintained at 20 ° C, cooling with an ice bath. Stirring is then continued for 1 hour and the solids are separated by vacuum filtration. The filter cake was washed with water and dried in vacuo at 85 ° C to give a white powder. 6.64 g of the title compound are obtained. MS - (+) - ion: M + 1 = 224.1 am.

e. (R) -3-tert-butoxy-2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid tert-butyl ester

To a mixture of 45 mg (0.2 mmol) of 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid, 76 mg (0.2 mmol) of benzotriazol-1-yl- (bis-dimethylaminomethylene) oxonium hexafluorophosphate (HBTU), 50, 8 mg of (R) -2-amino-3-tert-butoxypropionic acid tert-butyl ester hydrochloride (0.2 mmol) and 1 ml of dichloromethane are added with stirring 122.5 μl (0.7 mmol) of ethyldiisopropylamine. Stirring is continued at ambient temperature for 40 hours. The product was isolated from the reaction mixture by flash chromatography on silica gel using hexanes: ethyl acetate (9: 1) as an eluent to give a colorless oil. 27 mg of the title compound are obtained. MS - (+) - ion: M + 1 = 422.8 aem.

f. (R) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid

A mixture of 27 mg (0.06 mmol) of (R) -3-tert-butoxy-2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid tert-butyl ester and 2 ml of trifluoroacetic acid is stirred 2 hour at room temperature. Then the excess trifluoroacetic acid was evaporated in vacuo, the residue was dissolved in 2 ml of absolute ethanol and the solution was concentrated in vacuo to give a beige solid. 27 mg of the title compound are obtained. MS - (+) - ion: M + 1 = 310.9 aem.

Example A-3

(S) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid

Prepared by a method similar to that of Example A-2 e) and f) from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid of Example A-2 d) and (S) -2-amino-3 tert-butyl ether hydrochloride tert-butoxypropionic acid. MS - (+) - ion: M + 1 = 310.9 aem.

Example A-4

(R) -2 - [(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid

Obtained by a method similar to that of example A-2 e) and f), from 1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (can be obtained in accordance with US patent No. 6093730, 10/1998, Weidmann et al.) and (R) -2-amino-3-tert-butoxypropionic acid tert-butyl ester hydrochloride. MS - (+) - ion: M + 1 = 369.0 am.

Example A-5

(S) -2 - [(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid

Obtained by a method similar to that of example A-2 e) and f), from 1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (can be obtained in accordance with US patent No. 6093730, 10/1998, Weidmann et al.) and (S) -2-amino-3-tert-butoxypropionic acid tert-butyl ester hydrochloride. MS - (+) - ion: M + 1 = 369.0 am.

Example A-6

(R) -2 - [(1-Chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid

Obtained by a method similar to that of Example A-2 e) and f) from 1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (can be obtained in accordance with US patent No. 6093730, 10/1998, Weidmann et al.) and (R) -2-amino-3-tert-butoxypropionic acid tert-butyl ester hydrochloride. MS - (+) - ion: M + 1 = 369.0 am.

Example A-7

(S) -2 - [(1-Chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid

Obtained by a method similar to that of Example A-2 e) and f) from 1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (can be obtained in accordance with US patent No. 6093730, 10/1998, Weidmann et al.) and (S) -2-amino-3-tert-butoxypropionic acid tert-butyl ester hydrochloride. MS - (+) - ion: M + 1 = 369.0 am.

Example A-8

2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -2-methylpropionic acid

Prepared by a method similar to that of Example A-1 a) and b) from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid of Example A-2 d) and 2-amino-2-methylpropionic acid methyl ester hydrochloride. MS - (+) - ion: M + 1 = 308.9 am.

Example A-9

2 - [(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -2-methylpropionic acid

Obtained by a method similar to that of example A-1 a) and b), from 1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (can be obtained in accordance with US patent No. 6093730, 10/1998, Weidmann et al.) and 2-amino-2-methylpropionic acid methyl ester hydrochloride. MS - (+) - ion: M + 1 = 367.0 am.

Example A-10

(R) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3- (1H-imidazol-4-yl) propionic acid; trifluoroacetic acid salt

Prepared by a procedure similar to that of Example A-2 e), from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid of Example A-2 d) and (R) -2-amino-3- (1-trityl methyl ester hydrochloride) -1H-imidazol-4-yl) propionic acid, followed by removal of the protective group by the method of Example A-1 b) and then by the method of Example 2 f). MS - (-) - ion: M-1 = 359.1 aem.

Example A-11

(S) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3- (1H-imidazol-4-yl) propionic acid; trifluoroacetic acid salt

Prepared by a procedure similar to that of Example A-2 e), from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid of Example A-2 d) and (S) -2-amino-3- (1-trityl methyl ester hydrochloride) -1H-imidazol-4-yl) propionic acid, followed by removal of the protective group by the method of Example A-1 b) and then by the method of Example 2 f). MS - (-) - ion: M-1 = 359.1 aem.

Example A-12

(R) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid

Receive according to the method of example A-1 a) and b). MS - (-) - ion: M-1 = 359.1 aem.

Example A-13

(S) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 323.0 am.

Example A-14

(R) -2 - [(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 381.1 am.

Example A-15

(S) -2 - [(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 381.1 am.

Example A-16

(R) -2 - [(1-Chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 381.0 am.

Example A-17

(S) -2 - [(1-Chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 381.0 am.

Example A-18

(S) -2 - [(6-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid

Receive according to the method of example A-1 a) and b). MS - (-) - ion: M-1 = 429.0 am.

Example A-19

(R) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 371.0 am.

Example A-20

(S) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 371.0 am.

Example A-21

(R) -2 - [(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 429.0 am.

Example A-22

(S) -2 - [(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 429.0 am.

Example A-23

(R) -2 - [(1-Chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 429.0 am.

Example A-24

(S) -2 - [(1-Chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 429.0 am.

Example A-25

(R) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid

Receive by the method of example A-2 e) and f). MS - (-) - ion: M-1 = 385.0 am.

Example A-26

(S) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 387.1 am.

Example A-27

(R) -2 - [(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid

Receive by the method of example A-2 e) and f). MS - (-) - ion: M-1 = 443.0 ami.

Example A-28

(S) -2 - [(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid

Receive by the method of example A-2 e) and f). MS - (-) - ion: M-1 = 443.0 ami.

Example A-29

(R) -2 - [(1-Chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 445.1 am.

Example A-30

(S) -2 - [(1-Chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 445.1 am.

Example A-31

(R) -2 - [(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] pentanoic acid

Receive according to the method of example A-1 a) and b). MS - (+) - ion: M + 1 = 381.0 am.

Example A-32

(S) -2 - [(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] pentanoic acid

Receive according to the method of example A-1 a) and b). MS - (-) - ion: M-1 = 379.0 am.

Example A-33

(R) -1- (1-Chloro-4-hydroxyisoquinoline-3-carbonyl) pyrrolidine-2-carboxylic acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 321.0 am.

Example A-34

(S) -1- (1-Chloro-4-hydroxyisoquinoline-3-carbonyl) pyrrolidine-2-carboxylic acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 321.0 am.

Example A-35

(R) -1- (1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) pyrrolidin-2-

carboxylic acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 379.1 am.

Example A-36

(S) -1- (1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) pyrrolidin-2-

carboxylic acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 379.1 am.

Example A-37

(R) -6-amino-2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] hexanoic acid; trifluoroacetic acid salt

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 352.2 am.

Example A-38

(S) -6-amino-2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] hexanoic acid; trifluoroacetic acid salt

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 352.1 am.

Example A-39

(R) -6-amino-2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] hexanoic acid; trifluoroacetic acid salt

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 410.1 am.

Example A-40

(S) -6-amino-2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] hexanoic acid; trifluoroacetic acid salt

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 410.1 am.

Example A-41

(R) -6-amino-2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] hexanoic acid; trifluoroacetic acid salt

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 410.1 am.

Example A-42

(S) -6-amino-2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] hexanoic acid; trifluoroacetic acid salt

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 410.1 am.

Example A-43

(R) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] succinic acid

Receive according to the method of example A-1 a) and b). MS - (+) - ion: M + 1 = 338.9 aem.

Example A-44

(S) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] succinic acid

Receive by the method of example A-2 e) and f). MS - (-) - ion: M-1 = 337.0 am.

Example A-45

(R) -2 - [(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] succinic acid

Receive according to the method of example A-1 a) and b). MS - (+) - ion: M + 1 = 397.0 am.

Example A-46

(S) -2 - [(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] succinic acid

Receive by the method of example A-2 e) and f). MS - (+) - ion: M + 1 = 397.1 am.

Example A-47

(R) -2 - [(1-Chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] succinic acid

Receive according to the method of example A-1 a) and b). MS - (+) - ion: M + 1 = 397.0 am.

Example A-48

1 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] cyclopropanecarboxylic acid

Receive according to the method of example A-1 a) and b). MS - (-) - ion: M-1 = 305.0 am.

Example A-49

1 - [(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] cyclopropane

carboxylic acid

Receive according to the method of example A-1 a) and b). MS - (+) - ion: M + 1 = 365.0 ami.

Example A-50

Diditero [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

A mixture of 70 mg (0.25 mmol) of 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester of Example A-2c), 193 mg (2.5 mmol) of glycine-2,2-d ₂ and 5 ml 0, 5n a solution of sodium methoxide in methanol is refluxed with stirring for 15 hours. Then, the solvent was evaporated in vacuo, the residue was dissolved in 8 ml of water, and the solution was washed with ethyl acetate (2 x 20 ml). Adjust the pH of the solution to 3 by adding aqueous 1N. hydrochloric acid and the mixture is extracted with ethyl acetate (3x20 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give a white solid. 61 mg of the title compound are obtained. MS - (-) - ion: M-1 = 280.9 aem.

Example A-51

(R) -2 - [(6-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid

but. (R) -2 - [(6-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid methyl ester

6-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (0.33 g) was combined with D-alanine methyl ester hydrochloride (0.150 g) in a manner analogous to Example A-1a). 0.205 g of an almost white solid is obtained; MS - (+) - ion: M + 1 = 415.0 am.

b. (R) -2 - [(6-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino]

propionic acid

The white product (0.164 g) was obtained by a method similar to that of Example A-1b); MS - (+) - ion: M + 1 = 401.1 am.

Example A-52

(S) -2 - [(7-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid

but. (S) -2 - [(7-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid methyl ester

7-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (0.33 g) was combined with L-alanine methyl ester hydrochloride (0.150 g) by a method similar to that of Example A-1a). 0.264 g of a white solid is obtained; MS - (+) - ion: M + 1 = 415.0 am.

b. (S) -2 - [(7-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino]

propionic acid

The white product (0.216 g) was obtained by a method similar to that of Example A-1b); MS - (+) - ion: M + 1 = 401.9 aem.

Example A-53

(R) -2 - [(7-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid

but. (R) -2 - [(7-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid methyl ester

7-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (0.33 g) was combined with D-alanine methyl ester in a manner analogous to that of Example A-1a). 0.246 g of an almost white solid is obtained; MS - (+) - ion: M + 1 = 415.0 am.

b. (R) -2 - [(7-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino]

propionic acid

The white product (0.211 g) was obtained by a method similar to that of Example A-1b); MS - (+) - ion: M + 1 = 401.0 am.

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            Example A-54

(S) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid

but. (S) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid methyl ester

1-Chloro-4-hydroxyisoquinoline-3-carboxylic acid (0.55 g), 1.5 ml triethylamine, 0.55 g DECI and 0.56 g (L) -alanine methyl ester hydrochloride are stirred in 15 ml of methylene chloride at room temperature temperature 72 hours. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was separated and washed successively with 1M aqueous HCl, saturated aqueous solution.

NaHCO ₃ and saturated aqueous NaCl. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 0.133 g of an almost white solid. MS - (+) - ion: M + 1 = 308.9 daltons.

b. (S) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid

(S) -Metyl ether (0.116 g) described in Example A-54 a) is saponified / acidified according to a procedure similar to that of Example A-1 b), 0.087 g of a white solid is obtained; MS - (+) - ion: M + 1 = 294.9 aem.

Example A-55

(R) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid

but. (R) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid methyl ester

1-Chloro-4-hydroxyisoquinoline-3-carboxylic acid (0.55 g) was combined with D-alanine methyl ester (0.40 g) according to a similar procedure to that of Example A-54a) to give 0.200 g of an almost white solid ; MS - (+) - ion: M + 1 = 308.8 aem.

b. (R) -2 - [(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid

The white product (0.127 g) was obtained according to the procedure of Example A-1b); MS - (+) - ion: M + 1 = 294.9 aem.

Example A-56

(S) -2 - [(6-Isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino]

propionic acid

6-Isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (0.030 g) and

0.046 g of HATUs are allowed to react with 0.017 g of L-alanine methyl ester under conditions similar to those of Example A-1 a). The crude ether is treated with 0.014 g of NaOH in 0.1 ml of a mixture of methanol: water, 1: 1, at room temperature for 2 days, followed by acidification to pH ~ 2 with 1M hydrochloric acid, to obtain a solid product. The product is filtered off, washed with water and dried, yielding 0.023 g of an almost white solid, MS - (-) - ion: M-1 = 353.0 am.

Example A-57

(R) -2 - [(6-Isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino]

propionic acid

By a method similar to that of Example A-56, 0.030 g of 6-isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid was combined with D-alanine methyl ester hydrochloride, the product was hydrolyzed, and 0.022 g of an almost white solid was obtained. MS - (-) - ion: M-1 = 353.0.

Example A-58

(S) -2 - [(7-Isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino]

propionic acid

By a method similar to that of Example A-56, 0.040 g of 7-isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid was reacted with 0.020 g of L-alanine methyl ester hydrochloride, after hydrolysis of the intermediate ester, 0.047 g of a white solid substances. MS - (-) - ion: M-1 = 353.1.

Example A-59

(R) -2 - [(7-Isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino]

propionic acid

By a method similar to that of Example A-56, 0.040 g of 7-isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid was reacted with D-alanine methyl ester hydrochloride. The intermediate ester is hydrolyzed as in Example A-56 to obtain 0.042 g of a white solid. MS - (-) - ion: M-1 = 353.0 am.

Example A-60

2- (S) - {[7- (4-Chlorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid

but. 4- (4-chlorophenoxy) phthalonitrile

A mixture of 4-nitrophthalononitrile (5.0 g), 4-chlorophenol (3.13 ml) and potassium carbonate (7.99 g) in acetone (87 ml) was refluxed for 3 hours. After filtration and concentration, the residue was dissolved in ethyl acetate (100 ml). The solution was washed with NaOH (1N, 5x50 ml). The organic layer was dried, filtered, concentrated and diluted with dichloromethane. Filtration and washing through a plug of silica gel afforded 5.7 g of the title compound. ¹ H NMR (200 MHz, DMSO) δ 8.09 (d, J = 9 Hz, 1H), 7.83 (d, J = 2.6.1 H), 7.53 (d, J = 8.6 Hz, 2H), 7.42 (dd, J = 2.8, 8.6 Hz, 1H), 7.24 (d, J = 8.6, 2H).

b. 4- (4-chlorophenoxy) phthalic acid

A mixture of 1.31 g of 4- (4-chlorophenoxy) phthalonitrile, 45% potassium hydroxide (3.5 ml) and methanol (3.5 ml) is refluxed for 18 hours. Add 6N. HCl to pH 4. The precipitate was filtered off, washed with water and dried, yielding 1.45 g of the title compound. MS - (-) - ion: M-1 = 291.0.

c. [5- (4-Chlorophenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid butyl ester

A mixture of 500 mg of 4- (4-chlorophenoxy) phthalic acid and glycine n-butyl ester (286 mg) is heated at 250 ° C for 5 minutes. The reaction mixture was purified by chromatography using dichloromethane as the eluent to give 436 mg of the title compound. ¹ H NMR (200 MHz, DMSO) δ 7.48 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 9.0 Hz, 2H), 7.46 (m, 2H) , 7.29 (d, J = 9.0 Hz, 2H), 4.46 (s, 2H), 4.16 (t, J = 6.2 Hz, 2H), 1.61 (m, 2H) 1.38 (m, 2H); 0.92 (t, J = 7.0 Hz, 3H).

d. 6- and 7- (4-chlorophenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example A-2 b). A mixture of two isomers. MS - (-) - ion: M-1 = 386.1.

e. 1-Chloro-6- and -7- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of Example A-2 c). A mixture of two isomers. MS - (-) - ion: M-1 = 404.2.

f. 6- and 7- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 1-chloro-6- and -7- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (280 mg), 0.27 ml of 57% HI, glacial acetic acid (3 ml) and red phosphorus (43 mg) is refluxed for 25 minutes. Then the mixture was diluted with water, acidified with solid NaHCO ₃ to pH 8, extracted with ethyl acetate (2 times). The ethyl acetate layer was washed with sodium metabisulfite solution, saturated sodium bicarbonate solution, dried and concentrated. Purification by chromatography using hexanes / ethyl acetate gives 7- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (103 mg, comparative example A-60 a) (MS - (-) - ion: M-1 = 370.3) and 6- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (71 mg, comparative example A-60 b) (MS - (-) - ion: M-1 = 370, 3).

g. 2- (S) - {[7- (4-Chlorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino}

propionic acid

Prepared by a method similar to that of Example A-50 by reacting 7- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound of Example A-60 a) with L-alanine in a microwave reactor for 20 minutes at temperature 130 ° C. MS - (-) - ion: M-1 = 385.1.

Example A-61

2- (S) - {[6- (4-Chlorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid

Prepared by a procedure similar to that of Example A-50, by reacting 6- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound of Example A-60 b) with L-alanine in a microwave reactor for 25 minutes at at 130 ^C. MS - (-) - ion: M-1 = 385.1.

Example A-62

2 - {[7- (3,4-Difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid

but. 5- (3,4-difluorophenoxy) isoindole-1,3-dione

3,4-Difluorophenol (650 ml) was dried by azeotropic distillation with benzene and dissolved in a solution of sodium methoxide in methanol (0.5 M, 10 ml). Then methanol is removed under reduced pressure in a nitrogen atmosphere. To the resulting mixture was added a solution of 4-nitrophthalimide (769 mg) in anhydrous DMF (10 ml). The resulting mixture was boiled under nitrogen for 23 hours. The reaction mixture was cooled and 80 ml of water was added. The precipitate obtained is filtered off, washed with water (4 times) and dried, and the title compound is obtained, 685 mg. MS - (-) - ion: M-1 = 274.3.

b. [5- (3,4-Difluorophenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid methyl ester

5- (3,4-difluorophenoxy) isoindole-1,3-dione (680 ml), potassium carbonate (1 g), 3-pentanone (20 ml) and methyl bromoacetate (295 μl) are added to the pressure tube. The resulting mixture was heated to 105 ° C for 17 hours. The reaction mixture was diluted with 20 ml of water and extracted with ethyl acetate (2 times). The organic layer was dried and concentrated. The mixture was purified by silica gel chromatography using 4: 1 to 3: 1 hexanes / ethyl acetate mixtures to obtain 657 mg of the title compound. ¹ H NMR (200 MHz, DMSO): δ 7.95 (d, J = 9.0 Hz, 1H), 7.64-7.41 (m, 4H), 7.15-7.08 (m, 1H), 4.44 (s, 2H), 3.70 (s, 3H).

from. 6- and 7- (3,4-difluorophenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example A-2 b). A mixture of two isomers. MS - (-) - ion: M-1 = 388.1.

d. 1-Chloro-6- and -7- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of Example A-2 c). A mixture of two isomers is used directly in the next step.

e. 6- and 7- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

To a solution of 1-chloro-6- and -7- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ether (220 mg) in ethyl acetate (4 ml) was added 10% Pd / C (50%, wet, 88 mg) and then ammonium formate (340 mg). The resulting mixture was heated to boiling under reflux for 0.5 hour. After cooling, the reaction mixture was diluted with ethyl acetate and filtered through a Celite pad. The filtrate was concentrated and separated by chromatography to obtain 131 mg of 7- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound of Example A-62a) and 55 mg of 6- (3,4- butyl ether) difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid (compound of Example A-62b).

f. 2 - {[7- (3,4-Difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino}

propionic acid

Prepared by a method similar to that of Example A-50 by reacting 7- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound of Example A-62a) with L-alanine in a pressure tube for 3 days at 85 ° C. MS - (+) - ion: M-1 = 389.2.

Example A-63

2- (S) - [(4-Hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] propionic acid

but. 4-phenylsulfanylphthalic acid

A mixture of 5.06 g of 4-phenylsulfanylphthalonitrile (21.4 mmol), 10 ml of a 50% aqueous solution of KOH and 10 ml of methanol is refluxed with stirring for 3.5 days. The mixture is then diluted with 100 ml of water and acidified with concentrated hydrochloric acid. The precipitated product is filtered off with suction, washed thoroughly with water and dried in vacuo at 60 ° C. 5.75 g of the title compound are obtained. MS - (-) - ion: M-1 = 273.0.

b. (1,3-dioxo-5-phenylsulfanyl) -1,3-dihydroisoindol-2-yl) acetic acid

5.62 g of 4-phenylsulfanylphthalic acid (20.5 mmol) and 1.55 g of glycine (20.5 mmol) are carefully ground together in a mortar. Then the mixture is heated to 210-220 ° C in an oil bath. The molten mass is mixed with a spatula at the indicated temperature for 15 minutes, then cooled to ambient temperature in vacuo. 6.30 g of the title compound are obtained. MS - (-) - ion: M-1 = 311.8. ¹ H NMR (DMSO-d ₆ ): δ = 7.82 (d, 1H), 7.46-7.62 (m, 7H), 4.26 (s, 2H).

from. (1,3-dioxo-5-phenylsulfanyl) -1,3-dihydroisoindol-2-yl) acetic acid methyl ester

A mixture of 20 ml of methanol, 6.27 g of (1,3-dioxo-5-phenylsulfanyl-1,3-dihydroisoindol-2-yl) acetic acid (20 mmol) and 0.3 ml of concentrated sulfuric acid is refluxed with stirring 18 hours Then add 100 ml of a concentrated aqueous solution of sodium bicarbonate and the mixture is extracted with 100 ml of ethyl acetate. The organic phase was dried over MgSO ₄ and evaporated in vacuo. 6.30 g of the title compound are obtained; MS - (+) - ion: M + 1 = 328.0. ¹ H NMR (CDCl ₃ ): δ = 7.69 (d, 1H), 7.41-7.55 (m, 7H), 4.40 (s, 2H), 3.75 (s, 3H).

d. 1,4-dihydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ether (A) and 1,4-dihydroxy-6-phenylsulfanylisoquinoline-3-carboxylic acid butyl ether (B)

0.92 g of sodium (40 mmol) is dissolved in 100 ml of n-butanol with stirring. Then the temperature was raised from 95 to 100 ° C, a hot solution of 6.5 g of (1,3-dioxo-5-phenylsulfanyl-1,3-dihydroisoindol-2-yl) acetic acid methyl ester (19.85 mmol) in 20 was added. ml of n-butanol and stirring is continued at a temperature of 95-100 ° C for 1 hour. Then the solvent was evaporated in vacuo, 25 ml of aqueous 2N was added. HCl and 100 ml of ethyl acetate and the mixture was stirred vigorously for 1 hour, then filtered by suction. The filter cake was washed thoroughly with water and dried in vacuo at 60 ° C to obtain 4.43 g of a yellow solid. The resulting mixture of A and B (4.4 g) was separated by flash column chromatography on silica gel, eluting with dichloromethane: ethyl acetate (98: 2). Evaporation of the first fraction gives 1.99 g A. ¹ H NMR (CDCl ₃ ): δ = 10.48 (br s, 1H), 8.39 (br s, 1H), 8.24 (d, 1H) 8.01 (d, 1H), 7.35-7.55 (m, 6H), 4.39 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H). Evaporation of the second fraction gives 2.26 g of B. ¹ H NMR (CDCl ₃ ): δ = 10.38 (br s, 1H), 8.32 (br s, 1H), 8.24 (d, 1H) 7.86 (d, 1H), 7.37-7.56 (m, 6H), 4.39 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H).

e. 1-Bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester

To a solution of 4.59 g of phosphorus oxybromide (16 mmol) in 25 ml of anhydrous acetonitrile, 1.11 g of 1,4-dihydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (3 mmol) was added and the mixture was gently refluxed at stirring for 1 hour. Then, 5.04 g of sodium bicarbonate (60 mmol) was added, after which 8 ml of water was added dropwise. After stirring at room temperature for 90 minutes, the mixture was concentrated in vacuo to approximately one third of its volume, 40 ml of water was added and the mixture was extracted with 30 ml of ethyl acetate. The mixture is filtered by suction. The organic phase is separated, dried over MgSO ₄ and filtered through a pad of silica gel. Evaporation in vacuo afforded 0.885 g of the title compound. ¹ H NMR (CDCl ₃ ): δ = 11.84 (s, 1H), 8.21 (d, 1H), 7.91 (d, 1H), 7.40-7.55 (m, 6H), 4.46 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).

f. 4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester

A mixture of 432 mg of 1-bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ether (1 mmol), 63 mg of red phosphorus (2 mmol), 0.4 ml of an aqueous solution of 57% HI (3 mmol) and 1 ml of glacial acetic acid is refluxed with stirring for 30 minutes. Then, the reaction mixture was diluted with 25 ml of ethyl acetate, filtered by suction through a celite pad, washed with a solution of 0.2 g of NaHSO ₃ in 5 ml of water, and washed twice with 5 ml of concentrated aqueous sodium bicarbonate solution. The organic phase was dried over MgSO ₄ and evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with a mixture of hexanes: ethyl acetate, 85:15. 123 mg of the title compound are obtained. ¹ H NMR (CDCl ₃ ): δ = 11.85 (s, 1H), 8.60 (s, 1H), 8.23 (d, 1H), 7.38-7.63 (m, 7H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).

g. 2- (S) - [(4-Hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] propionic acid

A mixture of 4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester (0.20 g) and L-alanine (0.75 g) in a 0.5M NaOMe / MeOH solution (11.3 ml) is heated to reflux refrigerator for 36 hours. After cooling, the reaction mass is concentrated. The residue was suspended in water (50 ml) and extracted with ethyl acetate (50 ml), which was discarded. The aqueous layer is acidified with 2n. aqueous solution of HCl. Extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the title compound (0.15 g). MS - (-) - ion: M-1 = 367.1.

Example A-64

2- (R) - [(4-Hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] propionic acid

Obtained by a method similar to that of Example A-63 g) by reaction of 4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester with D-alanine. MS - (-) - ion: M-1 = 367.1.

Example A-65

2- (R) - [(4-Hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid

but. 4-phenoxyphthalic acid

Synthesized from 4-phenoxyphthalonitrile by a method similar to that of Example A-63 a). MS - (-) - ion: M-1 = 256.9. ¹ H NMR (DMSO-d ₆ ): δ = 7.93 (d, 1H), 7.07-7.52 (m, 7H).

b. (1,3-dioxo-5-phenoxy-1,3-dihydroisoindol-2-yl) acetic acid

Synthesized from 4-phenoxyphthalic acid by a method similar to that of Example A-63 b). MS - (+) - ion: M + 1 = 297.9. ¹ H NMR (DMSO-d ₆ ): δ = 7.87 (d, 1H), 7.17-7.52 (m, 7H), 4.26 (s, 2H).

from. (1,3-dioxo-5-phenoxy-1,3-dihydroisoindol-2-yl) acetic acid methyl ester

Synthesized from (1,3-dioxo-5-phenoxy-1,3-dihydroisoindol-2-yl) acetic acid in a manner analogous to that of Example A-63c). ¹ H NMR (CDCl ₃ ): δ = 7.83 (d, 1H), 7.05-7.46 (m, 7H), 4.41 (s, 2H), 3.76 (s, 3H).

d. 1,4-Dihydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ether (A) and 1,4-dihydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ether (B)

Synthesized from methyl ester of (1,3-dioxo-5-phenoxy-1,3-dihydroisoindol-2-yl) acetic acid according to a procedure analogous to that of Example A-63d). Compound A: ¹ H NMR (CDCl ₃ ): δ = 10.58 (br s, 1H), 8.37 (br s, 1H), 8.14 (d, 1H), 7.87 (d, 1H), 7.05-7.49 (m, 6H), 4.39 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H ) Compound B: ¹ H NMR (CDCl ₃ ): δ = 10.38 (br s, 1H), 8.38 (d, 1H), 8.28 (br s, 1H), 7.56 (d, 1H), 7.06-7.47 (m, 6H), 4.40 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H )

e. 1-Bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from 1,4-dihydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester according to a procedure similar to that of Example A-63 e). ¹ H NMR (CDCl ₃ ): δ = 11.89 (s, 1H), 8.35 (d, 1H), 7.63 (d, 1H), 7.08-7.52 (m, 6H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).

f. 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 208 mg of 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester (0.5 mmol), 49 mg of sodium acetate (0.6 mmol), 50 mg of 10% palladium on charcoal, 10 ml of methanol and 5 ml of ethyl acetate are stirred in a nitrogen atmosphere at 1 ATM for 15 hours. The mixture is then filtered by suction through a celite pad and concentrated in vacuo. The residue was partitioned between 2 ml of a semi-concentrated aqueous bicarbonate solution and 8 ml of ethyl acetate. The organic layer was dried over MgSO ₄ . Evaporated in vacuo to give 130 mg of the title compound. ¹ H NMR (CDCl ₃ ): δ = 11.89 (br s, 1H), 8.61 (s, 1H), 8.36 (d, 1H), 7.10-7.53 (m, 7H ), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).

g. 2- (R) - [(4-Hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid

Prepared by a procedure similar to that of Example A-63g) by reacting 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester with D-alanine under reflux for 5 days.

MS - (-) - ion: M-1 = 351.1.

Example A-66

2- (S) - {[4-Hydroxy-7- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} propionic acid

but. 4- (4-methoxyphenoxy) phthalonitrile

A mixture of 4-nitrophthalononitrile (4.00 g), 4-methoxyphenol (3.46 g) and potassium carbonate (6.39 g) in acetone (64 ml) is heated at the boil under reflux for 2 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated, and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with NaOH (1N, 50 ml), water and then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give the product (6.14 g). ¹ H NMR (200 MHz, CDCl ₃ ): δ 6.70 (d, J = 7.8 Hz, 1H), 7.21 (m, 2H), 6.96 (m, 4H), 3.84 ( s, 3H).

b. 4- (4-methoxyphenoxy) phthalic acid

Obtained by a method similar to that of Example A-63a). MS - (-) - ion: M-1 = 286.9.

from. [5- (4-Methoxyphenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid methyl ester

Obtained by a method similar to that of example A-63 b) and c). ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.74 (d, J = 8.6 Hz, 1H), 7.25 (m, 2H), 6.98 (m, 4H), 4.40 ( s, 2H), 3.83 (s, 3H), 3.75 (s, 3H).

d. 6- and 7- (4-methoxyphenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example A-63 d). MS - (+) - ion: M + 1 = 384.10.

e. 6- and 7- (4-methoxyphenoxy) -1-bromo-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of Example A-63 e). MS - (+) - ion: M + 1 = 448.05, 446.05.

g. 7- (4-Methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (A) and 6- (4-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (B)

To a solution of the above compound (2.78 g) in ethyl acetate (50 ml) was added 10% palladium on carbon (wet) (1.2 g) and then ammonium formate (5.9 g). The resulting mixture was refluxed for 4 hours. After cooling, the mixture was filtered and washed with ethyl acetate (100 ml). The filtrate was concentrated and the residue was purified by silica gel chromatography (33-50% ethyl acetate in hexanes) to obtain 7- (4-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (A) (0.74 g) (MS- ( +) - ion: M + 1 = 368.16) and 6- (4-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (B) (1.11 g)

(MS - (+) - ion: M + 1 = 368.17).

h. 2- (S) - {[4-Hydroxy-7- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} propionic acid

Prepared by a procedure similar to that of Example A-63 g) from 7- (4-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (Example A-66 a) and L-alanine. MS - (-) - ion: M-1 = 381.13.

Example A-67

2- (S) - [(7-Benzenesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid

but. 7-Benzenesulfonyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 7-benzenesulfanyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound 363 f) (165 mg) and m-chloroperbenzoic acid (77%) (377 mg) in methylene chloride (5 ml) was stirred at room temperature overnight . The reaction mixture is filtered. The filtrate was diluted with methylene chloride (20 ml) and washed successively with saturated aqueous sodium bicarbonate (2 x 20 ml), water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel column chromatography (eluted with 0-20% ethyl acetate in methylene chloride) to give the title compound, 120 mg. MS - (+) - ion: M + 1 = 386.11.

b. 2- (S) - [(7-Benzenesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid

Obtained by a method similar to that of Example A-63 g) from 7-benzenesulfonyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester and L-alanine. MS - (-) - ion: M-1 = 399.1.

Example A-68

(R) -2 - [(4-Hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino]

propionic acid

but. 1-Bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid

A mixture of 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester (3.52 g, 8.45 mmol; Example 65 e), 2N. an aqueous solution of NaOH (50 ml, 100 mmol) and EtOH (50 ml) are refluxed for 2 hours. Then the solution was concentrated in vacuo to Ѕ volume, diluted with water (180 ml) and acidified by adding aqueous 6N. HCl (20 ml). After stirring at room temperature for 30 minutes, the resulting suspension was subjected to vacuum filtration. The filter cake was washed thoroughly with water and dried in vacuo at 70 ° C to give the title compound as a white solid (3.05 g). ¹ H NMR (DMSO-d ₆ ): δ 8.33 (d, 1H), 7.20-7.61 (m, 7H).

b. 4-Benzyloxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carboxylic acid benzyl ester

To a solution of 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid (721 mg, 2 mmol) in anhydrous THF (100 ml), a 2.5 M solution of n-BuLi in hexanes (3.2 ml) is slowly added with stirring , 8 mmol) at -78 ° C. After stirring for another 5 minutes, MeOCH ₂ I (357 μl, 4 mmol) was added. Stirring was continued for another 15 minutes at ^-78 ° C before addition of water (50 ml) and aqueous 6N. HCl (1.5 ml). The mixture was allowed to warm to room temperature with stirring and concentrated in vacuo to approximately 1/3 of its volume. Before extracting the EtOAc mixture (100 ml), traces of iodine are removed by adding sodium metabisulfite. The organic phase was dried over MgSO ₄ and concentrated in vacuo to give a beige solid (576 mg). A mixture of the above yellowish solid (570 mg), benzyl bromide (0.97 ml, 8 mmol), K ₂ CO ₃ (2.76 g, 20 mmol) and acetone (40 ml) was refluxed for 3.5 days. Then the mixture was concentrated in vacuo. Water (15 ml) was added to the residue, and the mixture was extracted with EtOAc (60 ml). The organic phase is dried over MgSO ₄ and concentrated in vacuo to give a yellowish oil. Purification by flash chromatography on silica gel using hexanes: EtOAc 75:25 as the eluent afforded the title compound as a yellow oil (490 mg); MS - (+) - ion: M + 1 = 506.2.

c. 4-Benzyloxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carboxylic acid

A mixture of 4-benzyloxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carboxylic acid benzyl ester (480 mg, 0.95 mmol), KOH (325 mg, 5 mmol) and EtOH (10 ml) was stirred at room temperature for 48 hours, then the solvent was evaporated in vacuo. Water (10 ml) was added to the residue, the mixture was acidified by adding aqueous 6N. HCl and extracted with EtOAc (2x25 ml). The combined organic phases are dried over MgSO ₄ and concentrated in vacuo to afford the title compound as a beige solid (355 mg); MS - (-) - ion: M-1 = 414.1.

d. (R) -2 - [(4-benzyloxy-1-methoxymethyl-7-phenoxyisoquinolin-3- tert-butyl ester

carbonyl) amino] propionic acid

To a mixture of 4-benzyloxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carboxylic acid (79 mg, 0.19 mmol), Net ₃ (56 μl, 0.4 mmol) and CH ₂ Cl ₂ (5 ml), cooled with ice, ClCO ₂ -iBu (26.5 μl, 0.2 mmol) is added with stirring. After stirring for 15 minutes, (R) -alanine tert-butyl ether hydrochloride (36 mg, 0.2 mmol) was added and the mixture was allowed to warm to room temperature overnight with stirring. Then the mixture was concentrated in vacuo. Water (10 ml) and a few drops of aqueous 6N are added to the residue. Hcl. The mixture was extracted with EtOAc (2x15 ml). The organic phase is dried over MgSO ₄ and concentrated in vacuo. Purification by flash column chromatography on silica gel using EtOAc as eluent afforded the title compound as a beige oil (88 mg); MS - (+) - ion: M + 23 = 565.2.

e. (R) - [(4-Hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid tert-butyl ester

A mixture of tert-butyl ether (R) -2 - [(4-benzyloxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl)

amino] propionic acid (81 mg, 0.15 mmol), Pd / C (50 mg, 10% Pd), EtOAc (15 ml) was stirred in an atmosphere of H ₂ at normal pressure and room temperature for 18 hours. Then the mixture is filtered through a layer of celite. Celite and filter cake were washed thoroughly with EtOAc and the combined organic phases were concentrated in vacuo to give the title compound as a beige oil (63 mg); MS - (-) - ion: M-1 = 451.2.

f. (R) -2 - [(4-Hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino]

propionic acid

A mixture of (R) - [(4-hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid tert-butyl ester (59 mg, 0.13 mmol) and trifluoroacetic acid (4 ml) was stirred at room temperature temperature 4 hours. The mixture was then concentrated in vacuo and the residue was dissolved in EtOH. The solvent was evaporated in vacuo to give the title compound as a beige solid (52 mg). MS - (+) - ion: M + 1 = 397.1.

Example A-69

(S) -2 - [(4-Hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino]

propionic acid

but. (S) -2 - [(4-benzyloxy-1-methoxymethyl-7-phenoxyisoquinolin-3- tert-butyl ester

carbonyl) amino] propionic acid

Synthesized from (S) -alanine tert-butyl ester and 4-benzyloxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carboxylic acid (Example A-68c) by a method similar to that of Example A-68 d). MS - (+) - ion: M + 23 = 565.2.

b. (S) -2 - [(4-hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid tert-butyl ester

Synthesized from (S) -2 - [(4-benzyloxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid tert-butyl ester according to a procedure analogous to that of Example A-68e). MS - (-) - ion: M-1 = 451.2.

from. (S) -2 - [(4-hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl)

amino] propionic acid

Synthesized from tert-butyl ether (S) -2 - [(4-hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl)

amino] propionic acid in a manner analogous to that of Example A-68f). MS - (+) - ion: M + 1 = 397.1.

Example A-70

(S) -2 - [(4-Mercapto-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid

but. 4-Dimethylthiocarbamoyloxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester

To a solution of 1.5 g of 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester (Example A-65 f) in 6.3 ml of anhydrous DMF was added 578 mg of dimethylthiocarbamoyl chloride and 1.5 g of 1,4-diazabicyclo [2.2 .2] octane. The mixture was stirred overnight at room temperature. The mixture is poured into 30 ml of 1N. HCl and extracted three times with 30 ml of ethyl acetate. The organic fractions were washed with water and brine, dried over anhydrous sodium sulfate and concentrated to 1.9 g of the product. MS - (+) m / z 425.27 (M + 1).

b. 4-Dimethylcarbamoylsulfanyl-7-phenoxyisoquinoline-3-carboxylic acid butyl ester

A solution of 1.9 g of 4-dimethylthiocarbamoyloxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester in 22 ml of phenyl ether is heated at 190 ° C. for 2 hours. The solution was concentrated in vacuo to give a crude residue, which was purified by silica gel column chromatography, eluting with a gradient of 30-80% ethyl acetate in hexanes, and 1.73 g of MS were obtained - (+) m / z 425.07 (M + 1) .

from. 4-mercapto-7-phenoxyisoquinoline-3-carboxylic acid methyl ester

To a solution of 6.5 ml of 0.5n. 460 mg of 4-dimethylcarbamoylsulfanyl-7-phenoxyisoquinoline-3-carboxylic acid butyl ether are added to a solution of sodium methoxide in methanol. The resulting solution was heated at 50-60 ° C for 8 hours, cooled to room temperature and diluted with 10 ml of water and 7.0 ml of 1N. HCl. The resulting yellow precipitate was filtered through a porous (medium) Buchner filter to obtain 307 mg of product. MS - (+) m / z 312.08 (M + 1).

d. (S) -2 - [(4-Mercapto-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid

To a solution of 6.0 ml of a 0.5 M solution of sodium methoxide in methanol was added 100 mg of 4-mercapto-7-phenoxyisoquinoline-3-carboxylic acid methyl ester and 286 mg of L-alanine. The mixture was heated to 150 ° C. for 15 minutes using a CEM Discover microwave reactor. The resulting solution was acidified to pH 3 with 1N. HCl, diluted with 10 ml of water and extracted with 20 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to 114 mg of product. MS - (-) m / z 369.07 (M-1).

Example A-71

(S) -2 - {[1- (4-Chlorophenylsulfanyl) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid

but. 1-Bromo-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

The title compound is obtained from (1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid methyl ester according to a procedure analogous to that of Examples A-65 c) -f). ¹ H NMR (200 MHz, CD ₃ OD): δ 11.89 (s, 1H), 8.41 (m, 1H), 8.25 (m, 1H), 7.84 (m, 2H), 4 49 (t, J = 7.0 Hz, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H).

b. (S) -2 - {[1-Bromo-4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid

1-Bromo-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (400 mg) and 890 mg of (L) -alanine are suspended in 20 ml of a 0.5 M solution of sodium methoxide in methanol. The mixture was heated to 160 ° C. for 12 minutes using a CEM Discover microwave reactor. The resulting solution was concentrated to approximately 10 ml and 0.5N was added. HCl until pH 3 is reached. The solution is extracted three times with ethyl acetate, the organic fractions are dried over sodium sulfate and concentrated to a beige solid. MS - (-) m / z 337.14 (M-1).

from. (S) -2 - {[1- (4-Chlorophenylsulfanyl) -4-hydroxyisoquinoline-3-carbonyl] amino}

propionic acid

To a solution of 250 mg of (S) -2 - {[1-bromo-4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid in 0.7 ml of 1-methyl-2-pyrrolidinone 433 mg of 4-chlorobenzenethiol is added. The solution was heated at 210 ° C. for 30 minutes using a CEM Discover microwave reactor. The solution was concentrated in vacuo. The resulting residue was crystallized with methanol to give 18 mg of a beige solid. MS - (-) m / z 401.10 (M-1).

Example A-72

(R) -2 - {[1- (4-Chlorophenylsulfanyl) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid

The title compound is prepared from 1-bromo-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (Example A-71 a) and (D) -alanine under conditions analogous to the conditions of Example A-71 b-c). MS - (-) m / z 401.08 (M-1).

Example A-73

(S) -2 - {[7- (3-Fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid

but. 4- (3,4-difluorophenoxy) phthalonitrile

Obtained by a method similar to that of Example A-60 a). ¹ H NMR (200 MHz, DMSO): δ 8.14 (d, J = 9 Hz, 1H), 7.95 (d, J = 2.6.1 H), 7.56 (dd, J = 2, 6, 8.6 Hz, 1H), 7.19 (dt, J = 2.4, 9.2 Hz, 1H), 7.04 (m, 2H).

b. 4- (3-Fluoro-5-methoxyphenoxy) phthalic acid

Obtained by a method similar to that of example A-60 b). One of the fluorine atoms is replaced by a methoxy group during hydrolysis. MS - (-) ion: (M-1) 305.0.

from. [5- (3-Fluoro-5-methoxyphenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid butyl ester

Obtained by a method similar to that of Example A-60 c). ¹ H NMR (200 MHz, DMSO): δ 7.93 (d, J = 8.6 Hz, 1H), 7.43 (m, 2H), 6.79-6.63 (m, 3H), 4 41 (s, 2H), 4.10 (t, J = 6.2, 2H), 1.54 (m, 2H), 1.30 (m, 2H), 0.86 (t, J = 7 , 0, 3H).

d. 6- and 7- (3-fluoro-5-methoxyphenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example A-2 b). A mixture of two isomers. MS - (-) ion: M-1 = 400.1.

e. 1-Chloro-6- and -7- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of Example A-2 c). A mixture of two isomers. MS - (-) ion: M-1 = 418.3.

f. 6- and -7- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of Example A-62 e). The mixture of isomers was separated to obtain 7- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound of Example A-73 a) and 6- (3-fluoro-5-methoxyphenoxy) butyl ester - 4-hydroxyisoquinoline-3-carboxylic acid (compound of Example A-73 b). ¹ H NMR (200 MHz, CD ₃ OD): δ 8.73 (s, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.71 (s, 1H), 7.59 (m, 1H), 6.65-6.47 (m, 3H), 4.49 (t, J = 6.6 Hz, 2H), 3.81 (s, 3H), 1.87 (m, 2H), 1.56 (m, 2H), 1.03 (t, J = 7.4, 3H).

g. (S) -2 - {[7- (3-Fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino}

propionic acid

Prepared by a procedure similar to that of Example A-50, by reacting 7- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound of Example A-73 a) with L-alanine in a work tube under pressure for 3 days at 90 ° C. MS - (-) ion: M-1 = 399.1.

Example A-74

2- (S) - [(7-Cyclohexyloxy-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid

but. (5-Hydroxy-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid ethyl ester

Prepared by a method similar to that of Example D-100 c) from 4-hydroxyphthalic acid and the HCl salt of glycine ethyl ester. ¹ H NMR (200 MHz, DMSO-d ₆ ): δ 11.0 (br s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.17 (m, 2H), 4.35 (s, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.20 (t, J = 7.0 Hz, 3H).

b. (5-Cyclohexyloxy-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid ethyl ester

To a mixture of ethyl ether (5-hydroxy-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid (8.0 g) in anhydrous tetrahydrofuran (160 ml), cyclohexanol (3.2 g), diethyl azadicarboxylate (6.9 g) and then triphenylphosphine (12.6 g). The resulting mixture was stirred at room temperature overnight and concentrated. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography (eluted with 5% ethyl acetate in methylene chloride) to give the title compound (6.2 g). ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.73 (dd, J = 8.2, 0.8 Hz, 1H), 7.30 (br s, 1H), 7.12 (m, 1H ), 4.38 (m, 3H), 4.21 (q, J = 7.1 Hz, 2H), 2.02 (m, 2H), 1.82-1.25 (m, 13H).

from. 6- and 7-cyclohexyloxy-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Using a procedure similar to that of Example A-63 d), 7-cyclohexyloxy-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester is obtained (compound A-74c1, MS - (+) ion: M + 1 = 360.16) and 6-cyclohexyloxy-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester (compound A-74c2, MS - (+) ion: M + 1 = 360.18).

d. 1-Bromo-7-cyclohexyloxy-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 7-cyclohexyloxy-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ether (compound A-74c1) (1.3 g) and phosphorus oxybromide (1.35 g) in anhydrous toluene (25 ml) is heated in a microwave reactor ( sealed tube) at 130ºС for 15 min. After cooling, the reaction mixture was concentrated. The residue was treated with saturated aqueous sodium bicarbonate (100 ml) and stirred at room temperature for 20 minutes. Extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (1.2 g). MS - (+) - ion: M + 1 = 422.12, 424.12.

e. 7-Cyclohexyloxy-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

To a mixture of 1-bromo-7-cyclohexyloxy-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (936 mg) in ethyl acetate (25 ml) was added 10% Pd / C (50%, wet) (430 mg) and then ammonium formate (1.4 g). The resulting mixture was refluxed for 4 hours. After cooling, the reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography (3-10% ethyl acetate in methylene chloride) to give the title compound (550 mg). MS - (+) - ion: M + 1 = 344.22.

f. 2- (S) - [(7-Cyclohexyloxy-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid

A mixture of 7-cyclohexyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ether (80 mg) and L-alanine (207 mg) in a 0.5 M solution of sodium methoxide in methanol (3.7 ml) is heated in a microwave reactor (sealed tube) at 120 ° C for 40 minutes The reaction mixture was concentrated, dissolved in water (30 ml) and acidified with 2N. HCl to pH 4. Extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography to give the title compound (52 mg). MS - (+) - ion: M + 1 = 359.18.

Example A-75

2- (S) - {[7- (4-Fluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} propionic acid

but. 5- (4-Fluorophenoxy) isoindole-1,3-dione

A mixture of 5-nitroisoindole-1,3-dione (177 g, 0.904 mol), 4-fluorophenol (128 g, 1.13 mol), K ₂ CO ₃ (419 g, 3 mol) and DMF (2 L) is boiled with under reflux with stirring for 3 hours, then the mixture was poured into water (12 L) with stirring. The precipitate formed is isolated by vacuum filtration, washed with water (8 L) and dried in vacuo at 70 ° C to obtain the title compound as a beige powder (43.2 g). ¹ H NMR (CDCl ₃ ): δ = 7.79 (d, 1H), 7.57 (br s, 1H), 7.01-7.29 (m, 6H).

b. [5- (4-Fluorophenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid methyl ester

A mixture of 5- (4-fluorophenoxy) isoindole-1,3-dione (42.9 g, 167 mmol), methyl bromoacetic acid (21.1 ml, 223 mmol), K ₂ CO ₃ (62.3 g, 446 mmol) and Et ₂ CO (700 ml) are refluxed with stirring for 16 hours, then the mixture is concentrated in vacuo. Water (150 ml) was added to the residue, and the resulting suspension was extracted with EtOAc (1x750 ml, 1x250 ml). The combined organic phases were dried over MgSO ₄ and concentrated in vacuo to afford the title compound as a beige solid (49.7 g). ¹ H NMR (CDCl ₃ ): δ = 7.80 (d, 1H), 7.01-7.30 (m, 6H), 4.41 (s, 2H), 3.76 (s, 3H).

from. 7- (4-Fluorophenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Sodium (7.2 g, 310 mmol) was dissolved in n-butanol (300 ml) with stirring and at 70 ° C. Then the temperature was raised to 95-100 ° C and a solution of [5- (4-fluorophenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid methyl ester (49.4 g, 150 mmol) in hot n-butanol (300 ml). The mixture was stirred for another 90 minutes at 95-100 ° C and then allowed to cool to 60 ° C with stirring, then 2N was added. HCl (160 ml). The mixture was stirred vigorously for 30 minutes and then allowed to cool to room temperature. Then the mixture is subjected to vacuum filtration. The filter cake was washed thoroughly with water and dried in vacuo at 70 ° C to give a light yellow solid. Purification by flash column chromatography on silica gel using CH ₂ Cl ₂ : EtOAc (98: 2) as eluent gave the title compound (14.4 g, first fraction). ¹ H NMR (CDCl ₃ ): δ = 8.40 (br s, 1H), 8.14 (d, 1H), 7.80 (d, 1H), 7.42-7.48 (m, 1H ), 7.04-7.14 (m, 4H), 4.39 (t, 2H), 1.70-1.85 (m, 2H), 1.37-1.55 (m, 2H), 0.99 (t, 3H).

d. 1-Bromo-7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 7- (4-fluorophenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester (14.33 g, 38.6 mmol), POBr ₃ (44.7 g, 154.4 mmol) and anhydrous methyl cyanide ( 290 ml) was carefully refluxed with stirring for 75 minutes, then NaHCO ₃ (100.8 g, 1.2 mol) was added in small portions with stirring. Then slowly with stirring, water (200 ml) was added and the mixture was intensively stirred for 1 hour at room temperature, then concentrated in vacuo to approximately 1/2 of its volume. Water (200 ml) was added and the mixture was extracted with EtOAc (1x400 ml, 1x200 ml). The combined organic phases are dried over MgSO ₄ and evaporated in vacuo to give a beige solid. The beige solid was dissolved in CH ₂ Cl ₂ and purified by filtration through a pad of silica gel. After concentration in vacuo of the resulting solution in CH ₂ Cl ₂ , the title compound (11.4 g) is obtained. ¹ H NMR (CDCl ₃ ): δ = 11.89 (s, 1H), 8.36 (d, 1H), 7.57 (d, 1H), 7.44-7.50 (m, 1H), 7.08-7.16 (m, 4H), 4.47 (t, 2H), 1.78-1.93 (m, 2H), 1.38-1.58 (m, 2H), 0, 99 (t, 3H).

e. 7- (4-Fluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester

A mixture of 1-bromo-7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (434 mg, 1 mmol), Pd (PPh ₃ ) ₄ (116 mg, 0.1 mmol), trimethylboroxine (140 μl, 1 mmol), K ₂ CO ₃ (414 mg, 3 mmol) and 1,4-dioxane (8 ml) are refluxed with stirring for 2 hours. Then the mixture was concentrated in vacuo. Water (10 ml) was added to the residue. The mixture is acidified by adding aqueous 6n. HCl and extracted with EtOAc (40 ml). The organic phase was dried over MgSO ₄ and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes: EtOAc, 94: 6 as eluent, affords the title compound as a white solid (229 mg). MS - (+) - ion: M + 1 = 370.1.

f. 2- (S) - {[7- (4-Fluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino}

propionic acid

A mixture of 7- (4-fluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester (92 mg, 0.25 mmol), (S) -alanine (225 mg, 2.5 mmol) and 0, 5n a solution of MeOH in methanol (5 ml, 2.5 mmol) is heated in the microwave with stirring for 20 min at 140 ° C, then the mixture is concentrated in vacuo. Water (10 ml) was added to the residue, and the mixture was washed with EtOAc (2x25 ml). The aqueous solution thus purified was acidified by the addition of 6N. Hcl and extracted with EtOAc (1x25 ml). The organic phase was dried over MgSO ₄ and concentrated in vacuo to afford the title compound as a beige solid (69 mg). MS - (+) - ion: M + 1 = 385.1.

Example A-76

2- (S) - {[7- (4-Fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid

but. 7- (4-Fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 1-bromo-7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (4.34 g, 10 mmol, see example A-75d), sodium acetate (984 mg, 12 mmol), Pd / C (2.0 g, 10% wt. Pd, 50% water), EtOAc (400 ml) and MeOH (200 ml) were stirred under an atmosphere of H ₂ at normal pressure and room temperature for 2.5 hours, then the mixture is filtered through a layer of celite. Celite was washed with EtOAc (500 ml). The combined organic phases are concentrated in vacuo. The residue was added to a semi-concentrated NaHCO ₃ solution (50 ml) and the mixture was extracted with CH ₂ Cl ₂ (1 x 200 ml). The organic phase was dried over MgSO ₄ and concentrated in vacuo to give the title compound as a beige oil (3.45 g). MS - (+) - ion: M + 1 = 356.1.

b. 2- (S) - {[7- (4-Fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino}

propionic acid

A mixture of 7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (154 mg, 0.43 mmol), (S) -alanine (225 mg, 2.5 mmol) and 0.5N. a solution of MeONa in MeOH (5 ml, 2.5 mmol) is heated in a microwave oven with stirring for 20 min at 130 ° C, then the mixture is concentrated in vacuo. Water (15 ml) was added to the residue, and the mixture was washed with Et ₂ O (3x30 ml). The purified aqueous solution is acidified by adding 6N. HCl and extracted with EtOAc (1x30 ml). The organic phase was dried over MgSO ₄ and concentrated in vacuo to afford the title compound as a beige solid (79 mg). MS - (-) - ion: M-1 = 369.1.

Example A-77

2- (S) - [(4-Hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid

but. 1-chloro-4-hydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ether and 1-chloro-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ether (regioisomeric mixture)

A regioisomeric mixture of 1,4-dihydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ester of 1,4-dihydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester (40.63 g, 115) is added to POCl ₃ (300 ml). mmol, see example A-65 d). The mixture was gently refluxed with stirring for 30 minutes, then concentrated in vacuo. The residue was dissolved in EtOAc (800 ml) and water (400 ml) was added. With vigorous stirring, NaHCO ₃ (approximately 100 g) was added in small portions to the mixture. Then the mixture is stirred for 1 hour at room temperature, filtered through a layer of celite. The organic phase was separated, dried over MgSO ₄ and evaporated in vacuo to give a beige solid. The beige solid is dissolved in CH ₂ Cl ₂ and purified by filtration through a pad of silica gel. Concentration in vacuo of the resulting solution in CH ₂ Cl ₂ gives the title compound (15.51 g) as a beige solid. MS - (-) - ion: M-1 = 370.2.

b. 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid butyl ester

To a mixture of anhydrous 1,4-dioxane (200 ml), Pd (PPh ₃ ) ₄ (3.47 g, 3 mmol), trimethylboroxine (4.22 ml, 30 mmol) and K ₂ CO ₃ (12.44 g, 90 mmol) add the regioisomeric mixture of 1-chloro-4-hydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ether and 1-chloro-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester (11.15 g, 30 mmol). The mixture was refluxed under N ₂ with stirring for 3 hours and then stirred at room temperature for 48 hours. Then the mixture was concentrated in vacuo. Water (100 ml) was added to the residue, and the mixture was extracted with EtOAc (300 ml). The organic phase was dried over MgSO ₄ and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes: EtOAc (9: 1) as the eluent afforded the title compound as a yellowish solid (4.40 g, first fraction). MS - (+) - ion: M + 1 = 352.1.

from. 2- (S) - [(4-Hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid

A mixture of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid butyl ester (176 mg, 0.5 mmol), (S) -alanine (225 mg, 2.5 mmol) and 0.5N. a solution of MeONa in MeOH (5 ml, 2.5 mmol) is heated in a microwave oven with stirring for 20 min at 120 ° C, then the mixture is concentrated in vacuo. Water (15 ml) was added to the residue, and the mixture was washed with Et ₂ O (3x30 ml). The aqueous solution thus purified was acidified by the addition of 6N. HCl and extracted with EtOAc (1x30 ml). The organic phase was dried over MgSO ₄ and concentrated in vacuo to afford the title compound as a beige solid (108 mg). MS - (-) - ion: M-1 = 365.1.

Example A-78

2- (S) - [(4-Hydroxy-1-methyl-7-phenylsulfanylisoquinoline-3-carbonyl) amino]

propionic acid

but. 1-Bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid

1,4-Dihydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ether (Example A-63d, compound A) (29.0 g) and phosphorus oxybromide (67.5 g) in 600 ml of anhydrous acetonitrile are stirred at the boil with reflux for 4 hours. After cooling, the reaction mixture was concentrated, saturated sodium bicarbonate solution and ethyl acetate were added to the residue, and stirred overnight. The precipitate formed between the layers was collected and washed with water to give the title compound (10.2 g). MS - (+) - ion: M + 1 = 376.0, 378.1.

b. 1-bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid methyl ester

1-Bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid (10.0 g), potassium carbonate (3.7 g) and methyl sulfate (3.4 g) are suspended in 500 ml of acetone and stirred under reflux fridge overnight. The reaction mixture was concentrated and the residue was partitioned between 1N. hydrochloric acid and ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound (9.6 g). MS - (+) - ion: M + 1 = 389.9, 391.9.

e. 4-Hydroxy-1-methyl-7-phenylsulfanylisoquinoline-3-carboxylic acid methyl ester

1-Bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid methyl ester (0.2 g), tetrakis (triphenylphosphine) palladium (60 mg), methylboroxine (65 mg) and potassium carbonate in 1,4-dioxane ( 4 ml) is heated in a microwave reactor (sealed tube) for 10 min at 140 ° C. After cooling, the reaction mixture was concentrated and partitioned between 1N. hydrochloric acid and ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and separated by silica gel chromatography (eluting with a mixture of 2% ethyl acetate in methylene chloride) to give the title compound (47 mg). MS - (+) - ion: M + 1 = 326.1.

d. 2- (S) - [(4-Hydroxy-1-methyl-7-phenylsulfanylisoquinoline-3-carbonyl) amino]

propionic acid

Obtained by a method similar to that of Example A-74 f). ¹ H NMR (200 MHz, DMSO-d ₆ ): δ 13.26 (br s, 1H), 9.07 (s, 1H), 8.61 (s, 1H), 8.33 (d, J = 8.2 Hz 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.81 (br s, 2H), 7.52 (br s, 3H), 4.52 ( broad s, 1H), 2.91 (s, 3H), 1.49 (d, J = 7.0 Hz, 3H).

Example A-79

2- (S) - {[4-Hydroxy-7- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} propionic acid

but. 4- (4-Trifluoromethylphenoxy) phthalonitrile

Obtained by a method similar to that of example A-66 a). ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.74 (m, 2H), 7.47 (d, J = 8.6 Hz, 1H), 7.25 (m, 3H), 6.87 ( d, J = 8.9 Hz, 1H).

b. 4- (4-trifluoromethylphenoxy) phthalic acid

Obtained by a method similar to that of example A-66 b). ¹ H NMR (200 MHz, DMSO-d ₆ ): δ 8.24 (d, J = 9.0 Hz, 1H), 7.75 (m, 3H), 7.19 (m, 3H).

from. [1,3-dioxo-5- (4-trifluoromethylphenoxy) -1,3-dihydroisoindol-2-yl] acetic acid methyl ester

Obtained by a method similar to that of Example A-66 c). ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.86 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.40-7, 13 (m, 4H), 4.43 (s, 2H), 3.76 (s, 3H).

d. 7- (4-Trifluoromethylphenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example A-66 d). The two isomers are separated by chromatography to give the title compound. MS - (+) - ion: M + 1 = 422.0.

e. 1-Chloro-4-hydroxy-7- (4-trifluoromethylphenoxy) isoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of Example A-2 c). MS - (-) - ion: M-1 = 438.3.

f. 4-hydroxy-7- (4-trifluoromethylphenoxy) isoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of Example A-74 e). MS - (+) - ion: M + 1 = 406.1.

g. 2- (S) - {[4-Hydroxy-7- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino}

propionic acid

Obtained by a method similar to that of Example A-74 f). MS - (+) - ion: M + 1 = 421.2.

Example B-1

1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (2-aminoethyl) amide; trifluoroacetic acid salt

but. (1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid butyl ester

A mixture of 160 ml of butanol, 20.0 g of (1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid (94.6 mmol) and 2.0 ml of concentrated sulfuric acid is refluxed with stirring for 24 hours . Then 5 g of sodium bicarbonate are added in portions, stirring is continued at rt. 5 min and the solvent was evaporated in vacuo. The residue was partitioned between 100 ml of water and 100 ml of ethyl acetate. The organic phase is washed with 100 ml of brine, dried over sodium sulfate and evaporated in vacuo to give a yellowish oil, which later solidifies. 24.02 g of the title compound are obtained. MS - (+) - ion: M + 1 = 261.9.

b. 1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

4.41 g of sodium (190 mmol) are dissolved in 250 ml of n-butanol with stirring. After complete dissolution of sodium, the solution was allowed to cool to room temperature and a solution of 24.0 g (91.9 mmol) of butyl ether (1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid in 150 ml of butanol was added with stirring . The solution is heated to 100 ° C in 30 minutes and stirred at this temperature for 1 hour. Then the mixture was allowed to cool to room temperature and maintained at this temperature for 18 hours. Then the pH of the mixture was adjusted to 2-3 by adding aqueous 2N with stirring. of hydrochloric acid. Stirring was continued for 30 minutes, after which the solid component was filtered with suction. The filter cake was washed thoroughly with water and dried in vacuo at 50 ° C to give a white solid. 17.75 g of the title compound are obtained. MS - (+) - ion: M + 1 = 262.1.

from. 1-Chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 17.3 g (66.2 mmol) of butyl ester of 1,4-dihydroxyisoquinoline-3-carboxylic acid and 100 ml of phosphorus oxychloride is stirred at room temperature for 1 hour and then slowly heated with stirring for 2 hours at the boiling temperature under reflux . The mixture is refluxed gently for 30 minutes. After cooling to room temperature, the excess phosphorus oxychloride was evaporated in vacuo, the residue was dissolved in 100 ml of ethyl acetate. The solution was poured with stirring into 300 ml of a saturated aqueous solution of sodium bicarbonate. The precipitate formed is removed by vacuum filtration. The organic phase is separated and the aqueous phase is extracted with ethyl acetate (3 x 100 ml). The combined aqueous phases are dried over sodium sulfate, filtered through a plug of silica gel and evaporated in vacuo. A brown oil is obtained, which later solidifies. 11.37 g of the title compound are obtained. ¹ H NMR (CDCl ₃ ): δ = 11.91 (s, 1H), 8.41 (m, 1H), 8.29 (m, 1H), 7.83 (m, 2H), 4.49 ( t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).

d. 1-Chloro-4-hydroxyisoquinoline-3-carboxylic acid

A mixture of 9.23 g of 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ether (33 mmol), 90 ml of 2.5N. an aqueous solution of sodium bicarbonate, water (20 ml) and ethanol (110 ml) are refluxed with stirring for 2 hours. Then the pH of the mixture was adjusted to a value of 2 by adding concentrated aqueous hydrochloric acid. During the addition, the temperature of the mixture was maintained at 20 ° C. by cooling with an ice bath. Stirring is continued for 1 hour, then the solid component is separated by vacuum filtration. The filter cake was washed with water and dried in vacuo at 85 ° C to give a white powder. 6.64 g of the title compound are obtained. MS - (+) - ion: M + 1 = 224.1.

e. Butyl ether {2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] ethyl} carbamic acid

To a mixture of 45 mg (0.2 mmol) of 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid, 76 mg (0.2 mmol) of benzotriazol-1-yl- (bis-dimethylaminomethylene) oxonium hexafluorophosphate (HBTU), 32 μl (2-Aminoethyl) carbamic acid tert-butyl ester (0.2 mmol) and 1 ml of dichloromethane are added with stirring 96 μl (0.55 mmol) of ethyldiisopropylamine. Stirring is continued at room temperature for 5 days. The product was isolated from the reaction mixture by flash column chromatography on silica gel using hexanes: ethyl acetate 8: 2 as an eluent to give a beige gum. 8 mg of the title compound are obtained. MS - (-) - ion: M-1 = 364.0.

f. 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (2-aminoethyl) amide; trifluoroacetic acid salt

A mixture of 8 mg (0.022 mmol) of {2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] ethyl} carbamic acid tert-butyl ester and 2 ml of trifluoroacetic acid was stirred for 2 hours at room temperature. Then the excess trifluoroacetic acid was evaporated in vacuo, the residue was dissolved in absolute ethanol and the solution was concentrated in vacuo to give a beige solid. 8.5 mg of the title compound are obtained. MS - (+) - ion: M + 1 = 266.0.

Example B-2

1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (2-methoxyethyl) amide

To a mixture of 45 mg (0.2 mmol) of 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (Example A-1d), 76 mg (0.2 mmol) of benzotriazol-1-yl- (bis-dimethylaminomethylene) hexonium hexafluorophosphate (HBTU), 18 μl of 2-methoxyethylamine (0.2 mmol) and 1 ml of dichloromethane are added with stirring 96 μl (0.55 mmol) of ethyldiisopropylamine. Stirring is continued at room temperature for 12 days. The product was isolated from the reaction mixture by flash column chromatography on silica gel using hexanes: ethyl acetate (9: 1) as an eluent to give a white solid. 8.8 mg of the title compound are obtained. MS - (+) - ion: M + 1 = 281.0.

Example B-3

(2-Hydroxyethyl) 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid amide

Synthesized from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid of Example A-1 d) and 2-aminoethanol according to a procedure similar to that of Example 2. MS - (-) - ion: M-1 = 265.2.

Example B-4

(2-Dimethylaminoethyl) 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid amide

A mixture of 28 mg (0.1 mmol) of 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester of Example A-1 c), 116 μl (1 mmol) of N, N-dimethylethane-1,2-diamine and 0, 5 ml of absolute ethanol was stirred at room temperature for 18 hours. Then the solvent was evaporated in vacuo, the residue was suspended in 5 ml of water, and the mixture was extracted with ethyl acetate (2x35 ml). The combined organic phases are dried over sodium sulfate and evaporated in vacuo to give a yellowish solid. 29 mg of the title compound are obtained. MS - (+) - ion: M + 1 = 294.1.

Example B-5

(2-Acetylaminoethyl) 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid amide

A mixture of 56 mg (0.2 mmol) of 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester of Example B-1 c), 227 mg (2 mmol) of N- (2-aminoethyl) acetamide and 0.8 ml of absolute ethanol was stirred at room temperature for 3 days. Then the solvent was evaporated in vacuo, the residue was suspended in 3 ml of water, and the pH of the mixture was adjusted to 2-3 by adding aqueous 1N. HCl. The mixture was extracted with ethyl acetate (2x25 ml). The combined organic phases are dried over sodium sulfate and evaporated in vacuo to give a yellowish solid. 64 mg of the title compound are obtained. MS - (+) - ion: M + 1 = 308.1.

Example B-6

1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (2-hydroxyethyl) amide

Synthesized from butyl ester of 1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (can be obtained in accordance with US patent 6093730, 10/1998, Weidmann et al.) And 2-aminoethanol in a manner analogous to the method of example AT 5. MS - (+) - ion: M + 1 = 325.1.

Example B-7

1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (2-methoxyethyl) amide

Synthesized from butyl ester of 1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (can be obtained in accordance with US patent 6093730, 10/1998, Weidmann et al.) And 2-methoxyethylamine according to a procedure analogous to the method of example AT 5. MS - (+) - ion: M + 1 = 339.0.

Example B-8

1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (2-aminoethyl) amide; trifluoroacetic acid salt

Synthesized from 1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid butyl ester (can be prepared according to US Pat. No. 6,093,730, 10/1998, Weidmann et al.) And tert-butyl ether (2-aminoethyl) carbamic acid by a method similar to that of Example B-5, followed by deprotection by the method of Example B-1 f). MS - (+) - ion: M + 1 = 324.1.

Example B-9

(2-Dimethylaminoethyl) 1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid amide

Synthesized from butyl ester of 1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (can be obtained in accordance with US patent 6093730, 10/1998, Weidmann et al.) And N, N-dimethylethane-1,2 -diamine by a method similar to that of Example B-4, followed by deprotection by the method of Example B-1 f). MS - (+) - ion: M + 1 = 352.1.

Example B-10

1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (2-aminoethyl) amide; trifluoroacetic acid salt

Synthesized from 1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid butyl ether (can be prepared according to US Pat. No. 6,093,730, 10/1998, Weidmann et al.) And tert-butyl ether (2-aminoethyl) carbamic acid by a method similar to that of Example B-5, followed by deprotection by the method of Example B-1 f). MS - (+) - ion: M + 1 = 324.0.

Example B-11

1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (2-methoxyethyl) amide

Synthesized from butyl ester of 1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (can be obtained in accordance with US patent 6093730, 10/1998, Weidmann et al.) And 2-methoxyethylamine according to a procedure analogous to the procedure of example AT 5. MS - (-) - ion: M-1 = 337.1.

Example B-12

(2-Dimethylaminoethyl) 1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid amide

Synthesized from butyl ester of 1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (can be obtained in accordance with US patent 6093730, 10/1998, Weidmann et al.) And N, N-dimethylethane-1,2 -diamine by a method similar to that of Example B-4, followed by deprotection by the method of Example B-1 f). MS - (+) - ion: M + 1 = 352.1.

Example B-13

(2-Hydroxyethyl) 1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid amide

Synthesized from butyl ester of 1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (can be obtained in accordance with US patent 6093730, 10/1998, Weidmann et al.) And 2-aminoethanol in a manner analogous to the method of example AT 5. MS - (-) - ion: M-1 = 323.2.

Example C-1

(2-Hydroxy-1-hydroxymethylethyl) 1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid amide

0.035 mg of 1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid butyl ester and 0.088 g of 2-aminopropane-1,3-diol are dissolved in 1 ml of ethanol, and the mixture is refluxed for 24 hours. The reaction mixture was concentrated and the residue was dissolved in 10 ml of ethyl acetate. An ethyl acetate solution was extracted with 5 ml of 1M aqueous HCl and water, dried (sodium sulfate) and concentrated to give 0.042 g of a white solid. MS - (+) - ion: 355.1.

Example C-2

(2-Hydroxy-1-hydroxymethylethyl) 1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid amide

Obtained from 1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid butyl ether and 2-aminopropane-1,3-diol according to a procedure similar to that of Example C-1. MS - (-) - ion: 353.2.

Example C-3

(2-Hydroxy-1-hydroxymethylethyl) 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid amide

Obtained from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ether and 2-aminopropane-1,3-diol according to a procedure similar to that of Example C-1. MS - (-) - ion: 295.2.

Example D-1

[(4-Hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid

but. 4-phenylsulfanylphthalic acid

A mixture of 5.06 g of phenylsulfanylphthalonitrile (21.4 mmol), 10 ml of 50% aqueous KOH and 10 ml of methanol is refluxed with stirring for 3.5 days. The mixture was diluted with 100 ml of water and acidified with concentrated hydrochloric acid. The precipitated product is filtered off with suction, washed thoroughly with water and dried in vacuo at 60 ° C. 5.75 g of the title compound are obtained. MS - (-) - ion: M-1 = 273.0.

b. (1,3-dioxo-5-phenylsulfanyl-1,3-dihydroisoindol-2-yl) acetic acid

5.62 g of 4-phenylsulfanylphthalic acid (20.5 mmol) and 1.55 g of glycine (20.5 mmol) are carefully ground together in a mortar. Then the mixture is heated at 210-220 ° C in an oil bath. The molten mass is stirred with a spatula at this temperature for 15 minutes, then the mixture is allowed to cool to room temperature in vacuo. 6.30 g of the title compound are obtained. MS - (-) - ion: M-1 = 311.8.

from. (1,3-dioxo-5-phenylsulfanyl-1,3-dihydroisoindol-2-yl) acetic acid methyl ester

A mixture of 20 ml of methanol, 6.27 g of (1,3-dioxo-5-phenylsulfanyl-1,3-dihydroisoindol-2-yl) acetic acid (20 mmol) and 0.3 ml of concentrated sulfuric acid is refluxed for 18 hours . Then add 100 ml of a concentrated aqueous solution of sodium bicarbonate and the mixture is extracted with 100 ml of ethyl acetate. The organic phase is dried over

MgSO ₄ and evaporated in vacuo. 6.54 g of the title compound are obtained. MS - (+) - ion: M + 1 = 328.0.

d. 1,4-dihydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ether (A) and 1,4-dihydroxy-6-phenylsulfanylisoquinoline-3-carboxylic acid butyl ether (B)

0.92 g of sodium (40 mmol) is dissolved in 100 ml of n-butanol with stirring. Then the temperature was raised to 95-100 ° C, a hot solution of 6.5 g of (1,3-dioxo-5-phenylsulfanyl-1,3-dihydroisoindol-2-yl) acetic acid methyl ester (19.85 mmol) in 20 was added. ml of n-butanol and stirring is continued at a temperature of 95-100 ° C for 1 hour. Then the solvent is evaporated in vacuo, add 25 ml of aqueous 2n. HCl and 100 ml of ethyl acetate and the mixture was stirred vigorously for 1 hour, then filtered by suction. The filter cake was washed thoroughly with water and dried in vacuo at 60 ° C to obtain 4.43 g of a yellow solid. A mixture of A and B (4.4 g) was separated by flash column chromatography on silica gel, eluting with dichloromethane: ethyl acetate (98: 2). Evaporation of the first fraction gives 1.99 g A. ¹ H NMR (CDCl ₃ ): δ = 10.48 (br s, 1H), 8.39 (br s, 1H), 8.24 (d, 1H) 8.01 (d, 1H), 7.35-7.55 (m, 6H), 4.39 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H). Evaporation of the second fraction gives 2.26 g of B. ¹ H NMR (CDCl ₃ ): δ = 10.38 (br s, 1H), 8.32 (br s, 1H), 8.24 (d, 1H) 7.86 (d, 1H), 7.37-7.56 (m, 6H), 4.39 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H).

e. 1-Bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester

To a solution of 4.59 g of phosphorus oxybromide (16 mmol) in 25 ml of anhydrous acetonitrile, 1.108 g of 1,4-dihydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (3 mmol) was added and the mixture was gently refluxed for 1 hour. Then, 5.04 g of sodium bicarbonate (60 mmol) was added, after which 8 ml of water was added dropwise. After stirring at room temperature for 90 minutes, the mixture was concentrated in vacuo to approximately one third of its volume, 40 ml of water was added and the mixture was extracted with 30 ml of ethyl acetate. The mixture is filtered by suction. The organic phase is separated, dried over MgSO ₄ and filtered through a pad of silica gel. Evaporation in vacuo afforded 0.885 g of the title compound. ¹ H NMR (CDCl ₃ ): δ = 11.84 (s, 1H), 8.21 (d, 1H), 7.91 (d, 1H), 7.40-7.55 (m, 6H), 4.46 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).

f. 4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester

A mixture of 432 mg of 1-bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester (1 mmol), 63 mg of red phosphorus (2 mmol), 0.4 ml of 57% aqueous HI solution (3 mmol) and 1 ml of glacial acetic acid is refluxed with stirring for 30 minutes. Then the reaction mixture was diluted with 25 ml of ethyl acetate, filtered by suction through a layer of celite, washed with a solution of 0.2 g of NaHSO ₃ in 5 ml of water, and washed twice with 5 ml of concentrated aqueous sodium bicarbonate solution. The organic phase was dried over MgSO ₄ and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with hexanes: ethyl acetate (85:15). 123 mg of the title compound are obtained. ¹ H NMR (CDCl ₃ ):

δ = 11.85 (s, 1H), 8.60 (s, 1H), 8.23 (d, 1H), 7.38-7.63 (m, 7H), 4.49 (t, 2H) 1.87 (m, 2H); 1.47 (m, 2H); 0.98 (t, 3H).

g. [(4-Hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid

A mixture of 113 mg of 4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester (0.32 mmol), 244 mg of glycine (3.2 mmol) and 6.4 ml of 0.5N. a solution of sodium methoxide in methanol (3.2 mmol) is refluxed with stirring for 24 hours. Then, the solvent was evaporated in vacuo, the residue was dissolved in 25 ml of water, and the resulting solution was washed twice with 50 ml of ethyl acetate. Then the pH of the solution was adjusted to approximately 3 by adding concentrated hydrochloric acid, and the resulting suspension was extracted twice with 25 ml of ethyl acetate. The combined extracts were dried over MgSO ₄ and evaporated in vacuo. 103 mg of the title compound are obtained. ¹ H NMR (DMSO-d ₆ ): δ = 9.32 (t, 1H), 8.74 (s, 1H), 8.19 (d, 1H), 7.94 (d, 1H), 7, 45-7.65 (m, 6H); 4.02 (d, 2H).

Example D-2

[(4-Hydroxy-6-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Bromo-4-hydroxy-6-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester

Compound In Example D-1 d) (1.447 g, 4 mmol) was reacted with phosphorus oxybromide in a manner analogous to that of Example D-1 e). The crude product is purified by flash column chromatography on silica gel, eluting with dichloromethane. 0.985 g of the title compound is obtained by evaporation of the first fraction. ¹ H NMR (CDCl ₃ ): δ = 11.77 (s, 1H), 8.08 (d, 1H), 8.05 (s, 1H), 7.41-7.56 (m, 6H), 4.46 (t, 2H), 1.85 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).

b. 4-Hydroxy-6-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester

1-Bromo-4-hydroxy-6-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester (540 mg, 1.25 mmol) was reacted with red phosphorus and HI according to a procedure similar to that of Example D-1 f). The crude product is purified by flash column chromatography on silica gel, eluting with a mixture of hexanes: ethyl acetate (85:15). 150 mg of the title compound are obtained. ¹ H NMR (CDCl ₃ ): δ = 11.78 (s, 1H), 8.71 (d, 1H), 8.11 (t, 1H), 7.79 (d, 1H), 7.39- 7.54 (m, 6H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).

from. [(4-Hydroxy-6-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid

4-Hydroxy-6-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester (127 mg, 0.36 mmol) was reacted with glycine and sodium methylate in a manner analogous to Example D-1 g). 118 mg of the title compound are obtained. ¹ H NMR (DMSO-d ₆ ): δ = 9.33 (t, 1H), 8.80 (s, 1H), 8.11 (d, 1H), 7.79 (s, 1H), 7, 49-7.65 (m, 6H); 4.01 (d, 2H).

Example D-3

[(1-Chloro-4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Chloro-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester

A mixture of 554 mg of compound A (1.5 mmol) of Example D-1 d) and 5 ml of phosphorus oxychloride was gently refluxed with stirring for 30 minutes. The excess phosphorus oxychloride was evaporated in vacuo, the residue was dissolved in 15 ml of acetonitrile. 2.94 g of sodium bicarbonate (35 mmol) was added, after which 4 ml of water was added dropwise. After stirring for 1 hour, the mixture was concentrated in vacuo to approximately one third of its volume, 20 ml of water was added and the mixture was extracted twice with 20 ml of ethyl acetate. The combined organic phases are dried over MgSO ₄ and filtered through a pad of silica gel by suction. Evaporation in vacuo afforded 426 mg of the title compound. ¹ H NMR (CDCl ₃ ): δ = 11.85 (s, 1H), 8.23 (d, 1H), 7.95 (d, 1H), 7.50-7.57 (m, 6H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).

b. [(1-Chloro-4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid

1-Chloro-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester (194 mg, 0.5 mmol) was reacted with glycine and sodium methylate in a manner analogous to that of Example D-1 g). 168 mg of the title compound are obtained. ¹ H NMR (DMSO-d ₆ ): δ = 9.17 (t, 1H), 8.24 (d, 1H), 7.51-7.79 (m, 7H), 4.00 (d, 2H )

Example D-4

[(1-Chloro-4-hydroxy-6-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Chloro-4-hydroxy-6-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester

A mixture of 554 mg of compound B (1.5 mmol) of Example D-1 d) was reacted with phosphorus oxychloride in a manner analogous to that of Example D-3 a). The crude product is purified by flash column chromatography on silica gel, eluting with dichloromethane. 205 mg of the title compound are obtained by evaporation of the first fraction. ¹ H NMR (CDCl ₃ ): δ = 11.78 (s, 1H), 8.08 (d, 1H), 8.06 (s, 1H), 7.41-7.56 (m, 6H), 4.46 (t, 2H), 1.85 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).

b. [(1-Chloro-4-hydroxy-6-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid

1-Chloro-4-hydroxy-6-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester (194 mg, 0.5 mmol) was reacted with glycine and sodium methylate in a manner analogous to that of Example D-1 g). 155 mg of the title compound are obtained. ¹ H NMR (DMSO-d ₆ ): δ = 9.19 (t, 1H), 8.18 (d, 1H), 7.52-7.79 (m, 7H), 4.00 (d, 2H )

Example D-5

[(1-Bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid

1-Bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester (216 mg, 0.5 mmol) of Example D-1 e) is reacted with glycine and sodium methylate in the same manner as in Example D-1 g) 192 mg of the title compound are obtained. ¹ H NMR (DMSO-d ₆ ): δ = 9.15 (t, 1H), 8.22 (d, 1H), 7.52-7.74 (m, 7H), 4.01 (d, 2H )

Example D-6

[(1-Bromo-4-hydroxy-6-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid

1-Bromo-4-hydroxy-6-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester (216 mg, 0.5 mmol) of Example D-2 a) is reacted with glycine and sodium methylate in the same manner as in Example D-1 g) 194 mg of the title compound are obtained. ¹ H NMR (DMSO-d ₆ ): δ = 9.17 (t, 1H), 8.12 (d, 1H), 7.51-7.78 (m, 7H), 4.00 (d, 2H )

Example D-7

[(4-Hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

but. 4-phenoxyphthalic acid

Synthesized from 4-phenoxyphthalonitrile by a method similar to that of Example D-1 a). MS - (-) - ion: M-1 = 256.9.

b. (1,3-dioxo-5-phenoxy-1,3-dihydroisoindol-2-yl) acetic acid

Synthesized from 4-phenoxyphthalic acid by a method similar to that of Example D-1 b). MS - (+) - ion: M + 1 = 297.9.

c. Methyl ester (1,3-dioxo-5-phenoxy-1,3-dihydroisoindol-2-yl) acetic acid

Synthesized from (1,3-dioxo-5-phenoxy-1,3-dihydroisoindol-2-yl) acetic acid according to a procedure similar to that of Example D-1 c) (purification of the crude product by flash chromatography on silica gel, eluting with hexanes: ethyl acetate, 1: 1). ¹ H NMR (CDCl ₃ ): δ = 7.83 (d, 1H), 7.05-7.46 (m, 7H), 4.41 (s, 2H), 3.76 (s, 3H).

d. 1,4-Dihydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ether (A) and 1,4-dihydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ether (B)

Synthesized from methyl ester of (1,3-dioxo-5-phenoxy-1,3-dihydroisoindol-2-yl) acetic acid in a manner analogous to that of Example D-1 d). ¹ H NMR (CDCl ₃ ): δ = 10.58 (br s, 1H), 8.37 (br s, 1H), 8.14 (d, 1H), 7.87 (d, 1H), 7.05-7.49 (m, 6H), 4.39 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H). B: ¹ H NMR (CDCl ₃ ): δ = 10.38 (br s, 1H), 8.38 (d, 1H), 8.28 (br s, 1H), 7.56 (d, 1H) ), 7.06-7.47 (m, 6H), 4.40 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H) .

e. 1-Bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from 1,4-dihydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 e). ¹ H NMR (CDCl ₃ ): δ = 11.89 (s, 1H), 8.35 (d, 1H), 7.63 (d, 1H), 7.08-7.52 (m, 6H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).

f. 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester (208 mg, 0.5 mmol), 49 mg of sodium acetate (0.6 mmol), 50 mg of 10% palladium on charcoal, 10 ml of ethanol and 5 ml of ethyl acetate are stirred in a hydrogen atmosphere at 1 atm for 15 hours. The mixture is then filtered by suction through a celite pad and concentrated in vacuo. The residue was partitioned between 2 ml of a semi-concentrated aqueous sodium bicarbonate solution and 8 ml of ethyl acetate. The organic phase is dried over MgSO ₄ . Evaporation in vacuo gives 130 mg of the title compound. ¹ H NMR (CDCl ₃ ): δ = 11.89 (br s, 1H), 8.61 (s, 1H), 8.36 (d, 1H), 7.10-7.53 (m, 7H ), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).

g. [(4-Hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). ¹ H NMR (DMSO-d ₆ ): δ = 9.29 (t, 1H), 8.75 (s, 1H), 8.28 (d, 1H), 7.18-7.63 (m, 6H ), 4.01 (d, 2H).

On the other hand, the title compound is prepared as follows.

but'. 4-bromo-2-methylbenzoic acid ethyl ester

To 425 ml of ethanol add 25.3 g of 4-bromo-2-methylbenzoic acid and 5 ml of concentrated sulfuric acid. The mixture was heated at reflux for 3 days. The solution was cooled to room temperature, adjusted to pH neutral by adding sodium bicarbonate, and concentrated to approximately 100 ml volume under reduced pressure. The volume-reduced mixture was partitioned between ethyl acetate and water, and the organic phase was washed successively with saturated bicarbonate solution and brine. The organic phase is dried over anhydrous sodium sulfate and concentrated to 28.2 g of the product as a clear liquid. ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.78-7.73 (d, J = 8.2 Hz, 1H), 7.38-7.32 (m, 2H), 4.40-4 28 (q, J = 7 Hz, 2H), 2.57 (s, 3H), 1.42-1.35 (t, J = 7 Hz, 3H).

b '. 2-methyl-4-phenoxybenzoic acid ethyl ester

27.5 g of 4-bromo-2-methylbenzoic acid ethyl ester are dissolved in 120 ml of anhydrous toluene. To the solution were added 21.3 g of phenol, 73.6 g of Cs ₂ CO ₃ , 551 μl of ethyl acetate, 22 g of activated 4Å molecular sieves and 5.68 g of a 90% copper (I) trifluoromethanesulfonate / benzene complex. The reaction mixture was placed under nitrogen and heated at reflux for 48 hours. The resulting mixture was partitioned between water and ethyl acetate, and the mixture was filtered through a thin glass Schott filter to remove insoluble material. The organic fraction was washed three times with 1.0N. NaOH, once with brine, dried over anhydrous sodium sulfate and concentrated to 18.2 g of a light beige liquid. ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.93-7.88 (dd, J = 1.3, 7.8 Hz, 1H), 7.39-7.30 (m, 2H), 7 , 19-7.10 (t, J = 1.2, 7.4 Hz, 1H), 7.06-7.7.0 (m, 2H), 6.80-6.75 (m, 2H) 4.37-4.26 (q, J = 7.0 Hz, 2H); 2.56 (s, 3H); 1.40-1.33 (t, J = 7.0 Hz, 3H).

from'. 2 - {[(2,4-Dimethoxybenzyl) ethoxycarbonylmethylamino] methyl} -4-phenoxybenzoic acid ethyl ester

Ethyl N- (2,4-dimethoxybenzyl) glycinate is prepared according to literature procedures (Ananthan S. et al., J. Med. Chem. (1993), 36 (4), pp. 479-490). 13.0 g of 2-methyl-4-phenoxybenzoic acid ethyl ester are dissolved in 102 ml of carbon tetrachloride. To the solution was added 9.05 g of N-bromosuccinamide and 492 mg of benzoyl peroxide. The mixture was heated at reflux under nitrogen for 18 hours, cooled to room temperature and filtered through a pad of silica gel to remove all insoluble material. The resulting solution was concentrated to 16.5 g of crude oil.

In 10 ml of anhydrous DMF, 2.0 g of the oil described above is dissolved. To the solution was added 1.0 g of ethyl N- (2,4-dimethoxybenzyl) glycinate and 552 mg of potassium carbonate. The reaction mixture was stirred for 16 hours under nitrogen. The resulting mixture was poured into 80 ml of water and extracted three times with 50 ml of ethyl acetate. The combined organic fractions are washed successively with a semi-saturated bicarbonate solution and brine. The organic fractions were concentrated to an oily residue under reduced pressure and resuspended in 50 ml of ether and 10 ml of hexanes. The solution was cooled to 0 ° C. and filtered to remove traces of insoluble material. 4M HCl in dioxane was slowly added to the cold solution to obtain a solid precipitate. The solid salt was collected by filtration and washed twice with cold ether. The solid product is then dissolved by partitioning between 150 ml of ethyl acetate and 100 ml of an aqueous solution of sodium bicarbonate. The organic fractions were separated, washed with brine, dried over anhydrous sodium sulfate and concentrated to give 1.8 g of beige oil. MS - (+) m / z 508.13 (m + 1).

d '. 2- (2,4-Dimethoxybenzyl) -4-hydroxy-7-phenoxy-1,2-dihydroisoquinoline-3-carboxylic acid ethyl ester

460 mg of 2 - {[(2,4-dimethoxybenzyl) ethoxycarbonylmethylamino] methyl} -4-phenoxybenzoic acid ethyl ester was dissolved in 16 ml of anhydrous THF, and the resulting solution was cooled to -78 ° C under nitrogen. To the solution was added 1.95 ml of a 1.0 M solution of lithium bis (trimethylsilyl) amide in THF. The reaction mass is stirred at -78 ° C for 1.5 hours and at room temperature for 4.5 hours. The resulting solution was poured into a saturated aqueous solution of ammonium chloride and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to a yellow oil. The oil is purified by rapid passage through a column of silica gel, eluting with a gradient of 20-75% ethyl acetate in hexanes. The eluted fractions were concentrated under reduced pressure to 373 mg of a yellow oil, which was found to be a mixture of enol and keto tautomers of the target product. MS - (+) m / z 484.20 (m + 23).

e '. 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid ethyl ester

365 mg of 2- (2,4-dimethoxybenzyl) -4-hydroxy-7-phenoxy-1,2-dihydroisoquinoline-3-carboxylic acid ethyl ester are dissolved in 7.9 ml of dichloromethane. To the solution was added 92 μl of thionyl chloride. The reaction mass is stirred at room temperature for 6.5 hours, then 500 μl of ethanol is added and the reaction mass is stirred for another 10 minutes. The mixture was partitioned between ethyl acetate and sodium bicarbonate. The organic fraction was washed successively with 0.5 M HCl, water, brine, dried over anhydrous sodium sulfate and concentrated to 468 mg of a yellow oil. The oil was purified by flash chromatography on silica gel, eluting with a gradient of 15-50% ethyl acetate in hexanes, to give 232 mg of a crude product, which crystallized from ether and hexanes, to give 193 mg of an almost white solid. MS - (+) m / z 310.08 (m + 1).

f '. [(4-Hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

The title compound is obtained from 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid ethyl ester under conditions analogous to the conditions of Example D-1g).

Another alternative route for the synthesis of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid ethyl ester is presented below.

a. "2-Dibromomethyl-4-phenoxybenzoic acid ethyl ester

In a flask with 2-methyl-4-phenoxybenzoic acid ethyl ester (Example D-7 b ') (3.05 g), N-bromosuccinamide (4.65 g) and benzyl peroxide (115 mg), carbon tetrachloride (40 ml) was added . The resulting mixture was refluxed for 16 hours under nitrogen. Insoluble matters are filtered off and concentrated. The oil is diluted with 10% ethyl acetate in hexanes (50 ml) and filtered through a layer of silica gel, washed twice with the same solvent mixture. The filtrate solution was concentrated to give 5 g of 2-dibromomethyl-4-phenoxybenzoic acid ethyl ester as an oil. ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.07 (s, 1H), 7.86 (d, J = 9 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H) 7.41 (d, J = 7.6, 2H), 7.21 (m, 1H), 7.08 (m, 2H), 6.86 (dd, J = 2.5, 8.7, 1H), 4.37 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H).

b ". 2-Formyl-4-phenoxybenzoic acid ethyl ester

Ethyl 2-dibromomethyl-4-phenoxybenzoic acid (2.07 g) was dissolved in tetrahydrofuran (40 ml) and water (15 ml). Silver nitrate (2.56 g) was added. The resulting mixture was heated at the boil under reflux for 5 hours. The precipitate was filtered off and the reaction mixture was diluted with ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined ethyl acetate layer was washed with saturated sodium bicarbonate, brine and dried over magnesium sulfate. After concentration, the crude oil was diluted with a mixture of 20% ethyl acetate in hexanes (100 ml) and filtered through a pad of silica gel. Additionally washed twice. The filtrate solution was concentrated to afford the title compound, 1.13 g as an oil. ¹ H NMR (200 MHz, CDCl ₃ ): δ 10.62 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.42-7.35 (m, 3H), 7.20-7.14 (m, 2H), 7.04 (d, J = 8.2, 2H), 4.41 (q, J = 7.0 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H).

c. "2- (Ethoxycarbonylmethyliminomethyl) -4-phenoxybenzoic acid ethyl ester

Anhydrous dichloromethane (2 ml) was added to a darkened flask with glycine ethyl ester hydrochloride (62 ml), followed by triethylamine (124 μl). Then magnesium sulfate (pre-dried under vacuum with a heat gun, 100 mg) is added, after which a solution of 2-formyl-4-phenoxybenzoic acid ethyl ester (120 mg) in dichloromethane (1 ml) is added. The flask with ethyl 2-formyl-4-phenoxybenzoic acid was further washed with 0.5 ml of dichloromethane. The resulting mixture was stirred at room temperature under nitrogen for 15 hours. The mixture is filtered and washed with dichloromethane. After removing the solvent, the reaction mixture was diluted with ether (15 ml) and washed twice with brine and dried. Filtration and removal of solvent gives the title compound (160 mg) as an oil with good purity. ¹ H NMR (200 MHz, CDCl ₃ ): δ 9.02 (d, J = 1.2.1H), 7.94 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 2.4.1H), 7.40-7.32 (m, 2H), 7.20-7.11 (m, 1H), 7.06-6.97 (m, 3H), 4.41 (s, 2H), 4.35 (q, J = 7.0 Hz, 2H), 4.21 (q, J = 7.4 Hz, 2H), 1.39 (t, J = 7.0 Hz , 3H), 1.28 (t, J = 7.0 Hz, 3H).

d ". 4-Hydroxy-7-phenoxyisoquinoline-3-carboxylic acid ethyl ester

Potassium tert-butoxide (47 mg) was dried using a high vacuum pump at approximately 90 ° C for more than 1 hour. Anhydrous tetrahydrofuran (1.4 ml) was added under nitrogen atmosphere, after which a solution of 2- (ethoxycarbonylmethyliminomethyl) -4-phenoxybenzoic acid ethyl ester (60 mg) in tetrahydrofuran (1.6 ml) and an additional 0.5 ml of tetrahydrofuran were added. The mixture turns orange red. After stirring at room temperature for 2.5 hours, the mixture was refluxed for another 2.5 hours and then the reaction was stopped with water (5 ml). Ethyl acetate (30 ml) was added. The organic phase is separated, washed with brine and dried. Removal of solvent gives 26 mg of the title compound as an oil with good purity. Spectrum ¹ H NMR (200 MHz, CDCl ₃ ): identical to the spectrum of Example D-7 e ′).

Example D-8

[(4-Hydroxy-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Bromo-4-hydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from dihydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ester of Example D-7 d) by a procedure analogous to that of Example D-1 e). ¹ H NMR (CDCl ₃ ): δ = 11.76 (s, 1H), 8.22 (d, 1H), 7.68 (d, 1H), 7.10-7.55 (m, 6H), 4.46 (t, 2H), 1.85 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).

b. 4-hydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from 1-bromo-4-hydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-7 f). ¹ H NMR (CDCl ₃ ): δ = 11.76 (s, 1H), 8.74 (s, 1H), 7.93 (d, 1H), 7.69 (d, 1H), 7.10- 7.52 (m, 6H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).

from. [(4-Hydroxy-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 4-hydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). ¹ H NMR (DMSO-d ₆ ): δ = 9.33 (t, 1H), 8.82 (s, 1H), 8.23 (d, 1H), 7.20-7.63 (m, 7H ), 4.01 (d, 2H).

Example D-9

[(1-Chloro-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Chloro-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from butyl ester of 1,4-dihydroxy-7-phenoxyisoquinoline-3-carboxylic acid of example D-7 d) by a method similar to that of example D-3 a). ¹ H NMR (CDCl ₃ ): δ = 11.90 (s, 1H), 8.37 (d, 1H), 7.10-7.64 (m, 7H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).

b. [(1-Chloro-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 1-chloro-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester according to a procedure similar to that of Example D-1 g). ¹ H NMR (DMSO-d ₆ ): δ = 9.16 (t, 1H), 8.36 (d, 1H), 7.23-7.72 (m, 7H), 4.01 (d, 2H )

Example D-10

[(1-Chloro-4-hydroxy-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Chloro-4-hydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from 1,4-dihydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ester of Example D-7 d) by a method similar to that of Example D-3 a). ¹ H NMR (CDCl ₃ ): δ = 11.77 (s, 1H), 8.25 (d, 1H), 7.69 (d, 1H), 7.10-7.55 (m, 6H), 4.47 (t, 2H), 1.85 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).

b. [(1-Chloro-4-hydroxy-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 1-chloro-4-hydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). ¹ H NMR (DMSO-d ₆ ): δ = 9.19 (t, 1H), 8.31 (d, 1H), 7.23-7.74 (m, 7H), 4.00 (d, 2H )

Example D-11

[(1-Bromo-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester of Example D-7 e) by a method similar to that of Example D-1 g). MS - (+) - ion: M + 1 = 417.0.

Example D-12

[(1-Bromo-4-hydroxy-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 1-bromo-4-hydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ester of Example D-8 a) by a method similar to that of Example D-1 g). MS - (-) - ion: M-1 = 414.9.

Example D-13

{[7- (2,6-Dimethylphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

but. 4- (2,6-Dimethylphenoxy) phthalic acid

Synthesized from 4- (2,6-dimethylphenoxy) phthalonitrile according to a procedure similar to that of Example D-1 a). ¹ H NMR (CDC1 ₃ ): δ = 7.89 (d, 1H), 7.19 (d, 1H), 7.08 (br s, 3H), 6.79 (m, 1H), 2, 10 (s, 6H).

b. [5- (2,6-Dimethylphenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid methyl ester

4- (2,6-Dimethylphenoxy) phthalic acid is reacted with glycine in a manner analogous to that of Example D-1 b). The crude product is reacted with methanol in a manner analogous to that of Example D-1 c). ¹ H NMR (CDCl ₃ ): δ = 7.80 (d, 1H), 7.09-7.17 (m, 5H), 4.40 (s, 2H), 3.76 (s, 3H), 2.11 (s, 6H).

from. 7- (2,6-Dimethylphenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

0.79 g of sodium (34 mmol) is dissolved in 100 ml of n-butanol with stirring. Then the temperature was raised to 95-100 ° C, 5.70 g of [5- (2,6-dimethylphenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid methyl ester ( 16.8 mmol) and stirring was continued at 95-100 ° C for 3 hours. Then the solvent was evaporated in vacuo, 25 ml of aqueous 2N was added. HCl and 100 ml of ethyl acetate and the mixture was stirred vigorously for 30 minutes, then filtered with suction. The organic phase is separated from the filtrate, dried over MgSO ₄ and evaporated in vacuo to give a brown gum which is triturated with methanol. The resulting precipitate was filtered by suction and dried in vacuo to give 870 mg of a yellowish oil (A). The filtrate was evaporated in vacuo, dissolved in a small amount of methanol and stored overnight in the refrigerator. The resulting precipitate was filtered by suction and dried in vacuo to give 246 mg of a yellowish solid (B). A and B are combined and purified by flash column chromatography on silica gel, eluting with dichloromethane: ethyl acetate (98: 2). Evaporation of the first fraction gives 762 mg of the title compound. ¹ H NMR (CDCl ₃ ): δ = 8.31 (br s, 1H), 8.12 (d, 1H), 7.60 (d, 1H), 7.35 (m, 1H), 7, 09 (br s, 3H), 4.39 (t, 2H), 2.11 (s, 6H), 1.77 (m, 2H), 1.44 (m, 2H), 0.99 (t , 3H).

d. 1-Bromo-7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from 7- (2,6-dimethylphenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester according to a procedure similar to that of Example D-1 e). ¹ H NMR (CDCl ₃ ): δ = 11.88 (s, 1H), 8.33 (m, 1H), 7.35-7.40 (m, 2H), 7.13-7.16 (m , 3H), 4.46 (t, 2H), 2.14 (s, 6H), 1.83 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).

e. 7- (2,6-Dimethylphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from 1-bromo-7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-7 f). ¹ H NMR (CDCl ₃ ): δ = 11.87 (s, 1H), 8.35 (s, 1H), 8.36 (d, 1H), 7.47 (dd, 1H), 7.14 ( m, 2H), 6.87 (d, 1H), 4.48 (t, 2H), 2.14 (s, 6H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).

f. {[7- (2,6-Dimethylphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Synthesized from 7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester according to the procedure for Example D-1 g). MS - (+) - ion: M + 1 = 367.1.

Example D-14

{[1-Chloro-7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

but. 1-chloro-7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from 7- (2,6-dimethylphenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester of Example D-13 c) by a method similar to that of Example D-3 a). ¹ H NMR (CDCl ₃ ): δ = 11.89 (s, 1H), 8.35 (d, 1H), 7.34-7.43 (m, 2H), 7.13-7.14 (m , 3H), 4.47 (t, 2H), 2.14 (s, 6H), 1.85 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).

b) {[1-Chloro-7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino}

acetic acid

Synthesized from 1-chloro-7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester according to the procedure for Example D-1 g). MS - (-) - ion: M-1 = 398.9.

Example D-15

{[1-Bromo-7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Synthesized from 1-bromo-7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester of Example D-13 d) by a method similar to that of Example D-1 g). MS - (-) - ion: M-1 = 442.9.

Example D-16

[(1-Bromo-7-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. (5-Chloro-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid

Synthesized by a method similar to that of example D-1 b), using 5-chloroisobenzofuran-1,3-dione as the starting material instead of the corresponding phthalic acid. ¹ H NMR (DMSO-d ₆ / D ₂ O): δ = 8.01 (s, 1H), 7.93 (s, 2H), 4.32 (s, 2H).

b. (5-Chloro-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid methyl ester

Synthesized from (5-chloro-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid in a manner analogous to that of Example D-1 c). ¹ H NMR (CDCl ₃ ): δ = 7.67-7.86 (m, 3H), 4.43 (s, 2H), 3.76 (s, 3H).

from. 7-chloro-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ether (A) and 6-chloro-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ether (B)

Synthesized from (5-chloro-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid methyl ester according to a similar manner to that of Example D-1 d) (pure compound B was obtained by recrystallization from chloroform after chromatography). ¹ H NMR (CDCl ₃ ): δ = 8.46 (br s, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.73 (dd, 1H), 4, 41 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 1.00 (t, 3H). B: ¹ H NMR (CDCl ₃ ): δ = 8.34-8.38 (m, 2H), 8.12 (d, 1H), 7.64 (dd, 1H), 4.42 (t, 2H ), 1.77 (m, 2H), 1.46 (m, 2H), 1.00 (t, 3H).

d. 1-Bromo-7-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from 7-chloro-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ether according to a procedure analogous to that of Example D-1 e). ¹ H NMR (CDCl ₃ ): δ = 11.92 (s, 1H), 8.34 (d, 1H), 8.25 (d, 1H), 7.75 (dd, 1H), 4.49 ( t, 2H), 1.86 (m, 2H), 1.48 (m, 2H), 1.00 (t, 3H).

e. [(1-Bromo-7-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 1-bromo-7-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester according to a procedure similar to that of Example D-1 g). MS - (-) - ion: M-1 = 356.8.

Example D-17

[(1-Bromo-6-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Bromo-6-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from butyl ether 6-chloro-1,4-dihydroxyisoquinoline-3-carboxylic acid of example D-16 c) by a method similar to that of example D-1 e). ¹ H NMR (CDCl ₃ ): δ = 11.88 (s, 1H), 8.37 (d, 1H), 8.19 (d, 1H), 7.75 (dd, 1H), 4.49 ( t, 2H), 1.86 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).

b. [(1-Bromo-6-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 1-bromo-6-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester according to a procedure similar to that of Example D-1 g). MS - (-) - ion: M-1 = 356.9.

Example D-18

[(1-Bromo-4-hydroxy-7-trifluoromethylisoquinoline-3-carbonyl) amino] acetic acid

but. (1,3-dioxo-5-trifluoromethyl-1,3-dihydroisoindol-2-yl) acetic acid methyl ester

4-Trifluoromethylphthalic acid is reacted with glycine in a manner analogous to that of Example D-1 b). The crude product is then reacted with methanol in a manner analogous to that of Example D-1 c). ¹ H NMR (CDCl ₃ ): δ = 8.14 (s, 1H), 8.02 (m, 2H), 4.48 (s, 2H), 3.78 (s, 3H).

b. 1,4-dihydroxy-7-trifluoromethylisoquinoline-3-carboxylic acid butyl ether (A) and 1,4-dihydroxy-6-trifluoromethylisoquinoline-3-carboxylic acid butyl ether (B)

Synthesized from methyl ester (1,3-dioxo-5-trifluoromethyl-1,3-dihydroisoindol-2-yl) acetic acid in a manner analogous to that of Example D-1 d). ¹ H NMR (CDCl ₃ ): δ = 10.47 (br s, 1H), 8.76 (br s, 1H), 8.72 (d, 1H), 8.29 (m, 1H), 7.99 (m, 1H), 4.45 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 1.00 (t, 3H). B: ¹ H NMR (CDCl ₃ ): δ = 10.48 (br s, 1H), 8.44-8.57 (m, 3H), 7.91 (d, 1H), 4.44 (t , 2H), 1.77 (m, 2H), 1.46 (m, 2H), 1.01 (t, 3H).

from. 1-Bromo-4-hydroxy-7-trifluoromethylisoquinoline-3-carboxylic acid butyl ester

Synthesized from 1,4-dihydroxy-7-trifluoromethylisoquinoline-3-carboxylic acid butyl ether according to a procedure analogous to that of Example D-1 e). ¹ H NMR (CDCl ₃ ): δ = 11.96 (s, 1H), 8.52-8.56 (m, 2H), 7.99 (dd, 1H), 4.51 (t, 2H), 1.86 (m, 2H), 1.48 (m, 2H), 1.00 (t, 3H).

d. [(1-Bromo-4-hydroxy-7-trifluoromethylisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 1-bromo-4-hydroxy-7-trifluoromethylisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (-) - ion: M-1 = 391.0.

Example D-19

[(1-Bromo-4-hydroxy-6-trifluoromethylisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Bromo-4-hydroxy-6-trifluoromethylisoquinoline-3-carboxylic acid butyl ester

Synthesized from 1,4-dihydroxy-6-trifluoromethylisoquinoline-3-carboxylic acid butyl ester of Example D-18 b) in a manner analogous to that of Example D-1 e). MS - (-) - ion: M-1 = 390.3.

b. [(1-Bromo-4-hydroxy-6-trifluoromethylisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 1-bromo-4-hydroxy-6-trifluoromethylisoquinoline-3-carboxylic acid butyl ether according to a procedure analogous to that of Example D-1 g). MS - (-) - ion: M-1 = 390.9.

Example D-20

[(4-Hydroxy-1-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

but. (1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid methyl ester

Synthesized from (1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid in a manner analogous to that of Example D-1 c). ¹ H NMR (CDCl ₃ ): δ = 7.84-7.91 (m, 2H), 7.71-7.77 (m, 2H), 4.45 (s, 2H), 3.77 (s , 3H).

b. 1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from (1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid methyl ester according to a procedure analogous to that of Example D-1 d). (The solvent is not evaporated before the addition of hydrochloric acid, ethyl acetate is not added). ¹ H NMR (DMSO-d ₆ ): δ = 10.66 (br s, 1H), 10.55 (br s, 1H), 8.27 (d, 1H), 8.08 (d, 1H) ), 7.72-7.92 (m, 2H), 4.33 (t, 2H), 1.74 (m, 2H), 1.44 (m, 2H), 0.93 (t, 3H) .

from. 1-Chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from 1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester according to a procedure similar to that of Example D-3 a). ¹ H NMR (CDCl ₃ ): δ = 11.91 (s, 1H), 8.41 (m, 1H), 8.29 (m, 1H), 7.83 (m, 2H), 4.49 ( t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).

d. 4-hydroxy-1-phenoxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 1.399 g of 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (5 mmol) and 2.86 g of phenol are heated at 145-150 ° C. for 24 hours. After cooling to room temperature, the mixture was suspended in 50 ml of 2N. aqueous NaOH and the mixture was extracted with ethyl acetate (4x25 ml). The combined organic phases are washed with 2N aqueous solution. NaOH (3x25 ml), 50 ml of brine, dried over MgSO ₄ and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of hexanes: ethyl acetate (9: 1) and (95: 5). 0.650 g of the title compound are obtained. ¹ H NMR (CDCl ₃ ): δ = 11.52 (s, 1H), 8.32-8.39 (m, 2H), 7.72-7.86 (m, 2H), 7.13-7 42 (m, 5H), 4.31 (t, 2H), 1.69 (m, 2H), 1.37 (m, 2H), 0.93 (t, 3H).

e. [(4-Hydroxy-1-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 4-hydroxy-1-phenoxyisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (+) - ion: M + 1 = 339.1.

Example D-21

[(1,7-Dibromo-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. Ethyl ether (5-bromo-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid

Bromophthalimide (35 g, 155 mmol) and bromoethyl acetate (31 g, 186 mmol) are dissolved in 700 ml of acetone. Potassium carbonate (64.2 g, 465 mmol) was added and the resulting suspension was stirred at reflux for 18 hours. After cooling, the mixture is filtered. The filtrate was evaporated to obtain 48.12 g (154 mmol) of solid product. ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.00 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 4.41 (s, 2H), 4.21 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H).

b. 6- and 7-bromo-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Sodium (10.45 g) was dissolved in 460 ml of n-butanol with heating (45-50 ° C). The ester described above (68 g, 218 mmol) was dissolved in 460 ml of n-butanol (heated to homogeneity) and then added to the sodium solution. The combined mixture was stirred mechanically at 75 ° C for 1 hour. The mixture was stopped heating and stirred at room temperature overnight. The solution was acidified using 2N. HCl to pH ~ 3. The precipitate was collected by vacuum filtration and washed with water and then with methanol to obtain 59.4 g (175 mmol) of the product as a mixture of two isomers.

c. 7-Bromo-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

The above-described mixture of isomers (10 g) was subjected to flash chromatography on silica gel, eluting with a mixture of 10% ethyl acetate in methylene chloride to give 3 g of the product as a white solid. MS - (+) - ion: M + 1 = 342.02, 340.02.

d. 1,7-Dibromo-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

The above ester (2.4 g, 7.1 mmol) was dissolved in 150 ml of anhydrous acetonitrile. Phosphorus oxybromide (14.1 g, 49.4 mmol) was added. The mixture was stirred at reflux for 3 hours. After cooling, the reaction mixture was concentrated, the residue was taken up in ethyl acetate. The ethyl acetate mixture was poured into saturated sodium bicarbonate solution with effective stirring. The two phases are separated. The organic phase was dried over magnesium sulfate, filtered and concentrated to give 2 g (5.0 mmol) of product. MS - (+) - ion: M + 1 = 403.90.

e. [(1,7-Dibromo-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

The above ester (0.2 g, 0.5 mmol) was dissolved in 5 ml of ethanol. Glycine (0.24 g, 9.9 mmol) and sodium ethoxide (0.34 g, 5 mmol) are added to the solution. The mixture was stirred at reflux for 3 days. The mixture is evaporated. The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified using 1N. an aqueous solution of HCl to pH = 3-4, then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 0.17 g of the product as a white solid. ¹ H NMR (200 MHz, DMSO-d ₆ ): δ 9.26 (t, J = 6.2 Hz, 1H), 8.32 (d, J = 1.6 Hz, 1H), 8.23 ( d, J = 9.0 Hz, 1H), 8.11 (dd, J = 9.0, 1.6 Hz, 1H), 4.02 (d, J = 6.2 Hz, 2H).

Example D-22

[(7-Bromo-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. 7-Bromo-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

170 mg (0.5 mmol) of 7-bromo-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester are dissolved in 2 ml of anhydrous acetonitrile (Example D-21 c). Phosphorus oxychloride (536 mg, 3.5 mmol) was added and the resulting mixture was stirred at reflux for 4 hours. After cooling, the mixture was concentrated, the residue was taken up in ethyl acetate. The ethyl acetate mixture was poured into saturated sodium bicarbonate solution with effective stirring for 1 hour. The two phases are separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel chromatography, eluting with methylene chloride. 78 mg of product is obtained as a white solid. MS - (+) - ion: M + 1 = 359.96, 357.98.

b. [(7-Bromo-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

The above ester (75 mg, 0.21 mmol) was reacted with glycine (314 mg, 4.18 mmol) and sodium ethoxide (143 mg, 2.09 mmol) in a manner analogous to Example D-21 e). 58 mg of product are obtained. ¹ H NMR (200 MHz, CD ₃ OD): δ 8.44 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 9.0 Hz, 1H), 8.00 (dd , J = 9.0, 1.6 Hz, 1H); 4.17 (s, 2H).

Example D-23

[(6-Bromo-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. 6-Bromo-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

2.58 g (6.40 mmol) of 6- and 7-bromo-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester are dissolved in 30 ml of glacial acetic acid (Example D-21 b). A suspension of palladium (10% in activated carbon) in 10 ml of glacial acetic acid is added. The mixture is stirred in a hydrogen atmosphere (cylinder pressure) for 2 hours. The catalyst is filtered off through a pad of celite and washed with methylene chloride. The filtrate was concentrated, the residue was triturated with methylene chloride. The insoluble solid is filtered off and subjected to silica gel column chromatography, eluting with hexanes: ethyl acetate (3: 1), and 192 g of product are obtained. MS - (-) - ion: M-1 = 324.11, 322.13.

b. [(6-Bromo-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

The above ester (178 mg, 0.55 mmol) was reacted with glycine (1.23 g, 16.43 mmol) and sodium ethoxide (746 mg, 10.96 mmol) according to the procedure for Example D-12 e. The resulting product triturated with 30 ml of methanol, 58 mg of product are obtained. ¹ H NMR (200 MHz, CD ₃ OD): δ 8.72 (s, 1H), 8.46 (s, 1H), 7.98 (d, J = 8.8 Hz), 7.86 (d , J = 8.8 Hz, 1H), 4.14 (s, 2H).

Example D-24

[(1-Bromo-7-fluoro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. (5-Fluoro-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid methyl ester

A solid mixture of 5-fluoroisobenzofuran-1,3-dione (3.68 g, 22.15 mmol) and glycine (1.66 g, 22.15 mmol) was stirred at 200-220 ° C for 5 minutes. After cooling, the mixture was dissolved in 25 ml of acetone. Methyl sulfate (4.19 g, 33.23 mmol) and potassium carbonate (4.49 g, 33.23 mmol) are added. The mixture was stirred at reflux for 2 hours. After cooling, the mixture was diluted with 100 ml of ethyl acetate. Insoluble components are filtered off and the filtrate is concentrated. The residue was taken up in 200 ml of ethyl acetate and washed with water and brine. The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated to give 5.1 g of product. ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.88 (dd, J = 8.2, 4.3 Hz, 1H), 7.54 (dd, J = 6.8, 2.2 Hz, 1H ), 7.40 (m, 1H), 4.44 (s, 2H), 3.77 (s, 3H).

b. 7-Fluoro-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ether (A) and 6-fluoro-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ether (B)

The ester described above 3.0 g (12.66 mmol) is treated by a method similar to that of Example D-21 b) at 95-100 ° C for 2 hours, 2.5 g of product are obtained as a mixture of isomers. Isomeric mixtures were purified by silica gel chromatography, eluting with 5-20% ethyl acetate in methylene chloride. The first fraction was concentrated and recrystallized from 60 ml of ethanol to obtain 268 mg of solid product (A). The second fraction was concentrated to give 313 mg of solid product (B). For product A MS - (-) - ion: M-1 = 278.02. For product B MS - (-) - ion: M-1 = 278.03.

The difference between isomers A and B can be determined on silica gel plates for TCS using a mixture of 10% ethyl acetate in methylene chloride. A: R _f = about 0.79; B: R _f = about 0.53.

from. 1-Bromo-7-fluoro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

The above-described ether (A) (250 mg, 0.90 mmol) was brominated according to a procedure similar to that of Example D-21 d) (a mixture of 10% methanol in methylene chloride was used instead of ethyl acetate) to obtain 156 mg of a solid product. MS - (+) - ion: M + 1 = 344.00, 341.99.

d. [(1-Bromo-7-fluoro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

The ester described above (60 mg, 0.18 mmol) was reacted with glycine in a manner analogous to that of Example D-21 e). The reaction time is 48 hours. A mixture of 10% methanol in methylene chloride is used to extract the product. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 50 mg of product. MS - (-) - ion: M-1 = 343.02, 340.92. ¹ H NMR (200 MHz, acetone-d ₆ ): δ 13.56 (s, 1H), 8.81 (br s, 1H), 8.43 (dd, J = 9.0, 5.4 Hz , 1H), 7.79 (m, 2H), 4.29 (d, J = 6.2 Hz, 2H).

Example D-25

[(7-Fluoro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

In 5 ml of a mixture of methanol: water (4: 1), 42 mg (0.12 mmol) of the carboxylic acid described above are dissolved. Sodium carbonate (13 mg, 0.12 mmol) and palladium (wet, 10% dry matter on activated carbon) (40 mg) are added. The mixture is stirred in a hydrogen atmosphere (cylinder pressure) for 2 hours. The catalyst is filtered off through a pad of celite, washed with 10 ml of a mixture of methanol: water (4: 1) and then with 2 ml of water. The filtrate was concentrated to remove most of the methanol and acidified with 1N. HCl to pH = 3-4. The precipitate was filtered off and dried under high vacuum to obtain 14 mg of product. MS - (-) - ion: M-1 = 262.99. ¹ H NMR (200 MHz, CD ₃ OD): δ 8.69 (s, 1H), 8.38 (dd, J = 9.0, 5.5 Hz, 1H), 7.24 (dd, J = 9.3, 2.4 Hz, 1H), 7.60 (m, 1H), 4.14 (s, 2H).

Example D-26

[(1-Chloro-7-fluoro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. 1-chloro-7-fluoro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

135 mg (0.48 mmol) of 7-fluoro-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester are dissolved in 3 ml of anhydrous acetonitrile (product A, example D-24 b). Phosphorus oxychloride (1.24 g, 8.07 mmol) is added. The mixture was stirred at reflux for 6 hours. After cooling, the mixture was concentrated and suspended in 10 ml of a saturated aqueous solution of sodium bicarbonate. Stirred for 1 hour and extracted with 5% methanol in methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography, eluting with methylene chloride, to obtain 58 mg of product. MS - (-) - ion: M-1 = 296.12.

b. [(1-Chloro-7-fluoro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

The above ester (55 mg, 0.19 mmol) was reacted with glycine in a manner analogous to Example D-21 e). After acidification, the reaction mixture was extracted with 10% methanol in methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative TLC with a mixture of 10% methanol in methylene chloride to give 6 mg of product. ¹ H NMR (200 MHz, acetone-d ₆ ): δ 13.59 (s, 1H), 8.90 (br s, 1H), 8.47 (dd, J = 9.0, 5.1 Hz , 1H), 7.94 (dd, J = 9.7, 2.4 Hz, 1H), 7.81 (m, 1H), 4.28 (d, J = 6.2 Hz, 2H).

Example D-27

[(1-Chloro-4-hydroxybenzo [g] isoquinoline-3-carbonyl) amino] acetic acid

but. Ethyl (1,3-dioxo-1,3-dihydrobenzo [f] isoindol-2-yl) acetic acid

Benzo [f] isoindole-1,3-dione (2 g, 10.1 mmol) was reacted with ethyl bromoacetic acid in a manner analogous to that of Example D-21 a). The resulting crude product was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give 2.68 g (9.5 mmol) of product. ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.36 (s, 2H), 8.05 (m, 2H), 7.68 (m, 2H), 4.49 (s, 2H), 4, 22 (q, J = 7.0 Hz, 2H), 1.29 (t, 7.0 Hz, 3H).

b. 1,4-dihydroxybenzo [g] isoquinoline-3-carboxylic acid butyl ester

The isoindole ester described above (2.6 g, 9.2 mmol) was treated in a similar manner to that of Example D-21 b) to give 1.23 g (3.9 mmol) of product. ¹ H NMR (200 MHz, CDCl ₃ ): δ 10.73 (br s, 1H), 9.00 (s, 1H), 8.68 (s, 1H), 8.24 (br s, 1H ), 8.06 (m, 2H), 7.68 (m, 2H), 4.24 (t, J = 6.6 Hz, 2H), 1.80 (m, 2H), 1.47 (m , 2H), 1.00 (t, J = 7.4 Hz, 3H).

from. 1-Chloro-4-hydroxybenzo [g] isoquinoline-3-carboxylic acid butyl ester

The above-described ether (1 g, 3.2 mmol) was reacted with 5 ml of phosphorus oxychloride according to a procedure similar to that of Example D-22 a), without using acetonitrile as a co-solvent, 0.88 g (2.7 mmol) was obtained product. ¹ H NMR (200 MHz, CDCl ₃ ): δ 12.24 (s, 1H), 8.97 (s, 1H), 8.85 (s, 1H), 8.12 (m, 2H), 7, 70 (m, 2H), 4.51 (t, J = 7.0 Hz, 2H), 1.89 (m, 2H), 1.56 (m, 2H), 1.00 (t, J = 7 , 2 Hz, 3H).

d. [(Chloro-4-hydroxybenzo [g] isoquinoline-3-carbonyl) amino] acetic acid

The ester described above (0.88 g, 2.7 mmol) was reacted with glycine by a method similar to that of Example D-21 e). The resulting precipitate, after acidification, is filtered off and dried under high vacuum to give 0.30 g (0.9 mmol) of product. ¹ H NMR (200 MHz, DMSO-d ₆ ): δ 9.34 (br s, 1H), 9.00 (s, 1H), 8.92 (s, 1H), 8.34 (m, 2H ), 7.74 (m, 2H), 3.94 (d, J = 5.4 Hz, 2H).

Example D-28

[(1-Bromo-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Bromo-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

1,4-Dihydroxyisoquinoline-3-carboxylic acid butyl ester (2 g, 7.7 mmol) (Example D-20b) was dissolved in 100 ml of acetonitrile. Phosphorus oxybromide (15.4 g, 53.6 mmol) was added to the solution, and the mixture was stirred at 80 ° C. for 64 hours. 100 ml of water was added to the mixture and the mixture was stopped heating. The mixture was partitioned between ethyl acetate and water. The two phases are separated and the aqueous layer is extracted with ethyl acetate. The organic layers are combined, washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel to give 0.1 g (0.3 mmol) of product. ¹ H NMR (200 MHz, CDCl ₃ ): δ 11.89 (s, 1H), 8.41 (m, 1H), 8.25 (m, 1H), 7.84 (m, 2H), 4, 49 (t, J = 7.0 Hz, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H).

b. [(1-Bromo-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

The above-described isoquinoline ether (0.3 mmol) was reacted with glycine according to a procedure similar to that of Example D-21 e), 0.08 g (0.2 mmol) of product was obtained. ¹ H NMR (200 MHz, CD ₃ OD): δ 8.94 (br s, 1H), 8.34 (m, 1H), 8.24 (m, 1H), 7.86 (m, 2H) 4.18 (d, J = 6.2 Hz, 2H).

Example D-29

[(4-Hydroxy-6-phenylisoquinoline-3-carbonyl) amino] acetic acid

The title compound is prepared from [(1-chloro-4-hydroxy-6-phenylisoquinoline-3-carbonyl) amino] acetic acid (Example D-33) by a method similar to that described in detail in Example D-37. The final product is purified by silica gel chromatography using a gradient of 0 to 15% methanol in dichloromethane with 0.5% acetic acid to elute the target product. MS - (-): m / z 321.00 (M-1).

Example D-30

[(4-Hydroxy-7-phenylisoquinoline-3-carbonyl) amino] acetic acid

The title compound is prepared from [(1-chloro-4-hydroxy-7-phenylisoquinoline-3-carbonyl) amino] acetic acid (Example D-34) by a method similar to that described in detail in Example D-37. The final product is purified by silica gel chromatography using a gradient of 0 to 15% methanol in dichloromethane with 0.5% acetic acid to elute the target product. MS - (-): m / z 321.02 (M-1).

Example D-31

[(1-Chloro-4-hydroxy-6-phenylisoquinoline-3-carbonyl) amino] acetic acid

but. Methyl ester (5-bromo-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid

50.3 g of 4-bromophthalimide, 92.0 g of potassium carbonate and 24.5 ml of methyl bromoacetate are added to 888 ml of acetone. The resulting mixture was heated at the boiling point under reflux for 24 hours, and then cooled to room temperature. The mixture was filtered through a fine Schott glass filter to remove all solid material, and then the solution was concentrated in vacuo to give 66 g of the expected product as a white solid. ¹ H NMR (CDCl ₃ ): δ = 3.76 (s, 3H), 4.43 (s, 2H), 7.71-7.75 (m, 1H), 7.85-7.90 (dd , 1H); 8.00 (m, 1H).

b. (1,3-dioxo-5-phenyl-1,3-dihydroisoindol-2-yl) acetic acid methyl ester

6.0 g of bromphthalimide described above are dissolved in 70 ml of ethylene glycol dimethyl ether. 3.7 g of phenylboronic acid, 13 g of cesium carbonate and 2 g of tetrakis (triphenylphosphine) palladium (0) are added to the solution. The mixture was stirred under nitrogen at 65 ° C. for 48 hours. The resulting mixture was poured into 250 ml of a half-saturated aqueous sodium bicarbonate solution and then extracted with 200 ml portions of ethyl acetate three times. The resulting organic fractions were washed successively with 200 ml of water, saturated sodium bicarbonate solution and brine, and then dried over sodium sulfate. The solution was concentrated to a residue (11 g), which was purified by silica gel chromatography using a gradient of 0 to 25% ethyl acetate in hexanes to elute the target product. 1.1 g of purified product are obtained. MS - (+) m / z 296.02 (M + 1).

c. 1,4-Dihydroxy-7-phenylisoquinoline-3-carboxylic acid butyl ether (A) and 1,4-dihydroxy-6-phenylisoquinoline-3-carboxylic acid butyl ether (B)

To 18.8 ml 0.5n. a solution of n-butoxide sodium in n-butanol add 1.4 g of the product described above. The resulting mixture was heated at 100 ° C for 2 hours, and then cooled to room temperature. The mixture is poured into 100 ml of 0.5N. aqueous hydrochloric acid and extracted with portions of ethyl acetate in 100 ml three times. The combined organic extracts are filtered to remove any insoluble material and then washed successively with water and brine. The solution was dried over sodium sulfate and concentrated in vacuo to a residue (1.1 g), which was purified by silica gel chromatography using a gradient of 0 to 20% ethyl acetate in dichloromethane to elute the two main products (R _f isomer A = 0.64, R _f isomer B = 0.48; 15% ethyl acetate: 85% dichloromethane).

Isomer A: 397 mg. MS - (+) m / z 388.11 (M + 1).

Isomer B: 195 mg. MS - (+) m / z 388.10 (M + 1).

d. 1-Chloro-4-hydroxy-6-phenylisoquinoline-3-carboxylic acid butyl ester

The title compound is prepared using isomer B described above, 1,4-dihydroxy-6-phenylisoquinoline-3-carboxylic acid butyl ester under conditions similar to those described in detail in Example D-39 d). MS - (+) m / z 356.06 (M + 1).

e. [(1-Chloro-4-hydroxy-6-phenylisoquinoline-3-carbonyl) amino] acetic acid

The title compound is prepared as follows: 95 mg of the ester described above and 300 mg of glycine are suspended in a solution of 5.4 ml of 0.5N. a solution of sodium methoxide in methanol. The mixture was refluxed for 42 hours and then cooled to room temperature. The mixture was diluted with 30 ml of aqueous bicarbonate and washed with 30 ml of ethyl acetate. The aqueous solution is acidified to pH 3 6n. aqueous hydrochloric acid and then extracted with ethyl acetate in portions of 35 ml three times. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 73 mg of the expected product, a white solid. MS - (-) m / z 354.99 (M-1).

Example D-32

[(1-Chloro-4-hydroxy-7-phenylisoquinoline-3-carbonyl) amino] acetic acid

The title compound is prepared from 1,4-dihydroxy-7-phenylisoquinoline-3-carboxylic acid butyl ester, Example D-33 c), Isomer A, by procedures similar to those described in detail in Examples D-39 d) and D-39 e).

1-Chloro-4-hydroxy-7-phenylisoquinoline-3-carboxylic acid butyl ester. MS - (+) m / z 356.09 (M + 1).

[(1-Chloro-4-hydroxy-7-phenylisoquinoline-3-carbonyl) amino] acetic acid. MS - (-) m / z 355.01 (M-1).

Example D-33

[(1-Bromo-4-hydroxy-6-phenylisoquinoline-3-carbonyl) amino] acetic acid

1,4-Dihydroxy-6-phenylisoquinoline-3-carboxylic acid butyl ester (161 mg), Example D-33 c, Isomer B, is suspended in 3 ml of anhydrous acetonitrile. 896 mg of phosphorus oxybromide was added and the mixture was refluxed for 5 hours. The mixture was cooled to room temperature, concentrated to a residue under reduced pressure, and suspended in a mixture of 40 ml of ethyl acetate and 40 ml of a semi-saturated aqueous sodium bicarbonate solution. The biphasic mixture was rapidly stirred for 10 minutes and then extracted with 40 ml portions of ethyl acetate three times. The combined organic extracts were concentrated in vacuo and purified by silica gel chromatography using a gradient of 0-5% ethyl acetate in dichloromethane to elute one major fraction. 26 mg of material is isolated and used directly in the next reaction.

The resulting residue and 58 mg of glycine are suspended in a solution of 1.4 ml of 0.5N. a solution of sodium methoxide in methanol. The mixture was refluxed for 18 hours, then cooled to room temperature and concentrated to approximately 0.5 ml under reduced pressure. The mixture was diluted with 30 ml of water and acidified to pH 3 6N. aqueous hydrochloric acid. The resulting precipitate was collected and washed with cold water twice. The solid was dried in vacuo to give 16 mg of the expected product. MS - (-) m / z 398.90, 400.92 (M-1, M + 1; Br isotopes).

Example D-34

[(1-Bromo-4-hydroxy-7-phenylisoquinoline-3-carbonyl) amino] acetic acid

The title compound is prepared from 1,4-dihydroxy-7-phenylisoquinoline-3-carboxylic acid butyl ester, Example D-33 c), Isomer A, using conditions similar to those described in detail in Example D-35. The final product is purified by silica gel column chromatography using a gradient of 0 to 10% methanol in dichloromethane with 0.5% acetic acid to elute the target product. MS - (-) m / z 389.91, 400.95 (M-1, M + 1; Br isotopes).

Example D-35

[(4-Hydroxy-5-phenylisoquinoline-3-carbonyl) amino] acetic acid

[(1-Chloro-4-hydroxy-5-phenylisoquinoline-3-carbonyl) amino] acetic acid (200 mg) (Example D-39 e) was suspended in a solution of 12 ml of MeOH and 4 ml of water. 45 mg of sodium carbonate and 100 mg of palladium, 10% on activated carbon are added, and the mixture is stirred for 18 hours in an atmosphere of hydrogen created by hydrogen from the balloon. The resulting mixture was diluted with methanol and aqueous sodium bicarbonate and then filtered through a pad of celite. The solution was concentrated under reduced pressure to approximately 6 ml, then diluted with 30 ml of a semi-saturated sodium bicarbonate solution and then acidified to pH 3 with concentrated aqueous hydrochloric acid. The aqueous solution was extracted with ethyl acetate in 30 ml portions three times. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to obtain 107 mg of the expected product as a white solid. MS - (+) m / z 323.08 (M + 1).

Example D-36

[(4-Hydroxy-8-phenylisoquinoline-3-carbonyl) amino] acetic acid

The title compound is obtained from [(1-chloro-4-hydroxy-8-phenylisoquinoline-3-carbonyl) amino] acetic acid, Example D-40, using conditions similar to those described in detail in Example D-37. MS - (+) m / z 323.06 (M + 1).

Example D-37

[(1-Chloro-4-hydroxy-5-phenylisoquinoline-3-carbonyl) amino] acetic acid

but. Biphenyl-2,3-dicarboxylic acid

15 g of 2-methyl-3-biphenylmethanol and 75 mg of cetyltrimethylammonium bromide were added to 150 ml of water, and the resulting mixture was cooled to 0 ° C in an ice bath. To the cooled mixture was added 48 g of potassium permanganate and the reaction mass was stirred at 0 ° C for 10 min, at room temperature for 16 hours, then at 70 ° C for 48 hours. A clear solution containing a black solid is filtered through a pad of celite and washed with 100 ml of dichloromethane. The aqueous solution is then acidified to pH 3 with 6n. aqueous hydrochloric acid and extracted four times with 150 ml portions of ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate and concentrated to 12.9 g of product. ¹ H NMR (d ₆ -DMSO): δ = 7.28-7.46 (m, 5H), 7.51-7.61 (m, 2H), 7.84-7.89 (dd, 1H) 13.0 (s, 2H).

b. (1,3-dioxo-4-phenyl-1,3-dihydroisoindol-2-yl) acetic acid methyl ester

The diacid described above (10.5 g) and 3.25 g of glycine are mixed with a mortar and pestle and then heated in an oil bath, maintaining it at a temperature of 210-230 ° for 15 minutes. The mixture was cooled and the resulting solid was used directly in the next reaction.

To a solution of the crude phthalimide product from the above reaction in 125 ml of acetone was added 7.4 g of potassium carbonate and 5.7 ml of methyl sulfate. The mixture is heated at the boil under reflux for 24 hours and then cooled to room temperature. The mixture was diluted with 500 ml of water and extracted with 500 ml of ethyl acetate three times. The combined organic fractions were washed with brine and dried over sodium sulfate. The solution was concentrated and the resulting solid was crystallized from ethyl acetate to give 5.0 g of a light yellow solid. ¹ H NMR (CDCl ₃ ): δ = 3.74 (s, 3H), 4.40 (s, 2H), 7.91-7.43 (m, 8H).

from. 1,4-dihydroxy-8-phenylisoquinoline-3-carboxylic acid butyl ether (A) and 1,4-dihydroxy-5-phenylisoquinoline-3-carboxylic acid butyl ether (B)

K 68.8 ml 0.5N a solution of n-butoxide sodium in n-butanol add 5.07 g of the product described above. The resulting mixture was heated to 95 ° C for 4 hours and then cooled to room temperature. 2.1 ml of acetic acid was added and the mixture was concentrated under reduced pressure to approximately 15 ml. The crude product was diluted with a half-saturated sodium bicarbonate solution and extracted with ethyl acetate three times. The combined organic fractions are washed with water, then with brine and dried over sodium sulfate. The solution was concentrated and the residue (5.3 g) was purified by silica gel chromatography using a gradient of 0 to 25% ethyl acetate in dichloromethane to elute the two main fractions (R _f isomer A = 0.68, R _f isomer B = 0.52, 15 % ethyl acetate: 85% dichloromethane).

Isomer A: 2.19 g. MS - (+) m / z 338.15 (M + 1).

Isomer B: 1.22 g. MS - (+) m / z 388.04 (M + 1).

d. 1-Chloro-4-hydroxy-5-phenylisoquinoline-3-carboxylic acid butyl ester

500 mg of isomer B described above are suspended in 5 ml of phosphorus oxychloride and heated at 100 ° C. for 1 hour. The reaction mixture was cooled, concentrated to a residue under reduced pressure, and then diluted with 30 ml of water and 30 ml of ethyl acetate with rapid stirring. The pH of the aqueous phase is checked and adjusted to approximately 7 by adding sodium bicarbonate. The biphasic mixture was stirred for 30 minutes and extracted with 30 ml of ethyl acetate 3 times. The combined organic fractions were washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate. The solution was concentrated under reduced pressure, the residue (494 mg) was purified by silica gel chromatography using a gradient of 5 to 20% ethyl acetate in dichloromethane to elute one major fraction. 442 mg of product is obtained. MS - (+) m / z 355.99 (M + 1).

e. [(1-Chloro-4-hydroxy-5-phenylisoquinoline-3-carbonyl) amino] acetic acid

In 24.4 ml of 0.5n. a solution of sodium methoxide in methanol is suspended 435 mg of the above ester and 1.0 g of glycine. The mixture was heated at the boil under reflux for 18 hours, then cooled to room temperature and concentrated to approximately 5 ml under reduced pressure. The mixture was diluted with 50 ml of water and acidified to pH 3 with 1N. aqueous hydrochloric acid. The resulting precipitate was collected and washed with cold water twice. The solid was dried in vacuo to give 414 mg of product. MS - (+) m / z 356.99 (M + 1).

Example D-38

[(1-Chloro-4-hydroxy-8-phenylisoquinoline-3-carbonyl) amino] acetic acid

The title compound is prepared from 1,4-dihydroxy-8-phenylisoquinoline-3-carboxylic acid butyl ester, Example D-39 c), Isomer A, using conditions analogous to the conditions described in detail in Examples D-39 d) and D- 39 e).

1-chloro-4-hydroxy-8-phenylisoquinoline-3-carboxylic acid butyl ester; MS - (+) m / z 356.05 (M + 1).

[(1-Chloro-4-hydroxy-8-phenylisoquinoline-3-carbonyl) amino] acetic acid; MS - (+) m / z 356.99 (M + 1).

Example D-39

[(1-Bromo-4-hydroxy-5-phenylisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Bromo-4-hydroxy-5-phenylisoquinoline-3-carboxylic acid butyl ester

In 15 ml of anhydrous acetonitrile, 411 mg of 1,4-dihydroxy-5-phenylisoquinoline-3-carboxylic acid butyl ester was suspended (Example D-39 c), isomer B). Phosphorus oxybromide 2.0 g was added and the reaction mixture was heated at the boil under reflux for 3.5 hours. The reaction mixture is cooled and poured into 75 ml of a saturated aqueous solution of sodium bicarbonate, cooled to 0 ° C. The mixture was stirred for 5 minutes and then extracted with ethyl acetate in 75 ml portions three times. The combined organic fractions were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue (434 mg) was purified by silica gel chromatography using a gradient of 0 to 25% ethyl acetate in hexanes to elute the product as one main fraction. Get 480 mg of the target product. MS - (+) m / z 422.02 (M + 23).

b. [(1-Bromo-4-hydroxy-5-phenylisoquinoline-3-carbonyl) amino] acetic acid

The title compound is prepared as follows. In 10 ml of 0.5n. a solution of sodium methoxide in methanol is suspended 200 mg of the above ester and 412 mg of glycine. The mixture was heated at the boil under reflux for 24 hours, then cooled to room temperature and concentrated to approximately 3 ml under reduced pressure. The mixture was diluted with 50 ml of water and acidified to pH 3 with 1N. aqueous hydrochloric acid. The resulting precipitate was collected and washed with cold water twice. The solid was dried in vacuo to give 188 mg of product. MS - (-) m / z 398.96, 400.95 (M-1, M + 1) Br isotopes.

Example D-40

[(1-Bromo-4-hydroxy-8-phenylisoquinoline-3-carbonyl) amino] acetic acid

The title compound is prepared from 1,4-dihydroxy-8-phenylisoquinoline-3-carboxylic acid butyl ester (Example D-39 c), Isomer A) using conditions similar to those described in detail in Example D-41.

1-Bromo-4-hydroxy-8-phenylisoquinoline-3-carboxylic acid butyl ester; MS - (+) m / z: 400.00, 402.03 (M + 1, M + 3; Br isotopes).

[(1-Bromo-4-hydroxy-8-phenylisoquinoline-3-carbonyl) amino] acetic acid; MS - (+) m / z: 398.95, 400.98 (M-1, M + 1, Br isotopes).

Example D-41

[(1-Ethylsulfanyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Ethylsulfanyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

52 mg of 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester are dissolved in 2 ml of ethanethiol (Example D-20 s) and heated in a sealed tube at 70 ° C for 24 hours and at 100 ° C for 48 hours . The resulting solution was concentrated in vacuo and the residue (54 mg) was purified by silica gel chromatography using a gradient of 0 to 20% ethyl acetate in hexanes to elute the product. 25 mg of product is obtained. MS - (+) m / z: 306.06 (M + 1).

b. [(1-Ethylsulfanyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

The title compound is prepared using the ester described above under conditions analogous to the conditions described in detail in Example D-39 e). MS - (-) m / z 304.98 (M-1).

Example D-42

{[4-Hydroxy-1- (4-methoxyphenylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid

To a solution of 100 mg of [(1-chloro-4-hydroxyisoquinolin-3-carbonyl) amino] acetic acid (US Pat. No. 6,093,730, described as N - ((1-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) glycine) in 1 ml of N, N-dimethylformamide add 1 ml of 4-methoxybenzenethiol. The solution was heated at 120-130 ^C in a sealed tube 72 h. The solution was concentrated in vacuo. The resulting residue (76 mg) was purified by silica gel chromatography using a gradient of 0 to 15% methanol in dichloromethane with 0.5% acetic acid to elute the product. 6 mg of product are obtained. MS - (+) m / z 385.05 (M + 1).

Example D-43

[(1-Chloro-4-hydroxy-7-iodisoquinoline-3-carbonyl) amino] acetic acid

but. (5-Iodo-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid

10 g of 4-iodophthalic acid are thoroughly mixed with 2.63 g of glycine and the mixture is heated to 200 ° C for 10 minutes. After cooling, the solid reaction mixture was extracted with ethyl acetate, after concentration 6.40 g of a beige solid was obtained. MS - (-) - ion. ¹ H NMR (200 MHz, methanol-d ₄ ): δ 8.26-8.18 (m, 2H), 7.68-7.61 (m, 1H), 4.39 (s, 1H).

b. Methyl ester (5-iodo-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid

The carboxylic acid of Example D-55 a) (6.4 g) is esterified for 3 hours with 2.7 g of dimethyl sulfate and 3.0 g of potassium carbonate in 25 ml of refluxing acetone. The reaction mixture was diluted with ethyl acetate, filtered and concentrated. The residue was dissolved in fresh ethyl acetate, the organic layer was washed (water, brine) and dried over sodium sulfate. Concentration of the dry, filtered solution in ethyl acetate gave 5.8 g of a light yellow solid. ¹ H NMR (200 MHz, chloroform-d): δ 8.24-8.20 (m, 1H), 8.14-8.06 (m, 1H), 7.62-7.56 (d, 1H ), 4.40 (s, 2H), 3.75 (s, 3H).

from. 4-Hydroxy-7-iodo-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid butyl ester and 4-hydroxy-6-iodo-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid butyl ester

Freshly chopped sodium metal (0.40 g) is dissolved in 22 ml of n-butanol at 65 ° C. under a nitrogen atmosphere. A mixture of 3.0 g of methyl ester (5-iodo-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid in 22 ml of n-butanol is added to a solution of sodium butoxide and the reaction mixture is heated at 80 ° C. within 2 hours. The cooled reaction mixture was acidified with 100 ml of 1M hydrochloric acid to give a solid precipitate. The solid is filtered off and separated by silica gel chromatography (eluent: dichloromethane: ethyl acetate, 19: 1) to obtain 0.219 g of 4-hydroxy-7-iodo-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid butyl ester (MS- (-) - ion, (M-1) = 386.0 ami) and 0.150 g of 4-hydroxy-6-iodo-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid butyl ester (MS - (-) -ion, (M-1) = 386.0 aem).

d. 1-Chloro-4-hydroxy-7-iodisoquinoline-3-carboxylic acid butyl ester

0.215 g of 4-hydroxy-7-iodo-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid was added to 5 ml of POCl ₃ at room temperature. The mixture was refluxed for 3 hours and POCl _{3 was} removed in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with saturated aqueous sodium bicarbonate, dried (MgSO ₄ ), filtered and concentrated to give 0.205 g of a white solid. ¹ H NMR (200 MHz, chloroform-d): δ 11.91 (s, 1H), 8.67 (m, 1H), 8.10 (m, 2H), 4.49 (t, J = 7 Hz , 2H), 1.95-1.75 (m, 2H), 1.60-1.39 (m, 2H), 1.00 (t, J = 7 Hz, 3H).

e. [(1-Chloro-4-hydroxy-7-iodisoquinoline-3-carbonyl) amino] acetic acid

To a mixture of 0.263 g of glycine in 4.7 ml of a 0.5 M sodium methoxide solution, 0.095 g of 1-chloro-4-hydroxy-7-iodisoquinoline-3-carboxylic acid butyl ester was added and the reaction mixture was refluxed for 18 hours. The mixture was concentrated, the residue was dissolved in water and the solution was acidified with 1M hydrochloric acid. The precipitate was extracted with ethyl acetate and the organic layer was washed with water, dried (MgSO ₄ ), filtered and concentrated to give 0.079 g of a light yellow product. MS - (-) - ion, (M-1) = 406.9 aem.

Example D-44

[(1-Chloro-4-hydroxy-6-iodisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Chloro-4-hydroxy-6-iodisoquinoline-3-carboxylic acid butyl ester

By a method similar to that of Example D-43 d), 0.150 g of 4-hydroxy-6-iodo-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid butyl ester was reacted with 5 ml of POCl ₃ to give 0.057 g almost white solid. ¹ H NMR (200 MHz, chloroform-d): δ 11.9 (s, 1H), 8.89 (m, 1H), 8.1 (m, 1H), 7.97 (m, 1H), 4 5 (t, J = 7 Hz, 2H), 2.0-1.8 (m, 2H), 1.65-1.4 (m, 2H), 1.00 (t, J = 7 Hz, 3H).

b. [(1-Chloro-4-hydroxy-6-iodisoquinoline-3-carbonyl) amino] acetic acid

The butyl ether of Example D-44 a) (0.053 g) was reacted with a mixture of 0.147 g of glycine in 2.6 ml of a 0.5 M solution of sodium methoxide in methanol under conditions similar to the conditions of Example D-55 e), 0.047 g of product was obtained in as an almost white solid. MS - (-) - ion, (M-1) = 406.9 aem.

Example D-45

[(4-Hydroxy-7-iodisoquinoline-3-carbonyl) amino] acetic acid

but. 4-hydroxy-7-iodisoquinoline-3-carboxylic acid butyl ester

The product of example D-43 d) (0.100 g) was dissolved in 1.5 ml of glacial acetic acid containing 0.015 g of red phosphorus and 56 μl of hydroiodic acid (d = 1,701 g / ml). The reaction mixture was refluxed for 1 hour, diluted with ethyl acetate and filtered through a pad of celite. The filtrate was washed with a saturated aqueous solution of thiosulfate and a saturated aqueous solution of bicarbonate, dried (MgSO ₄ ), filtered and concentrated to give a crude product. Silica gel chromatography of the crude product (eluent: CH ₂ Cl ₂ : ethyl acetate, 99: 1) gave 0.073 g of a white solid. ¹ H NMR (200 MHz, chloroform-d): δ 11.9 (s, 1H), 8.70 (s, 1H), 8.40-8.30 (m, 1H), 8.12-8, 05 (m, 1H), 8.05-7.96 (m, 1H), 4.48 (t, J = 7 Hz, 2H), 1.95-1.80 (m, 2H), 1.60 -1.40 (m, 2H), 0.99 (t, J = 7 Hz, 3H).

b. [(4-Hydroxy-7-iodisoquinoline-3-carbonyl) amino] acetic acid

Obtain 0.042 g of the product by introducing into the reaction of butyl ether of example D-45 a) with a mixture of 0.142 g of glycine in 2.5 ml of a 0.5 M solution of sodium methoxide in methanol in a manner analogous to the method of example D-55 e). MS - (-) - ion, (M-1) = 373.0 am.

Example D-46

[(1-Bromo-4-hydroxy-7-methylisoquinoline-3-carbonyl) amino] acetic acid

but. 4-hydroxy-7-methyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid butyl ester

From 5.0 g of 4-methylphthalic acid after a sequence of reactions similar to the reactions of examples D-43a) -D-43c), 0.213 g of 4-hydroxy-7-methyl-1-oxo-1,2-dihydroisoquinolin-3 butyl ester are obtained -carboxylic acid. MS - (-) - ion, M-1 = 274.1.

b. 1-Bromo-4-hydroxy-7-methylisoquinoline-3-carboxylic acid butyl ester

0.210 g of the ester of Example D-46 a) is added to 3.5 ml of acetonitrile. 1.52 g of phosphorus oxybromide was added and the mixture was refluxed for 6 hours, cooled and dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated aqueous NaHCO ₃ , dried (MgSO ₄ ), filtered and concentrated to give 0.266 g of crude product. Silica gel chromatography of the crude material (eluent: methylene chloride) gave 0.094 g of a white solid. ¹ H NMR (200 MHz, chloroform-d): δ 11.85 (s, 1H), 8.30-8.20 (d, 1H), 8.00 (br s, 1H), 7.70- 7.60 (m, 1H), 4.47 (t, J = 7 Hz, 2H), 2.62 (s, 3H), 1.95 -1.75 (m, 2H), 1.60-1 35 (m, 2H), 1.00 (t, J = 7 Hz, 3H).

from. [(1-Bromo-4-hydroxy-7-methylisoquinoline-3-carbonyl) amino] acetic acid

The butyl ether of Example D-46 b) (0.094 g) was reacted with a mixture of 0.312 g of glycine in 5.5 ml of a 0.5 M sodium methoxide solution in a similar manner to that of Example D-55 e), 0.083 g of an almost white solid . MS - (-) - ion, M-1 = 339.0 am.

Example D-47

[(1-Bromo-7-butoxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Bromo-7-butoxy-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

7-Butoxy-4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid butyl ester (0.150 g) was reacted with phosphorus oxybromide in a manner analogous to that of Example D-46 b), yielding 0.105 g of almost white solid. ¹ H NMR (200 MHz, chloroform-d): δ 11.82 (s, 1H), 8.68 (s, 1H), 8.26 (d, 1H), 7.35 (dd, 1H), 7 , 19 (d, 1H), 4.49 (t, J = 7 Hz, 2H), 4.12 (t, J = 7 Hz, 2H), 1.95-1.75 (m, 4H), 1 70-1.40 (m, 4H); 1.05-0.95 (m, 6H).

b. [(1-Bromo-7-butoxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

The butyl ether of Example D-47 a) (0.100 g) was reacted with a mixture of glycine in a methanol solution of sodium methoxide in the same manner as in Example D-11 e), and 0.094 g of a white solid was obtained. MS - (-) - ion, M-1 = 397.0 am.

Example D-48

[(1-Bromo-6-butoxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Bromo-6-butoxy-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

6-Butoxy-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (0.175 g) was reacted with phosphorus oxybromide in the same manner as in Example D-46 b) to give 0.073 g of an almost white solid. ¹ H NMR (200 MHZ, chloroform-d): δ 11.84 (s, 1H), 8.13 (d, 1H), 7.60 (m, 1H), 7.42-7.35 (m, 1H), 4.48 (t, J = 7 Hz, 2H), 4.15 (t, J = 7 Hz, 2H), 1.95-1.75 (m, 4H), 1.65-1, 40 (m, 4H); 1.05-0.95 (m, 6H).

b. [(1-Bromo-6-butoxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

The butyl ether of Example D-48 a) (0.068 g) was reacted with a mixture of glycine in a methanol solution of sodium methoxide in the same manner as in Example D-43 e), 0.063 g of a white solid was obtained. MS - (-) - ion, M-1 = 397.0 am.

Example D-49

[(6-Benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) methylamino] acetic acid

0.33 g of 6-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid, 0.5 ml of triethylamine, 0.400 g of HATU and 0.165 g of ethyl N-methylaminoacetate hydrochloride are mixed in 15 ml of dichloromethane and the reaction mixture is stirred at room temperature. temperature 18 hours. Silica gel chromatography gives 0.232 g of an almost white solid. MS - (+) - ion: 429.0 ami. The obtained intermediate product (0.208 g) was dissolved in 10 ml of a solution of NaOH in methanol (1.5 M) and the mixture was stirred at room temperature for 3 hours. The solvent was removed on a rotary evaporator, the residue was dissolved in water and the aqueous layer was extracted with 50 ml of ethyl acetate. The aqueous layer was acidified to pH 1 with aqueous HCl, a solid precipitate was obtained. The solid is filtered off with suction, washed with water and dried in a vacuum oven (80 ° C) to give 0.180 g of a white solid. MS - (+) - ion: 401.0 ami.

Example D-50

[(1-Chloro-4-hydroxyisoquinoline-3-carbonyl) methylamino] acetic acid

Obtained from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid in a manner analogous to that of Example D-49. MS - (+) - ion: 294.9 aem.

Example D-51

[(1-Chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) methylamino] acetic acid

Prepared from 1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid in a manner analogous to that of Example D-49. MS - (+) - ion: 353.0 ami.

Example D-52

[(1-Chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) methylamino] acetic acid

Prepared from 1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid in a manner analogous to that of Example D-49. MS - (+) - ion: 353.0 ami.

Example D-53

[Carboxymethyl- (1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

Obtained from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid and ethyl ester (ethoxycarbonylmethylamino) acetic acid in a manner analogous to that of Example D-49. MS - (+) - ion: 339.0 ami.

Example D-54

[Carboxymethyl- (1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino]

acetic acid

Prepared from 1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid and ethyl ester (ethoxycarbonylmethylamino) acetic acid in a manner analogous to that of Example D-49. MS - (+) - ion: 397.0 ami.

Example D-55

{[4-Hydroxy-1- (naphthalen-2-yloxy) isoquinoline-3-carbonyl] amino} acetic acid

but. 4-hydroxy-1- (naphthalen-2-yloxy) isoquinoline-3-carboxylic acid butyl ester

Synthesized from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ether and naphthalene-2-ol according to a procedure similar to that of Example D-20 d).

MS - (+) - ion, M + 1 = 388.1 am.

b. {[4-Hydroxy-1- (naphthalen-2-yloxy) isoquinoline-3-carbonyl] amino} acetic acid

Synthesized from 4-hydroxy-1- (naphthalen-2-yloxy) -isoquinoline-3-carboxylic acid butyl ester according to a procedure similar to that of Example D-1 g). MS - (+) - ion, M + 1 = 389.1.

Example D-56

{[4-Hydroxy-1- (pyridin-3-yloxy) isoquinoline-3-carbonyl] amino} acetic acid

but. 4-Hydroxy-1- (pyridin-3-yloxy) isoquinoline-3-carboxylic acid butyl ester

Synthesized from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ether and pyridin-3-ol according to a procedure analogous to that of Example D-20 d). MS - (+) - ion, M + 1 = 339.1 am.

b. {[4-hydroxy-1- (pyridin-3-yloxy) isoquinoline-3-carbonyl] amino} acetic acid

Synthesized from 4-hydroxy-1- (pyridin-3-yloxy) -isoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 340.1.

Example D-57

{[4-Hydroxy-1- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

but. 4-hydroxy-1- (4-methoxyphenoxy) isoquinoline-3-carboxylic acid butyl ester

Synthesized from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester and 4-methoxyphenol according to a procedure similar to that of Example D-20 d). MS - (+) - ion, M + 1 = 368.1 am.

b. {[4-Hydroxy-1- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

Synthesized from 4-hydroxy-1- (4-methoxyphenoxy) isoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 369.1.

Example D-58

{[4-Hydroxy-1- (3-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

but. 4-hydroxy-1- (3-methoxyphenoxy) isoquinoline-3-carboxylic acid butyl ester

Synthesized from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester and 3-methoxyphenol according to a procedure similar to that of Example D-20 d). MS - (+) - ion, M + 1 = 368.1.

b. {[4-Hydroxy-1- (3-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

Synthesized from 4-hydroxy-1- (3-methoxyphenoxy) isoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (-) - ion, M-1 = 367.0.

Example D-59

{[1- (3-Fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

but. 1- (3-Fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester and 3-fluorophenol according to a procedure similar to that of Example D-20 d). MS - (+) - ion, M + 1 = 356.1.

b. {[1- (3-Fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Synthesized from 1- (3-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 357.09.

Example D-60

{[1- (4-Fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

but. 1- (4-Fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester and 4-fluorophenol according to a procedure similar to that of Example D-20 d). MS - (+) - ion, M + 1 = 356.1.

b. {[1- (4-Fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Synthesized from 1- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 357.0.

Example D-61

{[1- (2-Fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

but. 1- (2-Fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester and 2-fluorophenol according to a procedure similar to that of Example D-20 d). MS - (+) - ion, M + 1 = 356.1.

b. {[1- (2-Fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Synthesized from 1- (2-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 357.11.

Example D-62

{[4-Hydroxy-1- (2-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

but. 4-hydroxy-1- (2-methoxyphenoxy) isoquinoline-3-carboxylic acid butyl ester

Synthesized from 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester and 2-methoxyphenol according to a procedure similar to that of Example D-20 d). MS - (+) - ion, M + 1 = 368.13.

b. {[4-Hydroxy-1- (2-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

Synthesized from 4-hydroxy-1- (2-methoxyphenoxy) -4-isoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 369.09.

Example D-63

{[1- (4-Acetylaminophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

but. 4-Acetoxy-1- (4-acetylaminophenoxy) isoquinoline-3-carboxylic acid butyl ester

4-Hydroxy-1-phenoxyisoquinoline-3-carboxylic acid butyl ester (261 mg, 0.77 mmol; see Example D-20 d)) was dissolved in concentrated H ₂ SO ₄ (4 ml) at room temperature. The solution was cooled to 0 ° C. and KNO ₃ (79 mg, 0.77 mmol) was added slowly with stirring. The mixture was stirred at 0 ° C for 2 hours, then poured into ice water (100 ml) with stirring. The mixture was extracted with EtOAc (3x30 ml). The combined organic phases are washed with aqueous NaHCO ₃ and brine, dried and concentrated in vacuo. The residue was dissolved in a mixture of EtOAc (20 ml) and MeOH (10 ml). Sodium acetate (70 mg, 0.85 mmol) and Pd / C (75 mg, 10% wt. Pd) were added and the mixture was stirred in an H ₂ atmosphere (1 atm) at room temperature for 24 hours. The mixture is then filtered through a pad of celite. Celite and the filter cake were washed with hot MeOH (3x4 ml) and the combined organic phases were concentrated in vacuo. The resulting residue (150 mg, total 380 mg) was dissolved in EtOAc (8 ml). Triethylamine (325 μl, 2.3 mmol) was added and the solution was cooled to 0 ° C. Then acetic anhydride (110 μl, 1.15 mmol) was slowly added with vigorous stirring. The mixture was allowed to warm to room temperature overnight and then stirred for another 20 hours at room temperature. Then EtOAc (50 ml) was added. The mixture was washed with aqueous NaHCO ₃ and brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a mixture of CH ₂ Cl ₂ : MeOH from 100: 1 to 100: 3 as eluent to obtain 150 mg of 4-acetoxy-1- (4-acetylaminophenoxy) isoquinoline-3-carbon butyl ether acids. MS - (+) - ion, M + 1 = 437.11.

b. {[1- (4-Acetylaminophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

4-acetoxy-1- (4-acetylaminophenoxy) isoquinoline-3-carboxylic acid butyl ester (150 mg, 0.34 mmol), glycine (290 mg, 3.4 mmol) and 7.8 ml of 0.5N. a solution of sodium methoxide in methanol (3.9 mmol) is refluxed with stirring over the weekend. The solvent was evaporated in vacuo and the residue was dissolved in 25 ml of water. Then the pH of the solution was adjusted to approximately 2 and the resulting suspension was extracted with ethyl acetate (3x30 ml). The combined extracts were dried over MgSO ₄ and evaporated in vacuo. Recrystallization of the residue from methanol / CH ₂ Cl ₂ gave 86 mg of the title compound. MS - (+) - ion, M + 1 = 396.15.

Example D-64

{[4-Hydroxy-1- (4-methanesulfonylaminophenoxy) isoquinoline-3-carbonyl] amino} acetic acid

4-Hydroxy-1-phenoxyisoquinoline-3-carboxylic acid butyl ester (261 mg, 0.77 mmol; see Example D-20 d)) was dissolved in concentrated H ₂ SO ₄ (4 ml) at room temperature. The solution was cooled to 0 ° C. and KNO ₃ (79 mg, 0.77 mmol) was added slowly with stirring. The mixture was stirred at 0 ° C for 2 hours, then poured into ice water (100 ml) with stirring. The mixture was extracted with EtOAc (3x30 ml). The combined organic phases are washed with aqueous NaHCO ₃ and brine, dried and concentrated in vacuo. The residue was dissolved in a mixture of EtOAc (20 ml) and MeOH (10 ml). Sodium acetate (70 mg, 0.85 mmol) and Pd / C (75 mg, 10% wt. Pd) were added and the mixture was stirred in an H ₂ atmosphere (1 atm) at room temperature for 24 hours. The mixture is then filtered through a pad of celite. Celite and the filter cake were washed with hot MeOH (3x4 ml) and the combined organic phases were concentrated in vacuo. The resulting residue (150 mg, total residue 380 mg) was dissolved in CH ₂ Cl ₂ (8 ml). Triethylamine (165 μl) was added and the solution was cooled to -20 ° C. Then, MeSO ₂ Cl (36 μl) was added slowly with vigorous stirring. The mixture was allowed to warm to room temperature overnight and then stirred for another 20 hours at room temperature. Then EtOAc (50 ml) was added. The mixture was washed with aqueous NaHCO ₃ and brine, dried and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using CH ₂ Cl ₂ : MeOH, 100: 1 to 100: 3 as eluent. Glycine (293 mg, 3.4 mmol) and 7.8 ml of 0.5N are added to the purified product (168 mg). a solution of sodium methoxide in methanol (3.9 mmol) and the mixture is refluxed with stirring over the weekend. The solvent was evaporated in vacuo and the residue was dissolved in 30 ml of water. Then the pH of the solution was adjusted to approximately 2 and the resulting suspension was extracted with ethyl acetate (3x30 ml). The combined extracts were dried over MgSO ₄ and evaporated in vacuo. Recrystallization of the residue from methanol / CH ₂ Cl ₂ gives 89 mg of the title compound. MS - (+) - ion, M + 1 = 432.12.

Example D-65

[(4-Hydroxy-1-phenylaminoisoquinoline-3-carbonyl) amino] acetic acid

but. 4-hydroxy-1-phenylaminoisoquinoline-3-carboxylic acid butyl ester

A mixture of 1-bromo-4-hydroxyisoquinoline-3-carboxylic acid butyl ether (810 mg, 2.5 mmol; Example D-28 a) and aniline (3 ml) was stirred in a microwave pressure tube at 150 ° C. within 20 minutes The reaction is repeated on the same scale. The two reaction mixtures were combined, EtOAc (100 ml) was added and the mixture was washed with H ₂ O (5x30 ml, pH = 1-2). The organic phase is dried and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using hexanes / EtOAc as eluent to give 770 mg of 4-hydroxy-1-phenylaminoisoquinoline-3-carboxylic acid butyl ester.

MS - (+) - ion, M + 1 = 337.21.

b. [(4-Hydroxy-1-phenylaminoisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from butyl ester of hydroxy-1-phenylaminoisoquinoline-3-carboxylic acid in a manner analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 338.14.

Example D-66

{[4-Hydroxy-6- (pyridin-3-yloxy) isoquinoline-3-carbonyl] amino} acetic acid

but. 4- (pyridin-3-yloxy) phthalonitrile

A mixture of 4-nitrophthalononitrile (3.46 g, 20 mmol), pyridin-3-ol (1.90 g, 20 mmol), K ₂ CO ₃ (8.29 g, 60 mmol) and DMF (50 ml) was stirred at room temperature overnight. Then the reaction mixture is mixed with another charge of the same reaction, carried out on the same scale. Then the solid components are filtered off and the filtrate is concentrated in vacuo. Water was added to the residue, and the mixture was extracted with EtOAc. The organic phase is washed with brine, dried and evaporated in vacuo. The residue was recrystallized from EtOAc / MeOH to give 8.3 g of the title compound. ¹ H NMR (CDCl ₃ ): δ = 8.56-8.59 (m, 1H), 8.45-8.47 (m, 1H), 7.76 (d, 1H), 7.42-7 44 (m, 2H); 7.22-7.32 (m, 2H).

b. 4- (Pyridin-3-yloxy) phthalic acid

Synthesized from 4- (pyridin-3-yloxy) phthalonitrile according to a procedure similar to that of Example D-1 a). MS - (+) - ion, M + 1 = 260.2.

from. [1,3-dioxo-5- (pyridin-3-yloxy) -1,3-dihydroisoindol-2-yl] acetic acid

Synthesized from 4- (pyridin-3-yloxy) phthalic acid according to a procedure similar to that of Example D-1 b). MS - (+) - ion, M + 1 = 299.25.

d. [1,3-dioxo-5- (pyridin-3-yloxy) -1,3-dihydroisoindol-2-yl] acetic acid methyl ester

Synthesized from [1,3-dioxo-5- (pyridin-3-yloxy) -1,3-dihydroisoindol-2-yl] acetic acid in a manner analogous to that of Example D-1 c). MS - (+) - ion, M + 1 = 313.21.

e. 1,4-Dihydroxy-6- (pyridin-3-yloxy) isoquinoline-3-carboxylic acid butyl ester and 1,4-dihydroxy-7- (pyridin-3-yloxy) isoquinoline-3-carboxylic acid butyl ester

Synthesized from [1,3-dioxo-5- (pyridin-3-yloxy) -1,3-dihydroisoindol-2-yl] acetic acid methyl ester according to a procedure analogous to that of Example D-1 d). However, after adding 2n. HCl (pH adjusted to 8-9), the mixture was extracted three times with EtOAc. The combined organic phases are dried and concentrated in vacuo. The residue was taken up in MeOH and stored overnight in a refrigerator. The precipitate formed is filtered off, washed with a small amount of cold MeOH and dried in vacuo to give a regioisomeric mixture of the title compounds as a white solid. 1,4-dihydroxy-6- (pyridin-3-yloxy) isoquinoline-3-carboxylic acid butyl ester and 1,4-dihydroxy-7- (pyridin-3-yloxy) isoquinoline-3-carboxylic acid butyl ester are not separated. MS - (+) - ion, M + 1 = 355.09.

f. 1-Chloro-4-hydroxy-6- (pyridin-3-yloxy) isoquinoline-3-carboxylic acid butyl ester and 1-chloro-4-hydroxy-7- (pyridin-3-yloxy) isoquinoline-3-carboxylic butyl ester acid

Synthesized from a regioisomeric mixture of 1,4-dihydroxy-6- (pyridin-3-yloxy) -isoquinoline-3-carboxylic acid butyl ester and 1,4-dihydroxy-7- (pyridin-3-yloxy) -isoquinoline-3-carboxylic butyl ester acid in a manner analogous to that of Example D-43 d). Regioisomers are not separated.

MS - (+) - ion, M + 1 = 373.01.

g. 4-Hydroxy-6- (pyridin-3-yloxy) isoquinoline-3-carboxylic acid butyl ester (A) and 4-hydroxy-7- (pyridin-3-yloxy) isoquinolin-3-carboxylic acid butyl ester (B)

Synthesized from a regioisomeric mixture of 1-chloro-4-hydroxy-6- (pyridin-3-yloxy) isoquinoline-3-carboxylic acid butyl ether and 1-chloro-4-hydroxy-7- (pyridin-3-yloxy) isoquinoline butyl ether -3-carboxylic acid by a method similar to that of example D-7 f). The regioisomers are separated by flash column chromatography on silica gel, eluting with a mixture of CH ₂ Cl ₂ : EtOAc (90:10 to 80:20). Evaporation of the first fraction gives the B. isomer. MS - (+) - ion, M + 1 = 339.09. Evaporation of the second fraction gives the isomer A. MS - (+) - ion, M + 1 = 339.10.

h. {[4-Hydroxy-6- (pyridin-3-yloxy) isoquinoline-3-carbonyl] amino} acetic acid

Synthesized from 4-hydroxy- (6-pyridin-3-yloxy) -isoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 340.06.

Example D-67

{[4-Hydroxy-7- (pyridin-3-yloxy) isoquinoline-3-carbonyl] amino} acetic acid

Synthesized from 4-hydroxy-7- (pyridin-3-yloxy) -isoquinoline-3-carboxylic acid butyl ester (Example D-66 g) according to a procedure analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 340.06.

Example D-68

[(1-Chloro-4-methoxyisoquinoline-3-carbonyl) amino] acetic acid

but. [(1-Chloro-4-methoxyisoquinoline-3-carbonyl) amino] acetic acid methyl ester

A mixture of [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid (56 mg, 0.2 mmol; can be prepared according to US Pat. No. 6,093,730, 10/1998, Weidmann et al.), MgSO ₄ (57 μl, 0.6 mmol), KHCO ₃ (306 mg, 3 mmol) and acetone (4 ml) are refluxed with stirring for 48 hours. The solvent was evaporated and water (4 ml) was added to the residue. The mixture was extracted with EtOAc (3x20 ml). The combined organic phases are dried over MgSO ₄ and evaporated in vacuo to give a brown oil. Purification by flash column chromatography on silica gel using hexanes: EtOAc (7: 3) as an eluent gave the title compound as a pale yellow oil (21 mg). MS - (+) - ion, M + 1 = 308.9.

b. [(1-Chloro-4-methoxyisoquinoline-3-carbonyl) amino] acetic acid

A mixture of [(1-chloro-4-methoxyisoquinoline-3-carbonyl) amino] acetic acid methyl ester (21 mg, 0.07 mmol), KOH (23 mg, 0.35 mmol) and EtOH (1 ml) was stirred at room temperature temperature for 1 hour. Then the solvent was evaporated in vacuo. The residue was dissolved in water (2 ml) and the pH of the solution was adjusted to 2-3 by adding 1N. aqueous HCl. The mixture was extracted with EtOAc (4 x 10 ml). The combined organic phases are dried over Mg ₂ SO ₄ and evaporated in vacuo to afford the title compound as a pale yellow solid (18 mg). MS - (+) - ion, M + 1 = 295.0.

Example D-69

[(1-Chloro-4-ethoxyisoquinoline-3-carbonyl) amino] acetic acid

but. [(1-Chloro-4-ethoxyisoquinoline-3-carbonyl) amino] acetic acid ethyl ester

A mixture of [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid (56 mg, 0.2 mmol; can be obtained in accordance with US patent No. 6093730, 10/1998, Weidmann et al.), Et ₂ SO ₄ (59 μl, 0.44 mmol), KHCO ₃ (306 mg, 3 mmol) and Et ₂ CO (4 ml) are refluxed with stirring for 18 hours. The solvent was evaporated and water (4 ml) was added to the residue. The mixture is stirred vigorously for 5 minutes, then filtered. The filter cake was dissolved in EtOAc and the solution was dried over MgSO ₄ . The resulting brown solid was dissolved in EtOAc (0.5 ml) and hexanes added. The mixture was incubated for 14 hours at room temperature, then the solvent was decanted from the precipitate formed. The precipitate was dried in vacuo to give the title compound as white crystals (8 mg). MS - (+) - ion, M + 1 = 337.0.

b. [(1-Chloro-4-ethoxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from [(1-chloro-4-ethoxyisoquinoline-3-carbonyl) amino] acetic acid ethyl ester according to a procedure analogous to that of Example D-68 b). MS - (+) - ion, M + 1 = 309.0.

Example D-70

[(4-Hydroxy-1-methoxyisoquinoline-3-carbonyl) amino] acetic acid

but. 4-Benzyloxy-1-hydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester (26.13 g, 100 mmol, example D-20 b), PhCH ₂ Br (18.2 ml, 150 mmol), MeONa (0.5 M in MeOH, 200 ml, 100 mmol) was stirred at room temperature for 48 hours. Then, the solvent was evaporated, and EtOAc (100 ml) was added to the residue. The mixture is stirred vigorously for 10 minutes and then filtered. The filtrate was washed with 2.5 N. aqueous solution of NaOH (2x100 ml) and 2n. aqueous HCl (1x100 ml). The organic phase was dried over MgSO ₄ and evaporated in vacuo. The residue was recrystallized from a mixture of MeOH (500 ml) / water (300 ml). The resulting yellow material was further purified by flash column chromatography on silica gel using a mixture of hexanes: EtOAc: NEt ₃ (65: 30: 5) as the eluent to give 10.8 g of a yellow solid. An additional 2 g of this material was purified by flash column chromatography on silica gel using hexanes: EtOAc: NEt ₃ (75: 20: 5) as an eluent to give 1.57 g of the title compound as a pale yellow solid. ¹ H NMR (CDCl ₃ ): δ = 8.88 (br s, 1H), 8.46 (d, 1H), 8.42 (d, 1H), 7.26-7.96 (m, 7H ), 5.06 (s, 2H), 4.38 (t, 2H), 1.69 (m, 2H), 1.37 (m, 2H), 0.91 (t, 3H).

b. 4-Benzyloxy-1-methoxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 4-benzyloxy-1-hydroxyisoquinoline-3-carboxylic acid butyl ester (1 eq.), Me ₃ OBF ₄ (6 eq.), KHCO ₃ (14 eq.) And CH ₂ Cl ₂ (10 ml / mmol butyl ether 4-benzyloxy-1-hydroxyisoquinoline-3-carboxylic acid) was stirred at room temperature for 24 hours. Then water (10 ml / mmol) was added and the mixture was extracted with CH ₂ Cl ₂ (40 ml / mmol). The organic phase was separated, dried over MgSO ₄ and evaporated in vacuo to give a yellowish solid. The crude product was purified by flash column chromatography on silica gel using a mixture of hexanes: EtOAc (85:15) as eluent. Evaporation of the first fraction gives the title compound as a colorless oil, yield 20%. ¹ H NMR (CDCl ₃ ): δ = 8.21-8.25 (m, 1H), 8.05-8.09 (m, 1H), 7.33-7.73 (m, 7H), 5 13 (s, 2H), 4.38 (t, 2H), 4.16 (s, 3H), 1.69 (m, 2H), 1.37 (m, 2H), 0.94 (t, 3H).

from. 4-hydroxy-1-methoxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 4-benzyloxy-1-methoxyisoquinoline-3-carboxylic acid butyl ester (164 mg, 0.45 mmol), Pd / C (50 mg, 10% wt. Pd) and EtOAc (15 ml) was stirred under H ₂ at normal pressure and room temperature for 16 hours. Then the mixture is filtered through a layer of celite. Celite and filter cake were washed thoroughly with EtOAc and the combined organic phases were concentrated in vacuo to give the title compound as a white solid (115 mg). ¹ H NMR (CDCl ₃ ): δ = 11.48 (s, 1H), 8.27-8.32, (m, 1H), 8.17-8.21 (m, 1H), 7.65- 7.78 (m, 2H), 4.43 (t, 2H), 4.10 (s, 3H), 1.87 (m, 2H), 1.54 (m, 2H), 1.02 (t , 3H).

d. [(4-Hydroxy-1-methoxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 4-hydroxy-1-methoxyisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (-) - ion, M-1 = 275.0.

Example D-71

[(1-Ethoxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Ethoxy-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 4-benzyloxy-1-hydroxyisoquinoline-3-carboxylic acid butyl ether (422 mg, 1.2 mmol, example D-70 a), KHCO ₃ (2.22 g, 22 mmol) and 1 M solution

Et ₃ OBF ₄ in CH ₂ Cl ₂ (10 ml, 10 mmol) was stirred at room temperature for 16 hours and then refluxed with stirring for another 3 days. According to TLC, 4-benzyloxy-1-hydroxyisoquinoline-3-carboxylic acid butyl ester does not react under such conditions. Then, more KHCO ₃ (2.22 g, 22 mmol) and a 1M solution of Et ₃ OBF ₄ in CH ₂ Cl ₂ (10 ml, 10 mmol) were added and the mixture was concentrated in vacuo. Then 1,2-dichloroethane (10 ml) was added and the mixture was refluxed with stirring for 16 hours. Then the solvent was evaporated in vacuo. Water (25 ml) was added to the residue, and the mixture was extracted with EtOAc (2x50 ml). The combined organic phases were dried over MgSO ₄ and evaporated in vacuo to give a yellowish solid (374 mg). Purification by flash silica gel column chromatography using hexanes: EtOAc (85:15) as an eluent gave a yellowish oil (104 mg). Chromatographic purification was repeated using hexanes: EtOAc (99: 2, then 99: 1) as the eluent to afford the title compound as a colorless oil (60 mg). ¹ H NMR (CDCl ₃ ): δ = 11.45 (s, 1H), 8.20-8.32 (m, 2H), 7.64-7.78 (m, 2H), 4.38-4 59 (m, 4H), 1.84 (m, 2H), 1.54 (m, 5H), 1.01 (t, 3H).

b. [(1-Ethoxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 1-ethoxy-4-hydroxyisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 291.0.

Example D-72

[(4-Acetoxy-1-phenylisoquinoline-3-carbonyl) amino] acetic acid

but. [(1-Oxo-3-phenyl-1H-indene-2-carbonyl) amino] acetic acid methyl ester

A mixture of 1-oxo-3-phenyl-1H-indene-2-carboxylic acid (2.13 g, 8.5 mmol; can be prepared according to MR Barvian et al. In Bioorg. Med. Chem. Lett., 1997, 7, 2903-2908) and SOCl ₂ (17 ml) were refluxed with stirring for 15 minutes. Excess SOCl _{2 was} evaporated in vacuo. The residue was dissolved in anhydrous CH ₂ Cl ₂ (20 ml) and then the solution was concentrated in vacuo to remove the last trace of SOCl ₂ . The residue was dissolved in anhydrous CH ₂ Cl ₂ (20 ml). The solution was cooled in an ice bath, then glycine methyl ester hydrochloride (1.27 g, 10 mmol) was added, and then NEt ₃ (3.52 ml, 25 mmol, was added dropwise) with stirring. The ice bath was removed and stirring was continued at room temperature for 45 minutes, then the mixture was concentrated in vacuo. Water (10 ml), 2N was added to the residue. an aqueous solution of HCl (15 ml) and the mixture was extracted with ethyl acetate (1x70 ml). The organic phase was dried over MgSO ₄ and evaporated in vacuo to give an orange solid (2.77 g). Purification by flash chromatography on silica gel using 2: 1 hexanes: EtOAc as eluent afforded the title compound as an orange solid (2.11 g). MS - (+) - ion, M + 1 = 322.0.

b. [(4-Acetoxy-1-phenylisoquinoline-3-carbonyl) amino] acetic acid methyl ester

[(1-Oxo-3-phenyl-1H-indene-2-carbonyl) amino] acetic acid methyl ester (1.864 g, 5.8 mmol) was dissolved in a mixture of concentrated H ₂ SO ₄ (16 ml) and glacial acetic acid ( 16 ml) at 50-60 ° C. Then, NaN ₃ (985 mg, 15 mmol) was added in portions with stirring so that the temperature did not exceed 60 ° C. Stirring is continued at 50-60 ° C. for another 30 minutes, then the mixture is poured onto ice (200 g). The resulting mixture was made alkaline by adding concentrated aqueous NH ₃ (55 ml, D = 0.89 g / ml) and extracted with CH ₂ Cl ₂ (2 x 100 ml). The combined organic phases are dried over MgSO ₄ and then filtered through silica gel. The filtrate is discarded. Silica gel was washed with EtOAc (approximately 400 ml). The resulting solution was concentrated in vacuo to give a dark oil (250 mg). Further purification by silica gel column chromatography using EtOAc as the eluent and then EtOAc: hexanes (7: 3) gave the title compound as a beige solid (19 mg). ¹ H NMR (CDCl ₃ ): δ = 7.11-7.98 (m), 3.75 (d, 2H), 3.68 (s, 1H), 2.19 (s, 3H).

from. [(4-Acetoxy-1-phenylisoquinoline-3-carbonyl) amino] acetic acid

A mixture of [(4-acetoxy-1-phenylisoquinoline-3-carbonyl) amino] acetic acid methyl ester (3.8 mg, 0.01 mmol) and aqueous 6N. HCl (1 ml) was stirred at room temperature for 16 hours, then the pH of the solution was adjusted to approximately 8 by adding concentrated aqueous NaHCO ₃ solution. The solution was washed with EtOAc (2x10 ml), then acidified by adding aqueous 2N. HCl. The mixture was then extracted with EtOAc (2 x 10 ml). The combined organic phases are dried over MgSO ₄ and evaporated in vacuo to give the title compound as a yellow oil (1.9 mg). MS - (+) - ion, M + 1 = 364.9.

Example D-73

[(4-Hydroxy-1-phenylisoquinoline-3-carbonyl) amino] acetic acid

but. 4-hydroxy-1-phenylisoquinoline-3-carboxylic acid ethyl ester

A mixture of 4-acetoxy-1-phenylisoquinoline-3-carboxylic acid ethyl ester (671 mg, 2 mmol; can be prepared according to DA Walsh et al., J. Med. Chem. 1978, 21, 582-585), n-BuOH (60 ml) and concentrated H ₂ SO ₄ (1.7 ml) are refluxed with stirring for 4 hours, then the reaction mixture is added with stirring to a concentrated aqueous solution of NaHCO ₃ (60 ml). Then EtOAc (120 ml) was added and the mixture was vigorously stirred for 15 minutes. The organic phase was separated, dried over MgSO ₄ and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes: EtOAc (95: 5) as an eluent gave the title compound as a solid (126 mg). ¹ H NMR (CDCl ₃ ): δ = 11.96 (s, 1H), 8.44-8.49 (m, 1H), 8.01-8.05 (m, 1H), 7.43-7 80 (m, 7H); 4.56 (q, 2H); 1.49 (t, 3H).

b. [(4-Hydroxy-1-phenylisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 4-hydroxy-1-phenylisoquinoline-3-carboxylic acid ethyl ester in a manner analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 323.1.

Example D-74

[(1-Ethoxy-4-phenylisoquinoline-3-carbonyl) amino] acetic acid

but. 1-chloro-4-phenylisoquinoline-3-carboxylic acid ethyl ester

A mixture of 1-hydroxy-4-phenylisoquinoline-3-carboxylic acid ethyl ester (1.17 g, 4 mmol; can be prepared according to A. Marsili et al., Ann. Chim. (Rome), 1962, 52, 112-120) and conc. POCl ₃ (10 ml) was refluxed with stirring for 1 hour. Then the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50 ml), concentrated aqueous NaHCO ₃ solution (40 ml) was added, and the mixture was stirred vigorously for 1 hour. Then the organic phase is separated, dried over MgSO ₄ and concentrated in vacuo to give the title compound as a yellowish solid (1.20 g). MS - (+) - ion, M + 1 = 312.0.

b. [(1-Chloro-4-phenylisoquinoline-3-carbonyl) amino] acetic acid methyl ester

A mixture of ethyl ester of 1-chloro-4-phenylisoquinoline-3-carboxylic acid (1.184 g, 3.8 mmol), 2N. an aqueous solution of NaOH (15 ml, 30 mmol) and EtOH (15 ml) are refluxed with stirring for 2.5 hours. Then the mixture is concentrated to 1/2 of its volume. The solution was then acidified by adding concentrated HCl and the resulting suspension was extracted with EtOAc (2x50 ml). The combined organic phases were dried over MgSO ₄ and evaporated in vacuo to give a yellowish solid (1.018 g). To 996 mg of the resulting yellowish solid, SOCl ₂ (7 ml) was added and the mixture was refluxed with stirring for 1 hour. Then, excess SOCl _{2 was} evaporated. The residue was dissolved in anhydrous CH ₂ Cl ₂ (10 ml) and then the solution was again concentrated in vacuo to remove the last trace of SOCl ₂ . The residue was dissolved in anhydrous CH ₂ Cl ₂ (8 ml). The solution was cooled in an ice bath, then glycine methyl ester hydrochloride (507 mg, 4 mmol) was added with stirring, and then NEt ₃ (1.55 ml, 11 mmol, was added dropwise). The ice bath was removed and stirring was continued at room temperature for 1 hour, then the mixture was concentrated in vacuo. Water (15 ml) was added to the residue, and the mixture was extracted with ethyl acetate (1 x 50 ml). The organic phase was dried over MgSO ₄ and evaporated in vacuo to give a beige solid (1.07 g). Recrystallization from a mixture of MeOH (30 ml) / water (10 ml) gives the title compound as a slightly yellow solid (430 mg). MS - (+) - ion, M + 1 = 355.0.

c. [(1-Ethoxy-4-phenylisoquinoline-3-carbonyl) amino] acetic acid

A mixture of [(1-chloro-4-phenylisoquinoline-3-carbonyl) amino] acetic acid methyl ester (177 mg, 0.5 mmol), KOH (325 mg, 5 mmol) and EtOH (10 ml) was stirred at room temperature 90 min, then the solvent is evaporated in vacuo. The residue was dissolved in water (10 ml). The solution was acidified by addition of concentrated aqueous HCl and extracted with EtOAc (2 x 15 ml). The combined organic phases are dried over MgSO ₄ and concentrated in vacuo to afford the title compound as a slightly yellowish substance (169 mg). MS - (+) - ion, M + 1 = 351.0.

Example D-75

[(1-Chloro-4-phenylisoquinoline-3-carbonyl) amino] acetic acid

A mixture of [(1-chloro-4-phenylisoquinoline-3-carbonyl) amino] acetic acid methyl ester (50 mg, 0.14 mmol, Example D-74 b) and aqueous 6N. HCl was stirred at room temperature for 11 days, then the solution was neutralized by adding a concentrated aqueous solution of NaHCO ₃ . The mixture was extracted with EtOAc (50 ml). The organic phase was dried over MgSO ₄ and concentrated in vacuo to afford the title compound as a white solid (35 mg). MS - (+) - ion, M + 1 = 341.0.

Example D-76

[(4-Phenylisoquinoline-3-carbonyl) amino] acetic acid

but. [(4-Phenylisoquinoline-3-carbonyl) amino] acetic acid methyl ester

A mixture of [(1-chloro-4-phenylisoquinoline-3-carbonyl) amino] acetic acid methyl ester (177 mg, 0.5 mmol, example D-74 b), Pd / C (50 mg, 10% wt. Pd) , sodium acetate (49 mg, 0.6 mmol), MeOH (10 ml) and EtOAc (5 ml) are stirred in an atmosphere of H ₂ at normal pressure and temperature for 2 hours. Then the mixture is filtered through celite. Celite and filter cake were washed thoroughly with EtOAc and the combined organic phases were concentrated in vacuo. Concentrated aqueous NaHCO ₃ solution (10 ml) was added to the residue, and the mixture was extracted with EtOAc (2 x 15 ml). The combined organic phases are dried over MgSO ₄ and concentrated in vacuo to afford the title compound as a colorless gum (154 mg). MS - (+) - ion, M + 1 = 321.0.

b. [(4-Phenylisoquinoline-3-carbonyl) amino] acetic acid

A mixture of [(4-phenylisoquinoline-3-carbonyl) amino] acetic acid methyl ester (144 mg, 0.45 mmol), KOH (325 mg, 5 mmol) and EtOH (10 ml) was stirred at room temperature for 18 hours, then the solvent evaporated in vacuo. The residue is dissolved in water. The pH of the solution was adjusted to 3-4 by adding concentrated aqueous HCl. Then the solution was extracted with EtOAc (2x25 ml). The combined organic phases are dried over MgSO ₄ and concentrated in vacuo to afford the title compound as a yellowish solid (127 mg).

MS - (+) - ion, M + 1 = 307.1.

Example D-77

[(4-Hydroxy-1-methylisoquinoline-3-carbonyl) amino] acetic acid

but. 1-bromo-4-hydroxyisoquinoline-3-carboxylic acid

A mixture of 1-bromo-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (8.18 g, 25 mmol, example D-28 a), 2N. aqueous NaOH (80 ml, 160 mmol) and EtOH (80 ml) are refluxed with stirring for 2 hours. The mixture is then concentrated in vacuo to 1/2 of its volume, diluted with water (200 ml) and acidified by adding concentrated aqueous HCl. After stirring at room temperature for 1 hour, the resulting suspension was subjected to vacuum filtration. The filter cake was washed thoroughly with water and dried in vacuo at 75 ° C to give the title compound as a white solid (6.10 g). ¹ H NMR (DMSO-d ₆ ): δ = 8.30-8.37 (m, 1H), 8.16-8.22 (m, 1H), 7.93-8.03 (m, 2H) .

b. 4-hydroxy-1-methylisoquinoline-3-carboxylic acid methyl ester

To a solution of 1-bromo-4-hydroxyisoquinoline-3-carboxylic acid (670 mg, 2.5 mmol) in anhydrous THF (100 ml), a 2.5 M solution of n-BuLi in hexanes (4 ml, 10 mmol) is slowly added at - 78 ° C with stirring. After stirring for another 5 minutes, MeI (316 μl, 5 mmol) was added. Stirring is continued for another 10 min at -78 ° C, then water (50 ml) and 2N are added. aqueous HCl (6 ml). The mixture was allowed to warm to room temperature with stirring and then concentrated in vacuo to approximately 1/2 volume. The resulting precipitate was filtered off with suction, washed with water, dried in vacuo at 80 ° C and recrystallized from EtOH to give a light beige solid (141 mg). A mixture of 102 g of the obtained light beige solid, Me ₂ SO ₄ (48 μl, 0.5 mmol), KHCO ₃ (1.0 g, 10 mmol) and acetone (10 ml) is refluxed with stirring for 15 hours. Then the mixture was concentrated in vacuo. Water (20 ml) was added to the residue, and the mixture was extracted with EtOAc (3 x 20 ml). The combined organic phases are dried over MgSO ₄ and concentrated in vacuo to afford the title compound as a beige solid. ¹ H NMR (CDCl ₃ ): δ = 11.66 (s, 1H), 8.39-8.44 (m, 1H), 8.02-8.09 (m, 1H), 7.74-7 81 (m, 2H); 4.08 (s, 3H); 2.90 (s, 3H).

from. [(4-Hydroxy-1-methylisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 4-hydroxy-1-methylisoquinoline-3-carboxylic acid methyl ester according to a procedure analogous to that of Example D-1 g). MS - (-) - ion, M-1 = 259.0.

Example D-78

[(4-Hydroxy-1-methoxymethylisoquinoline-3-carbonyl) amino] acetic acid

but. 4-Benzyloxy-1-methoxymethylisoquinoline-3-carboxylic acid benzyl ester

To a solution of 1-bromo-4-hydroxyisoquinoline-3-carboxylic acid (670 mg, 2.5 mmol, example D-77 a) in anhydrous THF (100 ml), a 2.5 M solution of n-BuLi in hexanes is slowly added with stirring 4 ml, 10 mmol) at -78 ° C. After stirring for another 5 minutes, MeOCH ₂ I (446 μl, 5 mmol) was added. Stirring is continued for another 5 minutes at -78 ° C, then water (50 ml) and 6N are added. aqueous HCl (2 ml). The mixture was allowed to warm to room temperature with stirring, then concentrated in vacuo to approximately 1/3 of its volume and extracted with EtOAc (50 ml). The organic phase is washed with a solution of sodium metabisulfite (0.5 g) in water (10 ml), then dried over MgSO ₄ and concentrated in vacuo to give a yellowish solid (432 mg). A mixture of 429 mg of the obtained yellowish solid, benzyl bromide (0.6 ml, 5 mmol), K ₂ CO ₃ (2.07 g, 15 mmol) and acetone (40 ml) was refluxed for 2.5 days. Then the mixture was concentrated in vacuo. Water (40 ml) was added to the residue, and the mixture was extracted with EtOAc (50 ml). The organic phase was dried over MgSO ₄ and concentrated in vacuo to give a brown oil. Purification by flash chromatography on silica gel using a mixture of hexanes: EtOAc (6: 4) as an eluent gives the title compound as a yellow oil (201 mg). MS - (+) - ion, M + 1 = 414.1.

b. 4-benzyloxy-1-methoxymethylisoquinoline-3-carboxylic acid

A mixture of 4-benzyloxy-1-methoxymethylisoquinoline-3-carboxylic acid benzyl ester (198 mg, 0.48 mmol), KOH (325 mg, 5 mmol) and EtOH (10 ml) was stirred at room temperature for 18 hours, then the solvent was evaporated in vacuum. Water (25 ml) was added to the residue, and the mixture was washed with Et ₂ O (2x25 ml). Then the solution is acidified by adding aqueous 6n. HCl and extracted with EtOAc (25 ml). The organic phase was dried over MgSO ₄ and concentrated in vacuo to afford the title compound as a yellow oil (140 mg). MS - (+) - ion, M + 1 = 324.1.

c. [(4-Benzyloxy-1-methoxymethylisoquinoline-3-carbonyl) amino] acetic acid benzyl ester

To a mixture of 4-benzyloxy-1-methoxymethylisoquinoline-3-carboxylic acid (120 mg, 0.37 mmol), NEt ₃ (109 μl, 0.78 mmol) and CH ₂ Cl ₂ (7 ml), cooled in an ice bath, ClCO ₂ -iBu (52 μl, 0.39 mmol) was added with stirring. After stirring for 15 minutes, glycine benzyl ester hydrochloride (79 mg, 0.39 mmol) was added and the mixture was stirred for another 15 minutes, then the bath was removed. Stirring is continued at room temperature for another 1.5 hours. Then the mixture was concentrated in vacuo. Water (10 ml) and a few drops of 6N are added to the residue. aqueous HCl. The mixture was extracted with EtOAc (15 ml). The organic phase was dried over MgSO ₄ and concentrated in vacuo to give a yellowish oil. Purification by flash column chromatography on silica gel using hexanes: EtOAc (7: 3) as the eluent gave the title compound as a yellow oil (141 mg). MS - (+) - ion, M + 1 = 471.1.

d. [(4-Hydroxy-1-methoxymethylisoquinoline-3-carbonyl) amino] acetic acid

A mixture of [(4-benzyloxy-1-methoxymethylisoquinoline-3-carbonyl) amino] acetic acid benzyl ester (134 mg, 0.285 mmol), Pd / C (100 mg, 10% wt. Pd), EtOAc (10 ml) and MeOH (50 ml) was stirred in an atmosphere of H ₂ at normal pressure and a temperature of 18 hours. Then the mixture is filtered through a layer of celite. Celite and filter cake were washed thoroughly with EtOAc and the combined organic phases were concentrated in vacuo to give the title compound as a beige solid (74 mg). MS - (-) - ion, M-1 = 289.2.

Example D-79

[(1-Dimethylcarbamoyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. 4-Benzyloxy-1-dimethylcarbamoylisoquinoline-3-carboxylic acid benzyl ester

To a solution of 1-bromo-4-hydroxyisoquinoline-3-carboxylic acid (670 mg, 2.5 mmol, example D-77 a) in anhydrous THF (100 ml), a 2.5 M solution of n-BuLi in hexanes is slowly added with stirring 4 ml, 10 mmol) at -78 ° C. After stirring for another 5 minutes, ClCONMe ₂ (468 μl, 5 mmol) was added. Stirring is continued for another 25 minutes at -78 ° C, then water (50 ml) and 6N are added. aqueous HCl (2 ml). The mixture was allowed to warm to room temperature with stirring, then concentrated in vacuo to approximately 1/3 of the volume and extracted with EtOAc (2x50 ml). The combined organic phases were dried over MgSO ₄ and concentrated in vacuo to give a yellow solid (501 mg). A mixture of 492 mg of the resulting yellow solid, benzyl bromide (0.6 ml, 5 mmol), K ₂ CO ₃ (2.07 g, 15 mmol) and acetone (40 ml) was refluxed with stirring for 2.5 days. Then the mixture was concentrated in vacuo. Water (20 ml) was added to the residue, and the mixture was extracted with EtOAc (50 ml). The organic phase was dried over MgSO ₄ and concentrated in vacuo to give a brown oil. Purification by flash chromatography on silica gel using hexanes: EtOAc (6: 4) as the eluent as the eluent gave the title compound as a yellow oil (311 mg). MS - (+) - ion, M + 1 = 441.1.

b. 4-Benzyloxy-1-dimethylcarbamoylisoquinoline-3-carboxylic acid

A mixture of 4-benzyloxy-1-dimethylcarbamoylisoquinoline-3-carboxylic acid benzyl ester (308 mg, 0.7 mmol), KOH (325 mg, 5 mmol) and EtOH (10 ml) was stirred at room temperature for 18 hours, then the solvent was evaporated in vacuum. Water (25 ml) was added to the residue, and the mixture was washed with Et ₂ O (2x25 ml). Then the solution is acidified by adding 6N. aqueous HCl and extracted with EtOAc (2x25 ml). The combined organic phases are dried over MgSO ₄ and concentrated in vacuo to afford the title compound as a yellowish gum (220 mg). MS - (+) - ion, M + 1 = 351.0.

from. [(4-Benzyloxy-1-dimethylcarbamoylisoquinoline-3-carbonyl) amino] acetic acid benzyl ester

To a mixture of 4-benzyloxy-1-dimethylcarbamoylisoquinoline-3-carboxylic acid (210 mg, 0.6 mmol), NEt ₃ (175 μl, 1.25 mmol) and CH ₂ Cl ₂ (12 ml), cooled in an ice bath, ClCO ₂ -iBu (83 μl, 0.63 mmol) was added with stirring. After stirring for 15 minutes, glycine benzyl ester hydrochloride (127 mg, 0.63 mmol) was added and the mixture was stirred for another 15 minutes, then the ice bath was removed. Stirring is continued at room temperature for another 1.5 hours. Then the mixture was concentrated in vacuo. Water (10 ml) and a few drops of 6N are added to the residue. aqueous HCl. The mixture was extracted with EtOAc (15 ml). The organic phase was dried over MgSO ₄ and concentrated in vacuo to give a yellowish oil. Purification by flash column chromatography on silica gel using hexanes: EtOAc (7: 3) as eluent afforded the title compound as a slightly yellowish gum (211 mg). MS - (+) - ion, M + 1 = 498.1.

d. [(1-Dimethylcarbamoyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

A mixture of benzyl ether [(4-benzyloxy-1-dimethylcarbamoylisoquinoline-3-carbonyl) amino] acetic acid (209 mg, 0.42 mmol), Pd / C (100 mg, 10% wt. Pd), EtOAc (10 ml) and MeOH (50 ml) was stirred in an atmosphere of H ₂ at normal pressure and room temperature for 18 hours. Then the mixture is filtered through a layer of celite. Celite and filter cake were washed thoroughly with EtOAc and the combined organic phases were concentrated in vacuo to afford the title compound as a brown solid (122 mg). MS - (+) - ion, M + 1 = 316.1.

Example D-80

[(4-Hydroxy-1-methyl-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

but. 1-bromo-4-hydroxy-6-phenoxyisoquinoline-3-carboxylic acid

Synthesized from 1-bromo-4-hydroxy-6-phenoxyisoquinoline-3-carboxylic acid butyl ester (Example D-8a) in a manner analogous to that of Example D-77a). ¹ H NMR (DMSO-d ₆ ): δ = 8.20 (d, 1H), 7.21-7.74 (m, 7H).

b. 4-Benzyloxy-1-methyl-6-phenoxyisoquinoline-3-carboxylic acid benzyl ester

To a solution of 1-bromo-4-hydroxy-6-phenoxyisoquinoline-3-carboxylic acid (721 mg, 2 mmol) in anhydrous THF (100 ml), a 2.5 M solution of n-BuLi in hexanes (3.2 ml) is slowly added with stirring , 8 mmol) at -78 ° C. After stirring for a further 10 minutes, MeI (253 μl, 4 mmol) was added dropwise. Stirring is continued for another 15 minutes at -78 ° C, then water (50 ml) and 2N are added. Hcl (5 ml). The mixture was allowed to warm to room temperature with stirring, then concentrated in vacuo to approximately 1/3 of its volume. The precipitate formed is filtered off with suction, washed with water and dried in vacuo to give a beige solid (758 mg). A mixture of 738 mg of the resulting beige solid, benzyl bromide (1.0 ml, 8 mmol), K ₂ CO ₃ (2.76 g, 20 mmol) and acetone (50 ml) was refluxed with stirring for 3 days. Then the mixture was concentrated in vacuo. Water (30 ml) was added to the residue, and the mixture was extracted with EtOAc (50 ml). The organic phase was dried over MgSO ₄ and concentrated in vacuo to give a yellowish oil. Purification by flash column chromatography on silica gel using hexanes: EtOAc (8: 2) as an eluent gave a beige solid. Recrystallization from MeOH gives the title compound as a slightly yellowish solid (172 mg). MS - (+) - ion, M + 1 = 476.1.

from. 4-Benzyloxy-1-methyl-6-phenoxyisoquinoline-3-carboxylic acid

Synthesized from 4-benzyloxy-1-methyl-6-phenoxyisoquinoline-3-carboxylic acid benzyl ester according to a procedure similar to that of Example D-78 b). MS - (+) - ion, M + 1 = 386.1.

d. [(4-Benzyloxy-1-methyl-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid benzyl ester

Synthesized from 4-benzyloxy-1-methyl-6-phenoxyisoquinoline-3-carboxylic acid in a manner analogous to that of Example D-78 c). MS - (+) - ion, M + 1 = 533.0.

e. [(4-Hydroxy-1-methyl-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from [(4-benzyloxy-1-methyl-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid benzyl ester according to a procedure analogous to that of Example D-78 d). MS - (+) - ion, M + 1 = 353.1.

Example D-81

[(4-Hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid

Synthesized from 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester (Example D-7 e) by a method similar to that of Example D-77 a). MS - (+) - ion, M + 1 = 359.9.

b. 4-Benzyloxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid benzyl ester

Synthesized from MeI and 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid in a manner analogous to that of Example D-78 a). MS - (+) - ion, M + 1 = 476.1.

from. 4-Benzyloxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid

Synthesized from 4-benzyloxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid benzyl ester according to a procedure similar to that of Example D-78 b). MS - (+) - ion, M + 1 = 386.0.

d. [(4-Benzyloxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid benzyl ester

Synthesized from 4-benzyloxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid in a manner analogous to that of Example D-78 c). MS - (+) - ion, M + 1 = 533.0.

e. [(4-Hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from [(4-benzyloxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid benzyl ester according to a procedure analogous to that of Example D-78d). MS - (+) - ion, M + 1 = 351.1.

Example D-82

[(4-Benzyloxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

A mixture of [(4-benzyloxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid benzyl ester (160 mg, 0.3 mmol; example D-81 d), KOH (325 mg, 5 mmol) and EtOH (10 ml) was stirred at room temperature for 18 hours, then the solvent was evaporated in vacuo. Water (5 ml) was added to the residue, and the mixture was washed with Et ₂ O ( ₂ x 20 ml). Then the solution is acidified by adding 6N. aqueous Hcl and extracted with EtOAc (2x20 ml). The combined organic phases are dried over MgSO ₄ and concentrated in vacuo to afford the title compound as a beige gum (93 mg). MS - (+) - ion, M + 1 = 443.0.

Example D-83

[(4-Ethoxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

but. 4-Ethoxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ethyl ester

To a solution of 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid (721 mg, 2 mmol; Example D-81 a) in anhydrous THF (100 ml), a 2.5 M solution of n-BuLi in hexanes (3.2 ml, 8 mmol) at -78 ° C. After stirring for another 5 minutes, MeI (253 μl, 4 mmol) was added dropwise. Stirring is continued for another 15 minutes at -78 ° C, then water (100 ml) and 2N are added. aqueous Hcl (5 ml). The mixture was allowed to warm to room temperature with stirring, then concentrated in vacuo to approximately 1/2 of its volume and extracted with EtOAc (300 ml). The organic phase was dried over MgSO ₄ and concentrated in vacuo to give an orange solid (462 mg). A mixture of 440 mg of the obtained orange solid, EtI (0.61 ml, 7.5 mmol), K ₂ CO ₃ (3.0 g, 21.7 mmol) and acetone (45 ml) was refluxed with stirring for 16 hours . Then the mixture was concentrated in vacuo. Water (30 ml) was added to the residue, and the mixture was extracted with EtOAc (2x50 ml). The combined organic phases are dried over MgSO ₄ and concentrated in vacuo to give a brown oil. Purification by flash silica gel column chromatography using hexanes: EtOAc (8: 2) as an eluent gave a yellowish oil (34 mg). ¹ H NMR (CDCl ₃ ): δ = 8.22 (d, 1H), 7.07-7.50 (m, 7H), 4.50 (q, 2H), 4.20 (q, 2H), 2.80 (s, 3H); 1.43-1.58 (m, 6H).

b. 4-ethoxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid

Synthesized from 4-ethoxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid ethyl ester in a manner analogous to that of Example D-78 b). MS - (+) - ion, M + 1 = 324.1.

from. [(4-Ethoxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid tert-butyl ester

Synthesized from glycine tert-butyl ester hydrochloride and 4-ethoxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid in a manner analogous to Example D-78 c). MS - (+) - ion, M + 1 = 437.1.

d. [(4-Ethoxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

A mixture of [(4-ethoxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid tert-butyl ester (14 mg, 0.032 mmol) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hours. Then the mixture was concentrated in vacuo, the residue was dissolved in EtOH (5 ml). The mixture was evaporated in vacuo to afford the title compound as a yellowish solid (12 mg). MS - (-) - ion, M-1 = 381.1.

Example D-84

[(1-Dimethylcarbamoyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino]

acetic acid

but. 4-Benzyloxy-1-dimethylcarbamoyl-7-phenoxyisoquinoline-3-carboxylic acid benzyl ester

Synthesized from 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid (Example D-81 a) by a procedure similar to that of Example D-79 a) (use 6 equivalents of ClCONMe ₂ , the reaction mixture after adding ClCONMe ₂ stirred at -78 ° C for 75 min, then add water and HCl). MS - (+) - ion, M + 1 = 533.2.

b. 4-Benzyloxy-1-dimethylcarbamoyl-7-phenoxyisoquinoline-3-carboxylic acid

Synthesized from 4-benzyloxy-1-dimethylcarbamoyl-7-phenoxyisoquinoline-3-carboxylic acid benzyl ester according to a procedure analogous to that of Example D-79 b). MS - (-) - ion, M-1 = 441.1.

from. [(4-Benzyloxy-1-dimethylcarbamoyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid benzyl ester

Synthesized from 4-benzyloxy-1-dimethylcarbamoyl-7-phenoxyisoquinoline-3-carboxylic acid in a manner analogous to that of Example D-79 c). MS - (+) - ion, M + 1 = 590.0.

d. [(1-Dimethylcarbamoyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino]

acetic acid

Synthesized from benzyl ether [(4-benzyloxy-1-dimethylcarbamoyl-7-phenoxyisoquinoline-3-carbonyl) amino]

acetic acid in a manner analogous to that of Example D-79 d). MS - (+) - ion, M + 1 = 410.0.

Example D-85

[(4-Hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

but. 4-Benzyloxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carboxylic acid benzyl ester

Synthesized from 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid (Example D-81 a) in a manner analogous to that of Example D-78 a). MS - (+) - ion, M + 1 = 506.2.

b. 4-Benzyloxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carboxylic acid

Synthesized from 4-benzyloxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carboxylic acid benzyl ester according to a procedure similar to that of Example D-78 b). MS - (+) - ion, M + 1 = 414.1.

from. [(4-Benzyloxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid benzyl ester

Synthesized from 4-benzyloxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carboxylic acid in a manner analogous to that of Example D-78 c). MS - (+) - ion, M + 1 = 563.1.

d. [(4-Hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from [(4-benzyloxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid benzyl ester according to a procedure analogous to that of Example D-78 d). MS - (+) - ion, M + 1 = 383.0.

Example D-86

[(4-Hydroxy-1-p-tolylisoquinoline-3-carbonyl) amino] acetic acid

but. 4-Benzyloxy-1-bromoisoquinoline-3-carboxylic acid butyl ester

A mixture of 1-bromo-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (6.48 g, 20 mmol; Example D-28 a), benzyl bromide (3.6 ml, 30 mmol), K ₂ CO ₃ (12.44 g, 90 mmol) and acetone (300 ml) are refluxed for 2.5 days. The solvent was evaporated in vacuo. Water (100 ml) was added to the residue, and the mixture was extracted with EtOAc (100 ml). The organic phase was dried over MgSO ₄ and evaporated in vacuo to give the title compound as a yellowish solid. MS - (+) - ion, M + 1 = 414.1.

b. 4-Benzyloxy-1-p-tolylisoquinoline-3-carboxylic acid butyl ester

4-Benzyloxy-1-bromisoquinoline-3-carboxylic acid butyl ether (207 mg, 0.5 mmol) and Pd (PPh ₃ ) ₄ (23 mg, 0.02 mmol) are dissolved in THF (3 ml) and the solution is stirred 10 min, then a solution of p-tolylboronic acid (68 mg, 0.5 mmol) in EtOH (0.5 ml) and a solution of Na ₂ CO ₃ (106 mg, 1 mmol) in water (0.5 ml) are added. The resulting mixture was refluxed for 4 hours. Then the mixture was concentrated in vacuo. Water (2 ml) was added to the residue, and the mixture was extracted with EtOAc (10 ml). The organic phase was dried over MgSO ₄ and evaporated in vacuo to give a yellowish oil (225 mg). Purification by flash column chromatography on silica gel using hexanes: EtOAc (94: 6) as the eluent afforded the title compound as a colorless oil. MS - (+) - ion, M + 1 = 426.2.

from. 4-hydroxy-1-p-tolylisoquinoline-3-carboxylic acid butyl ester

Synthesized from 4-benzyloxy-1-p-tolylisoquinoline-3-carboxylic acid butyl ester according to a procedure similar to that of Example D-78 d) (EtOAc was used as solvent). MS - (+) - ion, M + 1 = 336.2.

d. [(4-Hydroxy-1-p-tolylisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 4-hydroxy-1-p-tolylisoquinoline-3-carboxylic acid butyl ester according to a procedure similar to that of Example D-1 g). MS - (+) - ion, M + 1 = 337.1.

Example D-87

{[7- (4-Fluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} acetic acid

but. 1-Bromo-7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from 7- (4-fluorophenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester (Example D-96 e) in a manner analogous to Example D-1 e). ¹ H NMR (CDCl ₃ ): δ = 11.89 (s, 1H), 8.36 (d, 1H), 7.44-7.57 (m, 2H), 7.08-7.25 (m , 4H), 4.47 (q, 2H), 1.85 (m, 2H), 1.50 (m, 2H), 0.99 (t, 3H).

b. 7- (4-Fluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester

A mixture of 1-bromo-7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (434 mg, 1 mmol), Pd (PPh ₃ ) ₄ (116 mg, 0.1 mmol), trimethylboroxine (140 μl, 1 mmol), K ₂ CO ₃ (414 mg, 3 mmol) and 1,4-dioxane (8 ml) are refluxed with stirring for 2 hours. Then the mixture was concentrated in vacuo. Water (10 ml) was added to the residue. The mixture is acidified by adding 6N. aqueous Hcl and then extracted with EtOAc (40 ml). The organic phase was dried over MgSO ₄ and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes: EtOAc (94: 6) as eluent afforded the title compound as a white solid (229 mg). MS - (+) - ion, M + 1 = 370.1.

C. {[7- (4-Fluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} acetic acid

Synthesized from 7- (4-fluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 371.1.

The method described above can be used to synthesize other intermediates used in the invention.

Example D-88

{[1-Chloro-4-hydroxy-7- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

but. 4- (4-methoxyphenoxy) phthalonitrile

A mixture of 4-nitrophthalononitrile (4.00 g), 4-methoxyphenol (3.46 g) and potassium carbonate (6.39 g) in acetone (64 ml) was refluxed for 2 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with NaOH (1N, 50 ml), water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give the product (6.14 g). ¹ H NMR (200 MHz, CDCl ₃ ): δ 6.70 (d, J = 7.8 Hz, 1H), 7.21 (m, 2H), 6.96 (m, 4H), 3.84 ( s, 3H).

b. 4- (4-methoxyphenoxy) phthalic acid

Obtained by a method similar to that of example D-1 a). MS - (-) - ion, M-1 = 286.9.

c. [5- (4-Methoxyphenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid methyl ester

Obtained by a method similar to that of example D-37 b). ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.74 (d, J = 8.6 Hz, 1H), 7.25 (m, 2H), 6.98 (m, 4H), 4.40 ( s, 2H), 3.83 (s, 3H), 3.75 (s, 3H).

d. 6- and 7- (4-methoxyphenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-21 b). MS - (+) - ion, M + 1 = 384.10.

e. 7- (4-Methoxyphenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-21 c). MS - (+) - ion, M + 1 = 384.11.

f. 1-Chloro-4-hydroxy-7- (4-methoxyphenoxy) isoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-43 d). MS - (+) - ion, M + 1 = 402.0.

g. {[1-Chloro-4-hydroxy-7- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino}

acetic acid

Obtained by a method similar to that of example D-1 g). MS - (-) - ion, M-1 = 400.96.

Example D-89

{[4-Hydroxy-7- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

Synthesized from {[1-chloro-4-hydroxy-7- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid in a manner analogous to that of Example D-25. MS - (-) - ion, M-1 = 367.0.

Example D-90

{[1-Chloro-4-hydroxy-6- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

but. 6- (4-Methoxyphenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

6- and 7- (4-methoxyphenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester obtained in Example D-88 e) is isolated. MS - (+) - ion, M + 1 = 384.1.

b. 1-Chloro-4-hydroxy-6- (4-methoxyphenoxy) isoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-43 d). MS - (+) - ion, M + 1 = 402.0.

from. {[1-Chloro-4-hydroxy-6- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

Obtained by a method similar to that of example D-1 g). MS - (+) - ion, M + 1 = 403.0.

Example D-91

{[4-Hydroxy-6- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

Prepared by a method similar to that of Example D-2 a) from {[1-chloro-4-hydroxy-6- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid. MS - (-) - ion, M-1 = 367.0.

The compounds of examples D-92 to D-99 were prepared in a manner analogous to the method described in examples D-88 to D-91.

Example D-92

{[1-Chloro-4-hydroxy-7- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

but. 4- (4-Trifluoromethylphenoxy) phthalonitrile

¹ H NMR (200 MHz, CDCl ₃ ): δ 7.74 (m, 2H), 7.47 (d, J = 8.6 Hz, 1H), 7.25 (m, 3H), 6.87 ( d, J = 8.9 Hz, 1H).

b. 4- (4-trifluoromethylphenoxy) phthalic acid

¹ H NMR (200 MHz, DMSO-d ₆ ): δ 8.24 (d, J = 9.0 Hz, 1H), 7.75 (m, 3H), 7.19 (m, 3H).

from. [1,3-dioxo-5- (4-trifluoromethylphenoxy) -1,3-dihydroisoindol-2-yl] acetic acid methyl ester

¹ H NMR (200 MHz, CDCl ₃ ): δ 7.86 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.40-7, 13 (m, 4H), 4.43 (s, 2H), 3.76 (s, 3H).

d. 6- and 7- (4-trifluoromethylphenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of two isomers.

e. 7- (4-Trifluoromethylphenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

MS - (+) - ion, M + 1 = 422.0.

f. 1-Chloro-4-hydroxy-7- (4-trifluoromethylphenoxy) isoquinoline-3-carboxylic acid butyl ester

MS - (-) - ion, M-1 = 438.3.

g. {[1-Chloro-4-hydroxy-7- (4-trifluoromethylphenoxy) isoquinolin-3-

carbonyl] amino} acetic acid

MS - (-) - ion, M-1 = 439.0.

Example D-93

{[4-Hydroxy-7- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

MS - (-) - ion, M-1 = 405.1.

Example D-94

{[1-Chloro-4-hydroxy-6- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

a. 1,4-dihydroxy-6- (4-trifluoromethylphenoxy) isoquinoline-3-carboxylic acid butyl ester

MS - (+) - ion, M + 1 = 422.0.

b. 1-Chloro-4-hydroxy-6- (4-trifluoromethylphenoxy) isoquinoline-3-carboxylic acid butyl ester

¹ H NMR (200 MHz, CDCl ₃ ): δ 11.82 (s, 1H), 8.30 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.54 (dd, J = 9.0, 2.7 Hz, 1H), 7.18 (d, J = 8.2 Hz, 2H), 4.48 (t, J = 7.0 Hz, 2H), 1.85 (m, 2H), 1.46 (m, 2H), 0.98 (t, J = 7.0 Hz, 3H).

from. {[1-Chloro-4-hydroxy-6- (4-trifluoromethylphenoxy) isoquinolin-3-

carbonyl] amino} acetic acid

MS - (-) - ion, M-1 = 439.1.

Example D-95

{[4-Hydroxy-6- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

MS - (-) - ion, M-1 = 405.0.

Example D-96

{[1-Chloro-7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

but. 4- (4-Fluorophenoxy) phthalonitrile

¹ H NMR (200 MHz, CDCl ₃ ): δ 7.71 (d, J = 8.6 Hz, 1H), 7.23-7.15 (m, 6H).

b. 4- (4-Fluorophenoxy) phthalic acid

¹ H NMR (200 MHz, CDCl ₃ ): δ 7.74 (d, J = 8.9 Hz, 1H), 7.33-7.15 (m, 6H).

from. [5- (4-Fluorophenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid methyl ester

¹ H NMR (200 MHz, CDCl ₃ ): δ 7.80 (d, J = 7.4 Hz, 1H), 7.28 (m, 2H), 7.08 (m, 4H), 4.41 ( s, 2H); 3.76 (s, 3H).

d. 6- and 7- (4-fluorophenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of two isomers.

e. 7- (4-Fluorophenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

MS - (+) - ion, M + 1 = 372.1.

f. 1-Chloro-7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

¹ H NMR (200 MHz, CDCl ₃ ): δ 11.90 (s, 1H), 8.36 (d, J = 9.0 Hz, 1H), 7.56 (m, 2H), 7.10 ( m, 4H), 4.47 (t, J = 7.0 Hz, 2H), 1.85 (m, 2H), 1.46 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

g. {[1-Chloro-7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

MS - (-) - ion, M-1 = 389.0.

Example D-97

{[7- (4-Fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

MS - (-) - ion, M-1 = 355.1.

Example D-98

{[1-Chloro-6- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

but. 6- (4-Fluorophenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

MS - (+) - ion, M + 1 = 372.1.

b. 1-chloro-6- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

¹ H NMR (200 MHz, CDCl ₃ ): δ 11.77 (s, 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.50 (dd, J = 9.0.2.3 Hz, 1H), 7.10 (m, 4H), 4.46 (t, J = 7.0 Hz, 2H), 1, 85 (m, 2H), 1.45 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

from. {[1-Chloro-6- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

MS - (-) - ion, M-1 = 389.1.

Example D-99

{[6- (4-Fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

MS - (-) - ion, M-1 = 355.1.

Example D-100

{[4-Hydroxy-7- (pyridin-4-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid

but. 4- (pyridin-4-ylsulfanyl) phthalonitrile

A mixture of 4-nitrophthalononitrile (17.28 g), pyridin-4-thiol (10.68 g) and potassium carbonate (25.17 g) in N, N-dimethylformamide (160 ml) is heated to 85 ° C and stirred for 3 hours . After cooling, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (eluent: 15-30% ethyl acetate in methylene chloride) to obtain the title compound 13.29 g. ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.59 (d, J = 6.2 Hz, 2H), 7.68 (m, 3H), 7.24 (d, J = 6.3 Hz, 2H).

b. 4- (pyridin-4-ylsulfanyl) phthalic acid

Obtained by a method similar to that of example D-1a. MS - (+) - ion, M + 1 = 276.1.

from. [1,3-dioxo-5- (pyridin-4-ylsulfanyl) -1,3-dihydroisoindol-2-yl] acetic acid butyl ester

A solid mixture of 4- (pyridin-4-ylsulfanyl) phthalic acid (11.40 g) and glycine n-butyl ester hydrochloride (6.95 g) is heated in an oil bath (250 ° C) with effective stirring for 20 minutes, until the evaporation of water bubbles will not stop. After cooling, the mixture was partitioned between ethyl acetate (300 ml) and saturated aqueous sodium bicarbonate (150 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (300 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give 10.70 g of the title compound. MS - (+) - ion, M + 1 = 371.2.

d. 6- and 7- (Pyridin-4-ylsulfanyl) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Receive according to the method of example D-21 b).

e. 6- and 7- (Pyridin-4-ylsulfanyl) -1-chloro-4-hydroxyisoquinolin-3-carboxylic acid butyl ester

Receive according to the method of example D-43 d). MS - (+) - ion, M + 1 = 389.1.

f. 6- and 7- (Pyridin-4-ylsulfanyl) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-1 f). The crude product is purified by silica gel chromatography (50-80% ethyl acetate in methylene chloride) to give 7- (pyridin-4-ylsulfanyl) -1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-100A, MS- ( +) - ion, M + 1 = 355.04) and 6- (pyridin-4-ylsulfanyl) -1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ether (compound D-100B, MS - (+) - ion, M + 1 = 355.13).

g. {[4-Hydroxy-7- (pyridin-4-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid

Receive according to the method of example D-1 g). MS - (+) - ion, M + 1 = 356.1.

Example D-101

{[4-Hydroxy-6- (pyridin-4-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid

Prepared by a procedure similar to that of Example D-1 g) from 6- (pyridin-4-ylsulfanyl) -1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-100B). MS - (+) - ion, M + 1 = 356.1.

Example D-102

[(7-Benzenesulfinyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. 7-Benzenesulfinyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Suspension of a mixture of 4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester (300 mg) and OXONE ^® (Dupont Specialty Chemicals, Willmington, DE, USA) (366 mg) in a methanol / water mixture (3: 2, 5 ml ) stirred at room temperature for 4 hours. The reaction mixture was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium bicarbonate and water. Dry over magnesium sulfate and filter. The filtrate was concentrated and the residue was purified by silica gel chromatography (0-50% ethyl acetate in methylene chloride) to give the title compound, 7-benzenesulfinyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-102A) (50 mg) (MS- ( +) - ion, M + 1 = 370.1) and 7-benzenesulfonyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ether (compound D-102В) (90 mg) (MS - (+) - ion, M + 1 = 386.1).

b. [(7-Benzenesulfinyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

Prepared by a method similar to that of Example D-1 g) from 7-benzenesulfinyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-102A). MS - (+) - ion, M + 1 = 371.1.

Example D-103

[(7-Benzenesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

Prepared by a method similar to that of Example D-1 g) from 7-benzenesulfonyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-102B). MS - (+) - ion, M + 1 = 387.1.

Example D-104

[(6-Benzenesulfinyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. 6-Benzenesulfinyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Prepared by a method similar to that of Example D-18 a) from 4-hydroxy-6-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester. Two compounds were isolated by chromatography: the title compound 6-benzenesulfinyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-104A, MS - (+) - ion, M + 1 = 370.1) and 6- butyl ether benzenesulfonyl-4-hydroxyisoquinoline-3-carboxylic acid (compound D-104B, MS - (+) - ion, M + 1 = 386.1).

b. [(6-Benzenesulfinyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

Prepared by a procedure similar to that of Example D-1 g) from 6-benzenesulfinyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-104A). MS - (-) - ion, M-1 = 369.0.

Example D-105

[(6-Benzenesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

Prepared by a procedure similar to that of Example D-1 g) from 6-benzenesulfonyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-104B). MS - (-) - ion, M-1 = 385.1.

Example D-106

[(6-amino-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. Ethyl ether (5-nitro-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid

To a solution of a mixture of 5-nitroisoindole-1,3-dione (26.2 g) and ethyl bromoacetic acid (25.1 g) in acetone (500 ml) was added potassium carbonate (57.8 g). The resulting mixture was refluxed overnight (18 hours). After cooling, the reaction mass is filtered and washed with ethyl acetate. The filtrate was concentrated and the residue was triturated with ether (200 ml). The solid product is collected and washed with ether. Dry in vacuo to give the title compound (231.9 g). ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.69 (m, 2H), 8.07 (d, J = 8.2 Hz, 1H), 4.48 (s, 2H), 4.24 ( q, J = 7.0 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H).

b. (5-amino-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid ethyl ester

To a solution of ethyl ether (5-nitro-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid (10.0 g) in glacial acetic acid (150 ml) was added 10% palladium / C (50 % wet) (2.0 g). The mixture is intensively stirred in an atmosphere of H ₂ (cylinder pressure) at room temperature (18 hours). The catalyst is filtered through a pad of celite and washed with methylene chloride. The filtrate was concentrated to give the title compound (7.0 g). ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.59 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.81 (dd, J = 8.2, 2.0 Hz, 1H), 4.38 (br s, 2H), 4.36 (s, 2H), 4.20 (q, J = 7.0 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H).

from. [5-Benzhydrylydenamino) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid ethyl ester

To a mixture of ethyl ether (5-amino-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid (3.48 g), benzophenol (2.81 g) and DABCO (4.72 g) chlorobenzene (112 ml) titanium tetrachloride (1.99 g) is slowly added. The resulting mixture was heated at the boil under reflux for 2.5 hours. After cooling, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate. The filtrate was concentrated and the residue was purified by silica gel chromatography (25-40% ethyl acetate in hexanes) to give the title compound (3.03 g). MS - (+) - ion, M + 1 = 413.3.

d. 6- and 7- (Benzhydrylydenamino) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-21 b). MS - (+) - ion, M + 1 = 441.2.

e. 6- and 7-amino-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-43 d). The crude product is purified by chromatography on silica gel (elution with a mixture of 50% ethyl acetate in hexanes) to give the title compound. MS - (+) - ion, M + 1 = 295.1.

f. 6- and 7-amino-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

To a solution of 6- and 7-amino-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (220 mg) in ethyl acetate (5 ml) was added 10% Pd / C (50% wet, 110 mg) and then formate ammonium (471 ml). The resulting mixture was heated to boiling under reflux for 0.5 hour. After cooling, the reaction mixture was diluted with ethyl acetate (50 ml) and filtered. The filtrate was concentrated. The title compounds are obtained, 182 mg. MS - (+) - ion, M + 1 = 261.2.

g. 6- and 7-amino-4- (4-methoxybenzenesulfonyloxy) isoquinoline-3-carboxylic acid butyl ester

A mixture of 6- and 7-amino-4-hydroxyisoquinoline-3-carboxylic acid butyl ether (180 mg), 4-methoxybenzenesulfonyl chloride (145 mg) and triethylamine (85 mg) in methylene chloride (7 ml) was stirred at room temperature for 18 hours. The mixture was diluted with water (20 ml) and acidified to pH 4 with 0.1N. an aqueous solution of HCl. The two phases are separated and the aqueous layer is extracted with methylene chloride. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (55-80% ethyl acetate in hexanes) to give two products: 7-amino-4- (4-methoxybenzenesulfonyloxy) isoquinoline-3-carboxylic acid butyl ester (compound D-106A) (79 mg ) (MS - (+) - ion, M + 1 = 431.1) and 6-amino-4- (4-methoxybenzenesulfonyloxy) isoquinoline-3-carboxylic acid butyl ester (compound D-106B) (70 mg) (MS - (+) - ion, M + 1 = 431.1).

h. [(6-amino-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

Prepared from 6-amino-4- (4-methoxybenzenesulfonyloxy) isoquinoline-3-carboxylic acid butyl ester (compound D-106B) in a manner analogous to that of Example D-1 g). MS - (-) - ion, M-1 = 260.1.

Example D-107

{[4-Hydroxy-7- (4-methoxybenzenesulfonylamino) isoquinoline-3-carbonyl] amino} acetic acid

but. 7 - [(N, N-di-4-methoxybenzenesulfonyl) amino] -4- (4-methoxybenzenesulfonyloxy) isoquinoline-3-carboxylic acid butyl ester

A mixture of 7-amino-4- (4-methoxybenzenesulfonyloxy) isoquinoline-3-carboxylic acid butyl ether (compound D-106A) (75 mg), 4-methoxybenzenesulfonyl chloride (140 mg) and triethylamine (76 mg) in methylene chloride (2 ml) in a sealed vessel, heat in a microwave reactor to 120 ° C for 10 minutes After cooling, the reaction mixture was concentrated and purified by silica gel chromatography (eluting with 5-10% ethyl acetate in methylene chloride) to give the title compound (68 mg). MS - (+) - ion, M + 1 = 770.99.

b. {[4-Hydroxy-7- (4-methoxybenzenesulfonylamino) isoquinoline-3-carbonyl]

amino} acetic acid

A mixture of the above ester (68 mg) and glycine (86 mg) in a mixture of 0.5N. sodium methoxide / methanol (2.7 ml) in a sealed vessel is heated in a microwave reactor (150 ° C, 17 min). After cooling, the reaction mixture was concentrated. The residue was dissolved in water (10 ml) and extracted with ethyl acetate (15 ml). The aqueous layer is acidified with 2n. aqueous solution of HCl to pH 4 and extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was triturated with methanol and ethyl acetate / hexanes (1: 1) gave the title compound (14 mg). MS - (-) - ion, M-1 = 430.

Example D-108

{[4-Hydroxy-7- (3-phenylureido) isoquinoline-3-carbonyl] amino} acetic acid

but. 6- and 7- (3-phenylureido) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 6- and 7-amino-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (160 mg) and phenylisocyanate (73 mg) in methylene chloride (4 ml) was stirred at room temperature (18 hours) and concentrated. The residue was triturated with ethyl acetate / methylene chloride (1: 1, 8 ml). The insoluble solid is filtered off and washed with methylene chloride (5 ml). Dried to obtain 7- (3-phenylureido) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-108A) (82 mg). MS - (+) - ion, M + 1 = 380.18. The filtrate was concentrated and the residue was purified by silica gel chromatography, then crystallized from methanol to give 6- (3-phenylureido) -4-hydroxyisoquinoline-3-carboxylic acid (compound D-108B) (82 mg). MS - (+) - ion, M + 1 = 380.15.

b. {[4-Hydroxy-7- (3-phenylureido) isoquinoline-3-carbonyl] amino} acetic acid

Obtained from 7- (3-phenylureido) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-108A) in a manner analogous to that of Example D-1 g). MS - (-) - ion, M-1 = 379.07.

Example D-109

{[4-Hydroxy-6- (3-phenylureido) isoquinoline-3-carbonyl] amino} acetic acid

Obtained from 6- (3-phenylureido) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-108B) in a manner analogous to that of Example D-1 g). MS - (-) - ion, M-1 = 379.08.

Example D-110

[(4-Hydroxy-1-phenylsulfanylisoquinoline-3-carbonyl] amino} acetic acid

The title compound is prepared as follows. To a solution of 250 mg of [(1-chloro-4-hydroxyisoquinolin-3-carbonyl) amino] acetic acid (US Pat. No. 6,093,730, described as N - ((1-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) glycine) in 1 ml of 1-methyl-2-pyrrolidinone add 1.2 ml of benzothiol. The solution is heated at 130-150 ° C in a sealed tube for 16 hours. The solution was concentrated in vacuo. The resulting residue was crystallized from methanol to give 91 mg of a beige solid. MS - (-) m / z 353.07 (M-1).

Example D-111

{[1- (4-Chlorophenylsulfanyl) -4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

The title compound is prepared from [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid (US Pat. No. 6,093,730) and 4-chlorobenzenethiol under conditions analogous to the conditions of Example D-110. MS - (+) m / z 389.06 (M + 1).

Example D-112

[(4-Hydroxy-1-p-tolylsulfanylisoquinoline-3-carbonyl] amino} acetic acid

The title compound is prepared from [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid (US Pat. No. 6,093,730) and 4-methylbenzenethiol under conditions analogous to the conditions of Example D-110. MS - (-) m / z 367.09 (M-1).

Example D-113

{[4-Hydroxy-1- (pyridin-2-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid

The title compound is prepared from [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid (US Pat. No. 6,093,730) and 2-mercaptopropyridine under conditions analogous to the conditions of Example D-110. The final product is purified by silica gel column chromatography using a gradient of 3-15% methanol in dichloromethane with 0.5% acetic acid to elute the product. MS - (-) m / z 354.10 (M-1).

Example D-114

{[4-Hydroxy-1- (3-methoxyphenylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid

The title compound is prepared from [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid (US Pat. No. 6,093,730) and 3-methoxybenzenethiol under conditions analogous to the conditions of Example D-110. The final product is precipitated from a solution of ethyl acetate using hexanes. MS - (-) m / z 385.12 (M-1).

Example D-115

{[4-Hydroxy-1- (2-methoxyphenylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid

The title compound is prepared from [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid (US Pat. No. 6,093,730) and 2-methoxybenzenethiol under conditions analogous to the conditions of Example D-110. The final product is crystallized from dichloromethane. MS - (-) m / z 383.08 (M-1).

Example D-116

{[4-Hydroxy-1- (naphthalen-2-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid

The title compound is prepared from [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid (US Pat. No. 6,093,730) and 2-naphthalentiol under conditions similar to those of Example D-110. The final product is purified by trituration of the crude product twice with methanol and twice with dichloromethane. MS - (+) m / z 405.08 (M + 1).

Example D-117

[(1-Benzenesulfinyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

The title compound is prepared as follows. 50 mg of [(4-hydroxy-1-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid are dissolved in 0.3 ml of 1-methyl-2-pyrrolidinone and 0.7 ml of dichloromethane, example D-110. The solution was cooled to 0 ° C. and 26 mg of 75% 3-chloroperbenzoic acid was added. The solution was stirred for 2 hours at room temperature, then concentrated in high vacuum. The resulting residue was triturated with ethyl acetate to give 32 mg of the product as a white solid. MS - (-) m / z 369.08 (M-1).

Example D-118

[(1-Benzenesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

The title compound is prepared as follows. 50 mg of [(4-hydroxy-1-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid are dissolved in 0.1 ml of 1-methyl-2-pyrrolidinone and 0.7 ml of dichloromethane, example D-110. 72 mg of 75% 3-chloroperbenzoic acid was added to the solution. The solution was stirred for 6 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic fraction was dried over anhydrous magnesium sulfate and concentrated to a residue. The resulting residue was triturated with ethyl acetate to give 28 mg of the product as a white solid. MS - (-) m / z 385.09 (M-1).

Example D-119

{[4-Hydroxy-7- (pyridin-2-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid

but. 4- (pyridin-2-ylsulfanyl) phthalonitrile

10 g of 2-mercaptopropyridine, 14.2 g of 4-nitrophthalonitrile and 22.6 g of potassium carbonate are suspended in 250 ml of acetone and refluxed for 4 hours. The solution is filtered through a pad of celite and a coarse glass Schott filter to remove residual solids. The solution was concentrated to a crude residue and purified by silica gel column chromatography, eluting with a gradient of 0-10% ethyl acetate in dichloromethane. 6.4 g of product are obtained. ¹ H NMR (200 MHz, CDCl ₃ ): δ = 8.49-8.53 (m, 1H), 7.84-7.83 (dd, 1H), 7.76-7.71 (m, 2H ), 7.68-7.64 (dd, 1H), 7.40-7.36 (dt, 1H), 7.27-7.20 (m, 1H).

b. {[4-Hydroxy-7- (pyridin-2-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid

The title compound is prepared from 4- (pyridin-2-ylsulfanyl) phthalonitrile in a manner analogous to that of Example D-1. MS - (+) m / z 356.01 (M + 1).

Example D-120

{[4-Hydroxy-6- (pyridin-2-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid

The title compound is prepared from 4- (pyridin-2-ylsulfanyl) phthalonitrile in a manner analogous to that of Example D-119. MS - (+) m / z 356.02 (M + 1).

Example D-121

{[1-Chloro-4-hydroxy-6,7-diphenoxyisoquinoline-3-carbonyl] amino} acetic acid

but. 4,5-diphenoxyphthalonitrile

5.0 g of 4,5-dichlorophthalonitrile are dissolved in 50 ml of DMSO.

14.3 g of phenol are added and the solution is heated to 90 ° C. 6.9 g of potassium carbonate are added every five minutes until the total amount is 55.2 g. The mixture is stirred at 90 ° C for 30 minutes, then cooled and poured into 500 ml of ice water. The resulting solid precipitate was collected and crystallized from methanol to give 3.6 g of product. ¹ H NMR (200 MHz, CDCl ₃ ): δ = 7.49-7.38 (m, 4H), 7.32-7.25 (m, 2H), 7.15 (s, 2H), 7, 10-7.02 (m, 4H).

b. {[1-Chloro-4-hydroxy-6,7-diphenoxyisoquinoline-3-carbonyl] amino} acetic acid

The title compound is synthesized from 4,5-diphenoxyphthalonitrile in a manner analogous to that of Example D-7a-d) and Example D-9a-b). MS - (+) m / z 465.05 (M + 1).

Example D-122

[(4-Hydroxy-6,7-diphenoxyisoquinoline-3-carbonyl) amino] acetic acid

The title compound is synthesized from 4,5-diphenoxyphthalonitrile, Example D-121a), in a manner analogous to that of Example D-7. MS - (+) m / z 431.07 (M + 1).

Example D-123

({4-Hydroxy-7- [4- (toluene-4-ylsulfonylamino) phenoxy] isoquinoline-3-carbonyl} amino] acetic acid

but. 1-Chloro-4-hydroxy-6- (4- nitrophenoxy) isoquinoline-3-carboxylic acid butyl ester

200 mg of 1-chloro-4-hydroxy-6-phenoxyisoquinoline-3-carboxylic acid are dissolved in 3 ml of concentrated sulfuric acid, example D-10a). The reaction mixture was cooled to -20 ° C and 60 mg of potassium nitrate was slowly added to the solution with stirring. The reaction is carried out at a temperature of from -10 to -20 ° C with stirring for 15 minutes and poured into ice water. The aqueous mixture was extracted twice with ethyl acetate. The organic fractions were washed successively with saturated bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated to a residue under reduced pressure. The resulting solid was triturated with ethyl acetate, followed by methanol to give 103 mg of a white solid. MS - (+) m / z 417.07 (M + 1).

b. 6- (4-Aminophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

100 mg of 1-chloro-4-hydroxy-6- (4-nitrophenoxy) isoquinoline-3-carboxylic acid butyl ester are dissolved in 3 ml of THF and 3 ml of methanol. To the mixture were added 20 mg of sodium acetate and 25 mg of 10% palladium on charcoal, and the reaction mixture was stirred in a hydrogen atmosphere (balloon) overnight. The resulting solution was filtered through a pad of celite and concentrated to a residue. The crude material was purified by silica gel column chromatography, eluting with a gradient of 0-20% ethyl acetate in dichloromethane, to give 59 mg of the product. MS - (-) m / z 351.27 (M-1).

from. 4-hydroxy-7- [4- (toluene-4-sulfonylamino) phenoxy] isoquinoline-3-carboxylic acid butyl ester

58 mg of 6- (4-aminophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester, 15.8 mg of pyridine and 34 mg of p-toluenesulfonyl chloride are dissolved in 0.3 ml of dry dichloromethane. The mixture was stirred for 16 hours and then partitioned between 0.25N. HCl and ethyl acetate. The organic fraction was washed successively with water, saturated bicarbonate and brine, then dried over anhydrous sodium sulfate and concentrated to obtain 84 mg of a crude solid. The crude material was triturated with ethyl acetate to give 42 mg of a white solid. ¹ H NMR (200 MHz, CDCl ₃ ): δ = 11.7 (s, 1H), 8.72 (d, 1H), 7.93-7.88 (d, 1H), 7.69-7, 65 (d, 2H), 7.56-7.54 (m, 2H), 7.44-7.39 (dd, 1H), 7.27-7.13 (m, 5H), 7.00- 6.96 (d, 2H), 4.46 (t, 2H), 2.4 (s, 3H), 1.87-1.82 (quintet, 2H), 1.48-1.40 (quintet, 2H), 1.00-0.95 (t, 3H).

d. ({4-Hydroxy-7- [4- (toluene-4-sulfonylamino) phenoxy] isoquinoline-3-carbonyl}

amino] acetic acid

To a solution of 1.85 ml of a 0.5 M solution of sodium methoxide in methanol was added 42 mg of 4-hydroxy-7- [4- (toluene-4-sulfonylamino) phenoxy] isoquinoline-3-carboxylic acid butyl ester and 70 mg of glycine. The resulting mixture was heated at reflux for 24 hours and then cooled to room temperature. The reaction mixture was poured into 0.2N. an aqueous solution of HCl and then extracted with ethyl acetate three times. The organic fractions were dried over anhydrous sodium sulfate and concentrated to 41 mg of a white solid. MS - (+) m / z 508.10 (M + 1).

Example D-124

{[4-Hydroxy-7- (4-nitrophenoxy) isoquinoline-3-carbonyl] amino} acetic acid

but. 4-hydroxy-7- (4-nitrophenoxy) isoquinoline-3-carboxylic acid butyl ester

2.0 g of 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester are dissolved in 15 ml of TFA. Example D-7f). 0.375 ml of fuming nitric acid was slowly added to the solution, and the resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated in vacuo, the obtained residue was purified by silica gel column chromatography, eluting with 0-20% ethyl acetate in dichloromethane. The crude product is triturated with methanol to give 1.0 g of a white solid. MS - (+) m / z 383.01 (M + 1).

b. {[4-Hydroxy-7- (4-nitrophenoxy) isoquinoline-3-carbonyl] amino} acetic acid

The title compound is synthesized from 4-hydroxy-7- (4-nitrophenoxy) isoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (-) m / z 382.06 (M-1).

Example D-125

[(4-Mercapto-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

but. 4-Dimethylthiocarbamoyloxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester

To a solution of butyl ether of 1.5 g of 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid, example D-7f) in 6.3 ml of anhydrous DMF, 578 mg of dimethylthiocarbamoyl chloride and 1.5 g of 1,4-diazabicyclo are added [2.2. 2] octane. The mixture was stirred overnight at room temperature. The mixture is poured into 30 ml of 1N. HCl and extracted three times with 30 ml of ethyl acetate. The organic fractions were washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give 1.9 g of product. MS - (+) m / z 425.27 (M + 1).

b. 4-Dimethylcarbamoylsulfanyl-7-phenoxyisoquinoline-3-carboxylic acid butyl ester

A solution of 1.9 g of 4-dimethylthiocarbamoyloxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester in 22 ml of phenyl ether is heated at 190 ° C. for 2 hours. The solution was concentrated in vacuo to give a crude residue, which was purified by silica gel column chromatography, eluting with a gradient of 30-80% ethyl acetate in hexanes, and 1.73 g of the title compound are obtained. MS - (+) m / z 425.07 (M + 1).

from. 4-mercapto-7-phenoxyisoquinoline-3-carboxylic acid methyl ester

K 6.5 ml 0.5N 460 mg of 4-dimethylcarbamoylsulfanyl-7-phenoxyisoquinoline-3-carboxylic acid butyl ether are added to a solution of sodium methoxide in methanol. The resulting solution was heated to 50-60 ° C for 8 hours, cooled to room temperature and diluted with 10 ml of water and 7.0 ml of 1N. HCl. The resulting yellow precipitate was collected by filtering the solution through a Buchner medium-pore filter to obtain 307 mg of product. MS - (+) m / z 312.08 (M + 1).

d. [(4-Mercapto-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

To 4.3 ml of a 0.5 M solution of sodium methoxide in methanol, 75 mg of 4-mercapto-7-phenoxyisoquinoline-3-carboxylic acid methyl ester and 181 mg of glycine are added. The mixture was heated to 150 ° C. for 10 min using a CEM Discover microwave reactor (City, State). The resulting solution was cooled and acidified with 1N. HCl solution, a yellow precipitate is obtained. The precipitate was collected by filtering the solution through a Buchner medium pore filter to obtain 68 mg of product. MS - (-) m / z 353.02 (M-1).

Example D-126

[(4-Mercapto-7-trifluoromethylisoquinoline-3-carbonyl) amino] acetic acid

but. 4-hydroxy-7-trifluoromethylisoquinoline-3-carboxylic acid butyl ester

The title compound is prepared from 4-trifluoromethylphthalic acid under conditions analogous to the conditions of Example D-7a-f). MS - (+) m / z 314.1 (M + 1).

b. [(4-Mercapto-7-trifluoromethylisoquinoline-3-carbonyl) amino] acetic acid

The title compound is prepared from 4-hydroxy-7-trifluoromethylisoquinoline-3-carboxylic acid butyl ester under conditions analogous to the conditions of Example D-125. MS - (-) m / z 328.33 (M-1).

Example D-127

{[7- (4-Besolsulfonylaminophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

The title compound is synthesized from 4-hydroxy-7- (4-nitrophenoxy) isoquinoline-3-carboxylic acid butyl ester (Example D-124a) by a procedure analogous to that of Examples D-123b-d), replacing p-toluenesulfonyl chloride with benzenesulfonyl chloride in step c . MS - (+) m / z 494.09 (M + 1).

Example D-128

{[4-Hydroxy-7- (4-methanesulfonylaminophenoxy) isoquinoline-3-carbonyl] amino} acetic acid

The title compound is prepared from 4-hydroxy-7- (4-nitrophenoxy) isoquinoline-3-carboxylic acid butyl ester (Example D-124a) by a procedure similar to that of Examples D-123b-d), replacing p-toluenesulfonyl chloride with methanesulfonyl chloride in step c . MS - (-) m / z 430.03 (M-1).

Example D-129

{[7- (4-Chlorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

but. 4- (4-chlorophenoxy) phthalonitrile

Obtained by a method similar to that of example D-88 a). ¹ H NMR (200 MHz, DMSO): δ 8.09 (d, J = 9 Hz, 1H), 7.83 (d, J = 2.6.1H), 7.53 (d, J = 8, 6 Hz, 2H), 7.42 (dd, J = 2.8, 8.6 Hz, 1H), 7.24 (d, J = 8.6, 2H).

b. 4- (4-chlorophenoxy) phthalic acid

Obtained by a method similar to that of example D-1 a). MS - (-) - ion, M-1 = 291.0.

from. [5- (4-Chlorophenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid butyl ester

Obtained by a method similar to that of example D-100 c). ¹ H NMR (200 MHz, DMSO): δ 7.48 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 9.0 Hz, 2H), 7.46 (m, 2H ), 7.29 (d, J = 9.0 Hz, 2H), 4.46 (s, 2H), 4.16 (t, J = 6.2 Hz, 2H), 1.61 (m, 2H ), 1.38 (m, 2H), 0.92 (t, J = 7.0 Hz, 3H).

d. 6- and 7- (4-chlorophenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-1d). A mixture of two isomers. MS - (-) - ion, M-1 = 386.1.

e. 1-Chloro-6- and -7- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-43 d). A mixture of two isomers. MS - (-) - ion, M-1 = 404.2.

f. 6- and 7- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-1f). The two isomers are separated to give 7- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-129A), MS - (-) - ion, M-1 = 370.3) and butyl ether 6 - (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid (compound D-129B), MS - (-) - ion, M-1 = 370.3).

g. {[7- (4-Chlorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Prepared by a procedure similar to that of Example D-37 e) from 7- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-129A). MS - (-) - ion, M-1 = 371.0

Example D-130

{[6- (4-Chlorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Obtained according to a procedure similar to that of Example D-37 e), from 6- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-129B). MS - (-) - ion, M-1 = 371.1.

Example D-131

{[6- (3-Fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

but. 4- (3,4-difluorophenoxy) phthalonitrile

Obtained by a method similar to that of example D-88 a). ¹ H NMR (200 MHz, DMSO): δ 8.14 (d, J = 9 Hz, 1H), 7.95 (d, J = 2.6.1 H), 7.56 (dd, J = 2, 6, 8.6 Hz, 1H), 7.19 (dt, J = 2.4, 9.2 Hz, 1H), 7.04 (m, 2H).

b. 4- (3-Fluoro-5-methoxyphenoxy) phthalic acid

Obtained by a method similar to that of example D-1 a). One of the two fluorine atoms is replaced by a methoxy group during hydrolysis. MS - (-) - ion, M-1 = 305.0.

from. [5- (3-Fluoro-5-methoxyphenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid butyl ester

Obtained by a method similar to that of example D-100 c). ¹ H NMR (200 MHz, DMSO): δ 7.93 (d, J = 8.6 Hz, 1H), 7.43 (m, 2H), 6.79-6.63 (m, 3H), 4 41 (s, 2H), 4.10 (t, J = 6.2, 2H), 1.54 (m, 2H), 1.30 (m, 2H), 0.86 (t, J = 7 , 0, 3H).

d. 6- and 7- (3-fluoro-5-methoxyphenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-1 d). A mixture of two isomers. MS - (-) - ion, M-1 = 400.1.

e. 1-Chloro-6- and -7- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-43 d). A mixture of two isomers. MS - (-) - ion, M-1 = 418.3.

f. 6- and 7- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

To a solution of 1-chloro-6- and 7- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ether (176 mg) in ethyl acetate (3 ml) was added 10% Pd / C (50% wet, 70 mg) and then ammonium formate (264 mg). The resulting mixture was heated at the boil under reflux for 0.5 hour. After cooling, the reaction mass was diluted with ethyl acetate and filtered through a pad of celite. The filtrate was concentrated and separated by chromatography to obtain 64 mg of 7- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-131A) and 74 mg of 6- (3-fluoro butyl ether) -5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid (compound D-131B). ¹ H NMR (200 MHz, CD ₃ OD): δ 8.73 (s, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.71 (s, 1H), 7.59 (m, 1H), 6.65-6.47 (m, 3H), 4.49 (t, J = 6.6 Hz, 2H), 3.81 (s, 3H), 1.87 (m, 2H), 1.56 (m, 2H), 1.03 (t, J = 7.4, 3H).

g. {[6- (3-Fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino}

acetic acid

Prepared by a procedure similar to that of Example D-37 e) from 6- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-131B). MS - (-) - ion, M-1 = 385.1.

Example D-132

{[7- (3-Fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Prepared by a procedure similar to that of Example D-37 e) from 7- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-131 A). MS - (-) - ion, M-1 = 385.1.

Example D-133

{[7- (3,4-Difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

but. 5- (3,4-difluorophenoxy) isoindole-1,3-dione

3,4-Difluorophenol (650 mg) was dried by azeotropic distillation with benzene and dissolved in a solution of sodium methoxide in methanol (0.5 M, 10 ml). Then methanol is removed under reduced pressure in a nitrogen atmosphere. Then, a solution of 4-nitrophthalimide (769 mg) in anhydrous DMF (10 ml) was added to the resulting mixture. The resulting mixture was refluxed under nitrogen for 23 hours. The reaction mixture was cooled and 80 ml of water was added. The precipitate obtained is filtered off, washed with water (4 times) and dried, and the title compound 685 mg is obtained. MS - (-) - ion, M-1 = 274.3.

b. [5- (3,4-Difluorophenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid methyl ester

5- (3,4-difluorophenoxy) isoindole-1,3-dione (680 mg), potassium carbonate (1 g), 3-pentanone (20 ml) and methyl bromoacetate (295 μl) are added to the pressure tube. The resulting mixture was heated at 105 ° C for 17 hours. The reaction mixture was diluted with 20 ml of water and extracted with ethyl acetate (2 times). The organic layer was dried and concentrated. The mixture was purified by silica gel chromatography using hexanes: ethyl acetate (4: 1) and hexanes: ethyl acetate (3: 1) to give the title compound (657 mg). ¹ H NMR (200 MHz, DMSO): δ 7.95 (d, J = 9.0 Hz, 1H), 7.64-7.41 (m, 4H), 7.15-7.08 (m, 1H), 4.44 (s, 2H), 3.70 (s, 3H).

from. 6- and 7- (3,4-difluorophenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-1 d). A mixture of two isomers. MS - (-) - ion, M-1 = 388.1.

d. 1-Chloro-6- and -7- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-43 d). A mixture of two isomers is directly transferred to the next step.

e. 6- and 7- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-131 f). The two isomers are separated to give 7- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-133A) and 6- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3- butyl ester carboxylic acid (compound D-133B).

f. {[7- (3,4-Difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Prepared by a procedure similar to that of Example D-37 e) from 7- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-133A). MS - (-) - ion, M-1 = 373.2.

Example D-134

{[6- (3,4-Difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Prepared by a procedure similar to that of Example D-37 e) from 6- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-133B). MS - (-) - ion, M-1 = 373.2.

Example D-135

{[4-Hydroxy-7- (4-trifluoromethoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

but. 5- (4-Trifluoromethoxyphenoxy) isoindole-1,3-dione

Obtained by a method similar to that of example D-133 a). MS - (-) - ion, M-1 = 322.3.

b. [1,3-dioxo-5- (4-trifluoromethoxyphenoxy) -1,3-dihydroisoindol-2-yl] acetic acid methyl ester

Obtained by a method similar to that of example D-133 b) under reflux overnight. ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.83 (d, J = 8.6, 1H), 7.34-7.24 (m, 4H), 7.09 (d, J = 8, 6, 2H); 4.42 (s, 2H); 3.76 (s, 3H).

from. 1,4-dihydroxy-6- and 7- (3-trifluoromethoxyphenoxy) isoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-1 d). A mixture of two isomers. MS - (-) - ion, M-1 = 436.2.

d. 1-Chloro-4-hydroxy-6- and 7- (3-trifluoromethoxyphenoxy) isoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-43 d), using a microwave reactor, toluene as solvent and 1.5 equivalent of POCl ₃ . A mixture of two isomers is directly transferred to the next step.

e. Butyl ether 4-hydroxy-6- and 7- (3-trifluoromethoxyphenoxy) isoquinoline-3-carboxylic acid

Obtained by a method similar to that of example D-131 f). The two isomers are separated to give 4-hydroxy-7- (3-trifluoromethoxyphenoxy) isoquinoline-3-carboxylic acid butyl ester (compound D-135A), MS - (+) - ion, M + 1 = 422.2) and butyl ether 4-hydroxy-6- (3-trifluoromethoxyphenoxy) isoquinoline-3-carboxylic acid (compound D-135B), MS - (+) - ion, M-1 = 420.6).

f. {[4-Hydroxy-7- (4-trifluoromethoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

Prepared by a procedure similar to that of Example D-37 e) from 4-hydroxy-7- (3-trifluoromethoxyphenoxy) isoquinoline-3-carboxylic acid butyl ester (compound D-135 A). MS - (-) - ion, M-1 = 421.2.

Example D-136

{[4-Hydroxy-6- (4-trifluoromethoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

Prepared by a procedure similar to that of Example D-37 e) from 4-hydroxy-6- (3-trifluoromethoxyphenoxy) isoquinoline-3-carboxylic acid butyl ester (compound D-135B). MS - (-) - ion, M-1 = 421.1.

Example D-137

{[7- (3,5-Difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

but. [5- (3,5-Difluorophenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid ethyl ester

Ethyl ether (5-nitro-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid (2 g), 3,5-difluorophenol (1.12 g) was added to a 80 ml microwave reaction vessel potassium carbonate (1.39 g) and dimethylacetamide (27 ml). The resulting mixture was reacted in a microwave reactor at 100 ° C for 10 minutes. Water (280 ml) was added and the resulting precipitate was filtered off, washed with water and dried. Further purification by silica gel chromatography affords 0.94 g of the title compound. ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.86 (d, J = 8.2 Hz, 1H), 7.41-7.31 (m, 2H), 6.67-6.57 (m , 3H), 4.41 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H).

b. 6- and 7- (3,5-difluorophenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-1 d). A mixture of two isomers. MS - (+) - ion, M + 1 = 390.1.

from. 1-chloro-6- and 7- (3,5-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-43 d), except that the reaction was carried out in a microwave reactor at 135 ° C for 10 min using toluene as a solvent and 1.5 equivalent of POCl ₃ . A mixture of two isomers. MS - (-) - ion, M-1 = 406.2.

d. 6- and 7- (3,5-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-131 f). The two isomers are separated to give 7- (3,5-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-137A) (MS - (-) - ion, M-1 = 372.2) and butyl 6- (3,5-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid ester (compound D-137B) (MS - (+) - ion, M + 1 = 374.1).

e. {[7- (3,5-Difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Prepared by a procedure similar to that of Example D-37 e) from 7- (3,5-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-137A). MS - (-) - ion, M-1 = 373.1.

Example D-138

{[6- (3,5-Difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Prepared by a procedure similar to that of Example D-37 e) from 6- (3,5-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-137B). MS - (-) - ion, M-1 = 373.1.

Example D-139

({7- [4- (4-Fluorophenoxy) phenoxy] -4-hydroxyisoquinoline-3-carbonyl} amino) acetic acid

but. {5- [4- (4-Fluorophenoxy) phenoxy] -1,3-dioxo-1,3-dihydroisoindol-2-yl} acetic acid ethyl ester

Prepared by a method similar to that of Example D-137 a) by reaction of (5-nitro-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid ethyl ester with 4- (4-fluorophenoxy) phenol. ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.80 (d, J = 8.0 Hz, 1H), 7.31 (m, 2H), 7.06-7.01 (m, 8H), 4.39 (s, 2H); 4.21 (q, J = 7.2, 2H); 1.30 (t, J = 7.3, 3H).

b. 6- and 7- [4- (4-fluorophenoxy) phenoxy] -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-1 d). A mixture of two isomers. MS - (-) - ion, M-1 = 462.1.

from. 1-chloro-6- and 7- [4- (4-fluorophenoxy) phenoxy] -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-137 c). A mixture of two isomers. MS - (+) - ion, M + 1 = 482.1.

d. 6- and 7- [4- (4-fluorophenoxy) phenoxy] -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-131f). The two isomers are separated to give 7- [4- (4-fluorophenoxy) phenoxy] -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-139A), MS - (+) - ion, M + 1 = 448.1 ) and 6- [4- (4-fluorophenoxy) phenoxy] -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-139B), MS - (+) - ion, M + 1 = 448.2).

e. ({7- [4- (4-Fluorophenoxy) phenoxy] -4-hydroxyisoquinoline-3-carbonyl} amino) acetic acid

The title compound is prepared following a procedure analogous to that of Example D-37 e) from 7- [4- (4-fluorophenoxy) phenoxy] -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-139A). MS - (-) - ion, M-1 = 447.1.

Example D-140

({6- [4- (4-Fluorophenoxy) phenoxy] -4-hydroxyisoquinoline-3-carbonyl} amino) acetic acid

The title compound is prepared following a procedure analogous to that of Example D-37 e) from 6- [4- (4-fluorophenoxy) phenoxy] -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-139B). MS - (-) - ion, M-1 = 447.1.

Example D-141

{[7- (3-Chloro-4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

but. 5- (3-Chloro-4-fluorophenoxy) isoindole-1,3-dione

The named product is obtained by a method similar to that of Example D-133 a). MS - (-) - ion, M-1 = 290.5.

b. [5- (3-Chloro-4-fluorophenoxy) -1,3-dioxo-1,3-dihydroisoindol-2-yl] acetic acid methyl ester

The title product is obtained by a method similar to that of Example D-133b). ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.83 (d, J = 8.2 Hz, 1H), 7.32-7.14 (m, 4H), 6.99 (m, 1H), 4.42 (s, 2H); 3.77 (s, 3H).

from. 6- and 7- (3-chloro-4-fluorophenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-1 d). A mixture of two isomers. MS - (-) - ion, M-1 = 404.1.

d. 1-chloro-7- (3-chloro-4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-137 c). A mixture of two isomers. MS - (-) - ion, M-1 = 422.2.

e. 6- and 7- (3-Chloro-4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-1 f). The two isomers are separated to give 7- (3-chloro-4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-141A). ¹ H NMR (200 MHz, CDCl ₃ ): δ 11.91 (s, 1H), 8.64 (s, 1H), 8.38 (d, J = 9.0 Hz, 1H), 7.46 ( d, J = 9.4.1H), 7.24-7.16 (m, 3H), 7.04-6.98 (m, 1H), 4.50 (t, J = 6.8, 2H ), 1.88 (q, J = 7.2, 2H), 1.58-1.40 (m, 2H), 0.99 (t, J = 7.2, 3H). 6- (3-Chloro-4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ether (compound D-141B), MS - (+) - ion, M + 1 = 390.1) are also obtained.

f. {[7- (3-Chloro-4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Prepared by a procedure similar to that of Example D-37 e) from 7- (3-chloro-4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-141A). MS - (-) - ion, M-1 = 389.0.

Example D-142

{[6- (3-Chloro-4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Prepared by a procedure similar to that of Example D-37 e) from 6- (3-chloro-4-fluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-141B). MS - (-) - ion, M-1 = 389.0.

Example D-143

{[7- (4-Chlorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} acetic acid

but. 6- and 7- (4-chlorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester

Prepared by a method similar to that of Example D-87 b), from a mixture of 1-chloro-6- and 7- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (obtained in Example D-129e). However, pH regulation is excluded from the procedure. Two isomers are separated, 7- (4-chlorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester is obtained (compound of Example D-143a), MS - (+) - ion, M-1 = 386.1 ) and 6- (4-chlorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester (compound of Example D-143b), MS - (+) - ion, M-1 = 386.1).

b. {[7- (4-Chlorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} acetic acid

Prepared by a procedure similar to that of Example D-37 e), from 7- (4-chlorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester (compound of Example D-143a) by reaction in a work tube under pressure overnight at 90 ° C. MS - (-) - ion, M-1 = 385.0.

Example D-144

{[6- (4-Chlorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} acetic acid

Prepared by a procedure similar to that of Example D-37 e) from 6- (4-chlorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester (compound of Example D-143b) by reaction in a work tube pressure overnight at 90 ^C. MS - (-) - ion, M-1 = 385.0.

Example D-145

{[7- (3,5-Difluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} acetic acid

but. 6- and 7- (3,5-difluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of Example D-87 b), from a mixture of 1-chloro-6- and 7- (3,5-difluorophenoxy) -4-hydroxyisoquinoline-3-carboxylic acid butyl ester (obtained in Example D-137c) ) In the method of processing the mixture regulation of the pH value is excluded. Two isomers are separated, 7- (3,5-difluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester is obtained (compound of Example D-145 a1), MS - (-) - ion, M-1 = 386.3), and 6- (3,5-difluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester (compound of Example D-145 a2), MS - (-) - ion, M-1 = 386.3).

b. {[7- (3,5-Difluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino}

acetic acid

Prepared by a procedure similar to that of Example D-37 e) from 7- (3,5-difluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester (compound of Example D-145a1) by reaction in a tube for work under pressure during the night at 90 ° C. MS - (-) - ion, M-1 = 387.1.

Example D-146

{[4-Hydroxy-7- (4-methoxyphenoxy) -1-methylisoquinoline-3-carbonyl] amino} acetic acid

but. 6- and 7- (4-methoxyphenoxy) -1-bromo-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 6- and 7- (4-methoxyphenoxy) -1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-88 d) (3.0 g) and phosphorus oxybromide (3.4 g) in anhydrous toluene ( 40 ml) is heated in a microwave reactor (sealed tube) for 15 min at 130 ° C. After cooling, the reaction mixture was concentrated and saturated aqueous sodium bicarbonate (100 ml) was added. Stirred for 20 minutes and then ethyl acetate (2 x 100 ml) was added. The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (3.1 g). MS - (+) - ion, M + 1 = 446.05, 448.05.

b. 6- and 7- (4-methoxyphenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester

A mixture of 6- and 7- (4-methoxyphenoxy) -1-bromo-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (232 mg), Pd (PPh ₃ ) ₄ (60 mg), trimethylboroxine (65 mg) and potassium carbonate (216 mg) in dioxane (4 ml) is heated in a microwave reactor (sealed tube) for 10 min at 120 ° C. After cooling, the reaction mixture was diluted with water (15 ml). Acidify 2n. HCl to pH 4. Extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and separated by silica gel chromatography (eluting with a mixture of 25 to 50% ethyl acetate in hexanes) to give 7- (4-methoxyphenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester (35 mg) (compound D -146 b1) (MS - (+) - ion, M + 1 = 382.18) and 6- (4-methoxyphenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester (61 mg) (compound D-146 b2), MS - (+) - ion, M + 1 = 382.16).

from. {[4-Hydroxy-7- (4-methoxyphenoxy) -1-methylisoquinoline-3-carbonyl] amino}

acetic acid

Obtained from 7- (4-methoxyphenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester (compound D-146 b1) according to a procedure similar to that of Example D-107 b) (microwave reactor, temperature 120 ° C. , reaction time 10 min). MS - (-) - ion, M-1 = 381.09.

Example D-147

{[4-Hydroxy-6- (4-methoxyphenoxy) -1-methylisoquinoline-3-carbonyl] amino} acetic acid

Prepared from 6- (4-methoxyphenoxy) -4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester (compound D-146 b2) in a manner analogous to that of Example D-146 c). MS - (-) - ion, M-1 = 381.10.

Example D-148

[(6-Cyclohexyloxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. (5-Hydroxy-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid ethyl ester

Obtained by a method similar to that of Example D-100 c) from 4-hydroxyphthalic acid and the HCl salt of glycine ethyl ester. ¹ H NMR (200 MHz, DMSO-d ₆ ): δ 11.0 (br s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.17 (m, 2H), 4.35 (s, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.20 (t, J = 7.0 Hz, 3H).

b. (5-Cyclohexyloxy-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid ethyl ester

To a mixture of ethyl ether (5-hydroxy-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid (8.0 g) in anhydrous tetrahydrofuran (160 ml), cyclohexanol (3.2 g), diethyl azadicarboxylate (6.9 g) and then triphenylphosphine (12.6 g). The resulting mixture was stirred at room temperature overnight and concentrated. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography (eluted with 5% ethyl acetate in methylene chloride) to give the title compound (6.2 g). ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.73 (dd, J = 8.2, 0.8 Hz, 1H), 7.30 (br s, 1H), 7.12 (m, 1H ), 4.38 (m, 3H), 4.21 (q, J = 7.1 Hz, 2H), 2.02 (m, 2H), 1.82-1.25 (m, 13H).

from. 6- and 7-cyclohexyloxy-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

By a method similar to that of Example D-1 d), 7-cyclohexyloxy-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester is obtained (compound D-148с1), MS - (+) - ion, M + 1 = 360, 16) and 6-cyclohexyloxy-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ether (compound D-148c2), MS - (+) - ion, M + 1 = 360.18).

d. 1-Bromo-6-cyclohexyloxy-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Prepared by a procedure similar to that of Example D-146 a) from 6-cyclohexyloxy-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-148 c2). MS - (+) - ion, M + 1 = 422.10, 424.10).

e. 6-Cyclohexyloxy-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

To a mixture of 1-bromo-6-cyclohexyloxy-4-hydroxyisoquinoline-3-carboxylic acid butyl ether (1.0 g) in ethyl acetate (20 ml) was added 10% Pd / C (50% wet, 460 mg) and then ammonium formate (1.5 g). The resulting mixture was refluxed for 4 hours. After cooling, the reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography (5-10% ethyl acetate in methylene chloride) to give the title compound (640 mg). MS - (+) - ion, M + 1 = 344.22.

f. [(6-Cyclohexyloxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

Obtained by a method similar to that of example D-146 c). MS - (-) - ion, M-1 = 343.15.

Example D-149

[(7-Cyclohexyloxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Bromo-7-cyclohexyloxy-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Prepared by a procedure similar to that of Example D-146 a) from 7-cyclohexyloxy-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-148c1). MS - (+) - ion, M + 1 = 422.12, 424.12.

b. 7-cyclohexyloxy-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-148 e). MS - (+) - ion, M + 1 = 344.22.

from. [(7-Cyclohexyloxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

Obtained by a method similar to that of example D-146 c). MS - (-) - ion, M-1 = 343.17.

Example D-150

[(7-Cyclohexyloxy-4-hydroxy-1-methylisoquinoline-3-carbonyl) amino] acetic acid

but. 7-cyclohexyloxy-4-hydroxy-1-methylisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-146 b). MS - (+) - ion, M + 1 = 358.21.

b. [(7-Cyclohexyloxy-4-hydroxy-1-methylisoquinoline-3-carbonyl) amino] acetic acid

Obtained by a method similar to that of example D-146 c). MS - (+) - ion, M + 1 = 359.15.

Example D-151

[(7-Cyclohexylsulfanyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. Ethyl ester (5-cyclohexylsulfanyl-1,3-dioxo-1,3-dihydroisoindol-2-yl) acetic acid

A mixture of 5-nitroisoindole-1,3-dione (10.0 g), cyclohexanethiol (9.1 g) and potassium carbonate (18.7 g) in acetone (260 ml) was refluxed overnight. After cooling, the mixture was diluted with water (250 ml) and then acidified with 6N. HCl to pH 4. The precipitate was collected and dried in vacuo to give the intermediate 5-cyclohexylsulfanylisoindole-1,3-dione (15.6 g). The resulting intermediate was dissolved in acetone (170 ml), and bromoethyl acetate (10.6 g) and potassium carbonate (23.8 g) were added to the mixture. The mixture was refluxed overnight. After cooling, the reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated and purified by silica gel chromatography (10-50% ethyl acetate in methylene chloride) to give the title compound (13.1 g). ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.73 (m, 2H), 7.56 (dd, J = 7.8, 1.6 Hz, 1H), 4.40 (s, 2H), 4.21 (q, J = 7.0 Hz, 2H), 3.37 (m, 1H), 2.07-1.28 (m, 13H).

b. 6- and 7-cyclohexylsulfanyl-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ester

Obtained by a method similar to that of example D-21 b). MS - (+) - ion, M + 1 = 376.20.

c. 6- and 7-cyclohexylsulfanyl-1-chloro-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 6- and 7-cyclohexylsulfanyl-1,4-dihydroxyisoquinoline-3-carboxylic acid butyl ether (1.0 g) and phosphorus oxychloride (491 mg) in anhydrous toluene (14 ml) is heated in a microwave reactor (sealed tube) (180 ° C, 30 min). After cooling, the reaction mixture was quenched with saturated sodium bicarbonate. It is stirred at room temperature for 20 minutes and extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (0.5 g). MS - (+) - ion, M + 1 = 394.12.

d. 6- and 7-cyclohexylsulfanyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

Using a procedure similar to that of Example D-1 f), 7-cyclohexylsulfanyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (128 mg) (compound D-151 d1) (MS - (+) - ion, M + 1 = 360.15) and 6-cyclohexylsulfanyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (130 mg) (compound D-151 d2), MS - (+) - ion, M + 1 = 360.17).

e. [(7-Cyclohexylsulfanyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

Prepared by a procedure similar to that of Example D-1g) from 7-cyclohexylsulfanyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-151 d1). MS - (-) - ion, M-1 = 359.11.

Example D-152

[(7-Cyclohexanesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid

but. 7-cyclohexanesulfonyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester

A mixture of 7-cyclohexylsulfanyl-4-hydroxyisoquinoline-3-carboxylic acid butyl ester (compound D-151 d1) (64 mg) and m-chloroperbenzoic acid (111 mg) in methylene chloride (2 ml) was stirred at room temperature overnight. The mixture was diluted with methylene chloride (50 ml) and washed successively with saturated aqueous sodium bicarbonate (2x50 ml), water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography (eluted with 3-15% ethyl acetate in methylene chloride) to give the title compound (70 mg). MS - (+) - ion, M + 1 = 392.20.

b. [(7-Cyclohexanesulfonyl-4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid

Obtained by a method similar to that of example D-146 c). MS - (-) - ion, M-1 = 391.05.

Example D-153

[(4-Hydroxy-1-isobutylisoquinoline-3-carbonyl) amino] acetic acid

but. 4-Benzyloxy-1-isobutylisoquinoline-3-carboxylic acid butyl ester

A mixture of 4-benzyloxy-1-bromoisoquinoline-3-carboxylic acid butyl ester (207 mg, 0.5 mmol, see example D-86a), Pd (PPh ₃ ) ₄ (58 mg, 0.05 mmol), 2- methylpropylboronic acid (78 mg, 0.75 mmol), K ₂ CO ₃ (207 mg, 1.5 mmol) and 1,4-dioxane (4 ml) are refluxed with stirring for 48 hours. Then the mixture was concentrated in vacuo. Water (5 ml) was added to the residue, and the mixture was extracted with EtOAc (2 x 20 ml). The organic phase was dried over MgSO ₄ and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel using hexanes: EtOAc (88:12) as eluent to give the title compound as a yellowish oil (136 mg). MS - (+) - ion, M + 1 = 392.3.

b. 4-hydroxy-1-isobutylisoquinoline-3-carboxylic acid butyl ester

A mixture of 4-benzyloxy-1-isobutylisoquinoline-3-carboxylic acid butyl ester (125 mg, 0.32 mmol), Pd / C (50 mg, Aldrich, 10% wt. Pd) and EtOAc (15 ml) was stirred at normal pressure and temperature in an atmosphere of H ₂ within 24 hours. The mixture is filtered through a pad of celite. The filtrate was concentrated in vacuo to afford the title compound as a yellowish oil (87 mg). MS - (+) - ion, M + 1 = 302.2.

from. [(4-Hydroxy-1-isobutylisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 4-hydroxy-1-isobutylisoquinoline-3-carboxylic acid butyl ether according to a procedure analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 303.2.

Example D-154

[(4-Hydroxy-1-pyridin-2-yl-isoquinoline-3-carbonyl) amino] acetic acid

but. 4-Benzyloxy-1-pyridin-2-yl-isoquinoline-3-carboxylic acid butyl ester

To a solution of pyridin-2-yl-boronic acid (323 mg, 2.5 mmol) in EtOH (2.5 ml), toluene (15 ml), 4-benzyloxy-1-bromoisoquinoline-3-carboxylic acid butyl ether (1.035 mg) are successively added. 2.5 mmol, see example D-86 a), Pd (PPh ₃ ) ₄ (292 mg, 0.25 mmol) and an aqueous solution of 2 M Na ₂ CO ₃ (2.5 ml, 5 mmol). The mixture was then refluxed under N ₂ for 24 hours. Then the mixture was concentrated in vacuo. Water (15 ml) was added to the residue, and the mixture was extracted with EtOAc (30 ml). The organic phase was dried over MgSO ₄ and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using CH ₂ Cl ₂ : MeOH (98: 2) as an eluent gave a dark oil, which was further purified by flash column chromatography on silica gel using CH ₂ Cl ₂ : MeOH (99: 1) as an eluent and then preparative TLC using a mixture of CH ₂ Cl ₂ : MeOH (98: 2) as an eluent (must be repeated several times), the title compound is obtained as a yellow oil (19 mg). MS - (+) - ion, M + 1 = 413.2.

b. 4-hydroxy-1-pyridin-2-yl-isoquinoline-3-carboxylic acid butyl ester

Synthesized from 4-benzyloxy-1-pyridin-2-yl-isoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-153 b). MS - (-) - ion, M-1 = 321.4.

from. [(4-Hydroxy-1-pyridin-2-yl-isoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 4-hydroxy-1-pyridin-2-yl-isoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 324.1.

Example D-155

[(1-Ethyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

but. 4-hydroxy-7-phenoxy-1-vinylisoquinoline-3-carboxylic acid butyl ester

A mixture of 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester (416 mg, 1 mmol, see Example D-28 a), Pd (PPh ₃ ) ₄ (118 mg, 0.1 mmol) , a complex of 2,4,6-trivinylcyclotriboroxane-pyridine (241 mg, 1 mmol), K ₂ CO ₃ (414 mg, 3 mmol) and 1,4-dioxane (8 ml) are refluxed under N ₂ for 3 hours Then the mixture was concentrated in vacuo. Water (5 ml) was added to the residue, and the mixture was extracted with EtOAc (20 ml). The organic phase was dried over MgSO ₄ and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes: EtOAc (98: 2) as an eluent gave the title compound as a yellowish solid (65 mg). MS - (+) - ion, M + 1 = 364.1.

b. 1-Ethyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester

Synthesized from 4-hydroxy-7-phenoxy-1-vinylisoquinoline-3-carboxylic acid butyl ester according to a procedure similar to that of Example D-153 b). MS - (+) - ion, M + 1 = 366.1.

from. [(1-Ethyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid

Synthesized from 1-ethyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid butyl ester according to a procedure analogous to that of Example D-1 g). MS - (+) - ion, M + 1 = 367.1.

Example D-156

[(1-Dimethylaminomethyl-4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl)

amino] acetic acid

but. 1-Dimethylaminomethyl-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester

A mixture of 4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ester (177 mg, 0.5 mmol, see Example D-1f), N, N-dimethylmethyleneammonium iodide (94 mg, 0.5 mmol), K ₂ CO ₃ (104 mg, 0.75 mmol) and anhydrous CH ₂ Cl ₂ (3 ml) were stirred at room temperature for 2.5 hours, then the mixture was concentrated in vacuo. Water (15 ml) was added to the residue, the mixture was acidified by adding 6N. Hcl and then washed with Et ₂ O (3x30 ml). The mixture was then neutralized by adding concentrated aqueous NaHCO ₃ solution and extracted with EtOAc (20 ml). The organic phase was dried over MgSO ₄ and concentrated in vacuo to give the title compound as a dark oil (34 mg). MS - (+) - ion, M + 1 = 411.1.

b. [(1-Dimethylaminomethyl-4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl)

amino] acetic acid

Synthesized from 1-dimethylaminomethyl-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ether according to a procedure analogous to that of Example D-1g). MS - (+) - ion, M + 1 = 412.0.

Example D-157

[(4-Hydroxy-1-methyl-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid

but. 1-Bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid

1,4-dihydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid butyl ether (Example D-1d, compound A) (29.0 g) and phosphorus oxybromide (67.5 g) in 600 ml of anhydrous acetonitrile are stirred at reflux refrigerator for 4 hours. After cooling, the reaction mixture was concentrated, saturated sodium bicarbonate solution and ethyl acetate were added to the residue, and stirred overnight. The precipitate formed between the layers was collected and washed with water to give the title compound (10.2 g). MS - (+) - ion, M + 1 = 376.0, 378.1.

b. 1-bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid methyl ester

1-Bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid (10.0 g), potassium carbonate (3.7 g) and methyl sulfate (3.4 g) are suspended in 500 ml of acetone and stirred under reflux fridge overnight. The reaction mixture was concentrated, the residue was partitioned between 1N. hydrochloric acid and ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated to give the title compound (9.6 g). MS - (+) - ion, M + 1 = 389.9, 391.9.

from. 4-hydroxy-1-methyl-7-phenylsulfanylisoquinoline-3-carboxylic acid methyl ester

1-Bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylic acid methyl ester (0.2 g), tetrakis (triphenylphosphine) palladium (60 mg), trimethylboroxine (65 mg) and potassium carbonate in 1,4-dioxane ( 4 ml) is heated in a microwave reactor (sealed tube) for 10 min at 140 ° C. After cooling, the reaction mixture was concentrated and partitioned between 1N. hydrochloric acid and ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and separated by silica gel chromatography (eluted with 2% ethyl acetate in methylene chloride) to give the title compound (47 mg). MS - (+) - ion, M + 1 = 326.1.

d. [(4-Hydroxy-1-methyl-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid

Obtained by a method similar to that of example D-146 c). MS - (+) - ion, M + 1 = 369.1.

Example D-158

{[4-Hydroxy-1-methyl-7- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid

but. 4-hydroxy-1-methyl-7- (4-trifluoromethylphenoxy) isoquinoline-3-carboxylic acid butyl ester

Prepared by a method similar to that of Example D-157d) from 4-hydroxy-1-chloro-7- (4-trifluoromethylphenoxy) isoquinoline-3-carboxylic acid butyl ester (Example D-92f). MS - (+) - ion, M + 1 = 420.2.

b. {[4-Hydroxy-1-methyl-7- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl]

amino} acetic acid

Obtained by a method similar to that of example D-146 c). MS - (+) - ion, M + 1 = 421.2.

Claims (53)

1. The compound represented by formula I

where q is zero;
p is zero or one;
R ^a represents —COOH or —WR ⁸ ; provided that if R ^a is —COOH, then p is zero, and if R ^a is —WR ⁸ , then p is one;
W is selected from an oxygen atom and —NR ⁹ -, where R ^{9 is} selected from the group consisting of a hydrogen atom, acyl and alkyl; and R ^{8 is} selected from the group consisting of a hydrogen atom and an alkyl;
R ¹ selected from the group consisting of
hydrogen atom
alkyl
alkyl substituted with one group selected from alkoxy and dialkylamino,
halogen atom
heteroaryl containing up to six carbon atoms, one of which is nitrogen,
aminoacyl
aryl
alkyl substituted aryl, and
-XR ⁶ , where X represents an oxygen atom, -S (O) _n - or -NR ⁷ , where n is zero, one or two, R ^{6 is} selected from the group consisting of
alkyl, aryl,
aryl substituted with one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamido, heteroaryl containing up to six carbon atoms, one of
which is nitrogen, and R ⁷ represents a hydrogen atom or aryl;
R ² and R ^{3 are} independently selected from the group consisting of
hydrogen atom, amino,
amino substituted with alkoxy substituted phenylsulfonyl,
alkyl
alkyl substituted up to three times with a halogen atom,
aryl
halogen atom
-NR ⁶ C (O) NR ⁶ R ⁶ , and
—XR ⁶ , where X is an oxygen atom or —S (O) _n -, where n is zero, one or two, each of R ^{6 is} independently selected from the group consisting of
hydrogen atom
alkyl
alkyl substituted with aryl,
aryl
aryl substituted with one or two groups selected from
halogen atom
alkyl
alkyl substituted up to three times with halogen,
alkoxy
alkoxy substituted up to three times with halogen,
aryloxy substituted with halogen,
nitro
alkylsulfonamido,
arylsulfonamido and
alkyl substituted arylsulfonamide,
cycloalkyl
heteroaryl containing up to six carbon atoms, one of which is nitrogen,
with the proviso that if X is —SO ₂ -, then R ⁶ cannot be a hydrogen atom;
or R ² and R ³ , together with the carbon atoms to which they are attached, are combined to form an aryl group;
R ⁴ and R ^{5 are} independently selected from a hydrogen atom and aryl;
R is selected from the group consisting of hydrogen, deuterium and methyl;
R 'is selected from the group consisting of
hydrogen atom
deuterium
alkyl and
alkyl substituted with one group selected from
hydroxy
amino,
carboxyl
aryl
aryl substituted with one hydroxy and
heteroaryl containing up to five carbon atoms, two of which may be nitrogen;
on the other hand, R and R ′ and the carbon atom to which they are attached can be combined to form cycloalkyl;
R "is selected from a hydrogen and alkyl atom, or R" together with R 'and the nitrogen atom to which they are attached can be combined to form a heterocyclic group containing up to six carbon atoms, one of which is nitrogen;
R '"is selected from the group consisting of
hydroxy
alkoxy
alkoxy substituted with aryl,
acyloxy
aryl
—S (O) _n —R ¹⁰ where R ¹⁰ is hydrogen and n is zero;
or its pharmaceutically acceptable salts, esters or amides;
provided that if the substituents R, R 'and R "represent a hydrogen atom and q is zero, and the substituent R ^a is either —COOH (p is zero) or —WR ⁸ (p is 1), and W represents an oxygen atom, and R ⁸ represents a hydrogen atom, then at least one of the following occurs:
1) R ¹ represents fluorine, bromine, iodine, alkyl, alkyl, substituted with one group selected from alkoxy and dialkylamino, heteroaryl containing up to six carbon atoms, one of which is nitrogen, aminoacyl, aryl, aryl, substituted at least one alkyl, and -XR ⁶ , where X represents an oxygen atom, -S (O) _n - or -NR ⁷ -, where n is zero or two, R ^{6 is} selected from the group consisting of alkyl, aryl, aryl, substituted with one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamido, and heteroaryl containing to six carbon atoms, one of which is nitrogen and R ⁷ is hydrogen or aryl; or
2) R ² represents alkyl substituted by at least one halogen atom, aryl, fluorine, bromine, iodine, —XR ⁶ , where X represents an oxygen atom or —S (O) _n -, where n is zero, one or two, R ^{6 is} selected from the group consisting of alkyl, alkyl substituted by at least one aryl, aryl, aryl substituted by at least one group selected from a halogen atom, alkyl, alkyl substituted by at least one group selected from a halogen atom, alkoxy, alkoxy substituted with at least one group selected from a halo atom ene, aryloxy, substituted with at least one group selected from halogen, nitro, alkylsulfonamido, arylsulfonamido and alkyl-substituted arylsulfonamide, and heteroaryl containing up to six carbon atoms, one of which is nitrogen; provided that
a) if R ² is substituted alkyl, such a substituent does not include trifluoromethyl;
b) —XR ^{6 is} not an alkoxy group; and
c) if —XR ⁶ is a substituted alkoxy group, such a substituent does not include benzyl or benzyl substituted with a substituent selected from the group consisting of (C ₁ -C ₅ ) -alkyl and (C ₁ -C ₅ ) -alkoxy, or does not include fluoroalkoxy substituent of the formula
-O- [CH ₂ ] _x -C _f H _{(2f + 1-g)} F _g ,
where x is zero or one; f takes integer values from 1 to 5; and g takes integer values from 1 to (2f + 1); or
3) R ³ is alkyl substituted by at least one halogen atom, aryl, bromine, iodine, —XR ⁶ , where X is an oxygen atom or —S (O) _n -, where n is zero, one or two , R ^{6 is} selected from the group consisting of alkyl, alkyl substituted by at least one aryl, aryl, aryl substituted by at least one group selected from a halogen atom, alkyl, alkyl substituted by at least one group selected from an atom halogen, alkoxy, alkoxy substituted with at least one group selected from a halogen atom, riloksi substituted with at least one group selected from halogen, nitro, alkylsulfonamido, arylsulfonamido and alkyl substituted arylsulfonamide, and heteroaryl containing up to six carbon atoms, one of which is nitrogen; provided that
a) if R ³ is substituted alkyl, such a substituent does not include trifluoromethyl;
b) —XR ^{6 is} not an alkoxy group; and
c) if —XR ⁶ is a substituted alkoxy group, such a substituent does not include benzyl or benzyl substituted with a substituent selected from the group consisting of (C ₁ -C ₅ ) -alkyl and (C ₁ -C ₅ ) -alkoxy, or does not include fluoroalkoxy substituent of the formula
-O- [CH ₂ ] _x -C _f H _{(2f + 1-g)} F _g ,
where x is zero or one; f takes integer values from 1 to 5; and g takes integer values from 1 to (2f + 1); or
4) R ⁴ represents aryl;
5) R ⁵ represents aryl;
and under the following additional conditions:
if the substituents R ¹ , R ³ , R ⁴ and R ⁵ represent a hydrogen atom, then the substituent R ^{2 is} not a bromine atom. 2. The compound according to claim 1, where the specified compound is represented by formula IA

where the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R, R ', R ", R'" and q are as defined above; or
its pharmaceutically acceptable salts, esters or amides. 3. The compound according to claim 1, where the specified compound is represented by formula IB

where the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ", R '", WR ⁸ and q are as defined above; or
its pharmaceutically acceptable salts, esters or amides. 4. The compound according to claim 1, where the specified compound is represented by formula IC

where the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R, R ′, R ″, R ″, WR ⁸ and q are as defined above; or
its pharmaceutically acceptable salts, esters or amides. 5. The compound according to claim 1, where the specified compound is represented by formula ID

where the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ", R '" and q are as defined above; or
its pharmaceutically acceptable salts, esters or amides. 6. The compound according to claim 1, where the substituent R ¹ selected from the group including
(3-methoxyphenyl) sulfanyl;
(dimethylamino) methyl;
(N, N-dimethylamino) carbonyl;
2-fluorophenoxy;
2-methoxyphenoxy;
4- (methylcarbonylamino) phenoxy;
4- (methylsulfonamido) phenoxy;
4-chlorophenoxy;
4-chlorophenyl;
4-chlorophenylsulfanyl;
4-fluorophenoxy;
4-methoxyphenoxy;
4-methoxyphenylsulfanyl;
4-methylphenyl;
bromine;
butoxy;
chlorine;
ethoxy;
ethyl;
ethylsulfanyl;
fluorine;
hydrogen;
iodine;
isopropoxy;
isopropyl;
methoxy;
methoxymethyl;
methyl;
naphthylsulfanyl;
naphth-2-yloxy;
phenoxy;
phenyl;
phenylamino;
phenylsulfanyl;
phenylsulfonyl;
pyridin-1-ylsulfanyl;
pyridin-2-yl;
pyridin-2-ylsulfanyl;
pyridin-3-yloxy; and
pyridin-4-ylsulfanyl. 7. The compound according to claim 1, where the Deputy R ² selected from the group including
(4-methoxy) phenylsulfonylamino;
2,6-dimethylphenoxy;
3,4-difluorophenoxy;
3,5-difluorophenoxy;
3-chloro-4-fluorophenoxy;
3-methoxy-4-fluorophenoxy;
3-methoxy-5-fluorophenoxy;
4- (methylsulfonamido) phenoxy;
4- (phenylsulfonamido) phenoxy;
4-CF ₃ -O-phenoxy;
4-CF ₃ -phenoxy;
4-chlorophenoxy;
4-fluorophenoxy;
4- (4-fluorophenoxy) phenoxy;
4-methoxyphenoxy;
4-nitrophenoxy;
benzyloxy;
bromine;
butoxy;
CF ₃ ;
chlorine;
cyclohexyloxy;
cyclohexylsulfanyl;
cyclohexylsulfonyl;
fluorine;
hydrogen;
iodine;
isopropoxy;
methyl;
phenoxy;
phenyl;
phenylsulfanyl;
phenylsulfinyl;
phenylsulfonyl;
phenylurea;
pyridin-1-ylsulfanyl;
pyridin-3-yloxy group; and
pyridin-4-ylsulfanyl. 8. The compound according to claim 1, where the Deputy R ³ selected from the group including
an amino group;
A (4-methyl) phenylsulfonylaminophenoxy group;
3,4-difluorophenoxy group;
3,5-difluorophenoxy group;
3-fluoro-5-methoxyphenoxy group;
3-chloro-4-fluorophenoxy;
4-CF ₃ -O-phenoxy;
4-CF ₃ -phenoxy;
4-chlorophenoxy;
4-fluorophenoxy;
4- (4-fluorophenoxy) phenoxy group;
4-methoxyphenoxy;
benzyloxy group;
bromine;
butoxy group;
CF ₃ ;
chlorine;
cyclohexyloxy group;
hydrogen;
iodine;
isopropoxy group;
phenoxy group;
phenyl;
phenylsulfanyl;
phenylsulfonyl;
phenylsulfinyl;
phenylurea;
pyridin-1-ylsulfanyl;
pyridin-3-yloxy group and
pyridin-4-ylsulfanyl. 9. The compound according to claim 1, where the substituents R ² and R ³ together with the carbon atom to which they are attached form an aryl group. 10. The compound of claim 9, wherein said aryl group is phenyl. 11. The compound according to claim 1, where the substituent R ⁴ represents phenyl. 12. The compound according to claim 1, where the substituent R ⁵ represents phenyl. 13. The compound according to claim 1, where the Deputy R is selected from the group comprising a hydrogen atom, deuterium and methyl. 14. The compound according to claim 1, where the substituent R 'is selected from the group including
4-aminobutyl; 4-hydroxybenzyl; benzyl; carboxymethyl; deuterium; hydroxymethyl; imidazol-4-ylmethyl; isopropyl; methyl; and drank. 15. The compound according to claim 1, where the substituents R, R 'and the carbon atom to which they are attached form cycloalkyl. 16. The compound of claim 15, wherein said cycloalkyl is cyclopropyl. 17. The compound according to claim 1, where the substituent R "represents a hydrogen atom. 18. The compound according to claim 1, where the substituents R ', R "and the carbon atom and the nitrogen atom, respectively, with which they are connected, form a heterocyclic group containing up to six carbon atoms, one of which is nitrogen. 19. The compound of claim 18, wherein said heterocyclic group is pyrrolidinyl. 20. The compound according to claim 1, where the substituent R ″ is selected from the group consisting of hydroxy, benzyloxy; ethoxy; thiol; methoxy; methylcarbonyloxy; and phenyl. 21. The compound according to claim 1, where WR ^{8 is} selected from the group comprising amino; dimethylamino; hydroxy; methoxy; and methylcarbonylamino. 22. The compound according to claim 1, where the specified compound is represented by formula IIA

where q is zero;
R ¹ selected from the group consisting of a hydrogen atom, alkyl, alkyl, substituted by one group selected from alkoxy and dialkylamino, a halogen atom, heteroaryl containing up to six carbon atoms, one of which is nitrogen, aminoacyl, aryl, aryl, substituted by alkyl , and —XR ⁶ , where X is an oxygen atom, —S (O) _n - or —NR ⁷ -, where n is zero, one or two, R ^{6 is} selected from the group consisting of alkyl, aryl, aryl, substituted with one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamido, hetero reel containing up to six carbon atoms, one of which is nitrogen and R ⁷ is hydrogen or aryl;
R ² and R ^{3 are} independently selected from the group consisting of a hydrogen atom, alkyl, alkyl substituted up to three times by a halogen atom, aryl, halogen atom, and —XR ⁶ , where X represents an oxygen atom or —S (O ) _n -, where n is zero, one or two, R ^{6 is} selected from the group consisting of alkyl, alkyl substituted with aryl, aryl, aryl substituted with one or two groups selected from a halogen atom, alkyl, alkyl substituted with three times with a halogen atom, alkoxy, alkoxy substituted up to three times with a halogen atom, aryloxy substituted with one them with a halogen atom, nitro, alkylsulfonamido, arylsulfonamido and alkyl-substituted arylsulfonamide, and heteroaryl containing up to six carbon atoms, one of which is nitrogen;
R ⁴ and R ^{5 are} independently selected from a hydrogen atom and aryl;
R is selected from the group consisting of hydrogen and methyl;
R ′ is selected from the group consisting of alkyl and alkyl substituted with hydroxy, amino, carboxyl, aryl, aryl substituted with one hydroxy, and heteroaryl containing up to five carbon atoms, two of which may be nitrogen; on the other hand, R and R ′ may be combined to form cycloalkyl;
R "is selected from a hydrogen and alkyl atom; or R" together with R 'and the nitrogen atom to which they are attached can be combined to form a heterocyclic group containing up to six carbon atoms, one of which is nitrogen;
or its pharmaceutically acceptable salts, esters or amides. 23. The compound according to claim 1, where the specified compound is represented by formula IIB

where q is zero;
W is selected from the group consisting of an oxygen atom and —NR ⁹ -, where R ^{9 is} selected from the group consisting of a hydrogen atom, acyl and alkyl;
R ^{8 is} selected from the group consisting of a hydrogen atom and an alkyl;
R "is selected from a hydrogen atom and an alkyl;
R ^{1 is} selected from the group consisting of a hydrogen atom, alkyl, alkyl substituted with one group selected from alkoxy and dialkylamino, a halogen atom, heteroaryl containing up to six carbon atoms, one of which is nitrogen, aminoacyl, aryl, aryl, substituted with one alkyl, and —XR ⁶ , where X represents an oxygen atom, —S (O) _n - or —NR ⁷ -, where n is zero, one or two, R ^{6 is} selected from the group consisting of alkyl, aryl, aryl substituted by one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamido, g a heteroaryl containing up to six carbon atoms, one of which is nitrogen, and R ⁷ represents a hydrogen atom or aryl;
R ² and R ^{3 are} independently selected from the group consisting of a hydrogen atom, alkyl, alkyl substituted up to three times by a halogen atom, aryl, halogen atom, and —XR ⁶ , where X represents an oxygen atom or —S (O ) _n -, where n is zero, one or two, R ^{6 is} selected from the group consisting of alkyl, alkyl substituted with aryl, aryl, aryl substituted with one or two groups selected from a halogen atom, alkyl, alkyl substituted with three times with a halogen atom, alkoxy, alkoxy substituted up to three times with a halogen atom, aryloxy substituted with one them with a halogen atom, nitro, alkylsulfonamido, arylsulfonamido and alkyl-substituted arylsulfonamide, and heteroaryl containing up to six carbon atoms, one of which is nitrogen;
R ⁴ and R ^{5 are} independently selected from a hydrogen atom and aryl;
or its pharmaceutically acceptable salts, esters or amides. 24. The compound according to claim 1, where the specified compound is represented by formula IIC

where q is zero;
R ^{1 is} selected from the group consisting of a hydrogen atom, alkyl, alkyl substituted with one group selected from alkoxy and dialkylamino, a halogen atom, heteroaryl containing up to six carbon atoms, one of which is nitrogen, aminoacyl, aryl, aryl, substituted with one alkyl, and —XR ⁶ , where X represents an oxygen atom, —S (O) _n - or —NR ⁷ -, where n is zero, one or two, R ^{6 is} selected from the group consisting of alkyl, aryl, aryl substituted by one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamido, g a heteroaryl containing up to six carbon atoms, one of which is nitrogen and R ⁷ represents a hydrogen atom or aryl;
R ² and R ^{3 are} independently selected from the group consisting of a hydrogen atom, alkyl, alkyl substituted up to three times by a halogen atom, aryl, halogen atom, and —XR ⁶ , where X represents an oxygen atom or —S (O ) _n -, where n is zero, one or two, R ^{6 is} selected from the group consisting of alkyl, alkyl substituted with aryl, aryl, aryl substituted with one or two groups selected from a halogen atom, alkyl, alkyl substituted with three times with a halogen atom, alkoxy, alkoxy substituted up to three times with a halogen atom, aryloxy substituted with one them with a halogen atom, nitro, alkylsulfonamido, arylsulfonamido and alkyl-substituted arylsulfonamide, and heteroaryl containing up to six carbon atoms, one of which is nitrogen;
R ⁴ and R ^{5 are} independently selected from a hydrogen atom and aryl;
R is selected from the group consisting of hydrogen and methyl;
R 'is selected from the group consisting of alkyl; or R and R ′ may be combined to form cycloalkyl;
R "is selected from the group consisting of a hydrogen atom and an alkyl, or R" together with R 'and the nitrogen atom to which it is attached forms a heterocyclic group containing up to six carbon atoms, one of which is nitrogen;
W is selected from the group consisting of an oxygen atom and —NR ⁹ -, where R ^{9 is} selected from the group consisting of a hydrogen atom, acyl and alkyl;
R ^{8 is} selected from the group consisting of a hydrogen atom and an alkyl; or
its pharmaceutically acceptable salts, esters or amides. 25. The compound according to claim 1, where the specified compound is represented by the formula IID

where q is zero;
R "is selected from a hydrogen atom and an alkyl;
R ^{1 is} selected from the group consisting of a hydrogen atom, alkyl, alkyl substituted with one group selected from alkoxy and dialkylamino, a halogen atom, heteroaryl containing up to six carbon atoms, one of which is nitrogen, aminoacyl, aryl, aryl, substituted with one alkyl, and —XR ⁶ , where X represents an oxygen atom, —S (O) _n - or —NR ⁷ -, where n is zero, one or two, R ^{6 is} selected from the group consisting of alkyl, aryl, aryl substituted by one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamido, g a heteroaryl containing up to six carbon atoms, one of which is nitrogen, and R ⁷ represents a hydrogen atom or aryl;
R ² and R ^{3 are} independently selected from the group consisting of a hydrogen atom, amino, amino substituted with alkoxy substituted phenylsulfonyl, alkyl, alkyl substituted up to three times with a halogen atom, aryl, halogen atom, and —XR ⁶ , where X represents is an oxygen atom or —S (O) _n -, where n is zero, one or two, R ^{6 is} selected from the group consisting of alkyl, alkyl substituted with aryl, aryl, aryl substituted with one or two groups selected from an atom halogen, alkyl, alkyl substituted up to three times by a halogen atom, alkoxy, alkoxy, for eschennogo to three times by halogen, aryloxy, substituted with one halogen atom, nitro, alkylsulfonamido, arylsulfonamido and alkyl-substituted arylsulfonamide, and heteroaryl containing up to six carbon atoms, one of which is nitrogen;
R ⁴ and R ^{5 are} independently selected from a hydrogen atom and aryl;
or its pharmaceutically acceptable salts, esters or amides. 26. A compound selected from the group including compounds such as
{[4-hydroxy-1- (naphthalen-2-yloxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-1- (pyridin-3-yloxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-1- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-1- (3-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[1- (3-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[1- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[1- (2-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-1- (2-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[1- (4-acetylaminophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-1- (4-methanesulfonylaminophenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
[(4-hydroxy-1-phenylaminoisoquinoline-3-carbonyl) amino] acetic acid;
{[4-hydroxy-6- (pyridin-3-yloxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-7- (pyridin-3-yloxy) isoquinoline-3-carbonyl] amino} acetic acid;
[(1-chloro-4-methoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-chloro-4-ethoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-1-methoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-ethoxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(4-acetoxy-1-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-1-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-ethoxy-4-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-chloro-4-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(4-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-1-methylisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-1-methoxymethylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-dimethylcarbamoyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-1-methyl-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(4-benzyloxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(4-ethoxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-dimethylcarbamoyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-1-p-tolylisoquinoline-3-carbonyl) amino]
acetic acid;
{[7- (4-fluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} acetic acid;
{[1-chloro-4-hydroxy-7- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-7- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[1-chloro-4-hydroxy-6- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-6- (4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[1-chloro-4-hydroxy-7- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-7- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[1-chloro-4-hydroxy-6- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-6- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[1-chloro-7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[1-chloro-6- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[6- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino) acetic acid;
{[4-hydroxy-7- (pyridin-4-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-6- (pyridin-4-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;
[(7-benzenesulfinyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(7-benzenesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(6-benzenesulfinyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(6-benzenesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(6-amino-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
{[4-hydroxy-7- (4-methoxybenzenesulfonylamino) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-7- (3-phenylureido) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-6- (3-phenylureido) isoquinoline-3-carbonyl] amino} acetic acid;
[(4-hydroxy-1-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;
{[1- (4-chlorophenylsulfanyl) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
[(4-hydroxy-1-p-tolylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;
{[4-hydroxy-1- (pyridin-2-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-1- (3-methoxyphenylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-1- (2-methoxyphenylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-1- (naphthalen-2-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;
[(1-benzenesulfinyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-benzenesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
{[4-hydroxy-7- (pyridin-2-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-6- (pyridin-2-ylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;
[(1-chloro-4-hydroxy-6,7-diphenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-6,7-diphenoxyisoquinoline-3-carbonyl) amino] acetic acid;
({4-hydroxy-7- [4- (toluene-4-ylsulfonylamino) phenoxy] isoquinoline-3-carbonyl} amino) acetic acid;
{[4-hydroxy-7- (4-nitrophenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
[(4-mercapto-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(4-mercapto-7-trifluoromethylisoquinoline-3-carbonyl) amino] acetic acid;
{[7- (4-benzenesulfonylaminophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-7- (4-methanesulfonylaminophenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[7- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[6- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[6- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[7- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[7- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[6- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-7- (4-trifluoromethoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-6- (4-trifluoromethoxyphenoxy) isoquinoline-3-carbonyl] amino} acetic acid;
2- (S) - {[7- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid;
2- (S) - {[6- (4-chlorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid;
2 - {[7- (3,4-difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid;
2- (S) - [(4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] propionic acid;
2- (R) - [(4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] propionic acid;
2- (R) - [(4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid;
2- (S) - {[4-hydroxy-7-
(4-methoxyphenoxy) isoquinoline-3-carbonyl] amino} propionic acid;
2- (S) - [(7-benzenesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;
(R) -2 - [(4-hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid;
(S) -2 - [(4-hydroxy-1-methoxymethyl-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid;
(S) -2 - [(4-mercapto-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid;
(S) -2 - {[1- (4-chlorophenylsulfanyl) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid;
(R) -2 - {[1- (4-chlorophenylsulfanyl) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid;
[(4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-6-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-chloro-4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-chloro-4-hydroxy-6-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-4-hydroxy-6-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-chloro-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-chloro-4-hydroxy-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-4-hydroxy-6-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
{[7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[1-chloro-7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[1-bromo-7- (2,6-dimethylphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
[(1-bromo-7-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-6-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-4-hydroxy-7-trifluoromethylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-4-hydroxy-6-trifluoromethylisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-1-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1,7-dibromo-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(7-bromo-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(6-bromo-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-7-fluoro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(7-fluoro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-chloro-7-fluoro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-chloro-4-hydroxybenzo [g] isoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-6-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-7-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-chloro-4-hydroxy-6-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-chloro-4-hydroxy-7-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-4-hydroxy-6-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-4-hydroxy-7-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-5-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-8-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-chloro-4-hydroxy-5-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-chloro-4-hydroxy-8-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-4-hydroxy-5-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-4-hydroxy-8-phenylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-ethylsulfanyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
{[4-hydroxy-1- (4-methoxyphenylsulfanyl) isoquinoline-3-carbonyl] amino} acetic acid;
[(1-chloro-4-hydroxy-7-iodisoquinoline-3-carbonyl) amino] acetic acid;
[(1-chloro-4-hydroxy-6-iodisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-7-iodisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-4-hydroxy-7-methylisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-7-butoxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-bromo-6-butoxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(6-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) methylamino] acetic acid;
[(1-chloro-4-hydroxyisoquinoline-3-carbonyl) methylamino] acetic acid;
[(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) methylamino] acetic acid;
[(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) methylamino] acetic acid;
[carboxymethyl- (1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[carboxymethyl- (1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] acetic acid;
1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (2-aminoethyl) amide (trifluoroacetic acid salt);
1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (2-methoxyethyl) amide;
1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (2-hydroxyethyl) amide;
1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (2-dimethylaminoethyl) amide;
1-chloro-4-hydroxyisoquinoline-3-carboxylic acid (2-acetylaminoethyl) amide;
1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (2-hydroxyethyl) amide;
1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (2-methoxyethyl) amide;
1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (2-aminoethyl) amide (trifluoroacetic acid salt);
1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (2-dimethylaminoethyl) amide;
1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (2-aminoethyl) amide (trifluoroacetic acid salt;
1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (2-methoxyethyl) amide;
1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (2-dimethylaminoethyl) amide;
1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (2-hydroxyethyl) amide;
(S) -2 - [(6-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;
(R) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid;
(S) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid;
(R) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid;
(S) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid;
(R) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid;
(S) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-hydroxypropionic acid;
2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -2-methylpropionic acid;
2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -2-methylpropionic acid;
(R) -2 - [(1-chloro-4-hydroxyisoquinolin-3-carbonyl) amino] -3- (1H-imidazol-4-yl) propionic acid (trifluoroacetic acid salt);
(S) -2 - [(1-chloro-4-hydroxyisoquinolin-3-carbonyl) amino] -3- (1H-imidazol-4-yl) propionic acid (trifluoroacetic acid salt);
(R) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid;
(S) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid;
(R) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid;
(S) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid;
(R) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid;
(S) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid;
(S) -2 - [(6-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-methylbutyric acid;
(R) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid;
(S) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid;
(R) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid;
(S) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid;
(R) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid;
(S) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3-phenylpropionic acid;
(R) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid;
(S) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid;
(R) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid;
(S) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid;
(R) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid;
(S) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] -3- (4-hydroxyphenyl) propionic acid;
(R) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] pentanoic acid;
(S) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] pentanoic acid;
(R) -1- (1-chloro-4-hydroxyisoquinoline-3-carbonyl) pyrrolidine-2-carboxylic acid;
(S) -1- (1-chloro-4-hydroxyisoquinoline-3-carbonyl) pyrrolidine-2-carboxylic acid;
(R) -1- (1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) pyrrolidine-2-carboxylic acid;
(S) -1- (1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) pyrrolidine-2-carboxylic acid;
(R) -6-amino-2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] hexanoic acid (trifluoroacetic acid salt);
(S) -6-amino-2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] hexanoic acid (trifluoroacetic acid salt);
(R) -6-amino-2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] hexanoic acid (trifluoroacetic acid salt);
(S) -6-amino-2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] hexanoic acid (trifluoroacetic acid salt);
(R) -6-amino-2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] hexanoic acid (trifluoroacetic acid salt);
(S) -6-amino-2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] hexanoic acid (trifluoroacetic acid salt);
(R) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] succinic acid;
(S) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] succinic acid;
(R) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] succinic acid;
(S) -2 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] succinic acid;
(R) -2 - [(1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carbonyl) amino] succinic acid;
1 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] cyclopropanecarboxylic acid;
1 - [(1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carbonyl) amino] cyclopropanecarboxylic acid;
diditero - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
(R) -2 - [(6-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;
(S) -2 - [(7-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;
(R) -2 - [(7-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;
(S) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;
(R) -2 - [(1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;
(S) -2 - [(6-isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;
(R) -2 - [(6-isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;
(S) -2 - [(7-isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;
(R) -2 - [(7-isopropoxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;
1-chloro-4-hydroxy-6-isopropoxyisoquinoline-3-carboxylic acid (2-hydroxy-1-hydroxymethylethyl) amide;
1-chloro-4-hydroxy-7-isopropoxyisoquinoline-3-carboxylic acid (2-hydroxy-1-hydroxymethylethyl) amide;
(2-hydroxy-1-hydroxymethylethyl) 1-chloro-4-hydroxyisoquinoline-3-carboxylic acid amide;
{[7- (3,5-difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[6- (3,5-difluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
({7- [4- (4-fluorophenoxy) phenoxy] -4-hydroxyisoquinoline-3-carbonyl} amino) acetic acid;
({6- [4- (4-fluorophenoxy) phenoxy] -4-hydroxyisoquinoline-3-carbonyl} amino) acetic acid;
{[7- (3-chloro-4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
{[6- (3-chloro-4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} acetic acid;
(S) -2 - {[7- (3-fluoro-5-methoxyphenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid;
2- (S) - [(7-cyclohexyloxy-4-hydroxyisoquinoline-3-carbonyl) amino] propionic acid;
2- (S) - {[7- (4-fluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} propionic acid;
2- (S) - {[7- (4-fluorophenoxy) -4-hydroxyisoquinoline-3-carbonyl] amino} propionic acid;
2- (S) - [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] propionic acid;
2- (S) - [(4-hydroxy-1-methyl-7-phenylsulfanylisoquinoline-3-carbonyl) amino] propionic acid;
2- (S) - {[4-hydroxy-7- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} propionic acid;
{[7- (4-chlorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} acetic acid;
{[6- (4-chlorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} acetic acid;
{[7- (3,5-difluorophenoxy) -4-hydroxy-1-methylisoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-7- (4-methoxyphenoxy) -1-methylisoquinoline-3-carbonyl] amino} acetic acid;
{[4-hydroxy-6- (4-methoxyphenoxy) -1-methylisoquinoline-3-carbonyl] amino} acetic acid;
[(6-cyclohexyloxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(7-cyclohexyloxy-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(7-cyclohexyloxy-4-hydroxy-1-methylisoquinoline-3-carbonyl) amino] acetic acid;
[(7-cyclohexylsulfanyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(7-cyclohexanesulfonyl-4-hydroxyisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-1-isobutylisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-1-pyridin-2-yl-isoquinoline-3-carbonyl) amino] acetic acid;
[(1-ethyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid;
[(1-dimethylaminomethyl-4-hydroxy-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;
[(4-hydroxy-1-methyl-7-phenylsulfanylisoquinoline-3-carbonyl) amino] acetic acid;
{[4-hydroxy-1-methyl-7- (4-trifluoromethylphenoxy) isoquinoline-3-carbonyl] amino} acetic acid; and
their pharmaceutically acceptable salts, esters and amides. 27. A pharmaceutical composition for the prophylaxis and pretreatment of a condition mediated at least partially by hypoxia inducing factor (HIF) and / or erythropoietin (EPO), comprising the compound of claim 1 and a pharmaceutically acceptable carrier or excipient. 28. A method of treating, preventing and pre-treating a condition mediated at least partially by hypoxia inducing factor (HIF) and / or erythropoietin (EPO), said method comprising administering to a mammal patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 1. 1 and a pharmaceutically acceptable excipient or carrier, provided that the compound is not selected from the group consisting of
N - ((1-chloro-4-hydroxy-7- (2-propyloxy) isoquinolin-3-yl) carbonyl) glycine,
N - ((1-chloro-4-hydroxy-6- (2-propyloxy) isoquinolin-3-yl) carbonyl) glycine,
N - ((1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino) acetic acid,
N - ((1-chloro-4-hydroxy-7-methoxyisoquinolin-3-yl) carbonyl) glycine,
N - ((1-chloro-4-hydroxy-6-methoxyisoquinolin-3-yl) carbonyl) glycine,
N - ((7-butyloxy-1-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) glycine,
N - ((6-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino) acetic acid,
N - ((7-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino) acetic acid,
N - ((8-chloro-4-hydroxyisoquinolin-3-yl) carbonyl) glycine,
N - ((7-butoxy-4-hydroxyisoquinoline-3-carbonyl) amino) acetic acid and
((7-benzyloxy-1-chloro-4-hydroxyisoquinoline-3-carbonyl) amino) acetic acid methyl ester. 29. The method according to p, where the specified condition is selected from the group including anemic diseases and myocardial infarction. 30. A method of inhibiting the activity of a hydrolysis enzyme that modifies the alpha subunit of a hypoxia-inducing factor, the method comprising contacting said enzyme with an inhibitory effective amount of a compound according to claim 1. 31. Composition for the prevention and preliminary treatment of a condition mediated at least partially by hypoxia inducing factor (HIF) and / or erythropoietin (EPO), containing the compound according to claim 1 or a mixture of compounds according to claim 1 in a combination of at least , with one additional therapeutic agent, which is erythropoietin. 32. The compound represented by formula

where R ¹ selected from the group consisting of
hydrogen atom
alkyl
alkyl substituted with one group selected from alkoxy and dialkylamino,
halogen atom
heteroaryl containing up to six carbon atoms, one of which is nitrogen,
aminoacyl
aryl
aryl substituted with one alkyl, and
-XR ⁶ , where X represents an oxygen atom, -S (O) _n - or -NR ⁷ -, where n is zero, one or two, R ^{6 is} selected from the group consisting of
alkyl
aryl
aryl substituted with one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamido,
heteroaryl containing up to six carbon atoms, one of which is nitrogen, and R ⁷ represents a hydrogen atom or aryl;
R ² selected from the group consisting of
hydrogen atom
amino substituted with alkoxy substituted phenylsulfonyl,
alkyl
alkyl substituted up to three times with a halogen atom,
aryl
halogen atom
-NR ⁶ C (O) NR ⁶ R ⁶ , and
-XR ⁶ , where X represents an oxygen atom or -S (O) _n -, where n is zero, one or two, each of R ^{6 is} independently selected from the group consisting of
alkyl
alkyl substituted with aryl,
aryl
aryl substituted with one or two groups selected from
halogen atom
alkyl
alkyl substituted up to three times with a halogen atom,
alkoxy
alkoxy substituted up to three times with a halogen atom,
aryloxy substituted with one halogen atom,
nitro
alkylsulfonamido,
arylsulfonamido and
alkyl substituted arylsulfonamide,
cycloalkyl
heteroaryl containing up to six carbon atoms, one of which is nitrogen,
with the proviso that if X is —SO ₂ -, then the substituent R ⁶ cannot be a hydrogen atom;
or its pharmaceutically acceptable salts, esters or amides;
provided that at least one of the following applies:
1) R ¹ represents fluorine, bromine, iodine, alkyl, alkyl, substituted with one group selected from alkoxy and dialkylamino, heteroaryl containing up to six carbon atoms, one of which is nitrogen, aminoacyl, aryl, aryl, substituted at least one alkyl, and -XR ⁶ , where X represents an oxygen atom, -S (O) _n - or -NR ⁷ -, where n is zero or two, R ^{6 is} selected from the group consisting of alkyl, aryl, aryl, substituted with one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamido, and heteroaryl containing up to six carbon atoms, one of which is nitrogen, and R ⁷ represents a hydrogen atom or aryl; or
2) R ² represents alkyl substituted by at least one halogen atom, aryl, fluorine, bromine, iodine, —XR ⁶ , where X represents an oxygen atom or —S (O) _n -, where n is zero, one or two, R ^{6 is} selected from the group consisting of alkyl, alkyl substituted by at least one aryl, aryl, aryl substituted by at least one group selected from a halogen atom, alkyl, alkyl substituted by at least one group selected from a halogen atom, alkoxy, alkoxy substituted with at least one group selected from a halo atom ene, aryloxy, substituted with at least one group selected from halogen, nitro, alkylsulfonamido, arylsulfonamido and alkyl-substituted arylsulfonamide, and heteroaryl containing up to six carbon atoms, one of which is nitrogen; provided that
a) if R ² is substituted alkyl, such a substituent does not include trifluoromethyl;
b) —XR ^{6 is} not an alkoxy group; and
c) if —XR ⁶ is a substituted alkoxy group, such a substituent does not include benzyl or benzyl substituted with a substituent selected from the group consisting of (C ₁ -C ₅ ) -alkyl and (C ₁ -C ₅ ) -alkoxy, or does not include fluoroalkoxy substituent of the formula
-O- [CH ₂ ] _x -C _f H _{(2f + 1-g)} F _g ,
where x is zero or one; f takes integer values from 1 to 5; and g takes integer values from 1 to (2f + 1);
and under the following additional condition:
if the substituents R ¹ , R ³ , R ⁴ and R ⁵ represent a hydrogen atom, then the substituent R ^{2 is} not a bromine atom. 33. The compound according to p, where R ¹ selected from the group including
4- (methylsulfonamido) phenoxy group;
4-chlorophenoxy;
4-fluorophenoxy;
4-methoxyphenoxy;
4-methoxyphenylsulfanyl;
bromine;
butoxy group;
chlorine;
fluorine;
hydrogen;
iodine;
isopropoxy group;
methyl;
phenoxy group;
phenyl;
phenylsulfanyl;
phenylsulfinyl;
phenylsulfonyl;
pyridin-1-ylsulfanyl;
pyridin-3-yloxy group; and
pyridin-4-sulfanyl. 34. The compound according to p, where the Deputy R ² selected from the group including
A (4-methoxy) phenylsulfonylamino group;
2,6-dimethylphenoxy group;
3,4-difluorophenoxy group;
3,5-difluorophenoxy group;
3-chloro-4-fluorophenoxy;
3-methoxy-4-fluorophenoxy;
3-methoxy-5-fluorophenoxy;
4- (methylsulfonamido) phenoxy group;
4- (phenylsulfonamido) phenoxy group;
4-CF ₃ -O-phenoxy;
4-CF ₃ -phenoxy;
4-chlorophenoxy;
4-fluorophenoxy;
4- (4-fluorophenoxy) phenoxy group;
4-methoxyphenoxy;
4-nitrophenoxy;
bromine;
butoxy group;
CF ₃ ;
chlorine;
cyclohexyloxy group;
cyclohexylsulfanyl;
cyclohexylsulfonyl;
fluorine;
hydrogen;
iodine;
isopropoxy group;
methyl;
phenoxy group;
phenyl;
phenylsulfanyl;
phenylsulfinyl;
phenylsulfonyl;
phenylurea;
pyridin-1-ylsulfanyl;
pyridin-3-yloxy group; and
pyridin-4-ylsulfanyl. 35. A pharmaceutical composition for the prevention and pretreatment of a condition mediated at least in part by hypoxia inducing factor (HIF) and / or erythropoietin (EPO), comprising the compound of claim 32 and a pharmaceutically acceptable carrier or excipient. 36. The compound of claim 25 of the general formula

or its pharmaceutically acceptable salts, esters or amides. 37. The compound of the formula

or its pharmaceutically acceptable salts, esters or amides. 38. The compound of claim 32 of the general formula

or its pharmaceutically acceptable salts, esters or amides. 39. The compound of claim 32 of the general formula

or its pharmaceutically acceptable salts, esters or amides. 40. The compound according to p. 32 of the General formula

or its pharmaceutically acceptable salts, esters or amides. 41. The compound of the formula

or its pharmaceutically acceptable salts, esters or amides. 42. The compound of claim 32 of the general formula

or its pharmaceutically acceptable salts, esters or amides. 43. The compound of claim 25 of the general formula

or its pharmaceutically acceptable salts, esters or amides. 44. The compound of claim 32 of general formula

or its pharmaceutically acceptable salts, esters or amides. 45. The compound of claim 25 of the general formula

or its pharmaceutically acceptable salts, esters or amides. 46. The compound of claim 32 of the general formula

or its pharmaceutically acceptable salts, esters or amides. 47. The compound of claim 32 of the general formula

or its pharmaceutically acceptable salts, esters or amides. 48. The compound of claim 25 of the general formula

or its pharmaceutically acceptable salts, esters or amides. 49. The compound of claim 32 of the general formula

or its pharmaceutically acceptable salts, esters or amides. 50. The compound of claim 25 of the general formula

or its pharmaceutically acceptable salts, esters or amides. 51. The compound of claim 25 of the general formula

or its pharmaceutically acceptable salts, esters or amides. 52. The compound of claim 32 of the general formula

or its pharmaceutically acceptable salts, esters or amides. 53. The compound of claim 32 of the general formula

or its pharmaceutically acceptable salts, esters or amides.