WO2018157801A1 - Cyano group-substituted fused bicyclic derivative, preparation method therefor, and application thereof - Google Patents

Abstract

The present invention relates to a cyano group-substituted fused bicyclic derivative, and a pharmaceutical composition comprising the compound. The compound or the pharmaceutical composition can be used for inhibiting xanthine oxidase and urate anion transporter 1, and reducing the uric acid level in blood. The present invention further relates to a method for preparing the compound and a method for preparing the pharmaceutical composition, and applications of the compound and the pharmaceutical composition in treating or preventing diseases associated with high uric acid levels in blood in mammals, especially humans.

Description

Cyano substituted fused bicyclic derivative, preparation method and use thereof Technical field

The invention belongs to the technical field of medicines, in particular to a cyano substituted fused bicyclic compound, a composition thereof, and a preparation method and use thereof, wherein the compound or composition inhibits xanthine oxidase and urate anion transport The use of body 1 activity and can be used to prevent or treat diseases associated with high blood uric acid levels.

Background technique

Uric acid is the terminal metabolite of human bismuth compounds. In humans, uric acid is mainly excreted by the kidneys, and its excretion accounts for nearly two-thirds of the total excretion. When uric acid is excessive or excretion disorder, uric acid accumulation causes an increase in blood uric acid concentration in the human body, which in turn leads to hyperuricemia. Under the normal sputum diet, the two fasting blood uric acid levels in the same day were higher than 420 μmol/L in men and higher than 360 μmol/L in women, which was hyperuricemia. Hyperuricemia can be classified into (1) excessive uric acid production, (2) poor uric acid excretion, and (3) mixed type. Such classification diagnosis can help to find the cause of hyperuricemia and give targeted treatment. .

As the concentration of uric acid in the blood is supersaturated, sodium urate begins to form crystals and deposits in the synovial membrane, bursa, cartilage and other tissues of the joint. When the uric acid level changes rapidly in the body, local trauma causes microcrystal release or urate crystals. When the protein coating changes, it causes a recurrent inflammatory reaction, which in turn induces gout. Gout refers to acute characteristic arthritis and chronic tophi stone diseases, including acute onset arthritis, tophi formation, tophus-induced chronic arthritis, urate nephropathy and urinary acid urinary tract stones. In severe cases, joint disability and Renal insufficiency. In addition, gout is associated with hypertension, metabolic syndrome, hyperlipidemia, diabetes, and insulin resistance (Terkeltaub RA. Clinical practice. Gout [J]. N Engl J Med. 2003, 349: 1647-1655 (Schlesinger N, Schumacher HR Jr. Gort: can management be improved? [J]. Curr Opin Rheumatol. 2001, 13: 240-244).

Hyperuricemia and gout are serious metabolic diseases that endanger human health; data suggest that approximately 5% to 12% of patients with hyperuricemia eventually develop gout. Uric acid is the material basis for hyperuricemia and gout. Therefore, lowering blood uric acid concentration can be used to prevent or treat hyperuricemia and gout, and to reduce the risk of other hyperuricemia and ventilation complications.

At present, drugs that lower uric acid levels have inhibitors of uric acid-producing drugs and uric acid-promoting drugs.

Uric acid is derived from dietary intake and endogenously synthesized steroids, which are ultimately produced by the oxidation of xanthine by xanthine oxidase. Therefore, Oxanthine oxidase is regarded as an important target for inhibiting uric acid production. Existing uric acid production inhibitors have been reported to be effective in the treatment of hyperuricemia and various diseases caused by it, but are also referred to as serious side effects such as poisoning syndrome, aplastic anemia, abnormal liver function, exfoliation. Dermatitis and history-synthesis syndrome, etc. (Kazuhide Ogino and 2persons, Nippon Rinsho (Japan Clinical), 2003, Vol. 61, Extra edition 1, pp. 197-201). Therefore, it is necessary to develop an agent that is effective and has low toxic side effects.

On the other hand, about 90% of hyperuricemia is caused by a decrease in uric acid excretion. The excretion of uric acid in the kidney mainly consists of four processes: filtration of the glomerulus, reabsorption of the renal tubules and collecting ducts, tubules and collections. Tube secretion and reabsorption after secretion, each process is completed by the corresponding protein, and finally only 8%-12% of uric acid excreted in vitro (Liu Ruoxi, Qi Luping, Wu Xinrong, Shandong Medicine [J], No. 52, 2012 Volume 28). Urate anion transporter 1 (URAT1) is a transmembrane transporter located on the brush border of renal proximal tubule epithelial cells, which is involved in the reabsorption of uric acid in renal proximal tubules by Enomoto et al. hURAT1 is encoded by the SLC22A12 gene on chromosome 11q13 and contains 10 exons and 9 introns, consisting of 555 amino acid residues, 12 transmembrane structures, and -NH ₂ and -COOH ends located inside the cell. The study found that the SLC22A12 gene in patients with renal hypouricemia is mutated and loses the ability to encode the mature protein of URAT1, thereby confirming that URAT1 is a causative gene of renal hypouricemia (Enomoto, Kimura H, Chairoungdua A, et al) .Molecular identification of a renal urate anion exchanger that regulates blood urate levels [J]. Nature, 2002, 417 (6887): 447-452), which is important for the uric acid reabsorption function of the kidney and has a uric acid value in the blood. Regulation is closely related. Therefore, substances with URAT1 inhibitory activity can promote the excretion of uric acid in the blood, and are used for treating and preventing diseases associated with high blood uric acid levels, including hyperuricemia, gout, tophi, gouty arthritis, and high uric acid. Hematologic-related renal disorders, urinary tract stones, and the like.

It has been reported that the combination of allopurinol and a uric acid excretion drug has a better blood uric acid effect than the use of allopurinol alone (S Takahashi, Ann. Rheum. Dis., 2003, 62, 572-575). Therefore, the combination of uric acid excretion drug and uric acid production inhibitor can achieve therapeutic effects that cannot be achieved by a single drug and avoid corresponding risks. For example, for uric acid excretion type hyperuricemia, uric acid excretion alone is used. It may cause a risk of urinary calculi, so a combination of uric acid production inhibitors can achieve the desired higher therapeutic effect.

It can inhibit both xanthine oxidase and URAT1 drugs, and will provide better therapeutic effects for patients, and is more convenient than combination therapy. These drugs have become the focus of research and development for the treatment of hyperuricemia, gout and diseases associated with hyperuricemia.

Summary of invention

The following merely summarizes some aspects of the invention and is not limited thereto. These and other parts are more fully explained later. All references in this specification are hereby incorporated by reference in their entirety. In the event that the disclosure of the specification differs from the cited document, the disclosure of this specification shall control.

The invention provides a compound having the dual inhibitory activity of xanthine oxidase and URAT1 for preparing or preventing diseases related to high blood uric acid value, such as hyperuricemia, tophi, gouty arthritis, Renal disorders and urolithiasis associated with hyperuricemia; the compounds of the present invention are excellent in inhibiting xanthine oxidase and URAT1, and have excellent physical and chemical properties as well as pharmacokinetic properties.

The invention also provides methods of preparing such compounds, and pharmaceutical compositions comprising these compounds, and methods of using the compounds or compositions to treat the above-described conditions in mammals, particularly humans.

Specifically:

In one aspect, the invention relates to a stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvent of a compound of formula (I) or a compound of formula (I) a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,

among them:

X and Z are each independently -N(R ^a )-, -O-, -S(O) _t -, -C(R ^b )=, -CR ^c R ^d - or -N=;

Y is -C(R ^e )=, -CR ^f R ^g - or -N=;

t is 0, 1 or 2;

Each R ^{a is} independently hydrogen, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl or C _3-6 cycloalkyl;

Each R ^{b is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylamino or C _1-6 haloalkoxy;

Each R ^{c is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylamino or C _1-6 haloalkoxy;

Each R ^{d is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylamino or C _1-6 haloalkoxy;

R ^e is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 haloalkyl amino, C _3-8 cycloalkyl, 3-8 membered heterocyclyl , phenyl or 5-10 membered heteroaryl;

R ^f is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 haloalkylamino, C _3-8 cycloalkyl, 3-8 membered heterocyclic , phenyl or 5-10 membered heteroaryl;

R ^g is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 haloalkylamino, C _3-8 cycloalkyl, 3-8 membered heterocyclic , phenyl or 5-10 membered heteroaryl;

R ¹ and R ² are each independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkane An oxy group, a C _1-6 alkylamino group or a C _1-6 haloalkoxy group;

Each R ^{3 is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy;

R is hydrogen, hydrazine, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _6-10 aryl a 5-10 membered heteroaryl or Q, wherein said C _1-6 alkyl group, C _1-6 hydroxyalkyl group, C _1-6 haloalkyl group, C _3-8 cycloalkyl group, 3-8 membered hetero The cyclic group, C _6-10 aryl, 5-10 membered heteroaryl and Q are independently, optionally 1, 2, 3, 4 or 5 selected from the group consisting of ruthenium, F, Cl, Br, I, hydroxy, amino, Substituent substitution of cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl or 3-6 membered heterocyclyl;

Q is a substituted or unsubstituted C _1-6 aliphatic hydrocarbon group, wherein 0-3 methylene groups are independently independently substituted with a group selected from -O-, -NH-, and -C(=O)-;

L ⁰ is a bond, -O-, -NH- or -S-;

L ¹ is -O-, -NH- or -S-;

L ² is -C _1-6 alkylene-, -C(=O)- or -NH-;

L ³ is a bond, -O-, -NH-, -C(=O)-, -C(=NH)-, -C(=O)-O-, -OC(=O)-, -C( =O)-N(R ⁴ )-, -N(R ⁴ )-C(=O)- or -C _1-6 alkylene-;

R ⁴ is hydrogen, hydrazine, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl or C _3-8 cycloalkyl;

-C(＝O)-CH(R ⁷)-N(R ⁸)(R ⁹)、

或Q； E is 氘, F, Cl, Br, I, hydroxy, amino, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _{a 1-6} hydroxyalkyl group, a C _1-6 alkylamino group, a C _3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a phenyl group, a 5-10 membered heteroaryl group,

-C(=O)-CH(R ⁷ )-N(R ⁸ )(R ⁹ ),

Or Q;

R ⁵ and R ⁶ are each independently hydrogen, deuterium or Q;

-(CH ₂) ₃NH-C(＝NH)-NH ₂或

R ⁷ is hydrogen, hydrazine, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoylmethyl, carbamoyl Ethyl, 1-hydroxyethyl, decylmethyl, carboxymethyl, carboxyethyl, -(CH ₂ ) ₄ NH ₂ ,

-(CH ₂ ) ₃ NH-C(=NH)-NH ₂ or

R ⁸ and R ⁹ are each independently hydrogen, deuterium, C _1-6 alkyl or C _1-6 haloalkyl;

n is 0, 1, 2 or 3.

In some embodiments, each R ^{a is} independently hydrogen, deuterium, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, or C _3-6 cycloalkyl;

Each R ^{b is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylamino or C _1-3 haloalkoxy;

Each R ^{c is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylamino or C _1-3 haloalkoxy;

Each R ^{d is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylamino or C _1-3 haloalkoxy;

R ^e is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 Haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, C _1-3 alkylamino, C _1-3 haloalkylamino, C _3-6 cycloalkyl, 3-6 membered heterocyclic , phenyl or 5-6 membered heteroaryl;

R ^f is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 Haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, C _1-3 alkylamino, C _1-3 haloalkylamino, C _3-6 cycloalkyl, 3-6 membered heterocyclic , phenyl or 5-6 membered heteroaryl;

R ^g is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 Haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, C _1-3 alkylamino, C _1-3 haloalkylamino, C _3-6 cycloalkyl, 3-6 membered heterocyclic , phenyl or 5-6 membered heteroaryl.

In other embodiments, each R ^{a is} independently hydrogen, deuterium, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, cyclopropyl. , cyclobutyl, cyclopentyl or cyclohexyl;

Each R ^{b is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy Base, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino or dimethylamino;

Each R ^{c is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy Base, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino or dimethylamino;

Each R ^{d is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy Base, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino or dimethylamino;

R ^e is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propyne , propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl , oxazolyl, pyridyl or pyrimidinyl;

R ^f is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propyne , propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl , oxazolyl, pyridyl or pyrimidinyl;

R ^g is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propyne , propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl , oxazolyl, pyridyl or pyrimidinyl.

In some embodiments, R ¹ and R ² are each independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl , C _1-3 alkoxy, C _1-3 alkylamino or C _1-3 haloalkoxy;

Each R ^{3 is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _1-3 haloalkoxy.

In other embodiments, R ¹ and R ² are each independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, difluoromethyl, trifluoromethyl , methoxy, ethoxy, isopropyloxy, difluoromethoxy, trifluoromethoxy, methylamino or dimethylamino;

Each R ^{3 is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, iso Propyloxy, difluoromethoxy or trifluoromethoxy.

In some embodiments, R is hydrogen, deuterium, C _1-4 alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl or Q, wherein said C _1-4 alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl 3-6 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl and Q may be independently optionally 1, 2, 3, 4 or 5 selected from the group consisting of ruthenium, F, Cl, Br , I, hydroxy, amino, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl or 3-6 membered heterocyclic Substituted for the substituent.

In other embodiments, R is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, t-butyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, difluoro. Methyl, trifluoromethyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl , thiomorpholinyl, phenyl, 2,3-dihydro-1H-indole, thiazolyl, pyrazolyl, oxazolyl, pyridyl, pyrimidinyl or Q, wherein said methyl, ethyl, Isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, difluoromethyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, 2,3-dihydro-1H-indole, thiazolyl, pyrazolyl, oxazolyl, Pyridyl, pyrimidinyl and Q are independently, optionally 1, 2, 3, 4 or 5 selected from the group consisting of hydrazine, F, Cl, Br, I, hydroxy, amino, cyano, nitro, methyl, ethyl, Trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, Substituents for cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl are substituted.

In some embodiments, L ² is -C _1-3 alkylene-, -C(=O)- or -NH-;

L ³ is a bond, -O-, -NH-, -C(=O)-, -C(=NH)-, -C(=O)-O-, -OC(=O)-, -C( =O)-N(R ⁴ )-, -N(R ⁴ )-C(=O)- or -C _1-3 alkylene-;

R ⁴ is hydrogen, hydrazine, C _1-3 alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl or C _3-6 cycloalkyl.

In other embodiments, L ² is methylene, ethylene, propylene, -C(=O)- or -NH-;

L ³ is a bond, -O-, -NH-, -C(=O)-, -C(=NH)-, -C(=O)-O-, -OC(=O)-, -C( =O)-N(R ⁴ )-, -N(R ⁴ )-C(=O)-, methylene, ethylene or propylene;

R ⁴ is hydrogen, hydrazine, methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl Base, cyclopentyl or cyclohexyl.

-C(＝O)-CH(R ⁷)-N(R ⁸)(R ⁹)、

或Q； In some embodiments, E is 氘, F, Cl, Br, I, hydroxy, amino, cyano, C _1-4 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _{1- 3} -haloalkoxy, C _1-3 hydroxyalkyl, C _1-3 alkylamino, C _3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl,

-C(=O)-CH(R ⁷ )-N(R ⁸ )(R ⁹ ),

Or Q;

R ⁵ and R ⁶ are each independently hydrogen, deuterium or Q;

-(CH ₂) ₃NH-C(＝NH)-NH ₂或

R ⁷ is hydrogen, hydrazine, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoylmethyl, carbamoyl Ethyl, 1-hydroxyethyl, decylmethyl, carboxymethyl, carboxyethyl, -(CH ₂ ) ₄ NH ₂ ,

-(CH ₂ ) ₃ NH-C(=NH)-NH ₂ or

R ⁸ and R ⁹ are each independently hydrogen, deuterium, C _1-3 alkyl or C _1-3 haloalkyl.

-C(＝O)-CH(R ⁷)-N(R ⁸)(R ⁹)、

或Q； In other embodiments, E is 氘, F, Cl, Br, I, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, t-butyl, difluoromethyl, tri Fluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, methylamino, Ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl Phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridyl, pyrimidinyl,

-C(=O)-CH(R ⁷ )-N(R ⁸ )(R ⁹ ),

Or Q;

R ⁵ and R ⁶ are each independently hydrogen, deuterium or Q;

-(CH ₂) ₃NH-C(＝NH)-NH ₂或

R ⁷ is hydrogen, hydrazine, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoylmethyl, carbamoyl Ethyl, 1-hydroxyethyl, decylmethyl, carboxymethyl, carboxyethyl, -(CH ₂ ) ₄ NH ₂ ,

-(CH ₂ ) ₃ NH-C(=NH)-NH ₂ or

R ⁸ and R ⁹ are each independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl or 2,2-difluoroethyl.

In some embodiments, the compound of formula (I) is a compound of formula (II), or a stereoisomer, geometric isomer, tautomer, nitrogen of a compound of formula (II). An oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof,

Wherein R, R ¹ , R ² , X, Z, R ^e , L ¹ , L ² , L ³ and E have the meanings as described herein.

In some embodiments, the compound of formula (I) is a compound of formula (III), or a stereoisomer, geometric isomer, tautomer, nitrogen of a compound of formula (III). An oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof,

Wherein R, R ¹ , R ² , X, Z, R ^e , L ¹ , L ² , L ³ and E have the meanings as described herein.

In another aspect, the present invention is directed to a pharmaceutical composition comprising a compound disclosed herein.

In some embodiments, the pharmaceutical compositions of the present invention further comprise a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or a combination thereof.

In other embodiments, the pharmaceutical composition of the present invention further comprises for preventing or treating hyperuricemia, tophi, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis The drug, the active ingredient of the drug is different from the compound disclosed in the present invention, the drug is colchicine, non-steroidal anti-inflammatory drug, glucocorticoid, uric acid-producing drug, uric acid excretion drug, urine alkalizing agent Or any combination of them.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for the prevention or treatment of hyperuricemia, tophi, gouty arthritis, and uric acid in a mammal A renal disorder associated with blood or urolithiasis, including mammals.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the preparation of a medicament for lowering blood uric acid levels.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for inhibiting xanthine oxidase and urate anion transporter 1.

In another aspect, the compounds or pharmaceutical compositions disclosed herein are useful for preventing or treating hyperuricemia, tophi, gouty arthritis, renal disorders associated with hyperuricemia, or urolithiasis in a mammal, Mammals include humans.

In another aspect, the compounds or pharmaceutical compositions disclosed herein are used to lower blood uric acid levels.

In another aspect, the compounds or pharmaceutical compositions disclosed herein are useful for inhibiting xanthine oxidase and urate anion transporter 1.

In another aspect, the present invention relates to a method of preventing or treating hyperuricemia, tophi, gouty arthritis, renal disorders associated with hyperuricemia or urolithiasis, comprising administering to a patient a therapeutically effective dose A compound or pharmaceutical composition disclosed herein.

In another aspect, the invention relates to a method of lowering blood uric acid levels, the method comprising administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition of the invention.

In another aspect, the present invention is directed to a method of inhibiting xanthine oxidase and urate anion transporter 1 using a compound or pharmaceutical composition disclosed herein.

In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound encompassed by formula (I), (II) or (III).

The results of the biological test indicate that the compound provided by the present invention can be used as a better xanthine oxidase and a urate anion transporter 1 inhibitor. Any of the embodiments of any of the aspects of the invention may be combined with other embodiments as long as they do not contradict each other. Furthermore, in any of the embodiments of any of the aspects of the invention, any of the technical features may be applied to the technical features in other embodiments as long as they do not contradict each other.

The foregoing description merely summarizes certain aspects of the invention, but is not limited thereto. These and other aspects are described in more detail below.

Detailed description of the invention

Definitions and general terms

Some embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and formulas. The invention is intended to cover all alternatives, modifications, and equivalents, which are within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the invention. The invention is in no way limited to the methods and materials described herein. Where one or more of the incorporated literature, patents, and similar materials are different or inconsistent with the present application (including but not limited to defined terms, terminology applications, described techniques, etc.), The application shall prevail.

It will be further appreciated that certain features of the invention are described in the various embodiments of the invention, and may be described in combination in a single embodiment. On the contrary, the various features of the invention are described in a single embodiment for the sake of brevity, but may be provided separately or in any suitable sub-combination.

Unless otherwise stated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. All patents and publications related to the present invention are hereby incorporated by reference in their entirety.

The following definitions used herein should be applied unless otherwise stated. For the purposes of the present invention, chemical elements are consistent with the CAS version of the Periodic Table of the Elements, and the Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007. , the entire contents of which is incorporated herein by reference.

The articles "a", "an" and "the" Therefore, the articles used herein are used to refer to the articles of one or more than one (ie, at least one). For example, "a component" refers to one or more components, that is, there may be more than one component contemplated for use or use in embodiments of the embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (eg, humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression that includes the subject matter of the invention, but does not exclude other aspects.

"Stereoisomer" refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .

"Chirality" is a molecule that has properties that cannot overlap with its mirror image; "non-chiral" refers to a molecule that can overlap with its mirror image.

"Enantiomer" refers to two isomers of a compound that are not superimposable but are mirror images of each other.

"Diastereomer" refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.

The stereochemical definitions and rules used in the present invention generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry Of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers. The 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity during the chemical reaction.

Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

Depending on the choice of starting materials and methods, the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists. The optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.

The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.

The racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ^nd Ed. Robert) E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention. A class of compounds.

In general, the term "substituted" means that one or more hydrogen atoms in the given structure are replaced by a substituent as described herein. Unless otherwise indicated, a substituted group may have one substituent substituted at each substitutable position of the group. When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, the substituents can be substituted at the various positions, either identically or differently.

The term "unsubstituted" means that the specified group does not have a substituent.

The term "optionally substituted with" may be used interchangeably with the term "unsubstituted or substituted by", ie the structure is unsubstituted or substituted by one or more substituents described herein. . The substituents of the present invention include, but are not limited to, D, F, Cl, Br, I, N ₃ , CN, NO ₂ , OH, SH, NH ₂ , alkyl, haloalkyl, alkenyl, alkynyl, alkane Oxyl, alkylamino, cycloalkyl, heterocyclic, aryl, heteroaryl, and the like.

In addition, it should be noted that the descriptions of the "individually" and "individually" and "independently" are interchangeable, unless otherwise explicitly indicated in the present invention. It should be understood in a broad sense, which can mean that the specific options expressed between the same symbols in different groups do not affect each other, and can also represent specific options expressed in the same group and between the same symbols. There is no influence between each other.

In each part of the specification, the substituents of the compounds disclosed herein are disclosed in terms of the type or range of groups. In particular, the invention includes each individual sub-combination of each member of the group and range of such groups. For example, the term "C _1-6 alkyl" refers particularly to the disclosure independently methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

In various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable recited for that group is understood to be a linking group. For example, if the structure requires a linking group and the definition of the Markush group for the variable is "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represent the attached An alkylene group or an arylene group.

The term "aliphatic hydrocarbon group" as used in the present invention means a saturated or partially unsaturated chain or cyclic hydrocarbon group, wherein the aliphatic hydrocarbon group may be optionally substituted by one or more substituents of the present invention. Replace. In some embodiments, the aliphatic hydrocarbyl group contains from 1 to 12 carbon atoms; in other embodiments, the aliphatic hydrocarbyl group contains from 1 to 6 carbon atoms; in some embodiments, the aliphatic hydrocarbyl group is 1- The 6 methylene groups may be replaced by groups such as -O-, -NH-, and -C(=O)-; in other embodiments, 1-3 methylene groups in the aliphatic hydrocarbyl group may be -O Substituting groups such as -, -NH- and -C(=O)-. Such examples include, but are not limited to, methoxymethyl, ethoxymethyl, ethylaminoethyl, n-propyloxymethyl, propionyloxymethyl, acetoxyethyl, acetamido Alkoxymethyl, and the like.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon group, wherein the alkyl group may be optionally one or more of the present invention. Substituted by the described substituents. Unless otherwise specified, an alkyl group contains from 1 to 20 carbon atoms. In one embodiment, the alkyl group contains from 1 to 12 carbon atoms; in another embodiment, the alkyl group contains from 3 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 -6 carbon atoms; in yet another embodiment, the alkyl group contains 1-4 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH) (CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl -2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1- Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) _2), 2-methyl-3-pentyl _{(-CH (CH 2 CH 3)} CH (CH 3) 2), 2,3- dimethyl 2-butyl _{(-C (CH 3) 2 CH} (CH 3) 2), 3,3- dimethyl-2-butyl _{(-CH (CH 3) C (} CH 3) 3), n-heptyl Base, just octyl, and so on.

The term "alkylene" denotes a saturated divalent hydrocarbon radical derived from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, an alkylene group contains from 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms; in another embodiment, the alkylene group contains 1-4 carbon atoms; in yet another embodiment, the alkylene group The group contains 1-3 carbon atoms; also in one embodiment, the alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), isopropylidene (-CH(CH ₃ )CH ₂ -) and the like.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical having at least one site of unsaturation, ie having a carbon-carbon sp ² double bond, wherein the alkenyl group may be optionally one or A number of substituents described herein are substituted, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 12 carbon atoms; in another embodiment, the alkenyl group contains 3 to 12 carbon atoms; in another embodiment, the alkenyl group comprises 2 -6 carbon atoms; in yet another embodiment, the alkenyl group contains 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH = CH _2), allyl (-CH ₂ CH = CH ₂₎ and the like.

The term "alkynyl" means a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one site of unsaturation, i.e., has a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted with one or more of the substituents described herein. In one embodiment, the alkynyl group contains 3 to 12 carbon atoms; in another embodiment, the alkynyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkynyl group comprises 2 - 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), 1-propynyl (-C≡C-CH ₃ ), and the like. .

The term "alkoxy" denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains from 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains from 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains from 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group can be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n- Propyloxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butyl Oxygen (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) ₃ ) ₃ ), 1-pentyloxy (n-pentyloxy, -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (-OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-l-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-l-butoxy (-OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), and so on.

The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino" wherein the amino groups are each independently substituted with one or two alkyl groups; The meaning of the invention is described. In some of these embodiments, the alkylamino group is a lower alkylamino group formed by one or two C _1-6 alkyl groups attached to a nitrogen atom. In other embodiments, the alkylamino group is an alkylamino group formed by one or two lower alkyl groups of C _1-4 attached to a nitrogen atom. Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N - Diethylamino and the like.

The term "haloalkyl", "haloalkoxy" or "haloalkylamino" denotes an alkyl, alkoxy or alkylamino group substituted by one or more halogen atoms, wherein alkyl, alkoxy or alkyl The amino group has the meaning as described herein, and such examples include, but are not limited to, trifluoromethyl, 2,2,3,3-tetrafluoropropyl, difluoromethoxy, trifluoromethoxy Base, trifluoromethylamino and the like.

The term "hydroxyalkyl" denotes an alkyl group substituted by one or more hydroxy groups, wherein alkyl has the meaning as described herein, and examples include, but are not limited to, hydroxymethyl, hydroxyethyl , 2-hydroxyethyl, 1,2-dihydroxyethyl and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic cyclic hydrocarbon group containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl contains 7 to 12 carbon atoms; in yet another embodiment, the cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl contains 3 to 6 carbon atom. The cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein.

The term "carbocyclyl" means a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic cyclic hydrocarbon group containing from 3 to 12 carbon atoms. Carbon bicyclic groups include spirocarbon bicyclic groups and fused carbon bicyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. In one embodiment, the carbocyclic group contains 3-8 carbon atoms; in yet another embodiment, the carbocyclic group contains 3-6 carbon atoms. Examples of the carbocyclic group further include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a 1-cyclopentyl-1-alkenyl group, a 1-cyclopentyl-2-alkenyl group, a 1-cyclopentyl group- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl Base, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. The carbocyclyl group may be independently unsubstituted or substituted with one or more substituents described herein.

The term "carbocyclic" means a non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic cyclic hydrocarbon containing from 3 to 12 carbon atoms. Suitable carbocycles include, but are not limited to, cycloalkanes, cyclic olefins, and cycloalkynes. In one embodiment, the carbocycle contains from 3 to 8 carbon atoms; in yet another embodiment, the carbocycle contains from 3 to 6 carbon atoms. Examples of the carbocyclic ring further include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cyclooctane, cyclodecane, cyclodecane. , cycloundecane, cyclododecane, and the like. The carbocyclic ring may be independently unsubstituted or substituted with one or more substituents described herein.

基、二氮杂

基、硫氮杂

基、2-氧杂-5-氮杂双环[2.2.1]庚-5-基。杂环基中-CH ₂-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 The term "heterocyclyl" refers to a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent monocyclic, bicyclic or tricyclic ring containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen. atom. Unless otherwise specified, the heterocyclic group may be attached through a carbon atom in the molecule other groups can also be attached via a nitrogen atom and other groups in the molecule, and -CH ₂ - groups may be optionally substituted with -C (= O) - Replacement. The sulfur atom of the ring can be optionally oxidized to an S-oxide. The nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, 2-pyrroline, 3-pyrrolyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl, diazepanyl, oxetanyl, thiaheptanyl, oxygen nitrogen miscellaneous

Base, diaza

Base

Base, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Examples of the -CH ₂ - group in the heterocyclic group substituted by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto group, 3,5-dioxopiperidinyl group and pyrimidindione group. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, a sulfolane group and a 1,1-dioxothiomorpholinyl group. The heterocyclyl group can be optionally substituted with one or more substituents described herein.

、二氮杂

、硫氮杂

、2-氧杂-5-氮杂双环[2.2.1]庚烷。杂环中-CH ₂-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷、氧代-1,3-噻唑烷、2-哌啶酮、3,5-二氧代哌啶和嘧啶二酮。杂环中硫原子被氧化的实例包括，但不限于，环丁砜、1,1-二氧代硫代吗啉。所述的杂环可以任选地被一个或多个本发明所描述的取代基所取代。 The term "heterocycle" refers to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic or tricyclic ring containing from 3 to 12 ring atoms, wherein at least one of the ring atoms is selected from the group consisting of nitrogen, sulfur and oxygen. Unless otherwise stated, a heterocyclic ring may be attached to other groups in the molecule through a carbon atom, or may be attached to other groups in the molecule through a nitrogen atom, and the -CH ₂ - group may be optionally -C(=O)- Alternative. The sulfur atom of the ring can be optionally oxidized to an S-oxide. The nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound. Examples of heterocycles include, but are not limited to, ethylene oxide, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazoline, pyrazolidine, imidazoline, Imidazolidine, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, 1,3-dioxocyclopentane, dithiocyclopentane, tetrahydropyran, dihydropyran, 2H-pyran, 4H- Pyran, tetrahydrothiopyran, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dithiane, thiazolidine, homopiperazine, homopiperidine, diazepane, oxygen Heterocyclic heptane, thiaheptane, oxazepine

Diaza

Thiazole

, 2-oxa-5-azabicyclo[2.2.1]heptane. Examples of the -CH ₂ - group substituted by -C(=O)- in the heterocyclic ring include, but are not limited to, 2-oxopyrrolidine, oxo-1,3-thiazolidine, 2-piperidone, 3 , 5-dioxopiperidine and pyrimidinedione. Examples of the sulfur atom in the heterocycle being oxidized include, but are not limited to, sulfolane, 1,1-dioxothiomorpholine. The heterocyclic ring may be optionally substituted with one or more substituents described herein.

The term "r atoms", where r is an integer, typically describes the number of ring atoms in the molecule in which the number of ring atoms is r. For example, a piperidinyl group is a heterocyclic alkyl group composed of 6 atoms, and a decahydronaphthyl group is a carbocyclic group composed of 10 atoms.

The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.

The term "heteroatom" refers to O, S, N, P, and Si, including any form of oxidation states of N, S, and P; forms of primary, secondary, tertiary, and quaternary ammonium salts; or nitrogen atoms in heterocycles. a form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR ¹⁰ (like N-substituted pyrrolidinyl) NR ¹⁰ ).

The term "halogen" or "halogen atom" means a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br) or an iodine atom (I).

The term "cyano" or "CN" denotes a cyano structure which may be attached to other groups.

The term "nitro" or "NO ₂ " denotes a nitro structure which may be attached to other groups.

The term "aryl" denotes a monovalent or multivalent monocyclic, bicyclic or tricyclic all-carbon ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least One ring is aromatic and has one or more attachment points attached to the rest of the molecule. In one embodiment, the aryl group is a monovalent or multivalent carbocyclic ring system composed of 6-10 ring atoms and having at least one aromatic ring therein. Examples of the aryl group may include a phenyl group, a naphthyl group, and an anthracenyl group. The aryl group may be independently and optionally substituted with one or more substituents described herein.

The term "aromatic ring" means a monocyclic, bicyclic or tricyclic all-carbon ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring is aromatic Family. In one embodiment, the aromatic ring is composed of 6-10 ring atoms, and at least one of the rings is an aromatic carbocyclic ring system. Examples of the aromatic ring may include benzene, naphthalene, and anthracene. The aromatic ring may be independently and optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring containing from 5 to 12 ring atoms, or from 5 to 10 ring atoms, or from 5 to 6 ring atoms, wherein at least one ring is aromatic And at least one aromatic ring contains one or more heteroatoms and one or more attachment points are attached to the remainder of the molecule. The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the heteroaryl is a heteroaryl group comprising from 5 to 12 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in another embodiment, hetero The aryl group is a heteroaryl group consisting of 5-6 atoms containing 1, 2, 3 or 4 hetero atoms independently selected from O, S and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, oxadiazolyl (eg 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl), oxatriazole (such as 1,2,3,4-oxazolyl), 2-thiazolyl, 4- Thiazolyl, 5-thiazolyl, isothiazolyl, 2-thiadiazolyl (eg 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiyl) Zozolyl), thiatriazole (such as 1,2,3,4-thiatriazolyl), tetrazolyl (such as 2H-1, 2,3,4-tetrazolyl, 1H-1, 2, 3 , 4-tetrazolyl), triazolyl (such as 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl), 2-thienyl, 3-thienyl, 1H-pyrazolyl (eg 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl), N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl) , 4-pyridazinyl), 2-pyrazinyl, triazinyl (such as 1,3,5-triazine), tetrazinyl (such as 1,2,4,5-four , 1,2,3,5-tetrazine); also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, fluorenyl (such as 2-indole) Base, fluorenyl, quinolyl (eg 2-quinolyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (eg 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1 , 2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

The term "heteroaromatic ring" or "heteroaromatic compound" means a monocyclic, bicyclic or tricyclic ring containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, at least one of which The ring is aromatic and at least one aromatic ring contains one or more heteroatoms. The heteroaryl or heteroaromatic compound is optionally substituted with one or more substituents described herein. In one embodiment, the heteroaryl or heteroaromatic compound is a heteroaryl or heteroaromatic group of 5 to 12 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. a compound; in another embodiment, the heteroaryl ring or heteroaromatic compound is a heteroaryl ring of 5-6 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N or Heteroaromatic compounds.

Examples of heteroaromatic or heteroaromatic compounds include, but are not limited to, furan, imidazole, isoxazole, oxazole, oxadiazole, oxatriazole, thiazole, isothiazole, thiadiazole, thiatriazole, tetra Oxazole, triazole, thiophene, 1H-pyrazole, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, tetrazine; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazole, benzofuran , benzothiophene, anthracene, anthracene, quinoline, isoquinoline, imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyridine, pyrazolo[1,5-a] Pyrimidine, imidazo[1,2-b]pyridazine, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[1,5-a Pyrimidine, [1,2,4]triazolo[1,5-a]pyridine, and the like.

As described herein, a ring system formed by a substituent attached to a central ring (as shown in formula b) represents a substituent which can be substituted at any substitutable position on the ring. For example, formula b represents that the substituent R ¹¹ may be mono- or polysubstituted at any position on the C ring that may be substituted, as shown by formulas c1 to c19.

As described herein, a ring system (as shown by formula d) formed by attachment of a linkage to the center of the ring represents that the linkage can be attached to the remainder of the molecule at any attachable position on the ring system. The formula d represents that any position of the possible connection on the D ring can be attached to the rest of the molecule.

As described herein, a ring system formed by the attachment of a substituent R to a central ring represents that the substituent R ¹² can only be substituted at any substitutable or any reasonable position on the ring to which it is attached. For example, the formula e represents that any position on the A ring that may be substituted may be substituted by R, as shown in formula f, formula g, formula h and formula i.

The term "protecting group" or "PG" refers to a substituent that is typically used to block or protect a particular functionality when reacted with other functional groups. For example, "protecting group of an amino group" refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl. (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent used to block or protect a hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "Carboxy protecting group" means a substituent of a carboxy group used to block or protect the functionality of a carboxy group. Typical carboxy protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane Ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenyl Phosphine) ethyl, nitroethyl, and the like. A general description of protecting groups can be found in the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The term "prodrug" as used in the present invention denotes a compound which is converted in vivo to a compound of formula (I). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug-like compound of the present invention may be an ester. In the prior invention, the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C ₁ -C ₂₄ ) ester, an acyloxymethyl ester, or a carbonic acid. Esters, carbamates and amino acid esters. For example, a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent. For a discussion of the completeness of prodrugs, refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

"Metabolic product" refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.

The "pharmaceutically acceptable salt" as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or by other methods described in the literature, such as ion exchange These salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid Salt, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C _{1 -8} sulfonate and aromatic sulfonate.

"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" means that the solvent molecule is an association formed by water.

When the solvent is water, the term "hydrate" can be used. In some embodiments, a molecule of the compound of the invention may be combined with a water molecule, such as a monohydrate; in other embodiments, a molecule of the invention may be combined with more than one water molecule, such as dihydrate. In still other embodiments, a molecule of the compound of the invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the compounds in a non-hydrated form.

The term "treating" any disease or condition as used herein means that all can slow, interrupt, prevent, control or stop the progression of a disease or condition, but does not necessarily mean that all symptoms of the disease or condition have completely disappeared, including Prophylactic treatment of the symptoms, especially in patients susceptible to such diseases or disorders. In some embodiments, it is meant to ameliorate a disease or condition (ie, slow or prevent or reduce the progression of the disease or at least one of its clinical symptoms). In other embodiments, "treating" refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or condition from the body (eg, stabilizing a detectable symptom) or physiologically (eg, stabilizing the body's parameters) or both. In other embodiments, "treating" refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.

The term "therapeutically effective amount" or "therapeutically effective amount" as used in the present invention refers to a biological or medical response capable of eliciting an individual (eg, reducing or inhibiting enzyme or protein activity, or ameliorating symptoms, alleviating a condition, slowing or delaying a disease). The amount of the compound of the invention that develops, or prevents disease, etc.). In a non-limiting embodiment, the term "therapeutically effective amount" refers to an amount effective to administer a compound of the invention to an individual in the following circumstances: (1) at least partially alleviating, inhibiting, preventing, and/or ameliorating (i) mediated by xanthine oxidase or urate anion transporter 1 (URAT1), or (ii) associated with xanthine oxidase or urate anion transporter 1 activity, or (iii) by xanthine oxidation a condition or disease characterized by an abnormal activity of the enzyme or urate anion transporter 1; or (2) reducing or inhibiting the activity of xanthine oxidase or urate anion transporter 1; or (3) reducing or inhibiting xanthine oxidation Expression of the enzyme or urate anion transporter 1. In another embodiment, the term "therapeutically effective amount" refers to at least partially reducing or inhibiting xanthine oxidase or urate anion transport when administered to a cell, or organ, or a non-cellular biological material, or a vehicle. Body 1 activity; or an amount of an effective compound of the invention that at least partially reduces or inhibits the expression of xanthine oxidase or urate anion transporter 1.

The term "administering" and "administering" a compound as used herein, is understood to mean providing a compound of the invention or a prodrug of a compound of the invention to an individual in need thereof. It will be appreciated that one skilled in the art can have an effect on blood uric acid concentration by treating an patient currently suffering from this disorder or prophylactically treating a patient suffering from such a disorder by using an effective amount of a compound of the present invention.

The term "composition" as used in the present invention refers to a product comprising a specified amount of a specified component, and any product produced directly or indirectly by a specified amount of a combination of specified components. The meaning of such terms in connection with a pharmaceutical composition includes products comprising the active ingredient (single or multiple) and inert ingredients (single or multiple) constituting the carrier, and mixing, compounding or agglomerating of any two or more components. Or any product that is decomposed by one or more components, or that is produced directly or indirectly by other types of reactions or interactions of one or more components. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by mixing a compound of the present invention with a pharmaceutically acceptable carrier.

Description of the compounds of the invention

The present invention discloses a class of cyano substituted fused bicyclic derivatives, stereoisomers, oxynitrides, solvates, metabolites, pharmaceutically acceptable salts thereof or prodrugs thereof, pharmaceutical preparations and compositions thereof It can be used as a xanthine oxidase and urate anion transporter 1 inhibitor, a symptom or disease with high uric acid value in human blood, such as hyperuricemia, tophi, gouty arthritis, and hyperuricemia. There are potential uses for the treatment of kidney disorders and urolithiasis.

In one aspect, the invention relates to a compound of formula (I) or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a compound thereof of the compound of formula (I) Prodrug,

Wherein R, R ¹ , R ² , R ³ , X, Y, Z, L ⁰ , L ¹ , L ² , L ³ , E and n have the meanings as described herein.

In some embodiments, X and Z are each independently -N(R ^a )-, -O-, -S(O) _t -, -C(R ^b )=, -CR ^c R ^d - or -N Wherein t, R ^a , R ^b , R ^c and R ^d have the meanings indicated in the present invention.

In some embodiments, Y is -C(R ^e )=, -CR ^f R ^g - or -N=; wherein R ^e , R ^f and R ^g have the meanings as described herein.

In some embodiments, t is 0, 1, or 2.

In some embodiments, each R ^{a is} independently hydrogen, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, or C _3-6 cycloalkyl.

In some embodiments, each R ^{b is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _{1 -6} alkoxy, C _1-6 alkylamino or C _1-6 haloalkoxy.

In some embodiments, each R ^{c is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _{1 -6} alkoxy, C _1-6 alkylamino or C _1-6 haloalkoxy.

In some embodiments, each R ^{d is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _{1 -6} alkoxy, C _1-6 alkylamino or C _1-6 haloalkoxy.

In some embodiments, R ^e is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne , C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 haloalkylamino, C _3-8 cycloalkyl, 3 -8 membered heterocyclic group, phenyl or 5-10 membered heteroaryl.

In some embodiments, R ^f is hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne , C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 haloalkylamino, C _3-8 cycloalkyl, 3 -8 membered heterocyclic group, phenyl or 5-10 membered heteroaryl.

In some embodiments, R ^g is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne , C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 haloalkylamino, C _3-8 cycloalkyl, 3 -8 membered heterocyclic group, phenyl or 5-10 membered heteroaryl.

In some embodiments, R ¹ is hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkane Oxy, C _1-6 alkylamino or C _1-6 haloalkoxy.

In some embodiments, R ² is hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkane Oxy, C _1-6 alkylamino or C _1-6 haloalkoxy.

In some embodiments, each R ^{3 is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _{1 -6} alkoxy or C _1-6 haloalkoxy.

In some embodiments, R is hydrogen, deuterium, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl or Q, wherein said C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl a 3-8 membered heterocyclic group, a C _6-10 aryl group, a 5-10 membered heteroaryl group, and Q are independently independently selected from 1, 2, 3, 4 or 5 selected from the group consisting of ruthenium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl or 3-6 membered heterocyclic Substituent substitution; wherein Q has the meaning as described in the present invention.

In some embodiments, Q is a substituted or unsubstituted _C1-6 aliphatic hydrocarbon group, wherein 0-3 methylene groups are independently selected from -O-, -NH-, and -C(=O)- Replacement of the group.

In some embodiments, L ⁰ is a bond, -O-, -NH-, or -S-.

In some embodiments, L ¹ is -O-, -NH-, or -S-.

In some embodiments, L ² is -C _1-6 alkylene-, -C(=O)-, or -NH-.

In some embodiments, L ³ is a bond, -O-, -NH-, -C(=O)-, -C(=NH)-, -C(=O)-O-, -OC(=O )-, -C(=O)-N(R ⁴ )-, -N(R ⁴ )-C(=O)- or -C _1-6 alkylene-; wherein R ⁴ has the present invention The meaning.

In some embodiments, R ⁴ is hydrogen, deuterium, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl, or C _3-8 cycloalkyl.

-C(＝O)-CH(R ⁷)-N(R ⁸)(R ⁹)、

或Q；其中，R ⁵、R ⁶、R ⁷、R ⁸、R ⁹和Q具有本发明所述的含义。 In some embodiments, E is 氘, F, Cl, Br, I, hydroxy, amino, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _{1- 6} haloalkoxy, C _1-6 hydroxyalkyl, C _1-6 alkylamino, C _3-8 cycloalkyl, 3-8 membered heterocyclic, phenyl, 5-10 membered heteroaryl,

-C(=O)-CH(R ⁷ )-N(R ⁸ )(R ⁹ ),

Or Q; wherein R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and Q have the meanings as described herein.

In some embodiments, R ⁵ and R ⁶ are each independently hydrogen, deuterium or Q; wherein Q has the meaning as described herein.

-(CH ₂) ₃NH-C(＝NH)-NH ₂或

In some embodiments, R ⁷ is hydrogen, deuterium, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoyl Methyl, carbamoylethyl, 1-hydroxyethyl, decylmethyl, carboxymethyl, carboxyethyl, -(CH ₂ ) ₄ NH ₂ ,

-(CH ₂ ) ₃ NH-C(=NH)-NH ₂ or

In some embodiments, R ⁸ and R ⁹ are each independently hydrogen, deuterium, C _1-6 alkyl, or C _1-6 haloalkyl.

In some embodiments, n is 0, 1, 2, or 3.

In some embodiments, the compound of the present invention is a compound of formula (I) or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, or a pharmaceutically acceptable compound of the compound of formula (I). a salt or a prodrug thereof, provided that -L ¹ -L ² -L ³ -E in the formula (I) is not a hydroxyl group or a difluoromethoxy group.

In other embodiments, each R ^{a is} independently hydrogen, deuterium, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl or C _3-6 cycloalkyl.

In still other embodiments, each R ^{a is} independently hydrogen, deuterium, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, cyclopropyl. , cyclobutyl, cyclopentyl or cyclohexyl.

In other embodiments, each R ^{b is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylamino or C _1-3 haloalkoxy.

In still other embodiments, each R ^{b is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, Trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino or dimethylamino.

In other embodiments, each R ^{c is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylamino or C _1-3 haloalkoxy.

In still other embodiments, each R ^{c is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, Trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino or dimethylamino.

In other embodiments, each R ^{d is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylamino or C _1-3 haloalkoxy.

In still other embodiments, each R ^{d is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, Trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino or dimethylamino.

In other embodiments, R ^e is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 Alkynyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, C _1-3 alkylamino, C _1-3 haloalkylamino, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl group or 5-6 membered heteroaryl group.

In still other embodiments, R ^e is hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allylic Base, ethynyl, propynyl, propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, di Methylamino, trifluoromethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl , thiazolyl, pyrazolyl, oxazolyl, pyridyl or pyrimidinyl.

In other embodiments, R ^f is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 Alkynyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, C _1-3 alkylamino, C _1-3 haloalkylamino, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl group or 5-6 membered heteroaryl group.

In still other embodiments, R ^f is hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allylic Base, ethynyl, propynyl, propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, di Methylamino, trifluoromethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl , thiazolyl, pyrazolyl, oxazolyl, pyridyl or pyrimidinyl.

In other embodiments, R ^g is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 Alkynyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, C _1-3 alkylamino, C _1-3 haloalkylamino, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl group or 5-6 membered heteroaryl group.

In still other embodiments, R ^g is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allylic Base, ethynyl, propynyl, propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, di Methylamino, trifluoromethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl , thiazolyl, pyrazolyl, oxazolyl, pyridyl or pyrimidinyl.

In other embodiments, R ¹ is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 Alkoxy, C _1-3 alkylamino or C _1-3 haloalkoxy.

In still other embodiments, R ¹ is hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, B. Oxy, isopropyloxy, difluoromethoxy, trifluoromethoxy, methylamino or dimethylamino.

In other embodiments, R ² is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 Alkoxy, C _1-3 alkylamino or C _1-3 haloalkoxy.

In still other embodiments, R ² is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, B. Oxy, isopropyloxy, difluoromethoxy, trifluoromethoxy, methylamino or dimethylamino.

In other embodiments, each R ^{3 is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _1-3 haloalkoxy.

In still other embodiments, each R ^{3 is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy Base, ethoxy, isopropyloxy, difluoromethoxy or trifluoromethoxy.

In other embodiments, R is hydrogen, deuterium, C _1-4 alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl , C _6-10 aryl, 5-6 membered heteroaryl or Q, wherein said C _1-4 alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl, C _3-6 cycloalkane The base, 3-6 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl and Q are independently independently selected from 1, 2, 3, 4 or 5 selected from the group consisting of ruthenium, F, Cl, Br. , I, hydroxy, amino, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl or 3-6 membered heterocyclic Substituent substitution; wherein Q has the meaning as described in the present invention.

In still other embodiments, R is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, t-butyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, difluoro Methyl, trifluoromethyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl , thiomorpholinyl, phenyl, 2,3-dihydro-1H-indole, thiazolyl, pyrazolyl, oxazolyl, pyridyl, pyrimidinyl or Q, wherein said methyl, ethyl, Isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, difluoromethyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, 2,3-dihydro-1H-indole, thiazolyl, pyrazolyl, oxazolyl, Pyridyl, pyrimidinyl and Q are independently, optionally 1, 2, 3, 4 or 5 selected from the group consisting of hydrazine, F, Cl, Br, I, hydroxy, amino, cyano, nitro, methyl, ethyl, Trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, Substituted by a substituent of cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl; wherein Q has the meaning as described herein.

In other embodiments, L ² is -C _1-3 alkylene-, -C(=O)- or -NH-.

In still other embodiments, L ² is methylene, ethylene, propylene, -C(=O)- or -NH-.

In other embodiments, L ³ is a bond, -O-, -NH-, -C(=O)-, -C(=NH)-, -C(=O)-O-, -OC(= O)-, -C(=O)-N(R ⁴ )-, -N(R ⁴ )-C(=O)- or -C _1-3 alkylene-; wherein R ⁴ has the present invention The meaning of the meaning.

In still other embodiments, L ³ is a bond, -O-, -NH-, -C(=O)-, -C(=NH)-, -C(=O)-O-, -OC(= O)-, -C(=O)-N(R ⁴ )-, -N(R ⁴ )-C(=O)-, methylene, ethylene or propylene; wherein R ⁴ has The meaning of the invention.

In other embodiments, R ⁴ is hydrogen, deuterium, C _1-3 alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl or C _3-6 cycloalkyl.

In still other embodiments, R ⁴ is hydrogen, deuterium, methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, difluoromethyl, trifluoromethyl , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

-C(＝O)-CH(R ⁷)-N(R ⁸)(R ⁹)、

或Q；其中，R ⁵、R ⁶、R ⁷、R ⁸、R ⁹和Q具有本发明所述的含义。 In other embodiments, E is hydrazine, F, Cl, Br, I, hydroxy, amino, cyano, C _1-4 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _{1 -3} haloalkoxy, C _1-3 hydroxyalkyl, C _1-3 alkylamino, C _3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl,

-C(=O)-CH(R ⁷ )-N(R ⁸ )(R ⁹ ),

Or Q; wherein R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and Q have the meanings as described herein.

-C(＝O)-CH(R ⁷)-N(R ⁸)(R ⁹)、

或Q；其中，R ⁵、 R ⁶、R ⁷、R ⁸、R ⁹和Q具有本发明所述的含义。 In still other embodiments, E is 氘, F, Cl, Br, I, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, t-butyl, difluoromethyl, tri Fluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, methylamino, Ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl Phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridyl, pyrimidinyl,

-C(=O)-CH(R ⁷ )-N(R ⁸ )(R ⁹ ),

Or Q; wherein R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and Q have the meanings as described herein.

In other embodiments, R ⁵ and R ⁶ are each independently hydrogen, deuterium or Q; wherein Q has the meaning as described herein.

-(CH ₂) ₃NH-C(＝NH)-NH ₂或

In other embodiments, R ⁷ is hydrogen, deuterium, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, methotrex Acylmethyl, carbamoylethyl, 1-hydroxyethyl, decylmethyl, carboxymethyl, carboxyethyl, -(CH ₂ ) ₄ NH ₂ ,

-(CH ₂ ) ₃ NH-C(=NH)-NH ₂ or

In other embodiments, R ⁸ and R ⁹ are each independently hydrogen, deuterium, C _1-3 alkyl or C _1-3 haloalkyl.

In still other embodiments, R ⁸ and R ⁹ are each independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl or 2,2-difluoroethyl. .

In some embodiments, the compound of formula (I) is a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (II). , hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug,

Wherein R, R ¹ , R ² , X, Z, R ^e , L ¹ , L ² , L ³ and E have the meanings as described herein.

In some embodiments, the compound of formula (I) is a compound of formula (III) or a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (III). , hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug,

Wherein R, R ¹ , R ² , X, Z, R ^e , L ¹ , L ² , L ³ and E have the meanings as described herein.

In another aspect, the invention relates to a compound, or a stereoisomer thereof, an oxynitride, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, to which one of the following is, but is in no way limited to:

In another aspect, the present invention is directed to a pharmaceutical composition comprising a compound disclosed herein.

In some embodiments, the pharmaceutical compositions of the present invention further comprise a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or a combination thereof.

In other embodiments, the pharmaceutical composition of the present invention further comprises for preventing or treating hyperuricemia, tophi, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis The drug, the active ingredient of the drug is different from the compound disclosed in the present invention, the drug is colchicine, non-steroidal anti-inflammatory drug, glucocorticoid, uric acid-producing drug, uric acid excretion drug, urine alkalizing agent Or any combination of them.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for the prevention or treatment of hyperuricemia, tophi, gouty arthritis, and uric acid in a mammal A renal disorder associated with blood or urolithiasis, including mammals.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the preparation of a medicament for lowering blood uric acid levels.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for inhibiting xanthine oxidase and urate anion transporter 1.

In another aspect, the compounds or pharmaceutical compositions disclosed herein are useful for preventing or treating hyperuricemia, tophi, gouty arthritis, renal disorders associated with hyperuricemia, or urolithiasis in a mammal, Mammals include humans.

In another aspect, the compounds or pharmaceutical compositions disclosed herein are used to lower blood uric acid levels.

In another aspect, the compounds or pharmaceutical compositions disclosed herein are useful for inhibiting xanthine oxidase and urate anion transporter 1.

In another aspect, the present invention relates to a method of preventing or treating hyperuricemia, tophi, gouty arthritis, renal disorders associated with hyperuricemia or urolithiasis, comprising administering to a patient a therapeutically effective dose A compound or pharmaceutical composition disclosed herein.

In another aspect, the invention relates to a method of lowering blood uric acid levels, the method comprising administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition of the invention.

In another aspect, the present invention is directed to a method of inhibiting xanthine oxidase and urate anion transporter 1 using a compound or pharmaceutical composition disclosed herein.

In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound encompassed by formula (I), (II) or (III).

Unless otherwise specified, stereoisomers, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of formula (I), (II), (III) are included within the scope of the invention.

The compounds disclosed herein may contain asymmetric or chiral centers and may therefore exist in different stereoisomeric forms. The present invention is intended to give all stereoisomeric forms of the compounds of formula (I), (II), (III), including but not limited to diastereomers, enantiomers, atropisomers And geometric (or conformational) isomers, as well as mixtures thereof such as racemic mixtures, are an integral part of the present invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the invention, and as disclosed herein are included in the present invention. . When stereochemistry is indicated by a solid wedge or dashed line indicating a particular configuration, then the stereoisomers of the structure are defined and defined herein.

The compounds of formula (I), (II), (III) may exist in different tautomeric forms, and all such tautomers are included within the scope of the invention.

The compounds of the formulae (I), (II) and (III) may be present in the form of a salt. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, and may be used in the preparation and/or purification of compounds of formula (I), (II), (III) and/or for separation An intermediate of the enantiomer of the compound of the formula (I), (II), or (III).

Pharmaceutically acceptable acid addition salts can be formed by the action of the compounds disclosed herein with inorganic or organic acids, such as acetate, aspartate, benzoate, besylate, bromide/hydrobromide , bicarbonate/carbonate, hydrogen sulfate/sulfate, camphor sulfonate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, fumarate, glucoheptane Sodalate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Acid salt, maleate, malonate, mandelate, methanesulfonate, methyl sulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oil Acid salt, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturate, propionate, stearate, succinate, sulfosapenyl Acid salts, tartrates, tosylates and trifluoroacetates.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid. , ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed by the action of the compounds disclosed herein with inorganic or organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of Groups I to XII of the Periodic Table. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts.

Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. .

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods. In general, such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K. The free base form of these compounds is prepared by reaction with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For example, "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and A list of additional suitable salts can be found in Use), Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Further, the compounds disclosed in the present invention, including their salts, may also be obtained in the form of their hydrates or in the form of their solvents (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed herein may form solvates either intrinsically or by design with pharmaceutically acceptable solvents, including water; thus, the invention is intended to include solvated and unsolvated forms of the compounds disclosed herein.

Any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched. Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, for example, those in which a radioisotope such as ³ H, ¹⁴ C and ¹⁸ F is present, or in which a non-radioactive isotope is present, such as ² Those compounds of H and ¹³ C. Such isotopically enriched compounds can be used for metabolic studies (using ¹⁴ C), reaction kinetic studies (using, for example, ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) of substrate tissue distribution assays, or may be used in patient radiation therapy. ¹⁸ F enriched compounds are particularly desirable for PET or SPECT studies. The isotopically enriched compound of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by the use of suitable isotopically labeled reagents in place of the previously used unlabeled reagents as described in the Examples and Preparations of the present invention.

In addition, substitution of heavier isotopes, particularly deuterium (i.e., ² H or D), may provide certain therapeutic advantages resulting from higher metabolic stability. For example, increased in vivo half-life or reduced dose requirements or improved therapeutic index. It should be understood that the hydrazine in the present invention is regarded as a substituent of the compound represented by the formula (I). Isotopic enrichment factors can be used to define the concentration of such heavier isotopes, particularly ruthenium. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotope abundance and the natural abundance of a given isotope. If a substituent of a compound of the invention is designated as hydrazine, the compound has at least 3500 for each of the specified hydrazine atoms (52.5% of ruthenium incorporation at each of the specified ruthenium atoms), at least 4,000 (60% of ruthenium incorporation), At least 4,500 (67.5% of cerium incorporation), at least 5,000 (75% of cerium incorporation), at least 5,500 (82.5% of cerium incorporation), at least 6,000 (90% of cerium incorporation), at least 6333.3 (95%) Iridium enrichment factor with at least 6466.7 (97% cerium incorporation), at least 6600 (99% cerium incorporation) or at least 6633.3 (99.5% cerium incorporation). The present invention can include pharmaceutically acceptable solvates wherein the solvent of crystallization may be isotopically substituted, for example D ₂ O, acetone -d _6, DMSO-d ₆ solvate of those.

In another aspect, the invention relates to intermediates for the preparation of compounds of formula (I), (II), (III).

In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound of formula (I), (II), (III).

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or a combination thereof. In another embodiment, the pharmaceutical composition can be in the form of a liquid, solid, semi-solid, gel or spray.

Pharmaceutical compositions, formulations and administrations of the compounds of the invention

The present invention provides a pharmaceutical composition comprising a compound of the present invention, such as a compound listed in the Examples; and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or a combination thereof.

The invention provides a method of treating, preventing or ameliorating a disease or condition comprising administering a safe and effective amount of a combination comprising a compound of the invention and one or more therapeutically active agents. Wherein the combination drug comprises one or more drugs for preventing or treating hyperuricemia, tophi, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis, the active ingredients of the drug and the present The compounds disclosed in the invention are different.

Drugs for preventing or treating hyperuricemia, tophi, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis include, but are not limited to, colchicine, non-steroidal anti-inflammatory drugs, and glucocorticoids. And inhibiting uric acid-producing drugs, uric acid excretion drugs, urinary alkalizing agents, or any combination thereof.

The drugs for treating hyperuricemia, tophi, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis are colchicine, indomethacin, etoricoxib, diclofenac, and bulu Fen, rofecoxib, celecoxib, meloxicam, prednisone, hydrocortisone succinate, allopurinol, probenecid, sulfinoxazolone, benzbromarone, oxicamol , febuxostat, recombinant Aspergillus flavus urate oxidase, PEGylated recombinant urate oxidase, sodium bicarbonate tablets, sodium potassium citrate mixture or any combination thereof.

The amount of the compound in the pharmaceutical composition disclosed in the present invention means an amount effective to detect inhibition of xanthine oxidase and urate anion transporter 1 in a biological sample or a patient. The dosage of the active ingredient in the compositions of the invention may vary, however, the amount of active ingredient must be such that an appropriate dosage form can be obtained. The active ingredient can be administered to a patient (animal and human) in need of such treatment at a dose that provides optimal pharmaceutical efficacy. The dosage chosen will depend on the desired therapeutic effect, on the route of administration and the duration of treatment. The dosage will vary from patient to patient, depending on the nature and severity of the disease, the weight of the patient, the particular diet of the patient, the concurrent use of the drug, and other factors that will be recognized by those skilled in the art. The dosage range is usually from about 0.5 mg to 1.0 g per patient per day, and may be administered in a single dose or in multiple doses. In one embodiment, the dosage range is from about 0.5 mg to 500 mg per patient per day; in another embodiment from about 0.5 mg to 200 mg per patient per day; in yet another embodiment about 5 mg per patient per day. To 50mg.

It will also be appreciated that certain compounds of the invention may exist in free form and be used in the treatment or, if appropriate, in the form of their pharmaceutically acceptable derivatives. Pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or can provide, directly or indirectly, a compound of the invention or a metabolite or residue thereof when administered to a patient in need thereof Any additional adduct or derivative of the substance.

The medicament or pharmaceutical composition disclosed herein can be prepared and packaged in a bulk form in which a safe and effective amount of a compound of formula (I) can be extracted and then administered to a patient in the form of a powder or syrup. Typically, administration to a patient at a dosage level between 0.0001 and 10 mg/kg body weight per day provides effective antagonism of xanthine oxidase and urate anion transporter 1. Alternatively, the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of formula (I). When prepared in unit dosage form, the pharmaceutical compositions disclosed herein may generally contain, for example, from 0.5 mg to 1 g, or from 1 mg to 700 mg, or from 5 mg to 100 mg of the compounds disclosed herein.

When the pharmaceutical composition of the present invention contains one or more other active ingredients in addition to the compound of the present invention, the weight ratio of the compound of the present invention to the second active ingredient may vary depending on each component. Effective dose. Usually, an effective dose of each is used. Thus, for example, when a compound of the invention is combined with another agent, the weight ratio of the compound of the invention to another agent will generally range from about 1000:1 to about 1:1000, such as from about 200:1 to about 1:200. . Mixtures of the compounds of the invention with other active ingredients are generally also within the above ranges, but in each case an effective dose of each active ingredient should be employed.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle that is associated with the administration of a dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions which would greatly reduce the efficacy of the compounds disclosed herein when administered to a patient and result in a pharmaceutical composition that is not pharmaceutically acceptable Interaction. In addition, each excipient must be pharmaceutically acceptable, for example, of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, pharmaceutically acceptable excipients can be selected based on their particular function in the composition. For example, certain pharmaceutically acceptable excipients can be selected which can aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients can be selected which can aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients that facilitate the carrying or transport of a compound of the present invention from one organ or part of the body to another organ or part of the body upon administration to a patient may be selected. Certain pharmaceutically acceptable excipients that enhance patient compliance may be selected.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents , solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, Preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function and provide alternative functionality depending on how many other excipients are present in the formulation and in the formulation. Agent.

The skilled artisan will have the knowledge and skill in the art to enable them to select the appropriate amount of suitable pharmaceutically acceptable excipient for use in the present invention. In addition, there are a number of resources available to the skilled artisan who describe pharmaceutically acceptable excipients and are used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York Various carriers for formulating pharmaceutically acceptable compositions, and well-known techniques for their preparation are disclosed, the respective contents of which are incorporated herein by reference. In addition to any conventional carrier medium that is incompatible with the compounds of the invention (e.g., produces any undesirable biological effects or otherwise interacts in a deleterious manner with any other component of the pharmaceutically acceptable composition), its use is encompassed by the present invention. Within the scope of.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some common methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Accordingly, in another aspect, the present invention is directed to a process for preparing a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, the process comprising Mix various ingredients. Pharmaceutical compositions comprising the compounds disclosed herein can be prepared, for example, by mixing at ambient temperature and atmospheric pressure.

The compounds disclosed herein are typically formulated in a dosage form suitable for administration to a patient by the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, for example, tablets, capsules, caplets, pills, tablets, powders, syrups, elixirs, suspensions, Solution, emulsion, sachet and cachet; (2) parenteral administration, such as sterile solutions, suspensions and reconstituted powders; (3) transdermal administration, such as transdermal patches (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes , sprays, foams and gels.

In one embodiment, the compounds disclosed herein can be formulated into oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhaled dosage form. In another embodiment, the compounds disclosed herein may be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated in a transdermal dosage form. In still another embodiment, the compounds disclosed herein may be formulated for topical administration.

The pharmaceutical composition provided by the present invention can be provided as a compressed tablet, a developed tablet, a chewable tablet, a fast-dissolving tablet, a reconstituted tablet, or an enteric coated tablet, a sugar-coated tablet or a film-coated tablet. The enteric coated tablet is a compressed tablet coated with a substance which is resistant to gastric acid but which dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. The sugar-coated tablet is a compressed tablet surrounded by a sugar coating which can be used to mask an unpleasant taste or odor and to prevent oxidation of the tablet. The film coated tablet is a compressed tablet covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The film coating imparts the same general characteristics as the sugar coating. The compressed tablet is a compressed tablet prepared over more than one compression cycle, including a multilayer tablet, and a press-coated or dry-coated tablet.

The tablet dosage form can be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including carriers Decomposing agents, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

The pharmaceutical composition provided by the present invention may be provided in a soft capsule or a hard capsule, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also known as dry-filled capsule (DFC), consists of two sections, one section being inserted into the other section, thus completely encapsulating the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerin, sorbitol or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those according to the invention, including methylparaben and propylparaben, and sorbic acid. The liquid, semi-solid and solid dosage forms provided herein can be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such a solution can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239 and 4,410,545. The capsules may also employ coatings as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein can be provided in liquid and semisolid dosage forms including emulsions, solutions, suspensions, elixirs, and syrups. The emulsion is a two-phase system in which one liquid is completely dispersed in the form of pellets in another liquid, which may be an oil-in-water or water-in-oil type. The emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers, and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. The aqueous alcohol solution may include a pharmaceutically acceptable acetal such as a di(lower alkyl) acetal of a lower alkyl aldehyde such as acetaldehyde diethyl acetal; and a water soluble solvent having one or more hydroxyl groups, such as Propylene glycol and ethanol. The tincture is a clear, sweet, hydroalcoholic solution. A syrup is an aqueous solution of a concentrated sugar such as sucrose, and may also contain a preservative. For liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier such as water for precise and convenient administration.

Other useful liquid and semisolid dosage forms include, but are not limited to, those comprising the active ingredients provided herein and the secondary mono- or poly-alkylene glycols, the mono- or poly-alkylene glycols comprising: 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-two Methyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, 750 refers to the approximate average molecular weight of polyethylene glycol. These formulations may further comprise one or more antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin. , cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and esters thereof, and dithiocarbamate.

Dosage unit formulations for oral administration can be microencapsulated as appropriate. It may also be prepared as a composition for prolonged or sustained release, for example by coating or embedding the particulate material in a polymer, wax or the like.

The oral pharmaceutical compositions provided herein can also be provided in the form of liposomes, micelles, microspheres or nanosystems. The micellar dosage form can be prepared by the method described in U.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders to reconstitute a liquid dosage form. The pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. The pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.

Colorants and flavoring agents can be used in all of the above dosage forms.

The compounds disclosed herein can also be combined with soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or palmitoyl residue substituted polyoxyethylene polylysine. Furthermore, the compounds disclosed herein can be combined with a class of biodegradable polymers used in the controlled release of drugs, for example, polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters. Crosslinked or amphiphilic block copolymers of polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.

The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed-, sustained-release, pulse-, controlled-, targeted-, and programmed release forms.

The pharmaceutical compositions provided herein can be formulated with other active ingredients that do not impair the intended therapeutic effect, or with a substance that complements the intended effect.

The pharmaceutical compositions provided by the present invention can be administered parenterally by injection, infusion or implantation for topical or systemic administration. Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and in liquids prior to injection. A solid form of the solution or suspension. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous carriers, water miscible vehicles, nonaqueous vehicles, antibiotics Microbial or antimicrobial growth preservatives, stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, multivalent Chelating or chelating agents, antifreeze agents, cryoprotectants, thickeners, pH adjusters, and inert gases.

Suitable aqueous vehicles include, but are not limited to, water, saline, saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic glucose injection, sterile water injection, dextrose, and Lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, plant-derived non-volatile oils, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil. Chain triglycerides, and palm seed oil. Water miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (eg, polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl- 2-pyrrolidone, N,N-dimethylacetamide and dimethyl sulfoxide.

CyDex,Lenexa,KS)。 Suitable antimicrobial or preservatives include, but are not limited to, phenol, cresol, amalgam, benzyl alcohol, chlorobutanol, methyl and propylparaben, thiomersal, benzalkonium chloride (eg benzethonium chloride), methylparaben and propylparaben and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and glucose. Suitable buffering agents include, but are not limited to, phosphates and citrates. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene tax refund sorbitol monooleate 80 and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, and sulfonate. Butyl ether 7-β-cyclodextrin

CyDex, Lenexa, KS).

The pharmaceutical compositions provided by the present invention may be formulated for administration in single or multiple doses. The single dose formulation is packaged in an ampoule, vial or syringe. The multi-dose parenteral formulation must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as is known and practiced in the art.

In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, including lyophilized powders and subcutaneously injected tablets, which are reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile dry insoluble product that has been reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile emulsion.

The pharmaceutical compositions can be formulated as a suspension, solid, semi-solid or thixotropic liquid for administration as an implanted reservoir. In one embodiment, the disclosed pharmaceutical compositions are dispersed in a solid internal matrix surrounded by an outer polymeric film that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse through.

Suitable internal substrates include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, plasticized Polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone Carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic acid and methacrylic acid, collagen, crosslinked polyvinyl alcohol and partially hydrolyzed polyvinyl acetate of the trainer.

Suitable external polymeric films include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, chloroprene Rubber, chlorinated polyethylene, polyvinyl chloride, copolymer of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polymer polyethylene terephthalate, butyl rubber chlorohydrin Rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer and ethylene/vinyloxyethanol copolymer.

In another aspect, the pharmaceutical compositions disclosed herein can be formulated into any dosage form suitable for inhalation administration to a patient, such as a dry powder, aerosol, suspension or solution composition. In one embodiment, the disclosed pharmaceutical compositions can be formulated in a dosage form suitable for inhalation administration to a patient with a dry powder. In yet another embodiment, the disclosed pharmaceutical compositions can be formulated in a dosage form suitable for inhalation administration to a patient by a nebulizer. Dry powder compositions for delivery to the lung by inhalation typically comprise a finely divided powder of the compound disclosed herein and one or more finely divided pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients which are particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di- and polysaccharides. Fine powders can be prepared, for example, by micronization and milling. Generally, the size-reduced (e.g. micronised) compound can be (e.g., as measured by laser diffraction method) is defined by the D ₅₀ value from about 1 to 10 microns.

Aerosol formulations can be formulated by suspending or dissolving the disclosed compounds in a liquefied propellant. Suitable propellants include chlorinated hydrocarbons, hydrocarbons, and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1 , 1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoro Pentane, butane, isobutane and pentane. Aerosols comprising the compounds disclosed herein are typically administered to a patient via a metered dose inhaler (MDI). Such devices are known to those skilled in the art

Aerosols may contain additional pharmaceutically acceptable excipients, such as surfactants, lubricants, cosolvents, and other excipients, which may be used by MDIs to improve the physical stability of the formulation, improve valve characteristics, Improve solubility or improve taste.

Pharmaceutical compositions suitable for transdermal administration can be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient can be delivered from the patch by ion permeation as generally described in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with a water or oil base, and a suitable thickening and/or gel and/or solvent. Such a matrix may include water, and/or oils such as liquid liquid paraffin and vegetable oils (such as peanut oil or castor oil), or solvents such as polyethylene glycol. Thickeners and gels for use depending on the nature of the matrix include soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or single Stearic acid glycerides and/or nonionic emulsifiers.

Lotions may be formulated with water or oil bases and usually contain one or more emulsifying, stabilizing, dispersing, suspending or thickening agents.

The topical powder can be formed in the presence of any suitable powder base such as talc, lactose or starch. Drops can be formulated with an aqueous or non-aqueous base comprising one or more dispersing agents, solubilizing agents, suspending agents or preservatives.

The topical preparation can be administered by applying one or more times per day to the affected area; a closed dressing covering the skin is preferably used. Adhesive depot systems enable continuous or extended administration.

Use of the compounds and compositions of the invention

The compounds or pharmaceutical compositions disclosed herein can be used to prepare for the treatment, prevention, amelioration, control or alleviation of hyperuricemia, tophi, gouty arthritis, and hyperuricemia in mammals, including humans. Drugs related to kidney disorders and urolithiasis can also be used to prepare other drugs for inhibiting xanthine oxidase and urate anion transporter 1.

Specifically, the amount of the compound in the composition of the present invention can effectively and detectably inhibit xanthine oxidase and urate anion transporter 1, and the compound of the present invention can be used as a prophylactic or therapeutic human hyperuricemia, tophi , gouty arthritis, kidney disorders associated with hyperuricemia and urolithiasis.

The compounds or compositions of the invention may be used, but are in no way limited to, administration to a patient using an effective amount of a compound or composition of the invention to prevent, treat or ameliorate hyperuricemia, tophi, in a mammal, including humans. , gouty arthritis, kidney disorders associated with hyperuricemia and urolithiasis.

In addition to being useful for human therapy, the compounds and pharmaceutical compositions of the present invention are also useful in veterinary treatment of pets, introduced species of animals, and mammals in farm animals. Other examples of animals include horses, dogs, and cats. Herein, the compounds of the invention include pharmaceutically acceptable derivatives thereof.

treatment method

In one embodiment, the methods of treatment disclosed herein comprise administering to a patient in need thereof a safe and effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention. Embodiments of the present disclosure include methods of treating the above mentioned diseases by administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention.

In one embodiment, a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein can be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes administration to the skin as well as intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein may be administered orally. In another embodiment, a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein can be administered by inhalation. In still another embodiment, the compounds disclosed herein or comprising a compound disclosed herein may be administered intranasally.

In one embodiment, a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein can be administered at a time, or several times at different time intervals, over a specified period of time, depending on the dosage regimen. For example, administration once, twice, three times or four times a day. In one embodiment, it is administered once a day. In yet another embodiment, the administration is twice daily. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the disclosed compounds or pharmaceutical compositions comprising the compounds disclosed herein depend on the pharmacokinetic properties of the compound, such as dilution, distribution and half-life, as determined by the skilled artisan. Furthermore, suitable dosage regimens of the disclosed compounds or pharmaceutical compositions comprising the compounds of the present invention, including the duration of implementation of the regimen, depend on the condition being treated, the severity of the condition being treated, the age of the subject being treated, and The physical condition, the medical history of the patient being treated, the nature of the concurrent therapy, the desired therapeutic effect, etc., are within the knowledge and experience of the skilled person. Such skilled artisans will also appreciate that the dosage regimen for the adjustment may be required for individual patient responses to the dosing regimen, or for individual patient needs to change over time.

The compounds disclosed herein can be administered simultaneously with, or before or after, one or more other therapeutic agents. The compounds of the present invention may be administered separately or in combination with other therapeutic agents in the form of a pharmaceutical composition.

The pharmaceutical compositions and combinations disclosed herein may comprise from about 1 to 1000 mg, or from about 1 to 500 mg, or from about 1 to 250 mg, or from about 1 to 150 mg, or from about 0.5 to 100 mg, or from about 50 to 70 kg of the individual, or A unit dosage form of about 1-50 mg of the active ingredient. The therapeutically effective amount of a compound, pharmaceutical composition, or combination thereof, will depend on the species, weight, age, and individual condition of the individual, the disorder or disease being treated, or the severity thereof. Physicians, clinicians, or veterinarians with common skills can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the development of a disease or disease.

The dosage characteristics cited above have been demonstrated in in vitro and in vivo assays using advantageous mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues, and specimens. The compounds disclosed in the present invention are used in vitro in the form of a solution, for example, an aqueous solution, and may also be used, for example, in the form of a suspension or an aqueous solution in the intestine of the body, parenterally, especially intravenously.

In one embodiment, a therapeutically effective amount of a compound disclosed herein is from about 0.1 mg to about 2,000 mg per day. The pharmaceutical composition thereof should provide a dose of from about 0.1 mg to about 2,000 mg of the compound. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide from about 1 mg to about 2,000 mg, from about 10 mg to about 1,000 mg, from about 20 mg to about 500 mg, or from about 25 mg to about 250 mg of the primary active ingredient or per dosage unit form. The combination of the main ingredients. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the main active ingredient.

Furthermore, the compounds disclosed herein can be administered in the form of a prodrug. In the present invention, a "prodrug" of a compound disclosed herein is a functional derivative which, when administered to a patient, ultimately releases the compound of the present invention in vivo. When a compound disclosed herein is administered in a prodrug form, one of skill in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of in vivo action of the compound; Changing the in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming the side effects or other difficulties faced by the compound. Typical functional derivatives for the preparation of prodrugs, including variants of compounds which are cleaved chemically or enzymatically in vivo. These variants comprising the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates are well known to those skilled in the art.

General synthetic procedure

For the purpose of describing the invention, the examples are set forth below. However, it is to be understood that the invention is not limited to the embodiments, but merely provides a method of practicing the invention.

In general, the compounds of the present invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for formulas (I), (II), (III). The following reaction schemes and examples are provided to further illustrate the contents of the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare a number of other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by modifications by those skilled in the art, such as appropriate protection of the interfering group, by the use of other known reagents in addition to those described herein, or The reaction conditions are subject to some conventional modifications. Additionally, the reactions or known reaction conditions disclosed herein are also recognized to be suitable for the preparation of other compounds of the invention.

The examples described below, unless otherwise indicated, all temperatures are set to degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant purchased it.

Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal. Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried using anhydrous sodium sulfate.

The following reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe. The glassware is dry.

The column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

Nuclear magnetic resonance spectroscopy was recorded using a Bruker 400 MHz or 600 MHz NMR spectrometer with CDC1 ₃ , DMSO-d ₆ , CD ₃ OD or acetone-d ₆ as solvent (in ppm) with TMS (0 ppm) or chloroform (7.26 ppm). ) as a reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet, single peak), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide) Peak), dd (doublet of doublets), dt (doublet of triplets). Coupling constant, expressed in Hertz (Hz).

The conditions for the determination of low resolution mass spectrometry (MS) data were: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 micron, 6 min, flow rate 0.6 mL/min. Mobile phase: 5 %-95% (CH ₃ CN containing 0.1% formic acid) in a ratio of (containing 0.1% formic acid in H ₂ O) was detected by UV at 210 nm / 254 nm using electrospray ionization (ESI).

The purity of the compound was determined by high performance liquid chromatography (HPLC) using Agilent 1260 HPLC (column model: Agilent zorbax Eclipse Plus C18) and detected by a DAD detector, and finally the compound purity was calculated by area normalization.

The following abbreviations are used throughout the invention:

AcOH acetic acid

AIBN azobisisobutyronitrile

CDC1 ₃ deuterated chloroform

CD ₃ OD deuterated methanol

DBU 1,8-diazabicycloundec-7-ene

DCM dichloromethane

DMAP 4-dimethylaminopyridine

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

DMSO-d ₆ deuterated dimethyl sulfoxide

g g

h hours

Min minute

Mm mmol

M mole per liter °C degrees Celsius

H ₂ SO ₄ sulfuric acid

HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

NBS N-bromosuccinimide

MeCN, CH ₃ CN acetonitrile

MeOH methanol

mL, ml ml

NMP N-methylpyrrolidone

RT, rt, r.t. room temperature

Rpm to every minute

Rt retention time

TFA trifluoroacetic acid

THF tetrahydrofuran

A typical synthetic procedure for the preparation of the compounds disclosed herein is shown in the synthetic scheme below. Wherein L represents a leaving group, including but not limited to a halogen atom and a trifluoromethanesulfonyloxy group; R ⁰ represents a hydrogen atom or a C _1-4 alkyl group, or two R ⁰ groups are bonded together to form a ring; It is noted that R, R ¹ , R ² , R ³ , X, Y, Z, L ⁰ , L ¹ , L ² , L ³ , E and n have the meanings as described in the present invention.

Synthetic scheme 1

Compound (I) can be produced by the following process:

The fused bicyclic compound (1) substituted with different substituents is catalyzed by a [palladium] catalyst and coupled with the boronic acid ester structure-containing compound (2) to obtain a compound (I);

Synthetic scheme 2

Compound (I-1) can be produced by the following procedure:

The compound (3) undergoes ester hydrolysis reaction under the action of an acid or a base to give a compound (4), and the compound (4) is further subjected to substitution or acylation to obtain a compound (I-1).

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in conjunction with the examples.

Example

Example 1: Methyl 4-(5-cyano-1-methyl-2-(trifluoromethyl)-1H-indol-7-yl)-2-hydroxybenzoate

First step 7-bromo-1-methyl-2-(trifluoromethyl)-1H-indole-5-carbonitrile

7-Bromo-2-(trifluoromethyl)-1H-indole-5-carbonitrile (0.50 g, 1.73 mmol) and DMF (10 mL) were added to a 50 mL two-neck bottle. Sodium hydride (0.50 g, 1.95 mmol, 60%) was added to the reaction flask at 0 ° C. After the addition was completed, the reaction mixture was stirred at 0 ° C for 0.5 h, then iodomethane (0.20 mL, 3.2) was added to the reaction mixture. (mmol), the reaction mixture was stirred at room temperature for a further 12 h. The organic solvent was evaporated under reduced pressure. EtOAc EtOAc m. The residue was subjected to EtOAcjjjjjjjjjj

MS (ES-API, pos.ion) m/z: 304.0 [M+2]

Step 2 4-(5-Cyano-1-methyl-2-(trifluoromethyl)-1H-indol-7-yl)-2-hydroxybenzoic acid methyl ester

7-Bromo-1-methyl-2-(trifluoromethyl)-1H-indole-5-carbonitrile (0.36 g, 1.19 mmol), 2-hydroxy-4-(4,4,5,5 Methyl tetramethyl-1,3,2-dioxolborolan-2-yl)benzoate (0.30 g, 1.08 mmol), [1,1'-bis(diphenylphosphine) ferrocene Iron] palladium dichloride dichloromethane complex (48 mg, 0.059 mmol) and DMF (8 mL) were added to a 50 mL two-necked bottle. Under a nitrogen atmosphere, an aqueous potassium carbonate solution (1.1 mL, 2M) was added to the reaction mixture, and the mixture was stirred at 90 ° C for 0.5 h. The reaction mixture was cooled to room temperature, and brine (EtOAc) was evaporated. The organic layer was washed with EtOAcq. The residue was subjected to EtOAcjjjjjjjjjj

MS (ES-API, pos.ion) m/z: 375.1 [M+1]

_{^{1 H NMR (400MHz, CDCl 3}} ) δ10.94 (s, 1H), 8.06 (d, J = 1.2Hz, 1H), 7.97 (d, J = 8.1Hz, 1H), 7.38 (d, J = 1.2Hz , 1H), 7.13 (s, 1H), 7.06 (d, J = 1.3 Hz, 1H), 6.96 (dd, J = 8.1, 1.6 Hz, 1H), 4.03 (s, 3H), 3.47 (s, 3H) .

Example 2: tert-butyl 4-(6-cyanobenzofuran-4-yl)-2-hydroxybenzoate

First step 3-(ethoxycarbonyl)-4-(furan-2-yl)-3-butenoic acid

Potassium tert-butoxide (126 g, 1123 mmol) and tert-butanol (350 mL) were added to a 1000 mL two-necked flask, and diethyl succinate (294 g, 1688 mmol) and furan-2-carbaldehyde (36.0 g) were added dropwise to the reaction flask. After a dropwise addition, the reaction mixture was stirred at 110 ° C for 3 h under nitrogen. The reaction mixture was cooled to room temperature. EtOAc (EtOAc m. The organic layer was washed with EtOAc EtOAc m. The residue was subjected to EtOAcjjjjjjjjjj

MS (ES-API, neg.ion) m/z: 223.1 [M-1]

The second step is ethyl 4-acetoxybenzofuran-6-carboxylate

Add 3-(ethoxycarbonyl)-4-(furan-2-yl)-3-butenoic acid (84.1 g, 375 mmol), sodium acetate (123 g, 1499 mmol) and acetic anhydride (350 mL) to a 1000 mL single-neck bottle. The reaction mixture was stirred at 180 ° C for 5 h. The reaction mixture was cooled to room temperature, acetic anhydride was removed under reduced pressure, and the residue was adjusted to weakly basic with 15% aqueous sodium carbonate. The aqueous phase was extracted with ethyl acetate (100 mL×2) and organic phases were combined. The organic layer was washed with EtOAc EtOAc m. The residue was subjected to EtOAcjjjjjjjjjj

MS (ES-API, pos.ion) m/z: 249.1 [M+1]

The third step 4-hydroxybenzofuran-6-carboxylic acid

Add ethyl 4-acetoxybenzofuran-6-carboxylate (24.8 g, 100 mmol), methanol (100 mL), tetrahydrofuran (100 mL) and water (100 mL) to a 1000 mL single-neck bottle, and add sodium hydroxide to the reaction flask. (12 g, 300 mmol), the mixture was stirred at room temperature for 12 h. The organic solvent was removed under reduced pressure and water (600 mL) was evaporated. The aqueous phase was then acidified with aq. EtOAc (EtOAc) EtOAc (EtOAc).

MS (ES-API, neg.ion) m/z: 177.0 [M-1]

The fourth step is methyl 4-methoxybenzofuran-6-carboxylate

4-Hydroxybenzofuran-6-carboxylic acid (1.78 g, 10 mmol), cesium carbonate (8.15 g, 25 mmol) and DMF (20 mL) were placed in a 100 mL single-necked flask, and methyl iodide (3.12 g, 22 mmol) was added dropwise to the reaction flask. After the addition was completed, the reaction mixture was stirred at room temperature for 24 h. A saturated aqueous solution of ammonium chloride (200 mL) was added and the aqueous phase was extracted with ethyl acetate (100 mL×2). The organic layer was washed with EtOAc EtOAc m. The residue was subjected to EtOAcjjjjjjjjjj

MS (ES-API, pos.ion) m/z: 207.1 [M+1]

Step 5 4-Methoxybenzofuran-6-carboxylic acid

Add methyl 4-methoxybenzofuran-6-carboxylate (2.06 g, 10 mmol), methanol (10 mL), tetrahydrofuran (10 mL) and water (10 mL) to a 100 mL single-neck bottle, and add sodium hydroxide to the reaction flask. (1.2 g, 30 mmol). The organic solvent was removed under reduced pressure and water (EtOAc) was evaporated. The aqueous phase was then acidified with aq. EtOAc (EtOAc) EtOAc (EtOAc).

MS (ES-API, neg.ion) m/z: 191.0 [M-1]

Step 6 4-Methoxybenzofuran-6-formyl chloride

4-Methoxybenzofuran-6-carboxylic acid (1.35 g, 7.05 mmol) and dichloromethane (20 mL) were added to a 100 mL single-necked flask, and the mixture was stirred at 90 ° C for 12 h. The thionyl chloride was removed under reduced pressure to give the title compound (yellow viscous liquid, 1.48 g, 100%).

Step 7 4-Methoxybenzofuran-6-carboxamide

Ammonia (20 mL, 28%) was added to a 100 mL single-necked flask, and a solution of 4-methoxybenzofuran-6-carbonyl chloride (1.48 g, 7.05 mmol) in dichloromethane (20 mL) was added dropwise. After the addition was completed, the reaction mixture was stirred at room temperature for 2 h. Water (100 mL) was added to the reaction mixture, and the aqueous layer was evaporated. The organic layer was washed with EtOAc EtOAc m. The residue was subjected to EtOAcjjjjjjjjjj

MS (ES-API, pos.ion) m/z: 192.0 [M+1]

Step 8 4-Methoxybenzofuran-6-carbonitrile

4-methoxybenzofuran-6-carboxamide (0.677 g, 3.54 mmol) and toluene (20 mL) were placed in a 50 mL single-necked flask, and phosphorus oxychloride (2.71, 17.7 mmol) was added dropwise to the reaction flask. The mixture was stirred at 120 ° C for 12 h. The reaction mixture was cooled to room temperature, and brine (EtOAc) was evaporated. The organic layer was washed with EtOAcq. The residue was subjected to EtOAcjjjjjjjjjj

MS (ES-API, pos.ion) m/z: 174.0 [M+1]

Step 9 4-Hydroxybenzofuran-6-carbonitrile

4-methoxybenzofuran-6-carbonitrile (1.73 g, 10 mmol) and DCM (20 mL) were added to a 100 mL single-necked flask, and boron tribromide (7.5 g) was added dropwise to the reaction flask at -70 °C. After 30 g), the reaction mixture was stirred at room temperature for 24 h. Ice water (200 mL) was added to the reaction mixture and the aqueous layer was evaporated. The organic layer was washed with EtOAc EtOAc m. The residue was subjected to EtOAcjjjjjjjjjj

MS (ES-API, neg.ion) m/z: 158.0 [M-1]

Step 10 6-Cyanobenzofuran-4-yltrifluoromethanesulfonate

4-Hydroxybenzofuran-6-carbonitrile (0.652 g, 4.1 mmol), pyridine (0.97 g, 12.3 mmol) and DCM (80 mL) were added to a 250 mL single-necked flask and added dropwise to the reaction flask at 0 ° C. Trifluoromethanesulfonic anhydride (1.35 g, 4.8 mmol) was added and the mixture was stirred at room temperature for 1 h. Concentrate under reduced pressure. The residue was subjected to EtOAcjjjjjjjjjj

MS (ES-API, pos.ion) m/z: 291.9 [M+1]

Step 11 4-(6-Cyanobenzofuran-4-yl)-2-hydroxybenzoic acid tert-butyl ester

6-Cyanobenzofuran-4-yl trifluoromethanesulfonate (0.419 g, 1.44 mmol), 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2 tert-Butyl dihydrohexylborolan-2-yl)benzoate (0.42 g, 1.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane The complex (53 mg, 0.065 mmol), potassium carbonate (0.362 g, 2.62 mmol) and anhydrous 1,4-dioxane (15 mL) were added to a 50 mL two-necked flask, and the reaction mixture was stirred at 90 ° C under nitrogen. 7h. The reaction mixture was cooled to room temperature, and brine (EtOAc) was evaporated. The organic layer was washed with EtOAcq. The residue was subjected to EtOAcjjjjjjjjjj

MS (ES-API, pos.ion) m/z: 336.1 [M+1]

_{^{1 H NMR (600MHz, CDCl 3}} ) δ11.20 (s, 1H), 7.94 (d, J = 8.2Hz, 1H), 7.89-7.87 (m, 2H), 7.62 (d, J = 1.1Hz, 1H) , 7.21 (d, J = 1.5 Hz, 1H), 7.09 (dd, J = 8.2, 1.7 Hz, 1H), 7.05 - 7.03 (m, 1H), 1.67 (s, 9H).

Example 3: 2-Acetoxy-4-(5-cyano-2-fluorobenzofuran-7-yl)benzoic acid

First step 2,3-dihydrobenzofuran-5-formaldehyde

2,3-Dihydrobenzofuran (601 g, 5.0 mol) and DMF (803 g, 10.98 mol) were added to a 5 L four-necked flask, and phosphorus oxychloride (1527 g) was slowly added dropwise to the reaction flask at 10 ° C. , 9.96 mol), when the dropwise addition, the temperature of the reaction system should not exceed 30 ° C. After the dropwise addition, the reaction mixture was slowly heated to 70 ° C and stirred for 8 h. The reaction mixture was cooled to room temperature, and the mixture was poured slowly, and then, and the mixture was stirred at room temperature for 1 hour. The aqueous phase was extracted with EtOAc (3 mL). 741g, 100%).

MS (ES-API, pos.ion) m/z: 149.0 [M+1]

The second step is 7-bromo-2,3-dihydrobenzofuran-5-formaldehyde

2,3-Dihydrobenzofuran-5-carbaldehyde (741 g, 5.0 mol) and DMF (1.5 L) were added to a 5 L four-necked flask, and NBS (1157 g, was added in portions to the reaction flask at 0 ° C, After 6.5 mol), the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was poured into a 5 L ice-water mixture, and the aqueous phase was extracted with ethyl acetate (1 L×2). Filtered and concentrated under reduced pressure. The residue was recrystallized from EtOAc (EtOAc:EtOAc)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ9.78 (s, 1H), 7.82 (s, 1H), 7.66 (d, J = 0.8Hz, 1H), 4.79 (t, J = 8.8Hz, 2H), 3.38 (t, J = 8.8 Hz, 2H);

The third step is 7-bromobenzofuran-5-formaldehyde

Add 7-bromo-2,3-dihydrobenzofuran-5-carbaldehyde (341 g, 1.5 mol), NBS (320 g, 1.8 mol), AIBN (2.3 g, 75 mmol) and chlorobenzene (1.5 L) to 5 L. In the vial, the reaction mixture was slowly warmed to 85 ° C for 4 h under nitrogen. The reaction mixture was cooled to room temperature, and brine (2 L) was evaporated. The organic layer was washed with EtOAc EtOAc m. The residue was subjected to EtOAcjjjjjjjjj

MS (ES-API, pos.ion) m/z: 225.9 [M+2]

The fourth step is 3,7-bromo-2-fluoro-2,3-dihydrobenzofuran-5-formaldehyde

Add 7-bromobenzofuran-5-carbaldehyde (22.5 g, 100 mmol), dibromohydantoin (18.6 g, 65 mmol) and dichloromethane (150 mL) to a 500 mL Teflon tube at 0 ° C. A hydrogen fluoride pyridine solution (125 mL, 65%) was added to the reaction tube. After the addition, the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was poured into a 500 mL ice-water mixture, and the aqueous layer was extracted with ethyl acetate (200 mL×2), and the organic phase was combined. The organic layer was washed with EtOAc EtOAc. The residue was subjected to EtOAcjjjjjjjjjj

MS (ES-API, pos.ion) m/z: 324.9 [M+3]

The fifth step is 7-bromo-2-fluorobenzofuran-5-formaldehyde

Add 3,7-bromo-2-fluoro-2,3-dihydrobenzofuran-5-carbaldehyde (3.24 g, 10 mmol), potassium fluoride (0.70 g, 12 mmol) and DMF (20 mL) to a 100 mL vial The reaction mixture was stirred at 100 ° C for 48 h under a nitrogen atmosphere. The reaction mixture was poured into aq. EtOAc (EtOAc) The organic layer was washed with EtOAc EtOAc m. The residue was subjected to EtOAcjjjjjjjjjj

_{^{1 H NMR (400MHz, CDCl 3}} ) δ9.99 (s, 1H), 7.97 (s, 2H), 6.09 (d, J = 6.6Hz, 1H);

¹⁹ F NMR (376 MHz, CDCl ₃ ) δ-107.30 (s, 1F).

The sixth step is 7-bromo-2-fluorobenzofuran-5-carboxaldehyde

7-Bromo-2-fluorobenzofuran-5-carbaldehyde (0.486 g, 2.0 mmol), N,N-diisopropylethylamine (0.517 g, 4.0 mmol), hydroxylamine hydrochloride (0.167 g, 2.4 mmol) And DCM (10 mL) was added to a 100 mL single-necked flask and the mixture was stirred at room temperature for 12 h under nitrogen. A saturated aqueous solution of sodium chloride (60 mL) was added and the mixture was evaporated. The organic layer was washed with EtOAcq. The residue was subjected to EtOAcjjjjjjjjjj

MS (ES-API, pos.ion) m/z: 258.9 [M+2]

Step 7 7-Bromo-2-fluorobenzofuran-5-carbonitrile

7-Bromo-2-fluorobenzofuran-5-carboxaldehyde oxime (0.439 g, 1.7 mmol) and acetic anhydride (8 mL) were added to a 50 mL single-necked flask, and the mixture was stirred at 150 ° C for 24 h under nitrogen. The reaction mixture was cooled to room temperature, and brine (EtOAc) was evaporated. The organic layer was washed with EtOAc EtOAc m. The residue was subjected to EtOAcjjjjjjjjjjj

MS (ES-API, pos.ion) m/z: 240.9 [M+2]

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.77 (s, 1H), 7.71 (s, 1H), 6.07 (d, J = 6.6Hz, 1H);

¹⁹ F NMR (376 MHz, CDCl ₃ ) δ - 106.46 (s, 1F).

Step 8 4-(5-Cyano-2-fluorobenzofuran-7-yl)-2-hydroxybenzoic acid tert-butyl ester

7-Bromo-2-fluorobenzofuran-5-carbonitrile (0.314 g, 1.31 mmol), 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-di tert-Butyl oxacycloborane-2-yl)benzoate (0.42 g, 1.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (53 mg, 0.065 mmol) and DMF (8 mL) were added to a 50 mL two-neck bottle. Under a nitrogen atmosphere, an aqueous potassium carbonate solution (1.3 mL, 2M) was added and the mixture was stirred at 90 ° C for 0.5 h. The reaction mixture was cooled to room temperature, and brine (EtOAc) was evaporated. The organic layer was washed with EtOAcq. The residue was subjected to EtOAcjjjjjjjjjj

MS (ES-API, pos.ion) m/z: 354.1 [M+1]

Step 9 4-(5-Cyano-2-fluorobenzofuran-7-yl)-2-hydroxybenzoic acid

Add tert-butyl 4-(5-cyano-2,3-dihydrobenzofuran-7-yl)-2-hydroxybenzoate (0.347 g, 0.98 mmol) and dichloromethane (15 mL) to a 100 mL one-neck bottle Trifluoroacetic acid (2 mL) was added and stirred at room temperature for 12 h. The organic solvent was evaporated under reduced pressure. EtOAcjjjjjjjj

MS (ES-API, neg.ion) m/z: 296.0 [M-1]

Step 10 2-Acetoxy-4-(5-cyano-2-fluorobenzofuran-7-yl)benzoic acid

4-(5-Cyano-2-fluorobenzofuran-7-yl)-2-hydroxybenzoic acid (0.892 g, 3.0 mmol), N,N-diisopropylethylamine (2.33 g, 18.0 mmol And DCM (20 mL) was added to a 100 mL single-necked flask, and acetyl chloride (0.707 g, 9.0 mmol) was added dropwise to the reaction flask at 0 ° C. After the dropwise addition, the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was poured into 100 mL of ice water and the aqueous layer was extracted with ethyl acetate (60 mL×2). The organic layer was washed with EtOAcq. The residue was subjected to EtOAcjjjjjjjjjj

MS (ES-API, neg.ion) m/z: 338.0 [M-1]

^{1 H NMR (400MHz, DMSO)} δ8.21 (d, J = 1.5Hz, 1H), 8.11-8.09 (m, 2H), 7.91 (dd, J = 8.2,1.7Hz, 1H), 7.76 (d, J =1.6 Hz, 1H), 6.60 (d, J = 6.4 Hz, 1H), 2.30 (s, 3H);

¹⁹ F NMR (376 MHz, DMSO) δ-109.04 (s, 1F).

Biological activity test

Test Example 1 XO (xanthine oxidase) inhibitory activity assay

1) Test method

The compound was diluted 2.5-fold with a buffer (50 mM potassium dihydrogen phosphate solution) at a concentration ranging from 2000 nM to 0.524 nM, and added to a 384-well plate at 30 μL/well; then 30 μL of yellow at a concentration of 21 mU/mL was added to each well.嘌呤 oxidase, centrifugation at 3000 rpm for 1 min, incubate for 10 min at room temperature; then add 30 μL of 600 μM substrate (xanthine) per well; set buffer treatment well (no compound, add the same concentration of enzyme and substrate) and negative control Well (no compound and enzyme, add the same concentration of substrate). After incubating for 5 min at room temperature, the absorbance at 290 nm was read using a PHERAstar FS plate reader, and the inhibition rate of the compound inhibiting xanthine oxidase activity was calculated by the following formula. The IC ₅₀ value was calculated using GraphPad Prism 5:

Inhibition rate (%) = [1 - (OD _{drug treatment well -} OD _{negative control well} ) / (OD _{buffer treatment well -} OD _{negative control well} )] × 100

2) Test results

Conclusion: The compounds of the present invention have a good inhibitory activity against XO.

Test Example 2 URAT1 (Uric Acid Anion Transporter 1) Inhibitory Activity Assay

1) Test method

Construction of a.hURAT1 stable expression cell line

The human URAT1 plasmid was transfected into HEK-293T cells, and a human URAT1 stably expressing cell strain was obtained by G418 (Geneticin, Geneticin) screening.

b. uric acid absorption inhibition

The human URAT1 stably expressing cells obtained in the above step were inoculated into a 96-well plate, the medium was removed after at least 12 hours of incubation, and the cells were washed with a chloride-free HBSS (Hanks Balanced Salt Solution) buffer; the compound was diluted four times with a buffer. A series of compound solutions from 200 μM to 0.8 nM were mixed with 45 μL of [8- ¹⁴ C] uric acid-containing buffer and added to a 96-well plate containing human URAT1 stably expressing cells (ie, The final concentration of the compound was 20 μM to 0.08 nM. At the same time, buffer wells (human URAT1 stably expressing cells, no drug added) and negative wells (HEK-293T cells, no drug added) were set; after incubating at 37 ° C for 5 min, the buffer was removed and used. The cells were washed with buffer, 50 μL of lysis buffer (100 mM NaOH solution) was added to each well, and the cells were lysed and shaken at 600 rpm for 10 min. 1000rpm centrifuge 5min, 45μL supernatant was pipetted into microplate Isoplate-96, was added to each well 150μL Ultima Gold ^TM XR, and 600rpm shaking 10min. The remaining amount of [8- ¹⁴ C] uric acid was counted using a MicroBeta Trilux scintillation/luminescence counter (PerkinElmer), and the IC ₅₀ value was calculated by XLfit software after calculating the inhibition rate of the compound inhibiting [8- ¹⁴ C] uric acid absorption by the following formula.

Inhibition rate (%) = [1 - (drug well ¹⁴ C uptake - negative well ¹⁴ C uptake) / (buffer well ¹⁴ C uptake - negative well ¹⁴ C uptake)] x 100;

Among them, the negative well was a non-vaccinated human URAT1 stably expressing cell well.

2) Test results

Conclusion: The compounds of the present invention have a good inhibitory activity against URAT1.

Test Example 3 uric acid test

1) Test method

Male Sprague-Dawley rats were fasted overnight before the experiment, and were randomly divided into groups according to body weight. Each group was given a single dose of vehicle (control group) and 20 mg/kg of test compound by gavage, respectively before and after administration. After 6 hours, blood was collected from the tail vein, and the blood was centrifuged at 3000 rpm for 15 min. After separating the serum, the serum uric acid level was measured using a Roche biochemical analyzer, and the percentage of uric acid reduction was calculated according to the following formula.

Blood uric acid decline rate = [(control blood uric acid value - blood uric acid value of the administration group) / blood uric acid value of the control group] × 100%

2) Test results

The compound of Example 3 had a significant uric acid lowering effect within 10 hours after oral administration, with a maximum uric acid reduction rate of up to 65%.

The above results indicate that the compound of the present invention has a good uric acid lowering action.

Test Example 4 Pharmacokinetic Evaluation

1) Test method

SD rats were fasted overnight after 15 hours of fasting and randomized according to body weight. The test compound was prepared in 5% DMSO + 5% Solutol (polyethylene glycol-12-hydroxystearate) + 90% Saline. (physiological saline). For the experimental group administered intravenously (iv), the test animals were given a dose of 1 mg/kg; for the test group administered orally (po), the test animals were given a dose of 5 mg/kg. Then, at time points 0, 0.083 (intravenous group only), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 hours, venous blood (about 0.2 mL) was taken and placed in EDTAK ₂ (ethylenediaminetetraacetic acid II). Potassium salts) In an anticoagulant tube, centrifuged at 11,000 rpm for 2 minutes, plasma was collected and stored at -20 ° C or -70 ° C until LC/MS/MS analysis. The drug concentration in plasma was measured at each time point, and the pharmacokinetic parameters were calculated according to the drug concentration-time curve.

The pharmacokinetic properties of the compounds of the invention were tested by the above tests.

2) Test results

Conclusion: The compound of the present invention has higher blood concentration and exposure level after oral administration, and has a lower clearance rate and good pharmacokinetic characteristics.

Finally, it should be noted that there are other ways to implement the invention. Accordingly, the embodiments of the present invention are to be construed as illustrative, but not limited to the description of the present invention, and may be modified within the scope of the invention or equivalents in the claims. All publications or patents cited herein are hereby incorporated by reference.

Claims (26)

A compound characterized by being a compound represented by the formula (I) or a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate or a solvent of the compound of the formula (I). a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,

among them: X and Z are each independently -N(R ^a )-, -O-, -S(O) _t -, -C(R ^b )=, -CR ^c R ^d - or -N=; Y is -C(R ^e )=, -CR ^f R ^g - or -N=; t is 0, 1 or 2; Each R ^{a is} independently hydrogen, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl or C _3-6 cycloalkyl; Each R ^{b is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylamino or C _1-6 haloalkoxy; Each R ^{c is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylamino or C _1-6 haloalkoxy; Each R ^{d is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylamino or C _1-6 haloalkoxy; R ^e is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 haloalkyl amino, C _3-8 cycloalkyl, 3-8 membered heterocyclyl , phenyl or 5-10 membered heteroaryl; R ^f is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 haloalkylamino, C _3-8 cycloalkyl, 3-8 membered heterocyclic , phenyl or 5-10 membered heteroaryl; R ^g is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 haloalkylamino, C _3-8 cycloalkyl, 3-8 membered heterocyclic , phenyl or 5-10 membered heteroaryl; R ¹ and R ² are each independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkane An oxy group, a C _1-6 alkylamino group or a C _1-6 haloalkoxy group; Each R ^{3 is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy; R is hydrogen, hydrazine, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _6-10 aryl a 5-10 membered heteroaryl or Q, wherein said C _1-6 alkyl group, C _1-6 hydroxyalkyl group, C _1-6 haloalkyl group, C _3-8 cycloalkyl group, 3-8 membered hetero The cyclic group, C _6-10 aryl, 5-10 membered heteroaryl and Q are independently, optionally 1, 2, 3, 4 or 5 selected from the group consisting of ruthenium, F, Cl, Br, I, hydroxy, amino, Substituent substitution of cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl or 3-6 membered heterocyclyl; Q is a substituted or unsubstituted C _1-6 aliphatic hydrocarbon group, wherein 0-3 methylene groups are independently independently substituted with a group selected from -O-, -NH-, and -C(=O)-; L ⁰ is a bond, -O-, -NH- or -S-; L ¹ is -O-, -NH- or -S-; L ² is -C _1-6 alkylene-, -C(=O)- or -NH-; L ³ is a bond, -O-, -NH-, -C(=O)-, -C(=NH)-, -C(=O)-O-, -OC(=O)-, -C( =O)-N(R ⁴ )-, -N(R ⁴ )-C(=O)- or -C _1-6 alkylene-; R ⁴ is hydrogen, hydrazine, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl or C _3-8 cycloalkyl; E is 氘, F, Cl, Br, I, hydroxy, amino, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _{a 1-6} hydroxyalkyl group, a C _1-6 alkylamino group, a C _3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a phenyl group, a 5-10 membered heteroaryl group,

-C(=O)-CH(R ⁷ )-N(R ⁸ )(R ⁹ ),

Or Q; R ⁵ and R ⁶ are each independently hydrogen, deuterium or Q; R ⁷ is hydrogen, hydrazine, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoylmethyl, carbamoyl Ethyl, 1-hydroxyethyl, decylmethyl, carboxylic acid methyl, carboxylic acid ethyl, -(CH ₂ ) ₄ NH ₂ ,

-(CH ₂ ) ₃ NH-C(=NH)-NH ₂ or

R ⁸ and R ⁹ are each independently hydrogen, deuterium, C _1-6 alkyl or C _1-6 haloalkyl; n is 0, 1, 2 or 3. The compound according to claim 1, wherein each R ^{a is} independently hydrogen, hydrazine, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl or C _3-6 cycloalkyl. ; Each R ^{b is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylamino or C _1-3 haloalkoxy; Each R ^{c is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylamino or C _1-3 haloalkoxy; Each R ^{d is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylamino or C _1-3 haloalkoxy; R ^e is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 Haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, C _1-3 alkylamino, C _1-3 haloalkylamino, C _3-6 cycloalkyl, 3-6 membered heterocyclic , phenyl or 5-6 membered heteroaryl; R ^f is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 Haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, C _1-3 alkylamino, C _1-3 haloalkylamino, C _3-6 cycloalkyl, 3-6 membered heterocyclic , phenyl or 5-6 membered heteroaryl; R ^g is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-3 Haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, C _1-3 alkylamino, C _1-3 haloalkylamino, C _3-6 cycloalkyl, 3-6 membered heterocyclic , phenyl or 5-6 membered heteroaryl. The compound according to claim 1 or 2, wherein each R ^{a is} independently hydrogen, hydrazine, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, 2-hydroxyl Ethyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Each R ^{b is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy Base, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino or dimethylamino; Each R ^{c is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy Base, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino or dimethylamino; Each R ^{d is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, methoxy Base, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino or dimethylamino; R ^e is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propyne , propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl , oxazolyl, pyridyl or pyrimidinyl; R ^f is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propyne , propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl , oxazolyl, pyridyl or pyrimidinyl; R ^g is hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propyne , propargyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylamino, ethylamino, dimethylamino, trifluoromethylamino , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl , oxazolyl, pyridyl or pyrimidinyl. The compound according to claim 1, wherein R ¹ and R ² are each independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 alkylamino or C _1-3 haloalkoxy; Each R ^{3 is} independently hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _1-3 haloalkoxy. The compound according to claim 1 or 4, wherein R ¹ and R ² are each independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, difluoromethyl. , trifluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, trifluoromethoxy, methylamino or dimethylamino; Each R ^{3 is} independently hydrogen, hydrazine, F, Cl, Br, I, hydroxy, amino, nitro, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, iso Propyloxy, difluoromethoxy or trifluoromethoxy. The compound according to claim 1, wherein R is hydrogen, hydrazine, C _1-4 alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl, 3-6 a heterocyclic group, a C _6-10 aryl group, a 5-6 membered heteroaryl group or Q, wherein said C _1-4 alkyl group, C _1-3 hydroxyalkyl group, C _1-3 haloalkyl group, C _{3 -6} cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl and Q are independently independently selected from 1, 2, 3, 4 or 5 selected from 氘, F , Cl, Br, I, hydroxy, amino, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl or 3-6 Substituent substitution of a heterocyclic group. The compound according to claim 1 or 6, wherein R is hydrogen, hydrazine, methyl, ethyl, n-propyl, isopropyl, t-butyl, hydroxymethyl, hydroxyethyl, 1,2-di Hydroxyethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperidine Azinyl, morpholinyl, thiomorpholinyl, phenyl, 2,3-dihydro-1H-indole, thiazolyl, pyrazolyl, oxazolyl, pyridyl, pyrimidinyl or Q, wherein Methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, difluoromethyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, ring Pentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, 2,3-dihydro-1H-indole, thiazolyl, pyrazole The radical, oxazolyl, pyridyl, pyrimidinyl and Q are, independently, optionally 1, 2, 3, 4 or 5 selected from the group consisting of ruthenium, F, Cl, Br, I, hydroxy, amino, cyano, nitro, Methyl, ethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropyloxy, cyclopropyl Substituted by a substituent of cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. The compound according to claim 1, wherein L ² is -C _1-3 alkylene-, -C(=O)- or -NH-; L ³ is a bond, -O-, -NH-, -C(=O)-, -C(=NH)-, -C(=O)-O-, -OC(=O)-, -C( =O)-N(R ⁴ )-, -N(R ⁴ )-C(=O)- or -C _1-3 alkylene-; R ⁴ is hydrogen, hydrazine, C _1-3 alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl or C _3-6 cycloalkyl. The compound according to claim 1 or 8, wherein L ² is methylene, ethylene, propylene, -C(=O)- or -NH-; L ³ is a bond, -O-, -NH-, -C(=O)-, -C(=NH)-, -C(=O)-O-, -OC(=O)-, -C( =O)-N(R ⁴ )-, -N(R ⁴ )-C(=O)-, methylene, ethylene or propylene; R ⁴ is hydrogen, hydrazine, methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl Base, cyclopentyl or cyclohexyl. The compound according to claim 1, wherein E is hydrazine, F, Cl, Br, I, hydroxy, amino, cyano, C _1-4 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy , C _1-3 haloalkoxy, C _1-3 hydroxyalkyl, C _1-3 alkylamino, C _3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl base,

-C(=O)-CH(R ⁷ )-N(R ⁸ )(R ⁹ ),

Or Q; R ⁵ and R ⁶ are each independently hydrogen, deuterium or Q; R ⁷ is hydrogen, hydrazine, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoylmethyl, carbamoyl Ethyl, 1-hydroxyethyl, decylmethyl, carboxylic acid methyl, carboxylic acid ethyl, -(CH ₂ ) ₄ NH ₂ ,

-(CH ₂ ) ₃ NH-C(=NH)-NH ₂ or

R ⁸ and R ⁹ are each independently hydrogen, deuterium, C _1-3 alkyl or C _1-3 haloalkyl. The compound according to claim 1 or 10, wherein E is hydrazine, F, Cl, Br, I, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, t-butyl, Difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy Ethyl, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl Thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridyl, pyrimidinyl,

-C(=O)-CH(R ⁷ )-N(R ⁸ )(R ⁹ ),

Or Q; R ⁵ and R ⁶ are each independently hydrogen, deuterium or Q; R ⁷ is hydrogen, hydrazine, methyl, hydroxymethyl, isopropyl, isobutyl, sec-butyl, benzyl, 4-hydroxybenzyl, methylthioethyl, carbamoylmethyl, carbamoyl Ethyl, 1-hydroxyethyl, decylmethyl, carboxylic acid methyl, carboxylic acid ethyl, -(CH ₂ ) ₄ NH ₂ ,

-(CH ₂ ) ₃ NH-C(=NH)-NH ₂ or

R ⁸ and R ⁹ are each independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl or 2,2-difluoroethyl. The compound according to claim 1, which is a compound represented by the formula (II) or a stereoisomer, a geometric isomer, a tautomer, an oxynitride of the compound of the formula (II). , hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug,

The compound according to claim 1, which is a compound represented by the formula (III) or a stereoisomer, a geometric isomer, a tautomer, an oxynitride of the compound of the formula (III). , hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug,

A compound having the structure of one of the following or a stereoisomer thereof, an oxynitride, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof:

A pharmaceutical composition comprising the compound of any one of claims 1-14. The pharmaceutical composition according to claim 15, further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof. The pharmaceutical composition according to claim 16, further comprising a medicament for preventing or treating hyperuricemia, tophi, gouty arthritis, renal disorder associated with hyperuricemia, and urolithiasis The active ingredient of the drug is different from the compound according to any one of claims 1 to 14, wherein the drug is colchicine, non-steroidal anti-inflammatory drug, glucocorticoid, uric acid-producing drug, uric acid excretion drug , urinary alkalizing agent or any combination thereof. Use of a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to any one of claims 15 to 17 for the preparation of a medicament for the prevention or treatment of hyperuricemia in a mammal, Tophi, gouty arthritis, kidney disorders associated with hyperuricemia or urolithiasis, including mammals. Use of a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to any one of claims 15 to 17 for the preparation of a medicament for lowering blood uric acid levels. Use of a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to any one of claims 15 to 17 for the preparation of a medicament for inhibiting xanthine oxidase and urate anion transport Body 1. The compound according to any one of claims 1 to 14 or the pharmaceutical composition according to any one of claims 15 to 17 for use in the prevention or treatment of hyperuricemia, tophi, gouty arthritis, and high in a mammal A renal disorder associated with uric acidemia or urolithiasis, including mammals. A compound according to any one of claims 1 to 14 or a pharmaceutical composition according to any one of claims 15 to 17 for use in lowering blood uric acid levels. The compound according to any one of claims 1 to 14 or the pharmaceutical composition according to any one of claims 15 to 17 for inhibiting xanthine oxidase and urate anion transporter 1. A method for preventing or treating hyperuricemia, tophi, gouty arthritis, renal disorder associated with hyperuricemia, or urolithiasis, the method comprising administering to a patient a therapeutically effective dose according to claims 1-14 A compound according to any one of the preceding claims, or a pharmaceutical composition according to any one of claims 15-17. A method of lowering uric acid levels in blood, the method comprising administering to a patient a therapeutically effective amount of a compound according to any one of claims 1-14 or a pharmaceutical composition according to any one of claims 15-17. A method of inhibiting xanthine oxidase and urate anion transporter 1 using the compound according to any one of claims 1-14 or the pharmaceutical composition according to any one of claims 15-17.