TW201225954A - Heterocyclic compound with substituent, pharmeacutical composition, and the use thereof - Google Patents

Abstract

This invention relates to novel compounds of Formula I, and a pharmaceutically acceptable salt thereof, a solvate thereof, a chelate thereof, a non-covalent complexs thereof, a prodrugs thereof. The invention also relates to pharmaceutical compositions comprising at least one compound of the invention, and the use of the compounds and compositions of the invention. These compounds of the invention can serve as hypoxia mimetics, for preparing medicines for moderating HIF levels or activity, or for preparing medicines for treating a condition associated with HIF levels or activity in a subject.

Description

201225954 j lyjoypu VI. Description of the invention: [Technology of the invention] The present invention relates to a class of heterozygous compounds containing a substituent <base> and their 'nuclear compounds, and the use of the compound or composition thereof as an oxygen deficiency analogy Use of hypoxia mimetics. The invention further relates to a method for the hypoxia inducible factor (HIF) level or activity in a subject to be administered to a south, and a medicament for preparing an indication relating to a hif level or activity, such as ischemia, anemia, wound healing, Auto-transplantation, allotransplantation, xeno-transplantation, hypertension, thalassemia, diabetes, cancer, and various inflammations. [Prior Art] The cell transcription factor HIF plays a crucial role in the homeostasis of intracellular oxygen in many organisms, and it is also a key regulatory factor when cells respond to hypoxia. A series of newly generated two red gold spheres, fetal hemoglobin production, blood stasis function, cell death and cell accretion are all important. In addition, 'HIF water will rise ^" 卩 and turn the pathological reaction of ischemia and hypoxia - the general Keke suction seven, the body is _ > nuclear protein dimer, by the receptor ~ heterodimer, hif is An intrinsic internal oxygen level regulation is the HIF monomer composition of pass = pair = oxygen. The body HIF monomer will be realized by hydroxylation of the hydrazine monomer, and the hydroxyl group and the proteasome will be decomposed. Adequately fine 201225954 J/ cypress (Lp Hippel-Lindau tumor suppressor protein'pVHL) binds to hydroxylated HIF-monomers, causing its dependence on ubiquitin proteolysis, but under hypoxic conditions Under the above process, the above process will be inhibited 'to make HIF stable, thus promoting the transcriptional activation of HIF complex. HIF-monomer hydroxylation mainly occurs on proline and aspartate residues and can be dependent on 2-oxidized glutaric acid (2-〇x〇glutarate) φ is regulated by an enzyme. This series of enzymes can be hydroxylated on human HIF1.

HIF prolyl hydr〇xylase isozymes (HIF pHDs) of Pro402 and pr〇564, and HIF inhibition factor (Fact〇rInhibitingHIF, FIH) which can hydroxylate Asn803 on human HIF1. Inhibition of PHDs or FIH increases the stability of HIF and promotes its transcriptional activation. See Schofield and Ratdiffe in 2004 in Nature Review: Molecular Cell Biology (NatureRev. M〇1.

Cell Biol.) Volume 15, pages 343-354. Therefore, there is a need to continually develop new therapeutic or high-efficiency new or improved drugs that are used to modulate (eg, increase the level or activity) of mF water: to treat HIF-related indications or diseases or discomforts, such as lack of Blood, anemia, wound healing, orthotopic transplantation, ectopic transplantation, allogeneic transplantation, systemic hypertension, thalassemia, diabetes, cancer, and inflammatory diseases are not listed here. In developing new or improved drugs for regulating HIF levels or actives, although not required, development has better chemical or biological properties such as solubility, bioavailability, pharmacokinetics, pharmacodynamics, toxicity, and / or low side effects such as low neovascular side effects and other better drugs 201225954 J / υονριι Also what people want. The compounds, compositions and methods described in the present invention are intended to meet the above needs. SUMMARY OF THE INVENTION An object of the present invention is to provide a substituent-containing heterocyclic compound as an oxygen-deficient mimetic. The present invention provides at least one compound of the formula (I), wherein

The structural formula (I) η is selected from any positive integer from 1 to 6;

Ri is selected from the group consisting of OH, SH, NH, NHC(0)R2, NHS02R2 and sulfonyl; R2 is selected from hydrazine, lower alkyl or lower alkyl containing a substituent; R3 and R4 are each independently selected from hydrazine, lower alkane a lower alkyl group containing a substituent, a lower alkyl group or a lower halogenated alkyl group having a substituent, or R3 and R4 are bonded to form a 3 to 6 membered ring or a substituted 3 to 6 membered ring;

Rs is selected from the group consisting of OH, SH, oxime 2, lower alkyl, lower alkyl containing a substituent, lower alkoxy, lower alkoxy or thioalkyl having a substituent; R6, R7, R8 and R9 are each independently selected From anthracene, alkyl, substituent-containing alkyl, alkenyl, substituted alkenyl, alkynyl, substituent-containing

201225954 j /voyyiL Block group, alkoxy group, substituent-containing alkoxy group, NR3R4, c(〇)〇h, 〇Ri2, sr12, so2r]2, CN, n〇2, halogen, aromatic hydrocarbon group, containing substitution Perfume-based hydrocarbon group, heterocyclic aromatic hydrocarbon group, substituted heterocyclic aromatic hydrocarbon group, aromatic, ketone silk, substituted aromatic hydrocarbon green group, miscellaneous ruthenium-based, heterocyclic aromatic hydrocarbon group having a substituent An alkyl group, a heterocycloalkyl group, a hetero group containing a substituent, a filament, a mercapto group having a substituent, an alkenyl group UlkenyMyD, a subunit having a substituent, an alknylsilyl group, and the like a substituent of a fast-radical base group containing a substituent of an alkoxycarbonyl group or _x_Ru; or an adjacent core and r6, a mixture of &, 1 and & and at least a pair of hearts to form a 4 to 7 dollar a ring or a 4- to 7-membered ring containing a substituent; X is selected from -N(Rio)-Y- or -YN(R10)-; Y is selected from C(〇), S〇2, alkenyl, and has a substituent Dilute, fast or substituted alkynyl;

Rio is selected from the group consisting of hydrazine, lower alkyl or lower alkyl containing a substituent;

Rii is selected from the group consisting of an anthracene, a cycloalkyl group, a substituted cycloalkyl group, a heterocycloalkyl group, a 3 = a hetero group, a hetero group, a hydrocarbon group, a substituted aromatic group, a heteroaromatic domain or a substituent. Heterocyclic aromatic hydrocarbon group; and

Rl2 is selected from the group consisting of H, an alkyl group, a substituent-containing alkyl group, an alkenyl group, a substituted base-containing dilute group, an alkynyl group, a substituent-containing lysyl group or nR3R4; or a pharmaceutically acceptable salt thereof, a homosolvate thereof, Its integrator, , non-covalent complex or its prodrug. In some embodiments of the invention, the guanidine is selected from the group consisting of 〇H or SH. In another preferred embodiment of the invention at 201225954 j/ueypn, the heart is 〇H. In some embodiments of the invention, R2 is selected from the group consisting of hydrazine, or a lower alkyl group such as a decyl group or an ethyl group. In some preferred embodiments of the invention, R2 is deuterium. / In some embodiments of the invention, the core and & are independently selected from H, lower alkyl or lower alkyl. In other embodiments of the invention 'R3 and R4 are each independently selected from hydrazine or lower alkyl, such as decyl or ethyl. In still other embodiments of the invention, R3 and R4 are deuterium, respectively. In some embodiments of the invention, the R7 and the carbon atom to which R4 is attached may form a 3 to 6 membered cycloalkyl or heterocycloalkyl ring, wherein the 3 to a fluorene cycloalkyl or heterocycloalkyl group The ring may be optionally substituted by hydrazine, 2, 3, 4 or 5 substituents, each independently selected from lower alkyl, lower alkoxy, lower haloalkyl, lower alkoxy, halogen or Hey. In some preferred embodiments of the invention, the hydrazine and the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl group, wherein the 3 to 6 membered cycloalkyl group can be optionally 1, 2, 3, 4 Or substituted with 5 substituents, each independently selected from lower alkyl, lower alkoxy, lower haloalkyl, lower halooxyl, halo or fluorene. In still other preferred embodiments of the invention, I and R4 form a 3- to 6-membered cycloalkyl group having no substituent with the carbon atom to which they are attached. In some preferred embodiments of the invention, the calipers 3 and the carbon atoms to which they are attached form a 3 to 6 membered heterocycloalkyl group, wherein the 3 to 6 membered heterocycloalkyl group can be optionally 1,2 Substituted by 3, 4 or 5 substituents, each of which is independently selected from the group consisting of lower alkyl, lower alkoxy, lower haloalkyl, lower alkoxy, halogen or OH. In still other preferred embodiments of the invention, the hetero-J sulphide group formed by R_3 and R_4 with the carbon atom to which they are attached contains at least one or two heteroatoms, wherein the heteroatoms are selected from the group consisting of ruthenium, S or N. In some further preferred embodiments of the invention, r3 and R4 form a 3 to 6 membered heterocycloalkyl group with the carbon atom to which they are attached, wherein the heterocycloalkyl group is selected from pyrrolidinyl, acridinyl, tetrahydrofuranyl or Tetrahydrofurfuryl. - In some embodiments, R5 is selected from the group consisting of OH, SH, NH2, or a lower alkane. In some embodiments of the invention, R5 is selected from OH or SH. In some preferred embodiments of the invention, r5 is 〇H. In other embodiments of the invention, R5 is selected from the group consisting of hydrazine H, NH2 or lower alkoxy, such as decyloxy, ethoxy, propoxy. In still other embodiments of the invention, R5 is selected from the group consisting of OH, lower alkoxy such as decyloxy, ethoxy, propoxy, or lower alkoxy containing substituents. In some embodiments of the invention, adjacent Han 6 and r 7 , 仏 and Lu R 8 or at least one of 尺 8 and R * 9 are joined together (plus two carbon atoms attached thereto) to form 4 To a 7-membered ring or a 4- to 7-membered ring containing a substituent. In some preferred embodiments of the invention, the 4 to 7 membered ring or the 4 to 7 membered ring containing the substituent contains at least one to three hetero atoms. In some embodiments of the invention, R6 and R7 are each independently selected from H, _, 〇H, lower alkyl, lower haloalkyl, lower alkoxy or lower halooxy. In some preferred embodiments of the invention, and R7 are each independently selected from the group consisting of hydrazine, halogen or lower alkyl, lower alkyl such as 201225954 j/uoypu methyl or ethyl, or lower chiral alkyl such as trifluoromethyl . In other embodiments of the invention, R6 and R7 are respectively hydrazine. In some embodiments of the invention, 118 and R9 are each independently selected from the group consisting of hydrazine, dentate, OH, lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy. In some preferred embodiments of the invention, R8 and R9 are each independently selected from the group consisting of hydrazine, halogen or lower alkyl 'lower alkyl such as methyl or ethyl, or lower haloalkyl such as trifluoromethyl. In other embodiments, the heart and R9 are respectively Η. In some embodiments of the invention, at least one of r6, r7, r8 and r9 is independently selected from halogen,! I-alkyl or haloalkoxy. In some embodiments of the invention, at least one of R6, R7, R8 and R9 is independently selected from alkoxy or alkoxy containing substituents. In some embodiments of the present invention, R6, R7, RA R9, independently, are selected from the group consisting of an alkyl group, a substituent-containing shot base, a block, or a silk-based basis. wire. In the present invention, at least one of the formulas '仏, 118 and 9' is independently selected from the group consisting of aromatic smokes: aromatic hydrocarbons containing substituents, impurities: yongshuimei, miscellaneous, and substituted A heterocyclic arylheteroalkyl group or a heterocycloalkyl group having a substituent. In other embodiments of the invention, the dilute group, the block group or the substituent-containing block group independently selected from the group consisting of fluorene and alkyl groups. Alkenyl groups, in some embodiments of the present invention, and at least the slow-selective palladium scheme in R9, the heart and the R wipes are hung in 201225954 heterocyclic aromatic hydrocarbon groups, wherein the miscellaneous "& pyridine", 3 The ratio of the bite group or the ratio of the base to the base is selected from the group consisting of a bite group, for example, a two-part ratio, in other preferred embodiments, a stopper or a (tetra) group. In the aromatic hydrocarbon group of the present invention, wherein the heterocyclic aromatic group: at least one is a heterocyclic ring 3 or a tetradentyl group, the radical is selected from the group, in the embodiments of the present invention, the heart and & In some preferred embodiments of the dentine 8 and R9 a stupid or substituent-containing (four) independently selected from the group consisting of substituents, at least in the embodiments of the invention, to the meta or meta position in the oxime and & , a silk-based or a functional group, a gas-based substituted stupid base. In some preferred embodiments of the invention, any one of r ^ R9 is selected from the group consisting of a halogen or an alkyl group, a halo group, and an alkane. An oxy or haloalkoxy-substituted phenyl group, and the other of ^ and h is selected from the group consisting of hydrazine, halogen, 0H, lower alkyl, lower haloalkyl, lower alkoxy or lower alkoxy. In still other preferred embodiments, any one of Rs and R9 is selected from the group consisting of a meta or a para position substituted with a methoxyl, an alkyl, a halogenated, an alkoxy or a halogenated alkoxy group. Phenyl, and the other of R and R9 is deuterium. In some embodiments of the invention, at least one of Rs and R9 is meta or para to halo, alkyl, haloalkyl, alkoxy or _ An oxy substituted pyridyl group. In some preferred embodiments, any one of r8 and % is selected from a meta or para position by a halogen, an alkyl group, a haloalkyl group, a ruthenium 201225954 oxy or a haloalkoxy group. a substituted pyridyl group, and the other one of the ruthenium 8 and R9 is selected from the group consisting of hydrazine, halogen, OH, lower alkyl, lower haloalkyl, lower alkoxy or lower i alkoxy. Further preferred in the present invention In the embodiment, any one of Rs and R9 is selected from pyridyl groups wherein the meta or para is substituted by halogen, alkyl, haloalkyl, alkoxy or alkoxy, and the other of r8 and R9 is In some embodiments of the invention, n is selected from any positive integer of 1, 2 or 3. In some preferred embodiments of the invention, n is selected from 1 or 2. Other preferred embodiments of the invention Where η is 1. In some embodiments of the invention, the compound of formula (I) Compound represented by any of formula (II),

Or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of ruthenium, dentate, lower-grade, lower-grade alkyl, lower alkoxy or lower alkoxy; R22 is selected from the group consisting of ruthenium , _, lower alkyl, lower haloalkyl, lower alkoxy or lower alkoxy; Ζ1 is selected from hydrazine or CR23; and 12 201225954 j/yjoypu R23 is selected from the group consisting of H, halogen, lower alkyl, lower halogen a thiol group, a lower alkoxy group or a lower dentate alkoxy group; wherein at least one of R21, R22 and R23 (if present) is selected from the group consisting of a pectin, a lower alkyl group, a lower ifi alkyl group, and a lower alkoxy group. Or lower halogenated alkoxy groups. In some embodiments of the invention, for a compound of formula (II), wherein R21 is selected from H, cn, F, decyl, ethyl, trifluoromethyl, decyloxy, ethoxy or trifluoromethane Oxygen. In some embodiments of the invention, for a compound of formula (II), wherein R22 is selected from the group consisting of H, cn, F, decyl, ethyl, trifluoromethyl, methoxy, ethoxy or trifluoromethane Oxygen. In some embodiments of the invention, for a compound of formula (II), wherein Z1 is N. In some embodiments of the invention, the compound of formula (II), wherein Z1 is CR23. In some embodiments of the invention 'for a compound of formula (II), wherein Z 1 is CR 23 and R 23 is selected from the group consisting of hydrazine, ci, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy. Or trifluoromethoxy. In some embodiments of the invention 'for a compound of formula (II), wherein Ζ1 is CR23', one of R21, R22 and R23 is selected from halo, lower alkyl, lower haloalkyl, lower alkoxy or lower Haloalkoxy, the other two of R21, R22 and R23 are hydrazine. In some embodiments 'for a compound of formula (II) or wherein Ζ1 is CR23, one of R21 and R23 is selected from the group consisting of halogen, lower 13 201225954 J / νο^ριι alkyl, lower haloalkyl, lower alkoxy Or a lower haloalkoxy group, the other of R21 and R23 is deuterium. In some preferred embodiments of the invention, R22 is hydrazine. In some embodiments of the invention, for a compound of formula (II), wherein Ζ1 is CR23, two of R21, R22 and R23 are each independently selected from the group consisting of dentate, lower alkyl, lower alkyl The lower alkoxy group or the lower haloalkoxy group, and the other one of R21, R22 and R23 is hydrazine. In some preferred embodiments of the invention, R23 is deuterium. In still other preferred embodiments of the invention, R22 is hydrazine. In some embodiments of the invention, for a compound of formula (Π), wherein Ζ1 is CR23' R21, R22 and R23 are each independently selected from halo, lower alkyl, lower haloalkyl, lower alkoxy or Lower haloalkoxy. In some embodiments of the invention, for the compound of formula (11), wherein Ζ1 is Ν, any one of R21 and R22 is selected from halogen, lower alkyl, lower dent alkyl, lower alkoxy or lower ! |Alkenyloxy, the other of R21 and R22 is hydrazine. In some embodiments of the invention, for a compound of formula (π) wherein Ζ1 is Ν, R21 and R22 are each independently selected from halo, lower alkyl, lower i-alkyl, lower alkoxy or lower Alkoxy group. In some embodiments of the invention, the compound of formula (8) is any compound of formula (Ila), 14 201225954 〇/uoypn

Structural Formula (Ila) or a pharmaceutically acceptable salt thereof, wherein

R is selected from the group consisting of hydrazine, halogen, lower alkyl, lower alkylene, lower calcined or lower calcined lower alkoxy; and R22 is selected from the group consisting of hydrazine, hydrazine, lower alkyl, lower!|alkylene, Lower alkoxy or lower functional lower alkoxy; wherein at least one of 'R21 and R22 is selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy or lower alkoxy. In some embodiments of the invention, for the compound of formula (Ila) wherein R21 is hydrogen, R22 is selected from the group consisting of halogen, lower alkyl, lower haloalkyl, lower alkoxy or lower alkoxy. In some embodiments of the invention, for a compound of formula (Ila), wherein R21 is hydrogen and R22 is selected from lower alkyl or lower haloalkoxy. In some embodiments of the invention, for a compound of formula (Ila), wherein R21 is hydrogen and R22 is selected from C!.3 alkyl or Cm haloalkyl. In some preferred embodiments, R22 is selected from the group consisting of a Cr alkyl group or a Cw haloalkyl group. In other preferred embodiments of the invention, R22 is selected from the group consisting of decyl, ethyl or qhaloalkyl. In some embodiments of the invention, for the formula (IIa) 15 201225954 j / υ δ ν ν ι Δ where R21 is hydrogen and R22 is selected from c10 alkyl. In some alternative embodiments of the invention, R22 is selected from the group consisting of decyl or ethyl. In other preferred embodiments of the invention, R22 is a fluorenyl group. In some embodiments of the invention, for a compound of formula (Ha) wherein R22 is hydrogen, R21 is selected from halo, lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy. In some embodiments of the invention, for the compound of formula (Ila) wherein R22 is hydrogen 'R21 is selected from lower alkyl or lower haloalkoxy. In some embodiments of the invention, for a compound of formula (IIa), wherein R22 is hydrogen and R21 is selected from Cw alkyl or Cw haloalkyl. In some preferred embodiments of the invention, R21 is selected from the group consisting of a Cr alkyl group or a Cm haloalkyl group. In other preferred embodiments of the invention, R21 is selected from the group consisting of methyl, ethyl or Ci-alkyl. In some embodiments of the invention, for a compound of formula (IIa), wherein R22 is hydrogen and R21 is selected from C.sub.3 alkyl. In another preferred embodiment of the invention 'R21 is selected from decyl or ethyl. In another preferred embodiment of the invention, R21 is a fluorenyl group. In some embodiments of the invention, for the compound of formula (IIa), wherein R21 and R22 are each independently selected from halo, lower alkyl, lower haloalkyl, lower alkoxy or lower alkoxy. In some embodiments of the invention, for the compound of formula (IIa), wherein R21 and R22 are each independently selected from lower alkyl or lower halooxy. In some embodiments of the invention, for the compound of formula (IIa) 201225954 j /Uftvpir compound' wherein r21 and R22 are each independently selected from Cw alkyl or haloalkyl. In some preferred embodiments of the invention, R21 and R22 are each independently selected from the group consisting of Ci-2 alkyl or c, _2 haloalkyl. In other preferred embodiments of the invention, 'r21 and: R22 are each independently selected from decyl, ethyl or Q haloalkyl. In some embodiments of the invention 'is for a compound of formula (Ila), wherein R 1 and r 22 are each independently selected from c13 alkyl. In other preferred embodiments of the invention, R2i and R22 are each independently selected from decyl or ethyl. In still other preferred embodiments of the invention, R21 and R22 are indenyl groups, respectively. ~ In some embodiments of the invention, the compound of formula (I) is any compound represented by formula (III),

Or a pharmaceutically acceptable salt thereof, wherein: R24 is selected from the group consisting of hydrazine, halogen, lower alkyl, lower haloalkyl, lower alkoxy or lower halogenated lower alkoxy; R25 is selected from the group consisting of hydrazine, hydrazine, and lower grade a lower halogenated alkyl group, a lower alkoxy group or a lower ii lower alkoxy group; Z2 is selected from N or CR26; and 17 201225954 j /υο^ριι R26 is selected from the group consisting of hydrazine, halogen, lower alkyl, lower halogen alkyl, a lower alkoxy group or a lower order lower alkoxy group; wherein at least one of R24, R25 and R26, if present, is selected from the group consisting of halogen, lower alkyl, lower il alkyl, lower alkoxy or lower haloalkoxy . In some embodiments of the invention, for the compound of formula (III) wherein R24 is selected from the group consisting of H, C, F, methyl, ethyl, trifluoromethyl, decyloxy, ethoxy or trifluoroanthracene Oxygen. In some embodiments of the invention, for the compound of formula (III) wherein R25 is selected from the group consisting of ruthenium, alpha, F, decyl, ethyl, trifluoromethyl, decyloxy, ethoxy or trifluoroanthracene Oxygen. In some embodiments of the invention, for a compound of formula (ΙΠ), wherein Ζ2 is Ν. In some embodiments of the invention, for the compound of formula (m), wherein Ζ2 is CR26. In some embodiments of the invention, for a compound of the formula wherein Z 2 is CR 26 and R 26 is selected from the group consisting of H, C, F, methyl, ethyl, trifluoromethyl, decyloxy, ethoxy or trifluoro Alkoxy. In some embodiments of the invention 'for a compound of formula (ΙΠ), wherein Ζ 2 is CR 26 , any one of R 24 , R 25 and R 26 is selected from the group consisting of halogen, lower alkyl, lower halo, lower alkoxy The base or lower halogenated alkoxy group, the other two of R24, R and R are oxime. In some embodiments of the invention, for a compound of formula (ΙΠ), wherein Ζ2 is CR26', any one of R24 and R26 is selected from the group consisting of a element, 201225954 / \j〇yun lower alkyl, lower halogenated alkyl , a lower alkoxy group or a lower alkoxy group, the other of R24 and R26 is ruthenium. In some preferred embodiments of the invention, R25 is Η. In some embodiments of the invention, for a compound of formula (III), wherein Ζ2 is CR26', any two of R24, R25, and R26 are each independently selected from halo, lower alkyl, lower haloalkyl, Lower alkoxy or lower haloalkoxy, the other of R24, R25 and R26 is deuterium. In still other preferred embodiments of the invention, R25 is η. In some embodiments of the invention, for a compound of formula (III), wherein Ζ2 is CR26, R24, R25 and R26 are each independently selected from halo, lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkyl Oxygen. In some embodiments of the invention, for a compound of formula (III), wherein Ζ2 is hydrazine, any one of R24 and R25 is selected from halo, lower alkyl, lower li-alkyl, lower alkoxy or lower The tooth alkoxy group, the other of R24 and R25 is hydrazine. In some embodiments of the invention, for a compound of formula (ΠΙ), wherein Ζ 2 is Ν ' R 24 and R 25 are each independently selected from halo, lower alkyl, lower haloalkyl, lower alkoxy or lower dentate Alkenyloxy. In some embodiments of the invention, the compound of the formula (ΠΙ) is any compound represented by the formula (Ilia), 19 201225954

Or a pharmaceutically acceptable salt thereof, wherein R24 is selected from the group consisting of ruthenium, a halo, a lower alkyl, a lower haloalkyl, a lower alkoxy or a lower ii lower alkoxy; and R25 is selected from the group consisting of ruthenium, halogen, lower alkane And a lower haloalkyl group, a lower alkoxy group or a lower halo alkoxy group; wherein at least one of R24 and R25 is selected from the group consisting of halogen, lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy. In some embodiments of the invention, for a compound of formula (Ilia) wherein R24 is deuterium, R25 is selected from halo, lower alkyl, lower haloalkyl, lower alkoxy or lower alkoxy. In some embodiments of the invention, for a compound of formula (Ilia), wherein R24 is H, R25 is selected from lower alkyl or lower i-alkoxy. In some embodiments of the invention, for a compound of formula (Ilia), wherein R24 is H, R25 is selected from C10 alkyl or CV3 haloalkyl. In some preferred embodiments of the invention, R25 is selected from the group consisting of C12 alkyl or Cl_2 haloalkyl. In other preferred embodiments of the invention, R25 is selected from the group consisting of methyl, ethyl or q-dentate alkyl. In some embodiments of the invention, for the 201225954 compound of formula (Ilia), wherein R24 is H and R25 is selected from CN3 alkyl. In other preferred embodiments of the invention, R25 is selected from the group consisting of decyl or ethyl. In other preferred embodiments of the invention, R25 is methyl. In some embodiments of the invention, for a compound of formula (Ilia), wherein R25 is hydrogen ' R24 is selected from the group consisting of halogen, lower alkyl, lower haloalkyl, lower alkoxy or lower alkoxy. In some embodiments of the invention, for a compound of formula (Ilia) wherein R25 is H, R24 is selected from lower alkyl or lower haloalkoxy. In some embodiments of the invention, for a compound of formula (Ilia) wherein R25 is H, R24 is selected from the group consisting of Cl3 alkyl or Cl3 haloalkyl. In some preferred embodiments of the invention, R24 is selected from the group consisting of Ci 2 alkyl or ci 2 haloalkyl. In still other preferred embodiments of the invention, r24 is selected from the group consisting of methyl, ethyl or ci-alkyl. In some embodiments of the invention, for a compound of formula (Ilia), wherein R25 3 u

- Some preferred embodiments of the invention R, in which g is γ", R24 is selected from decyl or ethyl. In another aspect of the invention

In some preferred embodiments, R is in the present invention, wherein R24 is a scheme wherein, for the lower haloalkyl group of formula (IIIa), the lower 2 R 5 is independently selected from halogen, lower alkyl, In the gas-burning or lower halogenated alkoxy group of the present invention. Compounds, wherein R24 and some of the schemes, are for the structural formula (Hla). The present invention is independently selected from the group consisting of lower alkyl or lower halogen 21 201225954 j /υο^ριι In some embodiments of the invention, for the compound of formula (Ilia), wherein R24 and R25 are each independently selected from Cw alkyl Or Cw haloalkyl. In some preferred embodiments of the invention, R24 and R25 are each independently selected from Cw alkyl or haloalkyl. In other preferred embodiments of the invention, R24 and R25 are each independently selected from the group consisting of fluorenyl or C! haloalkyl. In some embodiments of the invention, for a compound of formula (Ilia), wherein R24 and R25 are each independently selected from Cw alkyl. In other preferred embodiments of the invention, R24 and R25 are each independently selected from decyl or ethyl. In still other preferred embodiments of the invention, both R24 and R25 are fluorenyl groups. In some embodiments of the invention, the compound of formula (I), wherein the compound is preferably N-[(4-hydroxy-2-oxo-7-phenyl-2H-3-chromenyl)carbonyl]glycine N-[(4-hydroxy-2-oxo-7-(2-chloro-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo- 7-(3-Chloro-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-7-(4-chloro-phenyl)-2H-3 -chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-7-(3-trifluoromethyl-phenyl)-2H-3-chromenyl)carbonyl]glycine; N- [(4-Hydroxy-2-oxo-7-(4-trifluorodecyl-phenyl)-2H-3-chromenyl)carbonyl]glycine; 22 201225954 J /υο^ριι N-[(4- Hydroxy-2-oxo-7-(3-trifluorodecyloxy-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-7-( 4-trifluorodecyloxy-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-7-(3,4-dichloro-phenyl) -211-3-chromenyl)carbonyl]glycine; [[4-hydroxy-2-oxo-7-(3,4-difluoro-phenyl)-211-3-chromenyl)carbonyl]glycine ; N-[(4-hydroxy-2-oxo-7-(3,4,5-trifluoro-phenyl)-211-3-chromenyl)carbonyl] Acid; N-[(4-hydroxy-2-oxo-7-(3-decyloxy-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-) Oxo-7-(4-decyloxy-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-7-(3-indolyl-benzene) -2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-7-(4-indolyl-phenyl)-2H-3-chromenyl)carbonyl] Glycine; N-[(4-carbo-2-oxo-8-(2-a-phenyl)-2H-3-color: fcfp-based) tracing] glycine; N-[(4-hydroxy-2) -oxo-8-(3-a-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-(4-chloro-phenyl) -2H-3-alkenyl)carbonyl]glycine; 23

201225954 j /voyyiL N-[(4-Hydroxy-2-oxo-8-(3-trifluorodecyl-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxyl) -2-oxo-8-(4-trifluorodecyl-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-(3- Trifluoromethoxy-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-(4-trifluorodecyloxy-phenyl)- 2H-3-alkenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-(3,4-dichloro-phenyl)-211-3-chromenyl)carbonyl]glycine N-[(4-hydroxy-2-oxo-8-(3,4-difluoro-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-) Oxo-8-(3,4,5-trifluoro-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-(3-oxime) Oxy-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-(4-methoxy-phenyl)-2H-3-color Alkenyl) carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-(3-indolyl-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4- Hydroxy-2-oxo-8-(4-indolyl-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-7-(6-oxime) Oxy-3-pyridyl)-2H-3-chromenyl) Glycine; 24 201225954 j /uoypir Red N-[(4-hydroxy_2_oxo_7·(4_pyridyl)_2H_3_chromenyl)carbonyl]glycine; N_[(4-··2- Oxo-7-phenoxy-2H-3-chromo)aminol]glycine;

N-[(4-transyl-2-oxo-7u_alkenyl)-yl]glycine N-[(4-hydroxy-2-oxo-8-bromo-3-indolyl)carbonyl]glycine N-[(4-transoxy)n-carbonyl]glycine; or fluorenyl 1 oxo-o-trifluoromethylphenyl)·coffee-colored base) In addition, the present invention also provides A pharmaceutical composition comprising: at least one pharmaceutically acceptable adjuvant, adjuvant or carrier; and at least one therapeutically effective amount of a compound provided by the present invention or a pharmaceutically acceptable oxime. Further, the present invention further provides A pharmaceutical composition comprising at least one pharmaceutically acceptable leg, adjuvant or carrier; and at least one therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable H' combination thereof, at least a compound, for example Promote erythropoietin or chemotherapy drugs. Further, the present invention provides a use of a compound provided by the present invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for regulating (e.g., increasing) administration of a level or activity to HIF. The present invention still further provides the use of a compound provided by the present invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disorder associated with the modulation of ΗIF activity, the medicament comprising at least the invention 25 201225954 j /υο^ριι Known compounds. Furthermore, the present invention still further provides a use of a compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for a blood-related disease, which comprises the compound provided by the medicament or a pharmaceutically acceptable salt thereof. The present invention further provides that the human acceptable salt provided by the present invention is prepared for treating ischemic, poor, oral, oral, orthotopic transplantation, ectopic transplantation, and different Use of a combination of two or a combination of blood pressure, thalassemia, diabetes, cancer, inflammation, or the like, the compound of the present invention or a pharmaceutically acceptable compound thereof Provided is a compound of the present invention or a medicament thereof, which comprises at least one of the compounds of the present invention. The compound of the present invention or a medicament thereof In addition, the present invention further proceeds to the present invention. The compound, the salt is prepared for the regulation of intracellular: fine: the drug contains at least one of the two provided by the present invention. In addition, the present invention provides for the preparation of the fetus for raising the fetus in the subject. Application in Le, 'The drug contains at least one of the present invention or a pharmaceutically acceptable salt thereof. 26 201225954 J/voyuu Further, the present invention further provides a pharmaceutically acceptable salt for use in preparation Regulate the newborn in the body or its medicine a chemically acceptable salt. (4) ft. The present invention further provides a compound of the present invention or a compound of the same compound in the treatment of a disease, a drug thereof. a compound provided by the present invention or a pharmaceutically acceptable salt thereof in at least a package; ', Pharma:: providing a compound of the present invention or a drug thereof in the following step: The compound (4) hydroxylated is pharmaceutically acceptable as "0 &quot; compound = IF = further compound provided by the compound, wherein the inhibitory activity has a 1C50 value of 40 μM or less. The eight substances are re-introduced - the compounds provided, in which the said. The anti-infective activity IC50 value is 1〇μΜ or lower than _M. This is a detailed description of the case, or can be used to indicate the number of different components in the reaction, and in some cases, the value of the patent can be clearly defined. Correspondingly, the different parameters of the errors quoted in the digital scope of the digital moxibustion, I Bu's in the specification and the patent scope are different under the respective experimental conditions. Numerical parameters. 27 201225954 j/yjoypii This paper, when a certain times, the definitions cited in each reference formula are independent. The description described herein refers to multiple palm centers and/or Double bonds and articles may contain - or = isomers, such as double bond stereoisomers ('n=== in optical isomers or diastereomers. Correspondingly, purely included The oxime moiety contains the above-mentioned similar, ··. The structure includes the compound _ enantiomer, which also includes the simple two-domain and non-pair (such as pure geometric isomers, pure stereoisomers) The same as the enantiomer of the W, (4) Riga or pure The enantiomers of the isomers sigh these (10) bodies. The racemic and read isomerization mixtures utilize known separation techniques or palm synthesis; =: isomers or stereoisomers. ^ ^ Compounds of Structural Formula (I), Structural Formula (Π), Structural Formula (iia), Structural Formula (m), and Structural Formula (IIIa), including, but not limited to, the above structural formula (1), structural formula (8), structural formula a racemate of (na), structural formula (m) and a compound of formula (Ilia) or any mixture thereof. In the above case, the single corresponding isomer or diastereomer, such as optical The active form can be obtained by asymmetric synthesis or resolution of the racemate. The resolution of the racemate can be carried out, for example, by a conventional method such as resolving reagent recrystallization, or by chromatography such as using high pressure liquid chromatography. (high-pressure liquid chromatography, HPLC) column chromatography. Further 'structural formula (I), structural formula (II), structural formula (na), 28 201225954 structural formula (III) and compound of formula (IIIa) Including 双·configuration and E•configuration with double bond t (Lai or trans). All tautomers of these compounds are also included in the chemical structures of structural formula (I), structural formula (8), structural formula (IIa), and structural formula. Compounds, including but not reported, of structural compounds and all their pharmaceutically acceptable different forms. The second embodiment of the sigma-transfer acceptable form includes pharmaceutically acceptable salts, solvates, crystalline forms (including Poly(tetra) and cage structure), chelate, non-complex, prodrug or any mixture thereof. In: Certain embodiments of the invention, acceptable salt forms of the compounds of the invention. As follows, The term "compounds include a chelate thereof, a pharmaceutically acceptable compound thereof, a mixture thereof or a mixture thereof. \ k仕心植 as described above 'prodrugs are also included in the above chemical entities' such as 'the structural formula (1), structural formula (8), structural formula (IIa) structural formula (III) or structural formula (IIIa) Compounds for class derivatives. The term ''prodrug,' includes any compound of the compound of the formula (1), formula (8), formula (IIa) ^匕^ or formula (ma), such as by the mouth: "metabolism. _ precursor Examples include, for example, (IV) body ^, formula J, structural formula (11), structural formula (IIa) or structure ^, the compound is not (four) secret (such as alcoholic base _) of the oxime derivative 29 201225954 j / υο ^ριι substance, anthracene derivative, benzoquinone derivative, and other similar derivatives. The term "solvate" refers to a compound formed by any one compound and one solvent. Suitable solvates include pharmaceutically acceptable Solvates, such as hydrates, include monohydrates and hemihydrates. The substituents of the compounds of the invention mentioned herein in various places encompass various groups or ranges. In particular, the invention includes each or each Further combinations of members within the group or range. For example, the term "c alkyl" specifically indicates fluorenyl, ethyl and A alkyl (including propyl = and isopropyl), respectively. Ren Where more than one variable occurs, each variable may be selected from a different chemical structure in the Markush group used to define the variable. For example, one of the structures is described as having the same R compound on the same compound. The two R groups may be selected from different chemical structures used in the definition of the Markov group of R. It is further indicated that certain specificities of the invention set forth in the different embodiments are disclosed for the sake of clarity. The content may also be combined in a single entity. Accordingly, the various aspects of the invention as set forth in the <RTI ID=0.0> </ RTI> </ RTI> </ RTI> <RTIgt; Early singularity ~ Ring original:: Counting 1: is a · used to typically describe the number of sorrow atoms in a group of 6-membered heterogeneous hearts. For example, an example of a ring is pyridine. An example of a ring, thiophene is a 5-membered heterocyclic aromatic ring. The term "pine: ^,, _11« is privately derived from a parent alkane molecule. Carbon 201225954

j lyjoyyiL removes a saturated branched or linear monovalent hydrocarbon group formed by a hydrogen atom. Typical hospital bases include, but are not limited to, methyl, ethyl, propyl such as 1-propyl, 2-propyl, 1-cyclopropyl, butyl such as hydrazine-butyl, 2-butyl, 2 - mercapto-propyl propyl, 2-fluorenyl 2-propenyl, butylcyclobutyl, tert-butyl, and the like. In certain embodiments of the invention, the alkyl group may contain from 1 to 20 carbon atoms. The term "lower alkyl," as used herein, refers to an alkyl group containing from 1 to 6 carbon atoms.

The term "alkenyl" refers to an unsaturated, branched or cyclic group containing at least one carbon-carbon double bond formed by the removal of one hydrogen atom from a carbon of a parent olefin molecule. The double bond carried by the group may be in the z_ or E- (or cis or trans) configuration. Typical alkenyl groups include, but are not limited to, ethylene groups, propylene groups such as propylene + group, i propylene 2 _ group, 2- propylene small group, 2-propan-2-yl group, 1-ring two Ind-1-yl, 2-cyclopropyl small group, butenyl group such as buty-1-yl, 1-butan-2-yl, 2-methyl-1_propyl-1 -yl, 2-butyl Alkenyl, 2-butadiene-2-yl, u-butadiene, 1"3:butylene-2,ylcyclobutanyl,cyclobutanyl, acyclobutene-1 'Wait a similar group. In certain embodiments of the invention, the alkenyl group may contain from 2 to 20 carbon atoms. In the other aspects of the invention, the dilute group may contain 2 to 6 carbon atoms, such as "lower soil block" refers to a carbon formed from a parent block of smoke molecules; An unsaturated chain or a linear group containing at least one carbon-carbon triple bond. Typical alkynyl groups include, but are not limited to, ethyl fast, propyl, butynyl, 2 rhyme, 3 rhyme, 2 hexynyl, 31 201225954 J / UO^pil 3_hexynyl, etc. And similar groups. In certain embodiments of the invention, the alkynyl group can contain from 2 to 20 carbon atoms. In still other embodiments of the invention, the alkynyl group may contain from 2 to 6 carbon atoms, such as "lower alkynyl." The term "alkoxy" refers to -OR, wherein R is alkyl or cycloalkyl. Typical alkoxy groups include, but are not limited to, decyloxy, ethoxy, propyloxy, butoxy, cyclohexyloxy, and the like. The term "alkoxycarbonyl" refers to _C(〇)-〇R, wherein R is the above defined radical. "5-aromatic hydrocarbon group" refers to a monovalent aromatic hydrocarbon group formed by removing a hydrogen atom from a carbon of a parent aromatic hydrocarbon molecule. The aromatic hydrocarbon group includes all-carbons of 5- and 6-membered rings. An aromatic ring such as a benzene ring; wherein at least one ring is a two-membered ring system of an all-carbon aromatic ring, wherein === at least one of the rings is a ternary of the all-carbon aromatic ring; = two two; == including "yuan" and The heterocyclic group of the hetero atom of the lanthanum and S is fused to two or two: a certain aromatic hydrocarbon group may contain == into a heterocyclic aromatic 22, ^ 3 仏 _ The term "aryl hydrocarbyl di" fluorenyl group in the private (four) U (the material is the end === 32 201225954 J / υ ο ^ ρ η sub-one: the aromatic hydrocarbon group is substituted to form a glutamate U group including, but Not limited to, (4), 2 · phenyl soil - this base - 1 - vinyl, naphthylmethyl, 2-笑美] r its ... base-1-vinyl, naphthylbenzyl, 2_ phenylene Base, 2_奈当 Describes the specific terminology of a certain ketonediyl group == ke group. The term aryldiyl and aryl block in the group. In the === C group can be 6 to 3 a carbon source = two years old The group may be 丨 to ω. The f-cigarette group may contain 5 to 20 carbon atoms. The term "'group" refers to the _C(〇) group. The term "carboxy" refers to -C(0)〇H group. The term "cyano," refers to -CN. The group of oxime or ruthenium is formed by the second syllabus (10) fresh scales, and the system touches "ring burned beauty" ^基,等. A typical cyclic hydrocarbon group includes, but is not limited to. In some embodiments of the invention, the ring smoke is from 10 to 3 carbon atoms, for example, 3 to 6 carbon atoms. The earth ring ^.3 has 3 non-aromatically the remaining or non-saturated secret group of non-fragrance, and wherein - ❹(4): ^ = hydrogen atom) are respectively the same or different The _ sub-substitute of the j. Code (4) can replace the carbon material = but not limited to, N, P, 〇, s * Sl. When 'saturation' can be used, the term "heterocyclic green," or "hetero^ 33 201225954 J /υο^ριι typical heterocyclic hydrocarbon group includes, but is not limited to, from epoxide, imidazolidine, Morpholine, piperazine, piteridine, pyrazolidine '0', pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydrogen A similar molecule-derived group. The substituted heterocyclic hydrocarbon group also includes a heterocyclic hydrocarbon ring system having one or more oxo (= oxime) or oxide (_〇) substituents, such as cucurbital oxide, morphine oxide, Oxo-1-dairy-1-thiophene (l_oxo_l_thi〇morpholinyl)-1-thiophenan (l,l_di〇x〇_i_thi〇morpholinyl). "5 diseases" refers to any disease, discomfort, condition, and symptom. A _ 素 refers to a fluorine, gas, bromine or iodine group. "Aza-aromatic group" refers to a monovalent heterocyclic aromatic group formed from a parent heterocyclic aromatic hydrocarbon "group-: atom-removed-hydrogen atom" = a group-containing aroma group includes: a 5 to 7-membered heart or 1 Above, for example 1 to 4, or: too happy in the case! Up to 3, heteroatoms (selected from some of the remaining atoms are broken; or, exclusive heterocyclic aromatic: two certain implementations such as i to 4) or in the present invention: and the remaining ring ^ w miscellaneous thousand (selected from rose, oxime and 8), in the aromatic ring are all carbon atoms, and at least one of the heteroatoms of the ring aromatic hydrocarbon group includes - a dollar to ~ 7 her base, or a 5_元至== 34 201225954 The ring is fused to a 5- to 7-membered heterocyclic hydrocarbon group. A cyclic heterocyclic aromatic hydrocarbon system in which only one ring: a double hetero atom, the attachment site is in a heteroaromatic ring Or cyclic hydrocarbons. ^ =

When the total number of atoms or helium atoms exceeds one, this == is not adjacent to each other. In certain embodiments of the present invention, the total number of S and Q atoms of the heterocyclic aromatic hydrocarbons is less than two. In certain embodiments of the invention, the total number of S and deuterium atoms on the heterocyclic aromatic hydrocarbon group is no more than one. Further, the heterocyclic aromatic hydrocarbon group is not mutually contained or cross-linked with the aromatic hydrocarbon group defined above. Typical heterocyclic aromatic hydrocarbon groups, including, but not limited to, acridine, arsindole, carbazole, p- 0-carboline, chromane, Chromene, chromene. Cinnoline, furan, imidaz〇le, indazole, indole, dihydrogen. Ind〇line, D indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoindoline Isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perirnidine ), Philippine. Phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, ° ratio (pyran), σ Compared with pyrazine, 0 pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, 35 201225954

Pyrrolizine, quinaz〇line, qumolme, quinolizine, quinoxaline (quin〇xaHne), tetrazole (tetrazole), thiadiazole (thiadiaz〇) Le), thiazole (thiaz〇ie), diceset, (th10Phene), triazole, xanthene, and the like, and derivatives thereof. In certain embodiments of the invention, the heterocyclic aromatic hydrocarbon group may be a 5 to 2 united heterocyclic 'aromatic aryl group, for example, a M 1G united heterocyclic aromatic hydrocarbon group. In the present invention, certain heterocyclic (tetra)hydrocarbyl groups may be phenanthrene, p-, benzophenone,

, ridge material, material, butterfly-azine derived refers to the online ^ base if h =: tT ^ ete_W using, for example, a fixed hydrocarbyl group, can also be = term. Some of the groups in the present invention may be a 6f丨丨m heteroaryl hydrocarbon group which may be a fluorenyl group containing a fluorene group and a 2 fluorene heterocyclic aromatic ring. The heteroaryl group may be 5 as the term "stone fluorenyl," meaning - the green or the substituent containing a substituent, the core of the R is a phenyl group, a heterocyclic hydrocarbon group containing a substituent, a heterocyclic hydrocarbon group, : Ring aromatic hydrocarbons or containing: base of the heart:: the aromatic hydrocarbon group of the base, this "has already 8 meaning. Representative 22: Each group: 36 201225954 is not limited to, methyl base, base group. The base group, the sigma group, and the butyl group are referred to as SR, wherein r may be a burnt group, a substituent-containing alkyl group, a cyclic hydrocarbon group, a shirt group containing a substituent-ring compound, and a base group. , a heterocyclic ketone group, a heterocyclic ring, an aromatic hydrocarbon group having a substituent, and a heterocyclic aromatic hydrocarbon group substituted in the ίί3 group. Each of the above groups does not shoot/read a clear definition. Representative thioalkyl groups include,

龆/其圃 meaning, methylthio, ethylthio, propylthio, butylthio, and the like.寸 f 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯 浯Salt, refers to a salt of such a compound that is pharmaceutically acceptable and possesses the desired pharmaceutical activity of the parent compound. These salts include: (1) a salt formed by adding a mineral acid such as a salt of the eye, a sulfuric acid, an acid, a sulphuric acid, etc.; a salt formed by adding an organic acid, such as acetic acid, propionic acid, Acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxyl Benzene), benzoic acid, mandelic acid, sulfonic acid, 4, and the like, or (2) an acidic hydrogen atom on the parent compound is a metal ion, such as an alkali metal ion, an alkaline earth metal, or an aluminum ion. Substituting the resulting salt; or a salt complexed with an organic domain, such as ethylamine, diethylamine, diethylamine, N-mercaptoglucosamine, dicyclohexylamine, and the like. 37 201225954 The terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier," or "pharmaceutically acceptable adjuvant" mean, respectively, any of the compounds that can be administered to a subject with at least one compound of the invention. Excipients, carriers or adjuvants. The term "stereoisomer" refers to those isomers whose constituent atoms are arranged in a spatially different arrangement. Two stereoisomer terms which are structurally mirror images and optically active. The stereoisomers referred to above as "enantiomers", and those which are structurally non-image-imageable and optically active, are termed "diastereomers". The "treatment subject" may include animals and humans. As used herein, the terms "person," and the term "object," are used interchangeably. The term "substituent-containing" means that one or more hydrogen atoms in a group are each substituted by the same or different substituents. Typical substituents include, but are not limited to, -X, -R33, -_0H, =〇, _〇r33, SR33, -SH, =S, -NR33R34, =NR33, -CX3, -CF3, -CN, -N〇2, -S(〇)2r33 . -0S(02)0H &gt; -0S(0)2R33 &gt; -〇P(〇)(〇R33)(〇R34) &gt; -C(〇)R33 &gt; -C(S)R33 &gt; -C(0)0R33 &gt; -C(0)NR33R34 &gt; -C(0)0H ' -C(S)〇R33, _NR35C(〇)NR33R34, -NR35C( S) NR33R34, -NR35C(NR33)NR33R34, -C(NR33)NR33R34, -S(0)2NR33R34, -NR35S(〇)2R33, -NR35C(〇)R33 or s(o)r33; wherein each x is respectively Is a single halogen 'R33 and R34 are each independently selected from hydrogen, alkyl, substituent-containing alkyl, aromatic hydrocarbon group, substituted aromatic hydrocarbon group, arylalkyl group, substituted arylalkyl group, Cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heterocyclic aromatic hydrocarbon, substituted heterocyclic aromatic hydrocarbon, heteroarylalkyl, substituent-containing Heteroarylalkyl, 38 201225954 ^/υονριι盘 and 31&gt; 二画^^35 or _'况35' or any of R33 and r3, =, connected atoms form - or - - the above 4 i ΓΓ aryl group, a heterocyclic group or an aromatic hydrocarbon group substituted ^ Hyun group-containing substituent group. a substituent-containing Weyl group, a heterocyclic heteropoly, a heterocyclic aromatic group, a substituent-containing fluorenyl group or a substituent-containing heteroaryl group, or a hetero-D 36 group The atoms to which they are directly bonded form a heterocyclic aromatic hydrocarbon group of - or -, a hetero group containing a hetero group, a heterocyclic aromatic hydrocarbon group. In certain embodiments, the nitrogen on the aromatic ring of the amine ring may be replaced by one or more oxygen atoms to form the corresponding nitrogen oxide structure. , "Efficient therapeutic dose," refers to a therapeutic dose of a compound or not to treat a disease' or to treat a disease i-two 21^ bed symptoms 'sufficient for this disease, discomfort or ii: The specific "effective therapeutic dose" can vary depending on the difference in disease, the difference in discomfort, the difference in disease or slant, the severity of the disease, discomfort or symptoms, the age, and the weight. . In any case where possible, the appropriate dose can be readily determined by those skilled in the art. "Treatment for any disease or discomfort, refers to the alleviation or elimination of a disease discomfort, or at least one clinical symptom of the disease or discomfort, minus 39 201225954 j /υο^ριι less one disease, discomfort, or disease Or the risk of at least one clinical symptom occurring, reducing the progression of at least one clinical condition of a disease, discomfort or the disease or discomfort, reducing the risk of a disease, discomfort or at least one clinical symptom progression of the disease or discomfort. The term "treatment;" means inhibiting a disease or discomfort, either physical (such as stabilization of a significant symptom), physiological (such as stabilization of a physiological indicator), or both, or inhibiting at least One is not significant for the treated subject

Physical indicators. At the same time, 'm refers to the episode of the symptoms of the disease, which is already in the category of disease or discomfort or will be attacked, compared with the treatment of the disease (4), or the performance of the disease or Symptoms of discomfort. We will hereinafter detail some of the embodiments of the present invention that are described herein in detail (embodiment i, body;: Fang Zaiming's solution is not limited to those described in the case) ^= can be included in all embodiments of the invention

Replacement, modification, and equivalent. _ Various Corresponding Embodiments of the present invention are directed to ί: Compounds of the structural formula (1) ^

Structural Formula (I) 40 201225954 j / \j07yn and pharmaceutically acceptable salts thereof, homosolvates thereof, chelates thereof, non-covalent complexes thereof, prodrugs thereof, or any mixture of these compounds, Wherein, n is selected from any integer from 1 to 6; the core is selected from the group consisting of OH, SH, NR3R4, NHC(0)R2, NHS02R2, and sulfonyl; R2 is selected from the group consisting of hydrazine, lower alkyl or a lower alkyl group containing a substituent; R3 and I are each independently selected from η, lower alkyl, substituent-containing lower refractory, lower thioalkyl or substituted lower haloalkyl, or Rs and R4 are joined to form a 3 to 6 membered ring or a 3- to 6-membered ring containing a substituent; selected from OH, SH, NH2, lower alkyl, lower alkyl group having a substituent, lower alkoxy group, lower alkoxy group having a substituent or sulfanyl group, R6 , K, Rs and Re are each independently selected from H, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a substituted alkynyl group, NR3R4, C(〇) 〇H, 〇R12, SR12, S02R12, CN, N02, • Halogen, aromatic hydrocarbon group, substituted aromatic hydrocarbon group, heterocyclic aromatic hydrocarbon group Heterocyclic aromatic hydrocarbon group having a substituent, an aromatic hydrocarbon group alkyl group, a substituted aromatic hydrocarbon group alkyl group, a heterocyclic aromatic hydrocarbon group alkyl group, a heterocyclic aromatic hydrocarbon group containing a substituent, a heterocycloalkyl group, a substituted hetero a cycloalkyl group, an alkyl fluorenyl group, a substituted alkyl fluorenyl group, an alkenyl fluorenyl group, a substituted alkenyl fluorenyl group, an alkynyl fluorenyl group, a substituted alkynyl fluorenyl group, an alkoxy group, Alkoxy group having a substituent, a oxy group, alkoxycarbonyl group containing a substituent or _x_Rii; or at least one adjacent pair of R! and R6, R6 and R7, r7 201225954 J/uoypn teeth : or R8 and R9 are joined to form a "&quot; meta-base 4 to 7-membered ring; X is selected from _N(R]Q)-Y• or -YN(Rio)-; Y is selected from C(〇) , s〇2, a banyl group, a female group having a substituent, an alkynyl group or an alkynyl group having a substituent;

Riok self-priming, lower alkyl or lower-grade alkyl containing substituents;

Rii is selected from the group consisting of an anthracene, a cycloalkyl group, a substituted cycloalkyl group, a heterocycloalkyl group, a heterocyclic group containing a substituent, an aryl group, a substituted aryl hydrocarbon group, a heteroaryl hydrocarbon group or a substituted group. An arylhydrocarbyl group; and

Ri2 is selected from the group consisting of an anthracene, an alkyl group, a substituent-containing alkyl group, an alkenyl group, a substituent-containing alkenyl group, an alkynyl group, a substituent-containing alkenyl group or NR3R4. In certain embodiments of the compounds of formula (I), the core is selected from the group consisting of 〇H or SH. In certain embodiments of the compounds of formula (I), r2 is deuterium. In certain embodiments of the compounds of formula (I), the ampules 3 and 2 are each independently selected from the group consisting of hydrazine, lower alkyl such as methyl or ethyl, or lower alkyl containing substituents (eg, trans-substituents) Lower alkyl, such as methyl). In certain embodiments of the compounds of formula (I), r5 is selected from the group consisting of hydrazine, lower alkoxy groups such as decyloxy, ethoxy, propoxy, or lower alkoxy groups containing substituents. In certain embodiments of the compounds of formula (I), the ruler 3 and the oxime are joined together to form a 3- to 6-membered ring or a 3- to 6-membered ring containing a substituent. Wherein the 3- to 6-membered ring contains at least one hetero atom, such as at least two heteroatoms. 42 201225954 j/usypir In certain embodiments of the compounds of formula (i), the core and R6 are joined together to form a 4- to 7-membered ring or a 4- to 7-membered ring containing a substituent. The 4- to 7-membered ring contains at least one hetero atom, such as at least two heteroatoms, and at least 3 heteroatoms. In certain embodiments of the compounds of formula (I), at least one of r6, R7, R8 and R9 are each independently selected from halo or a group substituted with at least one halogen, such as haloalkyl or haloalkoxy, for example Trifluoromethyl. In certain embodiments of the compounds of formula (I), at least one of R6, heart, ^ and % are each independently selected from alkoxy or alkoxy containing substituents. In certain embodiments of the compounds of formula (I), &amp;, R7,

At least one of Rs and R9 is independently selected from the group consisting of an alkyl fluorenyl group, a substituted alkyl fluorenyl group, a substituted alkyl fluorenyl group, an alkynyl fluorenyl group or a substituted alkynyl fluorenyl group. In certain embodiments of the compounds of formula (I), at least one of the ruthenium 6, h, I and R9 are independently selected from the group consisting of an aryl hydrocarbyl group, a substituted aryl fe group, a heterofilament group, a substituent-containing green A nicotyl group, a heterocyclic alkyl group or a substituted arylalkyl group, for example, a d-containing group containing a substituent, a substituent group containing a substituent, a tetrazinyl group having a substituent, and a tetrahydro-containing substituent having a substituent σ base. In certain embodiments of the compound of formula (1), at least one of r6, R7, R8 and R9 is independently H, alkyl, substituent-containing alkyl, alkenyl, substituent-containing, silk Or alkynyl group containing a substituent, 43 201225954

For example, isopropyl, cyclopropyl, cyclohexyl A. The specific conjugate examples of the compounds of the pentyl, cycloalkenyl or cyclopentene containing the tree-formed composition and which are used in the various methods are listed in Table i. Tables, servants, and PP include information on their chemical knots, chemical names, knife placement, 虱 NMR ((10) kiss illusion data, and at least one synthetic method. These compounds disclosed in the present invention can inhibit bile Lysine anabolic enzymes, such as lysine ammonia oxidase. There are a variety of test methods that can be used to determine the inhibitory activity of a compound against a gas-trapping acid oxidase. The compounds disclosed herein can modulate the rise in calpa activity in vivo. High or reduced 'such as by stabilizing Hip. And 'the compounds disclosed herein may contain one or more palmar centers. These compounds may be prepared by pure or stereochemical methods such as 'pure pairings' Isomers or diastereomeric constructs, or mixtures of isomers in varying proportions. All such stereoisomers, as well as mixtures thereof in different ratios, are included within the scope of the invention. Stereoisomers' and mixtures of different ratios may be used, such as optically active starting compounds, or stereoselectors well known in the art. Alternatively, the racemic mixture of these compounds can be further resolved by a similar method using a reagent such as a palmar column, etc.. Some embodiments of the invention may be A pharmaceutical composition consisting of at least one drug 44 201225954 j /woypir 2 adjuvant, adjuvant or carrier, and an effective amount of a compound, wherein at least: shift: to: include deficiency, anemia, wound healing Orthotopic transplantation: 2. Allogeneic transplantation, hypertension, thalassemia, diabetes, imitation; effective agents for treating at least one disease of various inflammatory tissues, or other embodiments including the present invention Providing a combination of di- and per-acceptable salts in the preparation of a medicament for regulating sputum: η匕 to achieve a therapeutic disease. These diseases are selected from the group consisting of lack of blood, wound healing, orthotopic transplantation, Ectopic transplantation, allogeneic transplantation, 'Huangjian, thalassemia, diabetes, cancer and various diseases with less inflammation. - The other ones of the present invention include The use of a compound provided by the invention or a pharmaceutically acceptable salt thereof for the preparation of a disease of a patient: a discomfort or a condition. The diseases may include ischemia, anemia, wound healing, orthotopic transplantation, ectopic transplantation. , allogeneic transplantation, hypertension, thalassemia, diabetes, cancer, and various diseases of at least one of the diseases. ', Synthesis of the compounds of the present invention, including the salts thereof, can be synthesized by known organic synthesis techniques and by one or A plurality of possible synthetic routes to synthesize. The reaction for preparing the compounds of the present invention can be carried out in a solvent which is suitable and relatively easy to select by those skilled in the art of organic synthesis. 45 201225954 ^/uoypn Suitable solvents can be those A solvent which does not interact with the starting material (reactant), intermediate (intermediate product) or product in the reaction temperature range, for example, from the solvent freezing temperature to the boiling point of the solvent . A known reaction can be carried out in one solvent or a mixture of more than one solvent. Suitable solvents for a particular reaction step can be selected by the skilled artisan depending upon the particular reaction step. The preparation of the compounds of the invention may include protection and deprotection of various chemical groups. One skilled in the art can more readily determine the need for group protection and deprotection as well as the selection of suitable protecting groups. For the chemistry of the protecting group, see, for example, Wiley &amp; Sons LLC (New York), 1999, "Groups in Organic Synthesis" (edited by Tw Greene and PGM Wuts). And in this full text bow. These reactions can be monitored by any suitable method known in the art. For example, product formation can be by spectroscopy, such as nuclear magnetic resonance spectroscopy (such as 普 普 or C spectrum), infrared spectroscopy, spectrophotometry (such as UV-visible UV-visible), mass spectrometry or chromatography such as high performance liquid chromatography High performance liquid chromatography (HPLC) or thin layer chromatography (TLC) ° The compounds of the invention may be prepared, for example, by one or one of the general reaction pathways or techniques described in the context.

General path I 46 201225954

s 47 201225954 The above features and advantages of the present invention are more apparent, and the following detailed description will be given in detail with reference to the accompanying drawings. The following [Embodiment] (IV) includes, but is not limited to, the following examples to further illustrate the preparation of the compounds of the formula (1), formula (ι), formula (5), formula or formula (Ilia) described in the invention. The hydrazine of Example 1: (4) kiney generation · 7 _ base-based decolorized fine base] glycine

1 ml of phosphoric acid was incubated at 50 ° C until the reaction was completed. Cool to room temperature, add 500 ml of water 'at 5 (TC stir until the hydrolysis is complete. Cool to 〇. 〇 Filter out the precipitated 48 201225954 J / solid. Dry to give compound 2 (47 g). Compound 2 (25·9 g, 100 mmol) and 13.5 g of 1-Hydroxybenzotriazole anhydrous (HOBt) were dissolved in 400 ml of tetrahydrofuran (THF) at a temperature of 〇. 20.9 g of dicyclohexylcarbodiimide were added in portions. (Dicyclohexylcarbodiimide, DCC) and stirred at below 10 ° C overnight. The resulting reaction mixture was filtered, and the solid was filtered and collected to give a liquid A. 13.2 g (1 〇〇 mmol) of dimethyl malonate dissolved in dimethyl malonate In 800 ml of THF, then 7.2 g of sodium hydrogen hydride (70% oil dispersion) was added. The filtrate a was added under stirring, and reacted at room temperature for two hours. The THF was distilled off under reduced pressure, and 400 ml of decyl alcohol and 10% hydrochloric acid were added. The mixture was stirred overnight at room temperature of 400 ml. The solid formed was filtered and washed and dried with methanol 4 </ RTI> to give compound 3 (14 g). 13. g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g HC1 salt), 4.4 g sodium methoxide dispersed in 200 ml of sterol After stirring, the sterol was evaporated to dryness, and 200 mi of THF and 6.0 g of compound 3 were added, and the reaction was carried out at a temperature of 6 (TC) overnight. The THF was evaporated under reduced pressure, and the mixture was stirred for 2 hours by adding 400 ml of methanol. 4 5 g). Compound 4 (240 mg, 0.6 mmol), 85.4 mg (〇.7 mmol) phenyl boronic acid, MO mg (〇. 12 mm〇1) tetrakis(triphenylphosphine) (Pd(PPh3)4) Dissolved in 4 ml of dMF, 1 ml of 2N Na2C〇3, and reacted under nitrogen for 8 overnight at rc. After the reaction mixture was cooled to room temperature. (10) ml of water and ethyl acetate were added. (ethyl acetate) and mix. After separating and obtaining the organic layer and washing twice with water, the organic phase is quickly passed through the (four) column and then the solvent is removed. Then add 5 (f) 49 201225954 j /υο^ριι dichloromethane (DCM), 5 Methyl trifluoroacetic acid (CF3COOH) was stirred for 4 hours at room temperature. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from CH3OH-THF to give the title compound 6. </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; s, 1H), 9.55 (brs, lH), 8.05 (d, lH, J = 9.0 Hz), 7.85 (d, 1H, J = 9.0 Hz) ^7.83 ( t, 1H, J = 7.5 Hz) ' 7.82( Dd, 2H, J = 7.5, 7.5 Hz), 7.54 (dd, 2H, J = 7.5, 1.5 Hz), 7.46 (s, 1H), 4.14 (d, 2H, J = 6.0 Hz). Example 2 N-[(4-Hydroxy-2-oxo-7-(2-chloro-phenyl)-2H-3-chromenyl)carbonyl]

The preparation process was similar to that of Example 1, to give the title compound. LC-MS : [M-Η]· m/z 373 ; b-NMR ( 300 MHz, (CD3) 2SO) 5:13.05 (brs, 1H), 9.57 (brs, lH), 8.08 (d, lH, J =8.4 Hz), 7.66-7.32 (m, 6H), 4.15 (d, 2H, J = 6.0 Hz). Example 3 50 .201225954 j/u»ypit Synthesis of N-[(4-hydroxy-2-oxo-7-(3-gas-phenyl)-2H-3-chromenyl)carbonyl]glycine:

The preparation process was similar to that of Example 1, to give the title compound. LC-MS: [MH] m/z 373; NMR (300 MHz, (CD3)2SO) δ: 13.05 (br s,1H), 9.55 (brs,lH), 8.04 (d,lH,J=8.4 Hz), 7.92-7.81 (m, 4H), 7.59_7.55 (m, 2H), 4.14 (d, 2H, J = 6.0 Hz). Example 4

Synthesis of N-[(4-hydroxy-2-oxo-7-(4-a-phenyl)-2H-3-chromenyl)carbonyl]glycine: m

51 201225954

The preparation process was similar to that of Example 1, to give the title compound. LC-MS: [MH]'m/z373; NMR (300 MHz, (CD3)2SO) 3:9.55 (brs,lH), 8.05 (d,lH,J=8.4 Hz), 7.88 (d, 2H) , J = 8.7 Hz), 7.84 - 7.79 (m, 2H), 7.60 (d, 2H, J = 8.7 Hz), 4.14 (d, 2H, J = 6.0 Hz). Example 5 Synthesis of N-[(4-hydroxy-2-oxo-7-(3-trifluoromethyl-phenyl)-2H-3-chromenyl)carbonyl]glycine:

The preparation process was similar to that of Example 1, to give the title compound. LC-MS: [MH] m/z 406; NMR (300 MHz, (CD3) 2SO) δ: 9.58 (brs, 1H), 8.18 (s, lH), 8.16 (s, lH), 8.09 (d, lH, J=8.4 Hz), 7.97-7.76 (m, 4H), 4.15 (d, 2H, J=6.0

Hz) 实施 Example 6 ^ Synthesis of N-[(4-hydroxy-2-oxo-7-(4-trifluoromethylphenyl)-2H-3-chromenyl) benzyl]glycine: 52 201225954

The preparation process was similar to that of Example 1, to give the title compound. </ RTI> <RTI , 4.15 (d, 2H, J = 6.0 Hz). Example 7 Synthesis of N-[(4-hydroxy-2-oxo-7-(3-trifluoromethoxy-phenyl)-2H-3-chromenyl)carbonyl]glycine:

S 53 201225954

The preparation process was similar to that of Example 1, to give the title compound. LC-MS: [MH]'m/z422; ^-NMR (300 MHz, (CD3)2S 〇) δ: 9.57 (br s,1H), 8.08 (d,1H,J=8.1 Hz), 7.92-7.85 (m, 4H), 7.69 (t, lH), 7.50 (d, lH, J = 8.4 Hz), 4.15 (d, 2H, J = 6. Hz). Example 8 Synthesis of N_[(4-hydroxy-2-oxo-7-(4-trifluorodecyloxyphenyl)_2H-3-chromenyl)]glycine:

The preparation process was similar to that of Example 1, to give the title compound. LC-MS : [M-Η]* m/z 422 ; !H-NMR ( 300 MHz, (CD3)2SO ) δ : 9.56 (br s,1H), 8.09-7.81 (m,5H), 7.54 (d) , 2H, J = 8.4 Hz), 4.15 (d, 2H, J = 6.0 Hz). Example 9 Synthesis of N-[(4-hydroxy-2-oxo-7-(3,4-dichloro-phenyl)-2H-3-chromenyl)carbonyl]glycine: 54 201225954 j/voypu

The preparation process was similar to that of Example 1, to give the title compound. LC-MS: [MH] m/z 407; NMR (300 MHz, (CD3) 2SO) δ: 9.57 (brs, 1H), 8.15 (s, 1H), 8.05 (d, 1H, J = 8.1 Hz) 7.92-7.78 (m, 4H), 4.15 (d, 2H, J = 6.0 Hz). Example 10 Synthesis of N-[(4-hydroxy-2-oxo-7-(3,4-difluoro-phenyl)-211-3-chromenyl)carbonyl]glycine:

55 201225954 j /υο^ριι The preparation process was similar to that of Example 1, and the title compound was obtained. LC-MS : [M-Η]' m/z 374 ; ^-NMR (300 MHz, (CD3)2SO) δ: 9.55 (br s,1H), 8.07-7.98 (m,2H), 7.88-7.82 ( m, 2H), 7.66-7.59 (m, 2H), 4.14 (d, 2H, J = 6.0 Hz). Example 11 Synthesis of N-[(4-hydroxy-2-oxo-7-(3,4,5-trifluoro-phenyl)-2H-3-chromenyl)carbonyl]glycine:

The preparation process was similar to that of Example 1, to give the title compound. LC-MS : [M-Η]-m/z 392 ; NMR (300 MHz, (CD3) 2SO) δ: 9.55 (br s, 1 Η) ' 8.05 (d, 1H, J=8.4 Hz), 7.97 -7.85 (m, 4H), 4.14 (d, 2H, J = 6.0 Hz). Example 12 Synthesis of N-[(4-hydroxy-2-oxo-7-(3-decyloxy-phenyl).2Η-3-chromenyl)carbonyl]glycine: 56 201225954 j /υο^ριι

OH

The preparation process was similar to that of Example 1, to give the title compound. LC-MS: [MH]'m/z 368; NMR (300 MHz, (CD3) 2SO) δ: 9.55 (brs, 1H), 8.05 (d, 1H, J = 8.1 Hz), 7.86 (s, 1H), 7.83 (d, lH, J = 8.1 Hz), 7.49-7.38 (m, 3H), 7.06 (d, lH, J = 8.4 Hz), 4.15 (d, 2H, J = 6.0 Hz). Example 13 Synthesis of N-[(4-hydroxy-2-oxo-7-(4-decyloxy-phenyl)-2H-3-chromenyl)carbonyl]glycine:

57

201225954 0 W^VXX The preparation process was similar to that of Example 1, and the title compound was obtained. LC-MS: [MH]' m/z 368; ^-NMR (300 MHz, (CD3)2SO) δ: 9.56 (br s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.85-7.78 (m, 4H ) ' 7.09( d, 2H, J=9.0 Hz ) &gt; 4.14( d, 2H, J=6.0 Hz ) 〇 Example 14 N-[(4-hydroxy-2-oxo-7_(3) Synthesis of - mercapto-phenyl)-2H-3-chromenyl)carbonyl]glycine:

The preparation process was similar to that of Example 1, to give the title compound. LC-MS: [MH]'m/z 352; !H-NMR (300 MHz, (CD3)2SO) δ: 9.55 (br s,1H), 8.04 (d,1H,J=8.7 Hz), 7.80- 7.78 (m, 2H), 7.67-7.61 (m, 2H), 7.42 (t, lH, 7.8 Hz), 7.3 〇 (d, lH, J = 7.5 Hz), 4.14 (d, 2H, J = 6.0 Hz) , 2.50 (t, 3H, 1.8 Hz) ° Example 15 N_[(4-Hydroxy-2-oxo-7-(4-methyl-phenyl)-2H-3-chromenyl)carbonyl 58 201225954 J / V07U11 base] glycine synthesis:

The preparation process was similar to that of Example 1, to give the title compound. LC-MS : [M-Η]' m/z 352 ; ^-NMR ( 300 MHz, (CD3) 2SO) δ : 9.56 (br s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.79 -7.73 (m, 4H), 7.34 (d, 2H, J = 8.4 Hz), 4.13 (d, 2H, J = 6.0 Hz), 2.50 (t, 3H, 1.8 Hz). Example 16 Synthesis of N-[(4-hydroxy-2-oxo-8-phenyl-2H-3-chromoyl)carbonyl]glycine: 59 201225954 j f\j〇ypu.

The preparation was similar to that of Example 1. 27 g of the reactant 7 was first dissolved in 130 mL of acetic anhydride (Ac 2 〇) and added to 1 mL of h3p〇4, and the reaction was kept at a temperature of 50 C. After the reaction was completed, 'cooled to room temperature', 5 ml of water was added to stir, and the hydrolysis was completed at a temperature of 50 °C. The reaction mixture was cooled to EtOAc to give a solid crystals. 13 g of compound 8 and 6.8 g of HOBt were dissolved in 200 mL of THF, and 10.4 g of DCC was added in portions at a temperature below 0 ° C and spoiled overnight at 1 Torr. The resulting reaction mixture was filtered to remove the solid and the filtrate was collected to give filtrate B. 6.6 g (100 mmol) of dinonyl malonate was dissolved in 400 mi of THF, then 3.8 g of sodium hydride (70% dispersion in oil) was added, and the above filtrate B was added thereto with stirring, and reacted at room temperature for two hours. The THF was distilled off under reduced pressure. To a solution of methanol 2 〇〇 ml~, 201225954 j / υ «νριι 10% hydrochloric acid 200 ml, stirred at room temperature overnight. The formed solid was filtered and washed with 200 ml of decyl alcohol and dried to give compound 9 (6 g). 13.5 g of glycine tert-butyl ester hydrochloride, 4.4 g of sodium sterol was dispersed in 200 mL of methanol, and the mixture was uniformly stirred, and the methanol was evaporated to dryness. 200 ml of THF and 6.0 g of compound 9 were added, and the reaction was carried out at 60 ° C overnight. The THF was evaporated to dryness under reduced pressure, and then stirred for 400 hr. 240 mg (0.6 mmol) of compound 1 〇, 85.4 mg (0.7 mmol) of phenylboronic acid, 140 mg (0.12 mmol) (Pd(PPh3)4 ) dissolved in 4 ml of DMF, _lml 2N NaaCO3' under nitrogen protection at temperature 8〇. His knees reacted overnight. After the reaction was completed, the reaction mixture was cooled to room temperature. Add 100 mL of water and 100 mL of ethyl acetate and stir. After separating the organic layer and washing twice with water, the organic phase was quickly passed through a silica gel column and the solvent was removed. Further, 5 mL of DCM and 5 ml of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was depressurized under reduced pressure. The obtained product was further purified using ΓΉιΟΗ-ΊΓΤΓΡ έ crystals to give the title compound 12HMS: m/Z; ^-NMR (300 MHz, (CD3)2S 〇) δ: 9.51 (br s, 1H) ^ 8.03 s , 1H, J: 8.1, 15 Hz), 7 86 Ud, 2H, J = 7.5, 1.5 Hz), 7.65-7.45 (m, 6H). Example 17 N_[(4_基基氧氧-8&lt;2_气_笨基) 2h3色稀基) 叛基] Synthesis of glycine· 61 201225954 〇/uo^pu

The preparation process was similar to that of Example 16 to give the title compound. LC-MS : [M-Η]' m/z 373 ; ^-NMR (300 MHz, (CD3) 2SO ) δ : 9.47 ( br s, 1H), 8.10 ( m, 1H), 7_77 (m, 1H) , 7.67-7.50 (m, 5H), 4.14 (d, 2H, J = 6.0 Hz). Example 18 Synthesis of N-[(4-hydroxy-2-oxo-8-(3-gas-phenyl)-2H-3-chromenyl)carbonyl]glycine: m

Νν

201225954 j /υο^ριι The preparation process was similar to that of Example 16 to give the title compound. LC-MS: [MH]'m/z 373; NMR (300 MHz, (CD3)2SO) δ: 9.51 (br s,1H), 8.06 (dd, 1H, J=8.1, 1.5 Hz), 7.89 (m, lH), 7.73 (s, lH), 7.61-7.54 (m, 4H), 4.15 (d, 2H, J = 6.0 Hz). Example 19 Synthesis of N-[(4-hydroxy-2-oxo-8-(4-chloro-phenyl)-2H-3-chromenyl)carbonyl]glycine:

The preparation process was similar to that of Example 16 to give the title compound. LC-MS: [MH]'m/z 373; NMR (300 MHz, (CD3)2SO) δ: 9.49 (br s, 1H), 8·04 (dd, 1H, J=8.1, 1.5 Hz) , 7.86 (m, lH), 7.69-7.53 (m, 5H), 4.15 (d, 2H, J = 6.0 Hz). Example 20 N-[(4-Hydroxy-2-oxo-8-(3-trifluorodecyl-phenyl)-2H-3-chromenyl) 63

201225954 J / U1X carbonyl] glycine synthesis:

OH

The preparation process was similar to that of Example 16 to give the title compound. LC-MS: [MH]-m/z 406; NMR (300 MHz, (CD3) 2SO) δ: 9.52 (br s,1H), 8.09-7.76 (m,6H), 7.58 (t,lH, 7.8 Hz), 4.15 (d, 2H, J = 6.0 Hz). Example 21 N-[(4-Hydroxy-2-oxo-8-(4-trifluoromethyl-phenyl)-2H-3-chromenyl)

64 .3 201225954 J /Uftypu The preparation process was similar to that of Example 16 to give the title compound. LC-MS: [Μ-Η]Ίη/ζ406; 'H-NMR (300 MHz, (CD3)2S〇) 5:9.5〇 (brs, 1H), 8.09 (dd, lH, 7.8, 1.5 Hz), 7 93-7.86 (m, 5H), 7.59 (t, lH, 7.8 Hz), 4.15 (d, 2H, J = 6. 〇 Hz). Example 22 Synthesis of N-[(4-carbo-2-oxo-8-(3-difluoromethoxy-phenyl)-2H-3-chromoyl)carbonyl]glycine:

The preparation process was similar to that of Example 16 to give the title compound. LC-MS: [MH]'m/z422; NMR (300 MHz, (CD3)2SO) δ: 9.52 (brs, 1H) ' 8.07 (dd, 1H, 7.8, 1.5 Hz) '7.91(dd, 1H , 7.5, 1.5 Hz), 7.7 〇 - 7.68 (m, 3H), 7.57 (t, 1H, 7.8 Hz), 7.49 (brs, 1H), 4.15 (d, 2H, J = 6_0 Hz). Example 23 Synthesis of N-[(4-hydroxy-2-oxo-8-(4-trifluoromethoxy-phenyl)-2H-3-chromenyl)carbonyl]glycine: 65 201225954 j /υο ^ριι

The preparation process was similar to that of Example 16 to give the title compound. LC-MS: [MH]'m/z422; NMR (300 MHz, (CD3) 2SO) S: 9.50 (brs, lH), 8.06 (dd, lH, 8.1, 1.5 Hz), 7.89 (m, 1H) ), 7.78 (d, 2H, J = 8.7 Hz), 7.60-7.54 (m, 3H), 4.15 (d, 2H, J = 6.0 Hz). Example 24

Synthesis of 1^-[(4-carbo-2-oxo-8-(3,4-dichloro-phenyl)-211-3-chromo)]yl]glycine:

201225954 J / VU7U11. The preparation process was similar to that of Example 16 to give the title compound. LC-MS: [MH]'m/z407; NMR (300 MHz, (CD3)2SO) δ: 9.51 (brs, 1H) ' 8.06 (dd, 1H, 8.1, 1.5 Hz) '7.95-7.89 (m ,2H) ' 7.82 (d, 1H, J=8.4Hz) ' 7.65 (dd, 1H, J=8.4, 1·5Ηζ), 7.56 ( t,lH, J=7.5 Hz), 4.15( d,2H,J =6.0 Hz). Example 25 Synthesis of N-[(4-hydroxy-2-deutero-8-(3,4-diphenyl)-2H-3-chromenyl)carbonyl]glycine:

The preparation process was similar to that of Example 16 to give the title compound. LC-MS: [MH]* m/z 374; ^-NMR (300 MHz, (CD3)2SO) 6:9.51 (brs, 1H) '7.88 (dd, 1H, J=7.5, 1.2 Hz) '7.82- 7.75 (m, 2H), 7.68-7.53 (m, 3H), 4.15 (d, 2H, J = 6.0 Hz). Example 26 N-[(4-Hydroxy-2-oxo-8-(3,4,5-trifluoro-phenyl)-2H-3-chromenyl) 67 201225954 J / νο^μχχ carbonyl]glycine Synthesis:

The preparation process was similar to that of Example 16 to give the title compound. LC-MS: [MH]'m/z 399; NMR (300 MHz, (CD3)2SO) 6:9.51 (brs, 1H) '8.07 (dd, 1H, J=7.8, 1.5 Hz) '8.01- 7.97 (m, 1H), 7.92 - 7.89 (m, lH), 7.71-7.66 (m, lH), 7.63 (t, 1H, J = 7.8 Hz), 4.15 (d, 2H, J = 6.0 Hz). Example 27 Synthesis of N-[(4-hydroxy-2-oxo-8-(3-decyloxy-phenyl)-2H-3-chromenyl)carbonyl]glycine: 68

The preparation process was similar to that of Example 16 to give the title compound. LC-MS : [M-Η]' m/z 368 ; JH-NMR ( 300 MHz, (CD3) 2SO) δ : 9.52 (br s, 1H) ' 8.07 (dd, 1H, J=7.8, 1.5 Hz) , 7.87 (dd, 1H, J=7.8, 1.5 Hz) ' 7.55 (t, 1H, J=7.8 Hz), 7.45 (t, 1H, J=7.8 Hz), 7.20-7.18( m,2H), 7.06- 7.03 ( m, 1H), 4.15 (d, 2H, J = 6.0 Hz). Example 28

Synthesis of N-[(4-hydroxy-2-oxo-8-(4-decyloxy-phenyl)-2H-3-chromenyl)carbonyl]glycine:

69 201225954 J t WO^pil The preparation process was similar to that of Example 16 to give the title compound. LC-MS: [MH]'m/z 368; ^-NMR (300 MHz, (CD3)2SO) δ: 9.51 (br s, 1H), 7.98 (d, 1H, J=7_8 Hz), 7.83-7.80 (m, lH), 7.59-7.50 (m, 3H), 7.09 (d, 2H, J = 8.7 Hz), 4.15 (d, 2H, J = 6.0 Hz). Example 29 Synthesis of N-[(4-hydroxy-2-oxo-8-(3-indolyl-phenyl)-2H-3-chromenyl)carbonyl]glycine:

The preparation process was similar to that of Example 16 to give the title compound. LC-MS : [M-Η]' m/z 352 ; ^-NMR (300 MHz, (CD3) 2SO) 5:9.52 (brs, 1H) '8.03 (dd, 1H, J=7.8, 1.5 Hz) ' 7.84-7.82 (m, 1H), 7.57-7.52 (m, lH), 7.43-7.42 (m, 3H), 7.29 (br s, 1H), 4.14 (d, 2H, J = 6.0 Hz), 2.51 (t , 3H, J = 1.8 Hz). Example 30 201225954 Synthesis of N-[(4-hydroxy-2-oxo-8-(4-indolyl-phenyl)-2H-3-chromenyl)carbonyl]glycine: oh

The preparation process was similar to that of Example 16 to give the title compound. LC-MS: [MH]' m/z 352; NMR (300 MHz, (CD3) 2SO) δ: 9.53 (br s,1H), 8.02-7.99 (m,1H), 7.84-7.82 (m, 1H), 7.57-7.51 (m, 3H), 7.36-7.33 (m, 2H), 4.14 (d, 2H, J = 6.0 Hz), 2.51 (t, 3H, J = 1.8 Hz).

Example 31 Synthesis of N-[(4-hydroxy-2-oxo-7-(6-decyloxypyridin-3-yl)-2H-3-chromenyl)carbonyl]glycine:

S 201225954 J / V/07U11 The preparation process was similar to that of Example 1, and the title compound was obtained. LC-MS : [M-Η]' m/z 369 ; ^-NMR (300 MHz, (CD3) 2SO) 5: 9.54 (brs, lH), 8.69 (d, lH, J = 1.8 Hz), 8.21 ( dd, lH, J = 8.7, 1.8 Hz), 8.023 (d, 1H, 8.1 Hz), 7.85-7.80 (m, 2H), 6.98 (d, 1H, 8.7 Hz), 4.14 (d, 2H, J =6.0 Hz), 2.51 (m, 3H). Example 32 Synthesis of N-[(4-hydroxy-2-oxo-7-(4-indolyl)-2H-3-chromenyl)carbonyl]glycine:

The preparation process was similar to that of Example 1, to give the title compound. LC-MS: [M-H]· m/z 339. Example 33 Synthesis of N-[(4-hydroxy-2-oxo-7-(4-oxaridinyl)-2H-3-chromenyl)carbonyl]glycine: 72 201225954 J / UO^Uli

OH

The preparation process was similar to that of Example 1, to give the title compound. LC-MS: [MH]'m/z 339; !H-NMR (300 MHz, (CD3)2SO) 3:9.55 (brs,lH), 9.12 (s, 1H), 8.73 (s,lH),8 · 38 (d, 1H, J = 8.1 Hz), 8.11 (d, 1H, J = 8.4 Hz), 7.97 (s, 1H), 7.90 (d, lH, J = 8.4 Hz), 7.69-7.65 (m, lH), 4.16 (d, 2H, J = 6.0 Hz). Example 34 Synthesis of N-[(4-hydroxy-2-oxo-7-phenoxy-2h_3_chromenyl)carbonyl]glycine:

The preparation process of the title compound was obtained in a similar manner to Example 1, 73 a 201225954 LC-MS: [MH] m/z 354; 'H-NMR (300 MHz, (CD3)2S〇) δ: 9.47 (brs, 1H) ^ 8.99 ( d, 1H, 8.7 Hz) &gt; 7.55-7.49 ( m, 2H), 7.33 (t, 1H, J = 7.5 Hz), 7.24 - 7.21 (m, 2H), 7.05 - 7.01 (m, 1H) , 6.96 (d, 1H, J = 2.4 Hz), 4.12 (d, 2H, J = 6. 〇 Hz). Example 35 Combination of N-[(4-hydroxy-2-oxo-7-bromo-3-chromenyl)carbonyl]glycine

The preparation process was similar to the intermediate product 4 of Example 1, and then the title compound was obtained after deprotection of the tert-butyl group on the carboxyl group by a similar route. LC-MS: [M-Η]- m/z 341; ^-NMRX 300 MHz, (CD3)2SO) δ: 9.53 (brs, 1H) ' 7.93-7.86 ( (m, 2H) ' 7.68-7.65 ( m , 1H), 4.14 (m, 2H). Example 36 Synthesis of N-[(4-hydroxy-2-oxo-8-bromo-3-chromenyl)carbonyl]glycine:

The preparation process was similar to the intermediate product 10 of Example 16, and then the title compound was obtained after deprotection of the tert-butyl group on the carboxyl group by a similar route. LC-MS: [Μ-ΗΓ m/z 341; ^-NMRX 300 MHz, (CD3) 2SO) 74 201225954 j/υο^ρπ 6:9.51 (brs,lH), 8.12 (d,lH,J=7.8 Hz ), 8.00 ( d, lH, J = 7.8 Hz), 7.40 (t, 1H, J = 7.8 Hz), 4.15 (d, 2H, J = 6.0 Hz). Example 37 Synthesis of N-[(4-hydroxy-2-oxo-6-bromo-3-chromenyl)carbonyl]glycine: 〇

The preparation process was similar to that of Example 36 to give the title compound. LC-MS: [MH] m/z 341;]H-NMR (300 MHz, (CD3)2SO) δ: 9.56 (br s,1H), 8.07 (d, 1H, J=2.4 Hz), 7.99 (dd, 1H, J=9.0, 2.4Hz), 7.49 (d, lH, J=9.0 Hz), 4.14 (d, 2H, J=6.0)

Hz). Example 38: Synthesis of Ν·[(4-carbo-2-oxo-8-(3-trifluorodecylphenyl)_2h_3-chromenyl)carbonyl]alanine: 75 201225954

♦

OH

The preparation procedure was similar to that of Example 20 except that one of the steps was not the use of glycine tert-butyl ester hydrochloride but the title compound of the title obtained by the alanine tert-butyl salt. LC-MS : [MH]- m/z 420 ; !Η-ΝΜΚ ( 300 MHz, (CD3) 2SO ) δ : 9.59 ( br s, 1H) &gt; 8.09-8.03 (m, 2H), 7.95 ( dd, 2H, J=7.5, 1.5 Hz), 7.86-7.76 (m, 2H), 7.59 (t, 1H, 7.5 Hz), 4.57 (m, 1H), 1.48 (d, 1H, J = 7.2 Hz). Effect test HIF-PHD2 enzyme activity test HIF-PHD2 activity is determined by using a homogeneous time-resolved fluorescence resonance energy transfer (homogeneous TR-FRET) technique, see also US Patent US 2008/004817 or the literature Dao J Η et al, Anal Biochem. 2009, 384: 213-23. To each well of a half-zone 96-well microtiter plate: 2 μΐ^ test compound in DMSO solution; and 40 μιη test buffer solution containing 600 nM full-length PHD2 (50 mM Tris pH 7.4/0.01% Tween - 20 (Tween-20)/0.1 mg/ml BSA/1 mM sodium ascorbate/20 pg/ml over 76 201225954

J /VO!/piI

Catalase (Catalase) /10 μΜ FeS04). After pre-incubation for 30 minutes at room temperature, add 8 μ!^ substrate (〇.2 μΜ 2-oxoglutarate and 0.5 μΜ HIF-la biotin-binding peptide-DLDLEMLAPYIPMDDDFQL (HIF-la peptide) The final concentration of biotinyl-DLDLEMLAPYIPMDDDFQL) initiates an enzymatic reaction. After reacting for 2 hours at room temperature, the reaction was terminated by adding 50 μιη quencher-detector mixture, so that the final reaction solution contained 1 mM ortho-phenanthroline, 0.1 mM EDTA, 0.5 nM anti-(His 6LANCE (anti-(His)6LANCE) reagent, 100nMAF647-labeled streptavidin and 30 nM (His)6-VHL-extension protein B-extension protein C ((His)6-VHL-elonginB -elonginC) complex. The relative fluorescence ratio of the time-resolved fluorescence signal at 665 nm and 620 nm was measured, and then the percent inhibition was calculated by comparison with the non-inhibited control sample in the parallel test. The IC50 values of the compounds prepared in Examples 1-38 of the present invention in the HIF-PHD2 enzyme activity assay are shown in Table 1 below. Table 1 Compound Enzyme Test IC50 (nM) Example 1 250 Example 2 150 Example 3 150 Example 4 150 Example 5 150 77 201225954 J /UO^pil Example 6 150 Example 7 150 Example 8 150 Example 9 150 Example 10 150 Example 11 150 Example 12 150 Example 13 150 Example 14 300 Example 15 150 Example 16 350 Example 17 200 Example 18 90 Example 19 150 Example 20 100 Example 21 90 Example 22 100 Example 23 150 Example 24 30 Example 25 150 Example 26 150 Example 27 150 Table 1 continued Table 78 201225954 / WO^Ull Compound ~----- Enzyme Test (nM) Example 28 - --- 80 Embodiment 29 ----- 150 Embodiment 3 0 80 Embodiment 31 Embodiment 32 - Embodiment 33 200 Embodiment 34 150 Embodiment 35 150 Embodiment 36 300 Example 37 One----- 700 Example 38 _ = Table 1 shows the shell material visible. 'The examples shown have the inhibitory activity against the coffee, and the smaller the IC5G value, the activity to PHD2 =

The better: inhibition of PHD2 results in a series of downstream physiological signals: m, to prepare a drug for treating the disease of the present day. Detection of the production of Erythr〇p〇ietin (EPO) in normal mice. Male C57BL/6 mice at 8 weeks old were dosed at 20 mg/kg, 6 mg/kg and 100 mg/kg. Test compounds orally. Among the compounds, the compounds prepared in Example 16, Example 20, Example 22 and Example 29 were used. Six hours after administration, blood was taken from the orbital vein and serum was collected (see Robinson A, et al., Gastroenterology. 2008, 79 201225954 J/uoypu 134: 145-55; HsiehMM, et al., Blood. 2007, ll〇: 2l4〇 _7). The EPO content of the samples was analyzed by electrochemiluminescence-based immunoassay (MSD) according to the manufacturer's instructions. The test results are shown in Figure 。. The results of the knife-w round armor test showed that the compounds prepared in Example 16, Example 20, Example 22 and Example 29 of the present invention achieved the desired induction of EPO production in vivo by inhibition of PHD2. The formation of Ep〇 can directly lead to the synthesis of hemoglobin in the body and the production of red blood cells, which is an important characterization of the application of the compounds of the present invention in various diseases of Yang Lai. ~ Hematology test in normal mice Male C57BL/6 mice, 8 weeks old, were administered once a day at a dose of 6 mg/kg π. The compounds used were blank and the compounds prepared in Examples 16 and 29, and blood was taken from the orbital veins at i days, 3 days, and 5 days after administration. Automated blood analyzer MEK-6318K (Automated Hematology Analyzer MEK 6318K) was used to detect various blood parameters, such as erythrocyte counts (RBC), hemoglobin han (hem 〇 〇 〇 咖 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (hematocrit value, HCT) and the like. The test results are shown in Figures 2 and 3. The results of the tests shown in Fig. 2 and Fig. 3 indicate that the compound provided in the present invention (4) is capable of increasing RBC and HGB in the living body, and thus it is understood that the compound of the present invention has an effect of increasing the number of red blood cells and the concentration of hemoglobin in the living body. Pharmacokinetic Study 201225954 ό/usypn A single oral dose of 50 mg/kg of test compound solution was administered to fasted male CD (SD) IGS rats (η=6/group). The compounds used were the compounds prepared in Examples 16, 20, 22 and 29. Plasma samples were taken from the orbital veins of each rat at 15 minutes, 3 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, and μ hours, respectively. The plasma concentration of the test compound in the plasma sample was measured by HPLC. As shown in Figure 4. ,

The above examples show the activity of the enzyme level, and the weathering in mice, . The superior properties of the compound, and the future; to prepare the drug for the treatment of the corresponding indications for the present invention = 士述实关 is only to fully explain the present invention: the scope of protection of the invention is patented] Implementation. This does not deviate from the essence of the present invention. The basic one = nor = open two ===; step map 'and public characteristics, including abstracts and drawings, ^ is ^ disclosed by the present invention Alternative features for each similar purpose are replaced by the same, equivalent or unless otherwise specified by the invention: two = two 81 201225954 having equivalent or her characteristics (four) material, _ - specific in this article = for the description, for this It will be apparent to those skilled in the art that the various aspects of the present invention based on the teachings of the present invention may be apparent. This secret should also fall within the scope of the handle. The parent references cited in this article should be referenced in their entirety. While the invention has been described above by way of example, it is not intended to limit the invention, and the invention may be modified and modified without departing from the spirit and scope of the invention. Therefore, the scope of the invention is defined by the scope of the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the effect of the compounds of the examples shown on EPO levels in mice after 4 hours of administration of different compounds. Figure 2 shows the effect of the example compound on red bi^d cell counts (RBC) in mice on day 9 after daily doses of 6 mg/kg for 7 consecutive days. Figure 3 shows the effect of the example compound on hemoglobin (HGB) in mice on day 9 after a daily dose of 6 mg/kg for 7 consecutive days. Figure 4 shows the pharmacokinetic profile of the compounds of the examples shown in rats after a single oral dose of 5 mg/kg. [Main component symbol description] Benefit #&gt;*% 82

Claims (1)

201225954 jwueypir VII. Patent application scope: 1. A compound of formula (I), wherein Rs η is selected from any integer from 1 to 6; R! is selected from OH, SH, NR3R4, NHC(0)R2, NHS02R2 and sulfonyl; R2 is selected from hydrazine, lower alkyl or lower alkyl containing a substituent; And R4 are each independently selected from the group consisting of hydrazine, lower alkyl, lower alkyl containing a substituent, lower il alkyl or a lower alkyl group containing a substituent, or Rs and R4 are joined to form a 3 to 6 membered ring. Or a 3- to 6-membered ring containing a substituent; Rs is selected from the group consisting of OH, SH, NH2, a lower alkyl group, a lower alkyl group having a substituent, a lower alkoxy group, a lower alkoxy group having a substituent or a sulfanyl group; R6, K and R9 are each independently selected from H, alkyl, substituted=alkyl, anthracene, substituted alkenyl, block, fi(4), C(〇)〇H, 〇Rl2 , SRl2, S〇2Rl2, CN, n〇2, n-fragrant 35-based, substituted aromatic hydrocarbon group, heterocyclic aromatic hydrocarbon A, 3-dihydro-aromatic hydrocarbon group, aromatic hydrocarbon-based silk di-aromatic alkyl group, Heterocyclic aromatic cigarettes of the tetra-substituent group, the chitosan-based group, and the anthracene-substituted heterocyclic aromatic tobacco 83 201225954 j/ueypii ίϊίμ heterocyclic filament, substituted heterocyclic filament, silk county, containing ς, silk shout, alkenyl silk, dilute base wire containing substituent, block two stone, silk 7 base of ^ substituent, oxy group, substituted oxygenated earth, calcined base wire, containing wire丝基麟 or ·x_Rii ; or adjacent hearts and r6, 仏 and R7, 仏 and R8, or at least - pairs of 仏 and r9 are joined to form a 4- to 7-membered ring or a substituent-containing a 4- to 7-membered ring; X is selected from -N(Rio)-Y- or -YN(R10)_; Y is selected from C(O), S〇2, alkenyl, substituted alkenyl, alkynyl or a substituent-containing alkynyl group; Rio is selected from the group consisting of an anthracene, a lower alkyl group or a lower alkyl group containing a substituent; a core 1 is selected from the group consisting of an anthracene, a heterocycloalkyl group, a heterocyclic alkyl group having a substituent, an aromatic hydrocarbon group, and a substituent. An aromatic hydrocarbon group, a heterocyclic aromatic hydrocarbon group or a heterocyclic aromatic hydrocarbon group having a substituent; and a core 2 selected from the group consisting of an anthracene, an alkyl group, a substituent-containing alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, and a substituent Alkynyl or NR3R4; or a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex thereof, or prodrug thereof. 2. The compound of claim 1, wherein the heart is selected from OH or SH. 3. The compound of claim 1 or 2, wherein the heart is selected from the group consisting of hydrazine or lower alkyl. 4. The compound as described in any one of claims 1 to 3 wherein 'R3 and the core are each independently selected from the group consisting of hydrazine, lower alkyl or lower 84 201225954 ό /u»ypit halogenated alkyl. 5. The compound 'wherein' and the &lt;&apos;&gt; are joined to form a 3 to 6 membered ring or a substituted 3 to 6 membered ring, as described in any one of claims 1 to 3. 6. The compound of claim 5, wherein the 3 to 6 membered ring or the substituted 3 to 6 membered ring contains at least one or at least two heteroatoms. The compound according to any one of claims 1 to 6, wherein the 'R5 is selected from the group consisting of hydrazine H, SH, NH2, or a lower alkoxy group. 8. The compound according to any one of claims 1 to 7 wherein at least one pair of adjacent R6 and r7, r7 and r8, or at least one of R8 and R_9 are joined together to form 4 to 7 A ring or a 4- to 7-membered ring containing a substituent. 9. The compound of claim 8, wherein the 4 to 7 membered ring or the 4 to 7 membered ring containing the substituent contains at least one to three hetero atoms. Φ 10. The compound according to any one of the preceding claims, wherein at least one of 'I, R_7, r8 and r9 is independently selected from halogen or a group substituted by at least one halogen. group. 11. The compound according to any one of the preceding claims, wherein at least one of R6, R?, r8 and r9 is independently selected from alkoxy or alkoxy group containing a substituent. . 12. The compound according to any one of the preceding claims, wherein at least one of R6, I, Han 8 and r9 is independently selected from the group consisting of alkane 85 201225954 3/u»ypn a filament, a county silk or a substituent-containing block, wherein at least one of the compounds Li R?, R8 and R9 according to any one of items 1 to 7 of the invention is independently selected from the group consisting of aryl, bis: The aromatic hydrocarbon group or heterocyclic aromatic hydrocarbon group of the substituent contains a substituted heterocyclic aromatic hydrocarbon group, a heterocyclic group, and a heterocyclic group having a substituent. In the case of soil, 1 at least one of the formulas &lt;&amp;&gt;&gt;&gt;, and the ruler 9 of any one of the claims 1 to 7 is independently selected from the group consisting of H, pit base, Kunji, and substituted The group of the base group, the block group or 15. The compound of any one of R8 and R9, independently selected from the group consisting of the substituent-containing aromatic hydrocarbon group and the substituent-containing group. Heterocyclic aromatic hydrocarbon group. The compound of any one of the preceding claims, wherein at least one of the 'R8^R9' is independently selected from the group consisting of a phenyl group or a substituent having a substituent. 17. The compound according to any one of claims 1 to 14, wherein at least one of R8 and R9 is a meta or para position by a halogen, a thiol group, a halogenated alkyl group, an alkoxy group. A phenyl or acridine group substituted with an alkoxy group. 18. The compound of claim 1, wherein the compound &amp; matter is at least one compound of formula (II), 86 201225954 3/u»ypit OH zy^^21 R22 structural formula (II) or a pharmaceutically acceptable salt thereof, wherein R21 is selected from the group consisting of hydrazine, _, lower alkyl, lower alkyl, lower alkoxy or lower haloalkoxy; 22 R is selected from the group consisting of ruthenium, decano, lower alkyl, lower alkyl, lower oxygen Or a lower ii oxime; Z1 is selected from N or CR23; and 23 R is selected from the group consisting of hydrazine, _ s, lower alkyl, lower haloalkyl, lower alkoxy or lower halooxy; At least one of R22 and R23 is selected from the group consisting of halogen, lower alkyl, lower alkyl, lower alkoxy or lower ii alkoxy. 19. The compound as described in claim 18, wherein ζι is CR23. The compound according to the invention, wherein R and R are each independently selected from the group consisting of hydrazine, hydrazine, fluorenyl, ethyl, trifluoromethyl, decyloxy, ethoxy. Base or trifluoromethoxy group. 21. The compound according to claim a or the above, wherein Z 疋 CR , R is selected from the group consisting of jj, ci, f, methyl, ethyl, trimethyl, methoxy, ethoxy. Or trioxomethoxy. The compound of claim 18, wherein one of Z 疋 CR ' R, R 22 and r 23 is selected from the group consisting of halogen, lower alkyl, lower haloalkyl, lower alkoxy or lower. The alkoxy group, the other two of R21, R22 and R23 are oxime. 23. The compound of claim 18, wherein one of Ζ疋CR 'R 1 and R23 is selected from the group consisting of halogen, lower alkyl, lower haloalkyl, lower alkoxy or lower alkaloid The other one of the oxy groups, R21 and R23, is H. 24. The compound of claim 23, wherein R22 is hydrazine. The compound of claim 18, wherein Ζ1 is CR23', and two of R21, R22 and R23 are each independently selected from the group consisting of halogen, lower succinyl, and lower dentate alkyl, The lower alkoxy group or the lower alkoxy group, and the other one of R21, R22 and R23 is H. 26. The compound of claim 25, wherein R22 is H. 27. The compound of claim 18, wherein Z1 is CR23, and R21, 尺22 and R23 are each independently selected from the group consisting of halogen, lower alkyl, lower i-alkyl, lower alkoxy. Or a lower alkoxy group. The compound of claim 18 or 19, wherein Z1 is one of N'R21 and R22 is selected from the group consisting of halogen, lower alkyl, lower halogen alkyl, lower alkoxy or lower haloalkoxy The other one of R2i and R22 is Η. 29. The compound of claim 18 or 19, wherein 88 201225954 j/U6ypir Z1 is N, and R21 and R22 are each independently selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy or Lower haloalkoxy. The compound of claim 18, wherein the compound is at least one compound of the formula (Ila), Or a pharmaceutically acceptable salt thereof, wherein R21 is selected from the group consisting of hydrazine, halogen, lower leuco, lower halogen alkyl, lower alkoxy or lower haloalkoxy; and R22 is selected from hydrazine, _ a lower alkyl group, a lower haloalkyl group, a lower alkoxy group or a lower alkoxy group; wherein at least one of 'R and R22 is selected from the group consisting of halogen, lower alkyl, lower alkyl, lower alkoxy or Lower dentate alkoxy. 31. The compound of claim 30, wherein R2i is Η' R22 is selected from the group consisting of a functional element, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group or a lower alkoxy group. 32. The compound of claim 30, wherein R2i is deuterium and R22 is selected from lower alkyl or lower haloalkyl. 33. The compound of claim 30, wherein R2! is hydrazine and R22 is selected from Cw alkyl or Cw haloalkyl. 89 201225954 j/usypn 34. The compound of claim 33, wherein R22 is selected from the group consisting of methyl, ethyl or q-dentylalkyl. 35. The compound of claim 30, wherein R22 is Η' R21 is selected from the group consisting of halogen, lower alkyl, lower haloalkyl, lower alkoxy or lower alkoxy. 36. The compound of claim 30, wherein R22 is Η' R21 is selected from the group consisting of lower alkyl or lower haloalkyl. 37. The compound of claim 36, wherein R21 is selected from the group consisting of methyl, ethyl or hydrazine! The letter is based on burning. 38. The compound of claim 30, wherein R21 and R22 are each independently selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy or lower alkoxy. 39. The compound of claim 30, wherein R21 and R22 are each independently selected from a C02 alkyl group or a Cm haloalkyl group. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is at least one compound of the formula (III), Or a pharmaceutically acceptable salt thereof, wherein: R24 is selected from the group consisting of hydrazine, arginine, lower alkyl, lower alkyl, lower 201225954 jt\j〇yyu alkoxy or lower alkoxy; R25 is selected from Η, i|, a lower alkyl group, a lower halogenated alkyl group, a lower alkoxy group or a lower halogenated alkoxy group; Z2 is selected from N or CR26; and R26 is selected from the group consisting of ruthenium, _ s, lower alkyl, lower halogen alkyl, Lower alkoxy or lower il alkoxy; wherein at least one of 'R24, R25 and R26 is selected from halogen, lower alkyl, lower alkyl, lower alkoxy or lower il alkoxy. 41. The compound of claim 40, wherein Z2 is CR26. 42. The compound of claim 40, wherein R24 and R25 are each independently selected from the group consisting of H, a, F, decyl, ethyl, trifluoromethyl, decyloxy, ethoxy. Or three It oxime. 43. The compound of any one of claims 4 to 42 wherein 'Z2 is CR26 and r26 is selected from the group consisting of η, a, F, thiol, ethyl, trifluoromethyl, oxime Base, ethoxy or trifluoromethoxy group. The compound according to any one of claims 40 to 42, wherein Z2 is CR26, and one of R24, R25 and R26 is selected from the group consisting of halogen, lower alkyl, lower alkyl, lower alkane Oxy or lower alkoxy, the other two of R24, R25 and R26 are H. 45. The compound of any one of claims 40 to 42 wherein 'Z2 is CR26, one of R24 and R26 is selected from the group consisting of a nutrient, a lower alkyl group, a lower il generation wire, and a lower alkoxy group. Or lower calcined oxy group, the other one of R24 and R26 is H. 91 201225954 J AV; 〇ypil 46. The compound of claim 45, wherein R25 is hydrazine. 47. The compound of any one of claims 40 to 42 wherein Ζ2 is CR26, two of R24, R25 and R26 are each independently selected from the group consisting of halogen, lower alkyl, lower alkyl The other of the radicals, lower alkoxy or lower halogenated alkoxy groups 'R24, R25 and R26 is hydrazine. 48. The compound of claim 47, wherein R25 is hydrazine. 49. The compound of any one of claims 40 to 42 wherein ''2' is CR26, and R24, R25 and R26 are each independently selected from the group consisting of halogen, lower alkyl, lower alkyl, lower alkane Oxy or lower alkoxy. The compound according to any one of claims 40 to 49, wherein Ζ2 is one of Ν' R24 and R25 is selected from the group consisting of halogen, lower alkyl, lower alkyl, lower alkoxy Or a lower alkoxy group, the other of R24 and R25 is hydrazine. 51. The compound of any one of claims 40 to 49, wherein Ζ2 is hydrazine, and R24 and R25 are each independently selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy or lower Alkoxy group. 52. The compound of claim 4, wherein the compound is at least one compound of the formula (Ilia), 92 201225954 3/u»ypit Or a pharmaceutically acceptable salt thereof, wherein R24 is selected from the group consisting of hydrazine, _ s, lower alkyl, lower haloalkyl, lower decyloxy or lower | | substituted alkyl; and R 25 is selected from hydrazine a dentate, a lower alkyl, a lower halogenated alkoxy, a lower alkoxy or a lower ii alkoxy; wherein 'at least one R24 and R25 are selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy or Lower dentate alkoxy. 53. The compound of claim 52, wherein R24 is Η' R25 is selected from the group consisting of dentate, lower alkyl, lower halogenated alkyl, lower alkoxy or lower i alkoxy. 54. The compound of claim 52, wherein R24 is hydrazine and R25 is selected from lower alkyl or lower haloalkyl. 55. The compound of claim 52, wherein R24 is deuterium and R25 is selected from Cw alkyl or Cw haloalkyl. 56. The compound of claim 55, wherein R25 is selected from the group consisting of decyl, ethyl or qhaloalkyl. 57. The compound of claim 52, wherein R25 is hydrazine and R24 is selected from the group consisting of _, lower alkyl, lower haloalkyl, lower alkoxy or lower halooxy. The compound of claim 52, wherein R25 is Η' R24 is selected from the group consisting of lower alkyl or lower haloalkyl. 59. The compound of claim 58 wherein R24 is selected from the group consisting of decyl, ethyl or q-alkyl. 60. The compound of claim 52, wherein R24 and R25 are each independently selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy or lower alkoxy. 61. The compound of claim 52, wherein R24 and R25 are each independently selected from a C02 alkyl group or a Cw haloalkyl group. 62. The compound of claim 1, wherein the compound is N-[(4-carbo-2-oxo-7-phenyl-2H-3-3-isoalkenyl)-yl]glycine N-[(4-trans-oxyxo-7_(2_gas_styl)·2Η·3_chromenyl)]-glycine; ν-[(4_ via oxy-oxo_7_(3_) Gas _phenyl)·2η_3_coloural alkenyl] glycine; Ν-[(4-hydroxy_2-oxo_7_(4_qi_phenyl)_2Η_3·chromenyl)carbonyl]glycine; « W Ν·[(4·搜基氧代_7_(4_Trifluoromethylphenyl)-2H_3_chromenyl) fluorenyl]glycine; Ν·[(4-hydroxy-2-yl)) Glycine; gas difluoromethoxy-phenyl) 2Η-3-color dilute 94 201225954 j/uoypn N-[(4-hydroxy-2-oxo-7-(4-trifluorodecyloxy-phenyl) -2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-7-(3,4-dichloro-phenyl)-2H-3-chromenyl)carbonyl Glycine; [[4-hydroxy-2-oxo-7-(3,4-difluoro-phenyl)-211-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2) -oxo-7-(3,4,5-trifluoro-phenyl)-211-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-7-(3-曱oxy-phenyl)-2H-3-chromenyl)carbonyl]gan Acid; N-[(4-hydroxy-2-oxo-7-(4-decyloxy-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-) Oxo-7-(3-indolyl-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-7-(4-methyl-phenyl) -2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-(2-chloro-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-(3-chloro-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-8) -(4-chloro-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-(3-trifluorodecyl-phenyl)-2H -3-chromenyl) carbonyl]glycine; 95 201225954 J/uoypn N-[(4-hydroxy-2-oxo-8-(4-trifluorodecyl-phenyl)-2H-3-chromenyl Carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-(3-trifluoromethoxy-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4) -hydroxy-2-oxo-8-(4-trifluorodecyloxy-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-) (3,4-dichloro-phenyl)-211-3-chromenyl)carbonyl]glycine; [[4-hydroxy-2-oxo-8-(3,4-difluoro-phenyl)- 211-3-chromene Carbonyl]glycine; [[4-hydroxy-2-oxo-8-(3,4,5-trifluoro-phenyl)-211-3-chromenyl)carbonyl]glycine; N-[(4 -hydroxy-2-oxo-8-(3-decyloxy-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-(4) -decyloxy-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-(3-methyl-phenyl)-2H-3- Alkenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-8-(4-methyl-phenyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4 -hydroxy-2-oxo-7-(6-decyloxy-3-acridinyl)-2H-3-chromenyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-7) -(4-dipyridyl)-2H-3-chromenyl)carbonyl]glycine; 96 201225954 37ϋ«9ριί acid [(hydroxy-2-oxo-7-phenoxyl 31 alkenyl) alkyl] Ammonia N-[(4. 经基_2•氧代_7_漠_3_色埽基) County] glycine; N-[(4-·-2-oxo wood desert winter dilute base) Glycine; N-[(4-hydroxy·2·oxo_6_演_3_色县), which rhyme-2-oxo-trifluoromethyl-phenyl)carboxy]alanine. The pharmaceutical composition 'where' the pharmaceutical composition contains: an H adjuvant or carrier which can be attached to the pain; and the effective family is as in the scope of claim (10) - The pharmaceutical composition according to claim 63, wherein the compound of any one of the above-mentioned claims, wherein And a pharmaceutical composition according to the invention of claim 64, wherein the chemotherapeutic agent is used. An additional compound is selected from the group consisting of erythropoietin-like drugs or the group 63 to &amp; </ RTI> of the drug described in any of the items, /, and 3 is as in the scope of claims 1 to 62, cup 1 and 15 ischemic thalassemia The use of a compound according to any one of claims 1 to 6 in the preparation of a medicament for the treatment of a discomfort or condition associated with HIF level or HIF activity is disclosed in the following paragraphs. Loss of C. 69. Use of a compound according to any one of claims 1 to 62 for the preparation of a medicament for treating a disease, disorder or condition in a patient, wherein the disease, discomfort or condition is selected from ischemia , anemia, wound healing, orthotopic transplantation, ectopic transplantation, allogeneic transplantation, systemic hypertension, thalassemia, diabetes, cancer or various inflammations, or a combination thereof: or a combination of two or more. Use of the compound of claim 69 for the manufacture of a medicament for treating a disease, disorder or condition in a patient, wherein the disease, discomfort or condition is selected from the group consisting of anemia, ischemia or thalassemia - The use of a compound according to any one of claims 1 to 62 for treating cells to regulate the amount of HIF in cells. 72. Patent Application Nos. 1 to 62 The compound of any one of the compounds wherein the compound has a HIF PHD inhibitory activity IC50 value of 40 μM or less. The compound of claim 72, wherein the compound HIF PHD inhibitory activity IC50 value is 10 μΜ or less than 10 μΜ ° 98