CN1993130B - Processes and intermediates for the preparation of fused heterocyclic kinase inhibitors - Google Patents

Abstract

The present invention is directed to intermediates that are useful for preparing pyrrolotriazines, and processes for preparing such intermediates.

Description

Processes and intermediates for the preparation of fused heterocyclic kinase inhibitors

related application

This application claims priority under Title 35 119(e) to U.S. Provisional Application No. 0/583,459, filed June 28, 2004, and U.S. Provisional Application No. 60/612,563, filed September 23, 2004 , the contents of which are hereby incorporated by reference.

field of invention

The present invention relates to intermediates for the preparation of pyrrolotriazines and processes for the preparation of the intermediates. It has been found that pyrrolotriazines can be used in the treatment of cancer by inhibiting the activity of protein tyrosine kinases. Pharmaceutical compositions comprising these compounds are also useful in the treatment of non-cancerous diseases associated with signal transduction pathways operating through growth factors and anti-angiogenic receptors such as c-Met.

Background technique

Hepatocyte growth factor (HGF), also known as scatter factor (SF) due to its ability to disrupt population formation in vitro, is a mesenchymal substance known to induce multiple pleiotropic responses in normal and neoplastic cells The source of cytokines (Sonnenberg et al., J.Cell Biol.123:223-235, 1993; Matsumato et al., Crit.Rev.Oncog.3:27-54, 1992; and Stoker et al., Nature 327:239- 242, 1987). These responses are well known to include epithelial and endothelial cell proliferation, disintegration of epithelial cell colonies into individual cells, stimulation of epithelial cell motility (motogenesis), cell survival, induction of cell morphogenesis (Montesano et al., Cell 67:901-908, 1991) and promote invasion (Stella et al., Int.J.Biochem.Cell Biol.12:1357-62, 1999 and Stuart et al., Int.J.Exp.Path.81:17-30, 2000), all of which constitute A critical step in transfer. In addition, HGF has been reported to promote angiogenesis (Bussolino et al., J. Cell Biol. 119:629-641, 1992). Furthermore, HGF plays a decisive role in tissue regeneration, wound healing and normal embryonic processes, all of which depend on cell motility and cell proliferation.

HGF initiates these physiological processes through high-affinity binding to its associated receptor, the Met protein tyrosine kinase receptor, an established proto-oncogene (Park et al., Proc. Natl. Acad. Sci. USA 84: 6379-83, 1987 and Bottaro et al., Science 251:802-4, 1991). The mature form of Met consists of a highly glycosylated external α-subunit with a large ectodomain as well as a β-subunit, a transmembrane portion and a cytoplasmic tyrosine kinase domain. Ligand occupancy induces dimerization of Met, which leads to autophosphorylation of activated receptors. Activation of Met promotes a signal transduction cascade defined by the transphosphorylation of key cytoplasmic tyrosine residues responsible for the recruitment of multiple effector proteins (Furge et al., Oncogene 19:5582-9, 2000). These include the p85 subunit of PI3-kinase, phospholipase Cγ (Gaul et al., Oncogene 19:1509-18, 2000), Grb2 and Shc adapter proteins, protein phosphatases SHP2 and Gabl. The latter adapter proteins appear to be the major downstream docking molecules that are phosphorylated in response to ligand occupancy to form tyrosines (Schaeper et al., J. Cell Biol. 149:1419-32, 2000; Bardelli et al., Oncogene 18:1139-32). 46, 1999 and Sachs et al., J. Cell Biol. 150:1375-84, 2000). Activation of other signaling molecules has been reported in HGF-stimulated cells, most notably Ras, MAP kinases, STATs, ERK-1, ERK-2, and FAK (Tanimura et al., Oncogene 17:57-65, 1998; Lai et al. et al., J. Biol. Chem. 275:7474-802000 and Furge et al., Oncogene 19:5582-9, 2000). The role of many of the above signaling molecules has been well established in cell proliferation.

Met, also known as hepatocyte growth factor receptor (HGFR), is prominently expressed in epithelial cells, but has also been identified in endothelial cells, myoblasts, hematopoietic cells and motor neurons. Both HGF overexpression and Met activation are associated with onset and progression in many different types of tumors and in the exacerbation of metastatic disease. Initial evidence linking Met to cancer has been supported by the identification of kinase domain missense mutations that predispose individuals to papillary renal carcinoma (PRC) and hepatocellular carcinoma (HCC) (Lubensky et al., Amer. J. Pathology, 155:517-26, 1999). Mutated forms of Met have also been identified in ovarian cancer, childhood HCC, gastric cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, colorectal metastases (Christensen et al., Cancer Res., 63:7345-55 , 2003; Lee et al., Oncogene, 19:4947-53, 2000 and Direnzo et al., Clin. Cancer Res., 1:147-54, 1995). In addition, other evidence supporting a role for Met in cancer is based on the overexpression of HGF and Met receptors in a variety of tumors, including thyroid, ovarian and pancreatic cancers. In addition, it has also been shown to be amplified in liver metastases from colon cancer (Rong et al., Cancer Res. 55:1963-1970, 1995; Rong et al., Cancer Res. 53:5355-5360, 1993; Kenworthy et al. People, Br. J. Cancer 66:243-247, 1992 and Scarpino et al. J. Pathology 189:570-575, 1999). TPR-Met, an activated form similar to BCR/Abl in CML, has been published and characterized in human gastric cancer (PNAS 88:4892-6, 1991). In a recent study of patients with invasive breast cancer and non-small cell lung cancer, receptor or ligand expression was a predictor of reduced survival, further linking Met to tumor progression (Camp et al., Cancer 86: 2259-651999 and Masuya et al., Br. J. Cancer, 90:1555-62, 2004). In general, most human tumors and tumor cell lines of mesenchymal origin do not express HGFR and/or HGF appropriately.

Numerous experimental data support the role of HGF and Met in tumor invasion, growth, survival and progression and ultimately cause metastasis. During the incubation period, transgenic expression of HGF causes a metastatic phenotype (Takayama et al., PNAS, 94:701-6, 1997) and expanded/overexpressed Met spontaneously transforms NIH-3T3 cells (Cooper et al., EMBO J., 5 : 2623-8, 1986).

Biologics such as ribozymes, antibodies, and antisense RNA targeting HGF or Met have been shown to inhibit tumorigenesis (Stabile et al., Gene Therapy, 11:325-35, 2004; Jiang et al., Clin. Cancer Res, 9: 4274-81, 2003 and Genentech US 6,214,344, 2001). Thus, small molecule kinase modulators targeting Met are expected to have therapeutic potential for the treatment of cancers where Met receptor activation plays a decisive role in the initiation and progression of primary tumors and secondary metastases. Furthermore, HGF is well known to regulate angiogenesis, a crucial process in tumor growth and spread. Thus, such modulators may affect angiogenesis-dependent diseases as well as other diseases, which may include diabetic retinopathy, macular degeneration, obesity and inflammatory diseases such as rheumatoid arthritis, among others.

Summary of the invention

The present invention relates to a process for the preparation of pyrrolotriazine compounds useful in the treatment of cancer.

In one embodiment of the present invention, there is provided a method for preparing a compound of formula V:

Wherein R ^a and R ^b are alkyl, the method comprises the following steps:

make the following compound

wherein R ^c is C(O) ₂ R ^e , wherein R ^e is an alkyl or substituted alkyl, such as methyl, ethyl, butyl, tert-butyl or benzyl,

Contact with an alkyl organometallic reagent (such as a Grignard reagent or an organolithium reagent) for a period of time and under conditions sufficient to produce compound V. In some preferred embodiments, the organometallic reagent is methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium bromide, methylmagnesium iodide, ethylmagnesium iodide, methyllithium or Ethyllithium.

According to another embodiment of the present invention, a method for preparing a compound of formula VI is provided:

The method comprises making the compound of formula V

wherein R ^a and R ^b are alkyl groups, are contacted with an acid (such as an organic acid, an inorganic acid, a Lewis acid, or an acidic ion exchange resin) in the presence of a peroxide for a period of time under conditions sufficient to produce compound VI, and can be further A step of quenching the reaction by adding a reducing agent such as sodium metabisulfite, sodium bisulfite, sodium thiosulfate or sodium bisulfite is included.

In some embodiments of the present invention, the acid is selected from p-toluenesulfonic acid, methanesulfonic acid, _BF3 -OEt, trifluoroacetic acid, formic acid, sulfuric acid, nitric acid, acidic zeolites and acidic ion exchange resins.

In one embodiment of the present invention, there is provided a method for preparing a compound of formula VII:

Wherein P is a protecting group, and the method comprises the following steps:

Make formula VI compound

With acylating reagents (such as formic acid, acetyl chloride, acetic anhydride, pivaloyl chloride, pivalic anhydride, benzoyl chloride, di-tert-butyl dicarbonate) or alkylating reagents (such as methyl iodide, methyl bromide, disulfuric acid Methyl ester, dimethyl carbonate, chloromethyl methyl ether, 3,4-dihydro-2H-pyran, benzyl chloride, benzyl bromide, 4-methoxybenzyl chloride or 4-methoxy benzyl bromide) for a period of time under conditions sufficient to effect the acylation or alkylation reaction to form compound VII.

According to another embodiment of the present invention, there is provided a method for preparing a compound of formula X:

Wherein L is a leaving group and P is a protecting group, the method comprises the following steps:

Make formula VII compound

With reagents such as phenylphosphonodichloride, thionyl chloride, phosphorus oxybromide, trifluoromethanesulfonic anhydride, phosphorus oxychloride, phosphorus pentachloride, or mixtures of phosphorus oxychloride and phosphorus pentachloride in sufficient quantities to form compounds Exposure to conditions X for a period of time.

In one embodiment of the present invention, there is provided a method for preparing a compound of formula IX:

where R ² is H, halogen, cyano, NO ₂ , OR ⁵ , NR ⁶ R ⁷ , alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted Heteroaryl, heterocyclyl, substituted heterocyclyl, aralkyl, substituted aralkyl, heterocycloalkyl or substituted heterocycloalkyl; and R ⁵ , R ⁶ and R ⁷ are H, alkyl, cycloalkane base, aryl or heteroaryl, the method comprises the following steps:

Make formula VII compound

wherein P is a protecting group and L is a leaving group, is contacted with the substituted phenol for a period of time and under conditions sufficient to form compound IX.

illustrate

The present invention relates to processes and intermediates for the preparation of pyrrolotriazine compounds. Pyrrolotriazine compounds have been found to be useful in the treatment of cancer. See, eg, US Patent Application No. 09/573829 and US Patent Application No. 60/612,563, filed September 23, 2004, the entire contents of which are hereby incorporated by reference.

The following definitions of various terms are used to describe the compounds of the present invention. These definitions apply to terms throughout the specification (unless they are defined otherwise in specific instances) either alone or as part of a larger group.

Unless otherwise limited, the term "alkyl" as used herein alone or as part of another group refers to a monovalent alkane (hydrocarbon) derived group containing 1 to 12 carbon atoms. Preferably the alkyl group has 1 to 6 carbon atoms. The alkyl group is an optionally substituted linear, branched or cyclic saturated hydrocarbon group. The alkyl groups may be substituted at any available point of attachment. Alkyl groups substituted by other alkyl groups are also referred to as "branched chain alkyl groups". Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl Base, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl, etc. Exemplary substituents include, but are not limited to, one or more of the following groups: alkyl, aryl, halogen (such as F, Cl, Br, I), haloalkyl (such as _CCl3 or _CF3 ), alkoxy group, alkylthio group, hydroxyl group, carboxyl group (-COOH), alkoxycarbonyl group (-C(O)R), alkylcarbonyloxy group (-OCOR), amino group (-NH ₂ ), carbamoyl group (-NHCOOR - or -OCONHR-), urea (-NHCONHR-) or thiol (-SH). In some preferred embodiments of the invention, the alkyl groups are substituted with substituents such as amino, heterocycloalkyl (e.g., morpholine, piperazine, piperidine, azetidine), hydroxyl, methoxy radical or heteroaryl (eg, pyrrolidine).

The term "alkenyl" used herein alone or as part of another group refers to a straight chain, branched chain or cyclic hydrocarbon group containing 2 to 10 carbon atoms and at least one carbon-carbon double bond. The alkenyl group may also be substituted at any available point of attachment. For alkenyl, exemplary substituents include those listed for alkyl, and particularly include C ₃ -C ₇ cycloalkyl, such as cyclopropyl, cyclopentyl, and cyclohexyl, which may be further Substituted by, for example, amino, oxo, hydroxy, and the like.

The term "alkynyl" used herein alone or as part of another group refers to a straight chain, branched chain or cyclic hydrocarbon group containing 2 to 10 carbon atoms and at least one carbon-carbon triple bond. The alkynyl group may also be substituted at any available point of attachment. For alkynyl groups, illustrative substituents include those listed above for alkyl groups, such as amino, alkylamino, and the like.

The subscript numbers following the symbol "C" define the number of carbon atoms that a particular group may contain. For example, "C ₁ -C ₆ alkyl" refers to a straight or branched saturated carbon chain containing 1 to 6 carbon atoms; examples include methyl, ethyl, n-propyl, isopropyl, n-butyl , sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl and n-hexyl. Depending on the context, "C ₁ -C ₆ alkyl" may also refer to a C ₁ -C ₆ alkylene group bridging two groups; examples include propane-1,3-diyl, butane-1,4- Diyl, 2-methylbutane-1,4-diyl, etc. "C ₂ -C ₆ alkenyl" means a straight or branched carbon chain containing at least one carbon-carbon double bond and having 2 to 6 carbon atoms; examples thereof include vinyl, propenyl, isopropenyl, butene group, isobutenyl, pentenyl and hexenyl. Depending on the context, "C ₂ -C ₆ alkenyl" may also refer to a C ₂ -C ₆ alkenylene bridging two groups; examples thereof include ethylene-1,3-diyl (ethenylene), 2- Methyl-2-butene-1,4-diyl, 2-hexene-1,6-diyl and the like. "C ₂ -C ₆ alkynyl" means a straight or branched carbon chain containing at least one carbon-carbon triple bond and 2 to 6 carbon atoms; examples thereof include ethynyl, propynyl, butynyl and hexynyl .

The terms "alkoxy" or "alkylthio" as used herein alone or as part of another group denote a group as described above bonded through an oxygen linkage (-O-) or a sulfur linkage (-S-), respectively. of alkyl.

The term "alkoxycarbonyl" as used herein alone or as part of a group denotes an alkoxy group bonded through a carbonyl group. An alkoxycarbonyl group is represented by the formula -C(O)OR, wherein the R group is a straight or branched C _1-6 alkyl, cycloalkyl, aryl or heteroaryl.

The term "alkylcarbonyl" as used herein alone or as part of another group refers to an alkyl group bonded through a carbonyl or -C(O)R.

The term "alkylcarbonyloxy" as used herein alone or as part of a group denotes an alkylcarbonyl group bonded through an oxygen linkage.

The term "aralkyl" as used herein alone or as part of a group denotes an aromatic ring bonded through an alkyl group as described above, such as benzyl.

The term "aryl" as used herein alone or as part of another group refers to monocyclic or bicyclic aromatic rings (such as phenyl and substituted phenyl, etc.) and fused groups such as naphthyl and phenanthrenyl, etc. wait. Thus, aryl contains at least one ring having at least 6 carbon atoms, of which there may be up to five of said rings, containing up to 22 atoms, and having between adjacent carbon atoms or suitable heteroatoms Alternating (resonant) double bonds. The aryl group can be optionally substituted by one or more groups, including but not limited to halogen (such as Br, F or Cl), alkyl (such as methyl, ethyl, propyl), alkoxy (such as methyl oxy or ethoxy), hydroxyl, carboxyl, carbamoyl, alkoxycarbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkane The group S(O) _m (m=0, 1, 2) or thiol.

The term "amino" as used herein by itself or as part of a group refers to _-NH2 . "Amino" may be optionally substituted by one or two substituents which may be the same or different, such as alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cyclohetero Alkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, carbonyl or carboxyl. These substituents may be further substituted with carboxylic acid, any of the alkyl or aryl substituents set forth herein. In some embodiments, the amino group is substituted with a carboxyl or carbonyl group, thereby forming an N-acyl or N-carbamoyl derivative.

The term "cycloalkyl" used herein by itself or as part of other groups refers to a fully saturated or partially unsaturated hydrocarbon ring of 3 to 9 carbon atoms, preferably 3 to 7 carbon atoms. Furthermore, the cycloalkyl group may be substituted. Substituted cycloalkyl refers to the above ring with one, two or three substituents selected from halogen, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo ( =O), hydroxyl, alkoxy, thioalkyl, -CO ₂ H, -C(=O)H, CO ₂ , -alkyl, -C(=O)alkyl, ketone, =N-OH , =NO-alkyl, aryl, heteroaryl, heterocyclyl, five-membered or six-membered ketal (ie 1,3-dioxolane or 1,3-dioxane), -NR'R ", C(=O)NR'R", CO ₂ NR'R", C(=O)NR'R", NR'CO ₂ R", NR'C(=O)R", SO ₂ NR'R" and NR'SO ₂ R", wherein each R' and R" are independently selected from hydrogen, alkyl, substituted alkyl and cycloalkyl, or R' and R" are taken together to form a heterocycle or heteroaryl ring.

The term "heteroaryl" as used herein alone or as part of another group refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic rings having at least one heteroatom (O, S, or N) in at least one ring. Group, 9-membered or 10-membered bicyclic group and 11-14-membered tricyclic group. Each heteroatom-containing heteroaryl ring may contain 1 or 2 oxygen or sulfur atoms and/or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings constituting the bicyclic or tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or unsaturated. The fluorine and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. Heteroaryls that are bicyclic or tricyclic must contain at least one fully aromatic ring, but other fused rings may be aromatic or non-aromatic. The heteroaryl group can be attached to any available nitrogen or carbon atom on any ring. The heteroaryl ring system may contain zero, one, two or three substituents selected from the group consisting of halogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, nitro, cyano, Hydroxy, alkoxy, thioalkyl, -CO ₂ H, C(=O)H, -CO ₂ -alkyl, -C(=O)alkyl, phenyl, benzyl, phenethyl, benzene Oxygen, thiophenyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, heteroaryl, -NR'R", -C(=O)NR'R", -CO ₂ NR'R", - C(=O)NR'R", -NR'CO ₂ R", -NR'C(=O)R", -SO ₂ NR'R", and -NR'SO ₂ R", wherein each R' and R" is independently selected from hydrogen, alkyl, substituted alkyl and cycloalkyl, or R' and R" are taken together to form a heterocyclic or heteroaryl ring.

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, diazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furan group, thienyl group, oxadiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group and triazinyl group, etc.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolyl, iso Quinolinyl, benzimidazolyl, benzopyranyl, pyrindenyl, benzofuryl, chromonyl (chromonyl), coumarinyl (coumarinyl), benzopyranyl, cinnolinyl, quinolyl Oxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolyl and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

The term "heterocycloalkyl" as used herein alone or as part of another group means a ring in which one carbon atom is replaced by a heteroatom selected from O, S or N and in which up to three other carbon atoms may be replaced by the Heteroatom-substituted cycloalkyl (non-aromatic). The term "heterocycloalkyl" as used herein alone or as part of another group means a stable, saturated or part of a 5-7 membered ring containing carbon atoms and other atoms selected from nitrogen, sulfur and/or oxygen atoms. Unsaturated monocyclic system. The heterocycle may be a 5, 6 or 7 membered monocyclic ring and may contain one, two or three heteroatoms selected from nitrogen, oxygen and/or sulfur. The heterocyclic ring can be optionally substituted means that the heterocyclic ring can be substituted at one or more substitutable ring positions by one or more groups independently selected from the following groups: alkyl (preferably lower alkyl) , heterocycloalkyl, heteroaryl, alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably lower alkylamino), dialkylamino (preferably di[lower] alkylamino) , cyano, halogen, haloalkyl (preferably trifluoromethyl), alkanoyl, methylaminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkylamido (preferably lower alkylamido), alkoxy ylalkyl (preferably lower alkoxy[lower]alkyl), alkoxycarbonyl (preferably lower alkoxycarbonyl), alkylcarbonyloxy (preferably lower alkylcarbonyloxy) and aryl (preferably phenyl ), said aryl is optionally substituted by halogen, lower alkyl and lower alkoxy. Examples of the heterocycloalkyl group include piperazine, piperidine, morpholine, homomorpholine, thiomorpholine, pyrrolidine and azetidine.

Heteroaryl or heterocycloalkyl may also be an 8-11 membered bicyclic ring consisting of carbon atoms and containing one, two or three heteroatoms selected from nitrogen, oxygen and/or sulfur atoms. Some preferred bicyclic rings include benzodioxol, quinoxaline, indolyl and quinolinyl. The term "optionally substituted" herein referring to "heteroaryl" or "heterocycloalkyl" means that the heterocyclyl may be at one or more substitutable ring positions independently selected from The group substitution of: alkyl (preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably lower alkylamino), dialkylamino (preferably di[lower] Alkylamino), cyano, halogen, haloalkyl (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkylamido (preferably lower alkylamido) , alkoxyalkyl (preferably lower alkoxy [lower] alkyl), alkoxycarbonyl (preferably lower alkoxycarbonyl), alkylcarbonyloxy (preferably lower alkylcarbonyloxy) and aryl ( Preferably phenyl), said aryl is optionally substituted by halogen, lower alkyl and lower alkoxy.

The term "heteroatom" refers to an independently selected O, S or N. It should be noted that any heteroatom having an unsaturated valence is considered to have a hydrogen atom saturating its valence.

The term "halogen" refers to independently selected chlorine, bromine, fluorine or iodine.

In preferred embodiments of the present invention, processes and intermediates for the preparation of compounds of formula I and II are provided:

Including its pharmaceutically acceptable salts, wherein:

^R is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted Alkynyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl;

Each ^R2 is independently ^H , halogen, cyano, _NO2 , ^OR5 , ^NR6R7 , alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl, heterocyclyl, substituted heterocyclyl, aralkyl, substituted aralkyl, heterocycloalkyl or substituted heterocycloalkyl;

B is O, NR ⁸ , S, SO, SO ₂ , CR ⁹ R ¹⁰ ;

V is NR ¹¹ or (CR ⁴⁷ R ⁴⁸ ) _p -;

W or X is independently C or N;

Y is O, S or NR ¹² ;

Z is -CR ¹³ R ¹⁴ -, -(CR ¹³ R ¹⁴ ) _m NR ¹⁵ -;

l is 0-4;

m is 0~2;

n is 0-4;

p is 0 to 4, with the proviso that if p is 0, then ^R is not phenyl;

A is:

R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹¹ and R ¹⁵ are each independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, hetero Aryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl;

^R is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl;

R and ^R are independently H, halogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl ^, or substituted Heterocycloalkyl;

R ¹² is H, alkyl, substituted alkyl, CN, NO ₂ or SO ₂ NH ₂ ;

R ¹³ , R ¹⁴ , R ¹⁵ , R ⁴⁷ and R ⁴⁸ are independently H, halogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted hetero Aryl, heterocyclic, substituted heterocyclic or together form a carbocyclic or heterocyclic ring with 3 to 8 atoms;

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ⁶⁰ are independently H, halogen, NO ₂ , cyano, OR ²⁶ , NR ²⁷ R ²⁸ , CO ₂ R ²⁹ , C(O)NR ³⁰ R ³¹ , SO ₂ R ³² , SO ₂ NR ³³ R ³⁴ , NR ³⁵ SO ₂ R ³⁶ , NR ³⁷ C(O)R ³⁸ , NR ³⁹ CO ₂ R ⁴⁰ , -CO(CH ₂ ) _l R ⁴¹ , -CONH(CH ₂ ) _l R ⁴² , alkylaminoalkyl, alkylaminoalkynyl, C ₁ ~C ₆ alkyl, substituted C ₁ ~C ₆ alkyl, C ₃ ~C ₇ cycloalkyl, substituted C ₃ ~C ₇ cycloalkyl, alkene substituted alkenyl, alkynyl, substituted alkynyl, hydroxyalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heterocycloalkyl or substituted Heterocycloalkyl;

R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R 32 , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ and ^{R 42} independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heterocyclic Alkyl or substituted heterocycloalkyl.

Certain compounds of formula I and formula II can generally be prepared according to the following schemes. These compounds can be readily synthesized using synthetic methods well known to those skilled in the art. Tautomers and solvates (eg, hydrates) of the compounds of formula I and formula II are also included within the scope of the present invention. Methods of solvation are generally known in the art. Accordingly, the compounds of the present invention may be in free or hydrated form and may be obtained by the methods exemplified in the following schemes.

In general, desired fused heterocycles can be prepared by utilizing the synthetic routes shown in Schemes 1-3. Leaving groups (Lg) of heterocycles (A, whose unoccupied positions can optionally be substituted), such as halo (or trifluoromethylsulfonyl), can be replaced with substituted phenols 2 to give ethers 3 (Scheme 1 ). Groups A-Lg can be prepared according to the general methods listed in the following documents, for example, Hunt, J.T. et al. WO 00/071129; Hunt, J.T. et al. J.Med.Chem.2004, 47, 4054 4059 ; Leftheris, K. et al. WO 02/040486; Mastalerz H. et al. WO 03/042172; Dyckman, A. et al. WO 03/091229; Vite, G.D. et al. WO 04/054514; 082208; Thibault, C. et al. Org. Lett. 2003, 5, 5023-5025; Zhang, Z. et al. J. Org. Chem. 2002, 67, 2345-2347; Itoh, T. et al. J. Heterocyclic Chem .1982, 19, 513-517; Tedder, M.E. et al. Bioorg. Med. Chem. Lett. 2004, 14, 3165-3168; Dorn, H. et al. J. Prakt. Chem. Y.S. et al. J.Med.Chem.1989,32,945-951; Temple, C.Jr. et al. J.Org.Chem.1972,37,3601-3604; Hurst, J. et al. EP119774; Hurst, Jr. Ward, R.W. et al. EP152910; Luzzio, M.J. et al. WO 01/094353; Marx, M.A. et al. WO 03/000194; Boschelli, D.H. et al. WO 04/048386; He, M. et al. WO 05 /021554; Barker, J.M. et al. J.Chem.Res., Synopses 1986,4,122-123, the entire contents of which are hereby incorporated by reference.Under catalytic hydrogenation conditions, with for example zinc powder and ammonium chloride or Adam's catalyst (Platinum(IV) oxide) reduces the nitro group of intermediate 3 to give aniline 4. Treating aniline 4 with isocyanate 5 (X=O) or isothiocyanate 5 (X=S) respectively gives the desired acyl Urea or acylthiourea6.

plan 1

Lg = leaving group, such as halogen

X=O or S

G is O, S or NR ²¹

D is CR ²⁰ or N

V = as defined above

Alternatively, appropriately substituted anilines 7 can be treated with isocyanates 5 (X=O) or isothiocyanates 5 (X=S) to afford phenols 8 (Scheme 2). The desired compound 6 can be obtained by reacting the intermediate 8 with the heterocycle (A-Lg)1.

Scenario 2

Lg = leaving group, such as halogen

X=O or S

G is O, S or NR ²¹

D is CR ²⁰ or N

V = as defined above

In general, the amide derivatives described in the present invention can be prepared using the chemistry shown in Scheme 3. For example, aniline 9 (derived from Scheme 1) can be acylated with compound 10 to give amide 11. Hydrolysis of ester 11 with eg sodium hydroxide can afford carboxylic acid 12. Then, the desired compound 13 can be obtained from intermediate 12 using known amide bond forming conditions. Alternatively, using carboxylic acid 14 and a coupling agent such as benzotriazol-1-yloxytris(trimethylamino)phosphonium hexafluorophosphate, 1-(dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride or bromotripyrrolidinylphosphonium hexafluorophosphonate) can directly convert aniline 9 to compound 13. Treatment of aniline 9 with acid chloride 15 (X=Cl) or carboxylic acid 15 (X=OH) and a coupling agent can afford amides of type 16.

Option 3

G is O, S or NR ²¹

D is CR ²⁰ or N

V = as defined above

Substituted heterocyclic derivatives such as pyrrolotriazine compounds 26a/b (Scheme 5) can be prepared using the synthetic routes shown in Schemes 4 and 5. Carboxylate 17, in which R may be an alkyl or aryl group (such as phenyl), can be contacted with not more than 2 equivalents of an alkyl or aryl organometallic reagent, such as a Grignard reagent, organolithium, organozinc, etc., This gives tertiary alcohol 18 (Scheme 4). The reaction is usually carried out in an ethereal solvent such as tetrahydrofuran, dibutyl ether or diethyl ether, or any other non-reactive solvent such as benzene, toluene or hexane. Tertiary alcohols 18 can be rearranged to form hydroxypyrrolotridioides by treating them with acid mixtures in the presence of hydrogen peroxide or organic peroxides (e.g., tert-butyl hydroperoxide, cumyl hydroperoxide) Zine 19. Almost any acid can be used as a catalyst for oxidative rearrangement, and the reaction has been demonstrated with organic, inorganic, and Lewis acids. Some acids that have been used in this type of reaction include: p-toluenesulfonic acid, methanesulfonic acid, formic acid, sulfuric acid, nitric acid, _BF3 - _OEt2 , trifluoroacetic acid, acidic zeolites and acidic ion exchange resins. The concentration of the acid can be varied, and the concentration and strength of the acid is used to control the kinetics of the reaction. The concentration of peroxide can be 30-50%. Any reducing agent that reacts to decompose hydrogen peroxide can be used to quench the reaction, including but not limited to sodium metabisulfite, sodium bisulfite, sodium thiosulfate, sodium dithionite. Various bases can be used to control the pH while quenching the reaction. Hydroxypyrrolotriazines 19 can be reacted with a variety of acylating reagents to give 20 (where, for example, P can be pivalate). Compound 20 can be contacted with an appropriate halogenating reagent (eg, phosphorus oxychloride, _POCl3 ) to provide compound 21 (L=Cl). In addition to _POCl3 , other reagents that can be used to achieve this transformation include _PCl5 , _PCl5 / _POCl3 mixtures, PhP(O) _Cl2 , _SOCl2 . Amines are typically used to catalyze this reaction, including _Et3N , _PhNMe2 , DABCO, and the like. Additionally, formamides (such as, for example, N,N-dimethylformamide) and alkylamides (such as N-methylpyrrolidone) can also be used to catalyze the reaction. The reaction can be carried out in any reagent inert to the halogenating reagent, including benzene, toluene, THF, and the like.

Option 4

Appropriately protected imidate 21 (Scheme 5) can be treated with optionally substituted phenol 2 to afford intermediate 22. Phenol 23 derived from compound 22 by deprotection (using sodium hydroxide in the case of P = pivalate) can be converted to ether 24 by Mitsunobu reaction with alcohol. Reduction of the nitro substituent of compound 24 using the same conditions as described in Scheme 1 above can provide aniline 25. By utilizing the chemistry described in Schemes 1 and 3 above, aniline 25 can be converted to the desired acylurea, acylthiourea or amide 26a/h.

Option 5

Using the chemistry described in Scheme 6, amine compound 30 can be prepared. Reduction of ester 27 with, for example, diisobutylaluminum hydride (DIBAL-H) can provide alcohol 28. Oxidation of compound 28 with, for example, Dess-Martin periodinane (1,1,1-tris(acyloxy)-1,1-dihydro-1,2-phenyliodoyl-3-(1H)-one) , so that aldehyde 29 can be obtained. Reductive amination of aldehyde 29 with an appropriately substituted amine in the presence of a reducing agent (eg, sodium triacetoxyborohydride) can afford the desired amine 30 .

Option 6

Using the chemistry shown in Scheme 7, a variety of substituents, such as optionally substituted aryl, heteroaryl or vinyl groups, can be introduced into pyrrolo[2,1-f][1,2,4]tri on the 5-position of the oxazine ring. Aminopyrrole compound 31 can be cyclized in the presence of formamide to give 5-chloropyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (32). Treatment of intermediate ₃₂ with POCl at elevated temperature in the presence of a base such as Hunig's base affords 4,5-dichloropyrrolo[2,1-f][1,2,4]triazine ( 33). Coupling of an appropriately substituted phenol 2 with compound 33 in the presence of a base such as potassium carbonate can afford intermediate 34. The nitro group of compound 34 can be reduced using zinc powder and ammonium chloride to give aniline 35. Palladium-mediated coupling reactions with various boronic acids can provide intermediate 35, which can be converted to the desired compound 37 or 38 using the chemistry described above.

Option 7

Substitution at the 5-position of the pyrrolo[2,1-f][1,2,4]triazine ring can also be accomplished by coupling triethylammonium salt 39 with an appropriately substituted phenol 7 followed by a base such as Treatment with amines (HNR'R") in the presence of Hunig's base) affords anilines 40 (Scheme 8). Anilines 40 can be further treated as previously described to afford the desired compounds 41 or 42.

Option 8

Alternatively, at high temperature, in carbon tetrachloride, 5-methyl-4-(methylthio)pyrrolo[2,1-f][1,2,4]triazine (43) can be obtained with, for example, N -bromosuccinimide (NBS) and 2,2'-azobisisobutyronitrile (azobisisobutyronitrile) for bromination. Treatment of the above brominated intermediate with an amine (HNR'R") in the presence of a base such as Hunig's base can afford intermediate 44. Using, for example, 3-chloroperbenzoic acid (m-CPBA), the compound Oxidation of the thiomethyl group of 44. Treatment of the sulfone intermediate with the phenoxide derived from compound 7 and sodium bis(trimethylsilyl)amide (NaHMDS) affords the aniline intermediate 45.

Option 9

Pyrrolo[2,3-b]pyridine intermediate 50 can be prepared using the chemistry shown in Scheme 10. Using the synthetic sequence described by Thibault C. and co-workers (Org. Lett. 2003, 5, 5023-5025) illustrated in Scheme 10, 4-chloro-1H-pyrrolo[2,3-b]pyridine (49) can be prepared from commercially available 1H-pyrrolo[2,3-b]pyridine (46). Treatment of intermediate 49 with phenol 2 at elevated temperature affords key intermediate 50, which can be converted to the desired compound using the chemistry described in Schemes 1 and 3.

The following examples and preparations describe the manner and method of making and using the invention and are illustrative rather than limiting. It should be understood that there are other embodiments which fall within the spirit and scope of the invention as defined by the appended claims.

Example

All reactions were performed under dry nitrogen or argon atmosphere with constant magnetic stirring. All evaporations and concentrations were performed under reduced pressure on a rotary evaporator. Commercially available reagents were used as obtained without further purification. Solvents were commercial anhydrous grades and were used without further drying or purification. Flash chromatography was performed using silica gel (EMerck Kieselgel 60, 0.040-0.060 mm).

Analytical reverse phase (RP) HPLC was performed using a Phenomenex Luna C18 S5 4.6 mm x 50 mm column or a YMC S5 ODS 4.6 x 50 mm column. In each case, a linear gradient of 4 minutes (from 100% A: %0 B to 0% A: 100% B) was applied with the following mobile phase system at flow = 4 mL/min: A = 90% _H2 O/MeOH + 0.2% H ₃ PO ₄ ; B = 90% MeOH/H ₂ O + 0.2% H ₃ PO ₄ and detection at 220 nm.

Preparative reverse phase (RP) HPLC was performed in the following manner using a linear gradient elution with _H2O /MeOH mixture buffered with 0.1% trifluoroacetic acid and detection at 220 nm on one of the following columns: Shimadzu S5 ODS- VP 20×100mm (flow rate=9mL/min), or YMC S10 ODS 50×500mm (flow rate=50mL/min) or YMC S10 ODS 30×500mm (flow rate=20mL/min).

All final products were characterized by ¹ H NMR, RP HPLC, electrospray ionization (ESIMS) or air pressure stream ionization (API MS) mass spectrometry. ¹ H NMR spectra were obtained from 500 MHz JEOL or 400 MHz Bruker instruments. ¹³ C NMR spectra were recorded at 100 or 125 MHz. Signal intensities relative to solvent peaks are expressed in units of d (parts per million, ppm), and peak overlap is defined as follows: s, singlet; d, doublet; dd, double doublet; dm, double multiplet; t, triplet; q, quartet; br s, broad singlet; m, multiplet.

六氟磷酸盐；DIBAL-H：二异丁基氢化铝；Na(OAc)₃BH：三乙酰氧基硼氢化钠；HOAc：乙酸；TFA：三氟乙酸；LjHMDS：双(三甲基甲硅烷)氨基锂；m-CPBA：m-氯：3-氯过苯甲酸；AIBN：2，2’-偶氮二异丁腈；DMSO：二甲亚砜；MeCN：乙腈；MeOH：甲醇；EtOAc：乙酸乙酯；DMF：二甲基甲酰胺；THF：四氢呋喃；DCE：1，2-二氯乙烷；Et₂O：乙醚。For commonly used reagents, the following abbreviations apply: Boc or BOC: tert-butyl carbamate; Fmoc: 9H-fluorenylmethyl carbamate; NMM: N-methylmorpholine; Ms: methylsulfonyl; DIEA or DIPEA : Diisopropylethylamine or Hunig's base; NMP: N-methylpyrrolidone; BOP reagent: benzotriazol-1-yloxytris(trimethylamino)phosphonium hexafluorophosphate; DCC: 1,3 -Dicyclohexylcarbodiimide; EDCI: 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; RT: room temperature; tR: retention time; h: hour; min: minute ; PyBrOP: bromotripyrrolidinylphosphonium hexafluorophosphate; TBTU: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluorocarbon ; DMAP: 4-N, N-dimethylaminopyridine; HOBt: hydroxybenzotriazole; HATU: O-(7-azabenzotriazol-1-yl)-N, N, N', N '-Tetramethyl

Hexafluorophosphate; DIBAL-H: diisobutylaluminum hydride; Na(OAc) ₃ BH: sodium triacetoxyborohydride; HOAc: acetic acid; TFA: trifluoroacetic acid; LjHMDS: bis(trimethylsilane ) lithium amide; m-CPBA: m-chloro: 3-chloroperbenzoic acid; AIBN: 2,2'-azobisisobutyronitrile; DMSO: dimethylsulfoxide; MeCN: acetonitrile; MeOH: methanol; EtOAc: Ethyl acetate; DMF: dimethylformamide; THF: tetrahydrofuran; DCE: 1,2-dichloroethane; _Et2O : diethyl ether.

Example 1

1-(3-fluoro-4-(6-methoxy-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenyl)-3 -(2-Phenylacetyl)thiourea

A) 6-(1-hydroxy-1-methyl-ethyl)-5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one

Under an inert atmosphere, prepare 1.9 kg of ethyl 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (prepared generally according to the method described in U.S. Patent Application No. 09/573829) and 17.9 kg THF, and cooled to -10°C. To the above mixture was added 14.2 kg of methylmagnesium chloride as a 3M THF solution at a rate to maintain the reaction temperature < 35°C. The above reaction mixture was kept at 25-45°C until the reaction was complete, and then cooled to 0°C. A solution of 9.9 kg ammonium chloride dissolved in 36.7 kg water was prepared and cooled to 5°C. The above organic reaction mixture was added to the ammonium chloride solution at such a rate that the internal temperature was maintained <15°C. The phases were allowed to stabilize, the lower aqueous phase was drained and re-extracted with an additional 9.5 kg THF. To the combined organic phases was added 8.6 kg EtOAc and the mixture was washed with 7.6 kg saturated aqueous sodium chloride. The reaction mixture was filtered and then the solvent was removed in vacuo (temperature <40°C) to about 1/3 of the original volume. Additional EtOAc was added and distillation continued until the concentration of THF was <7%. The resulting slurry was cooled to 0-5°C and the solids were collected by filtration. The resulting wet cake was washed with cold (-10°C) EtOAc and dried under vacuum at 40°C to give 1.5 kg of 6-(1-hydroxy-1-methyl-ethyl)-5 -Methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one, the purity is 96-99%.

B) 6-Hydroxy-5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one

A 1 L 3 neck round bottom flask was equipped with a mechanical stirrer and an ice/acetone cooling bath. Add 20 g of 6-(1-hydroxy-1-methyl-ethyl)-5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazine-4- Ketone, 235 mL THF and 47 mL 50% aqueous hydrogen peroxide. It was observed that its temperature rose from -7°C to 7.3°C and the above mixture became a solution. To the above mixture was added a pre-cooled solution of 28.5 mL of water and 63 mL of methanesulfonic acid over a period of 40 minutes, maintaining the temperature between -5°C and -0.7°C. The above solution was _stirred at -2°C for 95 minutes until HPLC showed that the reaction was complete; % ammonia, the reaction mixture was quenched while maintaining it at -2°C. The above mixture was stirred at room temperature for 20 minutes; its pH was 6.80 and the peroxide value was determined to be negative. The layers were separated and the aqueous layer was extracted with 100 mL THF. The two organic layers were combined and concentrated, and 280 mL of solvent was removed. To the thick slurry obtained above was added 250 mL of water and continued to concentrate until 88 mL of solvent had been removed. The resulting slurry was filtered and the resulting filter cake was washed twice with 25 mL of water, then with 25 mL of acetonitrile. It was dried to constant weight by suction on the filter to give 12.51 g of 6-hydroxy-5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazine-4- Ketone, yield 75.9%, purity 96.5%.

C) 2,2-Dimethyl-propionic acid 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6- base ester

2.9kg 6-hydroxyl-5-methyl-3H-pyrrolo[2,1-f][[1,2,4]triazin-4-one, 4.6kg diisopropylethylamine and 17.0kg THF The mixture was cooled to 0-10°C and then treated with 2.6 kg of pivaloyl chloride at a rate to maintain the temperature <20°C. The above mixture was stirred until the reaction was determined by HPLC to be complete, then 17.8 kg of toluene was added thereto, followed by 20.6 kg of 15% potassium dihydrogen phosphate aqueous solution. The phases were separated and the organic phase was washed with 10.2 kg of water. The resulting organic phase was filtered and then vacuum distilled at a maximum temperature of 65°C. Make-up toluene can be added and distillation continued until the THF concentration is <8% and the total reaction volume is reduced to 31 L. The resulting slurry was cooled to 20-25°C and treated with 20.3 kg of heptane for 1.5 hours. The resulting slurry was cooled to 0-5°C and held for 1 hour, then the solid was collected by filtration and dried to give 4.0 kg of 2,2-dimethyl-propionic acid 5-methyl-4- Oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-6-yl ester with a purity of 95-99%.

D) 4-Chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate

To 5-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (300mg, 1.20mmol), A mixture of phosphorus oxychloride (368 mg mL, 2.4 mmol) and DIEA (0.5 mL, 2.80 mmol) was added back to acetonitrile (10 mL). The reaction was heated at 85-90C for 4 hours and then allowed to cool to room temperature. The resulting mixture was diluted with ethyl acetate (10 mL) and water (5 mL). The organic layer was separated, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel (eluting with 1-25% EtOAc/ _CH2Cl2 ) to give _the title compound as a white solid (250 mg , 78%).

E) 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate

To 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (250mg, 0.94mmol), 2-fluoro-4-nitro To a mixture of phenol (176 mg, 1.12 mmol, Aldrich) and _K2CO3 (154 mg, 1.12 mmol) was added DMF (5 _mL ). The reaction was stirred at room temperature for 24 hours. The reaction was quenched with water (5 mL) and _CH2Cl2 (10 mL) _. The organic layer was separated, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel (eluting with 1-25% EtOAc/ _CH2Cl2 ) to give _the title compound as a white solid (160 mg , 44%).

F) 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol

To 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ylpivalate (80mg, To a solution of 0.2 mmol) in THF (1 mL) was added NaOH in MeOH/ _H2O (0.2 mL, 1 M). The above solution immediately turned red. After 5 minutes, the reaction was quenched with EtOAc (5 mL) and _H2O (5 mL). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give the title compound (52 mg, 85%) as a yellow solid.

G) 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-5-methylpyrrolo[2,1-G][1,2,4]triazine

To 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol (52mg, 0.17mmol) To a solution in DMF (2 mL) was added Cs ₂ CO ₃ (65 mg, 0.2 mmol), and the resulting mixture was stirred at room temperature for 10 min. A DMF solution of iodomethane (0.2 mL, 0.2 mmol, 1 M) was added thereto and the resulting reaction solution was stirred at room temperature for 2 hours. The reaction was quenched with EtOAc (5 mL) and _H2O (5 mL). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give the title compound (35 mg, 65%) as a yellow solid.

H) 3-fluoro-4-(6-methoxy-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)aniline

并且在真空下对其进行浓缩。通过SCX萃取柱柱体(用氨水的甲醇溶液(2M)洗脱)对上述产品混合物进行纯化，从而得到为白色固体的标题化合物(15mg，50％)。To 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-5-methylpyrrolo[2,1-f][1,2,4]triazine (35mg, 0.11mmol ) in THF (1.0 mL) was added MeOH (1.0 mL), followed by the addition of Zn (100 mg, 1.5 mmol) and NH ₄ Cl (43 mg, 0.80 mmol). The above reaction was heated at 60°C for 3 hours. Filter the above solution

And it was concentrated under vacuum. The above product mixture was purified by SCX extraction cartridge eluting with ammonia in methanol (2M) to afford the title compound (15 mg, 50%) as a white solid.

I) 2-phenyl-1-cyanatoethanone (thiocyanatoethanone)

To a solution of NaSCN (49 mg, 0.60 mmol) in EtOAc (2 mL) was added phenylacetyl chloride (0.066 mL, 0.50 mmol, Aldrich) to give a 0.25 M solution of 2-phenyl-1-thiocyanatoethanone. After 10 minutes, an aliquot of the reaction mixture was reacted with 4-(phenoxy)aniline to form the corresponding thiocyanate detected by LCMS (ESI ⁺ ) m/z 363 (M+H)+, whether the reaction was Complete the measurement. The obtained 2-phenyl-1-thiocyanatoethanone can be used directly without isolation or further purification.

J) 1-(3-fluoro-4-(6-methoxy-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenyl) -3-(2-phenylacetyl)thiourea

To 3-fluoro-4-(6-methoxy-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)aniline (7.5mg, 0.026mmol ) in CH ₂ Cl ₂ (1 mL) was added a solution of 2-phenyl-1-thiocyanatoethanone (0.133 mL, 0.033 mmol, 0.25 M in ethyl acetate). The reaction was stirred at room temperature for 20 minutes, concentrated in vacuo and _purified by flash chromatography on silica gel (eluting with 1-25% EtOAc/ _CH2Cl2 ) to give the title compound as a pale yellow solid ( 6.1 mg, 50%). ¹ H NMR (CDCl ₃ )δ8.51(s, 1H), 7.87(m, 1H), 7.83(s, 1H), 7.47(m, 5H), 7.31(m, 4H), 3.89(s, 3H) , 3.74 (d, 2H, J=10.5Hz), 2.44 (s, 3H); MS (ESI ⁺ ) m/z 466 (M+H) ⁺ .

Example 2

1-(3-fluoro-4-(6-methoxy-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenyl)-3 -(2-(4-fluorophenyl)acetyl)thiourea

A) 2-(4-fluorophenyl)-1-cyanothioethanone

To a solution of NaSCN (49 mg, 0.60 mmol) in EtOAc (2 mL) was added 4-fluorophenylacetyl chloride (0.066 mL, 0.50 mmol, Aldrich). The reaction was stirred at room temperature for 1 hour to give a 0.25 M solution of 2-(4-fluorophenyl)-1-thiocyanatoethanone in EtOAc, which was used without further purification.

B) 1-(3-fluoro-4-(6-methoxy-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenyl) -3-(2-(4-fluorophenyl)acetyl)thiourea

In a manner similar to that described for compounds H and J in Example 1, 3-fluoro-4-(6-methoxy-5-methylpyrrolo[2,1-f][1,2,4]tri The title compound was prepared from azin-4-yloxy)aniline and 2-(4-fluorophenyl)-1-thiocyanatoethanone. ¹ H NMR (CDCl ₃ ) δ.8.49(s, 1H), 7.88(m, 1H), 7.83(s, 1H), 7.45(s, 1H), 7.28(m, 5H), 7.12(m, 2H) , 3.89(s, 3H), 3.71(s, 2H), 2.44(s, 3H); MS(ESI ⁺ ) m/z 484(M+H) ⁺ .

Example 3

4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)ureido)phenoxy)-5-methylpyrrolo[2,1-f][1,2 , 4] Triazin-6-yl ethyl carbamate

A) 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ylethylcarbamate

To 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol (25mg, 0.082mmol, implementation To a mixture of compound F) of Example 1, DIEA (0.017 mL, 0.1 mmol) in CH ₂ Cl ₂ (5 mL) was added ethyl isocyanate (0.078 mL, 0.1 mL), and it was stirred at room temperature for 2 hours. The above reaction was quenched with water (5 mL). The organic layer was separated, dried and concentrated in vacuo. The above mixture was purified by flash chromatography (1-5% methanol/ _CH2Cl2 ) to afford the title compound (12.5 mg, 32% ₎ as a white solid.

B) 4-(4-Amino-2-fluorophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ylethylcarbamate

并且在真空下对其进行浓缩，从而得到为白色固体的标题化合物(8mg，70％)。To 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ylethylcarbamate ( 12.5 mg, 0.033 mmol) in ethanol (2 mL) were added Zn (20 mg, 0.3 mmol) and NH ₄ Cl (20 mg, 0.37 mmol). The above reaction was stirred at room temperature for 1 hour, filtered

And it was concentrated under vacuum to give the title compound (8 mg, 70%) as a white solid.

C) 2-(4-fluorophenyl)acetyl isocyanate

To 4-fluorophenylacetamide (fluorophenylacetamide) (77mg, 0.50mmol, see generally, J.Med.Chem.2003,46,4333-4341, the entire content of which is hereby incorporated by reference) in dichloroethane (2mL ) solution/suspension was added oxalyl chloride (0.175 mL, 2.00 mmol). The above reaction was heated at 80°C for 24 hours, then it was heated at 70°C for two days. At this point, most of the solids had dissolved and the reaction solution turned yellow. LC/MS analysis revealed a peak with a molecular weight of 211 corresponding to methyl 2-(4-fluorophenyl)acetylcarbamate obtained by quenching the isocyanate with methanol. The reaction was concentrated in vacuo to give a yellow syrup. The resulting slurry was redissolved in dichloroethane (2 mL) and concentrated again in vacuo. The resulting residue was redissolved in dichloroethane (2 mL) to obtain a 0.25 M solution of 2-(4-fluorophenyl)acetylisocyanate in dichloroethane, which could be directly used in subsequent reactions to apply.

D) 4-(2-fluoro-4-(3-(2-(4-fluorophenyl) acetyl) ureido) phenoxy) -5-methylpyrrolo [2,1-f] [[ 1,2,4]triazin-6-ylethylcarbamate

To 4-(4-amino-2-fluorophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ylethylcarbamate (10mg , 0.029 mmol) in CH ₂ C1 ₂ (1 mL) was added 2-(4-fluorophenyl)acetyl isocyanate solution (2 mL, 0.25 M in dichloroethane). The reaction was stirred at room temperature for 1 hour, analysis by LC/MS indicated consumption of the initial carbamate. The mixture was concentrated in vacuo, the residue was suspended in methanol and filtered to give the title compound. The filtrate was purified by flash chromatography to give more title compound as a light yellow solid (combined yield 5.9 mg, 40%). ¹ HNMR (CDCl ₃ ) δ.10.63(s, 1H), 8.42(s, 1H), 7.88(s, 1H), 7.82(s, 1H), 7.67(dd, 1H, J=12.1, 2.2Hz), 7.28(m, 4H), 7.10(m, 2H), 3.73(s, 3H), 3.36(m, 2H), 2.48(s, 3H), 1.26(m, 3H); MS(ESI ⁺ ) m/z 525(M+H) ⁺ .

Example 4

4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)thioureido)phenoxy)-5-methylpyrrolo[2,1-f][1, 2,4] Triazin-6-yl ethyl carbamate

To 4-(4-amino-2-fluorophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ylethylcarbamate (8mg , 0.023mmol, the CH ₂ Cl ₂ (1mL) solution of compound B) prepared in Example 4 was added 2-(4-fluorophenyl)-1-cyanothioethanone (0.120mL, 0.025mmol, in ethyl acetate 0.25M in ester, compound A) of Example 2. The above reaction was stirred at room temperature for 1 hour, concentrated in vacuo and purified by silica gel flash chromatography (eluting with 1-25% EtOAc/ _CH2Cl2 ) to give 100 as _a light yellow solid The title compound (5.4 mg, 43%). ¹ H NMR (CDCl ₃ ) δ.12.41(s, 1H), 8.58(s, 1H), 7.88(m, 3H), 7.28(m, 5H), 7.12(m, 2H), 3.72(s, 2H) , 3.37(m, 2H), 2.46(m, 3H), 1.26(m, 3H); MS(ESI ⁺ ) m/z 541(M+H) ⁺ .

Example 5

4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)thioureido)phenoxy)-5-methylpyrrolo[2,1-f][1, 2,4] Ethyl triazine-6-carboxylate

A) 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester

To ethyl 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (24 mg, 0.10 mmol, Preparation: See U.S. Patent No. 6,670,357, inter alia is Example 61, the disclosure of which is incorporated herein by reference), 2-fluoro-4-nitrophenol (20 mg, 0.125 mmol) and K ₂ CO ₃ (28 mg, 0.20 mmol) in a mixture was added DMF (0.5 mL) . The above reaction was heated at 70 °C for 20 minutes, it was cooled to room temperature and 2 mL of water was added. The resulting mixture was filtered, and the resulting solid was washed with water and dried to give the title compound (36 mg, 100%) as a light yellow solid.

B) ethyl 4-(4-amino-2-fluorophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ylcarboxylate

To ethyl 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (36mg, 0.1 mmol) in THF (1.0 mL) was added MeOH (0.7 mL), followed by the addition of Zn (130 mg, 2.0 mmol) and NH ₄ Cl (53 mg, 1.0 mmol). The above reaction was heated at 70°C overnight. LC/MS analysis indicated major starting material. The solution was shaken vigorously and then heated to 75°C. After 4 hours, LC/MS analysis showed the desired product and many other peaks. The above reaction mixture was filtered through a strainer and the filtrate was concentrated to give 55 mg of a brown residue. The resulting residue was suspended in THF and passed through an HPLC filter to form a clear filtrate. The filtrate was concentrated in vacuo to give 54 mg of the title compound as a crude mixture which was used in the next step without further purification.

C) 4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)thioureido)phenoxy)-5-methylpyrrolo[2,1-f][ 1,2,4] Ethyl triazine-6-carboxylate

CH ₂ Cl ₂ (0.6mL) suspension was added 2-(4-fluorophenyl)-1-cyanothioethanone solution (0.5mL, 0.12mmol, 0.25M in ethyl acetate, the compound of Example 2 A). The reaction was stirred at room temperature for 15 minutes, LC/MS analysis showed major starting material. The reaction was warmed to 45°C and after 30 minutes most of the suspension had dissolved, resulting in a cloudy solution. LC/MS analysis showed the main desired product. The reaction was shaken for an additional 2 h at room temperature, evaporated to dryness and purified by column chromatography eluting with 1-7% ethyl acetate/dichloromethane to afford the title compound as a white solid ( 9 mg, 17% overall yield over 3 steps). ¹ H NMR (CDCl ₃ ) δ12.45(s, 1H), 8.66(s, 1H), 8.18(s, 1H), 7.92(dd, 1H, J=11.4, 2.4Hz), 7.90(s, 1H) , 7.41(m, 1H), 7.29(m, 3H), 7.12(m, 2H), 4.38(q, 2H, J=7.1Hz), 3.73(s, 2H), 2.82(s, 3H), 1.40( t, 3H, J=7.1Hz); MS (ESI ⁺ ) m/z 526 (M+H) ⁺ .

Example 6

4-(4-(3-(2-(4-fluorophenyl)acetyl)thioureido)phenoxy)-5-methylpyrrolo[2,1-f][1,2,4] Ethyl triazine-6-carboxylate

A) 1-(2-(4-fluorophenyl)acetyl)-3-(4-hydroxyphenyl)thiourea

To a solution of 4-aminophenol (11 mg, 0.1 mmol, Aldrich) in _CH2Cl2 (0.55 mL) was added a solution of 2-(4-fluorophenyl)-1 _- thiocyanatoethanone (0.5 mL, 0.125 mmol, 0.25 M in ethyl acetate, compound A) of example 2. The reaction was stirred at room temperature for 10 minutes, LC/MS analysis showed the formation of the title compound. This crude reaction mixture was used directly in the next reaction.

B) 4-(4-(3-(2-(4-fluorophenyl)acetyl)thioureido)phenoxy)-5-methylpyrrolo[2,1-f][1,2, 4] Ethyl triazine-6-carboxylate

To ethyl 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (7.2 mg, 0.03 mmol) (for preparation, see US Patent 6,670,357, The disclosure of which is incorporated herein by reference) and DABCO (7 mg, 0.06 mmol) in acetonitrile (0.5 mL) at room temperature were added 1-(2-(4-fluorophenyl)acetyl)-3-(4-hydroxybenzene base) Thiourea (0.5 mL, 0.05 mmol). The reaction was shaken at room temperature. After 30 minutes, LC/MS analysis indicated mostly product. The reaction was stirred overnight at room temperature. The resulting mixture was evaporated to dryness. The resulting residue was purified by silica gel chromatography (1% methanol/dichloromethane) to give the desired product with impurities. A second purification of the above product by silica gel chromatography (1-6% ethyl acetate/dichloromethane) did not remove all impurities. The resulting solid mixture was washed with methanol and dried to give the title compound (6 mg, 39%) as a yellow solid. ¹ H NMR (CDCl ₃ ) δ12.32(s, 1H), 8.62(s, 1H), 8.16(s, 1H), 7.91(s, 1H), 7.76(m, 2H), 7.29(m, 4H) , 7.12(m, 2H), 4.38(q, 2H, J=7.1Hz), 3.72(s, 2H), 2.82(s, 3H), 1.40(t, 3H, J=7.1Hz); MS(ESI ⁺ )m/z 508(M+H) ⁺ .

Example 7

4-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)thioureido)phenoxy)-5-methylpyrrolo[2,1-f][1, 2,4] Triazin-6-yl pivalate

To 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea (60 mg, 0.19 mmol, compound A of Example 3), 4-chloro- 5-Methylpyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (50 mg, 0.19 mmol, compound D of Example 1) and 1,4-diazepine To a mixture of heterobicyclo[2.2.2]octane (DABCO, 21.3 mg, 0.19 mmol) was added MeCN (5 mL). The reaction was stirred at room temperature for 1 hour and concentrated in vacuo. _The resulting residue was purified by flash chromatography (eluting with 1-15% MeOH/ _CH2Cl2 ) to afford the title compound (91 mg, 86%) as a white solid. ¹ H NMR (CDCl ₃ ) δ.12.40(s, 1H), 8.54(s, 1H), 7.87(m, 3H), 7.29(m, 4H), 7.12(m, 2H), 3.71(s, 2H) , 2.43(s, 3H), 1.39(s, 9H); MS(ESI ⁺ ) m/z 554(M+H) ⁺ .

Example 8

4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine -6-ylpivalate

A) 1-(3-fluoro-4-hydroxyphenyl)-3-(2-phenylacetyl)thiourea

To a solution of 4-amino-3-fluorophenol (50 mg, 0.3 mmol) in _CH2Cl2 (2 _mL ) was added a solution of 2-phenyl-1-thiocyanatoethanone (2 mL, 0.4 mmol, in ethyl acetate is 0.2M, compound I) of Example 1. The reaction was stirred at room temperature for 20 minutes, LC/MS analysis showed the formation of the title compound. The above mixture was concentrated to give a residue which was used without further purification.

B) 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-5-methylpyrrolo[2,1-f][1,2,4] Triazin-6-yl pivalate

To the vial was added 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (13.3 mg, 0.19 mmol, Example 1 Compound D), 1-(3-fluoro-4-hydroxyphenyl)-3-(2-phenylacetyl)thiourea (16 mg, 0.05 mmol), cesium carbonate (a spatula tip) and DMF (2 mL) , and heated to 100° C. for 26 hours. The above mixture was concentrated under vacuum. The residue obtained above was concentrated by flash chromatography to give the title compound (6.2 mg, 25%) as a white solid. ¹ H NMR (CDCl ₃ ) δ.12.46(s, 1H), 8.50(s, 1H), 7.88(m, 3H), 7.40(m, 4H), 7.31(m, 2H), 3.75(s, 3H) , 2.44(s, 3H), 1.40(s, 9H); MS(ESI ⁺ ) m/z 536(M+H) ⁺ .

The present invention provides following technical scheme in the following aspects:

Aspect 1, the compound of formula V:

Wherein R ^a and R ^b are each methyl, ethyl or propyl.

Aspect 2, the compound of formula VI or VII:

Wherein P is a protecting group, and the protecting group is methyl ether, methoxymethyl ether, tetrahydropyranyl ether, benzyl ether, substituted benzyl ether, tert-butyl carbonate, formate, ethyl Ester, pivalate or benzoate, the substituents of the benzyl ether are selected from halogen, alkyl, alkoxy, hydroxyl, carboxyl, carbamoyl, alkoxycarbonyl, nitro, alkeneoxy group, trifluoromethyl group, amino group, cycloalkyl group, aryl group, heteroaryl group, cyano group, alkyl S(O) _m or thiol, m=0,1,2.

Aspect 3, the compound of formula VIII:

Wherein P is a protecting group and L is a leaving group, said protecting group is methyl ether, methoxymethyl ether, tetrahydropyranyl ether, benzyl ether, substituted benzyl ether, tert-butyl carbonate ester, formate, acetate, pivalate or benzoate, and the leaving group is Cl, Br or -OSO ₂ CF ₃ , and the substituent of the benzyl ether is selected from halogen, Alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkoxycarbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S(O) _m or thiol, m=0,1,2.

Aspect 4, the method for preparing the compound of formula V:

Wherein R ^a and R ^b are alkyl, the method comprises the following steps:

make the following compound

Wherein R ^c is CO ₂ ^Re , wherein R ^e is a C ₁ -C ₁₂ alkyl or a substituted C ₁ -C ₁₂ alkyl, reacted with an alkyl organometallic reagent for a period of time, wherein the alkyl organometallic reagent is Grignard reagent or organolithium reagent, wherein the substituent of the alkyl group is selected from the group consisting of alkyl, aryl, halogen, haloalkyl, alkoxy, alkylthio, hydroxyl, carboxyl, alkoxycarbonyl, alkylcarbonyloxy group, amino, carbamoyl, urea, thiol, amino, heterocycloalkyl or heteroaryl.

Aspect 5. The method of aspect 4, wherein R ^e is methyl, ethyl, butyl, tert-butyl or benzyl.

Aspect 6. The method according to aspect 5, wherein the organometallic reagent is methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium bromide, methylmagnesium iodide, ethylmagnesium iodide, methyl Lithium or ethyllithium.

Aspect 7, the method for preparing the compound of formula VI:

VI

including compounds of formula V

Wherein R ^a and R ^b are C ₁ -C ₁₂ alkyl, contact with acid for a period of time in the presence of peroxide, wherein said acid is organic acid, inorganic acid, Lewis acid or acidic ion exchange resin, said peroxide The substance is hydrogen peroxide or an organic peroxide.

Aspect 8. The method of aspect 7, wherein the acid is selected from p-toluenesulfonic acid, methanesulfonic acid, _BF3 -OEt, trifluoroacetic acid, formic acid, sulfuric acid, nitric acid, acidic zeolites and acidic ion exchange resins.

Aspect 9. The method of aspect 7, wherein the concentration of the peroxide is 30%-90%.

Aspect 10. The method of aspect 7, wherein the concentration of the peroxide is 30%-50%.

Aspect 11, the method of aspect 7, further comprising the step of quenching the reaction by adding a reducing agent, wherein the reducing agent is sodium metabisulfite, sodium bisulfite, sodium thiosulfate or sodium bisulfite.

Aspect 12. A method for preparing a compound of formula VH:

Wherein P is a protecting group, and the protecting group is methyl ether, methoxymethyl ether, tetrahydropyranyl ether, benzyl ether, substituted benzyl ether, tert-butyl carbonate, formate, ethyl Ester, pivalate or benzoate, the substituents of the benzyl ether are selected from halogen, alkyl, alkoxy, hydroxyl, carboxyl, carbamoyl, alkoxycarbonyl, nitro, alkeneoxy Base, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S(O) _m or thiol, m=0, 1, 2,

The method includes the following steps:

Make formula VI compound

Contact with an acylating agent or an alkylating agent for a period of time, wherein the acylating agent is formic acid, acetyl chloride, acetic anhydride, pivaloyl chloride, pivalic anhydride, benzoyl chloride, di-tert-butyl dicarbonate, and the The alkylating agent is selected from methyl iodide, methyl bromide, dimethyl sulfate, dimethyl carbonate, chloromethyl methyl ether, 3,4-dihydro-2H-pyran, benzyl chloride, benzyl bromine, 4-methoxybenzyl chloride or 4-methoxybenzyl bromide.

Aspect 13. A method for preparing a compound of the following formula:

Wherein L is a leaving group and P is a protecting group, the leaving group is Cl, Br or -OSO ₂ CF ₃ , and the protecting group is methyl ether, methoxymethyl ether, tetra Hydropyranyl ether, benzyl ether, substituted benzyl ether, tert-butyl carbonate, formate, acetate, pivalate or benzoate, the substituents of said benzyl ether are selected from halogen, Alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkoxycarbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S(O) _m or mercaptan, m=0, 1, 2,

The method includes the following steps:

make the following compound

contacting for a period of time with a reagent which is phenylphosphonyl dichloride, thionyl chloride, phosphorus oxybromide, trifluoromethanesulfonic anhydride, phosphorus oxychloride, phosphorus pentachloride or phosphorus oxychloride and Mixtures of phosphorus pentachloride.

Aspect 14. A method for preparing a compound of formula IX:

wherein R ² is H, halogen, cyano, NO ₂ , OR ⁵ , NR ⁶ R ⁷ , C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, C ₃ -C ₉ cycloalkyl, substituted C ₃ -C ₉ cycloalkyl, C ₆ -C ₂₂ aryl, substituted C ₆ -C ₂₂ aryl, 5-14 membered heteroaryl, substituted 5-14 membered heteroaryl, 5-11 membered Heterocyclic group, substituted 5-11 membered heterocyclic group, C ₆ -C ₂₂ aryl C ₁ -C ₁₂ alkyl, substituted C ₆ -C ₂₂ aryl C ₁ -C ₁₂ alkyl, 5-11 membered Heterocycloalkyl or substituted 5-11 membered heterocycloalkyl; and R ⁵ , R ⁶ and R ⁷ are H, C ₁ -C ₁₂ alkyl, C ₃ -C ₉ cycloalkyl, C ₆ -C ₂₂ Aryl or 5-14 membered heteroaryl; wherein the alkyl organometallic reagent is a Grignard reagent or an organolithium reagent; wherein the substituent of the alkyl is selected from the group consisting of alkyl, aryl, halogen, haloalkyl, alkane Oxygen, alkylthio, hydroxyl, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, amino, carbamoyl, urea, thiol, amino, heterocycloalkyl or heteroaryl; The substituent is selected from halogen, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo (=O), hydroxyl, alkoxy, thioalkyl, -CO ₂ H, - C(=O)H, CO ₂ , -alkyl, -C(=O)alkyl, ketone, =N-OH, =NO-alkyl, aryl, heteroaryl, heterocyclyl, five-membered or Hexaketal, -NR'R", C(=O)NR'R", CO ₂ NR'R", C(=O)NR'R", NR'CO ₂ R", NR'C(= O)R", _SO2NR'R " and _NR'SO2R ", wherein each R' and R" is independently selected from hydrogen, alkyl, substituted alkyl and cycloalkyl, or R' and R" Taken together to form a heterocyclic or heteroaryl ring; the substituents of the aryl are selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, carboxyl, carbamoyl, alkoxycarbonyl, nitro, alkenyloxy, tri Fluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S(O) _m or thiol, m=0, 1, 2; the substituent of the heteroaryl is selected from halogen , alkyl, substituted alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxyl, alkoxy, thioalkyl, -CO ₂ H, C(=O)H, -CO ₂ - Alkyl, -C(=O)alkyl, phenyl, benzyl, phenethyl, phenoxy, phenylthio, cycloalkyl, substituted cycloalkyl, heterocyclyl, heteroaryl, -NR'R",-C(=O)NR'R", -CO ₂ NR'R", -C(=O)NR'R", -NR'CO ₂ R", -NR'C(=O)R ", -SO ₂ NR'R" and -NR'SO ₂ R", wherein each R' and R" are independently selected from hydrogen, alkyl, substituted alkyl and cycloalkyl, or R' and R" together form a heterocycle or Aryl ring; the substituents of the heterocyclyl and heterocycloalkyl are selected from the group consisting of alkyl, heterocycloalkyl, heteroaryl, alkoxy, nitro, monoalkylamino, dialkylamino, cyano , halogen, haloalkyl, alkanoyl, methylaminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkylamido, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyloxy and aryl, The aryl is optionally substituted by halogen, lower alkyl and lower alkoxy; the method comprises the steps of:

Make formula VII compound

Wherein P is a protecting group and L is a leaving group, said protecting group is methyl ether, methoxymethyl ether, tetrahydropyranyl ether, benzyl ether, substituted benzyl ether, tert-butyl carbonate ester, formate, acetate, pivalate or benzoate, and the leaving group is Cl, Br or -OSO ₂ CF ₃ , and the substituent of the benzyl ether is selected from halogen, Alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkoxycarbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S(O) _m or mercaptan, m=0, 1, 2,

Exposure to substituted phenols for a period of time.

Claims (14)

1. Formula V compound:

Wherein R ^a and R ^b are each methyl, ethyl or propyl. 2. Compounds of formula VI or VII:

Wherein P is a protecting group, and the protecting group is methyl ether, methoxymethyl ether, tetrahydropyranyl ether, benzyl ether, substituted benzyl ether, tert-butyl carbonate, formate, ethyl Ester, pivalate or benzoate, the substituents of the benzyl ether are selected from halogen, alkyl, alkoxy, hydroxyl, carboxyl, carbamoyl, alkoxycarbonyl, nitro, alkeneoxy group, trifluoromethyl group, amino group, cycloalkyl group, aryl group, heteroaryl group, cyano group, alkyl S(O)m or thiol, m=0,1,2. 3. The compound of formula VIII: Wherein P is a protecting group and L is a leaving group, said protecting group is methyl ether, methoxymethyl ether, tetrahydropyranyl ether, benzyl ether, substituted benzyl ether, tert-butyl carbonate ester, formate, acetate, pivalate or benzoate, and the leaving group is Cl, Br or -OSO ₂ CF ₃ , and the substituent of the benzyl ether is selected from halogen, Alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkoxycarbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S(O) _m or thiol, m=0,1,2. 4. The method for preparing formula V compound: Wherein R ^a and R ^b are alkyl, the method comprises the following steps: make the following compound Wherein R ^c is CO ₂ ^Re , wherein R ^e is a C ₁ -C ₁₂ alkyl or a substituted C ₁ -C ₁₂ alkyl, reacted with an alkyl organometallic reagent for a period of time, wherein the alkyl organometallic reagent is Grignard reagent or organolithium reagent, wherein the substituent of the alkyl group is selected from the group consisting of alkyl, aryl, halogen, haloalkyl, alkoxy, alkylthio, hydroxyl, carboxyl, alkoxycarbonyl, alkylcarbonyloxy group, amino, carbamoyl, urea, thiol, amino, heterocycloalkyl or heteroaryl. 5. The method of claim 4, wherein ^Re is methyl, ethyl, butyl, t-butyl or benzyl. 6. The method according to claim 5, wherein said organometallic reagent is methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium bromide, methylmagnesium iodide, ethylmagnesium iodide, methyl Lithium or ethyllithium. 7. The method for preparing formula VI compound: including compounds of formula V Wherein R ^a and R ^b are C ₁ -C ₁₂ alkyl, contact with acid for a period of time in the presence of peroxide, wherein said acid is organic acid, inorganic acid, Lewis acid or acidic ion exchange resin, said peroxide The substance is hydrogen peroxide or an organic peroxide. 8. The method of claim 7, wherein the acid is selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid, _BF3 -OEt, trifluoroacetic acid, formic acid, sulfuric acid, nitric acid, acidic zeolites and acidic ion exchange resins. 9. The method of claim 7, wherein the concentration of said peroxide is between 30% and 90%. 10. The method of claim 7, wherein the concentration of said peroxide is 30% to 50%. 11. The method of claim 7, further comprising the step of quenching the reaction by adding a reducing agent, wherein the reducing agent is sodium metabisulfite, sodium bisulfite, sodium thiosulfate, or sodium bisulfite. 12. The method for preparing the compound of formula VII:

Wherein P is a protecting group, and the protecting group is methyl ether, methoxymethyl ether, tetrahydropyranyl ether, benzyl ether, substituted benzyl ether, tert-butyl carbonate, formate, ethyl Ester, pivalate or benzoate, the substituents of the benzyl ether are selected from halogen, alkyl, alkoxy, hydroxyl, carboxyl, carbamoyl, alkoxycarbonyl, nitro, alkeneoxy Base, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S(O) _m or thiol, m=0, 1, 2, The method includes the following steps: Make formula VI compound

Contact with an acylating agent or an alkylating agent for a period of time, wherein the acylating agent is formic acid, acetyl chloride, acetic anhydride, pivaloyl chloride, pivalic anhydride, benzoyl chloride, di-tert-butyl dicarbonate, and the The alkylating agent is selected from methyl iodide, methyl bromide, dimethyl sulfate, dimethyl carbonate, chloromethyl methyl ether, 3,4-dihydro-2H-pyran, benzyl chloride, benzyl bromine, 4-methoxybenzyl chloride or 4-methoxybenzyl bromide. 13. A process for the preparation of compounds of the formula: Wherein L is a leaving group and P is a protecting group, the leaving group is Cl, Br or -OSO ₂ CF ₃ , and the protecting group is methyl ether, methoxymethyl ether, tetra Hydropyranyl ether, benzyl ether, substituted benzyl ether, tert-butyl carbonate, formate, acetate, pivalate or benzoate, the substituents of said benzyl ether are selected from halogen, Alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkoxycarbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S(O) _m or mercaptan, m=0, 1, 2, The method includes the following steps: make the following compound

contacting for a period of time with a reagent which is phenylphosphonyl dichloride, thionyl chloride, phosphorus oxybromide, trifluoromethanesulfonic anhydride, phosphorus oxychloride, phosphorus pentachloride or phosphorus oxychloride and Mixtures of phosphorus pentachloride. 14. The method for preparing the compound of formula IX:

wherein R ² is H, halogen, cyano, NO ₂ , OR ⁵ , NR ⁶ R ⁷ , C ₁ -C ₁₂ alkyl, substituted C ₁ -C ₁₂ alkyl, C ₃ -C ₉ cycloalkyl, substituted C ₃ -C ₉ cycloalkyl, C ₆ -C ₂₂ aryl, substituted C ₆ -C ₂₂ aryl, 5-14 membered heteroaryl, substituted 5-14 membered heteroaryl, 5-11 membered Heterocyclic group, substituted 5-11 membered heterocyclic group, C ₆ -C ₂₂ aryl C ₁ -C ₁₂ alkyl, substituted C ₆ -C ₂₂ aryl C ₁ -C ₁₂ alkyl, 5-11 membered Heterocycloalkyl or substituted 5-11 membered heterocycloalkyl; and R ⁵ , R ⁶ and R ⁷ are H, C ₁ -C ₁₂ alkyl, C ₃ -C ₉ cycloalkyl, C ₆ -C ₂₂ Aryl or 5-14 membered heteroaryl; wherein the alkyl organometallic reagent is a Grignard reagent or an organolithium reagent; wherein the substituent of the alkyl is selected from the group consisting of alkyl, aryl, halogen, haloalkyl, alkane Oxygen, alkylthio, hydroxyl, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, amino, carbamoyl, urea, thiol, amino, heterocycloalkyl or heteroaryl; The substituent is selected from halogen, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo (=O), hydroxyl, alkoxy, thioalkyl, -CO ₂ H, - C(=O)H, CO ₂ , -alkyl, -C(=O)alkyl, ketone, =N-OH, =NO-alkyl, aryl, heteroaryl, heterocyclyl, five-membered or Hexaketal, -NR'R", C(=O)NR'R", CO ₂ NR'R", C(=O)NR'R", NR'CO ₂ R", NR'C(= O)R", _SO2NR'R " and _NR'SO2R ", wherein each R' and R" is independently selected from hydrogen, alkyl, substituted alkyl and cycloalkyl, or R' and R" Taken together to form a heterocyclic or heteroaryl ring; the substituents of the aryl are selected from the group consisting of halogen, alkyl, alkoxy, hydroxyl, carboxyl, carbamoyl, alkoxycarbonyl, nitro, alkenyloxy, tri Fluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S(O) _m or thiol, m=0, 1, 2; the substituent of the heteroaryl is selected from halogen , alkyl, substituted alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxyl, alkoxy, thioalkyl, -CO ₂ H, C(=O)H, -CO ₂ - Alkyl, -C(=O)alkyl, phenyl, benzyl, phenethyl, phenoxy, phenylthio, cycloalkyl, substituted cycloalkyl, heterocyclyl, heteroaryl, -NR'R",-C(=O)NR'R", -CO ₂ NR'R", -C(=O)NR'R", -NR'CO ₂ R", -NR'C(=O)R ", -SO ₂ NR'R" and -NR'SO ₂ R", wherein each R' and R" are independently selected from hydrogen, alkyl, substituted alkyl and cycloalkyl, or R' and R" together forming a heterocycle or Heteroaryl ring; the substituents of the heterocyclyl and heterocycloalkyl are selected from the group consisting of alkyl, heterocycloalkyl, heteroaryl, alkoxy, nitro, monoalkylamino, dialkylamino, cyano radical, halogen, haloalkyl, alkanoyl, methylaminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkylamido, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyloxy and aryl , the aryl is optionally substituted by halogen, lower alkyl and lower alkoxy; the method comprises the following steps: Make formula VII compound

Wherein P is a protecting group and L is a leaving group, said protecting group is methyl ether, methoxymethyl ether, tetrahydropyranyl ether, benzyl ether, substituted benzyl ether, tert-butyl carbonate ester, formate, acetate, pivalate or benzoate, and the leaving group is Cl, Br or -OSO ₂ CF ₃ , and the substituent of the benzyl ether is selected from halogen, Alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkoxycarbonyl, nitro, alkenyloxy, trifluoromethyl, amino, cycloalkyl, aryl, heteroaryl, cyano, alkyl S(O) _m or mercaptan, m=0, 1, 2, Contact with substituted phenols for a period of time.