TW201305153A - Triazopyridines and triazopyrazines and the composition and use thereof - Google Patents

Abstract

Compounds of formula (1) as c-Met inhibitor and pharmaceutical composition containing said compound, wherein R1-R5, X and Y are as defined in the specification.

Description

Triazolopyridine and triazolopyrazine compounds, compositions and uses thereof

The present invention relates to the field of medicine, and in particular to a c-Met inhibitor and its medical use.

The c-Met protein is a protein product encoded by the c-Met proto-oncogene. It is a 190Kd transmembrane heterodimer with tyrosine kinase activity and is also a Hepatocyte Growth Factor (HGF) receptor. . The HGF/c-Met signaling pathway has been shown to display a variety of cellular responses, including mitogenic, proliferative, morphological differentiation and pro-angiogenic activities. Inhibition of the HGF/c-Met signaling pathway has significant potential for the treatment of cancer.

The present invention provides a compound of structural formula 1:

And a pharmaceutically acceptable salt thereof, wherein X is N; Y is selected from -O-, -S- or -N(R ⁷ )-; R ^{1 is} selected from aryl and heteroaryl, aryl and heteroaryl a lower alkyl group optionally substituted by halogen, -CF ₃ , -CF ₂ H, a lower alkyl group, a hydroxy group, a lower alkyl group substituted with a lower alkoxy group, a lower alkyl group substituted by -NR ¹³ R ¹⁴ , a heterocyclic ring Substituted lower alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C( O) R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ Substituting one or more groups of -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic, heteroaryl, aryl, alkenyl, alkynyl Or X is N; Y is deleted; and R ¹ is a fused bicyclic heteroaryl group, which may optionally be halogen, -CF ₃ , -CF ₂ H, lower alkyl, hydroxy Substituted lower alkyl, lower alkoxy substituted lower alkyl, NR ¹³ R ¹⁴ substituted lower alkyl, heterocyclic substituted lower alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O )OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic, heteroaryl, aryl, alkenyl, alkynyl Substituted by one or more groups; or X is C(R ⁶ ); Y is -O-, -S- or -N(R ⁷ )-, or a deletion; R ¹ is a heteroaryl group, the heteroaryl group a lower alkyl group optionally substituted by halogen, -CF ₃ , -CF ₂ H, a lower alkyl group, a hydroxy group, a lower alkyl group substituted with a lower alkoxy group, a lower alkyl group substituted by -NR ¹³ R ¹⁴ , a heterocyclic ring Substituted lower alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C( O) R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ Substituting one or more groups of -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic, heteroaryl, aryl, alkenyl, alkynyl ; R ² and R ³ are independently selected from hydrogen and alkyl, or R ² together form from 3 to 7-membered cycloalkyl or heterocycloalkyl and R ³ and the carbon atoms to which they are attached, ; R ⁴ is selected from halo, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, any of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be optionally substituted with one or more Substituted, these groups are selected from: lower alkanes, which may optionally be selected from the group consisting of hydroxyl, lower alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ ,- Substituted by one or more groups of NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ ; lower alkoxy group, which may be optionally selected from the group consisting of halogen, hydroxy and lower alkane Substituted by one or more groups in the oxy group; a cycloalkoxy group, which may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy and lower alkoxy; heterocycloalkoxy , which may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy and lower alkoxy; heterocycles, which may optionally be selected from the group consisting of lower alkyl, halogen, hydroxy and lower alkoxy Substituted by one or more groups in the group; heteroaryloxy, which may optionally be Substituted by one or more groups selected from the group consisting of lower alkyl, halogen, hydroxy, and lower alkoxy; aryl, which may be optionally selected from the group consisting of lower alkyl, halogen, hydroxy, and lower alkoxy Substituted by one or more groups; a heteroaryl group which may be optionally substituted with one or more groups selected from the group consisting of lower alkyl, halogen, hydroxy and lower alkoxy; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ;-NR ¹³ R ¹⁴ ;-NR ¹³ C(O)R ¹¹ ;-NR ¹³ S(O) _n R ¹² ;-NR ¹³ S(O) _n NR ¹³ R ¹⁴ ;-NR ¹³ C(O)OR ¹² ;-NR ¹³ C(O)NR ¹³ R ¹⁴ ;-C(O)NR ¹³ R ¹⁴ ;-S(O) _n R ¹² ; and -S (O) _n NR ¹³ R ¹⁴ ; R ^{5 is} selected from the group consisting of hydrogen, halogen, OH, NH ₂ , CF ₃ , —CF ₂ H, alkyl, alkenyl and alkynyl; R ^{6 is} selected from hydrogen, —OH, —NH ₂ , -NHC(O)R ¹¹ , halogen and alkyl; R ^{7 is} selected from hydrogen and lower alkyl; each n is independently 0, 1 or 2; R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently Selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic, each of which may be optionally selected from the group consisting of halogen, lower alkyl, in addition to hydrogen. Hydroxyl and Alkoxy of one or more groups substituted; or R ¹³ form a heterocyclic ring together with R ¹⁴ and the nitrogen atom they are attached, the heterocyclic ring containing one or two substituents selected from -O -, - S a hetero atom of - and -N(R ¹⁵ )-, wherein the heterocyclic ring may in turn be optionally substituted with one or more groups selected from the group consisting of halogen, lower alkyl, hydroxy and lower alkoxy; and R ¹⁵ Selected from hydrogen, lower alkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -S(O) _n R ¹² and -S(O) _n NR ¹³ R ¹⁴ ; conditions are:

R ¹ is not a substituted or unsubstituted phenyl or 4-pyridyl group;

When X is N, R ² is hydrogen or methyl, R ³ and R ⁵ are hydrogen, and Y is deleted again, R ¹ is not quinoline-6-yl, 7-fluoroquinolin-6-yl, 3-quino Oxazolin-6-yl, 2,3-dihydrobenzofuran-5-yl or 2,3-dihydrobenzodioxan-6-yl;

When X is N, R ² , R ³ and R ⁵ are hydrogen, Y is -O- or -N(R ⁷ )-, R ¹ is quinoline-6-yl, 7-fluoroquinolin-6-yl, When 3-quinazolin-6-yl, 2,3-dihydrobenzofuran-5-yl or 2,3-dihydrobenzodiox-6-yl, R ⁴ is not halogen, alkyl, Cycloalkyl, heterocyclic and aryl.

The invention also provides a composition comprising at least one compound of the invention and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

The invention also provides a medicament for contacting a receptor for inhibiting c-Met activity comprising an effective amount of at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof.

The invention also provides a medicament for the treatment of cancer effective for inhibiting c-Met comprising an effective amount of at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof.

The following words, phrases and symbols used in the specification are generally defined as follows unless otherwise indicated. The following description of the meaning of the abbreviations and terms in the whole text: a short line "-" between two letters and symbols indicates a site to which a substituent is attached. For example, -CONH ₂ is attached to another group through a carbon atom.

The term "alkyl" refers to a straight or branched chain alkane containing from 1 to 10 carbon atoms. For example, alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. "Lower alkyl" means a straight or branched chain alkane having from 1 to 4 carbon atoms.

The term "alkoxy" refers to a straight or branched alkane group attached through an oxygen atom, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec. Butoxy, tert-butoxy, n-pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methyl Pentyloxy and similar groups. Alkoxy groups typically have from 1 to 6 carbon atoms bonded through an oxygen bridge. "Lower alkoxy" refers to a straight or branched alkoxy group wherein the alkyl moiety includes from 1 to 4 carbon atoms.

The term "alkenyl" refers to a straight or branched chain alkane containing one or more C=C double bonds and having between 2 and 10 carbon atoms. For example, alkenyl groups include, but are not limited to, ethenyl, 2-propenyl, 2-butenyl.

The term "alkynyl" refers to a straight or branched chain alkane having one or more C≡C triple bonds and having between 2 and 10 carbon atoms. For example, alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl.

The term "cycloalkyl" refers to a saturated or partially unsaturated cyclic alkane containing from 3 to 12 carbon atoms. For example, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The ring may be saturated or may contain one or more double bonds (ie, partially unsaturated), but is not fully conjugated.

"Aryl" includes: a 5-6 membered carbon aromatic ring, such as benzene; a bicyclic ring wherein at least one ring is a carbon aromatic ring such as naphthalene, anthracene and 1,2,3,4-tetrahydroquinoline; And a tricyclic ring in which at least one ring is a carbon aromatic ring, such as hydrazine.

For example, an aryl group includes a 5-6 membered carbon aromatic ring and a 5-7 membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, provided that the point of attachment is in the carbon aromatic ring on. A divalent radical is formed by a substituted benzene derivative and a free valence state of the atom on the ring, which is designated as a substituted phenylene radical. A divalent free radical derived from a monovalent polycyclic hydrocarbon radical named at the end of a "base" by reducing a free valence hydrogen atom, the name being the addition of a "subunit" after the corresponding monovalent radical, For example, a naphthyl group having two points of attachment is referred to as a naphthylene group. However, the aryl group does not contain, nor does it overlap in any way with the heterocyclic aryl groups respectively defined below. Thus, as defined herein, if one or more carbon aromatic rings are ring bonded to a heteroaromatic ring, the resulting ring system is a heteroaryl group rather than an aryl group.

The term "halogen" includes fluoro, chloro, bromo and iodo.

The term "heteroaryl" refers to a 5-8 membered monocyclic aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S, such as from 1 to 4 heteroatoms, and in some embodiments, 1-3 heteroatoms, the other atoms on the ring are carbon atoms; 8-12 membered bicyclic aromatic hydrocarbons containing one or more heteroatoms selected from N, O and S, such as 1-4 heteroatoms, in some implementations In the scheme, it is 1-3 heteroatoms, the other atoms in the ring are carbon atoms; at least one of the rings is an aromatic ring; and the 11-14 membered tricyclic aromatic hydrocarbons, one or more selected from N, O and S The heteroatoms, such as from 1 to 4 heteroatoms, in some embodiments, are from one to three heteroatoms, the other atoms on the ring being carbon atoms; at least one of which is an aromatic ring.

For example, a heteroaryl group includes a 5-7 membered heteroaromatic ring and a 5-7 membered cycloalkyl group. For such a heterocyclic ring group in which the bicyclic rings are combined, only one of the rings contains one or more hetero atoms, and the chain sites are on the heteroaromatic ring.

When the total number of sulfur atoms and oxygen atoms on the heteroaryl group exceeds 1, these hetero atoms are not adjacent to each other. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group does not exceed two. In some embodiments, the total number of sulfur and oxygen atoms in the heteroaryl group does not exceed one.

Examples of heteroaryl groups include, but are not limited to, (the point of attachment is preferentially labeled 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl , 2,4-pyrimidinyl, 3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl, 2,4-imidazolyl, isoxazolyl, oxazolyl, thiazole, thiadiazole , tetrazolyl, thienyl, benzothienyl, furyl, benzofuranyl, benzimidazolyl, indanyl, pyridazinyl, triazolyl, quinolyl, pyrazolyl and 5 6,6,8-tetrahydroisoquinolinyl.

A divalent heteroaryl radical derived from a hydrogen atom whose name is terminated by a "base" by reducing a free valence hydrogen atom, which is named after the name of the corresponding monovalent radical. base". For example, a pyridyl group having two attachment sites is referred to as a pyridylene group. The aromatic heterocycle does not include or overlap with the aryl groups previously described.

Substituted heteroaryl groups also include substituted heteroaryl groups such as N-oxypyridyl groups by one or more oxygen (-O-) groups.

The term "heterocycle" refers to a monocyclic aliphatic ring, typically 3-7 members, comprising at least 2 carbon atoms and 1-3 heteroatoms, the heteroatoms being independently selected from the group consisting of oxygen, sulfur and nitrogen, and including the front a combination of the at least one hetero atom. "Heterocycle" also includes a 5-7 membered heterocyclic ring containing one or more nitrogen, oxygen or sulfur heteroatoms and a 5-6 membered carbon aromatic ring, provided that the attachment site is on the heterocyclic ring. The heterocycle can be saturated or it can have one or more double bonds (ie, partially unsaturated). The heterocyclic ring may be substituted by oxo. The link point with other atoms may be a carbon atom or a hetero atom.

Corresponding heterocycles include, for example, (linker position preferentially labeled 1), 1-pyrrolidino, 2-pyrroline, 2,4-imidazolidinyl, 2,3-pyrazolyl, 1-oxime Pyridyl, 2-acridinyl, 3-acridinyl, 4-acridinyl and 2,5-pyridazinyl. The morpholinyl group is also designed in this way, including 2-morpholinyl and 3-morpholinyl (the oxygen atom is preferentially referred to as 1). Substituted heterocycles also include rings having one or more oxo groups, for example, N-oxaacridinyl, N-oxymorpholinyl, 1-oxo-1-thiomorpholinyl, and 1,1 - Dioxo-1-thiomorpholinyl.

By "optional," "optional," or "optionally" is meant that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence or non-occurrence of the thing or situation. For example, "optionally substituted alkyl" includes "alkyl" and "substituted alkyl" as defined below. When any group contains one or more substituents, it will be understood by one of ordinary skill in the art that it does not include impractical high steric hindrance, synthetically unfeasible, and/or inherently labile substituents.

The term "substituted" as used herein means that one or more hydrogen atoms in a particular atom or group are replaced by a group selected from a specified range, provided that the valence of the particular atom is normal. When the substituent is oxo (for example: =0), it means that two hydrogens on the designated atom are replaced. Combinations and/or variations of substituents are permissible as long as the combination results in a stable compound or a useful synthetic intermediate. A stable compound or stable structure means that it is stable enough to be separated from the reaction mixture and at least useful in subsequent formulation processes. Unless otherwise stated, the substituents are named into the parent core structure. For example, to put it simply, when a cycloalkylalkyl group is used as a possible substituent, the attachment site for this substituent on the parent nucleus is on the alkyl group.

In some embodiments, "substituted with one or more groups" refers to the replacement of two hydrogen atoms in a particular atom or group by the same or different groups selected from the specified range of groups, respectively. In some embodiments, "substituted with one or more groups" refers to the replacement of three hydrogen atoms in a particular atom or group by the same or different groups selected from the specified range of groups, respectively. In some embodiments, "substituted with one or more groups" refers to the replacement of four hydrogen atoms in a particular atom or group by the same or different groups selected from the specified range of groups, respectively.

Such compounds include, but are not limited to, their optical isomers, racemates, and other mixtures. In these cases, a single enantiomer or diastereomer, such as an optically active structure, can be obtained by asymmetric synthesis or by resolution of a racemic mixture or mixture of diastereomers. Resolution of the racemic mixture or mixture of diastereomers can be carried out by conventional methods, for example by crystallization with a resolving agent, or by chromatography, for example by chiral high performance liquid chromatography (HPLC). Additionally, such compounds contain Z- and E-type (or cis- and trans-) compounds containing C=C double bonds. The compounds described herein exist in various tautomers, and the term "compound" includes all tautomeric forms of the compound. The compounds herein also include their different crystalline forms, including polycrystals and clathrates. Likewise, the term "salt" also includes all isomers, racemates, other mixtures, Z- and E-forms, tautomers, and crystalline forms of the compound.

The term "pharmaceutically acceptable salts" includes, but is not limited to, salts formed with inorganic acids such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, and Similar salts; also include salts with organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, sulfonate, p-toluene Sulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate and alkanoate such as acetate, HOOC-(CH ₂ ) _n -COOH wherein n is 0- 4 salts, and similar salts. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

Further, if the compound is a salt formed with an acid, the free domain thereof can be obtained by alkalizing the salt solution. Conversely, if the compound is in the free domain, the salt, especially the pharmaceutically acceptable salt, can be prepared by conventional procedures for the acid production from the domain, i.e., the free domain is dissolved in a suitable organic solvent and then treated with an acid. One of ordinary skill in the art can recognize a variety of synthetic methods that may be used to prepare non-toxic pharmaceutically acceptable salts.

"Solvate" such as "hydrate" is formed by the interaction of a solvent and a compound. The term "compound" shall include solvates of the compounds (including hydrates of the compounds). Similarly, "salts" also include solvates of salts (such as hydrates of salts). Suitable solvates are pharmaceutically acceptable, such as hydrates, which include monohydrates and hemihydrates.

A "chelate" is a compound that is coordinated to a metal ion at two (or more) points. The term "compound" shall include a chelate of the compound. Similarly, "salts" also include salts of salts.

A "non-covalent complex" is formed by the interaction of one compound and another molecule through a non-covalent bond. For example, the complex can be formed by van der Waals forces, hydrogen bonds, and electrostatic interactions (also known as ionic bonds). These non-covalent complexes are also included in the concept of the term "compound".

The term "hydrogen bond" refers to a form in which an electronegative atom (also referred to as a hydrogen bond acceptor) and a hydrogen atom (also referred to as a hydrogen bond donor) attached to another relatively electronegative atom. Suitable hydrogen bond donors and acceptors are found in various well-known books on medicinal chemistry (GC Pimentel and AL McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R. Taylor and O. Kennard, "Hydrogen Bond Geometry in Organic Crystals" , Accounts of Chemical Research, 17, pp. 320-326 (1984)).

The term "group", "base" or "fragment" as used herein is synonymous and is used to refer to a functional group or a fragment or other molecular fragment attached to a certain bond.

The term "active ingredient" means a biologically active chemical. In some embodiments, an "active ingredient" is a chemical that has a medicinal effect.

"Treatment", "treatment" or "mitigation" refers to the administration of a compound and/or a pharmaceutically acceptable salt thereof to an individual having cancer, having symptoms of cancer, or having a predisposition to cancer. Heal, treat, alleviate, relieve, alter, heal, improve, improve, or affect cancer, cancer, or cancer.

The term "effective amount" means that the compound of the invention and/or its pharmaceutically acceptable salt is effective to "treat" a disease or discomfort in an individual. In the case of cancer, an effective amount can cause any one of the visible or detectable changes in the individual as defined in the "treatment", "treatment" and "mitigation" previously defined. For example, an effective amount can reduce the number of cancer or tumor cells; reduce the size of the tumor; inhibit or prevent the invasion of tumor cells into peripheral organs, for example, tumors spread into soft tissues or bones; inhibit or prevent tumor metastasis; inhibit or prevent tumors Growth; to some extent alleviate one or more symptoms associated with cancer; reduce morbidity and mortality; improve quality of life; or a combination of the above effects. An effective amount can be an amount that reduces the symptoms of the disease by inhibiting c-Met activity. For cancer treatment, the effects of in vivo experiments can be measured by assessing, for example, survival, Time to Disease Progression (TTP), Response Rates (RR), duration of response, and/or quality of life. The skilled person has recognized that an effective amount can vary with the route of administration, the dosage of the excipient, and the combination with other drugs.

The term "inhibition" refers to a decrease in the basal activity of a biological activity or biological process. "Inhibiting c-Met activity" means direct or indirect, directly or indirectly, from the compound of the present invention and/or a pharmaceutically acceptable salt thereof, relative to the activity of c-Met in the absence of the compound of the present invention and/or a pharmaceutically acceptable salt thereof. The effect of this results in a decrease in the activity of c-Met. The decrease in activity may be caused by a direct interaction of the compound of the present invention and/or a pharmaceutically acceptable salt thereof with c-Met, or by a compound of the present invention and/or a pharmaceutically acceptable salt thereof and one or more other The interaction of the factors, in turn, ultimately affects the activity of c-Met. For example, a compound of the present invention and/or a pharmaceutically acceptable salt thereof can reduce its activity by directly binding to c-Met, and can reduce c-Met activity by directly or indirectly affecting other factors, or by direct or indirect It is desirable to reduce the amount of c-Met in cells or organs to reduce the activity of c-Met.

One or more preferred modes of the invention will be listed below.

The present invention provides a compound of structural formula 1:

And a pharmaceutically acceptable salt thereof, wherein X is N; Y is selected from -O-, -S- or -N(R ⁷ )-; R ^{1 is} selected from aryl and heteroaryl, aryl and heteroaryl a lower alkyl group optionally substituted by halogen, -CF ₃ , -CF ₂ H, a lower alkyl group, a hydroxy group, a lower alkyl group substituted with a lower alkoxy group, a lower alkyl group substituted by -NR ¹³ R ¹⁴ , a heterocyclic ring Substituted lower alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C( O) R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ Substituting one or more groups of -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic, heteroaryl, aryl, alkenyl, alkynyl Or X is N; Y is deleted; and R ¹ is a fused bicyclic heteroaryl group, which may optionally be halogen, -CF ₃ , -CF ₂ H, lower alkyl, hydroxy Substituted lower alkyl, lower alkoxy substituted lower alkyl, NR ¹³ R ¹⁴ substituted lower alkyl, heterocyclic substituted lower alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O )OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic, heteroaryl, aryl, alkenyl, alkynyl Substituted by one or more groups; or X is C(R ⁶ ); Y is -O-, -S- or -N(R ⁷ )-, or a deletion; R ¹ is a heteroaryl group, the heteroaryl group a lower alkyl group optionally substituted by halogen, -CF ₃ , -CF ₂ H, a lower alkyl group, a hydroxy group, a lower alkyl group substituted with a lower alkoxy group, a lower alkyl group substituted by -NR ¹³ R ¹⁴ , a heterocyclic ring Substituted lower alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C( O) R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ Substituting one or more groups of -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic, heteroaryl, aryl, alkenyl, alkynyl ; R ² and R ³ are independently selected from hydrogen and alkyl, or R ² together form from 3 to 7-membered cycloalkyl or heterocycloalkyl and R ³ and the carbon atoms to which they are attached, ; R ⁴ is selected from halo, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, any of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be optionally substituted with one or more Substituted, these groups are selected from: lower alkanes, which may optionally be selected from the group consisting of hydroxyl, lower alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ ,- Substituted by one or more groups of NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ ; lower alkoxy group, which may be optionally selected from the group consisting of halogen, hydroxy and lower alkane Substituted by one or more groups in the oxy group; a cycloalkoxy group, which may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy and lower alkoxy; heterocycloalkoxy , which may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy and lower alkoxy; heterocycles, which may optionally be selected from the group consisting of lower alkyl, halogen, hydroxy and lower alkoxy Substituted by one or more groups in the group; heteroaryloxy, which may optionally be Substituted by one or more groups selected from the group consisting of lower alkyl, halogen, hydroxy, and lower alkoxy; aryl, which may be optionally selected from the group consisting of lower alkyl, halogen, hydroxy, and lower alkoxy Substituted by one or more groups; a heteroaryl group which may be optionally substituted with one or more groups selected from the group consisting of lower alkyl, halogen, hydroxy and lower alkoxy; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ;-NR ¹³ R ¹⁴ ;-NR ¹³ C(O)R ¹¹ ;-NR ¹³ S(O) _n R ¹² ;-NR ¹³ S(O) _n NR ¹³ R ¹⁴ ;-NR ¹³ C(O)OR ¹² ;-NR ¹³ C(O)NR ¹³ R ¹⁴ ;-C(O)NR ¹³ R ¹⁴ ;-S(O) _n R ¹² ; and -S (O) _n NR ¹³ R ¹⁴ ; R ^{5 is} selected from the group consisting of hydrogen, halogen, OH, NH ₂ , CF ₃ , —CF ₂ H, alkyl, alkenyl and alkynyl; R ^{6 is} selected from hydrogen, —OH, —NH ₂ , -NHC(O)R ¹¹ , halogen and alkyl; R ^{7 is} selected from hydrogen and lower alkyl; each n is independently 0, 1 or 2; R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently Selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic, each of which may be optionally selected from the group consisting of halogen, lower alkyl, in addition to hydrogen. Hydroxyl and Alkoxy of one or more substituted groups; or R ¹³ form a heterocyclic ring together with R ¹⁴ and the nitrogen atom they are attached, the heterocyclic ring containing one or two substituents selected from -O -, - S a hetero atom of - and -N(R ¹⁵ )-, wherein the heterocyclic ring may in turn be optionally substituted with one or more groups selected from the group consisting of halogen, lower alkyl, hydroxy and lower alkoxy; and R ¹⁵ Selected from hydrogen, lower alkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -S(O) _n R ¹² and -S(O) _n NR ¹³ R ¹⁴ ; conditions are:

R ¹ is not a substituted or unsubstituted phenyl or 4-pyridyl group;

When X is N, R ² is hydrogen or methyl, R ³ and R ⁵ are hydrogen, and Y is deleted again, R ¹ is not quinoline-6-yl, 7-fluoroquinolin-6-yl, 3-quino Oxazolin-6-yl, 2,3-dihydrobenzofuran-5-yl or 2,3-dihydrobenzodioxan-6-yl;

When X is N, R ² , R ³ and R ⁵ are hydrogen, Y is -O- or -N(R ⁷ )-, R ¹ is quinoline-6-yl, 7-fluoroquinolin-6-yl, When 3-quinazolin-6-yl, 2,3-dihydrobenzofuran-5-yl or 2,3-dihydrobenzodiox-6-yl, R ⁴ is not halogen, alkyl, Cycloalkyl, heterocyclic and aryl.

In some embodiments, X is N; in some embodiments, X is C(R ⁶ ); in some embodiments, R ^{6 is} selected from the group consisting of hydrogen, halogen, and lower alkyl; in some embodiments, R ⁶ It is hydrogen.

In some embodiments, Y is -O-; In some embodiments, Y is -S-; In some embodiments, Y is -N (R ⁷⁾ -; In some embodiments, R ⁷ is hydrogen or methyl; in some embodiments, R ⁷ is hydrogen; in some embodiments, Y is absent.

In some embodiments, R ¹ is 8-10 membered heteroaryl, wherein heteroaryl can be optionally substituted with lower alkyl selected from halo, -CF ₃ , -CF ₂ H, lower alkyl, hydroxy. Lower alkoxy-substituted lower alkyl, NR ¹³ R ¹⁴ substituted lower alkyl, heterocyclic substituted lower alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ ,- CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic ring Substituting one or more of the heteroaryl, aryl, alkenyl and alkynyl groups. In some embodiments, R ¹ is 8-10 membered heteroaryl, wherein heteroaryl can be optionally substituted by lower alkyl selected from halo, lower alkyl, hydroxy substituted lower alkyl, and lower alkoxy. Replaced by one or more of the groups.

In some embodiments, R ^{1 is} selected from the group consisting of quinoline-6-yl, thieno[3,2-c]pyridin-2-yl, benzo[d]thiazol-6-yl, and imidazo[1,2- a] Pyridine-6-yl, which may be optionally substituted with one or more groups selected from the group consisting of halogen, lower alkyl, hydroxy-substituted lower alkyl and lower alkoxy substituted lower alkyl. In some embodiments, R ^{1 is} selected from quinolin-6-yl, which may be optionally one selected from the group consisting of halogen, lower alkyl, hydroxy-substituted lower alkyl, and lower alkoxy substituted lower alkyl or Replaced by multiple groups.

In some embodiments, R ^{1 is} selected from the group consisting of:

Any one of the rings may be optionally substituted by a lower alkyl group selected from the group consisting of halogen, -CF ₃ , -CF ₂ H, lower alkyl, hydroxy-substituted lower alkyl, lower alkoxy-substituted lower alkyl, NR ¹³ R ¹⁴ Alkyl, heterocyclic substituted lower alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O One or more of NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic, heteroaryl, aryl, alkenyl and alkynyl groups Replaced by a group. Any of the above positions on each ring can be attached as a connection point to the carbon supporting R ² and R ³ .

In some embodiments, R ^{1 is} selected from the following heteroaryl groups:

Any of which rings may be optionally substituted by one or more radicals, these radicals selected from halogen, -CF _3, -CF ₂ H, substituted lower alkyl, hydroxy-substituted lower alkyl, lower alkoxy Lower alkyl, NR ¹³ R ¹⁴ substituted lower alkyl, heterocyclic substituted lower alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O) NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C( O) OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic ring, heteroaryl group, aryl group , alkenyl, alkynyl. For the avoidance of doubt, the various rings described above are attached to the carbon supporting R ² and R ³ at the locations shown.

In some embodiments, R ² and R ^{3 are} independently selected from hydrogen and C ₁ -C ₆ alkyl; or R ² and R ³ together with the carbon atom to which they are attached form a cyclopropyl group. In some embodiments, R ² is hydrogen and R ^{3 is} selected from hydrogen and C ₁ -C ₆ alkyl. In some embodiments, R ² is hydrogen and R ^{3 is} selected from hydrogen and methyl. In some embodiments, both R ² and R ³ are hydrogen. In some embodiments, R ² and R ³ together with the carbon atom to which they are attached form a cyclopropyl group.

In some embodiments, R ⁴ is aryl, and the aryl group can be optionally substituted with one or more groups selected from the group consisting of lower alkyl groups, which can be optionally selected from the group consisting of hydroxyl groups, Lower alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , one of -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ or Substituted by a plurality of groups; lower alkoxy, which may be optionally substituted with one or more of halogen, hydroxy and lower alkoxy; heterocycle, which may optionally be selected from lower alkyl Substituted by one or more of a halogen, a hydroxyl group and a lower alkoxy group; a heteroaryloxy group which may optionally be selected from one or more selected from the group consisting of lower alkyl, halogen, hydroxy and lower alkoxy Substituted by a group; an aryl group, which may be optionally substituted with one or more groups selected from the group consisting of lower alkyl, halogen, hydroxy and lower alkoxy; heteroaryl, which may optionally be Substituted from lower alkyl, halogen, hydroxy and lower alkoxy Halogen; ^{cyano; -C (O) R 11;} -C (O) OR 11; -NR 13 R 14; -NR 13 C (O) R 11; -NR 13 S (O) n R 12; -NR ¹³ S(O) _n NR ¹³ R ¹⁴ ;-NR ¹³ C(O)OR ¹² ;-NR ¹³ C(O)NR ¹³ R ¹⁴ ;-C(O)NR ¹³ R ¹⁴ ;-S(O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ .

In some embodiments, R ⁴ is aryl, which may be optionally substituted by a lower alkyl group selected from the group consisting of halogen, hydroxy, lower alkoxy, lower alkyl, hydroxy-substituted lower alkyl, lower alkoxy, The hydroxy-substituted lower alkoxy group, the lower alkoxy-substituted lower alkoxy group and one or more groups of -NR ¹³ S(O) _n R ¹² are substituted.

In some embodiments, R ⁴ is phenyl, which may be optionally one or more selected from the group consisting of lower alkoxy, hydroxy-substituted lower alkoxy, and lower alkoxy-substituted lower alkoxy. Replaced by the regiment.

In some embodiments, R ⁴ is a heterocyclic ring, which is optionally substituted with one or more groups selected from the group consisting of lower alkyl, which may be optionally selected from hydroxy, lower alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S (O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ one or more groups Substituted; lower alkoxy, which may be optionally substituted by one or more of halogen, hydroxy and lower alkoxy; heterocycle, which may be optionally selected from lower alkyl, halo, hydroxy and Substituted by one or more groups in the lower alkoxy group; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ; -NR ¹³ R ¹⁴ ;-NR ¹³ C(O)R ¹¹ ; -NR ¹³ S(O) _n R ¹² ; -NR ¹³ S(O) _n NR ¹³ R ¹⁴ ; -NR ¹³ C(O)OR ¹² ; -NR ¹³ C(O)NR ¹³ R ¹⁴ ;-C (O)NR ¹³ R ¹⁴ ; -S(O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ .

In some embodiments, R ⁴ is selected from pyrrolidin-1-yl, piperidine-1-yl, tetrahydro -2H- pyran-4-yl, morpholin-4-yl and 6,7-dihydro- Thieno[3,2-c]pyridine-5(4H)-yl, any of which may be optionally substituted by one or more groups selected from lower alkyl, which may be The ground is selected from the group consisting of hydroxyl, lower alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR Substituted by one or more groups of ¹³ R ¹⁴ ; lower alkoxy, which may be optionally substituted by one or more of halogen, hydroxy and lower alkoxy; heterocyclic ring, optionally Substituted by one or more groups selected from the group consisting of lower alkyl, halogen, hydroxy and lower alkoxy; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ;-NR ¹³ R ¹⁴ ;-NR ¹³ C(O)R ¹¹ ;-NR ¹³ S(O) _n R ¹² ;-NR ¹³ S(O) _n NR ¹³ R ¹⁴ ;-NR ¹³ C(O)OR ¹² ;-NR ¹³ C(O)NR ¹³ R ¹⁴ ;-C(O)NR ¹³ R ¹⁴ ;-S(O) _n R ¹² ; and -S(O)nNR ¹³ R ¹⁴ .

In some embodiments, R ⁴ is selected from pyrrolidin-1-yl, piperidine-1-yl, tetrahydrofuran hydrogen -2 - pyran-4-yl, morpholin-4-yl and 6,7-dihydro- Thieno[3,2-c]pyridine-5(4-hydro)-yl, any of which may optionally be substituted by halogen, CF ₃ , —CF ₂ H, hydroxy, lower alkyl, hydroxy substituted Substituted by one or more of the alkyl and lower alkoxy substituted lower alkyl groups.

In some embodiments, R ⁴ is heteroaryl, which may be optionally substituted with one or more groups selected from lower alkyl, which may be optionally selected from hydroxy, lower alkoxy , CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ One or more groups of S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ Substituted; lower alkoxy, which may be optionally substituted by one or more of halogen, hydroxy and lower alkoxy; heterocycle, which may optionally be selected from lower alkyl, halogen, hydroxy And one or more groups in the lower alkoxy group; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ; -NR ¹³ R ¹⁴ ;-NR ¹³ C(O) R ¹¹ ; -NR ¹³ S(O) _n R ¹² ; -NR ¹³ S(O) _n NR ¹³ R ¹⁴ ; -NR ¹³ C(O)OR ¹² ; -NR ¹³ C(O)NR ¹³ R ¹⁴ ;- C(O)NR ¹³ R ¹⁴ ; -S(O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ .

In some embodiments, R ^{4 is} selected from the group consisting of 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazole-4 -yl,oxazol-2-yl, thiazol-2-yl, isoxazol-3-yl, isoxazol-5-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, thiophene- 2-Based, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, the above groups may be optionally substituted by one or more of the following groups selected from these groups From lower alkyl, which may be optionally selected from the group consisting of hydroxy, lower alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC (O) R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and Substituted by one or more groups of -NR ¹³ C(O)NR ¹³ R ¹⁴ ; lower alkoxy, which may be optionally substituted by one or more of halogen, hydroxy and lower alkoxy a heterocyclic ring which may be optionally substituted by one or more groups selected from the group consisting of lower alkyl, halogen, hydroxy and lower alkoxy; halogen; cyano; -C(O)R ¹¹ ;-C (O)OR ¹¹ ;-NR ¹³ R ¹⁴ ;-NR ¹³ C(O)R ¹¹ ;-NR ¹³ S(O) _n R ¹² ;-NR ¹³ S(O) _n NR ¹³ R ¹⁴ ;-NR ¹³ C(O)OR ¹² ;-NR ¹³ C(O)NR ¹³ R ¹⁴ ;-C(O)NR ¹³ R ¹⁴ ; -S(O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ .

In some embodiments, R ^{4 is} selected from the group consisting of 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazole-4 -yl,oxazol-2-yl, thiazol-2-yl, isoxazol-3-yl, isoxazol-5-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, thiophene- 2-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, the above groups may be optionally substituted by one or more of the following groups, these groups being selected From lower alkyl, which may be optionally selected from the group consisting of hydroxy, lower alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC (O) R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and Substituting one or more groups of -NR ¹³ C(O)NR ¹³ R ¹⁴ ; a heterocyclic ring, which may optionally be selected from one or more selected from the group consisting of lower alkyl, halogen, hydroxy and lower alkoxy Replaced by a group.

In some embodiments, R ^{4 is} selected from the group consisting of 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazole-4 -yl,oxazol-2-yl, thiazol-2-yl, isoxazol-3-yl, isoxazol-5-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, thiophene- 2-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, which may be optionally substituted by one or more groups selected from lower alkyl groups, wherein The lower alkyl group may be optionally substituted with one or more groups selected from a hydroxyl group, a lower alkoxy group, a cyano group or a halogen.

In some embodiments, R ⁴ is lower alkyl.

In some embodiments, R ⁵ is hydrogen.

In some embodiments, n is zero. In some embodiments, n is one. In some embodiments, n is 2.

The present invention also provides at least one compound selected from the group consisting of Compounds 1 to 332 and/or at least one pharmaceutically acceptable salt thereof.

The compound of the present invention and/or its pharmaceutically acceptable salt can be synthesized by a known method using a commercially available raw material. The synthesis of most of the compounds is shown in the following two routes. In each route, LG and LG' represent the same or different leaving groups. Y' is -NHR ⁷ , -OH, -SH, -B(OH) ₂ or B(OR') ₂ , and R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Y have been defined as before.

The obtained compound can be further modified by the peripheral position to obtain other target compounds of the present invention.

The synthetic chemical modifications described are well known in the art, such as R. Larock, Comprehensive Organic Transformations , VCHPublishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3 ^rd Ed., John Wiley and Sons ( 1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995) and It is published in subsequent versions.

The compound of the present invention and/or its pharmaceutically acceptable salt can be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable conditions before use.

The invention also provides a pharmaceutical composition comprising at least one compound of the invention and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

Compositions comprising a compound of the invention and/or a pharmaceutically acceptable salt thereof can be administered orally, parenterally, by inhalation spray, or in an implantable reservoir. The term "parenteral" as used herein, refers to subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intraspinal, intralesional, and intracranial injection or infusion. technology.

The compositions for oral administration can be any of the acceptable oral dosage forms including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions, and solutions. Commonly used tablet carriers include lactose and corn starch. Lubricants such as magnesium stearate are also often added to tablets. When administered orally in a capsule form, effective diluents can include lactose as well as dried corn starch. When orally administered as an aqueous suspension or emulsion, the active ingredient may be suspended or dissolved in an oil phase using an emulsifying or suspending agent. Add some sweeteners, flavors, or colors if needed.

Sterile injectable compositions (e.g., aqueous or oily suspensions) can be prepared according to any of the known techniques using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents. Sterile injectable compositions can also be prepared in a sterile injectable solution or dispersion in a non-toxic parenteral diluent or solvent, for example, a 1,3-butanediol solution. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution, and physiological saline. In addition, sterile low boiling oils, such as synthetic mono- or di-glycerides, are typically solvents or suspending media. Fatty acids, such as oleic acid and its glycerolipid derivatives, as well as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in the form of polyethoxylated, are commonly used in the preparation of injectable solutions. These oil solutions or suspensions may also contain a long chain alcohol diluent, dispersant, or carboxymethyl cellulose, or a similar dispersing agent.

The inhalant composition can be prepared according to known pharmaceutical formulation techniques and can be prepared in physiological saline with the addition of benzyl alcohol or other suitable preservatives, bioavailability absorption enhancers, fluorocarbons, and/or Or other solubilizing or dispersing agents known in the art.

Compositions for the skin can be formulated as oils, creams, lotions, ointments, and the like. Suitable carriers for the compositions may include: vegetable or mineral oil, white petrolatum (a white soft paraffin), branched chain fats or fats, animal fats, and high molecular weight alcohols (greater than 12 carbons). Preferred carriers may be those in which the active ingredient is soluble. In addition, emulsifiers, solubilizers, diluents, and antioxidants may be added as needed in addition to adding color or aroma components. Skin penetration enhancers can also be added to these typical formulations. Examples of such accelerators can be found in U.S. Patents 3,989,816 and 4,444,762.

The cream formulation may be a mixture of mineral oil, self-emulsified beeswax, and water, wherein the mixed active ingredients are dissolved in a small amount of oil, such as almond oil, and then doped therein. An example of such an emulsion is comprising about 40 parts by weight of water, about 20 parts by weight of beeswax, about 40 parts by weight of mineral oil, and about 1 part by weight of almond oil. The ointment can be prepared by mixing an active ingredient in a vegetable oil (for example, almond oil), and warm soft paraffin, and allowing the mixture to cool. An example of such an ointment is about 30% by weight of almond oil and about 70% by weight of white soft paraffin.

"Pharmaceutically acceptable carrier" means a carrier which is compatible with the active ingredient in the composition, even in some preferred modes, which is capable of stabilizing the active ingredient and which is not deleterious to the individual to be treated. For example, a cyclodextrin (a solubilizing agent capable of forming a specific, more soluble complex with the compound of the present invention and/or a pharmaceutically acceptable salt thereof) can be used as a carrier for pharmaceutical delivery of the active compound. Examples of other carriers include colloidal cerium oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10.

Suitable in vitro assays can be used to early evaluate the effect of the compounds of the invention and/or their pharmaceutically acceptable salts on inhibiting c-Met activity, and the effect of treating cancer can be further tested by in vivo experiments. For example, a compound of the present invention and/or a pharmaceutically acceptable salt thereof can be administered to an animal having a cancer such as a mouse model, and then the therapeutic effect thereof can be examined. Based on the above results, it is also possible to determine the dosage and mode of administration appropriate for the animal (e.g., human).

The present invention also provides a method of inhibiting c-Met activity, which comprises contacting a compound of the present invention and/or a pharmaceutically acceptable salt thereof in an amount effective to inhibit c-Met activity with the receptor. The invention therefore also provides a medicament for contacting a receptor for inhibiting c-Met activity comprising an effective amount of a compound of the invention and/or a pharmaceutically acceptable salt thereof.

The present invention also provides a medicament for treating a cancer which inhibits c-Met from being effective, which comprises an effective amount of a compound of the present invention and/or a pharmaceutically acceptable salt thereof.

The invention also provides a method of treating cancer, in particular a cancer against which c-Met is effective, comprising administering to a subject having cancer a therapeutically effective amount of a compound of the invention and/or a pharmaceutically acceptable salt thereof .

The compounds of the invention and/or their pharmaceutically acceptable salts can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in an individual having cancer. The term "cancer" as used herein, refers to a cellular disorder characterized by uncontrolled or non-adjustable cell proliferation, decreased cell differentiation, inappropriate invasion of surrounding tissues, and/or establishment of new growth at abnormal sites. ability. The term "cancer" includes, but is not limited to, solid tumors and hematological tumors. The term "cancer" encompasses diseases of the skin, tissues, organs, bones, cartilage, blood and blood vessels. The term "cancer" further encompasses primary cancers and metastatic cancers.

Non-limiting examples of solid tumors include pancreatic cancer, bladder cancer, colorectal cancer, breast cancer (including metastatic breast cancer), prostate cancer (including androgen-dependent and non-androgen-dependent prostate cancer), and renal cancer (including Metastatic renal cell carcinoma), hepatocellular carcinoma, lung cancer (including non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC) and lung adenocarcinoma), ovarian cancer ( Including progressive epidermal cancer or progressive primary peritoneal cancer), cervical cancer, gastric cancer, esophageal cancer, head and neck cancer (including head and neck squamous cell carcinoma), skin cancer (including malignant melanoma), neuroendocrine system cancer (including Metastatic neuroendocrine tumors, brain tumors (including, for example, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme), bone cancer, soft tissue sarcoma, and thyroid cancer.

Non-limiting examples of hematological tumors include acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML) (including chronic myeloid leukemia during accelerated phase and chronic blast crisis) Myeloid leukemia (CML-BP), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's disease (HD) ), non-Hodgkin's lymphoma (NHL) (including follicular lymphoma and mantle cell lymphoma), B-cell lymphoma, T-cell lymphoma (T- Cell lymphoma), multiple myeloma (MM), Waldenstrom's macroglobulinemia, myelodysplastic syndromes (MDS) (including refractory) Anemia (RA)), refractory anemia with ringed siderblasts (RARS), refractory anemia with excess blasts (RAEB), and excessive bud cell stubbornness Solid anemia combined with acute transformation (RAEB in transformation (RAEB-T)), and myeloproliferative syndrome.

In some embodiments, examples of cancers that can be treated include, but are not limited to, lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, stomach cancer, kidney cancer, liver cancer, brain Cancer, bone cancer and leukemia.

The present invention also provides a pharmaceutical combination for treating a cancer effective for inhibiting c-Met, comprising an effective amount of a compound of the present invention and/or a pharmaceutically acceptable salt thereof; and an amount of a compound different from the present invention and/or Or a therapeutic preparation of a pharmaceutically acceptable salt thereof (preferably an antitumor preparation).

In some embodiments, the compounds of the invention and/or pharmaceutically acceptable salts thereof, can be administered in combination with other therapeutic agents. In some embodiments, the additional therapeutic agent is a formulation that is typically administered to a patient having the disease or condition being treated. The compounds of the invention and/or their pharmaceutically acceptable salts can be administered in a single dosage form with other therapeutic preparations or in separate dosage forms. When administered in separate dosage forms, other therapeutic formulations can be administered prior to, concurrently with, or subsequent to administration of the compound of the invention and/or its pharmaceutically acceptable salts.

In some embodiments, the compounds of the invention and/or pharmaceutically acceptable salts thereof can be administered in combination with other anti-tumor agents. The term "anti-tumor preparation" as used herein refers to any preparation for treating a tumor in a tumor patient. Non-limiting examples of anti-tumor agents include: radiotherapeutic formulations, immunotherapeutic formulations, chemotherapeutic agents for DNA damage, and chemotherapeutic agents that interfere with cell replication.

Non-limiting examples of chemotherapeutic agents for DNA damage include inhibitors of local isomerase I (eg, irinotecan, topotecan, and camptothecin, and their analogs, Metabolites, and doxorubicin); topoisomerase II inhibitors (eg, etoposide, teniposide, and daunorubicin); alkylating agents (eg, melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, nitrosourea mustard (carmustine), lomustine, semustine, streptozocin, decarbazine, methotrexate, mitosis Molecular C (mitomycin C) and cyclophosphamide; DNA inserts (eg, cisplatin, oxaliplatin, and carboplatin); DNA inserts and freedom a base generator such as bleomycin; and a nucleoside mimicking agent such as 5-fluorouracil or capecitibine 2,2-difluorodeoxycytidine (gemcitabine), fludarabine (fludarabine), cytarabine, mercaptopurine, thioguanine, pentastatin ( Pentostatin) and hydroxyurea).

Chemotherapeutic agents that interfere with cell replication include: paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; sedatives (thalidomide) And related analogues (eg CC-5013 and CC-4047); protein tyrosine kinase inhibitors (eg imatinibmesylate and gefitinib); proteasome inhibition Agents (eg, bortezomib); NF-κB inhibitors, including lκB kinase inhibitors; bind to proteins overexpressed in tumors, thereby downregulating antibodies to cell replication (eg trastuzumab, Rituximab, cetuximab and bevacizuma; and other protein or enzyme inhibitors, these proteins or enzymes are known to be elevated in tumors, Overexpression or initiation, inhibition of these proteins or enzymes can inhibit cell replication.

The following examples are to be considered in all respects as illustrative and not restrictive. The data used (eg, volume, temperature, etc.) strives to ensure its accuracy, but there are also some experimental errors and offsets. Unless otherwise stated, parts are parts by weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure. All mass spectral data were measured by Agilent 6120 and 1100. All reagents (except intermediates) used in the present invention are obtained commercially. The names of all compounds (except reagents) were generated by the software Chemdraw 8.0.

A list of abbreviations used in the following examples:

AIBN azobisisobutyronitrile

BINAP bis-diphenylphosphonium naphthalene

Boc tert-butoxycarbonyl

Boc ₂ O di-tert-butyl dicarbonate

i-BuNO ₂ isobutyl nitrite

DMF N,N-dimethylformamide

DMAP 4-dimethylaminopyridine

DPPA diphenyl phosphate

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DEA N,N-diethylamine

Ee enantiomeric excess

Et ₃ N triethylamine

HATU 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate

HMTA hexamethyltetramine

NBS N-brominated diimide

Pd(dppf)Cl ₂ [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex

Pd ₂ (dba) ₃ tris(dibenzylideneacetone) dipalladium

Pd(PPh3) ₄ tetrakisphenylphosphine palladium

PPh ₃ triphenylphosphine

Ti(i-OPr) ₄ tetraisopropoxy titanium

Xantphos 4,5-bis-diphenylphosphino-9,9-dimethyloxaxan

Amine synthesis (NH in Route I and Route II) ₂ CR ¹ R ² R ³ ): Intermediate A:

Compound A-2

The raw material A-1 (7.23 g, 61.2 mmol) was dissolved in a mixed solvent of acetic acid (20 ml) and water (40 ml), and HMTA (9.42 g, 67.3 mmol) was added thereto, followed by stirring at 120 ° C 6 hours. After completion of the reaction, the mixture was cooled in an ice bath, and precipitated, which was filtered and dried to give the product 7.90 g. MS (m/z): 147 (M + 1) ⁺ .

Compound A-3

Starting material A-2 (5.0 g, 34.21 mmol) was dissolved in ethanol (150 ml), and sodium borohydride (1.30 g, 34.21 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 0.5 hr. MS (m/z): 149 (M + 1) ⁺ .

Compound A-4

The starting material A-3 (1.0 g, 6.75 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml), and then DPPA (3.71 g, 13.5 mmol) and DBU (0.821 g, 5.4 mmol) Reflow under protection for 6 hours. After completion of the reaction, the residue was evaporated. MS (m/z): 174 (M+1) ⁺ .

Compound A

Starting material A-4 (1.50 g, 8.63 mmol) was dissolved in ethyl acetate (150 ml), and then 10% Pd/C (1.10 g) was added, and the mixture was stirred at room temperature under hydrogen for 3 hours. After completion of the reaction, the mixture was filtered.

Intermediate B:

Compound B-2

Methylmagnesium bromide (42 ml, 3 M in diethyl ether) was gradually added dropwise to a solution of B-1 (7.88 g, 50.0 mmol) in anhydrous tetrahydrofuran (100 ml) at 0 ° C. The mixture was stirred at 0 ° C for 0.5 hour and then reacted at room temperature overnight. After completion of the reaction, the mixture was poured into EtOAc EtOAc. MS (m/z): 156 (M + 1) ⁺ .

Compound B-3

Starting material B-2 (6 g, 38.6 mmol) was dissolved in pyridine (80 ml), and 85% hydrazine hydrate (9.1 g, 154.4 mmol) was added thereto, and the reaction mixture was refluxed overnight. After cooling, it was concentrated, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ MS (m/z): 134 (M + 1) ⁺ .

Compound B-4

The starting material B-3 was dissolved in ethyl acetate (300 ml), and (Boc) ₂ O (16.4 g, 75 mmol), DMAP (610 mg, 5 mmol) and Et ₃ N (10 g) were sequentially added thereto. , 100 mmol), stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated, and the residue was purified mjjjjj MS (m/z): 134.

Compound B-5

Starting material B-4 (699 mg, 3 mmol) was dissolved in carbon tetrachloride (15 ml), and NBS (641 mg, 3.6 mmol) and AIBN (70 mg, 0.3 mmol) were added thereto, and the reaction was refluxed overnight. . After completion of the reaction, the solid was filtered off, the mixture was washed with saturated aqueous sodium sulfate, dried over anhydrous sodium sulfate and evaporated. MS (m/z): 212 (M+1) ⁺ .

Compound B-6

The crude product B-5 was dissolved in DMF (6 ml), and sodium azide (390 mg, 6 mmol) was added thereto, and reacted at 80 ° C for 1.5 hours. After cooling, water was added, and the mixture was evaporated, evaporated, evaporated, evaporated

Compound B

The starting material B-6 (152 mg, 0.87 mmol), PPh ₃ (465 mg, 1.74 mmol) and 1 ml of aqueous ammonia was added to 20 ml of tetrahydrofuran, stirred overnight at room temperature. After completion of the reaction, the mixture was evaporated. EtOAc mjjjjjjjj MS (m/z): 149 (M + 1) ⁺ .

Intermediate C:

Compound C-2

The starting material C-1 (1.01 g, 7.29 mmol) and potassium carbonate (1.10 g, 7.96 mmol) were dissolved in a mixed solvent of DMF (10 ml) and water (1 ml), and thioglycolic acid was added dropwise to the solution. Methyl ester (0.709 ml, 7.93 mmol) was stirred at 40 ° C for 3 h. After completion of the reaction, it was poured into ice water, and the precipitated solid was filtered to obtain a product. MS (m/z): 209 (M + 1) ⁺ .

Compound C-3

Compound C-2 (930 mg, 4.47 mmol) was dissolved in 50% hypophosphite (35 ml), and a solution of sodium nitrite (620 mg, 8.98 mmol) in water (small amount) was added dropwise under ice bath. In the solution, the reaction solution was further stirred under ice bath for 3 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to about 7.0, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and evaporated. MS (m/z): 194 (M + 1) ⁺ .

Compound C-4

The raw material C-3 (600 mg, 3.1 mmol) was dissolved in anhydrous tetrahydrofuran (30 ml), and the solution of lithium aluminum hydride (472 mg, 12.4 mmol) in tetrahydrofuran was slowly added dropwise thereto under ice cooling, and then Stirring was continued at 0 ° C for 30 minutes. After completion of the reaction, methanol was added to quench and the product was isolated by chromatography. MS (m/z): 166 (M + 1) ⁺ .

Compound C-5

The material C-4 (17 mg, 0.1 mmol) was dissolved in dry dichloromethane (20 mL). Get the product. MS (m/z): 184 (M + 1) ⁺ .

Compound C

The starting material C-5 (183 mg, 1 mmol) was dissolved in a methanol solution of ammonia (7 M, 10 ml), and then reacted in a closed system at 50 ° C for 16 hours, cooled, and concentrated to give a residue. The product was isolated by column chromatography. Yield: 61%. MS (m/z): 165 (M + 1) ⁺ .

Intermediates D and D':

Compound D-2

The raw material D-1 (1.4 g, 10 mmol) was dissolved in a mixed solvent of 10 ml of DMF and 1 ml of water, and K ₂ CO ₃ (1.66 g, 12 mmol) was slowly added thereto under cooling in an ice bath. Methyl α-mercaptoacetate (1.07 mL, 12 mmol) was then reacted at 45 ° C overnight. After completion of the reaction, ice water was added, and a solid precipitated, which was filtered and dried to give the product 1.23 g. MS (m/z): 194 (M+1) ⁺ .

Compound D-3

Starting material 0-2 (15 g, 77.6 mmol) was dissolved in 250 ml of dry tetrahydrofuran, and LiAlH ₄ (4.42 g, 116.4 mmol) was slowly added portionwise, and then the reaction was stirred for 1 hour. After completion of the reaction, it was quenched with EtOAc EtOAc. (10.3 g).

Compound D-4

Starting material D-3 (3.2 g, 19.4 mmol) was dissolved in dry tetrahydrofuran, and DPPA (8 g, 6.26 ml, 29.1 mmol) was added thereto, stirred for 5 minutes, and then DBU (4.43 g) was added at 0 °C. , 4 ml, 29.1 mmol, and the reaction solution was refluxed overnight. After cooling, water was added, extracted with diethyl ether, the organic phase was dried with Na ₂ SO _4, concentrated and the resulting residue was subjected to column chromatography was, to give 3.27 g product. MS (m/z): 191 (M+1) ⁺ .

Compound D

The starting material D-4 (3 g, 15.8 mmol) was dissolved in dry tetrahydrofuran (50 ml), and thereto was added Ph ₃ P (8.27 g, 31.5 mmol) and aqueous ammonia (2 mL) were stirred at rt overnight . After completion of the reaction, the mixture was concentrated.

Compound D'-1

The material D-2 (12 g, 62.1 mmol) was dissolved in a mixed solvent of methanol (50 ml) and water (15 ml), and LiOH. H ₂ O (5.2 g, 124.2 mmol) was added thereto and stirred overnight. . After completion of the reaction, the pH was adjusted to about 3 with a 1 N hydrochloric acid solution, filtered and dried to give a product. MS(m/z): 179(M) ⁺

Compound D'-2

The starting material D'-1 (11.5 g, 64.2 mmol) was dissolved in a mixed solvent of 200 ml of dichloromethane and 20 ml of DMF, and Et ₃ N (19.5 g, 26.6 ml, 192.6 mmol) and HATU were respectively added thereto. (36.6 g, 96.3 mmol), stirred at room temperature for 20 min then added N,O -dimethylhydroxylamine hydrochloride (6.9 g, 70.6 mmol). After the consumption of the starting material, the methylene chloride was evaporated under reduced pressure, and the residue was crystallised from ethyl acetate, and washed with water and saturated brine. MS(m/z): 223(M+1) ⁺

Compound D'-3

The material D'-2 (11.1 g, 50 mmol) was dissolved in dry THF (150 ml), and then a solution of MeMgBr in diethyl ether (3 M diethyl ether solution, 25 ML, 75 mmol), warmed to room temperature and stirred overnight. After completion of the reaction, quenched with saturated NH ₄ Cl solution, extracted with ethyl acetate, the organic phase was dried and concentrated to give the product. MS (m/z): 178 (M+1) ⁺

Compound D'-4

The material D'-3 (3.5 g, 1 mmol) was dissolved in tetrahydrofuran solution (50 ml) at 0 ° C, and LiAlH ₄ (1.13 g, 1.5 mmol) was added portionwise at this temperature. The reaction was stirred for 1 hour and then quenched with saturated NH ₄ Cl solution, filtered, and the filter cake was washed with an appropriate amount of tetrahydrofuran, and the filtrate was washed with saturated brine, concentrated and used directly in the next step.

Compound D’

This compound was prepared by the synthesis of intermediates A-3 to A. using D'-4 as a starting material.

Intermediate E:

Compound E- 2

This compound was prepared by the synthesis of Intermediate A-2 to A-3 using E-1 as a starting material. MS (m/z): 166 (M+1) ⁺ .

Compound E

This compound was prepared by the synthesis of Intermediate C-4 to C using E-2 as a starting material. MS (m/z): 165 (M+1) ⁺ .

Intermediate F:

Compound F-2

F-1 (14.0 g, 0.1 mol) was dissolved in methanol (250 ml), and concentrated sulfuric acid (2.0 ml) was added thereto, and the mixture was refluxed for 60 h. After cooling, it was concentrated, diluted with EtOAc EtOAc EtOAc.

Compound F-3

The starting material F-2 (13.4 g, 86.0 mmol) was dissolved in concentrated sulfuric acid (30 ml), and the mixture was evaporated. The mixed solution was stirred at 0 ° C for 30 minutes, then poured into ice water, and a solid was precipitated and filtered to give a product (14.8 g).

Compound F-4

The starting material F-3 (14.8 g, 73.6 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran (1:1, 300 ml), Raney nickel was added thereto, and after the hydrogen was replaced, the reaction liquid was stirred under a hydrogen atmosphere. hour. After completion of the reaction, the mixture was filtered, and the filtrate was evaporated. EtOAcjjjjjjjjjjjjj The organic phase was combined, dried over anhydrous sodium sulfate and evaporated

Compound F-5

Starting material F-4 (5.1 g, 30 mmol) was dissolved in toluene (120 ml), and acetic anhydride (16.0 g, 0.12 mol) and potassium acetate (1.5 g, 15.1 mmol) were added thereto, and stirred at 100 ° C. After 3 hours, it was cooled to room temperature, and isobutyl nitrite (10.5 g, 90.0 mmol) was added, and the reaction was continued at 100 ° C overnight. After the reaction was completed, water was added, and the mixture was evaporated.

Compound F-6

Starting material F-5 (4.5 g, 20.0 mmol) was dissolved in methanol (30 ml), and sodium borohydride (836 mg, 22.0 mmol) was slowly added thereto, and the reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, it was concentrated to give a residue. The residue was dissolved in dry EtOAc (EtOAc) (EtOAc) After the reaction was stirred at 0 ° C for 30 minutes, the reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The product was 2.9 g.

Compound F

This compound was prepared by the synthesis of Intermediate D-3 to D using F-6 as a starting material.

Intermediates G and G':

Compound G-1

Starting material F-5 (4.9 g, 21.8 mmol) was dissolved in methanol (15 ml), and then potassium hydroxide solution (6 N, 10 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a 6 N hydrochloric acid solution was added to adjust the pH to 5 to 6, and a solid was precipitated and filtered to give a product of 3.0 g.

Compound G-2

Starting material G-1 (3.0 g, 17.9 mmol) was dissolved in methanol (50 ml), and concentrated sulfuric acid (0.3 ml) was added thereto and refluxed for 2 days. After cooling, the solvent was evaporated, evaporated, evaporated, evaporated.

Compound G-3 and G'-3

Starting material G-2 (760 mg, 4.2 mmol) was dissolved in DMF (4 mL), and ethyl bromide (915 mg, 8.3 mmol) and K ₂ CO ₃ (1.7 g, 12.6 mmol), 110 The reaction was carried out at ° C for 3 hours. After cooling to room temperature, water was added, and the mixture was evaporated.

(G-3) MS(m/z): 211(M+1) ⁺

(G'-3) MS(m/z): 211(M+1) ⁺

Compound G

This compound was prepared from G-3 as a starting material according to the synthesis from Intermediate D-2 to D. MS (m/z): 182 (M+1) ⁺ .

Compound G'

This compound was prepared by the synthesis of intermediate D-2 to D using G'-3 as a starting material. MS (m/z): 182 (M+1) ⁺ .

Intermediates H and H':

Compound H-2

Starting material H-1 (880 mg, 5.0 mmol) was dissolved in 2 ml of methanol, 6 ml of aqueous ammonia was added thereto, and the mixture was heated at 80 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature. MS (m/z): 162 (M + 1) ⁺ .

Compound H

The raw material H-2 (805 mg, 5.0 mmol) was dissolved in dry 10 ml of tetrahydrofuran, and the mixture was cooled with ice, and LiAlH ₄ (570 mg, 15 mmol) was slowly added thereto. After the addition, the mixture was stirred for 0.5 hour. Slowly raise the temperature by 80 ° C and reflux overnight. After completion of the reaction, it was cooled to room temperature and purified by chromatography to give 720 mg. MS(m/z): 148(M+1) ⁺

Compound H'-1

The material H-1 (528 mg, 3.0 mmol) was dissolved in 5 ml of anhydrous tetrahydrofuran, cooled to 0 ° C, and sodium hydride (240 mg, 6 mmol) was slowly added thereto, and stirred under nitrogen for half an hour, then 2-(Trimethyldecyl)ethoxymethyl chloride (526 mg, 3.0 mmol) was added dropwise and allowed to react at room temperature for 2 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. MS(m/z): 307(M+1) ⁺

Compound H’

This compound was prepared by the synthesis of intermediate D-2 to D using H'-1 as a starting material. MS(m/z): 278(M+1) ⁺

Intermediate I:

This compound was prepared by the synthesis method of Intermediate H using I-1 as a raw material. MS(m/z): 148(M+1) ⁺

Intermediate J:

Compound J-2

Starting material J-1 (13 g, 0.1 mol) was dissolved in 195 ml of concentrated hydrochloric acid, and 25 g of tin particles were added portionwise to the solution at 0 °C. After most of the tin particles were dissolved, 70 ml of ethanol and anhydrous zinc chloride (6 g) were added, and the reaction liquid was heated to 85 ° C, and then malondialdehyde diethyl acetal (17.2 g, 0.078 mol) of ethanol (30 ml) was added. The solution was reacted at 85 ° C for 1 hour. After completion of the reaction, it was poured into ice, and the mixture was made basic with aqueous ammonia. The aqueous solution was extracted with dichloromethane, and the organic phase was concentrated to give a crude product which was purified by column chromatography. MS (m/z): 135 (M) ⁺ .

Compound J-3

Starting material J-2 (1.35 g, 10 mmol), dipotassium hydrogen phosphate (940 mg, 5.4 mmol), sodium hydrogencarbonate (840 mg, 10 mmol), anhydrous magnesium sulfate (2.0 g, 16.7 mmol) The mixture was suspended in chloroform (40 ml) and refluxed for 16 hours, and then liquid bromine (2.08 g, 13 mmol) was added dropwise to the solution, followed by refluxing for 24 hours. After cooling, it was filtered, and the residue was washed several times with dichloromethane, and the filtrate was concentrated, and the obtained crude product was purified by column chromatography. MS (m/z): 214 (M + 1) ⁺ .

Compound J-4

The raw material J-3 (107 mg, 0.5 mmol) and cuprous cyanide (60 mg, 0.67 mmol) were dissolved in 4 ml of anhydrous DMF, and Pd(PPh ₃ ) ₄ (57 mg, 0.05 was added to the solution. Millimol), nitrogen was replaced several times and reacted at 120 ° C for 5 hours. After cooling, the reaction mixture was concentrated and the residue was purified by column chromatography. MS (m/z): 161 (M + 1) ⁺ .

Compound J

Raw material J-4 (320 mg, 2 mmol) was dissolved in 25 ml of ammonia in ethanol, and Ranye nickel was added to the solution. The reaction solution was replaced with hydrogen and then reacted at room temperature for 2 hours. Filtration and concentration of the filtrate gave the product which was used without further purification. MS (m/z): 165 (M + 1) ⁺ .

Intermediate K:

Compound K-2

Starting material K-1 (4.0 g, 33.6 mmol) was dissolved in ethanol (160 ml), acetaldehyde aqueous solution (40%, 27.5 ml, 168 mmol) was added thereto, and the reaction mixture was refluxed for 4 hours. After cooling, the solvent was evaporated under reduced pressure, and the obtained residue was dissolved in water, and the mixture was adjusted to pH > 7 with a saturated aqueous solution of sodium hydrogencarbonate, and precipitated, filtered, and dried to give a pale product of 4.80 g.

Compound K

This compound was prepared from K-2 as a starting material according to the synthesis from Intermediate J-4 to J.

Intermediate L:

Compound L-2

The material L-1 (8.7 g, 73 mmol) was dissolved in DMF (35 ml), and then N,N-dimethylformamide dimethyl acetal (35 ml, 294 mmol) was added thereto, and then The reaction was carried out at 130 ° C overnight. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure to give Intermediate. The intermediate was dissolved in methanol (200 mL). pyridine (11.5 mL, 143 mmol) was evaporated. Warm reaction overnight. After completion of the reaction, the mixture was concentrated. EtOAc EtOAc m. MS (m/z): 145 (M+1) ⁺

Compound L

This compound was prepared by the synthesis method from Intermediate J-4 to J using L-2 as a raw material.

Intermediate M:

This compound was prepared by the synthesis of Intermediate J-4 to J using M-1 as a starting material. MS (m/z): 149 (M + 1) ⁺ .

Intermediate N:

This compound was prepared from 6-quinolinecarboxylic acid as described in the document US 2007/0265272 .

Intermediate O:

Compound O-2

The starting material O-1 (2.0 g, 11.5 mmol) was dissolved in dichloromethane (250 ml), 3 drops of DMF was added, and then cooled to 0 ° C, and chloroform (7.3 g, 57.5 mmol) was slowly added dropwise. After the addition, the reaction was carried out at room temperature overnight, and concentrated to give a product, 2.2 g.

Compound O-3

The raw material O-2 (2.2 g, 11.5 mmol) was dissolved in tetrahydrofuran (100 ml), and the mixture was stirred under ice-cooling, and aqueous ammonia (5 ml) was added thereto, and the mixture was reacted at room temperature for 1 hour. Concentration, the solid obtained was washed with water and dried to give 1.5 g. MS(m/z): 173(M+1) ⁺

Compound O-4

Starting material O-3 (1.2 g, 7.2 mmol) was dissolved in dichloromethane (50 ml), triethylamine (2.2 g, 21.8 mmol) was added and cooled to 0 ° C, slowly trifluoroacetic anhydride (1.9)克, 8.9 mmol) was added dropwise to the reaction mixture. After the addition was completed, the mixture was reacted at 0 ° C for 10 minutes, then quenched with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. Gram. MS (m/z): 154 (M) ⁺

Compound O

Starting material O-4 (540 mg, 3.5 mmol) was added to diethyl ether (15 ml), then Ti(Oi-Pr) ₄ (3.9 mmol, 1.16 ml) was added and the solution was cooled to -70 ° C and then Ethyl magnesium bromide (7.7 mmol, 3 M in diethyl ether) was added dropwise, and after stirring for 10 minutes, the temperature was naturally raised to room temperature, and the reaction was continued for 1.5 hours, then BF ₃ . OEt ₂ (7 mmol, 0.88) was added. ML), stir for 1 hour. After the reaction, 1N hydrochloric acid (11 ml), diethyl ether (40 ml), and aq. Filtration and concentration gave the crude product which was used directly in the next step. MS(m/z): 185(M+1) ⁺

Intermediate P:

Compound P-2

Starting material P-1 (5.7 g, 30 mmol), glycerol (11.04 g, 120 mmol), ferrous sulfate heptahydrate (1.92 g, 6.9 mmol) and nitrobenzene (2.22 g, 18 mmol) After stirring at room temperature for 10 minutes, concentrated sulfuric acid (9.7 g, 9.9 mmol) was slowly added thereto, and the reaction mixture was heated to reflux for 7 hr. After completion of the reaction, the mixture was cooled to room temperature, poured into ice water, and the mixture was adjusted to pH~8 with concentrated aqueous ammonia, and extracted with dichloromethane. The organic phase was combined, dried and concentrated, and the residue was purified by silica gel column chromatography. MS (m / z): 226 (M + 1) ⁺

Compound P

This compound was prepared by a synthesis method from Intermediate J-3 to J using P-2 as a raw material. MS (m / z): 177 (M + 1) ⁺

Intermediate Q:

Compound Q-2

Potassium thiocyanate (93 g, 961 mmol) and starting material Q-1 (15 g, 117 mmol) were added to acetic acid (125 ml) at 5 ° C, then cooled in an ice salt bath. A mixed solution of 10 ml of liquid bromine and 30 ml of acetic acid was slowly added dropwise, and the system was kept below 0 ° C when added dropwise. After the addition, the reaction was carried out at 0 ° C for 2 hours, then raised to room temperature and allowed to react overnight. After completion of the reaction, 60 ml of water was added, and the mixture was heated to 90 ° C, stirred for a while, and filtered while hot. The obtained cake was dissolved in 60 ml of acetic acid, and the mixture was warmed to 85 ° C, stirred for a while, and filtered while hot. The filtrate was combined, cooled to room temperature, adjusted to pH = 6 with saturated aqueous ammonia, and a solid precipitated, filtered, and dried to give the product 19 g. MS(m/z): 186(M+1) ⁺

Compound Q-3

Starting material Q-2 (19 g, 103 mmol) was added to a 20% aqueous sodium hydroxide solution (150 ml), and then 2 g of sodium sulfite was added and refluxed overnight. After cooling to room temperature, the mixture was adjusted to pH = 7 with formic acid, and a solid was precipitated and filtered to yield 16.4 g of product.

Compound Q-4

Starting material Q-3 (16.4 g, 103 mmol) was added to formic acid (80 ml), and the mixture was warmed to 110 ° C and reacted for 2 hours. After the reaction mixture was cooled to room temperature, the mixture was adjusted to pH = 7 with aqueous ammonia, and solid was precipitated and filtered to yield 14.5 g of product. MS(m/z): 171(M+1) ⁺

Compound Q-5

Starting material Q-4 (460 mg, 2.7 mmol), zinc cyanide (316 mg, 2.7 mmol), Pd ₂ (dba) ₃ (123 mg, 0.13 mmol), DPPF (150 mg, 0.27 mmol) They were separately added to a sealed tube containing 5 ml of DMF (1% aqueous), replaced with nitrogen, sealed, and warmed to 120 ° C, and allowed to react overnight. After cooling, it was concentrated and the residue was purifiedjjjjjjjj

Compound Q

This compound was prepared by the synthesis of Intermediates J-4 to J using Q-5 as a starting material. MS(m/z): 166(M+1) ⁺

Intermediate R:

Compound R-2

6.5 ml of triethylamine (46.7 mmol) was added to a solution of R-1 (5 g, 38.9 mmol) in 100 ml of tetrahydrofuran at 0 ° C, and then chloroformic ethyl ester (5.84 g, 4.78 ml, 42.8 mmol) in 5 ml of tetrahydrofuran was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure. The organic phase was dried and concentrated to give the product which was taken directly to next. MS(m/z): 229(M+1) ⁺

Compound R-3

Lawesson's reagent (8.5 g, 21 mmol) was added to a toluene solution (100 ml) of material R-2 (8 g, 35 mmol). After cooling, it was concentrated and the residue obtained was purified by column chromatography. MS(m/z): 209(M+1) ⁺

Compound R-4

NaBH ₄ (0.9 g, 24 mmol) was slowly added to a solution of R-3 (5 g, 24 mmol) in ethanol (100 ml) at 0 ° C, and stirred at room temperature for 1 hour. The residue obtained is taken up in ethyl acetate and washed with water. MS(m/z): 167(M+1) ⁺

Compound R

This compound was prepared by the synthesis of Intermediate A-3 to A using R-4 as a starting material. MS (m/z): 165 (M) ⁺

Intermediate S:

Compound S-2

Starting material S-1 (12.8 g, 100 mmol) was dissolved in 50 ml of dichloromethane, 3 ml of Et ₃ N was added, and then 8 ml of acetonitrile was slowly added dropwise, and stirred at room temperature overnight. After completion of the reaction, an aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with dichloromethane. MS (m/z): 171.6 (M+1) ⁺

Compound S-3

This compound is prepared by synthesizing the intermediate R-2 to R-3 using S-2 as a raw material. MS (m/z): 151.6 (M+1) ⁺

Compound S-4

This compound was prepared by the synthesis of Intermediate B-4 to B-5 using S-3 as a starting material.

Compound S

This compound was prepared by the synthesis of Intermediate C-5 to C using S-4 as a starting material. MS(m/z): 166(M+1) ⁺

Intermediates T and T':

Compound T-2

This compound was prepared by the method of synthesizing from the intermediates F-1 to F-2 using T-1 as a raw material.

Compound T

This compound was prepared from T-2 as a starting material according to the synthesis from Intermediate D-2 to D. MS (m/z): 165 (M+1) ⁺ .

Compound T’

This compound was prepared by the synthesis of intermediates D'-1 to D'-5 and D-4 to D using T-1 as a starting material. MS (m/z): 179 (M+1) ⁺ .

Preparation of intermediate boronic acid and boric acid esters:

Intermediate U:

Compound U-2

The feedstock U-1 (1.02 g, 10 mmol) and Et ₃ N (1 ml) was dissolved in 20 ml of methylene chloride, was slowly added dropwise 2 ml methanesulfonamide acyl chloride, stirred at room temperature for 1 hour. After completion of the reaction, it was poured into water, and the organic layer was dried over anhydrous sodium sulfate

Compound U-3

Starting material U-2 (1.8 g, 10 mmol), 4-bromo-pyrazole (1.46 g, 10 mmol) and potassium carbonate (1.4 g, 10 mmol) were dissolved in 10 mL DMF at 80 ° C Stir overnight. After completion of the reaction, the solvent was evaporated under reduced pressure. MS(m/z): 231(M+1) ⁺

Compound U

Starting material U-3 (1.13 g, 4.48 mmol), pinacol borate (861 mg, 3.73 mmol) and potassium acetate (12.43 g, 12.68 mmol) were dissolved in 5 ml of DMSO, then Pd ( Dppf) Cl ₂ (172 mg, 0.21 mmol), stirred at 80 ° C overnight under nitrogen. After completion of the reaction, it was poured into water, extracted with ethyl acetate, and the organic phase was purified by column chromatography to yield product 170 mg. MS(m/z): 279(M+1) ⁺

Intermediate V:

Starting material V-1 (3 g, 15 mmol) was dissolved in DMF (6 mL), and ethyl bromide (3.24 g, 30 mmol) and potassium carbonate (4.26 g, 30 mmol) were added thereto and reacted at 60 ° C overnight. After completion of the reaction, ethyl acetate was added, and the mixture was evaporated. MS(m/z): 223(M+1) ⁺

Intermediate W:

Compound W-1

This compound was prepared by the synthesis method of the intermediate V using 2-chlorocyclopentanone as a raw material. MS (m/z): 277 (M+1) ⁺

Compound W

The raw material W-1 (550 mg, 2 mmol) was dissolved in 5 ml of methanol, and sodium borohydride (150 mg, 4 mmol) was slowly added thereto, and stirred at room temperature for 1 hour. The residue was taken up in ethyl acetate. MS(m/z): 279(M+1) ⁺

Intermediate X:

This compound was prepared from 4-bromopyrazole according to the method described in the document US 2007 / 0265272 .

Other pyrazole boronic acids or boronic esters are prepared according to the synthesis of intermediate U-X.

Intermediate Y:

Intermediate Y-2

N-hydroxyphthalimide (20.0 g, 0.12 mol) was dissolved in acetone (400 ml), triethylamine (14.9 g, 0.15 mol) was added, stirred for a while, then 1-bromo-2 was added. 4-Dinitrobenzene Y-1 (30.2 g, 0.12 mol). After stirring at room temperature for 3 hours, the reaction mixture was poured into ice water, and a solid was precipitated, and the solid was filtered, washed with a small amount of ice methanol, and dried to give 38.1 g.

Intermediate Y-3

The starting material Y-2 (20.0 g, 60.7 mmol) was dissolved in dichloromethane (400 ml), and a solution of hydrazine hydrate in methanol (10 ml, 85% hydrazine hydrate dissolved in 60 ml of methanol) was added at 0 ° C, then After stirring at the same temperature for 6 hours, a 1N EtOAc solution (400 mL) was obtained, and the solid was filtered and washed with acetonitrile, the organic phase was separated, and the aqueous phase was extracted with dichloromethane. Concentration gave 7.9 g of product. MS (m/z): 183 (M-16) ^- .

Intermediate Y-4

4-Hydroxymethylpyridine (21.8 g, 0.20 mol) was dissolved in dichloromethane (200 ml), triethylamine (30.0 g, 0.30 mol) and tert-butyldimethylchloromethane (45.0 g) , 0.30 mol). The reaction mixture was stirred at room temperature for 4 hours, quenched with water and then EtOAc EtOAc EtOAc. Butyl dimethyl chloro oxime) methyl) pyridine.

This intermediate (8.9 g, 39.7 mmol) was dissolved in acetonitrile (27 mL). After completion of the reaction, concentration was carried out to give 17.1 g of crude material. MS (m/z): 239 (M-183) ⁺ .

Intermediate Y-5

The starting material Y-4 (13.4 g, 31.6 mmol) was dissolved in DMF (60 mL), methylpropiolate (2.7 g, 31.6 mmol) and potassium carbonate (6.5 g, 47.4 mmol) Stir at room temperature for 24 hours. After the reaction was completed, water was added, and the mixture was evaporated. MS (m/z): 321 (M + 1) ⁺ .

Intermediate Y-6

The material Y-5 (2.9 g, 9.1 mmol) was dissolved in dry tetrahydrofuran (20 ml), tetrabutylammonium fluoride (3.5 g, 13.7 mmol) was added, and the reaction mixture was stirred at room temperature for 10 minutes. The mixture was diluted with EtOAc (EtOAc)EtOAc.

Intermediate Y-7

Starting material Y-6 (1.9 g, 9.1 mmol) was dissolved in 40% sulfuric acid, and the reaction mixture was stirred at 80 ° C for 24 hours. After the reaction was cooled, 3N NaOH solution was added, the pH was adjusted to 7-8, and ethyl acetate was evaporated, and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. MS (m/z): 149 (M + 1) ⁺ .

Intermediate Y

This compound was prepared from Y-7 as a starting material according to the synthesis from Intermediate D-3 to D. MS (m/z): 148 (M+1) ⁺ .

Intermediate Z:

Intermediate Z-2

Starting material Z-1 (9.0 g, 59.21 mmol) was dissolved in anhydrous ethanol (160 ml), and 40% aqueous chloroacetaldehyde (48.6 ml, 296 mmol) was added thereto, and the mixture was heated under reflux for 4 hours. After completion of the reaction, the mixture was concentrated, and the residue was crystalljjjjjjjjjjjjjjjjjjjjj . MS (m/z): 177 (M+1) ⁺ .

Intermediate Z-3

The starting material Z-2 (5.0 g, 28.4 mmol) and N-methyl-N-methoxyamine (5.54 g, 56.8 mmol) were combined in anhydrous tetrahydrofuran (50 ml) under N ₂ Isopropylmagnesium chloride (56.8 ml, 113.6 mmol) was added thereto at -20 ° C over 30 minutes, and then the reaction was further stirred at this temperature for 30 minutes. After completion of the reaction, a 20% ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. MS (m/z): 206 (M+1) ⁺ .

Intermediate Z

This compound was prepared from Z-3 as a starting material in the same manner as the synthesis from the intermediate D'-2 to D'.

Intermediate 1:

Intermediate 1-2

Intermediate material 1-1 (1.39 g, 10 mmol) was added to a sealed bottle, dissolved in 2 ml of ethanol, and then 4 ml of a 40% aqueous solution of chloroacetaldehyde was added, stirred at room temperature for 5 minutes, and then stirred at 100 ° C overnight. After the reaction was cooled to room temperature, concentrated, and dried to give 1.63 g product, MS (m / z): 164 (M + 1) +.

Intermediate 1-3

Intermediate 1-2 (1.63 g, 10 mmol) was added to a reaction flask, 15 ml of dichlorohydrazine was added, and then 10 drops of N,N-dimethylformamide were added, and the reaction mixture was refluxed for 3 hours. After completion of the reaction, the solvent was evaporated, and the obtained residue was dissolved in 10 ml of methanol, stirred for a while, and then aqueous sodium hydrogen carbonate aqueous solution was adjusted to pH=7, and the mixture was purified by chromatography to give product 891 mg. MS (m/z): 178 (M + 1) ⁺ .

Intermediate 1-4

Intermediate 1-3 (891 mg, 5.03 mmol) was dissolved in 25 ml of ethanol, sodium borohydride (420 mg, 11.1 mmol) was added and stirred at room temperature for 2 hr. After completion of the reaction, concentration and purification by chromatography gave 630 mg. MS (m/z): 150 (M + 1) ⁺ .

Intermediate 1

This compound was prepared by the procedure described for Intermediates D-3 to D using Intermediate 1-4 as a starting material. MS (m/z): 149 (M + 1) ⁺ .

Intermediate 2:

Intermediate 2-2

The intermediate material 2-1 (1.0 g, 6.45 mmol) and zinc cyanide (770 mg, 6.58 mmol) were dissolved in 20 ml of N,N-dimethylformamide, and after nitrogen replacement, four were added. Triphenylphosphine palladium (400 mg, 3.46 mmol) was stirred at 110 ° C overnight under nitrogen. After completion of the reaction, it was concentrated and purified by column chromatography to yield 620 mg.

Intermediate 2

Intermediate 2-2 (620 mg, 4.31 mmol) was dissolved in 5 ml of ammonia/methanol solution, and Raney nickel was added, and the mixture was stirred at room temperature for 3 hours under hydrogen. After completion of the reaction, Raney nickel was filtered off and the organic phase was concentrated to give the product 600 mg. MS (m/z): 149 (M + 1) ⁺ .

Intermediate 3:

Intermediate 3-1

Intermediate material Y-3 (180 mg, 0.9 mmol) was added to a solution of 4-ethylpyridylpyridine (100 mg, 0.82 mmol) in 3 ml of acetonitrile and stirred at 40 ° C for 24 hours. After completion of the reaction, the solvent was evaporated to give 225 mg of product, which was used for the next step without purification.

Intermediate 3-2

Methyl propiolate (29 mg, 0.34 mmol) was added dropwise to Intermediate 3-1 (100 mg, 0.31 mmol) and K ₂ CO ₃ (60 mg, 0.43 mmol The solution was stirred at room temperature for 24 hours. After completion of the reaction, the insoluble matter was removed by filtration, the filtrate was concentrated, dissolved in ether, washed with water, the organic phase concentrated and purified by column chromatography to give 20 mg of product, MS (m / z): 219 (M + 1) +.

Intermediate 3-3

Intermediate 3-2 (90 mg, 0.41 mmol) was added to 2 ml of 50% sulfuric acid and stirred at 80 ° C for 3 hours. After completion of the reaction, it was cooled in an ice-bath, and aq.

Intermediate 3

This compound was prepared as Intermediate 3-3 starting from the intermediates D'-3 to D'. MS (m/z): 162 (M + 1) ⁺ .

Intermediate 4:

Intermediate 4-2

DMF-DMA (1.56 ml, 11.3 mol) was added to a solution of intermediate material 4-1 (1.56 g, 8.7 mmol) in 15 ml of isopropanol under nitrogen, and then warmed to 90 ° C for 3 hours. Thereafter, the temperature was lowered to 50 ° C, and hydroxylamine hydrochloride (0.781 g, 11.3 mmol) was added and stirred overnight. After completion of the reaction, it was cooled to room temperature, concentrated, and purified by column chromatography toiel MS (m/z): 186 (M + 1) ⁺ .

Intermediate 4-3

Intermediate 4-2 (820 mg, 4.4 mmol) was dissolved in 5 mL of dry THF, cooled to 0 ° C, and then, under a nitrogen atmosphere, trifluoroacetic anhydride (1.1 g, 5.28 mmol). hour. After completion of the reaction, an aqueous sodium hydrogencarbonate solution was added to pH = 8, concentrated, and purified by column chromatography to yield 400 mg. MS (m/z): 168 (M + 1) ⁺ .

Intermediate 4-4

Intermediate 4-3 (400 mg, 2.4 mmol) was dissolved in 5 mL of N,N-dimethylformamide and sodium azide (250 mg, 3.6 mmol). Stir for 2 hours. After completion of the reaction, the mixture was evaporated. MS (m/z): 175 (M + 1) ⁺ .

Intermediate 4

Intermediate 4-4 (340 mg, 1.9 mmol) was dissolved in 20 mL of methanol, and 30 mg of palladium/carbon was added, and the mixture was stirred at room temperature for 2 hours under hydrogen. After completion of the reaction, palladium on carbon was removed by filtration and concentrated to give a product (300 mg). MS (m/z): 149 (M + 1) ⁺ .

Intermediate 5:

Intermediate 5-2

The intermediate material 5-1 (350 mg, 2.92 mmol) was dissolved in 15 ml of ethanol, and 40% aqueous chloroacetaldehyde (4 ml) was added to the solution, and the mixture was stirred at 110 ° C overnight. After completion of the reaction, it was concentrated and purified by column chromatography to yield MS (m/z): 145.1 (M + 1) ⁺ .

Intermediate 5

Intermediate 5-2 (180 mg, 1.25 mmol) and Raney nickel were added to a solution of ammonia in methanol (15 ml, 1 mol/L), and the reaction was stirred for 2 hours under hydrogen. After the reaction was completed, it was filtered, and the filtrate was concentrated to give the product 160 mg. MS (m/z): 149.1 (M + 1) ⁺ .

Intermediate 6:

Intermediate 6-1

Propionaldehyde (20 ml, 265 mmol) was dissolved in 25 ml of dioxane, and the reaction mixture was cooled to 0 ° C, and liquid bromine (13.5 ml, 265 mmol) was slowly added dropwise thereto over one hour. Stirring was continued at this temperature for about 10 minutes until the reaction solution became colorless. Then, 200 ml of diethyl ether was added, and the mixture was washed successively with sodium hydrogen sulfate, sodium hydrogen carbonate and brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated.

Intermediate 6-2

2-Amino-5-cyanopyridine (1.2 g, 10.1 mmol) was dissolved in 80 ml of ethanol, and Intermediate 6-1 (6.9 g, 50.5 mmol) was added, and the mixture was stirred at 80 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, concentrated, and then water (20 ml) was added, and the mixture was adjusted to pH 7 with saturated sodium hydrogen carbonate. MS (m/z): 158 (M + 1) ⁺ .

Intermediate 6

Intermediate 6-2 (200 mg, 1.27 mmol) and Raney nickel were added to a solution of ammonia in methanol (30 mL, 1 mol/L), and hydrogenation was carried out for 2 hours. The reaction solution was filtered, and the filtrate was evaporated to ethylamine. MS (m/z): 162 (M + 1) ⁺ .

Intermediate 7:

Intermediate 7-2

The intermediate material 7-1 (1.43 g, 10 mmol) was added to 3 ml of acetic acid, and sodium acetate (3.03 g, 37 mmol) and 6 ml of 37% aqueous formaldehyde solution were sequentially added, and the mixture was stirred at 100 ° C overnight. . After cooling, the reaction mixture was adjusted to pH > MS (m/z): 174.0 (M + 1) ⁺ .

Intermediate 7-3

Intermediate 7-2 (346 mg, 2 mmol) was added to 20 ml of tetrahydrofuran, the reaction mixture was cooled to 0 ° C, sodium hydride (240 mg, 60%) was added, and the mixture was stirred at 0 ° C for 1 hour, then added Methyl iodide (615 mg, 4.3 mmol) was stirred at room temperature overnight. After completion of the reaction, the mixture was evaporated. MS (m/z): 188.0 (M + 1) ⁺ .

Intermediate 7

Intermediate 7-3 (300 mg, 1.6 mmol) and Raney nickel were added to a solution of ammonia in methanol (30 mL, 1 mol/L), and hydrogenation was carried out for 2 hours. The reaction solution was filtered through celite and concentrated to give the product 300 mg. MS (m/z): 192.0 (M + 1) ⁺ .

Intermediate 8:

Intermediate 8-2

Intermediate 8-1 (4.8 g, 44.4 mmol) and glycerol (20 g, 222 mmol) were added to 5 ml of water, stirred at room temperature for 5 minutes, and concentrated sulfuric acid (47 g was added dropwise thereto over 20 minutes. After 488 mmol, the reaction solution was stirred at 150 ° C for 30 minutes. After the reaction was completed, it was cooled to room temperature, poured into water, and the pH was adjusted to 13 with 6 NaOH solution, and extracted with ethyl acetate. The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate The product was separated by column chromatography to give 2.9 g. MS (m/z): 145 (M + 1) ⁺ .

Intermediate 8-3

Intermediate material 8-2 (2.9 g, 20.1 mmol) and selenium dioxide (2.2 g, 20.1 mmol) were added to 40 ml of dioxane and refluxed for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, concentrated, EtOAc EtOAc (EtOAc m. The isolated product was isolated in 1.81 g.

in Interbody 8-4

Intermediate 8-3 (1.0 g, 6.32 mmol) was dissolved in a mixed solvent of 15 ml of methanol and 15 ml of tetrahydrofuran, and NaBH ₄ (84 mg, 2.21 mmol) was added and the mixture was stirred for 30 minutes. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography.

Intermediate 8

This compound was prepared as the starting material of Intermediate 8-4 as described in Intermediate D-3 to D. MS (m/z): 160 (M + 1) ⁺ .

Intermediate 9

Intermediate 9-1

Intermediate Y-5 (2.9 g, 9.1 mmol) was dissolved in 20 ml of tetrahydrofuran, and (3.5 g, 13.7 mmol) of TBAF was added thereto, and the reaction mixture was stirred at room temperature for 10 minutes. After completion of the reaction, ethyl acetate and saturated brine were added, and the organic layer was dried over anhydrous sodium sulfate.

Intermediate 9

This compound was prepared as Intermediate 9-1 starting from the intermediates D-3 to D. MS (m/z): 148 (M+1) ⁺ .

Intermediate 10:

Intermediate 10-1

Intermediate F-5 (4.2 g, 18.7 mmol) was dissolved in 50 ml of methanol, and 5 ml of aqueous lithium hydroxide hydrate (3.1 g, 74.8 mmol) was added and stirred at room temperature overnight. After completion of the reaction, 1 equivalent of hydrochloric acid was added to adjust the pH to 5, and the product was obtained by filtration.

Intermediate 10:

This compound was prepared by the method described for the intermediates T-1 to T' using the intermediate 10-1 as a starting material. MS (m/z): 168 (M + 1) ⁺ .

Intermediate 11:

This compound was prepared by the method described for the intermediate Z-3 to Z using the intermediate Z-3 as a starting material.

Example 1:

Compound 1-a

2-Amino-3,5-dibromopyrazine (758 mg, 3.0 mmol), Intermediate A (442 mg, 3.0 mmol), ethyl isopropylamine (1160 mg, 9.0 mmol) were added separately Into ethanol (70 ml), after sealing, the reaction was carried out at 150 ° C overnight. After cooling, it was concentrated and the residue was purifiedjjjjjjjj MS (m/z): 319 (M+1) ⁺ .

Compound 1-b

Compound 1-a (48 mg, 0.15 mmol) was added to a mixed solvent of acetic acid and water (1.5 ml / 1.5 ml), and then NaNO ₂ (31 mg, 0.45 mmol) the reaction was stirred for 1.5 hours followed by addition of _{H 2 SO 4 (49%,} 0.1 ml), warmed to room temperature, and stirred overnight. After completion of the reaction, the mixture was adjusted to pH <~>> MS (m/z): 332 (M+1) ⁺ .

Compound 1

Compound 1-b (46 mg, 0.14 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1H-pyrazole (77 mg, 0.35 mmol), PdCl ₂ (dppf) (12 mg, 0.014 mmol) and cesium carbonate (137 mg, 0.42 mmol) were added to a mixture of dioxane and water, respectively. The solution (10:1, 8 mL) was sealed and stirred at 80 ° C overnight. After cooling, it was concentrated and the residue was purifiedjjjjjjj MS (m/z): 332 (M+H) ⁺

Examples 2-59, 265-269, 272, 274-277, 279-290, 293-296, 298-299, 301-305, 308-310, 316-317, 326, 328-329 and 331

The following compounds were prepared in accordance with the synthetic procedure of Example 1. The appropriate intermediate, boric acid or borate ester, and appropriate protecting groups are employed under suitable conditions.

* Compound 272 is prepared by using the compound 33 as follows:

Compound 33 (66 mg, 0.2 mmol) was dissolved in acetic acid (0.1 mL), sodium acetate (60 mg, 0.73 mmol) and 37% aqueous formaldehyde (0.2 mL, 2.8 mmol). The reaction was overnight. After completion of the reaction, water was added, and the mixture was made basic with saturated sodium carbonate.

Example 60:

Compound 60-a

The starting material, 3-nitro-2,6-dichloropyridine (106 mg, 0.55 mmol) was dissolved in isopropyl alcohol (3 ml), and then Na ₂ CO ₃ (116 mg, 1.1 mmol) and Intermediate R (100 mg, 0.61 mmol) was taken at room temperature overnight. After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was evaporated, evaporated, evaporated. MS(m/z): 322(M) ⁺

Compound 60-b

The compound 60-a (100 mg, 0.31 mmol) was dissolved in a mixed solvent of methanol (2 ml) and tetrahydrofuran (10 ml), and 10% Pd/C (20 mg) was added under a hydrogen atmosphere for 1 hour. Filtration, concentration of the filtrate and separation by column chromatography gave the product. MS(m/z): 292(M+1) ⁺

Compound 60-c

Compound 60-b (90 mg, 0.31 mmol) was dissolved in a mixed solvent of acetic acid (1 ml) and water (1 ml) at 0 ° C, then slowly added 0.5 ml of sodium nitrite (42.5 mg, 0.62 m) The solution was added, and at this temperature, stirring was continued for 1 hour. After the reaction, adjust to pH with 30% sodium hydroxide solution 9, a solid precipitated, filtered and dried to give the product. MS(m/z): 303(M+1) ⁺

Compound 60-d

Compound 60-c (64 mg, 0.21 mmol) and intermediate X (75 mg, 0.23 mmol) were added to a mixture of dioxane (1.5 ml) and water (0.15 ml) under nitrogen Pd(dppf)Cl ₂ (32.7 mg, 0.04 mmol) and cesium carbonate (98 mg, 0.3 mmol) were added thereto, and the mixture was stirred at 120 ° C overnight. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography. MS (m / z): 463 (M + 1) ⁺

Compound 60

The compound 60-d (20 mg, 0.04 mmol) was dissolved in hydrochloric acid / methanol (2 ml), and the mixture was stirred at room temperature for 1 hour, then concentrated, and the residue was purified by column chromatography. MS (m / z): 379 (M + 1) ⁺

Examples 61-76, 79, 81-151, 273, 291, 292, 297 and 332

The following compound was prepared according to the synthetic method of Example 60 . The appropriate intermediate, boric acid or borate ester, and appropriate protecting groups are employed under suitable conditions.

¹ Compound 94 was prepared by using the intermediate 94-a as follows:

Intermediate 94-a was prepared according to the procedure described in Example 60 using the corresponding intermediate and boronic acid, and under appropriate conditions as understood by those skilled in the art.

Intermediate 94-a (30 mg, 0.06 mmol) was dissolved in a mixed solvent of trifluoroacetic acid (2 ml) and dichloromethane (2 ml) and then stirred overnight. After completion of the reaction, the mixture was concentrated. The residue was crystalljjjjjjjjj

² Compound 98 was prepared from compound 61 using the following route:

Compound 61 was dissolved in dichloromethane, and triethylamine and ethyl hydrazine chloride were added thereto, and the reaction mixture was stirred at room temperature for 3 hr. After completion of the reaction, water was added, and the mixture was extracted with dichloromethane. The organic phase was combined, dried and concentrated.

³ Compound 94 Compound 101 is prepared as described below as starting material:

Compound 94 (18 mg, 0.044 mmol) was dissolved in dichloromethane (2 mL) and then triethylamine (1. Millimol), slowly warmed to room temperature and stirring was continued for 1 hour. After completion of the reaction, a saturated sodium hydrogencarbonate solution was added, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phase was combined, dried, concentrated, and purified by column chromatography.

⁴ Compound 104 is prepared by the method from Intermediate W-1 to W using Intermediate 104-a as a starting material:

Intermediate 104-a was prepared as described for compound 60 .

⁵ Compound 105 was prepared by using the intermediate 104-a as a starting material according to the following route:

A solution of the intermediate 104-a (37 mg, 0.1 mmol) eluted eluted eluted hour. After completion of the reaction, the mixture was concentrated.

Intermediate ⁶ Compound 108 is 108-a as a raw material in accordance with the following scheme, under appropriate conditions as described in Example 60 was prepared from:

Intermediate 108-a was prepared according to the procedure from Intermediate U-3 to U.

Compound 109 was prepared in a similar manner to compound 108 .

⁷ Compound 116 was prepared according to the method of Compound 94

Process ⁸ Compound 138 was prepared using _{(t-Bu) 3 HBF 4} / Pd2 (dba) 3 as a catalyst

⁹ Compound 148 was prepared according to the following scheme under the appropriate conditions as described in Example 60 .

Compound 149 was prepared in a similar manner to compound 148 using the appropriate conditions and reagents.

Example 152:

Compound 152

Intermediate material 152-a (68 mg, 0.2 mmol) (prepared from 6-aminomethylquinoline as in Example 1 ) and 3-amino-1-methylpyrazole (20 mg, 0.22 mmol) Dissolved in 1,4-dioxane (5 ml), added with cesium carbonate (72 mg, 0.22 mmol) and water (0.5 ml). After three times with nitrogen, Pd ₂ (dba) ₃ (0.02 mmol) , 18 mg) and Xantphos (0.04 mmol, 23 mg) were then stirred at 120 ° C overnight under nitrogen. After cooling, the solvent was evaporated, and the residue was purifiedjjjjjjjj MS(m/z): 358(M+1) ⁺

Examples 80 and 153-240

The following compound was prepared according to the synthetic procedure of Example 152 . The appropriate intermediates and amines, as well as the appropriate protecting groups, are employed under suitable conditions.

¹⁰ Compound 154 was prepared according to the following scheme, under the appropriate conditions described in Example 152 . Intermediate 154-a was prepared according to the procedure described in Example 244 under suitable conditions.

Compounds 177 and 239 were prepared in the same manner as compound 154 .

Example 244:

Intermediate 244-a (60 mg, 0.2 mmol) (prepared as described in Example 60), cesium carbonate (195 mg, 0.6 mmol) and 4,5,6,7-tetrahydrothiophene [ A solution of 3,2-c]pyridine hydrochloride (52 mg, 0.3 mmol) in EtOAc (EtOAc) MS (m/z): 399 (M + 1) ⁺ .

Examples 245-260

The following compound was prepared according to the synthetic procedure of Example 244 . The appropriate intermediate, amine, thiol/phenol or alcohol is employed under suitable conditions.

Example 261:

Compound 261-a

2,6-Dichloro-4-aminopyridine (3.0 g, 18 mmol) was slowly added to 20 ml of concentrated sulfuric acid, cooled to zero, and 2.6 ml of fuming nitric acid was added dropwise thereto, and the mixture was warmed to room temperature and stirred. After 1 hour, it was poured into ice, and the solid was precipitated, filtered, and dried to give 3.7 g of product.

Compound 261-b

Compound 261-a (3.7 g, 18 mmol) was added to 5 ml of concentrated sulfuric acid, and the reaction was heated at 60 ° C for half an hour. After cooling to room temperature, it was poured into ice water, adjusted to pH~7 with concentrated aqueous ammonia, filtered and dried to give the product 2.5 g. MS(m/z): 208(M+1) ⁺

Compound 261-c

Compound 261-b (208 mg, 1 mmol) was dissolved in 2 mL aqueous acetic acid and refluxed overnight. After completion of the reaction, the mixture was cooled to room temperature, and then a sodium carbonate solution was added to adjust pH = 8 and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated to give the product 240 mg. . MS (m/z): 250 (M+1)

Compound 261-d

Compound 261-c (240 mg, 0.96 mmol) and 6-aminomethylquinoline (150 mg, 0.96 mmol) were dissolved in acetonitrile (10 ml), and 0.5 ml of triethylamine was added and reacted at 80 ° C hour. After completion of the reaction, it was cooled to room temperature and purified by silica gel column chromatography to yield 220 mg. MS(m/z): 372(M+1) ⁺

Compound 261-e

Compound 261-d (220 mg, 0.593 mmol) was dissolved in a mixed solution of 5 ml of methanol and 5 ml of dichloromethane, and a catalytic amount of 10% Pd/C was added thereto, and the mixture was stirred at room temperature for 1 hour under 1 atmosphere of hydrogen. After the reaction is completed, Pd/C is filtered off, and the filtrate is concentrated to give the product, which is directly used for the next reaction. MS(m/z): 342(M+1) ⁺

Compound 261-f

The product 261-e from the previous step was dissolved in a mixed solvent of 2 ml of acetic acid and 2 ml of water, cooled to 0 ° C, and dissolved in 0.2 ml of an aqueous solution of sodium nitrite (180 mg, 2.6 mmol) at 0 ° C. The reaction was carried out for 1 hour. After completion of the reaction, the mixture was adjusted to pH = 7 with 30% sodium hydroxide and filtered to give the product, which was used directly for the next step. MS(m/z): 353(M+1) ⁺

Compound 261

Compound 261-f (80 mg, 0.227 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1H-pyrazole (50 mg, 0.24 mmol) and sodium carbonate (48 mg, 0.25 mmol) were dissolved in 10 ml of a mixed solvent of dioxane and 1 ml of water. After nitrogen replacement, Pd was added. Dppf)Cl ₂ (20 mg, 0.02 mmol), and the mixture was stirred at 100 ° C overnight under nitrogen. After completion of the reaction, it was cooled to room temperature and purified by column chromatography to give the product 7 mg. MS: 400 (M+1) ⁺ .

Example 262:

Compound 262-a

2,6-Dichloro-3-nitro-4-aminopyridine (624 mg, 3 mmol) and quinoline 6-methylammonium (316 mg, 2 mmol) were dissolved in 10 ml of acetonitrile and added thereto. 0.5 ml of triethylamine was stirred at 80 ° C for 1 hour. After completion of the reaction, it was cooled to room temperature and concentrated to give 658 mg. MS(m/z): 330(M+1) ⁺

Compound 262-b

Compound 262-a (658 mg, 2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1H-pyrazole (500 mg, 2.4 mmol) and sodium carbonate (424 mg, 4 mmol) were mixed in 20 ml of dioxane and 2 ml of water, and Pd(dppf)Cl ₂ was added after nitrogen replacement ( 160 mg, 0.2 mmol), stirred at 100 ° C overnight under nitrogen. After completion of the reaction, it was cooled to room temperature and purified by column chromatography to give the product 300 mg. MS(m/z): 376(M+1) ⁺

Compound 262-c

Compound 262-b (260 mg, 0.69 mmol) was added to HBF ₄ (5 mL) under ice-cooling, and then 0.5 ml of aqueous solution of nitrous acid (96 mg, 1.4 mmol) was added dropwise at 0 °C. Stir overnight. After completion of the reaction, a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was adjusted to pH = 6-7, filtered, and the filtrate was concentrated to give the product 200 mg. MS (m/z): 377 (M+1) ⁺

Compound 262-d

Compound 262-c (200 mg, 0.53 mmol) was dissolved in 10 ml of methanol, and then 10% Pd/C (20 mg) was added, and the mixture was stirred at room temperature for 1 hour under hydrogen atmosphere. After completion of the reaction, Pd/C was removed by filtration, and the filtrate was concentrated to give the product, 170 mg, which was used directly for the next step. MS(m/z): 347(M+1) ⁺

Compound 262

Compound 262-d (170 mg, 0.49 mmol) was dissolved in 3 ml of acetic acid and 3 ml of water, and sodium nitrite (69 mg, 10 mmol) aqueous solution (0.3 ml) was added dropwise at 0 ° C, then at 0 ° C Stir for 1 hour. After completion of the reaction, the pH was adjusted to 6-7 with a 30% aqueous sodium hydroxide solution and purified by column chromatography to yield 120 mg. MS(m/z): 358(M+1) ⁺

Example 263:

Compound 262 (120 mg, 0.336 mmol) was dissolved in phosphorus oxychloride (2 mL) and stirred at 110 ° C for one hour. After completion of the reaction, ice-cooled, the pH was adjusted to 7 with NaHCO ₃ solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give the product, 25 mg. MS: 376(M+1) ⁺

Example 264:

Compound 264-a

2,6-Dichloro-3-nitro-4-aminopyridine (832 mg, 4 mmol) was dissolved in 10 mL of tetrahydrofuran, DMAP (50 mg, 0.4 mmol) was added, followed by (Boc) ₂ O (1.0 g, 4.6 mmol) was stirred at room temperature for 2 h. After completion of the reaction, it was concentrated, and the residue was purified mjjjjjj

Compound 264-b

In a solution of 264-a (1.2 g, 3.9 mol) and 6-aminomethylquinoline (616 mg, 3.9 mmol) in acetonitrile (15 ml), 1 ml of triethylamine was added and stirred at 80 ° C for 1 hour. After completion of the reaction, it was cooled to room temperature and purified by a silica gel column to obtain 1.6 g of product. MS(m/z): 430(M+1) ⁺

Compound 264-c

Compound 264-b (860 mg, 2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl -1H-pyrazole (416 mg, 2 mmol) and sodium carbonate (424 mg, 4 mmol) were mixed in 20 ml of dioxane and 2 ml of water, and after nitrogen substitution, Pd (dppf) was added thereto. Cl ₂ (163 mg, 0.2 mmol) was then stirred at 80 ° C overnight under nitrogen. After completion of the reaction, it was cooled to room temperature, concentrated, and the residue was purified by column chromatography. MS(m/z): 476(M+1) ⁺

Compound 264-d

Compound 264-c (950 mg, 2 mmol) was dissolved in 10 mL of methanol, and then 10% Pd/C (95 mg, 0.1 eq.). After completion of the reaction, Pd/C was removed by filtration, and the filtrate was concentrated to give a product which was directly used for the next step. MS(m/z): 446(M+1) ⁺

Compound 264

Compound 264-d (890 mg, 2 mmol) was added to a mixed solution of acetic acid (95 ml) and water (5 ml), cooled to 0 ° C, and sodium nitrite dissolved in 0.5 ml of water was added dropwise thereto ( 300 mg, 4 mmol), stirred at 0 ° C for 1 hour. After the reaction was completed, the pH was adjusted to pH 8 with 30% sodium hydroxide, filtered and dried. The filter cake was dissolved in trifluoroacetic acid (3 ml), stirred at room temperature for 0.5 hour, then adjusted to pH=8 with sodium carbonate aqueous solution and concentrated. After purification by column chromatography, the product was obtained 190 mg. MS: 357(M+1) ⁺

Example 278:

Compound 33 (10 mg, 0.03 mmol) was dissolved in 3 ml of chloroform, and NBS (5.4 mg, 0.031 mmol) was added to the solution, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was chromatographed by preparative thin plate to give 11 mg of product, MS (m / z): 411.7 (M + 1) +.

Example 300

This compound was prepared in a similar manner as described in Example 278 using NCS as the reagent. MS (m/z): 365.9 (M + 1) ⁺ .

Example 306:

Starting material 306-a (60 mg, 0.13 mmol) (prepared as described in Example 1 ) was added to 0.1 mL of acetic acid, followed by sodium acetate (39 mg, 0.48 mmol) and 37% aqueous formaldehyde ( 0.13 ml), and the reaction solution was stirred at 100 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, adjusted to pH > 7 with sodium hydroxide solution, filtered, and the precipitated solid was collected, and then separated by column chromatography to give the product 10 mg. MS (m/z): 392.0 (M + 1) ⁺ .

Example 307:

Compound 33 (33 mg, 0.1 mmol) was added to a mixed solution of 0.2 ml of acetic acid and 0.4 ml of water, and then hexamethylenetetramine (16 mg, 0.11 mmol) was added, and the mixture was stirred at 120 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, adjusted to pH > 7 with sodium hydroxide, filtered, and the precipitated solid was collected. MS (m/z): 360.0 (M + 1) ⁺ .

Example 311:

Compound 311-a (10 mg, 0.022 mmol) (prepared according to the method described in Example 1 ) was dissolved in chloroform, and NBS (4.4 mg, 0.025 mmol) was added to the solution and allowed to react at room temperature for 1 hour. After the completion of the reaction, the solvent was evaporated under reduced pressure. the obtained crude product was dissolved in chloroform (2 ml) and methanol (2 ml), and the mixture was added to 6N HCl/methanol solution, and the reaction was continued for 30 minutes at room temperature, and adjusted with ammonia water. After pH=8, the crude product obtained by evaporation of the reaction mixture was purified by thin-layer chromatography. MS (m/z): 439.9 (M+1) ⁺ .

Example 312:

Compound 311-a (125 mg, 0.025 mmol) was dissolved in a mixed solvent of acetic acid (2 ml) and water (1 ml), and hexamethylenetetraammonium (79 mg, 0.56 mmol) was added to the solution. The reaction was carried out at 110 ° C for 2 hours. After completion of the reaction, the mixture was adjusted to pH = 8 with aqueous ammonia, and the solvent was evaporated under reduced pressure. MS (m/z): 389.4 (M+1) ⁺ .

Example 313:

Compound 312 (10 mg, 0.025 mmol) was dissolved in methanol, and sodium borohydride (4 mg, 0.051 mmol) was added to the solution, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure, and the crude product was purified by chromatography.

Example 318:

Compound 318-a

This compound was prepared in a similar manner to that described in Example 306 using compound 331 as starting material.

Compound 318

Compound 318-a (40 mg, 0.11 mmol) was dissolved in 30 mL of THF, cooled to 0 <0>C, and sodium hydride (22 mg, 0.53 micromoles, 60%). The reaction mixture was stirred at 0 ° C for 1 hour, then EtOAc (60 mg, 0.4. After completion of the reaction, it was treated with saturated aqueous sodium carbonate, and then evaporated. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. MS (m/z): 389.9 (M + 1) ⁺ .

Examples 319 and 320:

Compounds 319 and 320 were prepared in a similar manner as described in Example 327 . Compound 319 : MS: 388.9 (M + 1) ⁺ ; Compound 320 MS: 431 (M+1) ⁺

Example 321:

This compound was prepared in a similar manner as described in Example 318 using compound 272 as starting material. MS: 389.9 (M+1) ⁺ .

Example 322:

Compound 322-b

This compound was prepared in a similar manner as described in Example 307 .

Compound 322-c

This compound was prepared in a similar manner to that described in Example 1 using 322-b as a starting material.

Compound 322-d

This compound was prepared in a similar manner as described in Example 313 starting from 322-c . MS (m/z): 476.1 (M+H) ⁺ .

Compound 322-e

This compound was prepared in a similar manner as described in Example 318 starting from 322-d .

Compound 322

The material 322-e (40 mg, 0.082 mmol) was dissolved in methanol (15 ml), and then, to the solution, a solution of hydrogen chloride in methanol (0.5 ml, 5 mol/liter) was added, and the reaction mixture was stirred at 0 ° C for 1 hour. The reaction solution was concentrated to dryness, and the mixture was adjusted to pH >

Example 323:

Compound 323 was prepared according to the procedure described in Example 318 using compound 272 as material. MS: 403.9 (M+1) ⁺

Example 327:

Compound 33 (50 mg, 0.15 mmol) was dissolved in acetic acid (0.5 ml). To this was added ammonium chloride (61 mg, 0.9 mmol) and 37% aqueous formaldehyde (61 mg, 0.75 mmol). Stir at 55 ° C for 24 hours. After the completion of the reaction, the pH was adjusted to 7 with aqueous ammonia, concentrated, and the product was isolated by column chromatography to give 15 mg. MS (m/z): 374.8 (M + 1) ⁺ .

Example 330:

Compound 330-a:

Compound 331 (1.0 g) was dissolved in 100 ml of dichloromethane, cooled to -60-70 ° C, and O _{3 was added} thereto, and after reacting for 30 minutes, N _{2 was added} thereto for 10 minutes. Then, an aqueous Na ₂ SO ₃ solution was added thereto, stirred for 10 minutes, extracted with dichloromethane, and the organic phase was dried, concentrated, and then purified by column chromatography. MS (m/z): 322 (M+H) ⁺ .

Compound 330:

The compound 330-a (300 mg) obtained above was dissolved in 10 ml of HCl/methanol, and stirred at room temperature overnight. After completion of the reaction, it was concentrated, and the residue was basified by adding an appropriate aqueous sodium carbonate aqueous solution, and then 155 mg.

Examples 77 and 78:

Compound 332 was isolated by chiral HPLC to give chiral compounds 77 and 78 (HPLC conditions: Gilson system; column: Dicel IA 4.6 x 250 mm; mobile phase: n-hexane/isopropanol/diethylamine = 70/30/0.1; flow rate : 1 ml / min; detection light: UV 254 nm). One component, ee 98%, MS (m/z): 386 (M+1) ⁺ ; another component, ee 98%, MS (m/z): 386 (M+1) ⁺ .

Examples 270 and 271:

Compound 331 was isolated by chiral HPLC to give chiral compounds 270 and 271 (HPLC conditions: Gilson system; column: Dicel IA 20 x 250 mm; mobile phase: EtOH/CH3CN = 9/1; flow rate: 8 ml/min; detection light: UV 254 nm). One component, ee 98%, MS (m/z): 346 (M+1) ⁺ ; another component, ee 93%, MS (m/z): 346 (M+1) ⁺ .

Examples 314 and 315 :

Compound 310 was isolated by chiral HPLC to give chiral compound 314 and compound 315 (HPLC conditions: Gilson system; column: Dicel IA 20 x 250 mm; mobile phase: n-hexane/isopropanol/diethylamine: 6/4/0.1; Flow rate: 8 ml/min; detection light: 254 nm). One component, ee 95%, MS (m/z): 376 (M+1) ⁺ ; another component, ee 80%, MS (m/z): 376 (M+1) ⁺ .

Examples 324 and 325:

Compound 318 was isolated by chiral HPLC to give chiral compounds 324 and 325 (HPLC conditions: Gilson system; column: dicel IA, 20 x 250 mm IA; mobile phase: ethanol/methanol/diethylamine = 70/30/0.1; detection light : UV 254 nm). One component, ee 98%, MS (m/z): 390 (M+1) ⁺ ; another component, ee 90%, MS (m/z): 390 (M+1) ⁺ .

Example 333 Determination of inhibition of enzyme activity by c-met inhibitor by Tanscreener FP method

1. Reagents and materials

● Transcreenen ^TM KINASE Assy Kit: Bellbrook Labs., 3003-10K;

Recombinant human c-Met kinase: Invitrogen, PV3143;

● Poly E4Y (enzymatic reaction substrate peptide): Sigma, P0275; 5 mg / mL, dissolved in MilliQ water;

Enzymatic reaction buffer: 67 mM HEPES, 0.013% Triton X-100, 27 mM MgCl ₂ , 0.67 mM MnCl ₂ , 1.25 mM DTT, pH 7.4;

● 10mM ATP: Invitrogene, PV3227;

● 500 mM EDTA: Invitrogene, 15575-038;

● Greiner 96-hole blackboard: Greiner, 675076;

2. Prepare the reaction solution

● Compound dilution: 3 times gradient dilution of the test compound into deionized water containing 20% DMSO;

• Preparation of enzyme/substrate buffer: The recombinant human c-Met kinase and the reaction substrate Poly E4Y were diluted together in an enzymatic reaction buffer. The final concentrations were: c-Met (0.5 μg/mL) and Poly E4Y (62.5 μg/mL). Pre-cooling the enzyme/substrate buffer on ice before use;

● Preparation of ATP dilution: 10 mM ATP solution was diluted in the enzymatic reaction buffer, the final concentration was: 25 μM;

● Preparation of ADP dilution: 500μM ADP solution was diluted in the enzymatic reaction buffer, the final concentration was: 25μM;

● Prepare a standard curve solution according to the following table:

3. Enzymatic reaction

● Add 5 μL of diluted test compound or control solution to the corresponding wells of a 96-well blackboard (in which 5 μL of 20% DMSO is added to the positive control wells; 5 μL of 500 mM EDTA is added to the negative control wells);

● Add 10 μL of enzyme/substrate buffer to each well;

● Add 10 μL of ATP dilution to each well to initiate the enzymatic reaction and transiently oscillate the reaction plate;

● Add 5 μL of 20% DMSO, 10 μL of enzymatic reaction buffer and 10 μL of ATP standard curve solution to the wells of the standard curve.

The reaction was carried out at 28 ° C for 45 minutes while the reaction plate was shaken slightly.

4. Stop the enzyme reaction and detect ADP

● Prepare ADP test solution: Dilute ADP Alexa633 tracer (1:100), ADP antibody (1:158), and stop and assay buffer (1:10) in deionized water;

• Prepare a control solution containing free Tracer: Dilute ADP Alexa633 tracer (1:100), and stop and assay buffer (1:10) in deionized water;

● Prepare a control solution without Tracer: dilute the suspension and assay buffer (1: 10) in deionized water;

● react at 28 ° C for 1 h, shaking the reaction plate slightly;

● Detect the polarization fluorescence value of each hole on the TECAN F500. Excitation light: 610 nm, scattered light: 670 nm.

5. Data analysis

among them:

● The ADP concentration of the drug well refers to the ADP concentration of the well containing the drug to be tested.

• The ADP concentration of positive control wells refers to the ADP concentration of wells containing 20% DMSO.

● The ADP concentration is a conversion formula between the ADP concentration and the milli-bias (mP) derived from the standard curve. The milli-bias value per well is converted to the ADP concentration. The determination of the partial bias value is based on the polarization value read out per well according to the formula provided in the kit manual. The specific calculation formula can be found on the website of BellBrook Lab. (www.bellbrooklabs.com).

IC50 values were calculated using XL-Fit 2.0 software.

Experimental results:

Compounds 7,8,11,12,16,19,20,25,33,34,35,36,42,43,44,45,47,48,49,50,56,57,77,127,128,129,153,156,158,161,163,169,190,192,193,195,197,198,203,207,210,212,220,222,223,224,225,227,228,229,230, 254, 265, 270, 278, 279, 280, 300, 301, 303, 308, 314, 318, 325, 328, 332, 332 ,14,15,21,24,26,27,46,51,52,54,58,59,61,62,63,65,70,72,76,81,82,83,84,85,86 , IC ₅₀ values 87,88,89,90,91,95,97,102,104,111,112,113,115,117,130,131,132,133,134,135,136,137,140,141,144,145,146,147,150,152,155,157,160,162,164,165,166,168,172,173,176,177,179,180,182,183,185,186,188,189,191,194,196,199,200,202,213,214,215,217,218,221,226,235,237,238,239,240,245,246,248,250,252,253,255,258,259,266,267,268,271,272,274,275,276,277,281,282, 283,287,290,295,298,302,304,305,306,307,310,311,312,313,315,319,321,322,323,324,326,327,329,331 0.001uM greater than or equal to less than 0.1 uM.

Compounds 2,5,6,9,17,18,22,23,28,30,37,38,41,53,55,64,66,71,73,74,78,79,80,92,93 The IC ₅₀ value is greater than or equal to 0.1 uM and less than 1 uM , 94, 96, 98 , 99, 100, 101, 103, 105, 107, 108, 109, 110, 116, 118, 119, 120, 121, 122, 123, 126, 138, 142, 143, 154, 170, 174, 181, 187, 203, 205, 205, 208, 209, 216, 219, 231, 234, 236, 244, 247, 249, 288, 288, 292, 293, 294, 296, 299, 317, 317.

Claims (45)

Compound of Structural Formula 1: And a pharmaceutically acceptable salt thereof, wherein X is N; Y is selected from -O-, -S- or -N(R ⁷ )-; R ^{1 is} selected from aryl and heteroaryl, aryl and heteroaryl a lower alkyl group optionally substituted by halogen, -CF ₃ , -CF ₂ H, a lower alkyl group, a hydroxy group, a lower alkyl group substituted with a lower alkoxy group, a lower alkyl group substituted by -NR ¹³ R ¹⁴ , a heterocyclic ring Substituted lower alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C( O) R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ Substituting one or more groups of -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic, heteroaryl, aryl, alkenyl, alkynyl Or X is N; Y is deleted; and R ¹ is a fused bicyclic heteroaryl group, which may optionally be halogen, -CF ₃ , -CF ₂ H, lower alkyl, hydroxy Substituted lower alkyl, lower alkoxy substituted lower alkyl, NR ¹³ R ¹⁴ substituted lower alkyl, heterocyclic substituted lower alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O )OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic, heteroaryl, aryl, alkenyl, alkynyl Substituted by one or more groups; or X is C(R ⁶ ); Y is -O-, -S- or -N(R ⁷ )-, or a deletion; R ¹ is a heteroaryl group, the heteroaryl group a lower alkyl group optionally substituted by halogen, -CF ₃ , -CF ₂ H, a lower alkyl group, a hydroxy group, a lower alkyl group substituted with a lower alkoxy group, a lower alkyl group substituted by -NR ¹³ R ¹⁴ , a heterocyclic ring Substituted lower alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C( O) R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ Substituting one or more groups of -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic, heteroaryl, aryl, alkenyl, alkynyl ; R ² and R ³ are independently selected from hydrogen and alkyl, or R ² together form from 3 to 7-membered cycloalkyl or heterocycloalkyl and R ³ and the carbon atoms to which they are attached, ; R ⁴ is selected from halo, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, any of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be optionally substituted with one or more Substituted, these groups are selected from: lower alkanes, which may optionally be selected from the group consisting of hydroxyl, lower alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ ,- Substituted by one or more groups of NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ ; lower alkoxy group, which may be optionally selected from the group consisting of halogen, hydroxy and lower alkane Substituted by one or more groups in the oxy group; a cycloalkoxy group, which may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy and lower alkoxy; heterocycloalkoxy , which may be optionally substituted with one or more groups selected from the group consisting of halogen, hydroxy and lower alkoxy; heterocycles, which may optionally be selected from the group consisting of lower alkyl, halogen, hydroxy and lower alkoxy Substituted by one or more groups in the group; heteroaryloxy, which may optionally be Substituted by one or more groups selected from the group consisting of lower alkyl, halogen, hydroxy, and lower alkoxy; aryl, which may be optionally selected from the group consisting of lower alkyl, halogen, hydroxy, and lower alkoxy Substituted by one or more groups; a heteroaryl group which may be optionally substituted with one or more groups selected from the group consisting of lower alkyl, halogen, hydroxy and lower alkoxy; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ;-NR ¹³ R ¹⁴ ;-NR ¹³ C(O)R ¹¹ ;-NR ¹³ S(O) _n R ¹² ;-NR ¹³ S(O) _n NR ¹³ R ¹⁴ ;-NR ¹³ C(O)OR ¹² ;-NR ¹³ C(O)NR ¹³ R ¹⁴ ;-C(O)NR ¹³ R ¹⁴ ;-S(O) _n R ¹² ; and -S (O) _n NR ¹³ R ¹⁴ ; R ^{5 is} selected from the group consisting of hydrogen, halogen, OH, NH ₂ , CF ₃ , —CF ₂ H, alkyl, alkenyl and alkynyl; R ^{6 is} selected from hydrogen, —OH, —NH ₂ , -NHC(O)R ¹¹ , halogen and alkyl; R ^{7 is} selected from hydrogen and lower alkyl; each n is independently 0, 1 or 2; R ¹¹ , R ¹² , R ¹³ and R ¹⁴ are each independently Selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic, each of which may be optionally selected from the group consisting of halogen, lower alkyl, in addition to hydrogen. Hydroxyl and Alkoxy of one or more groups substituted; or R ¹³ form a heterocyclic ring together with R ¹⁴ and the nitrogen atom they are attached, the heterocyclic ring containing one or two substituents selected from -O -, - S a hetero atom of - and -N(R ¹⁵ )-, wherein the heterocyclic ring may in turn be optionally substituted with one or more groups selected from the group consisting of halogen, lower alkyl, hydroxy and lower alkoxy; and R ¹⁵ Selected from hydrogen, lower alkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -S(O) _n R ¹² and -S(O) _n NR ¹³ R ¹⁴ ; conditions are: R ¹ is not a substituted or unsubstituted phenyl or 4-pyridyl group; When X is N, R ² is hydrogen or methyl, R ³ and R ⁵ are hydrogen, and Y is deleted again, R ¹ is not quinoline-6-yl, 7-fluoroquinolin-6-yl, 3-quino Oxazolin-6-yl, 2,3-dihydrobenzofuran-5-yl or 2,3-dihydrobenzodioxan-6-yl; When X is N, R ² , R ³ and R ⁵ are hydrogen, Y is -O- or -N(R ⁷ )-, R ¹ is quinoline-6-yl, 7-fluoroquinolin-6-yl, When 3-quinazolin-6-yl, 2,3-dihydrobenzofuran-5-yl or 2,3-dihydrobenzodiox-6-yl, R ⁴ is not halogen, alkyl, Cycloalkyl, heterocyclic and aryl. The compound of claim 1, wherein X is N. The compound of claim 1, wherein X is C(R ⁶ ). The compound of claim 3, wherein R ^{6 is} selected from the group consisting of hydrogen, halogen, and lower alkyl. The compound of claim 3, wherein R ⁶ is hydrogen. The compound of any one of claims 1 to 5 wherein Y is -O-. The compound of any one of claims 1 to 5 wherein Y is -S-. The compound of any one of claims 1 to 5 wherein Y is -N(R ⁷ )-. The compound of claim 8, wherein R ⁷ is hydrogen or methyl. The compound of claim 8, wherein R ⁷ is hydrogen. The compound of any one of claims 1 to 5, wherein Y is deleted. The compound of any one of claims 1 to 11, wherein R ¹ is an 8-10 membered heteroaryl group, wherein the heteroaryl group may be optionally selected from the group consisting of halogen, -CF ₃ , -CF ₂ H, lower alkyl, hydroxy-substituted lower alkyl, lower alkoxy-substituted lower alkyl, NR ¹³ R ¹⁴ substituted lower alkyl, heterocyclic substituted lower alkyl, cycloalkyl, -C(O R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ is substituted with one or more of the heterocyclic, heteroaryl, aryl, alkenyl and alkynyl groups. The compound of claim 12, wherein R ¹ is an 8-10 membered heteroaryl group, wherein the heteroaryl group may be optionally selected from the group consisting of halogen, lower alkyl, hydroxy substituted lower alkyl and lower alkane. Substituting one or more of the oxy-substituted lower alkyl groups. The compound of claim 12, wherein R ^{1 is} selected from the group consisting of quinoline-6-yl, thieno[3,2-c]pyridin-2-yl, benzo[d]thiazole-6-yl, and Imidazo[1,2-a]pyridin-6-yl, which may optionally be one or more selected from the group consisting of halogen, lower alkyl, hydroxy-substituted lower alkyl and lower alkoxy substituted lower alkyl Replaced by a group. The compound of claim 12, wherein R ^{1 is} selected from the group consisting of quinoline-6-yl, which may be optionally substituted by halogen, lower alkyl, hydroxy-substituted lower alkyl and lower alkoxy Substituted by one or more groups of the lower alkyl group. The compound of any one of claims 1 to 11, wherein R ^{1 is} selected from the following heteroaryl groups: Any one of the rings may be optionally substituted by a lower alkyl group selected from the group consisting of halogen, -CF ₃ , -CF ₂ H, lower alkyl, hydroxy-substituted lower alkyl, lower alkoxy-substituted lower alkyl, NR ¹³ R ¹⁴ Alkyl, heterocyclic substituted lower alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² , -NR ¹³ C(O One or more of NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic, heteroaryl, aryl, alkenyl and alkynyl groups Replaced by a group. The compound of any one of claims 1 to 11, wherein R ^{1 is} selected from the group consisting of the following heteroaryl groups: Any of which rings may be optionally substituted by one or more radicals, these radicals selected from halogen, -CF _3, -CF ₂ H, substituted lower alkyl, hydroxy-substituted lower alkyl, lower alkoxy Lower alkyl, NR ¹³ R ¹⁴ substituted lower alkyl, heterocyclic substituted lower alkyl, cycloalkyl, -C(O)R ¹¹ , -C(O)OR ¹¹ , -CN, -C(O) NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C( O) OR ¹² , -NR ¹³ C(O)NR ¹³ R ¹⁴ , -NO ₂ , -S(O) _n R ¹² , -S(O) _n NR ¹³ R ¹⁴ , heterocyclic ring, heteroaryl group, aryl group , alkenyl, alkynyl. The compound of any one of claims 1 to 17, wherein R ² and R ^{3 are} independently selected from hydrogen and C ₁ -C ₆ alkyl; or R ² and R ³ are attached thereto The carbon atoms together form a cyclopropyl group. The compound of claim 18, wherein R ² is hydrogen, and R ^{3 is} selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl. The compound of claim 18, wherein R ² is hydrogen and R ^{3 is} selected from the group consisting of hydrogen and methyl. The compound of claim 18, wherein R ² and R ³ are both hydrogen. The compound of claim 18, wherein R ² and R ³ together with the carbon atom to which they are attached form a cyclopropyl group. The compound of any one of claims 1 to 22, wherein R ⁴ is an aryl group, and the aryl group may be optionally substituted by one or more groups selected from the group consisting of: An alkyl group, which may be optionally selected from the group consisting of hydroxyl, lower alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O R ¹¹ , -NR ¹³ C(O)R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and -NR Substituted by one or more groups of ¹³ C(O)NR ¹³ R ¹⁴ ; lower alkoxy, which may be optionally substituted by one or more of halogen, hydroxy and lower alkoxy; a ring, which may be optionally substituted with one or more groups selected from the group consisting of lower alkyl, halogen, hydroxy and lower alkoxy; heteroaryloxy, which may be optionally selected from lower alkyl, Substituted by one or more of a halogen, a hydroxyl group and a lower alkoxy group; an aryl group which may optionally be selected from one or more groups selected from the group consisting of lower alkyl, halogen, hydroxy and lower alkoxy Substituted; heteroaryl, which may be optionally selected from lower alkyl Halogen, hydroxyl and lower alkoxy groups; halo; ^{cyano; -C (O) R 11;} -C (O) OR 11; -NR 13 R 14; -NR 13 C (O) R 11; -NR ¹³ S(O) _n R ¹² ;-NR ¹³ S(O) _n NR ¹³ R ¹⁴ ;-NR ¹³ C(O)OR ¹² ;-NR ¹³ C(O)NR ¹³ R ¹⁴ ;-C(O)NR ¹³ R ¹⁴ ; -S(O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ . The compound of claim 23, wherein R ⁴ is an aryl group, which may be optionally selected from the group consisting of halogen, hydroxy, lower alkoxy, lower alkyl, hydroxy substituted lower alkyl, lower alkoxy The group-substituted lower alkyl group, the hydroxy-substituted lower alkoxy group, the lower alkoxy-substituted lower alkoxy group, and one or more groups of -NR ¹³ S(O) _n R ¹² are substituted. The compound of claim 23, wherein R ⁴ is phenyl, which may be optionally substituted by a lower alkoxy group selected from the group consisting of lower alkoxy, hydroxy-substituted lower alkoxy and lower alkoxy. Replaced by one or more of the groups. The compound of claim 23, wherein R ⁴ is a heterocyclic ring, which is optionally substituted by one or more groups selected from the group consisting of lower alkyl groups, which may optionally be selected from Hydroxy, lower alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O) R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ Substituted by one or more groups; lower alkoxy, which may be optionally substituted by one or more of halogen, hydroxy and lower alkoxy; heterocycle, which may optionally be selected from lower order Substituted by one or more of an alkyl group, a halogen, a hydroxyl group and a lower alkoxy group; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ; -NR ¹³ R ¹⁴ ;- NR ¹³ C(O)R ¹¹ ;-NR ¹³ S(O) _n R ¹² ;-NR ¹³ S(O) _n NR ¹³ R ¹⁴ ;-NR ¹³ C(O)OR ¹² ;-NR ¹³ C(O) NR ¹³ R ¹⁴ ; -C(O)NR ¹³ R ¹⁴ ; -S(O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ . The compound of claim 26, wherein the heterocyclic ring is selected from the group consisting of tetrahydropyrrol-1-yl, acridin-1-yl, tetrahydro-2H-pyran-4-yl, morpholine- 4-Based and 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl. The compound of claim 23, wherein R ⁴ is heteroaryl, which may be optionally substituted by one or more groups selected from lower alkyl, which may be optionally selected From hydroxy, lower alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ Substituted by one or more groups; lower alkoxy, which may be optionally substituted by one or more of halogen, hydroxy and lower alkoxy; heterocycle, which may optionally be selected from Substituted by one or more of the lower alkyl, halogen, hydroxy and lower alkoxy groups; halogen; cyano; -C(O)R ¹¹ ; -C(O)OR ¹¹ ; -NR ¹³ R ¹⁴ ; -NR ¹³ C(O)R ¹¹ ;-NR ¹³ S(O) _n R ¹² ;-NR ¹³ S(O) _n NR ¹³ R ¹⁴ ;-NR ¹³ C(O)OR ¹² ;-NR ¹³ C(O NR ¹³ R ¹⁴ ; -C(O)NR ¹³ R ¹⁴ ; -S(O) _n R ¹² ; and -S(O) _n NR ¹³ R ¹⁴ . The compound according to claim 28, wherein the heteroaryl group is selected from the group consisting of 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazole- 1-yl, 1H-imidazol-4-yl, oxazol-2-yl, thiazol-2-yl, isoxazol-3-yl, isoxazol-5-yl, 1H-pyrrol-2-yl, 1H Pyrrol-3-yl, thiophen-2-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl. The compound of claim 29, wherein the heteroaryl group may be optionally substituted with one or more of the following groups selected from lower alkyl groups, which may be optionally selected from Hydroxy, lower alkoxy, CN, halogen, -C(O)OR ¹¹ , -C(O)NR ¹³ R ¹⁴ , -NR ¹³ R ¹⁴ , -OC(O)R ¹¹ , -NR ¹³ C(O) R ¹¹ , -NR ¹³ S(O) _n R ¹² , -NR ¹³ S(O) _n NR ¹³ R ¹⁴ , -NR ¹³ C(O)OR ¹² and -NR ¹³ C(O)NR ¹³ R ¹⁴ Substituted by one or more groups; a heterocyclic ring, which may be optionally substituted with one or more groups selected from the group consisting of lower alkyl, halogen, hydroxy and lower alkoxy. The compound of claim 29, wherein the heteroaryl group may be optionally substituted with one or more groups selected from lower alkyl groups, wherein the lower alkyl group may be optionally one or A plurality of groups selected from a hydroxyl group, a lower alkoxy group, a cyano group or a halogen are substituted. The compound of any one of claims 1 to 22, wherein R ⁴ is a lower alkyl group. The compound of any one of claims 1 to 32, wherein R ⁵ is hydrogen. The compound of any one of claims 1 to 33, wherein n is 0. The compound of any one of claims 1 to 32, wherein n is 1. The compound of any one of claims 1 to 32, wherein n is 2. At least one compound selected from the group consisting of Compounds 1 to 332 and/or at least one pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising at least one compound of any one of claims 1 to 37 and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. A medicament for inhibiting c-Met activity, comprising at least one compound of any one of claims 1 to 37 and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier . A medicament for the treatment of cancer, comprising at least one compound of any one of claims 1 to 37 and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. A method of inhibiting c-Met activity, which comprises administering a compound according to any one of claims 1 to 37 and/or a pharmaceutically acceptable salt thereof, and a human, which are effective for inhibiting c-Met activity. Or animal contact. A method of treating cancer, the method comprising administering to a subject having cancer a therapeutically effective amount of the compound of any one of claims 1 to 37 and/or a pharmaceutically acceptable salt thereof. The use of the compound according to any one of claims 1 to 37 and/or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting c-Met activity. The use of a compound according to any one of claims 1 to 37 and/or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer. The pharmaceutical composition comprising an effective amount of the compound of any one of claims 1 to 37 and/or a pharmaceutically acceptable salt thereof; and an amount of other therapeutic agent, preferably an antitumor agent.