RU2792626C1 - New pan-raf kinase inhibitor and applications thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a pan-RAF kinase inhibitor, which is a compound with formula (Ia) or a pharmaceutically acceptable salt thereof, as well as to a pharmaceutical composition based on it. In general formula (Ia), R₁ is selected from the group consisting of H, pyridyl, morpholinyl, piperazinyl, 4-methyl-piperazin-1-ylphenyl, oxetan-3-yloxy, 2-morpholinoethoxy, 3-morpholinopropoxy and tetrahydrofuran-3-ylmethoxy; R₂ is selected from the group consisting of H, C_1-6 hydroxyalkoxy, C_1-6 alkoxy-C_1-6 alkoxy, tetrahydropyran-4-yloxy, tetrahydrofuran-3-yloxy, oxetan-3-yloxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-ylmethoxy and oxetan-3-ylmethoxy; R₃ is H; where R₁, R₂ and R₃ do not represent H at the same time; R₄ is selected from the group consisting of C_1-6 haloalkyl and C_1-6 cyanoalkyl; R₅ is selected from the group consisting of H, C_1-6 alkyl and 4-methyl-piperazin-1-ylmethyl.

EFFECT: providing a new selective pan-RAF kinase inhibitor that can be used to treat diseases mediated by RAF and/or RAS kinases.

8 cl, 5 dwg, 7 tbl, 189 ex.

Description

Technical field

The present invention provides a compound as a kinase inhibitor, a pharmaceutical composition containing said compound, and the use of said compound in therapy. In particular, the present invention describes a pyrazole or imidazole derivative useful for inhibiting RAF and/or RAS kinase and for treating a disease mediated by RAF and/or RAS kinase.

State of the art

The RAF gene family includes BRAF, ARAF and CRAF. BRAF is an oncogene located on the long arm of chromosome 7 and encodes a protein containing 766 amino acid residues. This protein is a serine/threonine-specific kinase that plays the role of an important transduction factor in the RAS/RAF/MEK/ERK signaling pathway. Only after phosphorylation by RAS kinase does the BRAF protein exhibit kinase activity to activate the next MEK protein in the cascade, and then the MEK protein activates the ERK protein. The ERK protein enters the cell nucleus and then activates various downstream proteins to drive the transcription of various downstream genes, leading to cell proliferation and division. When the V600E mutation occurs in BRAF, amino acid residue at position 600 of BRAF changes from valine to glutamate, and the BRAF protein is always in an activated state. In RAS-mutated tumors, continuous activation of the RAS protein results in the formation of a BRAF-BRAF homodimer or a BRAF-CRAF heterodimer downstream, which transmits an activation signal downstream and promotes malignant proliferation of tumor cells. Therefore, the development of small molecule targeted drugs targeting Pan-RAF can simultaneously inhibit cancer caused by the V600E mutation and the RAS mutation in BRAF.

Vemurafenib, dabrafenib, and LGX818 are currently approved as BRAF inhibitors for the treatment of BRAF-mutant melanoma. However, the above drugs do not work in a tumor carrying a RAS mutation. The reason is mainly that RAS mutation can lead to the formation of a dimer of BRAF and CRAF, and inhibition of BRAF can in turn activate CRAF. Secondly, commercially available BRAF inhibitors have a weak inhibitory effect on CRAF, and thus said BRAF inhibitors lose their anti-cancer effect. Therefore, research and development of RAF inhibitors has been focused on creating Pan-RAF inhibitors that can simultaneously act on BRAF and CRAF proteins and can effectively inhibit downstream MEK and ERK activity.

Brief description of the invention

The present invention provides a selective kinase inhibitor comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof:

Where

один из Y и Z представляет собой углерод, а другой представляет собой азот, предпочтительно Y представляет собой азот, и Z представляет собой углерод;X is selected from the group consisting of

one of Y and Z is carbon and the other is nitrogen, preferably Y is nitrogen and Z is carbon;

предпочтительно А представляет собой, и заместители R₄ и R₅ находятся в мета- и пара-положениях бензольного кольца, соответственно;ring A is selected from the group consisting of

preferably A is, and the substituents R ₄ and R ₅ are in the meta and para positions of the benzene ring, respectively;

где R₁, R₂ и R₃ не представляют собой Н одновременно;R ₁ , R ₂ and R ₃ are each independently selected from the group consisting of H, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 hydroxyalkoxy, C _3-6 cycloalkyl- C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 alkoxy, phenyl, pyridyl, phenyl-C _1-6 alkoxy, furyl-C _1-6 alkoxy, heterocycloalkyl optionally substituted with R ₆ , heterocycloalkylphenyl optionally substituted with R ₆ , heterocycloalkylcarbonyl optionally substituted with R ₆ , heterocycloalkyloxy optionally substituted with R ₆ , heterocycloalkyl-C _1-6 alkoxy optionally substituted with R ₆ , heterocycloalkyl-C _1-6 alkanoylamino optionally substituted with R ₆ , C _3-6 cycloalkyl C _{1- 6} alkanoylamino and C _1-6 alkylaminocarbonyl-C _1-6 alkoxy, or R ₁ together with R ₃ form

where R ₁ , R ₂ and R ₃ do not represent H at the same time;

и R₄ и R₅ не представляют собой Н одновременно;each of R ₄ and R ₅ is independently selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 cyanoalkyl, heterocycloalkyl-C _1-6 alkyl, optionally substituted with R ₆ , phenyl, optionally substituted R ₆ , heteroaryl optionally substituted with R ₆ , and aminosulfonyl, or R ₄ and R ₅ together form

and R ₄ and R ₅ do not represent H at the same time;

R ₆ is independently selected from the group consisting of oxo, C _1-6 alkyl, C _2-6 alkanoyl, C _1-6 alkylsulfonyl, C _1-6 alkylamino, C _2-6 alkanoyl, and C _1-6 haloalkyl.

"Heterocycloalkyl" as described above is preferably a 4-6 membered heterocycloalkyl containing oxygen and/or nitrogen atom(s), such as pyrrolidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, azetidinyl and the like. In addition, the nitrogen atom or carbon atom of these heterocycloalkyls may be optionally substituted with an R ₆ group selected from the group consisting of oxo (=O), C _1-6 alkyl, C _2-6 alkanoyl, C _1-6 alkylsulfonyl, C _{1 -6} alkylamino C _2-6 alkanoyl and C _1-6 haloalkyl.

где R₁, R ₂ и R₃ не представляют собой Н одновременно;In a preferred embodiment of the present invention, each R ₁ , R ₂ and R ₃ is independently selected from the group consisting of H, cyano, C _1-6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t- butyl and the like), C _1-6 hydroxyalkoxy (such as hydroxymethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy and the like), C _3-6 cycloalkyl-C _1-6 alkoxy (such as cyclopentylmethoxy and the like ), C _1-6 alkoxy-C _1-6 alkoxy (such as 2-methoxyethoxy and the like), phenyl, pyridyl (such as 2-pyridyl, 3-pyridyl, 4-pyridyl), phenyl-C _1-6 alkoxy (such as phenylmethoxy and the like), furyl-C _1-6 alkoxy (such as furan-3-ylmethoxy and the like), heterocycloalkyl optionally substituted with R ₆ (such as N-morpholinyl, piperazin-1-yl, 4- methyl-piperazin-1-yl and the like), heterocycloalkylphenyl optionally substituted with R ₆ (such as 4-methylpiperazinylphenyl and the like), heterocycloalkylcarbonyl optionally substituted R ₆ (such as 4-methylpiperizan-1-ylcarbonyl and the like), heterocycloalkyloxy, optionally substituted R ₆ (such as tetrahydropyran-4-yloxy, tetrahydrofuran-3-yloxy, oxetan-3-yloxy, azetidin-3-yloxy and the like), heterocycloalkyl-C _1-6 alkoxy optionally substituted with R ₆ (such as 2-morpholinoethoxy, 3-morpholinopropoxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-ylmethoxy, oxetan-3- ylmethoxy, pyrrolidin-3-ylmethoxy and the like), heterocycloalkyl-C _1-6 alkanoylamino optionally substituted with R ₆ (such as tetrahydropyran-4-ylformylamino, tetrahydrofuran-3-ylformylamino, tetrahydropyran-4-ylacetylamino, tetrahydrofuran-3-ylacetylamino , 3-methyloxetan-3-ylformylamino, 3-oxadicyclo[3.1.0]hexan-6-ylformylamino and the like), C _3-6 cycloalkyl-C _1-6 alkanoylamino (such as cyclopropylformylamino and the like), and C _{1- 6} alkylaminocarbonyl-C _1-6 alkoxy (such as dimethylaminocarbonylmethoxy and the like), or R ₁ and R ₃ together with form

where R ₁ , R ₂ and R ₃ do not represent H at the same time;

In another preferred embodiment, the present invention provides a selective Pan-RAF kinase inhibitor comprising a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof:

where R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined above. In a more preferred embodiment of the invention

R ₁ is selected from the group consisting of H, pyridyl, heterocycloalkyl, heterocycloalkylphenyl optionally substituted with C _1-6 alkyl, heterocycloalkyloxy, heterocycloalkyl-C _1-6 alkoxy and C _1-6 alkylaminocarbonyl-C _1-6 alkoxy;

R ₂ is selected from the group consisting of H, C _1-6 alkyl, C _1-6 hydroxyalkoxy, C _1-6 alkoxy-C _1-6 alkoxy, heterocycloalkyloxy, and heterocycloalkyl-C _1-6 alkoxy;

R ₃ is selected from the group consisting of H and C3 _-6 cycloalkyl C _1-6 alkanoylamino;

where R ₁ , R ₂ and R ₃ He represent H at the same time;

R ₄ is selected from the group consisting of C _1-6 haloalkyl and C _1-6 cyanoalkyl;

R ₅ is selected from the group consisting of H, C _1-6 alkyl and heterocycloalkyl-C _1-6 alkyl optionally substituted with C _1-6 alkyl.

In a particularly preferred embodiment, R ₁ is selected from the group consisting of 3-pyridyl, 4-pyridyl, N-morpholinyl, heterocycloalkyloxy, heterocycloalkyl-C _1-6 alkoxy and C _1-6 alkylaminocarbonyl-C _1-6 alkoxy; R ₄ is selected from the group consisting of C _1-6 haloalkyl and C _1-6 cyanoalkyl; each of R ₂ , R ₃ and R ₅ is H.

In another particularly preferred embodiment, R ₂ is selected from the group consisting of C _1-6 hydroxyalkoxy, C _1-6 alkoxy-C _1-6 alkoxy, heterocycloalkyloxy and heterocycloalkyl-C _1-6 alkoxy; R ₄ is selected from the group consisting of C _1-6 haloalkyl and C _1-6 cyanoalkyl; each of R ₁ , R ₃ and R ₅ is H.

In another embodiment, the present invention provides a selective Pan-RAF kinase inhibitor comprising a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof:

Where

и предпочтительно является

X is selected from the group consisting of

and preferably is

one of Y and Z is carbon and the other is nitrogen;

и предпочтительно является

ring A is selected from the group consisting of

and preferably is

и R₄ и R₅ не представляют собой Н одновременно;each of R ₄ and R ₅ is independently selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 cyanoalkyl, piperazinyl C _1-6 alkyl, optionally substituted with R ₆ , phenyl, optionally substituted R ₆ , imidazolyl optionally substituted with R ₆ , thienyl optionally substituted with R ₆ , pyridyl optionally substituted with R ₆ , and aminosulfonyl, or R ₄ and R ₅ together form

and R ₄ and R ₅ do not represent H at the same time;

R ₆ is independently selected from the group consisting of C _1-6 alkyl and C _1-6 haloalkyl.

In another respect, the present invention provides a pharmaceutical composition comprising a kinase inhibitor as described in the present invention, a pharmaceutically acceptable carrier or adjuvant, and optionally another therapeutic agent.

The present invention also relates to the use of the disclosed kinase inhibitor in the manufacture of a medicament for inhibiting RAF and/or RAS tyrosine kinase activity, and in the manufacture of a medicament for the treatment, prevention, or amelioration of a disease, disorder, or condition that is modulated by RAF and/or RAS activity, or depends on the specified activity, or is involved in it.

Description of drawings

Fig. 1a-1b illustrate the tumor inhibitory effect of test compounds in an A375 cell tumor transplanted mouse model.

Fig. 2a-2c illustrate the tumor inhibitory effect of test compounds in a Calu-6 tumor transplanted mouse model.

Fig. 3a-3b illustrate the tumor inhibitory effect of test compounds in a mouse model with transplanted tumor from HCT116 cells.

Fig. 4a-4b illustrate the tumor inhibitory effect of test compounds in a COLO205 cell tumor transplanted mouse model.

Fig. 5a-5b illustrate tumor inhibitory effects of test compounds in a BxPC3 tumor transplanted mouse model.

Detailed description of the invention

Terminology

Unless otherwise indicated, all technical and scientific terms used in the present description have the meaning accepted by experts in the field of technology to which the claimed invention relates.

Unless otherwise indicated, the present description uses conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology within the competence of a person skilled in the art. Unless specific definitions are given, the nomenclature used in analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry, as well as their laboratory procedures and techniques described in the present invention, are known in the art. Typically, the above techniques and procedures can be performed by conventional methods well known in the art and described in various general and more specific sources, which are cited and discussed throughout the text of this description.

The term "alkyl" refers to an aliphatic hydrocarbon group, which may be branched or straight chain. Depending on the structure, the alkyl group may be a mono-radical or a di-radical (ie, an alkylene group). In the present invention, the alkyl group is preferably "lower alkyl" having 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like. It should be understood that "alkyl" referred to in the present invention includes all possible configurations and conformations of alkyl that may be present. For example, "propyl" as used herein includes n-propyl, isopropyl. "Butyl" as used herein includes n-butyl, iso-butyl and tert-butyl. "Pentyl" as used herein includes n-pentyl, isopentyl, neopentyl, t-butyl and pent-3-yl.

The term "alkoxy" refers to a -O-alkyl group, where alkyl is as defined in the present invention. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.

The term "alkoxyalkyl" refers to an alkyl group, as defined in the present invention, substituted by an alkoxy group, as defined in the present invention.

The term "cycloalkyl" refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen. Cycloalkyl groups include groups containing 3 to 10 ring atoms. Depending on the structure, the cycloalkyl group may be a mono-radical or a di-radical (eg a cycloalkylene group). In the present invention, the cycloalkyl group is preferably a cycloalkyl having 3 to 8 carbon atoms, and more preferably a "lower cycloalkyl" having 3 to 6 carbon atoms. Representative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and diamantanyl.

The term "alkyl(cycloalkyl)" or "cycloalkylalkyl" means an alkyl radical, as defined in the present invention, substituted with a cycloalkyl group, as defined in the present invention. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

The term "aromatic" refers to a planar ring having a delocalized π electron system containing 4n+2 π electrons, where n is an integer. Aromatic rings can be five, six, seven, eight, nine, or more than nine atoms. Aromatic compounds may be optionally substituted. The term "aromatic" includes both carbocyclic aryl (eg phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (eg pyridine). This term includes monocyclic groups or polycyclic groups with fused rings (ie, rings that share a common pair of adjacent carbon atoms).

As used in the present invention, the term "aryl" refers to an aromatic ring, where each of the atoms forming the ring is a carbon atom. Aryl rings may be five, six, seven, eight, nine, or more than nine atoms. Aryl groups may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, phenanthreonyl, anthracenyl, fluorenyl, and indenyl. Depending on the structure, the aryl group may be a mono-radical or a di-radical (ie, an arylene group).

The term "aryloxy" refers to a -O-aryl group, where aryl is as defined in the present invention.

The term "heteroaryl" refers to an aryl group that contains one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N-containing "heteroaryl" moiety refers to an aromatic group in which at least one of the ring backbone atoms is a nitrogen atom. Depending on the structure, the heteroaryl group may be a mono-radical or a di-radical (ie, a heteroarylene group). Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanil, benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, furopyridinyl and the like.

The term "alkyl(aryl)" or "aralkyl" refers to an alkyl group, as defined in the present invention, substituted with an aryl group, as defined in the present invention. Non-limiting alkyl(aryl) includes benzyl, phenethyl, and the like.

The term "alkyl(heteroaryl)" refers to an alkyl group, as defined in the present invention, substituted by a heteroaryl group, as defined in the present invention.

As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, in which one or more backbone atoms is a heteroatom, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof. The heteroatom(s) may be located at any position in the heteroalkyl group or at the position where the heteroalkyl group is attached to the rest of the molecule.

As used herein, the term "heterocycloalkyl" or "heterocyclic group" refers to a non-aromatic ring, where one or more ring-forming atoms is a heteroatom selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring may be a monocyclic or polycyclic ring formed from three, four, five, six, seven, eight, nine, or more than nine atoms. The heterocycloalkyl ring may be optionally substituted. Examples of heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxatian, 1,4-oxathiine, 1,4-oxatian, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxol, 1, 3-dioxolane, 1,3-dithiol, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolan. Depending on the structure, the heterocycloalkyl group may be a mono-radical or a di-radical (ie, a heterocycloalkylene group).

The term "alkyl(heterocycloalkyl)" or "heterocycloalkylalkyl" refers to an alkyl group as defined herein substituted with a heterocycloalkyl group as defined herein.

The term "alkyloxy(heterocycloalkyl)" or "heterocycloalkylalkyloxy" refers to an alkyloxy group as defined herein substituted with a heterocycloalkyl group as defined herein.

The term "halogen" ("halo") or "halogen" ("halogen") refers to fluorine, chlorine, bromine and iodine.

The terms "haloalkyl", "haloalkoxy", and "haloheteroalkyl" include an alkyl, alkoxy, or heteroalkyl structure in which at least one hydrogen has been replaced by a halogen atom. In some embodiments, if two or more hydrogen atoms are replaced by halogen atoms, said halogen atoms are the same or different from each other.

The term "hydroxy" refers to the -OH group.

The term "cyano" refers to the -CN group.

The term "ester" refers to a chemical moiety with the formula -COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (linked through the ring carbon) and heterocyclic group (linked through the ring carbon).

The term "amino" refers to the -NH ₂ group.

The term "aminocarbonyl" refers to the group -CO-NH ₂ .

The term "alkylaminocarbonyl" refers to the group -CO-NH-R, where R represents an alkyl group, as defined in the present invention.

The term "amide" or "amido" refers to -NR-CO-R', where R and R' are each independently hydrogen or alkyl.

The term "alkylamino" refers to an amino substituent that is further substituted with one or two alkyl groups, specifically refers to the group -NRR', where R and R' are each independently selected from the group consisting of hydrogen or lower alkyl, provided that -NRR' is not -NH ₂ . "Alkylamino" includes a moiety of a compound where the nitrogen in -NH ₂ is attached to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like. "Dialkylamino" includes a moiety in which the nitrogen in -NH ₂ is attached to at least two other alkyl groups. Examples of the dialkylamino group include, but are not limited to, dimethylamino, diethylamino, and the like.

The term "alkylaminoalkyl" refers to an alkyl group as defined in the present invention substituted with an alkylamino as defined in the present invention.

The term "aminoalkyl" refers to a substituted alkyl that is further substituted with one or more amino groups.

The term "aminoalkoxy" refers to alkoxy-substituted which is further substituted with one or more amino groups.

The term "hydroxyalkyl" or "hydroxylalkyl" refers to an alkyl substituent that is further substituted with one or more hydroxyl groups.

The term "cyanoalkyl" refers to an alkyl substituent that is further substituted with one or more cyano groups.

The term "acyl" refers to the monovalent group left after the removal of the hydroxyl group from an organic or inorganic oxy acid having the general formula R-M(O)-, where M is usually C.

The term "carbonyl" refers to an organic functional group (C=O) formed by a carbon atom and an oxygen atom through a double bond.

The term "alkanoyl" or "alkyl carbonyl" refers to a carbonyl group that is additionally substituted with one alkyl group. Representative alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, and the like.

The term "arylcarbonyl" refers to a carbonyl group as defined above substituted with an alkyl as defined in the present invention.

The term "alkoxycarbonyl" refers to a carbonyl group that is further substituted with one alkoxy group.

The term "heterocycloalkylcarbonyl" refers to a carbonyl group that is further substituted with one heterocycloalkyl group.

The terms "alkylaminocarbonyl", "cycloalkylaminocarbonyl",

"arylaminocarbonyl", "aralkylaminocarbonyl", "heteroarylaminocarbonyl" refers to carbonyl substituted with alkylamino, cycloalkylamino, arylamino, aralkylamino or heteroarylamino as defined in the present invention, respectively.

The term "alkylcarbonylalkyl" or "alkylacylalkyl" refers to an alkyl group additionally substituted with one alkyl carbonyl ohm.

The term "alkylcarbonylalkoxy" or "alkylacylalkoxy" refers to an alkoxy group additionally substituted with one alkylcarbonyl.

The term "sulfonyl" or "sulfuryl" refers to the functional group left after removal of the hydroxyl group from the sulfonic acid, in particular the -S(=O)2 group.

The term "alkylsulfonyl" or "alkylsulfuryl" refers to -S(=O) ₂ -R, where R is an alkyl group.

The term "optional" means that one or more of the following events may or may not occur, and includes both events that occur and events that do not occur. The term "optionally substituted" or "substituted" means that said group may be substituted with one or more additional groups each independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, cyano, halogen, amide, nitro , haloalkyl, amino, methylsulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, and the like. Among others, the amino protecting group is preferably selected from the group consisting of pivaloyl, t _-6 utiloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trifluoroacetyl and the like.

As used herein, the term "tyrosine protein kinase" (TPK) refers to a class of kinases that catalyze the transfer of γ-phosphate from ATP to a tyrosine residue on proteins and that are capable of catalyzing the phosphorylation of a tyrosine residue of various protein substrates and thus have an important effect on cell growth, proliferation and differentiation.

As used herein, the terms "inhibit", "inhibitory" or "inhibitor" as used in relation to a kinase refer to the inhibition of phosphotransferase activity.

A "metabolite" of a compound described herein is a derivative of said compound that is formed from the metabolism of said compound. The term "active metabolite" refers to a biologically active derivative of a compound that is formed during the metabolism of said compound. As used herein, the term "metabolism" refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions) by which a particular substance is altered by the body. Thus, enzymes can cause specific structural changes. For example, cytochrome P450 catalyzes various redox reactions, while diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic acid molecule to an aromatic alcohol, an aliphatic alcohol, a carboxylic acid, an amine, and a free mercapto group. Additional information on metabolism can be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds described herein can be identified either by administering the compounds to the host and analyzing host tissue samples, or by incubating the compounds with liver cells in vitro and analyzing the resulting compounds. Both methods are well known in the art. In some embodiments, the metabolites of a compound are formed from oxidative processes and correspond to the corresponding hydroxy-containing compound. In some embodiments, the compound is metabolized to pharmacologically active metabolites. As used herein, the term "modulate" means to interact with a target, directly or indirectly, to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

As used herein, the term "target protein" refers to a protein molecule or portion of a protein capable of being bound by a selective binding compound. In some embodiments, the target protein is RAF tyrosine kinase (wild type, or various mutants, or a combination thereof), RAS tyrosine kinase (wild type, or various mutants, or a combination thereof), BCR/ABL (wild type, or various mutants, or a combination thereof), ABL (wild type or various mutants or a combination thereof), KIT (wild type or various mutants or a combination thereof), EGFR (wild type or various mutants or a combination thereof), FLT3 (wild type , or various mutants, or a combination thereof), VEGFR ₂ (wild type, or various mutants, or a combination thereof), RET (wild type, or various mutants, or a combination thereof), PDGFRα (wild type, or various mutants, or a combination thereof). combination), PDGFRβ (wild type, or various mutants, or combination thereof), FGFR1 (wild type, or various mutants, or combination thereof), FGFR2 (wild type, or various mutants, or combination thereof), FGFR ₃ (wild type , or a combination thereof), FGFR4 (wild type, or various mutants thereof, or a combination thereof).

As used herein, the term IC ₅₀ refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of the maximum response in the assay by which such response is measured.

As used herein, the term EC ₅₀ refers to the dose, concentration, or amount of a test compound that elicits a dose-dependent response at 50% maximum expression of a particular response that is induced, provoked, or potentiated by a particular test compound.

As used herein, the term GI ₅₀ refers to the drug concentration required to inhibit cell growth by 50%, that is, the drug concentration at which 50% of the cells (such as cancer cells) can be inhibited or controlled by the drug.

Novel kinase inhibitor according to the present invention

The present invention provides a selective Pan-RAF kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:

Where

один из Y и Z представляет собой углерод, а другой представляет собой азот;X is selected from the group consisting of

one of Y and Z is carbon and the other is nitrogen;

ring A is selected from the group consisting of

R ₁ , R ₂ and R ₃ are each independently selected from the group consisting of H, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _1-6 hydroxyalkoxy, C _3-6 cycloalkyl- C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 alkoxy, phenyl, pyridyl, phenyl-C _1-6 alkoxy, furyl-C _1-6 alkoxy, heterocycloalkyl optionally substituted with R ₆ , heterocycloalkylphenyl optionally substituted with R ₆ , heterocycloalkylcarbonyl optionally substituted with R ₆ , heterocycloalkyloxy optionally substituted with R ₆ , heterocycloalkyl-C _1-6 alkoxy optionally substituted with R ₆ , heterocycloalkyl-C _1-6 alkanoylamino optionally substituted with R ₆ , C _3-6 cycloalkyl-C _{1 -6} alkylamino, and C _1-6 alkylaminocarbonyl-C _1-6

alkoxy, or R ₁ and R ₃ together form, where R ₁ , R ₂ and R ₃ do not represent H at the same time;

и R₄ и R₅ не представляют собой Н одновременно;each of R ₄ and R ₅ is independently selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 cyanoalkyl, heterocycloalkyl-C1-6 alkyl, optionally substituted with R ₆ , phenyl, optionally substituted R ₆ , heteroaryl optionally substituted with R ₆ , and aminosulfonyl, or R ₄ and R ₅ together form

and R ₄ and R ₅ do not represent H at the same time;

R ₆ is independently selected from the group consisting of oxo (=)), C _1-6 alkyl, C _2-6 alkanoyl, C _1-6 alkylsulfonyl, C _1-6 alkylamino, C _2-6 alkanoyl, and C _1-6 haloalkyl.

In a preferred aspect, in formula (I), Y is nitrogen and Z is carbon.

и заместители R₄ и R₅ находятся в мета- и пара-положениях бензольного кольца, соответственно; более предпочтительно, R₄ не представляет собой Н, и R₅ представляет собой Н.In another aspect, in formula (I), ring A is

and substituents R ₄ and R ₅ are in the meta and para positions of the benzene ring, respectively; more preferably R ₄ is not H and R ₅ is H.

In some embodiments, R ₂ and R ₃ are H; and R ₁ is selected from the group consisting of phenyl, pyridyl, heterocycloalkyl optionally substituted with C _1-6 alkyl, heterocycloalkylphenyl optionally substituted with C _1-6 alkyl, heterocycloalkylcarbonyl optionally substituted with C _1-6 alkyl, heterocycloalkyloxy, heterocycloalkyl-C _{1- 6} alkoxy; and C _1-6 alkylaminocarbonyl-C _1-6 alkoxy.

In other embodiments, R ₁ is H; R ₂ is selected from the group consisting of H, cyano, C _1-6 alkyl, C _1-6 hydroxyalkoxy, C _3-6 cycloalkyl-C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 alkoxy, phenyl- C _1-6 alkoxy, furyl-C _1-6 alkoxy, heterocycloalkyloxy optionally substituted with R ₆ , heterocycloalkyl-C _1-6 alkoxy optionally substituted with R ₆ , heterocycloalkyl-C _1-6 alkanoylamino optionally substituted with C _1-6 alkyl, and C _1-6 alkylaminocarbonyl-C _1-6 alkoxy, where R ₆ is independently selected from the group consisting of oxo (C=), C _2-6 alkanoyl, C _1-6 alkylsulfonyl, C _1-6 alkylamino C _{2 -6} alkanoyl; R ₃ is selected from the group consisting of H and C _3-6 cycloalkyl-C _1-6 alkylamino; and R ₂ and R ₃ are not H at the same time.

In the present invention, "heterocycloalkyl" as indicated is preferably a 4-6 membered heterocycloalkyl containing oxygen and/or nitrogen atom(s), such as pyrrolidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, azetidinyl and the like. In addition, the nitrogen atom or carbon atom of these heterocycloalkyls may be optionally substituted with an R ₆ group selected from the group consisting of oxo (=O), C _1-6 alkyl, C _2-6 alkanoyl, C _1-6 alkylsulfonyl, C _{1 -6} alkylamino C _2-6 alkanoyl and C _1-6 haloalkyl.

In a preferred embodiment of the present invention, each R ₁ , R ₂ and R ₃ is independently selected from the group consisting of H, cyano, O-in alkyl (such as methyl, ethyl, n-propyl, isopropyl, n _-6 util, tert _{- 6} util and the like), C _1-6 hydroxyalkoxy (such as hydroxymethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy or the like), C _3-6 cycloalkyl-C _1-6 alkoxy (such as cyclopentylmethoxy or the like). like), C _1-6 alkoxy-C _1-6 alkoxy (such as 2-methoxyethoxy or the like), phenyl, pyridyl (such as 2-pyridyl, 3-pyridyl, 4-pyridyl), phenyl-C _1-6 alkoxy (such as phenylmethoxy or the like), furyl-C _1-6 alkoxy (such as furan-3-ylmethoxy and the like), heterocycloalkyl optionally substituted with R ₆ (such as N-morpholinyl, piperazin-1-yl, 4 -methylpiperazin-1-yl and the like), heterocycloalkylphenyl optionally substituted with R ₆ (such as 4-methylpiperazinylphenyl and the like), heterocycloalkylcarbonyl optionally substituted R ₆ (such as 4-methylpiperizan-1-ylcarbonyl and the like), heterocycloalkyloxy, optionally substituted R ₆ (such as tetrahydropyran-4-yloxy, tetrahydrofuran-3-yloxy, oxetan-3-yloxy, azetidin-3-yloxy and the like), heterocycloalkyl-C _1-6 alkoxy optionally substituted with R ₆ (such as 2-morpholinoethoxy, 3-morpholinopropoxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-ylmethoxy, oxetan-3 -ylmethoxy, pyrrolidin-3-ylmethoxy and the like), heterocycloalkyl-C _1-6 alkanoylamino optionally substituted with R ₆ (such as tetrahydropyran-4-ylformylamino, tetrahydrofuran-3-ylformylamino, tetrahydropyran-4-ylacetylamino, tetrahydrofuran-3- ylacetylamino, 3-methyloxetan-3-ylformylamino, 3-oxadicyclo[3.1.0]hexan-6-ylformylamino and the like), C _3-6 cycloalkyl-C _1-6 alkoylamino (such as cyclopropylformylamino and the like), and C _{1 -6} alkylaminocarbonyl-C _1-6 alkoxy (such as dimethylaminocarbonylmethoxy and the like) , where R ₁ , R ₂ and R ₃ do not represent H at the same time.

In another preferred embodiment, the present invention provides a selective Pan-RAF kinase inhibitor comprising a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof:

where R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined above.

In a more preferred embodiment of the invention

R ₁ is selected from the group consisting of H, pyridyl (such as 3-pyridyl, 4-pyridyl), heterocycloalkyl (such as N-morpholinyl, piperazin-1-yl), heterocycloalkyl phenyl optionally substituted with C _1-6 alkyl (such as 4-methylpiperazinylphenyl), heterocycloalkyloxy (such as tetrahydropyran-4-yloxy, oxetan-3-yloxy), heterocycloalkyl-C _1-6 alkoxy (such as 2-morpholinoethoxy, 3-morpholinopropoxy, tetrahydrofuran-3-ylmethoxy ) and C _1-6 alkylaminocarbonyl-C _1-6 alkoxy (such as dimethylaminocarbonylmethoxy);

R ₂ is selected from the group consisting of H, C _1-6 alkyl (such as methyl), C _1-6 hydroxyalkoxy (such as 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy), C _1-6 alkoxy-C _{1 -6} alkoxy (such as 2-methoxyethoxy), heterocycloalkyl oxe (such as tetrahydropyran-4-yloxy, tetrahydrofuran-3-yloxy, oxetan-3-yloxy, azetidin-3-yloxy) and heterocycloalkyl-C _1-6 alkoxy ( such as 2-morph olinoethoxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-ylmethoxy, oxetan-3-ylmethoxy, pyrrolidin-3-ylmethoxy);

R ₃ is selected from the group consisting of H and C _3-6 cycloalkyl C _1-6 alkanoylamino (such as cyclopropylformylamino);

where R ₁ , R ₂ and R ₃ do not represent H at the same time;

R ₄ is selected from the group consisting of C _1-6 haloalkyl (such as trifluoromethyl) and C _1-6 cyanoalkyl (such as 2-cyano-ethyl-2-yl), 2-cyano-prop-2-yl) ;

R ₅ is selected from the group consisting of H, C _1-6 alkyl (such as methyl) and heterocycloalkyl-C _1-6 alkyl optionally substituted with C _1-6 alkyl (such as 4-methyl-piperazin-1-ylmethyl).

In a particularly preferred embodiment, R ₁ is selected from the group consisting of 3-pyridyl a, 4-pyridyl, N-morpholinyl, heterocycloalkyl oke and (preferably oxetan-3-yloxy), heterocycloalkyl-C _1-6 alkoxy (preferably 3 -morpholinopropoxy, tetrahydrofuran-3-ylmethoxy) and C _1-6 alkylaminocarbonyl-C _1-6 alkoxy (preferably dimethylaminocarbonylmethoxy); R ₄ is selected from the group consisting of C _1-6 halogenated (preferably trifluoromethyl) and C _1-6 cyanoalkyl (preferably 2-cyano-ethyl-2-yl), 2-cyanoprop-2-yl); each of R ₂ , R ₃ and R ₅ is H.

In another particularly preferred embodiment, R ₂ is selected from the group consisting of C _1-6 hydroxyalkoxy (preferably 3-hydroxypropoxy, 4-hydroxybutoxy), C _1-6 alkoxy-C _1-6 alkoxy (preferably 2-methoxyethoxy), heterocycloalkyloxy (preferably tetrahydropyran-4-yloxy, tetrahydrofuran-3-yloxy, azetidin-3-yloxy) and heterocycloalkyl-C _1-6 alkoxy (preferably tetrahydropyran-4-ylmethoxy, oxetan-3-ylmethoxy); R ₄ is selected from the group consisting of C _1-6 haloalkyl (preferably trifluoromethyl) and C _1-6 cyanoalkyl (preferably 2-cyanoethyl-2-yl, 2-cyanoprop-2-yl); each of R ₁ , R ₃ and R ₅ is H.

In another preferred embodiment, the present invention provides a selective Pan-RAF kinase inhibitor comprising a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof:

Where

и предпочтительно представляет собой

X is selected from the group consisting of

and preferably is

one of Y and Z is carbon and the other is nitrogen;

и предпочтительно представляет собой;ring A is selected from the group consisting of

and preferably is;

и R₄ и R₅ не представляют собой Н одновременно; R₆ независимо выбран из группы, состоящей из C_1-6 алкила (такого как, метил, этил, н-пропил, изопропил, н-бутил, трет-бутил и тому подобное) и C_1-6 галогеналкила (такого как, трифторметил).R ₄ and R ₅ are each independently selected from the group consisting of H, C _1-6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and the like), C _1-6 haloalkyl (such as trifluoromethyl), C _1-6 cyanoalkyl (such as 2-cyanoethyl-2-yl, 2-cyanoprop-2-yl), piperazinyl C _1-6 alkyl optionally substituted with R ₆ (such as piperazin-1-ylmethyl ), phenyl optionally substituted with R ₆ , imidazolyl optionally substituted with R ₆ , thienyl optionally substituted with R ₆ , pyridyl optionally substituted with R ₆ , and aminosulfonyl, or R ₄ and R ₅ together form

and R ₄ and R ₅ do not represent H at the same time; R ₆ is independently selected from the group consisting of C _1-6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, and the like) and C _1-6 haloalkyl (such as trifluoromethyl ).

In a preferred embodiment, the present invention relates to the following compound, or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof:

This document considers any combination of the groups described above for various variables. It should be understood that the substituents and substitution patterns of the compounds proposed in the present invention can be selected by experts in the art to obtain chemically stable compounds that can be synthesized using methods known in the art, as well as the methods set forth in this description.

The present document describes a novel kinase inhibitor. Pharmaceutically acceptable salts, solvates, esters, acids, pharmaceutically active metabolites and prodrugs of these compounds are also described in the present invention.

In other embodiments, the compounds described herein are metabolized, when administered to an organism in need thereof, to produce a metabolite, which is then used to obtain the desired effect, including the desired therapeutic effect.

The compounds described herein may be formulated and/or administered as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts formed by reacting a compound in free base form with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid etc; or with an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 4-methylbicyclo-[ 2.2.2] oct-2-ene-1-carboxylic acid, 2-naphthalenesulfonic acid, tert _-6 utilyacetic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthoic acid, stearic acid, muconic acid and the like; (2) base addition salts formed such that an acid proton present on the parent compound is either replaced by a metal ion, such as an alkali metal (such as lithium, sodium, potassium), alkaline earth metal (such as magnesium, or calcium) ion or an aluminum ion; or coordinates with an organic base or an inorganic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, and the like. Suitable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

Appropriate counterions of pharmaceutically acceptable salts can be analyzed and identified using various methods, including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.

The salts are isolated using at least one of the following methods: filtration, precipitation with a precipitant followed by filtration, evaporation of the solvent or, in the case of aqueous solutions, lyophilization.

Screening and characterization of pharmaceutically acceptable salts, polymorphs and/or solvates can be carried out using various methods, including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, microscopy and elemental analysis. The various spectroscopic techniques used include, but are not limited to, Raman spectroscopy, FTIR, UVIS, and NMR (liquid and solid state). Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.

Pharmaceutical composition according to the present invention

The present invention also provides a pharmaceutical composition comprising at least one compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate, ester, acid, pharmaceutically active metabolite or prodrug of the compound, and a pharmaceutically acceptable carrier or excipient, and optionally others. therapeutic agents.

During treatment, it can be used alone or in combination with one or more other therapeutic agents. The drug containing the compound of the present invention may be administered to a patient by at least one route selected from injection, oral administration, inhalation, rectal and transdermal administration. Other therapeutic agents may be selected from the following: immunosuppressants (such as tacrolimus, cyclosporine, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or FTY720), glucocorticoids (such as prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone , hydrohydroxyprednisolone, beclomethasone, fluohydrocortisone acetate, deoxycorticosterone acetate, aldosterone), nonsteroidal anti-inflammatory drugs (such as salicylates, arylalkanoic acids, 2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs or sulfonanilides), allergy vaccines, antigamists, antileukotrienes, (3-agonists, theophylline, anticholinergics or other selective kinase inhibitors (such as mTOR, c-Met inhibitors) or anti-her2 antibodies. In addition, other therapeutic agents may also be rapamycin, crizotinib, tamoxifen, raloxifene, anastrozole , exemestane, l metrozole, Herceptin™ (trastuzumab), Glivecμ (imatinib), Taxol™ (paclitaxel), cyclophosphamide, lovastatin, minosin, cytarabine, 5-fluorouracil (5-FU), methotrexate (MTT), Taxotere™ (docetaxel), Zoladex™ ( goserelin), vincristine, vinblastine, nocodazole, teniposide, etoposide, Gemzar™ (gemcitabine), epothilone, navelbine, camptothecin, daunonibicin, d-actinomicin, moxantrone, amacrine, doxorubicin (adriamycin), epirubicin, or idarubicin. Alternatively, other therapeutic agents may be, for example, but not limited to, cytokines such as G-CSF (granulocyte column stimulating factor). Alternatively, other therapeutic agents may be, for example, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, adriamycin and 5-fluorouracil), AC (adriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin and cyclophosphamide ), ACT or ATC (adriamycin, cyclophosphamide and paclitaxel) or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).

In various embodiments of the present invention, when treating a patient in accordance with the present invention, the amount of a given agent will vary depending on such factors as the specific dosing regimen, the type of disease or condition and its severity, the distinguishing features (for example, weight) of the subject or host in need in treatment, but can be readily determined by a method known in the art according to the particular circumstances of the case, including, for example, the particular agent administered, the route of administration, the condition being treated, and the subject or host being treated. In general, doses used to treat adult humans are typically in the range of 0.02-5000 mg per day, eg about 1-1500 mg per day. The required dose may conveniently be presented as a single dose or as separate doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day. Those skilled in the art will appreciate that while the aforementioned dosage ranges are given, specific effective amounts may be appropriately adjusted depending on the condition of the patient and the judgment of the practitioner.

The use of drugs according to the present invention

A compound of the present invention, including a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof, or pharmaceutical composition thereof, can be used to inhibit RAF (wild-type or various mutants, or combinations) and/or RAS (wild-type or different mutants or combinations thereof). A compound of the present invention, or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite, or prodrug thereof, or a pharmaceutical composition thereof, may be used to treat, prevent, or alleviate one or more diseases selected from the group consisting of: solid tumors (including benign or especially malignant types), especially sarcomas, gastrointestinal stromal tumors (GISTs), colorectal cancer, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), neoplasia, thyroid carcinoma, systemic mastocytosis, eosinophilia syndrome, fibrosis, lupus erythematosus, disease " graft-versus-host disease, neurofibromatosis, pulmonary hypertension, Alzheimer's disease, seminoma, dysgerminoma, mast cell tumors, lung cancer, bronchial carcinoma, testicular intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, papillary/follicular thyroid carcinoma, malignant mfoma, non-Hodgkin's lymphoma, multiple endocrine neoplasia type 2, pheochromocytoma, thyroid carcinoma, parathyroid hyperplasia/adenoma, colon cancer, colorectal adenoma, ovarian cancer, prostate cancer, glioblastoma, brain tumor, malignant glioma, pancreatic cancer, malignant endothelioma of the pleura, hemangioblastoma, hemangioma, kidney cancer, liver cancer, adrenal carcinoma, bladder cancer, gastric cancer, rectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, neck and head tumors, and other proliferative states, etc., or combinations thereof. Particularly preferred for the treatment of head and neck cancer, thyroid carcinoma, melanoma, colorectal cancer, lung cancer, breast cancer, pancreatic cancer, esophageal cancer, liver cancer, leukemia, neoplasia, or the like, or a combination thereof.

Getting a connection

The compound of the present invention can be synthesized using standard synthetic methods known to those skilled in the art, or using methods known in the art in combination with the methods described in the present invention. In addition, solvents, temperatures, and other reaction conditions presented in the present invention may vary depending on the methods in the art. As an additional guide, the following synthesis methods may also be applied.

The reactions can be applied sequentially to obtain the compounds described in the present invention, or they can be used to synthesize building blocks, which are subsequently connected by the methods described in the present invention and/or known in the art.

In some embodiments, the present invention provides methods for preparing and using the tyrosine kinase inhibitor compounds described in the present invention. In certain embodiments, the compounds described in the present invention can be synthesized using the following synthesis schemes. Compounds can be synthesized using procedures similar to those described below using appropriate alternative starting materials.

Starting materials used for the synthesis of the compounds described in the present invention can be synthesized or can be obtained on a commercial basis. The compounds described in the present invention and other related compounds having different substituents can be synthesized using methods and materials known to those skilled in the art. General methods for preparing the compounds described in the present invention can be obtained from known reactions in this field, and the reactions can be modified using appropriate reagents and conditions that will be obvious to a person skilled in the art, to introduce various fragments into the molecules proposed in the present invention.

The reaction products can be isolated and purified, if necessary, using conventional methods, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such products can be characterized using conventional means, including physical constants and spectral data.

Example 1: N-(3-(4-([3,3'-bipyridyl]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide 1

Stage 1. Synthesis of 4-bromo-1-(2-methyl-5-nitrophenyl)-1H-pyrazole a:

Compounds 4-bromopyrazole (5 g, 1 eq.), 2-fluoro-1-methyl-4-nitrobenzene (5.5 g, 1.05 eq.) and potassium carbonate (13.1, 3 eq.) were mixed in DM FA (50 ml). The mixture was stirred overnight at 120° C. under nitrogen, then cooled and concentrated. Ethyl acetate (200 ml) was added to the concentrate. The resulting mixture was then washed successively with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then separated by column chromatography to give a yellow product a (5.2 g).

Stage 2. Synthesis of 1-(2-methyl-5-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole b:

Compound a (5 g, 1 eq.), bis(pinacolato)diborone (5.8 g, 1.3 eq.), potassium acetate (3.5 g, 2 eq.) and [1,1-bis(diphenylphosphino )ferrocene]palladium dichloride (0.72 g, 0.05 equiv.) was mixed in 1,4-dioxane (50 ml). The mixture was stirred overnight at 100° C. under nitrogen and then concentrated. The concentrate was separated using column chromatography to give yellow product b (4.0 g).

Stage 3. Synthesis of 5-(1-(2-methyl-5-nitrophenyl)-1H-pyrazol-4-yl)-3,3'-bipyridyl with:

Compound b (4.0 g, 1.1 eq.), 5-bromo-3,3'-bipyridyl (2.6 g, 1 eq.), potassium carbonate (3.0 g, 2 eq.) and tetrakis (triphenylphosphine)palladium (0.6 g, 0.05 eq.) was mixed in 1,4-dioxane (40 ml) and water (4 ml). The mixture was stirred overnight at 90° C. under nitrogen and then concentrated. The concentrate was separated using column chromatography to give a yellow product c (2.8 g).

Stage 4. Synthesis of 3-(4-([3,3'-bipyridyl]-5-yl)-1H-pyrazol-1-yl)-4-methylaniline d:

Compound c (2.8 g, 1 eq.) and palladium-carbon (0.5 g) were mixed in methanol (30 ml). The mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. Dichloromethane (100 ml) was then added to dilute the mixture. The resulting mixture was filtered and concentrated to give pale green product d (2.1 g).

Step 5. Synthesis of N-(3-(4-([3,3'-bipyridyl]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl) benzamide 1:

Compound d (0.05 g, 1 eq.), 4-methyl-3-(trifluoromethyl)benzoic acid (0.031 g, 1 eq.), HATU (0.064, 1.1 eq.) and diisopropylethylamine (0.020 g, 1 equiv.) was mixed in DMF (2 ml). The mixture was stirred at room temperature for 0.5 hour. Ethyl acetate (50 ml) was then added to dilute the mixture. The mixture was washed successively with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by HPLC to give product 1 (0.07 g). Exact weight (calculated): 513.17; MS(ESI) m/z(M+1)+: 514.17.

Example 2: N-(3-(4-([3,3'-bipyridyl]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 2

Compound 2 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 499.16; MS(ESI) m/z(M+1)+: 500.16.

Example 3: N-(3-(4-([3,3'-bipyridyl]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(2-cyanoprop-2-yl )benzamide 3

Compound 3 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 498.21; MS(ESI) m/z(M+1)+: 499.21.

Example 4: N-(3-(4-([3,3'-bipyridyl]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-5-(tert _-6 util)isoxazol- 3-carboxamide 4

Compound 4 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 478.21; MS(ESI) m/z(M+1)+: 479.21.

Example 5: N-(3-(4-([3,4'-bipyridyl]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(2-cyanoprop-2-yl )benzamide 5

Compound 5 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 498.21; MS(ESI) m/z(M+1)+: 499.21.

Example 6: N-(3-(4-([3,4'-bipyridyl]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(1-cyanoethyl)benzamide 6

Compound 6 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 484.20; MS(ESI) m/z(M+1)+: 484.20.

Example 7 N-(3-(4-([3,4'-bipyridyl]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide 7

Compound 7 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 513.17; MS(ESI) m/z(M+1)+: 514.17.

Example 8: N-(3-(4-([3,4'-bipyridyl]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-4-((4-methylpiperazin-1- yl)methyl)-3-(trifluoromethyl)benzamide 8

Compound 8 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 611.26; MS(ESI) m/z(M+1)+: 612.26.

Example 9 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(5-morpholinopyrid-3-yl)-1H-pyrazol-1-yl)phenyl)benzamide 9

Compound 9 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 506.24; MS(ESI) m/z(M+1)+: 507.24.

Example 10: 3-(1-cyanoethyl)-N-(4-methyl-3-(4-(5-morpholinopyrid-3-yl)-1H-pyrazol-1-yl)phenyl)benzamide 10

Compound 10 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 492.22 MS(ESI) m/z(M+1)+: 493.22.

Example 11 4-methyl-N-(4-methyl-3-(4-(5-morpholinopyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide 11

Compound 11 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 521.20; MS(ESI) m/z(M+1)+: 522.20.

Example 12: N-(4-methyl-3-(4-(5-morpholinopyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl) -3-(trifluoromethyl)benzamide 12

Compound 12 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 619.28; MS(ESI) m/z(M+1)+: 620.28.

Example 13 N-(3-(4-([3,4'-bipyridyl]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 13

Compound 13 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 499.16; MS(ESI) m/z(M+1)+: 500.16.

Example 14 N-(3-(4-([3,4'-bipyridyl]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-5-(tert-butyl)isoxazol-3 -carboxamide 14

Compound 14 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 478.21; MS(ESI) m/z(M+1)+: 479.21.

Example 15: 1-(3-(4-([3,4'-bipyridyl]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(5-(tert-butyl) isoxazol-3-yl)urea 15

Stage 1. Synthesis of phenyl (5-(tert _-6 util)isoxazol-3-yl)carbamate e

5-(tert-butyl)isoxazol-3-amine (5 g, 1 eq.), DIPEA (5.1 g, 1.1 eq.) and THF (20 ml) were mixed at 0°C under nitrogen atmosphere. Phenyl chloroformate (5.9 g, 1.05 eq.) was added to the mixture. The reaction was carried out for 0.5 hours at this temperature. The reaction mixture was then diluted with ethyl acetate (120 ml), washed successively with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting solid was washed with n-hexane and filtered to give a white solid e (7g).

Stage 2. Synthesis of 1-(3-(4-([3,4'-bipyridyl]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(5-(tert-butyl )isoxazol-3-yl)urea 15:

Compound f was synthesized using steps similar to those described in Example 1. Compound e (0.05 g, 1 eq), compound f (0.055 g, 1 eq) and DMSO (2 ml) were mixed. The mixture was stirred for 4 hours at 80°C. Then ethyl acetate (50 ml) was added. The resulting mixture was washed successively with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was separated by HPLC to give Compound 12 (0.06 g). Exact weight (calculated): 493.22; MS(ESI) m/z(M+1)+: 494.22.

Example 16 N-(4-methyl-3-(4-(5-morpholinopyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide 16

Compound 16 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 507.18; MS(ESI) m/z(M+1)+: 508.18.

Example 17 5-(tert-butyl)-N-(4-methyl-3-(4-(5-morpholinopyrid-3-yl)-1H-pyrazol-1-yl)phenyl)isoxazol-3-carboxamide 17

Compound 17 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 486.23; MS(ESI) m/z(M+1)+: 487.23.

Example 18: 1-(5-(t-butyl)isoxazol-3-yl)-3-(4-methyl-3-(4-(5-morpholinopyrid-3-yl)-1H-pyrazol-1-yl) phenyl)urea 18

Compound 18 was synthesized using steps similar to those described in examples 1 and 15. Exact weight (calculated): 501.24; MS(ESI) m/z(M+1)+: 502.24.

Example 19 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(5-(4-methylpiperazin-1-carbonyl)pyrid-3-yl)-1H-pyrazol- 1-yl)phenyl)benzamide 19

Compound 19 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 547.26; MS(ESI) m/z(M+1)+: 548.26.

Example 20 3-(1-cyanoethyl)-N-(4-methyl-3-(4-(5-(4-methylpiperazin-1-carbonyl)pyrid-3-yl)-1H-pyrazol-1-yl) phenyl)benzamide 20

Compound 20 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 533.25; MS(ESI) m/z(M+1)+: 534.25.

Example 21 N-(4-methyl-3-(4-(5-(4-methylpiperazin-1-carbonyl)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl) benzamide 21

Compound 21 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 548.21; MS(ESI) m/z(M+1)+: 549.21.

Example 22 5-(t-butyl)-N-(4-methyl-3-(4-(5-(4-methylpiperazin-1-carbonyl)pyrid-3-yl)-1H-pyrazol-1-yl) phenyl)isoxazole-3-carboxamide 22

Example 22 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 527.26; MS(ESI) m/z(M+1)+: 528.26.

Example 23 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(5-(4-methylpiperazin-1-yl)pyrid-3-yl)-1H-pyrazol- 1-yl)phenyl)benzamide 23

Compound 23 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 519.27; MS(ESI) m/z(M+1)+: 520.27.

Example 24 3-(1-cyanoethyl)-N-(4-methyl-3-(4-(5-(4-methylpiperazin-1-yl)pyrid-3-yl)-1H-pyrazol-1-yl) phenyl)benzamide 24

Compound 24 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 505.26; MS(ESI) m/z(M+1)+: 506.27.

Example 25: N-(4-methyl-3-(4-(5-(4-methylpiperazin-1-yl)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl) benzamide 25

Compound 25 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 520.21; MS(ESI) m/z(M+1)+: 521.21.

Example 26 5-(tert-butyl)-N-(4-methyl-3-(4-(5-(4-methylpiperazin-1-yl)pyrid-3-yl)-1H-pyrazol-1-yl) phenyl)isoxazole-3-carboxamide 26

Compound 26 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 499.26; MS(ESI) m/z(M+1)+: 500.26.

Example 27: 1-(5-(t-butyl)isoxazol-3-yl)-3-(4-methyl-3-(4-(5-(4-methylpiperazin-1-yl)pyrid-3-yl) -1Н-pyrazol-1-yl)phenyl)urea 27

Compound 27 was synthesized using steps similar to those described in examples 1 and 15. Exact weight (calculated): 514.28; MS(ESI) m/z(M+1)+: 515.28.

Example 28 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(5-phenylpyrid-3-yl)-1H-pyrazol-1-yl)phenyl)benzamide 28

Compound 28 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 497.22; MS(ESI) m/z(M+1)+: 498.22.

Example 29 N-(4-methyl-3-(4-(5-phenylpyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide 29

Compound 29 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 498.16; MS(ESI) m/z(M+1)+: 499.16.

Example 30: N-(4-methyl-3-(4-(5-(4-(4-methylpiperazin-1-yl)phenyl)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)- 3-(2-cyanoprop-2-yl)benzamide 30

Compound 30 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 595.31; MS(ESI) m/z(M+1)+: 596.31

Example 31: N-(4-methyl-3-(4-(5-(4-(4-methylpiperazin-1-yl)phenyl)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)- 3-(trifluoromethyl)benzamide 31

Compound 31 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 596.25; MS(ESI) m/z(M+1)+: 597.26.

Example 32: N-(4-methyl-3-(4-(5-(4-(4-methylpiperazin-1-yl)phenyl)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)- 2-(3-(trifluoromethyl)phenyl)acetamide 32

Compound 32 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 610.26; MS(ESI) m/z(M+1)+: 611.26.

Example 33 5-(t-butyl)-N-(4-methyl-3-(4-(5-(4-(4-methylpiperazin-1-yl)phenyl)pyrid-3-yl)-1H-pyrazole -1-yl)phenyl)isoxazol-3-carboxamide 33

Compound 33 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 575.30; MS(ESI) m/z(M+1)+: 576.30.

Example 34: N-(4-methyl-3-(4-(5-morpholinopyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide 54

Compound 34 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 521.20; MS(ESI) m/z(M+1)+: 522.20.

Example 35 3-(2-cyanoprop-2-yl)-N-(3-(4-(6-(cyclopropylformylamino)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)benzamide 35

Compound 35 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 504.22; MS(ESI) m/z(M+1)+: 505.22.

Example 36: N-(3-(4-(6-(cyclopropylformylamino)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 3 6

Compound 36 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 505.17; MS(ESI) m/z(M+1)+: 506.17.

Example 37: N-(5-(1-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetylamino)phenyl)-1H-pyrazol-4-yl)pyrid-2-yl)cyclopropanecarboxamide 37

Compound 37 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 519.18; MS(ESI) m/z(M+1)+: 520.18.

Example 38 3-(2-cyanoprop-2-yl)-N-(3-(4-(6-(cyclopropylformylamino)-4-methylpyrid-3-yl)-1H-pyrazol-1-yl)-4- methylphenyl)benzamide 38

Compound 38 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 518.24; MS(ESI) m/z(M+1)+: 519.24.

Example 39: N-(3-(4-(6-(cyclopropylformylamino)-4-methylpyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 39

Compound 39 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 519.18; MS(ESI) m/z(M+1)+: 520.18.

Example 40: N-(4-methyl-5-(1-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetylamino)phenyl)-1H-pyrazol-4-yl)pyrid-2- yl) cyclopropanecarboxamide 40

Compound 40 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 533.20; MS(ESI) m/z(M+1)+: 534.20.

Example 41 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(5-(2-morpholinoethoxy)pyrid-3-yl)-1H-pyrazol-1-yl )phenyl)benzamide 41

Step 1 Synthesis of 4-(2-((5-bromopyrid-3-yl)oxy)ethyl)morpholine g 2-morpholinoethanol (3 g, 1 eq), DIPEA (3.2 g, 1.1 eq) was mixed and THF (15 ml). Methylsufonyl chloride (2.7 g, 1.1 eq.) was added dropwise to the mixture at 0°C. The resulting mixture was stirred at temperature for 6 hours. The reaction solution was concentrated, eluted with ethyl acetate (100 ml), washed successively with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the product 2-morpholinoethyl methanesulfonate (3.8 g, 1 eq.). The product was mixed with _5-6 rompyrid-3-ol (2.8 g, 0.9 eq.), potassium carbonate (3.7 g, 2 eq.). The mixture was stirred in DMF (30 ml) at 70°C for 5 hours. The resulting mixture was then concentrated, eluted with ethyl acetate (150 ml), washed successively with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the product 4-(2-((5-bromopyrid-3-yl)oxy)ethyl)morpholine g (3.2 g).

Step 2 Compound 41 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 550.26; MS(ESI) m/z(M+1)+: 551.26.

Example 42: N-(4-methyl-3-(4-(5-(2-morpholinoethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide 42

Compound 42 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 551.21. MS(ESI) m/z(M+1)+: 552.21.

Example 43: N-(4-methyl-3-(4-(5-(2-morpholinoethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-2-(3-(trifluoromethyl)phenyl )acetamide43

Compound 43 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 565.23; MS(ESI) m/z(M+1)+: 566.23.

Example 44 N-(3-(4-(4-cyano-6-(cyclopropylformylamino)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(2-cyanoprop-2 -yl)benzamide 44

Compound 44 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 529.22; MS(ESI) m/z(M+1)+: 530.22.

Example 45: N-(3-(4-(4-cyano-6-(cyclopropylformylamino)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 45

Compound 45 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 530.16; MS(ESI) m/z(M+1)+: 531.16.

Example 46 N-(4-cyano-5-(1-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetylamino)phenyl)-1H-pyrazol-4-yl)pyrid-2- yl) cyclopropanecarboxamide46

Compound 46 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 544.18; MS(ESI) m/z(M+1)+: 545.18.

Example 47 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(5-(3-morpholino-propoxy)pyrid-3-yl)-1H-pyrazol-1-yl )phenyl)benzamide 47

Compound 47 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 564.28. MS(ESI) m/z(M+1)+: 565.28.

Example 48: N-(4-methyl-3-(4-(5-(3-morpholino propoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide 48

Compound 48 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 565.23; MS(ESI) m/z(M+1)+: 566.23.

Example 49: N-(4-methyl-3-(4-(5-(3-morpholino propoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-2-(3-(trifluoromethyl) phenyl)acetamide 49

Compound 49 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 579.24; MS(ESI) m/z(M+1)+: 580.24.

Example 50 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyrid-3-yl) -1H-pyrazol-1-yl)phenyl)benzamide 50

Compound 50 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 521.24; MS(ESI) m/z(M+1)+: 522.24.

Example 51: N-(4-methyl-3-(4-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)- 3-(trifluoromethyl)benzamide 51

Compound 51 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 522.18; MS(ESI) m/z(M+1)+: 523.18.

Example 52: N-(4-methyl-3-(4-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)- 2-(3-(trifluoromethyl)phenyl)acetamide 52

Compound 52 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 536.20; MS(ESI) m/z(M+1)+: 537.20.

Example 53: 3-(2-cyanoprop-2-yl)-N-(3-(4-(5-(2-(dimethylamino)-2-oxoethoxy)pyrid-3-yl)-1H-pyrazol-1- yl)-4-methylphenyl)benzamide 53

Compound 53 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 522.23; MS(ESI) m/z(M+1)+: 523.23.

Example 54 N-(3-(4-(5-(2-(dimethylamino)-2-oxoethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl )benzamide 54

Compound 54 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 523.18. MS(ESI) m/z(M+1)+: 524.18.

Example 55 N,N-dimethyl-2-((5-(1-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetylamino)phenyl)-1H-pyrazol-4-yl)pyride -3-yl)oxy)acetamide 55

Compound 55 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 537.19; MS(ESI) m/z(M+1)+: 538.19.

Example 56 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-((tetrahydro-2H-pyran-4-yl)oxy)pyrid-3-yl) -1Н-pyrazol-1-yl)phenyl)benzamide 56

Compound 56 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 521.24; MS(ESI) m/z(M+1)+: 522.24.

Example 57: N-(4-methyl-3-(4-(4-((tetrahydro-2H-pyran-4-yl)oxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)- 3-(trifluoromethyl)benzamide 57

Compound 57 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 522.19; MS(ESI) m/z(M+1)+: 523.20.

Example 58: N-(4-methyl-3-(4-(4-((tetrahydro-2H-pyran-4-yl)oxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)- 2-(3-(trifluoromethyl)phenyl)acetamide 58

Compound 58 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 536.20; MS(ESI) m/z(M+1)+: 537.20.

Example 59 3-(2-cyanoprop-2-yl)-N-(3-(4-(4-(2-(dimethylamino)-2-oxoethoxy)pyrid-3-yl)-1H-pyrazol-1- yl)-4-methylphenyl)benzamide 59

Compound 59 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 522.23; MS(ESI) m/z(M+1)+: 523.23.

Example 60 N-(3-(4-(4-(2-(dimethylamino)-2-oxoethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl )benzamide 60

Compound 60 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 522.23; MS(ESI) m/z(M+1)+: 523.23.

Example 61 N,N-dimethyl-2-((3-(1-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetylamino)phenyl)-1H-pyrazol-4-yl)pyride -4-yl)hydroxy)acetamide 61

Compound 61 was synthesized using steps similar to those described in Example 61. Exact weight (calculated): 537.19; MS(ESI) m/z(M+1)+: 538.19.

Example 62 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)methoxy)pyrid-3-yl)-1H-pyrazole -1-yl)phenyl)benzamide 62

Compound 62 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 521.24; MS(ESI) m/z(M+1)+: 522.24. Example 63: N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl )benzamide 63

Compound 63 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 522.18; MS(ESI) m/z(M+1)+: 523.18.

Example 64 N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-2-(3 -(trifluoromethyl)phenyl)acetamide 64

Compound 64 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 536.20; MS(ESI) m/z(M+1)+: 537.20.

Example 65 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(5-((tetrahydrofuran-3-yl)methoxy)pyrid-3-yl)-1H-pyrazole -1-yl)phenyl)benzamide 65

Compound 65 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 521.24; MS(ESI) m/z(M+1)+: 522.24.

Example 66 N-(4-methyl-3-(4-(5-((tetrahydrofuran-3-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl )benzamide 66

Compound 66 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 522.18; MS(ESI) m/z(M+1)+: 523.18.

Example 67: N-(4-methyl-3-(4-(5-((tetrahydrofuran-3-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-2-(3 -(trifluoromethyl)phenyl)acetamide 67

Compound 67 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 536.20; MS(ESI) m/z(M+1)+: 537.20.

Example 68 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)oxy)pyrid-3-yl)-1H-pyrazole -1-yl)phenyl)benzamide 68

Compound 68 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 507.22; MS(ESI) m/z(M+1)+: 508.22.

Example 69 N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)oxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl )benzamide 69

Compound 69 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 508.17; MS(ESI) m/z(M+1)+: 509.17.

Example 70 N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)oxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-2-(3 -(trifluoromethyl)phenyl)acetamide 70

Compound 70 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 522.18; MS(ESI) m/z(M+1)+: 523.18.

Example 71: N-(3-(4-([3,4'-bipyride]-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-2-(3-(trifluoromethyl)phenyl) acetamide 71

Compound 71 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 513.17; MS(ESI) m/z(M+1)+: 514.17.

Example 72 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrid-3-yl) -1Н-pyrazol-1-yl)phenyl)benzamide 72

Compound 72 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 535.25; MS(ESI) m/z(M+1)+: 536.25.

Example 73 3-(1-cyanoethyl)-N-(4-methyl-3-(4-(4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrid-3-yl)-1H-pyrazole -1-yl)phenyl)benzamide 73

Compound 73 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 521.24; MS(ESI) m/z(M+1)+: 522.25.

Example 74: N-(4-methyl-3-(4-(4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)- 3-(trifluoromethyl)benzamide 74

Compound 74 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 536.20; MS(ESI) m/z(M+1)+: 537.20.

Example 75: N-(4-methyl-3-(4-(4-((tetrahydro-2H-pyran-4-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)- 2-(3-(trifluoromethyl)phenyl)acetamide 75

Compound 75 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 550.21; MS(ESI) m/z(M+1)+: 551.21.

Example 76 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-(2-morpholinoethoxy)pyrid-3-yl)-1H-pyrazol-1-yl) phenyl)benzamide 76

Compound 76 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 550.26; MS(ESI) m/z(M+1)+: 551.26.

Example 77 3-(1-cyanoethyl)-N-(4-methyl-3-(4-(4-(2-morpholinoethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)benzamide 77

Compound 77 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 536.25; MS(ESI) m/z(M+1)+: 537.25.

Example 78 N-(4-methyl-3-(4-(4-(2-morpholinoethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-2-(3-(trifluoromethyl) phenyl)acetamide78

Compound 78 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 565.23; MS(ESI) m/z(M+1)+: 566.23.

Example 79 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-(oxetan-3-yloxy)pyrid-3-yl)-1H-pyrazol-1- yl)phenyl)benzamide 79

Compound 79 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 493.21; MS(ESI) m/z(M+1)+: 494.21.

Example 80 3-(1-cyanoethyl)-N-(4-methyl-3-(4-(4-(oxetan-3-yloxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl) benzamide 80

Compound 80 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 479.19; MS(ESI) m/z(M+1)+: 480.19.

Example 81: N-(4-methyl-3-(4-(4-(2-morpholinoethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide 81

Compound 81 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 521.21; MS(ESI) m/z(M+1)+: 522.22.

Example 82: N-(4-methyl-3-(4-(4-(oxetan-3-yloxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide 82

Compound 82 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 494.15; MS(ESI) m/z(M+1)+: 495.15.

Example 83: N-(4-methyl-3-(4-(4-(oxetan-3-yloxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-2-(3-(trifluoromethyl )phenyl)acetamide 83

Compound 83 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 508.17; MS(ESI) m/z(M+1)+: 509.18.

Example 84 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(5-(oxetan-3-yloxy)pyrid-3-yl)-1H-pyrazol-1- yl)phenyl)benzamide 84

Compound 84 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 493.21; MS(ESI) m/z(M+1)+: 494.21.

Example 85 3-(1-cyanoethyl)-N-(4-methyl-3-(4-(5-(oxetan-3-yloxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl) benzamide 85

Compound 85 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 479.19; MS(ESI) m/z(M+1)+: 480.19. Example 86 N-(4-methyl-3-(4-(5-(oxetan-3-yloxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-2-(3-(trifluoromethyl )phenyl)acetamide 86

Compound 86 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 508.17; MS(ESI) m/z(M+1)+: 509.17.

Example 87: 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-(oxetan-3-ylmethoxy)pyrid-3-yl)-1H-pyrazol-1- yl)phenyl)benzamide 87

Compound 87 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 507.22; MS(ESI) m/z(M+1)+: 508.22.

Example 88 3-(1-cyanoethyl)-N-(4-methyl-3-(4-(4-(oxetan-3-ylmethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl) benzamide 88

Compound 88 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 493.21; MS(ESI) m/z(M+1)+: 494.21.

Example 89: N-(4-methyl-3-(4-(4-(oxetan-3-ylmethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide 89

Compound 89 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 508.17; MS(ESI) m/z(M+1)+: 509.17.

Example 90: N-(4-methyl-3-(4-(4-(oxetan-3-ylmethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-2-(3-(trifluoromethyl )phenyl)acetamide 90

Compound 90 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 522.18; MS(ESI) m/z(M+1)+: 523.18.

Example 91 N-(3-(4-(4-(benzyloxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(2-cyanoprop-2-yl)benzamide 91

Compound 91 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 527.23; MS(ESI) m/z(M+1)+: 528.24.

Example 92: N-(3-(4-(4-(benzyloxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 92

Compound 92 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 528.17; MS(ESI) m/z(M+1)+: 529.17.

Example 93 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-2-yl)methoxy)pyrid-3-yl)-1H-pyrazole -1-yl)phenyl)benzamide 93

Compound 93 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 521.24; MS(ESI) m/z(M+1)+: 522.24.

Example 94 3-(1-cyanoethyl)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-2-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl )phenyl)benzamide 94

Compound 94 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 507.22; MS(ESI) m/z(M+1)+: 508.22.

Example 95: N-(4-methyl-3-(4-(4-((tetrahydrofuran-2-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl )benzamide 95

Compound 95 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 522.18; MS(ESI) m/z(M+1)+: 523.18.

Example 96: N-(4-methyl-3-(4-(4-((tetrahydrofuran-2-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-2-(3 -(trifluoromethyl)phenyl)acetamide 96

Compound 96 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 536.20; MS(ESI) m/z(M+1)+: 537.20.

Example 97 3-(2-cyanoprop-2-yl)-N-(3-(4-(4-(cyclopentylmethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)benzamide 97

Compound 97 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 519.26; MS(ESI) m/z(M+1)+: 520.26.

Example 98 3-(1-cyanoethyl)-N-(3-(4-(4-(cyclopentylmethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)benzamide 98

Compound 98 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 505.24; MS(ESI) m/z(M+1)+: 506.24.

Example 99: N-(3-(4-(4-(cyclopentylmethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 99

Compound 99 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 520.20; MS(ESI) m/z(M+1)+: 521.20.

Example 100: N-(3-(4-(4-(cyclopentylmethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-2-(3-(trifluoromethyl)phenyl)acetamide 100

Compound 100 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 534.22; MS(ESI) m/z(M+1)+: 535.22.

Example 101 3-(2-cyanoprop-2-yl)-N-(3-(4-(4-(furan-3-ylmethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4 -methylphenyl)benzamide 101

Compound 101 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 517.21; MS(ESI) m/z(M+1)+: 518.21.

Example 102 3-(1-cyanoethyl)-N-(3-(4-(4-(furan-3-ylmethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)benzamide 102

Compound 102 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 503.19; MS(ESI) m/z(M+1)+: 504.19.

Example 103: N-(3-(4-(4-(furan-3-ylmethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 103

Compound 103 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 518.15; MS(ESI) m/z(M+1)+: 519.15.

Example 104: N-(3-(4-(4-(furan-3-ylmethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-2-(3-(trifluoromethyl) phenyl)acetamide 104

Compound 104 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 532.17; MS(ESI) m/z(M+1)+: 533.17.

Example 105: (S)-3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)oxy)pyrid-3-yl) -1Н-pyrazol-1-yl)phenyl)benzamide 105

Compound 105 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 507.22; MS(ESI) m/z(M+1)+: 508.22.

Example 106: (R)-3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)oxy)pyrid-3-yl) -1Н-pyrazol-1-yl)phenyl)benzamide 106

Compound 106 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 507.22; MS(ESI) m/z(M+1)+: 508.22.

Example 107: (S)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)oxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)- 3-(trifluoromethyl)benzamide 107

Compound 107 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 508.17; MS(ESI) m/z(M+1)+: 509.17.

Example 108: (R)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)oxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)- 3-(trifluoromethyl)benzamide 108

Compound 108 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 508.17; MS(ESI) m/z(M+1)+: 509.17.

Example 109 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(5-morpholino-pyrid-3-yl)-1H-imidazol-1-yl)phenyl)benzamide 109

Compound 109 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 506.24; MS(ESI) m/z(M+1)+: 507.24.

Example 110: N-(4-methyl-3-(4-(5-(oxetan-3-yloxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide 110

Compound 110 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 506.24; MS(ESI) m/z(M+1)+: 507.24.

Example 111: N-(4-methyl-3-(4-(5-morpholinopyrid-3-yl)-1H-imidazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide 111

Compound 111 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 507.18; MS(ESI) m/z(M+1)+: 508.18.

Example 112: (S)-3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)methoxy)pyrid-3-yl) -1Н-pyrazol-1-yl)phenyl)benzamide 112

Compound 112 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 521.24; MS(ESI) m/z(M+1)+: 522.24.

Example 113: (R)-3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)methoxy)pyrid-3-yl) -1Н-pyrazol-1-yl)phenyl)benzamide 113

Compound 113 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 521.24; MS(ESI) m/z(M+1)+: 522.24.

Example 114: (S)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)- 3-(trifluoromethyl)benzamide 114

Compound 114 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 522.18; MS(ESI) m/z(M+1)+: 523.18.

Example 115: (R)-N-(4-methyl-3-(4-(4-((tetrahydrofuran-3-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)- 3-(trifluoromethyl)benzamide 115

Compound 115 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 522.18; MS(ESI) m/z(M+1)+: 523.18.

Example 116: N-(3-(4-(4-((1-acetylpyrrolidin-3-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-( 2-cyanoprop-2-yl)benzamide 116

Compound 116 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 562.26; MS(ESI) m/z(M+1)+: 563.26.

Example 117 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-((1-(methylsulfonyl)pyrrolidin-3-yl)methoxy)pyrid-3-yl )-1H-pyrazol-1-yl)phenyl)benzamide 117

Compound 117 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 598.23; MS(ESI) m/z(M+1)+: 599.23.

Example 118 3-(2-cyanoprop-2-yl)-N-(3-(4-(4-((1-(2-(dimethylamino)acetyl)pyrrolidin-3-yl)methoxy)pyrid-3- yl)-1Н-pyrazol-1 -yl)-4-methylphenyl)benzamide 118

Compound 118 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 605.31; MS(ESI) m/z(M+1)+: 606.31.

Example 119 N-(3-(4-(4-((1-acetylpyrrolidin-3-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-( trifluoromethyl)benzamide 119

Compound 119 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 563.21; MS(ESI) m/z(M+1)+: 564.21.

Example 120: N-(4-methyl-3-(4-(4-((1-(methylsulfonyl)pyrrolidin-3-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl) -3-(trifluoromethyl)benzamide 120

Compound 120 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 599.18; MS(ESI) m/z(M+1)+: 600.18.

Example 121: N-(3-(4-(4-((1-(2-(dimethylamino)acetyl)pyrrolidin-3-yl)methoxy)pyrid-3-yl)-1H-pyrazol-1-yl)- 4-methylphenyl)-3-(trifluoromethyl)benzamide 121

Compound 121 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 606.25; MS(ESI) m/z(M+1)+: 607.25.

Example 122: (8)-3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-((5-oxotetrahydrofuran-2-yl)methoxy)pyrid-3- yl)-N-pyrazol-1-yl)phenyl)benzamide 122

Compound 122 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 535.22. MS(ESI) m/z(M+1)+: 536.22.

Example 123: N-(3-(4-(4-((1-acetylazetidin-3-yl)oxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl))-3- (trifluoromethyl)benzamide 123

Compound 123 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 535.18; MS(ESI) m/z(M+1)+: 536.18.

Example 124: N-(4-methyl-3-(4-(4-((1-(methylsulfonyl)azetidin-3-yl)oxy)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl) -3-(trifluoromethyl)benzamide 124

Compound 124 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 571.15; MS(ESI) m/z(M+1)+: 572.15.

Example 125: N-(3-(1-(5-(3-(2-cyanoprop-2-yl)benzoylamino)-2-methylphenyl)-1H-pyrazol-4-yl)pyrid-4-yl)tetrahydro- 2Н-pyran-4-carboxamide 125

Stage 1. Synthesis of N-(3-bromopyrid-4-yl)tetrahydro-2H-pyran-4-carboxamide h

3-bromopyride-4-ylamine (1.0 g, 1 eq.), tetrahydro-2H-pyran-4-carboxylic acid (0.75 g, 1 eq.), HATU (2.4 g, 1.1 eq. .), DIPEA (0.75) and DMF (5 ml) were mixed and stirred at room temperature for 0.5 hour. The resulting mixture was then eluted with ethyl acetate (150 ml), washed successively with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give product h (1.3 g) which was used directly in the next step.

Step 2 Final Product Compound 125 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 548.25; MS(ESI) m/z(M+1)+: 549.25.

Example 126: N-(3-(1-(2-methyl-5-(3-(trifluoromethyl)benzoylamino)phenyl)-1H-pyrazol-4-yl)pyrid-4-yl)tetrahydro-2H-pyran-4 -carboxamide 126

Compound 126 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 549.19; MS(ESI) m/z(M+1)+: 550.19.

Example 127: N-(3-(1-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetylamino)phenyl)-1H-pyrazol-4-yl)pyrid-4-yl)tetrahydro- 2Н-pyran-4-carboxamide 127

Compound 127 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 563.24; MS(ESI) m/z(M+1)+: 564.24.

Example 128: N-(3-(1-(2-methyl-5-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazol-4-yl)pyrid-4-yl)tetrahydro- 2Н-pyran-4-carboxamide 128

Compound 128 was synthesized using steps similar to those described in examples 1, 125 and 15. Exact weight (calculated): 564.20. MS(ESI) m/z(M+1)+: 565.20.

Example 129: N-(3-(1-(5-(3-(5-(tert _-6 util)isoxazol-3-yl)ureido)-2-methylphenyl)-1H-pyrazol-4-yl)pyrid- 4-yl)tetrahydro-2H-pyran-4-carboxamide 129

Compound 129 was synthesized using steps similar to those described in examples 1, 125 and 15. Exact weight (calculated): 543.25; MS(ESI) m/z(M+1)+: 544.25.

Example 130 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-(2-(tetrahydro-2H-pyran-4-yl)acetylamino)pyrid-3- yl)-1H-pyrazol-1-yl)phenyl)benzamide 130

Compound 130 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 562.26; MS(ESI) m/z(M+1)+: 563.26.

Example 131 N-(4-methyl-3-(4-(4-(2-(tetrahydro-2H-pyran-4-yl)acetylamino)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl )-3-(trifluoromethyl)benzamide 131

Compound 131 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 563.21; MS(ESI) m/z(M+1)+: 564.21.

Example 132: N-(4-methyl-3-(4-(4-(2-(tetrahydro-2H-pyran-4-yl)acetylamino)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl )-2-(3-(trifluoromethyl)phenyl)acetamide 132

Compound 132 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 577.23; MS(ESI) m/z(M+1)+: 578.23.

Example 133: N-(3-(1-(2-methyl-5-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazol-4-yl)pyrid-4-yl)-2 -(tetrahydro-2H-pyran-4-yl)acetamide 133

Compound 133 was synthesized using steps similar to those described in examples 1, 125 and 15. Exact weight (calculated): 578.22; MS(ESI) m/z(M+1)+: 579.22.

Example 134 N-(3-(1-(5-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-methylphenyl)-1H-pyrazol-4-yl)pyrid-4 -yl)-2-(tetrahydro-2Н-pyran-4-yl)acetamide 134

Compound 134 was synthesized using steps similar to those described in examples 1, 125 and 15. Exact weight (calculated): 557.27; MS(ESI) m/z(M+1)+: 558.27.

Example 135: 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(4-(2-(tetrahydrofuran-3-yl)acetyl amino)pyrid-3-yl)- 1Н-pyrazol-1-yl)phenyl)benzamide135

Compound 135 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 548.25; MS(ESI) m/z(M+1)+: 549.25.

Example 136: N-(4-methyl-3-(4-(4-(2-(tetrahydrofuran-3-yl)acetylamino)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3- (trifluoromethyl)benzamide 136

Compound 136 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 549.19; MS(ESI) m/z(M+1)+: 550.19.

Example 137: N-(4-methyl-3-(4-(4-(2-(tetrahydrofuran-3-yl)acetylamino)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-2- (3-(trifluoromethyl)phenyl)acetamide 137

Compound 137 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 563.21; MS(ESI) m/z(M+1)+: 564.21.

Example 138: N-(3-(1-(2-methyl-5-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazol-4-yl)pyrid-4-yl)-2 -(tetrahydrofuran-3-yl)acetamide138

Compound 138 was synthesized using steps similar to those described in examples 1, 125 and 15. Exact weight (calculated): 564.20. MS(ESI) m/z(M+1)+: 565.20.

Example 139 N-(3-(1-(5-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-methylphenyl)-1H-pyrazol-4-yl)pyrid-4 -yl)-2-(tetrahydrofuran-3-yl)acetamide 139

Compound 139 was synthesized using steps similar to those described in examples 1, 125 and 15. Exact weight (calculated): 543.25; MS(ESI) m/z(M+1)+: 544.25.

Example 140: N-(3-(1-(5-(3-(2-cyanoprop-2-yl)benzoylamino)-2-methylphenyl)-1H-pyrazol-4-yl)pyrid-4-yl)tetrahydrofuran- 3-carboxamide 140

Compound 140 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 534.23; MS(ESI) m/z(M+1)+: 535.23.

Example 141: N-(3-(1-(2-methyl-5-(3-(trifluoromethyl)benzoylamino)phenyl)-1H-pyrazol-4-yl)pyrid-4-yl)tetrahydrofuran-3-carboxamide 141

Compound 141 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 535.18; MS(ESI) m/z(M+1)+: 536.18.

Example 142: N-(3-(1-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetylamino)phenyl)-1H-pyrazol-4-yl)pyrid-4-yl)tetrahydrofuran- 3-carboxamide 142

Compound 142 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 549.19; MS(ESI) m/z(M+1)+: 550.19.

Example 143: N-(3-(1-(2-methyl-5-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazol-4-yl)pyrid-4-yl)-3 -tetrahydrofurancarboxamide 143

Compound 143 was synthesized using steps similar to those described in examples 1, 125 and 15. Exact weight (calculated): 550.19; MS(ESI) m/z(M+1)+: 551.19.

Example 144: N-(3-(1-(5-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-methylphenyl)-1H-pyrazol-4-yl)pyrid-4 -yl)tetrahydrofuran-3-carboxamide 144

Compound 144 was synthesized using steps similar to those described in examples 1, 125 and 15. Exact weight (calculated): 529.24; MS(ESI) m/z(M+1)+: 530.24.

Example 145: N-(3-(1-(5-(3-(2-cyanoprop-2-yl)benzoylamino)-2-methylphenyl)-1H-pyrazol-4-yl)pyrid-4-yl)-3 -methyloxetane-3-carboxamide 145

Compound 145 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 534.23; MS(ESI) m/z(M+1)+: 535.23.

Example 146 3-methyl-N-(3-(1-(2-methyl-5-(3-(trifluoromethyl)benzoylamino)phenyl)-1H-pyrazol-4-yl)pyrid-4-yl)oxetan-3 -carboxamide 146

Compound 146 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 535.18; MS(ESI) m/z(M+1)+: 536.18.

Example 147 3-methyl-N-(3-(1-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetylamino)phenyl)-1H-pyrazol-4-yl)pyrid-4- yl)oxetane-3-carboxamide 147

Compound 147 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 549.19; MS(ESI) m/z(M+1)+: 550.19.

Example 148 3-methyl-N-(3-(1-(2-methyl-5-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazol-4-yl)pyrid-4- yl)oxetane-3-carboxamide 148

Compound 148 was synthesized using steps similar to those described in examples 1, 125 and 15. Exact weight (calculated): 550.19; MS(ESI) m/z(M+1)+: 551.19.

Example 149: N-(3-(1-(5-(3-(5-(tert _-6 util)isoxazol-3-yl)ureido)-2-methylphenyl)-1H-pyrazol-4-yl)pyrid- 4-yl)-3-methyloxetan-3-carboxamide 149

Compound 149 was synthesized using steps similar to those described in examples 1, 125 and 15. Exact weight (calculated): 529.24; MS(ESI) m/z(M+1)+: 530.24.

Example 150: N-(3-(1-(5-(3-(2-cyanoprop-2-yl)benzoylamino)-2-methylphenyl)-1H-pyrazol-4-yl)pyrid-4-yl)-3 -oxadicyclo[3.1.0]hexane-6-carboxamide 150

Compound 150 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 546.23; MS(ESI) m/z(M+1)+: 547.23.

Example 151: N-(3-(1-(2-methyl-5-(3-(trifluoromethyl)benzoylamino)phenyl)-1H-pyrazol-4-yl)pyrid-4-yl)-3-oxadicyclo[3.1. 0]hexane-6-carboxamide 151

Compound 151 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 547.18; MS(ESI) m/z(M+1)+: 548.18.

Example 152: N-(3-(1-(2-methyl-5-(2-(3-(trifluoromethyl)phenyl)acetylamino)phenyl)-1H-pyrazol-4-yl)pyrid-4-yl)-3 -oxadicyclo[3.1.0]hexane-6-carboxamide 152

Compound 152 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 561.19; MS(ESI) m/z(M+1)+: 562.19.

Example 153: N-(3-(1-(2-methyl-5-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-pyrazol-4-yl)pyrid-4-yl)-3 -oxadicyclo[3.1.0]hexane-6-carboxamide 153

Compound 153 was synthesized using steps similar to those described in examples 1, 125 and 15. Exact weight (calculated): 562.19; MS(ESI) m/z(M+1)+: 563.19.

Example 154 N-(3-(1-(5-(3-(5-(tert _-6 util)isoxazol-3-yl)ureido)2-methylphenyl)-1H-pyrazol-4-yl)pyrid-4 -yl)-3-oxadicyclo[3.1.0]hexane-6-carboxamide 154

Compound 154 was synthesized using steps similar to those described in examples 1, 125 and 15. Exact weight (calculated): 541.24; MS(ESI) m/z(M+1)+: 542.24.

Example 155 3-(2-cyanoprop-2-yl)-N-(3-(4-(4-(2-hydroxyethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl )benzamide 155

Compound 155 was synthesized using steps similar to those described in examples 1 and 125. Exact weight (calculated): 481.21; MS(ESI) m/z(M+1)+: 482.21.

Example 156: N-(3-(4-(4-(2-Hydroxyethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 156

Compound 156 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 482.15; MS(ESI) m/z(M+1)+: 483.15.

Example 157: 1-(5-(t-butyl)isoxazol-3-yl)-3-(3-(4-(4-(2-hydroxyethoxy)pyrid-3-yl)-1H-pyrazol-1-yl )-4-methylphenyl)urea 157

Compound 157 was synthesized using steps similar to those described in examples 1 and 41. Exact weight (calculated): 476.21; MS(ESI) m/z(M+1)+: 477.21.

Example 158: 1-(3-(4-(4-(2-Hydroxyethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl) urea 158

Compound 158 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 497.16; MS(ESI) m/z(M+1)+: 498.16.

Example 159 3-(2-cyanoprop-2-yl)-N-(3-(4-(4-(2-methoxyethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl )benzamide 159

Compound 159 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 495.22; MS(ESI) m/z(M+1)+: 496.22.

Example 160: N-(3-(4-(4-(2-Methoxyethoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 160

Compound 160 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 496.17; MS(ESI) m/z(M+1)+: 497.17.

Example 161 3-(2-cyanoprop-2-yl)-N-(3-(4-(4-(3-hydroxypropoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl )benzamide 161

Compound 161 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 495.22; MS(ESI) m/z(M+1)+: 496.22.

Example 162: N-(3-(4-(4-(3-Hydroxypropoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 162

Compound 162 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 496.17; MS(ESI) m/z(M+1)+: 497.17.

Example 163 3-(2-cyanoprop-2-yl)-N-(4-methyl-3-(4-(5-(piperizan-1-yl)pyrid-3-yl)1H-pyrazol-1-yl )phenyl)benzamide 163

Compound 163 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 505.25; MS(ESI) m/z(M+1)+: 506.25.

Example 164: N-(4-methyl-3-(4-(5-(piperizan-1-yl)pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)-3-(trifluoromethyl)benzamide 164

Compound 164 was synthesized using steps similar to those described in Example 1. Exact weight (calculated): 506.20; MS(ESI) m/z(M+1)+: 507.20.

Example 165 3-(2-cyanoprop-2-yl)-N-(3-(4-(4-(4-hydroxybutoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl )benzamide 165

Compound 165 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 509.24; MS(ESI) m/z(M+1)+: 510.24.

Example 166: N-(3-(4-(4-(4-Hydroxybutoxy)pyrid-3-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 166

Compound 166 was synthesized using steps similar to those described in Example 41. Exact weight (calculated): 510.18; MS(ESI) m/z(M+1)+: 511.18.

Example 167: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(4-methyl- 1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide 167

Stage 1. Synthesis of 4-bromo-1-(2-methyl-5-nitrophenyl)-1H-pyrazole i:

4-bromopyrazole (5 g, 1 eq.), 2-fluoro-1-methyl-4-nitrobenzene (5.5 g, 1.05 eq.), potassium carbonate (13.1, 3 eq.) were mixed in DMF (50 ml) and stirred overnight at 100° C. under nitrogen, and then cooled and concentrated. Ethyl acetate (200 ml) was added to the concentrate. The resulting mixture was washed successively with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and then separated by column chromatography to give a yellow product i (5.2 g).

Stage 2. Synthesis of 1-(2-methyl-5-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole j:

Compound i (5 g, 1 eq.), bis(pinacolato)diborone (5.8 g, 1.3 eq.), potassium acetate (3.5 g, 2 eq.) and [1,1'-bis( diphenylphosphino)ferrocene]palladium dichloride (0.72 g, 0.05 eq.) was mixed in 1,4-dioxane (50 ml). The mixture was stirred overnight at 100° C. under nitrogen and then concentrated. The concentrate was separated using column chromatography to give a yellow product j (4.0 g).

Step 3. 5-(1-(2-methyl-5-nitrophenyl)-1H-pyrazol-4-yl)1H-pyrrolo[2,3-b]pyridine k:

Compound j (4.0 g, 1.1 eq.), 5-bromo-1H-pyrrolo[2,3-b]pyridine (2.2 g, 1 eq.), potassium carbonate (3.0 g, 2 eq.) and tetrakis(triphenylphosphine)palladium (0.6 g, 0.05 eq.) were mixed in 1,4-dioxane (40 ml) and water (4 ml). The mixture was stirred overnight at 90° C. under nitrogen and then concentrated. The concentrate was separated using column chromatography to give a yellow product (2.8 g).

Stage 4. Synthesis of 3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylaniline l:

Compound k (2.8 g, 1 eq.) and palladium-carbon (0.5 g) were mixed in methanol (30 ml). The mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. Dichloromethane (100 ml) was then added to dilute the mixture. The resulting mixture was filtered and concentrated to give pale green product 1 (2.1 g).

Step 5. Synthesis of N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(4-methyl -1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide 167:

Compound 1 (0.05 g, 1 eq.), 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid (0.46 g, 1 eq.), HATU (0.072 , 1.1 eq.) and diisopropylethylenediamine (0.22 g, 1 eq.) were mixed in DMF (2 ml). The mixture was stirred at room temperature for 1 hour. Ethyl acetate (50 ml) was then added to dilute the mixture. The mixture was washed successively with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by HPLC to give Compound 167 (0.07 g). Exact weight (calculated): 541.18; MS(H3P)m/z(M+1)+: 542.19.

Example 168: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-4-((4-methylpiperazine -1-yl)methyl)-3-(trifluoromethyl)benzamide 168

Compound 168 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 573.24; MS(ESI) m/z(M+1)+: 574.25.

Example 169: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-4-methyl-3-( trifluoromethyl)benzamide 169

Compound 169 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 475.16; MS(ESI) m/z(M+1)+: 476.16.

Example 170: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 170

Compound 170 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 461.14; MS(ESI) m/z(M+1)+: 462.14.

Example 171: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(2-cyanoprop- 2-yl)benzamide 171

Compound 171 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 460.20; MS(ESI) m/z(M+1)+: 461.20.

Example 172: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-5-(tert-butyl) isoxazole-3-carboxamide 172

Compound 172 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 440.19; MS(ESI) m/z(M+1)+: 441.19.

Example 173: 1-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(5-(tert -butyl)isoxazol-3-yl)urea 173

Compound 173 was synthesized using steps similar to those described in examples 15 and 167. Exact weight (calculated): 455.20; MS(ESI) m/z(M+1)+: 456.20.

Example 174: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-imidazol-1-yl)-4-methylphenyl)-4-((4-methylpiperazine -1-yl)methyl)-3-(trifluoromethyl)benzamide 174

Compound 174 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 573.24; MS(ESI) m/z(M+1)+: 574.24.

Example 175: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-imidazol-1-yl)-4-methylphenyl)-4-methyl-3-( trifluoromethyl)benzamide 175

Compound 175 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 475.16; MS(ESI) m/z(M+1)+: 476.16.

Example 176: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-imidazol-1-yl)-4-methylphenyl)-3-(2-cyanoprop- 2-yl)benzamide 176

Compound 176 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 460.20; MS(ESI) m/z(M+1)+: 461.20.

Example 177: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-imidazol-1-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 177

Compound 177 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 461.14; MS(ESI) m/z(M+1)+: 462.14.

Example 178: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-imidazol-1-yl)-4-methylphenyl)-5-(tert-butyl) isoxazole-3-carboxamide 178

Compound 178 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 440.19; MS(ESI) m/z(M+1)+: 441.19.

Example 179: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(1-cyanoethyl) benzamide 179

Compound 179 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 466.18; MS(ESI) m/z(M+1)+: 467.18.

Example 180: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(4-trifluoromethylphenyl) benzamide 180

Compound 180 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 537.17; MS(ESI) m/z(M+1)+: 538.17.

Example 181: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-aminosulfonylbenzamide 181

Compound 181 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 472.13; MS(ESI) m/z(M+1)+: 473.13.

Example 182: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)quinoline-7-carboxamide 182

Compound 182 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 444.16; MS(ESI) m/z(M+1)+: 445.16.

Example 183: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(thien-3- yl)benzamide 183

Compound 183 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 475.14; MS(ESI) m/z(M+1)+: 476.14.

Example 184: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-3-(pyrid-2- yl) benzamide 184

Compound 184 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 470.18; MS(ESI) m/z(M+1)+: 471.18.

Example 185: N-(3-(4-(1H-pyrrolo[2,3-b]pyrid-5-yl)-1H-pyrazol-1-yl)-4-methylphenyl)-[1,1'-diphenyl ]-3-carboxamide 185

Compound 185 was synthesized using steps similar to those described in Example 167. Exact weight (calculated): 469.19; MS(ESI) m/z(M+1)+: 470.19.

Comparative Example 1: 3-trifluoromethyl-N-(4-methyl-3-(4-(pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)benzamide

Comparative compound 1 was synthesized using steps similar to those described in example 1. Exact weight (calculated): 422.14; MS(ESI) m/z(M+1)+: 423.14.

Comparative Example 2: 3-chloro-N-(4-methyl-3-(4-(pyrid-3-yl)-1H-pyrazol-1-yl)phenyl)benzamide

Comparative compound 2 was synthesized using steps similar to those described in example 1. Exact weight (calculated): 388.11; MS(ESI) m/z(M+1)+: 389.12.

Example 186 Effect on Cancer Cell Proliferation

The compounds of the present invention were tested for their effect on cancer cell growth (Table 2) to further evaluate the compounds of the present invention for their inhibitory effect on cancer cell proliferation and their selectivity in inhibiting cancer cell proliferation.

In the present example, a BaF3 primary mouse B cell (purchased from ATCC), a BaF3-FL-BRAF-V600E mouse cell (stably expressing the BRAF-V600E full-length mutant kinase), an A375 melanoma cell (expressing the BRAF-V600E mutant kinase purchased from Cobioer Biosciences Co., Ltd., Nanjing, China), COLO205 colorectal cancer cell (expressing BRAF-V600E mutant kinase purchased from ATCC, USA), OC _1- AML-3 human acute leukemia cell (expressing NRAS-Q61L mutant kinase acquired from Cobioer Biosciences Co., Ltd., Nanjing, China) and NB4 human acute leukemia cell (expressing KRAS-A18D mutant kinase, purchased from ATCC, USA). The above mutant cell line BaF3-FL-BRAF-V600E was obtained by the following method. The sequence of the full-length region of the mutant human BRAF-V600E kinase was amplified by PCR, incorporated into the MSCV-Puro vector (purchased from Clontech) and stably transfected into mouse BaF3 cells by the retroviral method, and the growth factor IL-3 was removed. Finally, a cell line dependent on the full-length BRAF-V600E protein having various carried mutations was obtained.

In this example, solutions of the test compound in DMSO at various concentrations (0.000508 μM, 0.00152 μM, 0.00457 μM, 0.0137 μM, 0.0411 μM, 0.123 μM, 0.370 μM, 1, 11 μM, 3.33 μM, 10 μM). Cells were incubated for 72 hours. The number of viable cells was determined using a cell viability kit Cell Titer-Glo (Promega, USA) by quantitative determination of ATP in viable cells. The Gbo values (units) of the compounds of the present invention were determined relative to each of the tested cells. The experimental results are shown in Table 2.

It has been experimentally shown that the compounds of the present invention can have comparable or even higher inhibitory activity against BaF3-FL-BRAF-V600E, A375 and COLO205 cell lines expressing BRAF-V600E compared to comparative compound 1 or even more high inhibitory activity compared to comparative compound 2. In OC _1- AML-3 and NB4 cells expressing NRAS mutation or KRAS mutation, the compounds of the present invention also showed comparable or better inhibitory activity compared to comparative compound 1 and comparative compound 2.

Example 187 Protease Activity Assay

The activity of Compound 16 and control compound PLX4032 (MedChem ExpR ₆ ss, China) against BRAF, BRAF V599E and RAF1 (cRAF) Y340 target sites was tested using Invitrogen (Carlsbad, USA).

The data indicate that Compound 16 of the present invention had a strong inhibitory effect on each of BRAF protein, BRAF-V600E protein and Y340D RAF1 protein (CRAF) in vitro, superior to control compound PLX4032.

Example 188: Study of pharmacokinetic parameters in rats

The example used SD rats (180-220 g, male) (purchased from the Experimental Animal Center of Anhui Medical University, China). Animals were kept in independently ventilated cages, 6 rats per cage. Feeding was carried out at a temperature of 20~26°C and a humidity of 35-75%. Illumination was 12 hours light / 12 hours dark. The corncob bedding was updated once a week. The rats received food and drinking water ad libitum. The rats were marked with a number on their tails. During the experiment, the breeding and use of animals strictly follow the rules of the Animal Care International Laboratory Evaluation and Accreditation Association.

Solutions of Compound 16 and Comparative Compound 1 were prepared as follows. 10 mg of test compound was accurately weighed into a sterile vial and dissolved in a small amount of DMSO, and then adjusted to a constant volume of 5 ml with 5% glucose solution to obtain a test solution via gavage at a concentration of 2 mg/ml. Accurately withdrawn 0.5 ml of the above test solution through a probe at a concentration of 2 mg/ml and adjusted to a constant volume of 5 ml with 4.5 ml of 5% glucose solution for intravenous administration of the test solution at a concentration of 0.2 mg/ml. The solution was prepared immediately before use in the experiment.

6 SD rats were randomly divided into two groups, and the synthesized compounds were administered by injection via gavage and tail vein, respectively. Approximately 0.3 ml of blood samples were collected from the retroorbital venous plexus 0 h before administration and 5 min, 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 9 h, 12 h , 24 h after administration for the probe group; and 0 hours before administration and 2 minutes, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 9 hours and 12 hours after administration for the tail vein group. Each of the collected blood samples was placed in a 1.5 ml centrifuge tube with heparin (Sigma, USA). The sample was centrifuged at 6000 rpm for 3 minutes to separate the plasma. 100 μl of the plasma in the top layer was placed in a new 1.5 ml centrifuge tube and stored at -80° C. for determination.

10 mg of the test compound standard was accurately weighed into a 10 ml volumetric flask and dissolved by adding methanol to obtain a constant volume and mixed evenly to obtain a 1 mg/ml stock solution. Then the initial solution was gradually diluted with methanol to obtain a series of working solutions at concentrations of 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1, 2, 5, 10, 20 µg/ml. The working solutions were placed in a refrigerator at 4°C for later use.

Used 11 centrifuge tubes. 10 μl of the above working solutions were respectively added to each of the centrifuge tubes, and then 90 μl of blank rat plasma were respectively added to each of the centrifuge tubes. The mixtures were stirred evenly so that the concentration of the compound in rat plasma was 1, 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000 ng/ml. Then, 20 µl of caffeine solution as an internal standard (200 ng/ml) (National Institutes for Food and Drug Control, China) was added thereto, and the resulting mixtures were vortexed for 10 s. Then 400 μl of methanol was added. The resulting mixtures were vortexed for 10 min and centrifuged at 16,000 rpm for 5 min. Thereafter, 70 μl of the supernatant was placed into the insertion tube of the sampling bottle. 5 µl of sample was injected for LC-MS/MS analysis. Rat plasma compound standard curve was obtained by linear regression performed by taking the ratio of sample peak area to internal standard peak area As/Ais as the vertical ordinate, taking the concentration C (µg/mL) as the horizontal ordinate, and taking 1/C ² as a weighting factor.

To 100 µl of test rat plasma stored at -80°C, 20 µl of caffeine solution (200 ng/ml) was added as an internal standard. The resulting mixture was vortexed for 10 s. Then 400 μl of methanol was added. The resulting mixture was vortexed for 10 min and centrifuged at 16,000 rpm for 5 min. Then 70 μl of the supernatant was placed in the insertion tube of the sampling bottle. For LC-MS/MS analysis, 5 μl of sample was injected.

LC-MS/MS analysis was carried out as follows. The experimental instrument was an API 4000 Triple Quad detector (AB SCIEX, USA); working software was Analyst 1.5.1 (Applied Biosystems Co., Ltd., USA); Shimadzu LC-30AD liquid pump, Shimadzu DGU-20A degassing unit, Shimadzu CTO-30A column oven, and SIL-30AC autosampler (Shimadzu Corporation, Japan) were used. Chromatography conditions were as follows. The chromatographic column was a Hanbon Hedera ODS-2 (Jiangsu Hanbon Science & Technology Co., Ltd., China), size (mm): 150×2.1, Pro. No.: H18100205.15; Serial No.: C981210513; the column temperature was 40°C; mobile phase A was an aqueous phase (containing 0.1% formic acid) and mobile phase B was methanol for gradient elution: 0-0.5 min, B 10%; 0.5-1.0 min, B 90%; 1.0-5.0 min, B 90%; 5.0-5.5 min, B 10%; 5.5-7 min, B 10%. The flow rate was 0.3 ml/min. The volume of the injected sample was 5 µl. Mass spectrometry conditions were as follows. The ion source was Turbo Spray; CAD was 10; curtain gas (CUR) was 25; the heating temperature was 500°C; ion source gas GS1 was 45; ion source gas GS2 was 45; the spraying voltage was 5500 V; and the source temperature was 500°C.

The results are shown in Table 4-7 below. The results showed that the highest blood Cmax of Compound 16 was higher than that of Comparative Compound 1 whether administered by intravenous injection or by gavage. When administered via a gastric tube, the maximum absorption of Compound 16 in vivo in rats was 1482 ng/ml, the cumulative concentration of the drug in AUC _0-t in vivo was 10930 h * ng / ml, and the oral bioavailability F% was 144.1%. On the other hand, the maximum in vivo drug absorption of comparative compound 1 in rats was 575.7 ng/mL, the cumulative drug concentration in AUC _0-t in vivo was 1012 h*ng/mL, and the oral bioavailability F% was 110, 7%. Thus, by introducing a substituent group on the pyridyl group, the compound of the present invention can have significantly improved absorption in rats and significantly improved oral bioavailability.

Example 189 Animal Drug Evaluation Experiment

This example shows the experimental results for Compound 16, Comparative Compound 1, and Control Compounds LY30019120 (purchased from MedChemExpress, China), PLX4032 (purchased from MedChemExpress, China), RAF709 (purchased from MedChemExpress, China), RAF265 (purchased from MedChemExpress, China). ) and PLX8394 (purchased from MedChemExpress, China) in Calu-6 degenerative lung cancer mouse models (expressing the KRAS Q61K mutant kinase, purchased from Cobioer Biosciences Co., Ltd., Nanjing, China), A375 melanoma cells (expressing the mutant BRAF-kinase). V600E, purchased from Cobioer Biosciences Co., Ltd., Nanjing, China), BxPC3 pancreatic cancer cells (expressing wild-type KRAS, BRAF V487-P492>A-deleted mutant kinase, purchased from Cobios Biosciences Co., Ltd., Nanjian , China), HCT116 colorectal cancer cells (expressing the KRAS G13D mutant kinase, purchased from ATCC, USA), colorectal cancer cells COLO205 (expressing the BRAF-V600E mutant kinase purchased from ATCC, USA).

The stages of the experiments were as follows:

(1) 4-6 week old female SCID mice (A375/COLO205) and nude mice (HCT116/Calu-6/BxPC3) purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. were reared at SPF in the laboratory . Drinking water and bedding were sterilized in an autoclave. All operations on mice were performed under aseptic conditions.

(2) On day 0, about 5×10 ⁶ cells of Calu-6 non-small cell lung cancer, HCT116 colorectal cancer, COLO205 colorectal cancer, A375 melanoma, and BxPC3 pancreatic cancer cells were injected subcutaneously into the left back of the mouse.

(3) Starting from the 14th day, castor oil diluent : ethanol : water (1:1:6) was orally administered to the respective mice every day (5 mice); Compound 16 at 50 mg/kg, 100 mg/kg and PLX4032 at 100 g/kg for transplanted A375 tumor; Compound 16 at 50 mg/kg, 100 mg/kg and 200 mg/kg, RAF709 at 100 g/kg, LY30019120 at 60 mg/kg, and Comparative Compound 1 at 100 mg/kg for Calu-6 transplanted tumor ; Compound 16 at 50 mg/kg, 100 mg/kg, RAF709 at 100 mg/kg and LY30019120 at 60 mg/kg for HCT116 transplanted tumor; Compound 16 at 25mg/kg, 50mg/kg, 100mg/kg, PLX4032 at 100mg/kg for transplanted COLO205 tumor; Compound 16 at 50 mg/kg, 200 mg/kg, LY3009120 at 100 mg/kg, RAF265 at 100 mg/kg and 100 mg/kg at 100 mg/kg for BxPC3 transplanted tumor. Starting from day 15, appropriate mice were administered orally with castor oil diluent : ethanol : water (1:1:6) every day.

(4) Starting from the 15th day, the length/width of subcutaneous tumors was measured every day with a caliper, and the weight of the mouse was recorded every day to determine the effect of Compound 16 on the weight of the mouse.

(5) For each of the model groups, mice were sacrificed on day 36, day 42, day 26, day 35, or day 42.

(6) The growth trend of subendothelial tumors was analyzed statistically. Tumor volume was calculated as follows: length × width × width / 2 mm ³ .

It was experimentally demonstrated that Compound 16 of the present invention had an inhibitory effect superior to control compounds in mouse transplanted tumor models of various cancer cells expressing KRAS, BRAF or NRAS mutations. Compared with Comparative Compound 1, in the calu6 cell transplanted tumor model, Comparative Compound 1 had a very strong toxicity since all mice died on day 8, while Compound 16 did not exhibit any toxicity. It has also been proven that the compound of the present invention administered as a morpholinyl substituent will have an unexpected pharmaceutical effect in vivo in mice without causing significant toxicity.

Industrial Applicability

The present invention provides a novel Pan-RAF kinase inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof. The present invention also relates to the use of a compound of formula (I) for the treatment or prevention of a disorder associated with RAF and/or RAS kinase activity. Thus, said inhibitor can be obtained as an appropriate drug and has industrial applicability.

Although the invention has been described in detail herein, the invention is not limited to the description, and modifications may be made by those skilled in the art based on the principles of the invention, and thus it should be understood that all modifications in accordance with the principles of the invention are within within the scope of protection of the invention.

Claims (22)

1. Pan-RAF kinase inhibitor, which is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

Formula (Ia), Where R ₁ is selected from the group consisting of H, pyridyl, morpholinyl, piperazinyl, 4-methyl-piperazin-1-ylphenyl, oxetan-3-yloxy, 2-morpholinoethoxy, 3-morpholinopropoxy and tetrahydrofuran-3-ylmethoxy; R ₂ is selected from the group consisting of H, C _1-6 hydroxyalkoxy, C _1-6 alkoxy-C _1-6 alkoxy, tetrahydropyran-4-yloxy, tetrahydrofuran-3-yloxy, oxetan-3-yloxy, tetrahydrofuran-3- ylmethoxy, tetrahydropyran-4-ylmethoxy and oxetan-3-ylmethoxy; R ₃ is H; where R ₁ , R ₂ and R ₃ do not represent H at the same time; R ₄ is selected from the group consisting of C _1-6 haloalkyl and C _1-6 cyanoalkyl; R ₅ is selected from the group consisting of H, C _1-6 alkyl and 4-methyl-piperazin-1-ylmethyl. 2. The pan-RAF kinase inhibitor according to claim 1, characterized in that R ₁ is selected from the group consisting of H, 3-pyridyl, 4-pyridyl, N-morpholinyl, piperazin-1-yl, 4-methyl-piperazin-1-ylphenyl, oxetan-3-yloxy, 3-morpholinopropoxy and tetrahydrofuran- 3-ylmethoxy; R ₂ is selected from the group consisting of H, 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy, 2-methoxyethoxy, tetrahydropyran-4-yloxy, tetrahydrofuran-3-yloxy, oxetan-3-yloxy, tetrahydropyran-4-ylmethoxy and oxetan-3-ylmethoxy; where R ₁ , R ₂ and R ₃ do not represent H at the same time; R ₄ is selected from the group consisting of trifluoromethyl, 2-cyanoethane-2-yl and 2-cyanoprop-2-yl; R ₅ is selected from the group consisting of H, methyl and 4-methyl-piperazin-1-ylmethyl. 3. The pan-RAF kinase inhibitor according to claim 1, wherein R ₁ is selected from the group consisting of N-morpholinyl and piperazin-1-yl; R ₄ is selected from the group consisting of C _1-6 haloalkyl and C _1-6 cyanoalkyl; each of R ₂ , R ₃ and R ₅ is H. 4. The pan-RAF kinase inhibitor according to claim 1, wherein R ₂ is selected from the group consisting of C _1-6 hydroxyalkoxy and C _1-6 alkoxy-C _1-6 alkoxy; R ₄ is selected from the group consisting of C _1-6 haloalkyl and C _1-6 cyanoalkyl; each of R ₁ , R ₃ and R ₅ is H. 5. The pan-RAF kinase inhibitor according to claim 1, selected from the group consisting of the following compounds or their pharmaceutically acceptable salts: No. Structure No. Structure 1

2

3

5

6

7

8

9

10

eleven

12

13

16

thirty

31

41

42

47

48

50

51

52

53

54

56

57

65

66

68

69

72

73

74

79

80

82

84

85

87

88

89

93

94

95

105

106

107

108

110

112

113

114

115

155

156

159

160

161

162

163

164

165

166

6. A pharmaceutical composition for inhibiting RAF and/or RAS tyrosine kinase activity, comprising an effective amount of a pan-RAF kinase inhibitor according to any one of paragraphs. 1-5 and a pharmaceutically acceptable carrier or excipient. 7. The pan-RAF kinase inhibitor according to any one of paragraphs. 1-5 for use in inhibiting RAF and/or RAS tyrosine kinase activity. 8. The pan-RAF kinase inhibitor according to any one of paragraphs. 1-5 for use in the treatment, prevention, or alleviation of a disease, disorder, or condition that is modulated by, or dependent on, or involved in, RAF and/or RAS tyrosine kinase activity, wherein said disease, disorder, or condition is a proliferative disease, selected from the group consisting of lung cancer, melanoma, pancreatic cancer and colorectal cancer.

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