TW201209050A - Compounds and compositions as protein kinase inhibitors - Google Patents

Abstract

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of B-Raf.

Description

201209050 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention provides a novel class of compounds, pharmaceutical compositions comprising the same, and the use of such compounds to treat or prevent diseases or conditions associated with abnormal or dysregulated kinase activity In particular, a method involving a disease or condition in which B Raf is abnormally activated. This application claims the priority of US Provisional Patent Application No. 61/238,073, filed on August 28, 2009, and US Provisional Patent Application No. 61/313, G39, filed on March 31, 2010. The entire disclosure of such claims is hereby incorporated by reference in its entirety in its entirety for all purposes. [Prior Art] Protein kinases represent a large family of proteins that play a central role in regulating a variety of cellular processes and maintaining control over cellular functions. Some non-limiting lists of these (4) include: receptor l-acid kinases such as platelet-derived growth factor receptor kinase (PDGF_R), nerve growth factor receptor trlcB, Met, and fibroblast growth factor receptor f (} Fr3; non-receptor alanine kinases such as Abl and fusion kinases BCR_AM, Uk, csk,

Fes, Bmx and c-src; and serine/threonine kinases such as B_Raf, sgk, MAP kinase (eg MKK4, MKK6, etc.) and sApK2a, SAPK2P and SAPK3. Abnormal kinase activity has been observed in many disease conditions. These disease conditions include benign and malignant proliferative disorders as well as diseases caused by improper activation of the immune system and nervous system. The novel compounds of the invention inhibit the activity of B_Raf or a mutant form thereof (e.g., V600E) and are therefore contemplated for use in the treatment of B_Raf related diseases. 150205.doc 201209050 SUMMARY OF THE INVENTION In one aspect, the invention provides a compound of formula I: r3

\ I R7 Η where: Y is selected from N and CR6; R! is selected from hydrogen, -XiRh, -Χ, ΟΧΑ^, -XlC(〇)NR8aR8b, -X, NR8aX2R8b > -XiNR8aC(0)X2〇 R8b . -X1NR8aC(0)X2NR8aR8b ^ - small 1184(〇)0-21181); wherein each x丨 is independently an alkyl group of Cl_4; and one to three hydrogens are optionally selected from the group consisting of hydroxyl and halogen. a group substituted with a cyano group, a cyano group, a C 4 alkyl group, a halogen-substituted C. 4 hospital group, a Ci 4 alkoxy group, and a halogen-substituted c1-4 alkoxy group; And Cl_4 alkylene; wherein R8a and Rsb are independently selected from the group consisting of hydrogen, (: 丨·6 alkyl, benzyl substituted C 6 alkyl, C: 3·8 cycloalkyl, heteroaryl and (: 3) · 8 heterocycloalkyl; wherein the cycloalkyl, heterocycloalkyl or heteroaryl group of Rsa or R8b is optionally independently selected from the group consisting of an amine group, a cyano 'Cm alkyl group, and a C. Substituting a group of alkoxy groups, a group substituted with a fluorene group, and a group substituted with a C group of a C. 4 alkoxy group; the limitation is that when the Ri is selected from the group consisting of: ΧιΝΗ (:(0)〇Ι18ΐ3& · ΧιΝυ(〇)() 2Κ8ΐ), not hydrogen; R2, R3, R5 and R6 are independently selected from hydrogen, _ group, cyano group, Ci-4 alkyl group, _ group Instead dagger-4 alkyl, c〗 · _ 4 alkoxy and substituted by the 150205.doc -4 - 201209050

Cl_4 alkoxy; & conditions are when R5 is a gas and Rl is selected from the group consisting of hydrogen, -X10X2R8a, _XiC(〇)NR8aR8b, _XiNR8aX, such as -XiNI^C(9)X2〇R8btXiNR8. In the case of 2R8b, ~ and ^ are not hydrogen; and the 'EM" is selected from the group consisting of -r9 and -NRloRii; wherein R9 is selected from the group consisting of Ci 6 and c3 8 cycloalkyl. 3_8 Heterocycloalkyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group of R9 is optionally (1) independently from the halo, cyano, CU4 alkyl, halogenated Cm alkyl.丨4 alkoxy group and (iv) group-substituted Ci 4 alkoxy group substituted; and ^. And R" is independently selected from the group consisting of hydrogen and r9; and the system I is selected from the group consisting of hydrogen and decane-4. _5 cycloalkyl and c3 5 heterocycloalkyl; wherein the alkyl, cyclodecyl or heterocyclic ring of R7 is optionally selected from the group consisting of ii group, cyano group, thiol group, Cl4 group, Substituted by a dentate group substituted with a phenyl group, a Cm alkoxy group, and a group substituted with a fluorinated alkoxy group; and an N-oxide derivative, a prodrug derivative, a protected derivative, and a mutual Isomers, individual isomers, and mixtures of isomers; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of such compounds. In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I or an N-oxide derivative thereof, an individual isomer and a mixture of isomers or a pharmaceutically acceptable salt thereof, and one or A wide variety of suitable excipients. In a first aspect, the invention provides a method of treating a disease in an animal wherein the inhibition of kinase activity, particularly B_Raf activity, prevents, inhibits or ameliorates the pathology and/or symptoms of the disease, the method comprising 150205.doc 201209050 A therapeutically effective amount of a hydrazine compound or an N-oxide derivative thereof, a mixture of individual isomers and isomers, or a pharmaceutically acceptable salt thereof. In a fourth aspect, the invention provides the use of a compound of the formula for the manufacture of a medicament for the treatment of a disease in an animal, wherein the kinase activity, in particular the B-Raf activity, in particular the mutant B-Raf (eg V600E), contributes to the pathology of the disease and/or symptom. In a fifth aspect, the invention provides a compound of formula I, an N-oxide derivative thereof, a prodrug derivative, a protected derivative, an individual isomer and a mixture of isomers, and a pharmaceutically acceptable compound thereof The method of salt. [Embodiment] The "alkyl group" which is a structural group and a structural component of another group (e.g., a halogen-substituted alkyl group and an alkoxy group) may be a straight chain or a branched chain. The ci4 alkoxy group includes a methoxy group, an ethoxy group, and the like. The C^-4 alkyl group substituted with a _ group means an alkyl group (branched chain or unbranched chain) in which any hydrogen may be substituted by halogen. For example, a halo group substituted (: 丨·4 alkyl group may be a trifluoromethyl group, a di II ethyl group, a pentacene ethyl group, and the like. Similarly, a Cw alkyl group substituted by a thiol group Any alkyl group (branched chain or unbranched chain) in which a hydrogen may be substituted by a hydroxyl group. For example, a hydrazine substituted with a hydroxy group "alkyl group includes a 2-hydroxyethyl group and the like. Similarly, a cyano group is substituted. The C1·6 alkyl group means any hospital group (branched or unbranched chain) in which a hydrogen can be substituted by a cyano group. "Aryl" means a monocyclic or fused bicyclic aromatic ring containing 6 to 10 ring carbon atoms in the stomach. Ring assembly ^ For example, the aryl group may be a phenyl group or a naphthyl group, preferably a phenyl group. "Extylene group" means a divalent group derived from an aryl group. 150205.doc 201209050 Cycloalkyl group Meaning, means containing a finger; a full or < or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic collection of t ring atoms. For example, 〇3.1〇cycloalkyl includes cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, etc. Oral "heteroaryl" as defined above for aryl, wherein one or more ring members are heteroatoms. For example ' Aryl includes pyridyl, indolyl, oxazolyl, quinoxalinyl, quinolyl, benzofuranyl, benzopiperidyl 'benzoguanadinyl, stupid [1,3] Oxafluoro, mesyl, benzimidazolyl, pyrimidinyl, furyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc. "Based" means a cycloalkyl group as defined in the present application, with the proviso that one or more of the specified ring carbons are selected from the group consisting of _〇_, _NR_, C(O)-, -s-, -s( Partial substitution of 0)- or -s(0)2- (wherein R is hydrogen, Cy alkyl or nitrogen protecting group). For example, the C3.8 heterocyclic ring used in the present application to describe the compound of the present invention The alkyl group includes 2H-Nan Nyenyl, 4Η-β-endanyl, decyl, 1,4-dioxin, morphine, 4, 4-dithiazide, Ν-thiomorpholinyl, Imidazolidin-2-one, tetrahydrofuranyl, piperazinyl, 1,3-tritithialidylpyrrolidinyl, pyrrolidinyl-2-one, piperidinyl, piperidinyl, 1,4- Dioxa-8-aza-spiro[4 5]癸_8_yl, etc. "_" (or halo) means chlorine, fluorine, bromine or iodine. MEK means phosphorylation of Mek. "pERK" means phosphorylated ERK. "Treatment" means a method of alleviating or alleviating a disease and/or its accompanying symptoms. The compound of the present invention is Chemdraw Ultra (l 〇.〇 version) And/or 150205.doc 201209050

The ChemAxon name generator (JChem 5 3) version is named. DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides compounds, compositions, and methods for treating kinase-associated diseases, particularly B_Raf kinase-associated diseases; for example, metastatic melanoma, solid tumors, brain tumors (such as glioblastoma multiforme (GBM)) ) 'Acute myeloablative white disease (AML), prostate cancer, stomach cancer, papillary thyroid cancer, low ovarian cancer and colorectal cancer. In a consistent embodiment, 'with respect to the compound of formula I, Ri is selected from _x and -X丨NHC(0)OR8b; wherein each X丨 is independently c丨-4 alkyl; and the work is up to 3 Hydrogen is optionally substituted with a group selected from the group consisting of a hydroxyl group, a mercapto group, a cyano group, a Ci 4 alkyl group, and a halogen-substituted C!·4 alkyl group; wherein R8a and R8b are independently selected from hydrogen and C!-6. The burning base is limited to the case that when it is _XiNHC(〇)〇R8b, R8b is not hydrogen. In another embodiment, a compound of formula la is provided:

Wherein: Y is selected from N and CR6; R2, R3, 5 and 6 are independently selected from the group consisting of hydrogen, from a base, a cyano group, a Ci_4 alkyl group, a halogen-substituted cN4 alkyl group, and a c14 daid*oxy group. And a C 1 ·4 alkoxy group substituted by a halogen group; the limitation is that when R 5 is a gas and R 1 is selected from the group consisting of hydrogen, -XlR8a, -Xl〇X2R8a, -XlNR8aX2R8b, _XlNR8aC(0)X2〇R8b and - XjNRsaSi^O). .:!^ 150205.doc 201209050 Department 3 R6 is not gas at the same time; R4 is selected from HNRi〇R"; where I has '(10) base, k ring base, cv8 heterocyclic alkyl, aryl and hetero-aromatic S Or a aryl group or a heteroaryl group of R9 in the case of (1) C, ▲ group independently selected from the group consisting of a dentate group, a cyano group, a C14 alkyl group, and a fluorenyl group. a CW oxy group and a group substituted with a cyano substituted Ci4 oxime; and R10 and R11 are independently selected from hydrogen and R9; and the ～ is selected from the group consisting of hydrogen, Cw alkyl, C3·5 cycloalkyl and C3·5 heterocycloalkyl; wherein the alkyl, bad alkyl or heterocycloalkyl group of I is optionally cleaved to 3 independently selected from halo, cyano, hydroxy, Ci.4 alkyl' a substituted Ci4 alkyl group, a ci4 alkoxy group, and a group substituted with a (:-4 alkoxy group). In another embodiment, 'R4 is -R9; wherein R9 is selected from C|.3 An alkyl group and a c3.8 ring-based group wherein the alkyl or cycloalkyl group of Rg is optionally substituted with 1 to 3 groups independently selected from the i group and the Cm alkyl group substituted with a functional group. In the examples, 'R2 is selected from the group consisting of hydrogen and fluorine; R3 is selected from the group consisting of gas, fluorine and methyl; and R5 is selected from hydrogen, And fluorine; Y is selected from N and CR6; and R6 is selected from hydrogen and deficient. In another embodiment, a compound selected from the group consisting of N-[(2S)-1-({4-[3- (3-Ga-5-methanesulfonylaminophenyl)-1-(propan-2-yl)-111-.pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl Ammonium carbamate; 1^-[(28)-1-[(4-{3-[2-fluoro_3-(propan-1-sulfonylamino)phenyl]-1-(propyl) 2-yl)-1仏.Bistazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl]carbamic acid methyl ester; >^-[(23)-b ({4- [3-(2-Fluoro-3-decanesulfonylaminophenyl)-1-(propan-2-yl)-1Η-.Bizozol-4-yl]σ-mididin-2-yl}amino "propan-2-yl]carbamic acid formazan; N-[(2S)_l-[(4-{3-[3-chloro-5-(propan-1-sulfonylamino)phenyl) ((propyl-2-yl)-1Η·°bazole-150205.doc 201209050 4-yl}pyrimidin-2-yl)amino]propyl,2-yl]amino decanoate;:^-[( 23)-1-({4-[3-(2,6-difluoro-3-methanesulfonylamino)-1-(propan-2-yl)-1 Η-pyrazol-4-yl Pyrimidine-2-yl}amino)propan-2-yl]amino decanoate; N-[(2S)-1-[(4-{3-[2,6-difluoro-3-() Propane-1-sulfonylamino)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidine-2-yl)amine Methyl]propan-2-yl]carbamic acid methyl ester; N-[(2S)-l-{[4-(3-{2-fluoro-3-[(3,3,3-trifluoropropane)] Amidino]phenylphenyl 1-(propan-2-yl)-1Η-. Bisazo-4-yl)pyrimidin-2-yl]amino}propan-2-yl]carbamic acid guanidine vinegar; N-[(2S)-l-({4-[3-(3-gas-2) -decanesulfonylaminopyridin-4-yl)-1-(propan-2-yl)·1Η-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]amino N-decyl decanoate; N-[(2S)-l-({4-[3-(3-fluoro-2-decanesulfonylamino)pyridin-4-yl)-prop (propan-2-yl) )-ΐΗ-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl] carbamic acid decyl ester, N-[(2S)-l-({4-[3-(2 - gas-3-ethanesulfonylamino-4,5-difluorophenyl)-1-(propan-2-yl)-iH-pyrazol-4-yl]pyrimidin-2-yl}amino) Propyl-2-yl]amino decanoate; difluoro_3_nonanesulfonylaminophenyl)-1-(propan-2-yl)·1Η_Πbazole_4_yl]pyrimidine_2• Ethyl)amino-2-yl]amino decanoate; + ^(prop-2-enyl)_3_(2,4,5-trifluoro-3-methanesulfonylamino)_1H_D ratio Oxazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]amino decanoate; -decanesulfonylaminophenyl)-1-(propan-2-yl)_1H-pyridyl Oxyl]pyrimidin-2-yl}amino)propan-2-yl]amino decanoate; N_[(2S) small ({4·[3_(3_ethanesulfonylamino-2,4) -difluorophenyl)····(Cet_2_yl)_111_pyrazole_4_ ] pyrimidine_2-yl}amino)propan-2-yl]amino decanoic acid A _ ; Ν·[(28)_2({4·[3_(5 备2_气_3_ 曱烷增和amp;k Fe-phenyl) small (propylidene)---- 吼 _ 4 _ _ ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) N N N N N N N N N N N N [3-(5-gas·2-gas-3-150205.doc -10· 201209050 methanesulfonylaminophenyl)-1-(oxacyclohexane-2-yl)-iH-pyrazole-4 Methyl-pyrimidin-2-yl}amino)propan-2-yl]carbamic acid methyl ester; n-[(2S)-1-[(4-{3-[2,4-difluoro-3- (propane-1-sulfonylamino)phenyl]_丨_(propan-2-yl)-iH-.biazole-4-yl}pyrimidin-2-yl)amino]propan-2-yl]amine N-[(2S)-1-({4-[3-(3-cyclopropanesulfonylamino)-2,5-difluorophenyl)-1-(propan-2-yl) Η-1Η-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]amino decanoate; N-[(28)-1-({4-[3-( 5-Chloro-3-cyclopropene calcination 醯amino-2-fluorophenyl)-1-(propan-2-yl)-1 Η-pyrazol-4-yl]pyrimidin-2-yl}amino)propyl 2-yl]carbamic acid oxime ester; and N-[(2S)-l-[(4-{3-[5-gas-2-fluoro-3-(propan-1-sulfonylamino)) -1-]-1-(propan-2-yl)-1Η-pyrazol-4-yl}pyrimidin-2-yl)amino]propyl-2-yl]amino decanoate . In another embodiment, a compound of formula lb is provided:

Wherein: R3 is selected from the group consisting of chlorine, fluorine and sulfhydryl; R5 is selected from the group consisting of fluorine and chlorine; and R7 is selected from the group consisting of ethyl and isopropyl. In another embodiment, a compound selected from the group consisting of N-[(2S)-; l-({4-[3-(5-chloro-2-fluoro-3-decanesulfonamidophenyl) is provided )-1-(propan-2-yl)-1 Η-pyrazol-4-yl]pyrimidin-2-yl}amino)propyl-2-yl]amino decanoic acid methyl ester; N-[(2S)- L-({4-[3-(2,5-Difluoro-3-methanesulfonylaminophenyl)-1-(propan-2-yl)-1Η-150205.doc -11 - 201209050 » than saliva 4-yl]pyrimidin-2-yl}amino)propan-2-yl]amino decanoate; gas-2-fluoro-3-methanesulfonylaminophenyl)·ι·ethyl·1Η -°~嗤-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamic acid methyl ester; Ν_ [(28)-1-({4-[3-(2-fluoro-) 3-methanesulfonylamino-5-methylphenyl)-1-(propan-2-yl)-1Η-η-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl Ammonium carbamate; N-[(2S)-l-({4-[3-(2- gas-3-decanesulfonylamino-5-methylphenyl)-1-(propyl-) 2-yl)-1Η-pyrazol-4-yl]pyrimidin-2-yl}amino)propyl-2-yl]amino decanoate; N-[(2S)-l-({4-[ 3-(2-chloro-5-fluoro-3-methanesulfonylaminophenyl)-1-(propan-2-ylpyrazol-4-yl)pyrimidin-2-yl}amino)propan-2- Amino group oxicilin, N-[(2R)-l-({4-[3-(5-gas-2-gas-) 3-Axyl phthalocyanine-1-(propan-2-yl)·ιη-° 嗤-4-yl]pyridin-2-yl}amino)propan-2-yl]amino N-decyl decanoate; N-[(2S)-l-({4-[3-(2,5-diox-3-methanesulfonylaminophenyl)-1-(propan-2-yl) than saliva Methyl 4-mercapto-2-yl}amino)propan-2-yl]carbamic acid methyl ester; and N-[(2S)-l-({4-[3-(5-gas-2) -Fluoro-3-methane-nonylaminophenyl)-1Η-°bizozol-4-yl]pyrimidin-2-yl}amino)propyl-2-yl]amino decanoic acid methyl ester. In another embodiment In the 'providing' a compound selected from the group consisting of N-[5-gas-3-(4-{2-[(2-cyanoethyl)amino]D-Midine_4-yl}-1_(C) 2_基比.Sodium-3-yl)-2-fluorophenyl]-methyl decylamine; N-{5-gas·3-[4-(2-{[2-(didecylamino)) Ethyl]amino} 啸-4-yl)-1-(propan-2-yl)-indole-. ratio. sit-3-yl]-2-fluorophenyl}decanesulfonamide; (5-Chloro-2-fluoro-3-{4-[2-(decylamino).Midine-4-yl]-1-(propan-2-yl)-1Η-pyrazol-3-yl } phenyl) decane decylamine; and Ν-{3-[4-(2-amino group. Bite-4-yl)-1-(propan-2-yl)_ιη-° ratio 0--3-yl]-5-chloro-2-fluorophenyl}decanesulfonamide. 150205.doc • 12· 201209050 In another embodiment, a compound selected from the examples and tables below is provided. In another embodiment, an intermediate compound selected from the group consisting of 3 bromo-5-chloro-2-fluoroaniline; cyano-(2-methylthio-pyrimidin-4-yl)-acetic acid tert-butyl ester; -isopropyl-4-(2-(methylthio)). _4_base ratio salicin-3-amine; 2-((2-benzylidene-1-ethylindenyl)methylene )_ malononitrile; 丨兴弘amino-丨isopropyl-1H-pyrazol-4-yl)ethanone; 1-(3-iodo.iisopropyl-1H_pyrazole_4_yl) Ethyl ketone; 1-(3-iodo-1-ethyl-1H-pyrazol-4-yl)ethanone; ^(i-iodo-indole-indolyl-1H-pyrazol-4-yl)ethanone; -(dimethylamino)isopropyl-1H-pyrazol-4-yl)prop-2-en-1-one; 3-(dimethylaminobisindole(I)-iodoethyl-1H-pyrazole_ 4_yl)prop-2-ene-fluorenone; 3-(dimethylamino) small (3 iodine-1-yl-1H-pyrazol-4-yl)prop-2-ene-i-ketone ;'(, iodine)·isopropyl*_1H_pyrazol-4-yl)pyrimidine-2-amine; 4-(3_iodo-indole-ethyl_1H-pyrazole-4-yl)pyrimidine-2-amine ; 4-(3-峨-1-mercapto-1H-. 嗤_4_yl) 0-pyridine 2_amine; 4 (3_A-1-1-isopropyl-1H-pyrazole-4- Pyrimidine alcohol; 2_chloro_4_(3iodoisopropyl-1HK4-carbimate; (s)_i_(4_(3_breaking small isopropyl_m. than saliva) 4- 4-ylpyrimidin-2-ylamino)propan-2-ylaminocarbazate; er-1-isopropyl-1 Η-吼. -4-yl).密 _2 _ _2 _2 _2 _2 旨 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ( ( ( ( ( ( ( ( ( ( ( ( ( ( T-butyl phenylamino)propan-2-ylamino decanoate; 3_(4_(3_iodo_1_isopropyl_1Η_. than sal-4-yl). -ylamino)propionitrile; 4_(3_Moth small isopropyl_ιη 口 azole I base)-Ν-methylpyrimidin-2-amine; Νΐ-(4_(3•破小isopropyl_1Η ·吼吐-4-基)^定-2-基μα dimethylethene^diamine; Ν·(3• desert·2,4-difluorophenyl)propane-1-sulfonamide; 3_ Fluorine heart iodopyridine-2-amine; 3_gas-150205.doc -13· 201209050 4-iodopyridin-2-amine; 3-bromo-2,5,6-trifluoromoutamine; 2,4· Dibromo-3,6-di-aniline; 3-bromo-2-a-methylaniline; 3-bromo-2,5-difluoroaniline; 3-bromo-5-chloro-2-fluorobenzoic acid ; 3_bromo-5-chloro-2-furoylamino decanoic acid tert-butyl S; 3-dimethyl-2-fluoro-5-methylphenylamino decanoic acid tert-butyl ester; 5-chloro _2_Fluorate 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)phenylaminopyruic acid tert-butyl vinegar; 2,6- Difluoro_3_(4,4,5,5-tetramethyldioxaboron-2-yl)phenylaminopyruic acid tert-butyl ester; Ν-(2,4-difluoro-3-(4) , 4, 5, 5 - four Base-1,3,2-dioxosin-2-yl)phenyl)propane_methanesulfonamide; 2_(2_fluoro_3_nitrophenyl)-4,4,5,5· Tetramethylidene-1,3,2-dioxaboron; 2,5-difluoro-3-(4,4,5,5-tetradecyl-^-dioxaboron-2-yl)aniline ; 2 chlorine _5 fluorine, 3_ (4,4,5,5-tetradecyl), 3,2_dioxaborate _2 yl) aniline; 2,5_two gas" _ (4,4' 5,5·tetradecyl-1,3,2-dioxaboronic-2-yl)aniline; 2-chloro-5-methyl-3-(4'4'5'5-tetramethyl], 3,2_dioxaboron-2-yl)aniline; 2_fluoro-5-methyl-3_(4,4'5'5-tetramethyl-1,3,2-dioxaboron-2- Phenylamino phthalic acid, second butyl ester, 3_fluoro-4·(4,4,5,5·tetramethyl-1,3,2-dioxaboroin-2-yl)pyro 2-amine; 2,3,6_three gas_5_(4,4,5,5_tetradecyldioxy-2-_2

2-yl) aniline. -tetramethyl-1,3,2-dioxaboron-2-yl)pyridyltetramethyl-1,3,2-dioxaboroin-2-yl)benzene-methyl_5-(4 , 4,5,5-tetramethyl-1,3,2-dioxaborazole _ The present invention also includes the compound of the present invention or its medicinal all suitable homotopic woven fabric a*. ~ _ ....

But the atomic mass and the naturally acceptable salt. The compound of the present invention or a pharmaceutically acceptable meaning thereof is a sub-performer of at least one atom having a different atomic mass as generally seen in the same atomic sequence. 150205.doc •14-201209050 Sub-substitution. Examples of isotopes which may be incorporated into the compounds of the invention and their pharmaceutically acceptable salts include, but are not limited to, hydrogen, carbon, nitrogen and oxygen: such as 2h, 3h, HC, %, 14c, 15n , 17〇, 18〇, , 18F, 36C1 and (1)! . Certain isotopic variations of the compounds of the invention and their pharmaceutically acceptable salts, e.g., those having a radioisotope (e.g., 3 thief %), are suitable for drug and/or matrix tissue distribution studies. In a particular example, 3H and "C isotope can be made by its ease of preparation and detectability: in other instances, substitution with an isotope (such as 2h) may provide some treatment due to higher metabolic stability. Such as in vivo + prolonged life or reduced dosage requirements. Isotopic variants of a compound of the invention or a pharmaceutically acceptable salt thereof can generally be prepared by conventional procedures using suitable isotopic variants of suitable reagents. In addition to enhancing MEK and ERK signaling in wild-type B_Raf cells, the agents also induce cell growth in cancer cell lines and promote fibroblast transformation and growth. Induction of downstream signaling has previously been attributed to the disclosed Raf pathway feedback loop. However, induction of pMEK and pERK can be performed within a few minutes of treatment with the Raf inhibitor, even before the reported feedback scalarization event was observed on B_Raf& c_Raf. Induction of signaling and cell growth were performed in a two-phase mode with low compounds The concentration (〇〇1〇1 μΜ) produced the maximum induction' and the higher compound concentration (1_1〇pM) produced less strong induction. The pattern was also observed in the biochemical assay of purified wild-type B_Raf or c_Raf and indicates a mechanism involved in the interaction of the two signaling subunits. In addition, Raf dimerization upregulates pMEK, which is not via the Raf molecule. Phosphorylation is achieved, and may be achieved by the activation of the 150205.doc •15·201209050 conformation of the kinase. Consistent with the model, the Raf inhibitor treatment induces the formation of B-Raf/C-Raf dimers in cells. Knockout of A-Raf or B-Raf by siRNA does not abolish the induction of ρΜΕκ and pERK by Raf inhibitors, and knocking out C-Raf only slightly reduces this induction. It is worth noting that knockout K-Ras mutants The K_Ras in the cells also only slightly reduced the induction, and the darkness was not mainly mediated by Ras. In summary, the data proposed the following model: Inhibition of binding to a Raf molecule induces dimerization and dimerization with Raf Molecular conformational activation. This explains why wild-type Raf and mutant Ras tumors are not sensitive to selective Raf kinase inhibitors and may also be importantly associated with indolence because of the induction of strong mitogenic signals. Leading to hyperplasia of normal tissues, understanding the mechanism of induction of Raf inhibitors can design improved inhibitors. The combination of MEK inhibitors and Raf inhibitors significantly inhibits erk signaling and thus reduces cell proliferation and transformation. Inhibitor treatment has produced dose-limiting toxicity in the clinic, so the combination of a Raf inhibitor and a MEK inhibitor may represent an excellent therapeutic strategy. The invention also includes combinations of the agents disclosed in the present invention with other agents. The present invention provides a combination with a MEK1/2 inhibitor. Figure 1 illustrates that the addition of a MEK small molecule inhibitor reverses the ERK signaling, cell growth and transformation induced by the Raf small molecule inhibitor. For example, |, style! Compound (Compound 9 of the present invention, that is, (8)_1 (4(3_(5 gas·2•Fluronium (methyl s-amino)phenyl) isopropyl isopropyl group 1HH4_ benzylamino) propyl- 2-methylaminocarbamic acid methyl acetate) can induce cell proliferation, such as the use of sw (tetra) cells for (10) (10) G 丨. The negative inhibition observed. γ 150205.doc -16 - 201209050 Axis shows negative inhibition and positive inhibition夂普1 ^ Each test is shown in 9 serial dilution series between 10 μΜ and 0.002 μΜ. Compound αι(ν_(an methyl Kb (6-(4-methylpiperazine-bupropamine)_ 4_base-flavor. Sit. 2_base (four) stupid)-3-(trimethylmethyl)benzamide as a control, Aumek inhibitor (PD0325901). In the absence and in You彳Λι隹 and presence! Test compound 9 in the case of μΜ, 〇1 μΜ and 〇〇ι ΜΕΚ inhibitor A3. Pharmacology and utility The compounds of the invention modulate kinase activity and are therefore suitable for treating the pathologies and/or symptoms of kinase-promoting diseases. Disease or condition. A case in which the compounds and compositions described herein are inhibited and the methods described herein are applicable to antagonistic kinases include (but Not limited to) B-Raf, including mutant forms of B-Raf. The mitogen-activated protein kinase (ΜΑρκ) pathway mediates the activity of a number of effector molecules that synergistically control cell proliferation, survival, differentiation, and migration. Factor, cytokine, or hormone-stimulated cells allow plasma membrane-associated Ras to bind to GTP, thereby allowing activation to recruit Raf. This interaction induces the kinase activity of Raf, allowing MApK/ERK (MEK) to directly acidify, thereby allowing extracellular signals. Related kinase (ERK) phosphorylation. Activated ERK subsequently phosphorylates a number of effector molecules (eg, kinases, bonitoses, transcription factors, and cytoskeletal proteins). Thus, the Ras_Raf_MEK-ERK f-Lu conduction pathway directs cells from the cell surface The receptor is transmitted to the nucleus and is required for example for cell proliferation and survival. The regulation of this signaling cascade is dominated by multiple isoforms of Ras (including K-Ras, N-Ras and H-Ras), Raf A variety of isoforms (A_Raf, B-Raf, c-Raf/Raf-1), a variety of isoforms (meK-1 and MEK-2) and ERK are the same as 150205.doc 17 201209050 The forms (ERK-1 and ERK-2) are further enhanced. Because human cancers with ι〇_2〇〇/0 have oncogenic Ras mutations' and many human cancers have activated growth factor receptors, this pathway is ideal for intervention. Header.

The basic role and location of Raf in the §5 multi-k conduction pathway has been confirmed by studies using dysregulated and dominant inhibitory mutants in mammalian cells and by biochemical and genetic techniques in model organisms. In the past, the focus on the anti-tumor drug target Raf has focused on its function as a downstream effector of Ras. However, recent findings suggest that Raf may have a prominent role in certain tumor formation without the need for a carcinogenic Ras dual gene. In particular, the activation duality of B-Raf and N-Ras has been identified in approximately 70% melanoma, 40% papillary squamous adenocarcinoma, 3% ovarian low cancer, and 10% colorectal cancer. About 90% of visceral cancers have K-Ras mutations. Most B-Raf mutations were found to be within the kinase domain where a single substitution (V600E) accounted for at least 80°/. . The mutated B-Raf protein activates the Raf-MEK-ERK pathway via higher kinase activity on MEK or via activation of C-Raf. Therefore, 'development of B-Raf kinase inhibitors is the treatment of many types of human cancers', especially metastatic melanoma, solid tumors, brain tumors (such as glioblastoma multiforme (GBM)), acute myeloid leukemia (AML). , lung cancer, papillary squamous adenocarcinoma, ovarian low cancer and colorectal cancer provide new treatment opportunities. Several Raf kinase inhibitors have been described to exhibit the efficacy of inhibiting tumor cell proliferation in vitro and/or in vivo assays (see, e.g., U.S. Patent Nos. 6,391,636, 6,358,932, 6,037,136, 5,717,100 No. 6,458,813, 6,204,467 and 6,268,391). Other patents and patent applications teach the use of a Raf kinase inhibitor 150205.doc 18 · 201209050 formulation for the treatment of leukemia (see, for example, U.S. Patent Nos. 6,268,391, 6,204,467, 6,756,410 and 6,281,193; And the treatment of breast cancer (see, for example, U.S. Patent Nos. 6,358,932, 5,717,100, 6,458,813, 6,268,391, 6,204,467 and 6,9 11,446). The data demonstrate that kinase inhibitors significantly inhibit signaling via the MAPK pathway, resulting in a significant reduction in B-Raf (V600E) tumors. The compounds of the invention inhibit the cellular processes involved in B Raf kinase by blocking the signaling cascade in such cancer cells and ultimately inducing cell arrest and/or death. According to the foregoing, the present invention further provides a method for preventing or treating diseases of the present invention: lung cancer, prostate cancer, gastric cancer 'pancreatic cancer, bladder cancer, colon cancer 'bone marrow disease 'prostate cancer' thyroid cancer, melanoma, adenoma, and Carcinoma of the ovary, eyes, liver, biliary tract and nervous system. Further, the present invention further provides a method for preventing or treating the above-mentioned diseases or conditions of an individual in need of such treatment. The method comprises administering to the individual a therapeutic effect (see "Administration and Pharmaceutical Composition" below)! A compound or a pharmaceutically acceptable salt thereof. For any of the above uses, the desired dose will vary depending on the mode of the music, the particular condition being treated, and the desired effect. Administration and Pharmaceutical Compositions The compounds of the present invention will be administered in a therapeutically effective amount, either alone or in combination with -or or more, in any of the commonly used and accepted modes known in the art. Severity of the disease, individual 150205.doc 201209050 Age and relative health, pan-variation. In general, the efficacy of the compound and other factors, and the dose of the systemic dose of kilograms (four) about 0.03 mg to the results of two or seven people in a mammal (such as humans). Within the scope of larger feeding, it is preferred to administer, for example, two doses per day at a dose of about 〇5 to about 2,000. Suitable for oral administration / four divided doses or in delayed form, the unit dosage form contains from about 1 mg to 500 mg of active ingredient. The compound of the present invention can be administered by any conventional means, in particular, by intestinal administration, and also, 如, j, such as! The mouth is administered, e.g., in the form of a lozenge or capsule, in the form of a buccal suspension of the injectable solution; for example, in the form of a lotion, gel, ointment or cream or in the form of a nasal or suppository. Pharmaceutical compositions comprising a compound of the invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent may be prepared by mixing, granulating or coating methods in a conventional manner Manufacturing. For example, the oral composition can be a key or gelatin capsule containing the active ingredient and a) a diluent such as lactose, dextrose, inexpensive sugar, mannost, sorbitol, cellulose and/or glycine Acid; b) Lubricant, such as dioxide, talc, stearic acid, its lock salt or about salt and/or polyethylene glycol; for the bond 'also contains c) binder, such as magnesium alumite! Lv, powder paste, gelatin, yellow gum, methyl cellulose, methine cellulose and/or polyethyl benzophanate; if necessary, containing disintegrators, such as starch, agar, alginic acid Or a salt thereof, or a foaming mixture; and /4e) an adsorbent, a coloring agent, a flavoring agent, and a sweet and injectable composition, which may be an aqueous isotonic solution or suspension, and the suppository may be a monthly emulsion or suspension. Liquid preparation. The compositions may be sterilized by 150205.doc -20·201209050 and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solution promoters, salts for regulating osmotic pressure, and/or buffers. In addition, it may also contain other therapeutically valuable substances. For example, the compounds of the invention may be formulated as a microemulsion preconcentrate (MEPC). formula! The compound was made up to 40 mg/ml in a mixture of 56% pEG4 〇〇, 29% ethoxylated EL (cremophor EL) and 15% oleic acid. The compound of the free formula is first prepared by vortexing/shocking. The compound of the present invention is added and the powder is dispersed into the vehicle using sonication. The mixture was heated with stirring in a water bath for about 1 hour, and sonicated every 15 minutes. This mixture was physically and chemically stable for about 1 week at room temperature. Formulations suitable for transdermal administration comprise an effective amount of a compound of the invention and a carrier. The carrier can include a pharmacologically acceptable absorbable solvent to aid passage through the skin of the subject. By way of example, the transdermal device is in the form of a bandage comprising a substrate 7L, a reservoir containing the compound and optionally a carrier, optionally delivered to the compound at a controlled and predetermined rate over a longer period of time. The rate of skin of the subject controls the barrier and the means for fastening the device to the skin. A matrix transdermal formulation can also be used. Formulations suitable for topical administration (e. g., to the skin and the eye) are preferably aqueous solutions, ointments, creams or gels well known in the art. These formulations may contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives. The compounds of the invention may be administered in a therapeutically effective amount in combination (pharmaceutical combination) with one or more therapeutic agents. For example, it may have a synergistic effect with other anti-tumor agents or anti-proliferative agents such as filament 150205.doc 21 201209050 cleavage inhibitor 'burning agent, antimetabolite, embedded Antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response regulation, sputum, antibodies, cytotoxins, anti-hormones, antiandrogens, anti-angiogenic agents, kinase inhibitors, pan A kinase inhibitor or growth factor inhibitor. The compounds of the present invention can be administered in a therapeutically effective amount in combination with - or a plurality of suitable excipients selected from the group consisting of corn starch, potato starch, tapioca starch, temple flour, pregelatinized starch, sugar, gelatin, natural gum, Synthetic gum, sodium alginate, alginic acid, tragacanth, guar gum, cellulose, sulfhydryl cellulose, cellulose acetate, m methyl fiber (IV) sodium 1-methylcellulose, thioglycolic acid, transpropyl Cellulose, microcrystalline cellulose, stone less acid, and polyethylene. Compared with singly ketone, talc, carbonic acid, powdered cellulose, dextrate, kaolin, mannitol, linalic acid, sorbitan, carbonic acid sodium, croscarmellose Sodium, spovidone, polacrilin potassium, hard-to-base sodium, clay, sodium stearate, calcium stearate, magnesium stearate, stearic acid, minerals Oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, hydrogenated vegetable oil, chemical oil, cottonseed oil, sunflower oil, sesame oil, olive oil, Corn oil, soybean oil, zinc hard laurate, sodium oleate, ethyl oleate, ethyl laurate, cerium oxide, and combinations thereof. An embodiment of the invention is the method of claim 12 or 13, which additionally comprises administering to the individual another therapeutic agent, the additional therapeutic agent comprising an anticancer drug, a pain drug, an antiemetic agent, an antidepressant or an anti-inflammatory agent. In addition, the additional therapeutic agent 150205.doc -22- 201209050 is a different Raf kinase inhibitor, or an inhibitor of ΜΕΚ, mTOR, HSP90, ΑΚΤ, ΡΙ3Κ, CDK9, ΡΑΚ, protein kinase C, MAP kinase, ΜΑΡΚ kinase or ERK. And administered to the individual in parallel with the compounds of the invention. For example, the addition of a combination of a MEK inhibitor and a Raf inhibitor significantly inhibits ERK signaling and thus reduces cell proliferation and transformation. Because treatment with MEK inhibitor alone has produced dose-limiting toxicity in the clinic, the combination of a Raf inhibitor and a MEK inhibitor represents an excellent therapeutic strategy. Examples of MEK inhibitors are AS703026 (EMD Serono), MSC1936369B (EMD Serono), GSK1120212 (GlaxoSmithKline), AZD6244 (Memorial Sloan-Kettering Cancer Center) 'PD-0325901 (Pfizer) ' ARRY-438 162 (Array BioPharma) ' RDEA119 (Ardea Biosciences, Inc.), GDC0941 (Genentech), GDC0973 (Genentech), TAK-733 (Millennium Pharmaceuticals, Inc.), R05126766 (Hoffmann-La Roche), and XL-518 (Exelixis). In another embodiment of the present invention, there is provided a combination and method for treating cancer comprising a therapeutically effective amount of a compound of the [invention] (Raf inhibitor) and at least one MEK protein kinase inhibitor. When the compound of the present invention is administered in combination with other therapies, the dose of the compound to be administered will of course vary depending on the type of co-drug used, the particular drug used, the condition to be treated, and the like. The invention also provides a pharmaceutical combination (e.g., kit) comprising: a) a first agent, which is a compound of the invention as disclosed herein, in free form or in a pharmaceutically acceptable salt form, and b) at least A coagent. The kit can contain instructions for its administration. 150205.doc -23- 201209050 The terms "co-administered" or "combined administration" or similar terms as used herein are intended to encompass the administration of a selected therapeutic agent to a single patient, and the inclusion of such agents may not necessarily be administered via the same route of administration. Or a treatment plan that is administered at the same time. The term "pharmaceutical combination" as used herein means a product obtained by mixing or combining the above active ingredients, and includes a fixed combination and a non-fixed combination of the active ingredients. The term "fixed combination" means that the active ingredient (e.g., a compound of the formula ~) and the auxiliary agent are administered to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredient (eg, a phantom compound) and the co-agent are administered to the patient simultaneously, in parallel, or sequentially (without a specific time limit) in the form of separate entities. The drug is administered to the patient in a therapeutically effective manner. Two compounds. The latter is also suitable for cocktail therapy, for example, administration of three or more active ingredients. Methods of Making Compounds of the Invention The invention also includes methods of preparing the compounds of the invention. In the reaction, it may be necessary to protect reactive functional groups (e.g., hydroxyl, amine, imido, thio or thiol, which are required in the final product) to avoid undesirably participating in the reaction. Conventional protecting groups can be used according to standard specifications, for example, see T. W. Greene and P. G. M. Wuts, "Protective Groups m Organic Chemistry", John Wiley and Sons, 1991. The compound of formula I can be prepared by carrying out the following reaction scheme j: I50205.doc •24·201209050 Reaction Scheme 1

R3

义 'P is a suitable protecting group (such as MEM, MOM, SEM, R4S〇2 and the like) and M is a leaving group (such as chlorine, bromine, moth, decyloxy, p-toluene) a decyloxy group and the like). The protecting group P can be removed by a compound of formula 2 (for example, when P is MEM, MOM or SEM, by treatment with a strong acid such as hydrogenated hydrogen in the presence of a protic solvent such as methanol or water) or when P In the case of a radix R4S〇2, the compound of formula I is synthesized by treatment with an aqueous solution of sodium carbonate or carbonic acid or a solution of decyl alcohol, optionally in the presence of a cosolvent such as hydrazine. It can be prepared by reacting a compound of formula 3 with an alkylating agent of formula 4 in the presence of a suitable solvent such as DMF, DMSO, and the like, and a suitable base such as potassium carbonate, sodium hydride, and the like. Compound of formula 2. The reaction is carried out at a temperature ranging from about 〇 ° C to about 150 ° C and can be completed in about 24 hours. The reaction mixture was further reacted as appropriate to remove any protection 150205.doc -25·201209050 base. The compound of formula 1 can also be prepared by carrying out the following reaction scheme II: Reaction Scheme 11

(5) R7 r4so2ci (6)

Wherein R, R2, R3, r4, 5 and Y are as defined in [Summary of the Invention]. By using a suitable base (for example, pyridine, triethylamine, 4-(N,N-didecylamino)pyridine and the like) and a suitable solvent (such as pyridine, dichlorodecane, 2-methyltetrahydrofuran) The compound of formula I is synthesized by reacting a compound of formula 5 with a reagent of formula 6 in the presence of an analog thereof. The reaction is carried out at a temperature ranging from about 〇〇c to about 100 C' and can be carried out for up to about 24 hours. The reaction mixture is further reacted as appropriate to remove any protecting groups. In some cases, the sulfonation reagent can be reacted twice to produce a bis-indolyl derivative. In this case, a suitable base (for example, sodium hydroxide or potassium hydroxide) can be used in the presence of a co-solvent such as toluene or 2-mercaptotetrahydrofuran in the presence of a protic solvent such as methanol or water. , or sodium carbonate or potassium carbonate) to convert the double-branched compound into a compound of formula a. The reaction is carried out at a temperature in the range of from about 20 ° C to about 100 ° C and can be completed in about 24 hours. The compound of formula I can also be prepared by carrying out the following reaction scheme III: 150205.doc -26- 201209050 Reaction Scheme m

R4 .... , ... V Gan" found the factory, IV50 is the leaving group (such as 峨, 、, preparation _ ^, 'milk, difluoro sulfonium sulfonyloxy and its similar earth mass) each R can be, for example, hydrogen, methyl And a similar group, or two r, groups may be attached to form a cyclic folate. Two R9. The groups may each be hydrogen' or two R9. The group - can represent a suitable nitrogen protecting group (e.g., one R9 〇 can be hydrogen and the other - R90 can be B0C). By suitable transition metal catalysts (such as bismuth (triphenylphosphine) palladium (0) or Pdc 丨 2 (dppf)), suitable solvents (such as DME, diming m, ethanol and the like) and suitable The compound of formula Ia is synthesized by reacting a compound of formula 7 with a compound of formula 8 in the presence of a base such as anhydrous potassium carbonate or aqueous sodium carbonate and the like. The reaction is carried out at a temperature in the range of from about 20 C to about 120 C and can take up to 150205.doc -27-201209050 for up to about 24 hours to complete. The reaction mixture is further reacted as appropriate to remove any protecting groups. The compound of formula ι can also be prepared by a Suzuki reacti scheme in which a compound of formula 7 is reacted with a hydrazine compound to give a compound of formula 9. After removal of the protecting group of the R% group (sulfonylation reaction as described for Reaction Scheme II), the compound of formula 13 is obtained. Those skilled in the art will appreciate that it is also possible to use alternative organometallic coupling reactions such as the use of tin reagents (StUle coupling) or zinc reagents (Negishi coupling) instead of the reaction scheme. Suzuki coupling reaction using a boron reagent. The compound of formula 7 can also be prepared by carrying out the following reaction scheme IV:

Reaction Scheme IV

F^NHz (1〇)

In this case, ruthenium is a leaving group (eg, gas, moth, moth, acetaminophen, and the like). Rso is a leaving group (eg, iodine, bromine, gas, trifluoromethane%) An oxy group and the like, and R7 is as defined in [Summary of the Invention]. The compound of the formula 7 can be produced by reacting an amine compound of the formula 10 with a compound of the formula 11. The reaction is carried out in a solvent such as isopropanol, DMSO, NMP or dioxane at a temperature of from about 251 to about 120 ° C in the presence of a suitable base such as triethylamine, potassium carbonate and the like. Go on. In some cases, the newly introduced h group can then be further converted to obtain the final desired & 150205.doc • 28 · 201209050 group. The formula ν of the compound as a subgroup of the compound of the formula 11 (wherein the scutellite yellow base) can be prepared by carrying out the following reaction scheme V:

Reaction process V

Wherein R? and Rso are as defined in [Summary of the Invention]. The compound of formula 12 can be reacted with a suitable oxidizing system (e.g., a solution of m-chloroperbenzoic acid in dichlorohydrazine in a solvent, or hydrazine XOneTM in an aqueous solution of decyl alcohol) at a temperature of from about -78 ° C to about 50 ° C. The solution of the solution and its analog) are reacted to prepare a compound of formula 11a. The reaction took up to about 24 hours to complete. Further, by combining the amine compound of the formula 13 with a suitable diazonium reagent system (for example, a nitrite complex copper (I) salt; isoamyl nitrite in combination with copper (I) iodide/diiodomethane; The compound of formula 12 (wherein R50 is chlorine, bromine or iodine) is prepared by reacting isoamyl nitrate with boron trifluoride, iodine and potassium iodide in acetonitrile; and analogs thereof. The reaction is carried out at a temperature of from about 〇 ° C to about 8 ° C and takes about 1 hour to about 6 hours to complete. 150205.doc 29· 201209050 A compound of formula η can be prepared by reacting a compound of formula U with a compound of formula 3, as described for Reaction Scheme I. Formula 25 can be prepared by hydrating the enamine nitrile compound of formula 15 with a hydrazine or hydrazine salt in a suitable solvent such as a brain such as ethanol and the like. (: At a temperature of about 峨, the initial reaction is carried out under the dish, and it can take about 1 hour to about 24 hours to complete. Or 'can be taken care of by the compound of formula 15 and the mono-substituted 2 Reaction The compound of formula 13 is prepared from the compound of formula 15 in a step-by-step procedure. The anti-reservoir is carried out at a temperature of from about KG to about _ and can take from about i to about 24 hours to complete. From the thief to a temperature of about 15 generations, the compound of formula 16 is reacted with dmf dma or Bredereck's reagent (Bredereck, s reagent) in the presence of a cosolvent such as DMF to prepare a hydrazine compound. The preparation is carried out from about 1 hour to about 24 hours. The mouth can be prepared by treating a compound of formula 17 with a suitable acid such as p-toluenesulfonic acid and the like in a suitable inert solvent such as toluene and the like. The compound of formula 16. The reaction is carried out at a temperature of from about 5 ° C to about 12 ° C and takes about 1 hour to about 24 hours to complete. Finally ' can be at about 25 〇 to about 8 (TC) At the temperature, in a suitable base (such as sodium hydride and its analogs) and a suitable solvent ( The compound of formula 17 is prepared by reacting 4-vapor-2-(methylthio)pyrimidine with t-butyl cyanoacetate in the presence of DMSq and its analogs. The reaction takes from about 1 hour to about 24 hours. The compound of formula llb, which is a subgroup of the compound of formula 11 (wherein ruthenium is self-priming), can be prepared by performing the following reaction scheme νι 150205.doc 30·201209050

Reaction Process VI

NT (21) R7 wherein R7 and Rso are as defined in [Summary of the Invention]. The compound of formula 1b can be prepared by reacting a compound of formula 2 with a suitable diazonium reagent system (eg, nitrous acid combined with a copper (1) salt; nitrous sodium I in combination with phthalic acid and potassium telluride). Where Μ is halogen). The reaction is carried out at a temperature of from about 〇〇c to about 8 (rc) and takes about 丨hours to about 6 hours to complete. Alternatively, at 〇.〇直〇4〇°C, in a carboxylic acid (such as trifluoro The compound of formula 2 is treated with a diazotization reagent (such as sodium nitrite and the like) in the presence of acetic acid and its analogs for about 5 hours to about 6 hours; followed by a (tetra) aqueous solution (such as potassium carbonate aqueous solution and the like). Treatment) to give compounds of formula 21 (such compounds may be interconverted 150205.doc • 31 · 201209050 in the form of a structure). Subsequently at temperatures of from about 50 ° C to about 110 ° C, as appropriate, such as N, N- The compound of formula 2 is treated with a chlorinating agent (such as phosphorus oxychloride and the like) in the presence of a base of decyl phenylamine or DIPEA, and optionally in the presence of an inert solvent such as acetonitrile or toluene and an additive such as DMF. From 1 hour to about 72 hours, a compound of formula 1 lb (wherein hydrazine is chlorine) is obtained. Further, it can be tested by a temperature of from about 50 ° C to about 180 ° C, such as lithium hydroxide and the like. In the presence of a suitable solvent (eg, second butanol, NMP, and In the analog), a compound of the formula 22 is prepared by reacting a compound of the formula 22 with a hydrazine or a hydrazine salt (for example, guanidine hydrochloride or cesium carbonate) for about 2 hours to about 48 hours. It can be prepared at about 5 (TC to about 15 (TC). The compound of formula 23 is prepared by reacting a compound of formula 23 with dmf DMA or a Bradney's reagent in the presence of a cosolvent such as DMF, as appropriate. The reaction takes about 1 hour to about 24 hours to complete. By combining the amine compound of formula 24 with a suitable diazonium reagent system (eg, 'nitrous acid combined with copper (I) salt; sodium nitrite in combination with stupid acid and potassium hydride; or isopropyl nitrite The ester is combined with the trifluorinated side _THF, angstrom, anion and acetonitrile to prepare a compound of the formula 23 (wherein Rw is chlorine, bromine or angstrom). The reaction is carried out at a temperature of from about 〇t to about 80 ° C, And it takes about 1 hour to about 6 hours to complete. Further 'in an inert solvent such as thf, acetamidine or cyclopropyl methyl ether at a temperature of from about 〇C to about 10 ° C, An organometallic test of a compound of formula 25 with a reagent such as a fluorenyl clock, a methyllithium-lithium bromide complex or a bismuthylmagnesium reagent The reaction is followed by treatment with a quenching aqueous solution to prepare a compound of formula 24, 150205.doc-32-201209050. The reaction takes about 2 hours to about 48 hours to complete. The compound of formula 26 can be reacted with a compound of formula 3 Preparation of a compound of formula 25 as described for Reaction Scheme I. Alternatively, an acid labile protecting group (e.g., an imine such as a phenylhydrazine group; or an amine decanoic acid) may be formed from a compound of formula 27 wherein two R' groups together An ester, such as a third butyl decanoate)) to prepare a compound of formula 25. The reaction is carried out by using an acidic aqueous reagent in a solvent such as ethanol at a temperature of from about 25 Å to about 10,000 Å. The compound of formula 27 is treated with (e.g., concentrated hydrochloric acid and the like). Preferably, the two R" groups together form an imine such as a phenylarylene group. Further, by forming a compound of formula 28 with a compound of formula 29 (wherein two r' groups form an acid labile protecting group (eg, an imine such as a benzylidene group; or a urethane such as an amide) The third butyl ester)) is reacted to prepare a compound of formula 27. The reaction is carried out at a temperature of from about 25 ° C to about 12 Torr, optionally in the presence of a catalyst such as DMAP, in a solvent such as toluene, methanol or ethanol. In progress, and takes about 丨 hours to about 24 hours to complete. The reaction is in the presence of a temperature of about -80 C to about 25 ° C, in the presence of (for example, n-butyl and its analogs) The lower step is carried out in an inert solvent such as THF and the like for about 0.5 hours to about 12 hours.

150205.doc -33- 201209050 Amine). The 弋8 compound or the compound of formula 8a can be prepared as described in Reaction Scheme VII below.

Reaction Scheme VII r3 r2

Nh2 (51)

(50) 〇R’ (8)

Wherein R 2 , R 3 , R 4 , 5 and 5 are as defined in the Summary of the Invention, and M is a leaving group (for example, iodine, bromine, gas, trifluorodecanesulfonyloxy and the like), and each R 'Can be, for example, hydrogen, a thiol group, and the like, or two R groups, which can be joined together to form a cyclic folate. The two R9 indenyl groups may each be hydrogen, or the two R9 indenyl groups together may represent a suitable nitrogen protecting group (e.g., one R9G may be hydrogen and the other R% may be BOC). It can be in a suitable solvent (such as toluene, dioxane and the like) in the presence of a suitable transition metal catalyzed ruthenium (e.g., PdCl2 (dppf)) and a suitable assay (e.g., potassium acetate and the like). A compound of formula 8 or a compound of formula 8a is prepared by reacting a compound of formula 50 or a compound of formula 5a with a diboron compound, such as bis(pinacolyl)diboron and the like, respectively. The reaction is carried out at a temperature of from about 2 (rc to about ι 2 (Γ:, and can take up to about 24 hours to complete. Again, the compound of formula 513 can be made as described for Reaction Scheme II) Sulfonated to prepare a compound of formula 5. 150205.doc -34· 201209050 Those skilled in the art will recognize that a compound of formula 51 or a compound of formula 50a (eg, 3-bromoaniline or N-BOC protected 3-bromoaniline). It can be prepared by a variety of methods including, but not limited to, the methods further described in the following examples. The compound of formula 70 can be prepared as described in Reaction Scheme VIII below: Reaction Scheme V111 h2n 丫, Rss OH (74) 0 R55 (73)

Rab^°YKi>^N3 -- R8, 〇YN 丫, h2 O R55 0 R55 (71) (10) wherein Ru is as defined in [Summary], and r55 is selected from C 4 alkyl or C substituted by a dentate group! · 4 alkyl. Can be used at about 25. The compound of formula 71 is treated with a suitable reduction system (e.g., hydrogenation over a palladium catalyst and the like) in a suitable solvent (e.g., ethanol or ethyl acetate) at a temperature of from 3 to about 75 ° C for about 0.5 hours to about The compound of formula 7 is prepared in 12 hours. Further, the compound of formula 71 is prepared by a two-step process consisting of converting the hydroxyl group of the compound of formula 73 to a suitable leaving group, followed by replacement with an azide anion. Steps, suitable reagents include phosphorus tribromide or a combination of decanoic acid chloride and a suitable test such as triethylamine. These reactions are in a suitable solvent from about 〇t to a force of 50 C. In the case of (for example, methylene chloride and the like), the substitution in the second step is at about 25. To a temperature of about 1 50T: suitable for less than seven 丨 / / 丨, h, The agent (for example, DMF or DMS0) is ordered with an azide reagent (for example, sodium azide and complex t/ /, W member). The reaction takes about 丨 to about 24 hours to complete. ^ ^者' conversion can be mistaken by hydrazoic acid (by azide salt (150205.doc -35- 201209050 such as azide Treatment of Formula 73 with a phosphine reagent (eg, triphenylphosphine and its analogs) and an azodicarboxylate reagent (eg, diethyl arsenate and its analogs) in the presence of sodium and acid. The compound is carried out in one step. The reaction is carried out at a temperature of from about -80 C to about 75 ° C and takes about 1 hour to about 24 hours to complete. It can be obtained by using a phthalic acid ester such as valerate and The compound of formula 73 is prepared by treating the compound of formula 74 with an alternative azoxylated hydrolytic reagent such as di-tert-butyl diacetate. The reaction is at a temperature of from about -8 (rc to about 25 〇c). It is carried out in an inert solvent (for example, dioxane and the like) and takes about 1 hour to about 12 hours to complete. A base such as diethylamine may be used as the reaction may be carried out at about 25°. At a temperature of C, it is carried out in a two-phase system consisting of a solvent such as THF or dioxane and an aqueous alkaline solution such as an aqueous solution of sodium hydrogencarbonate for about 2 hours to about 16 hours. The reaction scheme is prepared as follows:

Reaction Scheme IX

56 (76) η2ν (77) : 8b-°

R8,0

Nh2 (?5) p〇) wherein RSb is as defined in [Summary of the Invention], R55 is selected from a Ci4 alkyl group or a substituted alkyl group, and R56 is a suitable protecting group (for example, a stupidyloxy Ik group ( CBz)). The compound of the formula can be prepared by removing the protecting group of the compound of formula 75. For example, 'at a temperature of from about 25t to about 75<>, I50205.doc -36-201209050, optionally in the presence of an acid such as a hydrogenated hydrogen, in a suitable solvent (e.g., ethanol, decyl alcohol) The compound of formula 70 is prepared by treating a compound of formula 75 (wherein Cbz) for about 0.5 hours to about 12 hours with a suitable reduction system (e.g., hydrogenation over a palladium catalyst and similar systems) in MTBE or ethyl acetate. Alternatively, the removal of the sulfhydryl group can be carried out using a suitable hydrogen donor such as citric acid, citric acid or 1,4-3⁄4 hexadiene under transfer hydrogenation conditions. Further, the preparation can be carried out by reacting a compound of the formula with a chloroformate such as methyl phthalate and the like or an alternative alkoxycarbonylating agent such as di-t-butyl dicaprate. 75 compounds. The reaction is carried out in an inert solvent (e.g., dioxane methane and the like) at a temperature of from about -8 (rc to about 25 Torr) and takes about 1 hour to complete for 24 hours. Test, such as triethylamine. The reaction can also be carried out in a two (four) system consisting of a solvent (such as THF or dioxane) and an aqueous alkaline solution (such as aqueous sodium hydrogencarbonate) at a temperature of about 25 ° C. 2 J is seized to about 16 small-days. The protecting group can be prepared by removing the protecting group of the compound of formula 7 to select the protective conditions to preferentially or substantially obtain the mono-isomer of formula 76. The following conditions may be selected: it is shown that the mono-isomer of formula 77 is rarely preferentially or preferentially formed, such that the compound of formula 76 can still be separated in sufficient purity for further use. The manner in which the purity can be obtained can include the free base, Or salt crystallization. The compound of the formula % can be prepared by treating the compound of the formula 77 with a gas formic acid " (in the bean, R(R) is Cbz). The reaction is in the range of about -80 ° C to about 25 ° C. The predicate π _ and 'in' in the October agent (such as the two gas brothel and its analogues) And it takes about time, ^ ^ ^ ^ ^ 八J 芏, completed in 24 hours. It is possible to use a base such as triethylamine. The reaction of the female and the reaction can also be at about 25. (: at the temperature, by solvent (such as THF or - decane, decyl w, decane-cathene) is carried out in a two-phase system consisting of an aqueous alkaline solution (such as carbonic acid I50205.doc • 37·201209050 hydrogen hydride water) for about 2 hours to about 24 hours. A salt of a compound of formula 77 can be used in combination with a test such as triethylamine or sodium carbonate as a substitute for the free test. It will be understood by those skilled in the art that the compound of formula 70 can be a single enantiomer or enantiomer. The single enantiomer compound of the formula (9)' and the formula 7 can be obtained by using the appropriate single enantiomeric compound of the formula 74 or the formula 77 as a starting material. Detailed examples of the compound of the formula la can be found in the examples below. Other methods of preparing the compounds of the present invention can be prepared as pharmaceutically acceptable acid addition salts by reacting the free base form of the compound of the present invention with a pharmaceutically acceptable inorganic or organic acid. Alternatively, by making the invention The free acid form of the compound is reacted with a pharmaceutically acceptable inorganic or organic base to prepare a pharmaceutically acceptable base addition salt of the compound. Alternatively, the starting material or a salt of the intermediate may be used to prepare the present invention. Salt forms of the compounds. The free acid or free base forms of the compounds of the invention may be prepared separately from the corresponding addition salt or acid addition salt form. For example, by using a suitable base (eg, a solution of hydrogen, hydrogen) Treatment of the compound of the invention in the form of an acid addition salt with a sodium oxide and the like) can be converted to the corresponding free base by conversion of the compound of the invention in an addition salt form by treatment with an acid such as hydrochloric acid or the like. The corresponding free acid can be obtained by using a suitable inert organic solvent (for example, acetonitrile, ethanol, or two at 0 to 80 ° C). A reducing agent (for example, 150205.doc -38-201209050 sulfur, sulfur dioxide, diphenylphosphine, lithium borohydride, sodium borohydride, chlorinated pentachloride, three deserts or the like) The compound of the invention in a non-oxidized form is prepared from the ice oxide of the compound of the invention. Methods known to those of ordinary skill in the art (for example, for more details, see Saulnier et al. (1994), Bi〇organic and Medicinal Chemistry

Letters, Vol. 4, p. 1985) Preparation of prodrug derivatives of the compounds of the invention. For example, it can be suitably prepared by reacting a non-derivatized compound of the invention with a suitable amine sulfonating agent such as a decyloxyalkyl carbazate, a p-nitro ester or an analog thereof. Prodrug. Protected organisms of the compounds of the invention can be prepared in a manner known to those of ordinary skill in the art. A detailed description of techniques applicable to the generation and removal of protecting groups can be found in T. W. Greene, "Protecting Groups in 〇rganic Chemistry", 3rd edition, J〇hnWUeyands〇ns, inc i999. It is preferred in the process of the invention to prepare or form a compound of the invention in the form of a solvate (e.g., hydrate). The hydrate of the compound of the present invention is preferably prepared by recrystallization from an aqueous/organic solvent mixture using an organic solvent such as 1,4-oxaxahexane (4) (10) (4), tetrahydrod-f- or decyl alcohol. / vibratable by reacting a racemic mixture of a compound of the invention with an optically active resolving agent to form a diastereomeric compound, isolating the diastereomers and recovering the optically pure enantiomer to prepare individual A compound of the invention in stereoisomeric form. While enantiomeric resolution can be carried out using covalent diastereomeric derivatives of the compounds of the invention, the cleavable complex is preferred (e.g., crystalline diastereomeric salt). Diastereomers have unique physical properties (e.g., refining point, boiling point, solubility, reactivity, etc.) and can be readily separated by these differences by the benefit of 150205.doc -39.201209050. The diastereomers can be separated on the basis of solubility differences by chromatography or preferably by separation/analysis techniques. The optically pure enantiomer and the resolving agent are then recovered by any practical means which does not produce racemization. A more detailed description of techniques suitable for the resolution of stereoisomers of compounds from their racemic mixtures can be found in Jean Jaeques, Andre CoUet, S_el Η. Wilen, "E_ti〇mers, Racem_ _

Resolutions, John Wiley And S0ns, inc., 1981. In general, a compound of formula I can be prepared by a process involving: (a) a process of Reactions I to IX; and (b) converting a compound of the invention into a pharmaceutically acceptable salt, as appropriate; (c) optionally Conversion of the salt form of the compound of the invention to the non-salt form; (d) conversion of the non-oxidized form of the compound of the invention to a pharmaceutically acceptable N-oxide, as appropriate; (e) an oxide of the compound of the invention, as appropriate Converting the form to its non-oxidized form; (f) optionally interrogating individual isomers (eg, stereoisomers) of the compounds of the invention from a mixture of isomers; (g) optionally converting a non-derivatized compound of the invention A pharmaceutically acceptable prodrug derivative; and (h) optionally converting a prodrug derivative of the compound of the invention to its non-derivatized form. Where the preparation of the starting materials is not specifically described, the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the following examples 150205.doc • 40-201209050. Those skilled in the art will appreciate that the above transformations are merely representative of the methods of preparing the compounds of the present invention, and that other well known methods can be similarly employed. EXAMPLES The present invention is intended to illustrate the formula of the present invention! The following intermediates and examples of the preparation of the compounds are further exemplified by, but not limited to, such intermediates and examples. The abbreviations used are as follows: benzyloxy number (Cbz); third butoxycarbonyl (BOC); cell proliferation (CP); dichlorohydrazine (DCM); n, N-diisopropylethylamine (DIPEA) ; [ΐ, ι·_ bis(diphenylphosphino)ferrocene] digas palladium (II) (PdCl 2 (dppf)); ι, 2-dimethoxy ethane (DME); Ν, Ν _ Dimercaptoacetamide (DMA); hydrazine, hydrazine-didecylamino. Specific bite (DMAP); hydrazine, hydrazine-dimethyl decylamine (DMF); hydrazine, hydrazine-dimethyl decyl dimethyl acetal (Dmf DMA); dimethyl sulfoxide (DMSO); Ester (EtOAc); high pressure liquid chromatography (HPLC); isopropyl acetate (ipr〇Ac); methanesulfonyl (Ms); 2-mercaptotetrahydrooxo (2-mercaptoTHF); N - 曱基. Pilotone (NMP); tetrahydrofuran (THF); thin layer chromatography (TLC); and p-toluene (pTsOH). Intermediate: cyano-(2-methylthiocarbamate-4-yl)-acetic acid tert-butyl vinegar

To a suspension of sodium hydride (7.15 g, 179 mmol, 60% in oil) in DMSO (100 mL) was added <RTI ID=0.0>> After the evolution of hydrogen ceased, 4-chloro-2-methylthio 0S bit (13.7 g, 85 mmol) was added. The reactants were heated at 80 ° C for 16 small 150205.doc -41 - 201209050. The reaction mixture was then cooled to room temperature & was quenched with ice cold saturated EtOAc (300 mL). The solid was filtered and washed with water (2×200 mL). 300 mL of hexane was added to the solid, and the suspension was heated at 60 ° C for 1 hour, followed by cooling to room temperature. The solid was filtered and washed with EtOAc afforded title title: EtOAc: EtOAc: EtOAc: EtOAc (s, 9H); MS m/z: 266.0 (M+l). Intermediate: (2-indolethio-pyrimidin-4-yl)-acetonitrile

Add to the solution of the intermediate cyano-(2-methylthio-D-dimethyl-4-yl)-acetic acid tert-butyl (5.3 g, 20 mmol) in anhydrous benzene (100 mL) Benzoic acid (800 mg). The mixture was heated to reflux for 8 hours, cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with aq. The crude product was purified by EtOAc (EtOAc EtOAc (EtOAc) ), 2.57 (ί, 3Η) ; MS m/z: 166.0 (Μ+1). Intermediate: 4-(2-(indolyl) shouting. -4-yl)-1 H-° ratio jun-3-amine

Step 1: 3-(Dimethylamino)-2-(2-(methylthio)pyrimidin-4-yl)acrylonitrile. To the intermediate (2-indolyl-pyrimidin-4-yl)-acetonitrile (2 62 g, 15 7 mmol) was added dimethyl decylamine decyl acetal (30 mL) at 150205. • 42- 201209050 1 Heat the mixture for 16 hours at 〇〇 °C. The cooled reaction mixture was concentrated and the residue was used without further purification. Step 2: 4-(2-(indolyl)-Minidine-4-yl ratio. Raw-3-amine. At 80 °c, 'the crude 3-(didecylamino) of the previous step- A mixture of 2-(2-(indolyl)pyrimidin-4-yl)acrylonitrile (total amount) and hydrazine monohydrate (2.36 mL, 47 mmol) in dry ethanol (75 ml). The reaction mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. The crude product was purified using a methane solution as a solvent to give 4-(2-(indolyl)pyrimidin-4-yl)-1 -pyrazol-3-amine: !H NMR 400 MHz (DMSO-d6) δ 11.9 (s, 1Η), 8.3 (s, 1H), 7.87 (s, 1H), 7.23 (s, br 1H), 6.43 (s, 1H), 5.74 (s, 1H), 2.53 ($,3H) ; MS m/z: 208.0 (M+l). Intermediate: 1-isopropyl-4-(2-(indolyl)pyrimidin-4-yl)-1 -pyrazol-3-amine

The intermediate 4-(2-(methylthio)pyrimidin-4-yl)-1 Η-pyrazol-3-amine (10.0 g, 40 mmol) was dissolved in THF (200 mL). (6.3 mL, 63 mmol) and sodium decylate (25 wt. / hydrazine solution, in decyl alcohol, 14.3 ml '63 mmol). The mixture was heated at 50 ° C under a nitrogen atmosphere for 3 days, followed by concentration under vacuum. The residue was dissolved in EtOAc (EtOAc)EtOAcEtOAcEtOAc For the residue 150205.doc • 43· 201209050

Lithium chromatography (hexane/ethyl acetate as a dissolving agent) gave 1-isopropyl-4-(2-(indolyl)pyrimidin-4-yl)_1H-pyrazole-3- as a solid. Amine;]H NMR 400 MHz (CDC13) δ 8.23 (d, J=5.6 Hz, 1H), 7.60 (s, lH), 6.83 (d, J = 5.6 Hz, lH), 5.23 (d, J = 2.8 Hz) , 2H), 4.21-4.25 (m, 1H), 2.50 (s, 3H), 1.37 (d, J = 6.8 Hz, 6H); MS w/z: 250.1 (M+l). Similarly prepared 1-ethyl-4-(2-(methylthio)pyrimidin-4-yl)-1Η-pyrazol-3-amine and 1-mercapto-4-(2-(methylthio)) Bite _4_base) _lH-° than saliva-3-amine. Intermediate: 4-(3-iodo-1-isopropyl-m-pyrazol-4-yl)-2-(methylthio)pyrimidine

'Intermediate isopropyl thiolthio)pyrimidin-4-yl)-1 Η-pyrazole-3-amine (4. 〇g, 16.0 mmol), isoamyl nitrite (132 g) at 100 °C A mixture of 112 mmol) and diiododecane (3 〇 mL) was heated for 3 hours. The volatiles were removed in vacuo to give abr. EtOAc (md. ). Similarly prepared 4-(3-iodo-1 _ethyl-1H-. than salivyl-4-yl)·2_(thiol) stilbene; 4_(3_iododecyl-1Η-pyrazole-4- )-(methylthio)pyrimidine; and 4_(3_fill-1H-°boxazol-4-yl)-2-(methylthio)" Intermediate: 4-〇-Moth small... Hydrogen 31·Panol I base) Η Η 比 比 冬 冬 冬 冬 2- 2- 2- 2- 2- 2- 2- 2-.定150205.doc -44- 201209050

4-(3-Magido-1H-pyrazol-4-yl)-2-(indolylthio) was added at 60 °C. dense. A solution of (270 mg, 0.85 mmol) and p-toluenesulfonic acid monohydrate (32 mg, 〇 17 mmol) in 3,4 - s. The cooled mixture was diluted with ethyl acetate and the mixture was washed with water and brine then filtered and concentrated. The residue was chromatographed (10% ethyl acetate in hexanes) to afford the title compound. MS (m/z): 402.7 (M+1). Intermediate: 4-(3-Moth-1-isopropyl-1H-pyran-4-yl)-2-(indolyl sulphate)

To the intermediate 4-(3-iodo-1-isopropyl-iH-pyrazol-4-yl)-2-(indolylthio) is dense at 〇 °C. To a solution of (4.51 g' 12.5 mmol) in dioxane (60 mL) was added m-hexanes (3 65 g, 77 〇 / 〇 purity, 16 3 mmol). The mixture was stirred at 0&lt;0&gt;C under N2 for 3 h then diluted with ethyl acetate and washed with aqueous potassium carbonate and brine. The organic layer was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; MS w/z: 393.0 (M+1). Similarly prepared 4-(3-iodo-1-ethyl-1H-pyrazole-4-yl)-2-(methylsulfonate 150205.doc -45· 201209050 yl)pyrimidine; and 4-(3-iodine) -1, mercapto·1H_pyrazole·4_yl)_2_(methylsulfonyl)

Intermediate: 1-Benzindenyl-2-indolyl hydrazine Add isopropyl to a round bottom flask containing anhydrous sodium acetate (8.2 g, 〇.1 m〇l) in 125 ml of 50% ethanol. Base hydrazine hydrochloride (U1 g, m〇1) and phenylfurfural (10.6 g, 0.1 mol). The mixture was stirred at room temperature for 2 hours. The reaction was extracted with diethyl ether (3 x 250 mL). The organic layers were combined, washed with aqueous sodium bi hydrogen carbonate and brine and dried over sodium sulfate. Filtration, concentration and co-evaporation with benzene (3X) afforded the title compound. Ms m/z 163.3 (M+1). Using oxalic acid ethyl hydrazine as starting material, phenylarhenyl-2-ethyl hydrazine was prepared similarly by using decyl alcohol and triethylamine instead of ethanol and sodium acetate respectively; and methyl hydrazine was used as a starting material. The decyl alcohol was used as a solvent, and 1-benzylidene-2-ylidene oxime was similarly prepared without addition. Intermediate · 2-((2-Phenylfluorenyl-1-isopropylindenyl)methylene)-malononitrile

丫〒N

Ph^N^^^CN The solution of the intermediate 1 phenyl behenyl-2-isopropyl hydrazine (12.9 g' 0.079 mol) in 200 ml of anhydrous THF was cooled in a dry ice/acetone bath under an argon atmosphere. . To the solution was added n-butyllithium (1 6 M in hexane, &lt;66 m, 0.106 mol) via a syringe. After the addition was completed, the mixture was further stirred at a dry ice temperature for 5 minutes. A solution of 2-(ethoxymethylene)malononitrile (丨3 6 150205.doc • 46·201209050 iF (30 ml) was added. The ethyl acetate was extracted with a saturated aqueous solution of sodium chloride at dry ice. Stirring at dry ice temperature

The reaction mixture was collected by filtration, collected with a small amount of cold ethyl alcohol and washed with a small amount of cold ethyl alcohol, and a mixture of 0.5% of the mixture in thF (30 ml) was suspended in ethanol. 2_((2_benzylidenemethyl)propanenitrile in the form of a yellow solid was obtained by passing the oxime value. The mother liquor was concentrated and the solid was 2-((2-phenylene) Base i · isopropyl fluorenyl) subconcentrate mother liquor and chromatographic column chromatography (1: hexane / keto-1-isopropyl fluorenyl) methylene) malononitrile intermediate · 2- ((2-Benzylidene-1-ethyl acetate) as a dissolving agent) to purify the residue to obtain another benzoic acid

Alkyl-1-ethylindenyl)methylenemalononitrile

Add 2-(ethoxymethylene)malononitrile (152 g' 〇124 m〇1)Ki〇〇... Add the intermediate phenylarylene-2-ethyl hydrazine (184 g) to the bath , 0.124 mol). The mixture was allowed to stand at room temperature and a precipitate formed. The reaction mixture was further mixed for 16 hours. The sediment was collected on a filter and washed with a small amount of cold ethanol to give 2 - ((2 - </ RTI> <RTIgt; </ RTI> <RTIgt; </RTI> <RTIgt; 2-((2-Benzylmethyl-1-methylindenyl)-indenyl)malononitrile was similarly prepared. Intermediate .3 -Amino-l-isopropyl ratio. Sit-4-acetonitrile

150205.doc -47- 201209050 The intermediate 2_((2_benzylideneisopropyl)methylidene)malononitrile (9.42 g, 40 mm〇l), concentrated hydrochloric acid (5) A mixture of mi) and ethanol (5 〇 ml) was heated for 20 minutes. The reaction mixture was concentrated and diethyl ether (5 mL) was added. The mixture was sonicated and the upper ether layer was discarded. 20 ml of a 5 N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with dichloromethane (3 EtOAc). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) elute iH NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H)' 5.51 (s, 2 Η), 4.22 (m, 1H), 1.31 (d, J = 7 Hz, 6H); MS m/z 151.2 ( M+l). Similarly, 3-amino-1-ethyl-1H-pyrazole-4-indene nitrile was prepared; and 3-amino-1-indolyl-111-° ratio was taken. Intermediate. 1-(3-Amino-1-isopropyl-indole-indole ratio β-s--4-yl) ethyl ketone

Add bromine to a solution of the intermediate 3-amino-indole-isopropyl-1H_ (5.29 g, 36.5 mmol) in 200 ml of dry THF at 〇 ° C

The reaction mixture was heated under flowing for 4 hours. The mixture was cooled to 〇c&gt;c, followed by quenching with a 10% aqueous hydrochloric acid solution to reach a neutral pH. The reaction was extracted with a large amount of 9 _ 1 dioxane/isopropanol. The organic layers were combined and dried over sodium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography (1:1 ethyl acetate / hexanes to 9:1 EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc Title compound. 1H NMR (400 MHz, DMSO-dJ δ 8.18 (s, 1 Η), 5.62 (s, 2H), 4.23 (m, 1H), 2.20 (s, 3H), 1.37 (d, J = 7 Hz, 6H); MS w/z 168.2 (M+l). Similarly prepared 1-(3-amino-1-ethyl-iH-. than sal-4-yl)ethyl g; and 1-(3-amino) -1-mercapto-1H-. ratio. sit-4-yl) ethyl ketone. Intermediate: 1-(3-A-1-isopropyl-1H-. ratio. sit-4-yl) ethyl ketone

To the intermediate 1-(3-amino-i-isopropyl-1H-pyrazol-4-yl)acetamidine (3.97 g '24 mmol) and p-TsOH.H2O (9.07 g) at 〇 °C , 48 mmol, 2 eq.), sodium nitrite (2 97 g, 43 mmol, 1.8 eq.) and potassium iodide (8·〇g, 48 mmol, 2.0 eq.) in 20 ml of water were added dropwise in 150 ml of acetonitrile. Solution. The mixture was stirred at this temperature for 1 minute, then allowed to warm to room temperature and stirred for 3 hours. The mixture was concentrated, then diluted with water and neutralized to pH 9-1 with aqueous sodium carbonate. The mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with a sodium thiosulfate solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 4.53 (m, 1 Η), 2.37 (s, 3H), 1.41 (d, J = 7 Hz, 6H); MS m/z 279.1 ( M+1)° Preparation of 1-(3-Eth-1-ethyl-iH-n-pyran-4-yl)ethanone analogously; and i_(3_150205.doc -49-201209050 埃-1-曱 base -1 Η-° than β -4-yl) ethyl ketone. Intermediate: 3-(dimethylamino) 4-(3-iodo-1-isopropyl-1Η-pyrazol-4-yl)propan-2-en-1-one

The intermediate 1-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)ethanone (5.0 g' 18.0 mmol) and N,N-dimercaptoformamidine at 155 °C A mixture of the amine dimercaptoacetal (50 mL) was heated for 20 hours. The mixture was concentrated under vacuum to give the crude title compound. MS w/z 334.0 (M + 1). Similarly prepared 3-(didecylamino)-1-(3-iodo-1-ethyl-1H-pyrazol-4-yl)prop-2-en-1-one; and 3-(di) Amino)-1-(3-iodo-1-indenyl-1H-pyran-4-yl)propane-2 · 'thin-1 - steel. Intermediate · 4-(3-A-1-isopropyl-1H-. than 0--4-yl)-t-amine

At 11 ° ° C, under stirring, the crude intermediate (didecylamino)-1-(3-tao-1-isopropyl_ih-° is compared to salivary 4-base in a sealed reaction vessel ) propionate 2 - dilute 1-ketone (4.0 g, 12.0 mmol), guanidine hydrochloride (2.63 g, 27 6 mm 〇1), lithium oxychloride (63 5 mg, 27.6 mmol) and second butanol (5 〇) The mixture of ml) was heated for 20 hours. The cooled reaction mixture was concentrated, then water was added and the mixture was extracted with ethyl acetate. Drying the combined extracts with sulfuric acid steel, clearing 150205.doc •50- 201209050

(M+1) ° Ethyl ester, and the mixture was treated with ethyl acetate to wash the compound. MS m/2 3 3 0.0-pyrazol-4-yl)pyrimidine-2-amine; and similarly prepared 4-(3-iodo-1-ethyl-1H-pyrazole 4-(3-iodo-1- Mercapto-1H-pyrazole-4-yl)pyrimidine-2-amine intermediate: 4-(3-iodo-l-isopropyl-p-pyrazole-4-yl)pyrimidine-2-ol

To the intermediate 4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-amine (500 mg, 1.52 mm 〇i) and trifluoroacetic acid at 〇 ° C 15 μ) of the stirred mixture of δ was added in portions; s succinate (3 14 mg, 4.5 5 mm ο 1). The mixture was allowed to warm to room temperature and stirred for 1 hour, then the solvent was removed in vacuo. The crude mixture was diluted with EtOAc (EtOAc)EtOAc. MS m/z 331.0 (M+1) 〇 similarly prepared 4-(3-iodo-1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-ol; and 4-(3-iodo-1 -Methyl-1H-oxazol-4-yl)pyrimidin-2-ol. Intermediate: 2-Gas-4-(3-Moth-1-isopropyl-1Η-πΛβ--4-yl). dense. set

Intermediate U-(3-iodo-1-isopropyl-1Η-pyrazol-4-yl) 150205.doc -51 · 201209050 pyrimidin-2-ol (438 mg, 1_33 mmol) at U0 °C The solution in oxygenated phosphorus (1 〇 ml) was heated for 16 hours. The mixture was concentrated under vacuum, then aqueous sodium hydrogen sulfate was added carefully and mixture was extracted with ethyl acetate. The title compound was obtained as a yellow solid. MS m/z 349.0 (M+1). Similarly prepared 2-chloro-4-(3-moth-1-ethyl-1Η-α ratio η sit-4-yl) ring 〇&gt;; and 2-gas-4-(3-iodo-1- Mercapto-1Η-pyrazol-4-yl)pyrimidine. Intermediate. (S) -1 -Zhao Ke propan-2-ylamino citrate 〇 〇 /〇γΝν^〇Η 0 = at 〇 ° C, to (&lt;S)-alanine (10 g, 130 mmol) and sodium bicarbonate (32.8 g '390 mmol) in THF-H20 (1:1, 650 mL) were added dropwise EtOAc (11.4 mL, 143 mmol). The mixture was stirred and allowed to warm to room temperature over 4 hours, then extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc EtOAc. MS m/z 134.1 (M+1). Preparation of (and) -1-hydroxypropyl-2-ylcarbamic acid decyl ester using 〇R)-anilinol instead of (S)-alanamine; and using di-tert-butyl dicarbonate instead of decyl phthalate (S)-l-Hydroxypropan-2-ylaminodecanoic acid M-dimethylethyl ester was prepared analogously. Intermediate: (S)-l-azidopropan-2-ylaminocarbamate

丫n3 150205.doc ·52· 201209050 To the intermediate (S)-l-hydroxypropan-2-ylaminocarbazate (2.65 g, 20 mmol) and triethylamine (7 〇ml, 50 mmol) in anhydrous A solution of decanesulfonium (1·91 mL, 23·9 mmol) was added to a solution of methylene chloride (100 mL). The mixture was stirred at room temperature for 3 hr and then extracted with ethyl acetate. The organic layer was washed with a 1N aqueous solution of sodium chloride and brine, then dried over sodium sulfate, filtered and concentrated. The crude sulfonate product was then dissolved in dry DMF (70 mL) and sodium azide (5.2 g, 80 mmol) was added. The mixture was heated at 80 ° C for 2 hours under stirring. The cooled reaction mixture was concentrated and the residue was partitioned between ethyl acetate and brine. The organic layer was separated and washed with brine, dried over sodium sulfate < The residue was purified by silica gel chromatography (8: EtOAc/EtOAc) eluting to afford (s) s. MS w/z 159.1 (M+1). Similarly prepared (i?)-1-azidopropion-2-ylamino decanoic acid methyl ester; and (s) 1- 1-azidopropan-2-ylaminocarboxylic acid 1,i-difluorenyl Ethyl ester. Intermediate. (S)-l-Aminopropan-2-ylaminocarbamate

To a solution of the intermediate (S)-l-azidopropan-2-ylamino decanoate (2.86 g ' 18.2 mmol) in ethyl acetate (200 ml) was added 1 〇0 / 〇 palladium / Broken (wet, 286 mg). The flask was degassed and refilled with hydrogen (balloon, i atmosphere) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was passed through a pad of celite and washed with ethyl acetate. The filtrate was concentrated to give crude (s)-i-aminopropan-2-ylamino decanoic acid succinic acid, which was used without further purification. η NMR 400 MHz (CDC13) δ 4.79 (s, 1Η), 3.71-3.65 (m, 1H), 150205.doc -53- 201209050 3.66 (s, 3H), 2.75 (dd, 1H), 2.65 (dd, 1H), 1.14 (d, 3H); MS m/z 133.1 (M+l). Similarly prepared oxime of aminopropan-2-ylcarbamate; and (1,1-didecylethyl ester of phantom-l-aminopropan-2-ylaminocarbamate. Intermediate. (S)-l -(4-(3-峨-1-isopropyl-1H-0 is more than n--4-mercapto-2-ylamino)propan-2-ylamino decanoate

The intermediate 2-chloro-4-(3-iodo-1-isopropylindol-4-yl) was placed in a sealed vessel at 125 °C. dense. (1.4 g '4.01 mmol), (S)-l-aminopropyl-2-ylamino decanoate (0.8 g, 6 mmol) and triethylamine (2.8 ml, 20 mmol) in isopropanol The solution in (30 ml) and dioxane (20 mL) was heated for 48 hours. The cooled mixture was concentrated under vacuum, and aqueous sodium hydrogencarbonate was added to the residue. The mixture was extracted with EtOAc and dried over sodium sulfate. The crude residue was purified by EtOAc EtOAcjjjjjjj MS w/z 445.0 (M+1). Similarly prepared (R)-l-(4_(3 -A-1-isopropyl-1Η-11~°--4-yl)α-Bist _ 2 -ylamino)propan-2-ylamino (S)-l-(4-(3-Moth-1-isopropyl-1H-n-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylamine Tert-butyl carboxylic acid; 3-(4-(3-iodo-1-isopropylpyrazol-4-yl)pyrimidin-2-ylamino)propanenitrile; 4-(3-iodo-1-iso Propyl·1Η•pyrazol-4-yl)-indenyl-pyridylpyrimidine-2-amine; and Ν1-(4-(3•iodo-1-isopropyl-1Η-pyrazol-4-yl)pyrimidine -2-yl)-Ν2, Ν2-dimethyl 150205.doc -54- 201209050 乙院&gt; -1,2-diamine. Intermediate: N-(3-di-2,4-difluorophenyl)propan-1-rylate

3-bromo-2,4-difluoroaniline (4.16 g, 20 mmol, EP 184384), n-propyl sulphate (4.6 ml, 40 mmol), ° ° (8 ml) at room temperature A solution of DMAP (97 mg) and DCM (100 ml) was stirred for 16 hours. Aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a sodium hydrogencarbonate aqueous solution and brine. The crude product was purified by EtOAc (EtOAc:EtOAc) MS m/z 3 1 3.9 (M+1). Intermediate: 3-Fluoro-4-iodopyridin-2-amine

2-amino-3-fluoro-α ratio (io g, 8.9 mmol) was treated dropwise at -78 °C with n-butyl (ι_6 Μ, hexane, 13.9 ml, 22.3 mmol). A solution in anhydrous THF (40 ml). After the addition, the mixture was fed at -78 °C for 1 hour' followed by the addition of a solution of iodine (10.2 g, 40.1 mmol) in THF (20 ml). The mixture was extracted with ethyl acetate, and the organic extract was washed with sodium thio sulfate, sodium hydrogen carbonate and brine. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (8:1 to 2:1 hexanes/ethyl acetate as solvent) to afford the title compound. MS m/z 238.9 (M+1). 3-Ga4-iodopyridin-2-amine was prepared analogously. 150205.doc -55- 201209050 Intermediate: 3-bromo-2,5,6-trifluoroaniline

Add to the microwave tube! - Moist 2,3,4,5_tetrafluorobenzene (1. 〇 (2) and 28% chlorinated aqueous solution (5 mL). Heat the mixture under microwave irradiation for 2 hours at 150 °: then pour the mixture The title compound was obtained as a colorless liquid. iH NMR (400 MHz, CDC13) δ 6.75 (m ιΗ) 3.95 (br s, 2 Η) ppm ; MS m/z: 226, 228 (Μ+Η)+. Intermediate: 2,4·dibromo-3,6-dianiline

A mixture of 2,5-di-aniline (0.2 g), #-bromobutaneimide (0-48 g) and THF (20 mL) was stirred at room temperature for 2 hr. The solvent was removed and the residue was purified EtOAcjjjjjjjj MS m/z: 3 18 (M+H)+. Intermediate: 1,3-dibromo-2,5-dichlorobenzene

2,4-dibromo-3,6-dianiline (5.0 I50205.doc •56·201209050 g), tributyl phthalate (3 3 g) in a sealed tube at 5 °C The stirred mixture of Et 〇H (5 〇 mL) was heated for 2 hours. The mixture was concentrated and the residue was purified EtOAcjjjjjjjj Intermediate: 3-bromo-2-chloro-5-fluoroaniline

Br

Ηη2 Step 1: 3-Bromo-2-a-indole-(diphenylmethylene)_5-fluoroaniline. 2,6-dibromo-4-fluoro-1-chlorobenzene (865 mg, 3 mmol), benzophenone imine (0.61 ml, 3.6 mmol), Pd2 (dba) 3 at 8 (rc) a mixture of 137 mg, 0.15 mmol), sodium butoxide (432 mg, 45 mm (^), (s)_BINAp (28 mg, 0.45 mmol) and toluene (30 mi). The mixture was extracted and the combined organic phases were washed with brine. EtOAc EtOAcjjjjjjjjjjjjjjjjj The title compound is obtained as a powder.] VIS m/z 388.9 (Μ +1). Step 2: 3-bromo-2-chloro-5-fluoroaniline. 2 N hydrochloric acid (ΐ·5 ml, 1 equivalent The solution of 3-bromo-2-a-N-(diphenylmethylene)-5-fluoroaniline (1M in THF (20 ml) was taken and the mixture was stirred at room temperature for 2 hr. The mixture was extracted with EtOAc and EtOAc (EtOAc)EtOAc.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , get the fragrance _ j person a piece of A _ pollution of the title compound MS w/z 223.9 (M+1) 150205.doc •57_ 201209050 Methylbenzene is similarly prepared for 3-bromo-2,5-dianiline; 3-bromo-2·amin, and 3·&gt; Odor-2,5-di-gas amine.

Cl 3-bromo-2,5-di-aniline

3-wet-2-gas-5-mercaptoalkylamine, NH2 Cl

BrA Βγ j nh2 3-Oxo-2,5-difluoroaniline Intermediate: 3-bromo-5-chloro-2-fluorobenzoic acid

Add 2-bromo- dropwise to a solution of LDA in -78 ° C in THF (prepared from diisopropylamine (3 Μ w, 24 mmol) and n-BuLi (1.6 Μ '13_1 ml, 21 min〇i)) A solution of 4-gas-1-fluorobenzene (4.3 1 g, 20 mm 〇i). The mixture was stirred under _78 for 1 hour, then transferred slowly to a dry ice and THF (40 ml) at -78 °C. The mixture was stirred at -78 for 1 hour, then allowed to warm to room temperature (gas evolution was concentrated to a mixture, then treated with 50 ml of 1 N sodium hydroxide solution. The mixture was extracted with ethyl acetate (discarded). The aqueous layer was acidified with EtOAc (3 mL). Pollution. Title compound 3-,; odorous _5_chloro-2_1 benzoic acid 1h nmr: (400 MHz, CDC13) δ 7.93 (dd 1H 卜? R &lt;&lt; u, , IH, J-2.8, 5.6 Hz), 7.79 (dd, 1H, J=2.8, 5_6 Hz) ppm. Similarly prepared 3-bromo-2,6--1 芏田6,0-齓 carboxylic acid, and 3-bromo-2-fluoro _5-Mercaptobenzoic acid. 150205.doc -58- 201209050 Intermediate: 3-bromo-5-gas-2-fluorophenylcarbamic acid tert-butyl ester

Br,^Vf'NHBOC

F at a temperature of 110 ° C 'the crude intermediate 3-bromo-5-gas-2-fluorobenzoic acid (2.03 g, 8 mmol) - a base carbon sulfhydryl azide (2 · 〇 7 mL, 9.6 mmol , 1.2 eq.) and a solution of DIPEA (1_67 mL, 9.6 mmol, 1.2 eq.) in 1:1 third butanol / toluene (25 ml). The mixture was concentrated and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by EtOAc (EtOAc:EtOAc) Ms m/z: 267.8 (M+H)+ (M"Bu). Similarly, 3-bromo-2,6-difluorophenylaminodecanoic acid tert-butyl ester; and 3-bromo-2-fluoro-5-methylphenylaminodecanoic acid tert-butyl ester were prepared. Intermediate: 3-bromo-5·gas-2-fluoroaniline

Br^Y^NH2

F a solution of 3-bromo-5-vapor-2-fluorophenylcarbamic acid tert-butyl ester (900 mg, 2.78 mmol) in DCM/TFA (1:1, 20 mL) at room temperature Mix for j hours. The reaction mixture was concentrated, then the residue was dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate and brine. The organic layer was dried <RTI ID=0.0> MS m/z 223.9 (M+l) ° 150205.doc •59- 201209050 Intermediate: 5-bromo-3-indolyl-2-methylaniline

Mixing a heterogeneous reaction mixture of 4-bromo-2-methoxy-6-nitrotoluene (500 mg, 2.032 mmol), acetic acid (20 ml) and iron (1135 mg, 20.32 mmol) at room temperature 24 hours. The addition of acetic acid was carried out, followed by filtration of the mixture through Shixia vine and concentration of the filtrate. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with additional ethyl acetate. The combined organic phases were washed with EtOAc EtOAc m. MS w/z: 218.0 (M+H)+. Intermediate: 5-Gas-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl) phenylaminobenzoic acid tert-butyl ester

Intermediate l_bromo-5-gas-2-fluorophenylamino decanoic acid second butyl (1.45 g' 4.46 mmol), bis (pinacanolyl) in a sealed tube at 10 ° C Diboron (1.7 g, 6.69 mmol) 'potassium acetate (1.53 g, 15.6 mm 〇1), PdCl2 (dppf)-CH2Cl2 (163 mg '0.22 mmol) and two. A mixture of loo mi was heated for 16 hours. The crude reaction mixture was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude compound was diluted with hot hexane (6 〇〇 mL) and heated to 150205.doc • 60-201209050 6 5 ° C for 30 minutes, then cooled to room temperature. The mixture was passed through a brown mixture of celite and the filter cake was washed with hexane. The combined filtrate was concentrated to give the crude title compound. MS m/z 233 (Μ-pinacol-iBu). Similarly prepared 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaboroin-2-yl)aniline; 2,6-difluoro- 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborin-2-yl)phenylaminocarboxylic acid tert-butyl ester; N_(2,4-difluoro_3_ (4,4,5,5_tetradecyl-1,3,2-oxaboron-2-yl)phenyl)propane-indolesulfonamide; 2_(2_fluoro_3_ phenylene) Κ4,5,5·tetramethyl], 3,2_dioxo flavour; 2,5 digas _3_ (4'4'5,5-tetramethyl-ι, 3,2-diboron _2_yl) aniline; 2 gas _5 fluoro_3_ (4,4,5,5-tetramethyl-anthracene, 3,2-dioxo-flavored _2-yl) aniline; 2,5-diqi _3·(4,4,5,5-tetradecyl-1,3,2-dioxarosin-2-yl)aniline; 2_chloro-5_indolyl_ 3 (4,4,5, 5 tetradecyl _ι, 3,2-dioxaboron-2-yl) aniline; 2 fluoro·5 methyl-3-(4,4,5,5-tetraf-based sulphur dioxide _2 _ base) phenylaminocarboxylic acid tert-butyl S; 3_fluoro·4·(4,4,5,5,methyl-1,3,2·dioxy-2-yl)indole-2 - 月女' 2,3,6-difluoro_5-(4,4,5,5-tetramethyl-H2-dioxaboron-2-yl)aniline; 3-chloromethyl·dioxosole _2·基广比咬-2-amine; 3-gas-5-(4,4,5,5-tetradecyl-10-3,2-dioxosole-degraded_2_yl)benzene month female' 3-曱oxy-2- 5-(4,4,5,5-tetramethyl 4,3,2-dioxane 2 -yl) aniline. Intermediate: 2-fluoro-3-(4,4,5, 5-tetramethylborozepine-2-yl)aniline

Intermediate 1_(2_Fluor_3_nitrophenyl 150205.doc -61 - 201209050 4,4,5,5-tetradecyl-1,3,2-dioxy under 1 atmosphere of hydrogen A mixture of boron hydride (500 mg), 10 〇 / 〇 palladium / carbon (50 mg) and ethyl acetate (20 ml) was stirred for 16 hours. The mixture was flushed with nitrogen and filtered. , which was used without further purification. MS m/z 237.1 (M+1). N-[(2S)-l-[(4-{3-[2,6-difluoro-3-(propane-1) -sulfonylamino)phenyl]-1-(propan-2-yl)-1Η-β than 嗤-4-yl}bitid-2-yl)amino]propan-2-yl]carbamic acid Ester (Compound 7 in Table 1)

At 80 °〇, the crude intermediate 1^-(2,4-difluoro-3-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl) Phenyl)propane sulfonamide (854 mg), intermediate (S)-; l-(4-(3-exchange-1-isopropyl-iH-°bizozol-4-yl)pyrimidine- 2-Aminoamino)propan-2-ylamino decanoate (350 mg, 90% pure), hydrazine (triphenylphosphine), (0) (90 mg), 2 Μ sodium carbonate aqueous solution (6 ml A mixture of toluene (50 ml) and ethanol (6 ml) was heated for 16 hours. The cooled mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (7: 1 to 4: 1 DCM / methanol as solvent) to give the title compound. Example 2 N-[(2S)-l-({4-[3-(2-gas_5·fluoro_3_methanesulfonylaminophenyl)(prop-2-yl)-1Η·pyrazole-4 Methyl-pyrimidin-2-yl}amino)propan-2-ylaminocarbamate (Compound 15 in Table 1) 150205.doc •62· 201209050

Step 1: (s)-1-(4-(3-(3-Amino-2- gas-5-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidine-2 Methylamino)propan-2-ylamino decanoate. The crude intermediate 2-gas-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboromid-2-yl)aniline (at 85 ° C) 214 mg), intermediate (S)-l-(4-(3-iodo-1-isopropyl-1H-indazol-4-yl)pyrimidin-2-ylamino)propan-2-ylamino Methyl decanoate (68 mg ' 0.14 mmol), hydrazine (triphenylphosphine) _ palladium (〇) (16 mg), 2 Μ aqueous sodium carbonate solution (3 ml), benzene (18 ml) and ethanol (3 ml The mixture was heated for 16 hours. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (6: i to 40:1 DCM / methanol as solvent) to afford (4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidine-2- The title compound (46 mg) was contaminated with the propylamino)propan-2-ylamino decanoic acid. MS m/z 462.1 (M+1). Step 2: (S)-l-(4-(3-(2_Vinefluoro_3_(decanesulfonylamino)phenyl)-1- 1-isopropyl-1H-.Bizozol-4-yl) Pyrimidine-2-ylamino)propan-2-ylcarbamic acid formazan The aniline product of Step 1 (46 mg) was obtained at /m. A mixture of α (2 ml), diethylamine (1 mL), DCM (4 ml) and decanesulfonium chloride (23 〇 3 mmol) was stirred for 16 hours. The crude reaction mixture was concentrated, then the residue was dissolved in a mixture of toluene (9 ml), ethanol (1 mi), sodium carbonate (2 g) and water (1 〇 ml). The stirred mixture was heated at 8 rc for 16 hours. The crude product was purified by EtOAc (EtOAc:EtOAc:EtOAc: Example 3]\-[(28)-1-[(4-{3-[5-Gas-2-fluoro-3-(propyl- 1)-phenyl)phenyl]_1_ (prop-2- Methyl)-1Η·pyrazol-4-yl}pyrimidin-2-yl)amino]propyl-2-yl]carbamic acid methyl ester (Compound 1 in Table 1)

Step 1: (S)-l-(4-(3-(5-Chloro-2-fluoro-3-(t-butoxycarbonylamino)phenyl)-1-isopropyl-1H-pyrazole 4-yl)pyrimidin-2-ylamino)propan-2-ylamino decanoate. The crude intermediate 5-gas-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxos-2-yl)phenyl at 80 ° C Tert-butyl carbamic acid (2 〇g), intermediate (S)-l-(4-(3- decate-1-isopropyl-1Η-» than sept-4-yl) β 密 bite 2_ Ethyl propyl) propan-2-ylamino decanoate (6 〇〇 mg, 1.34 mmol), hydrazine (triphenylphosphine) palladium (0) (150 mg '0.13 mmol), 2 Μ sodium carbonate aqueous solution ( A mixture of 6 7 ml, 13.5 mmol), hydrazine (80 mL) and ethanol (6 mL) was heated for 16 hours. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (80:1 to 60:1 DCM / methanol) as the solvent. MS m/z 562.1 (M+1) 〇Step 2: (S)-1-(4-(3-(3-Amino-5-)-2-fluorophenyl)-1-isopropyl- 1 Η -»Bizozol-4-yl)pyrimidin-2-ylamino)propan-2-ylamino decanoate. Partially purified (third butoxy 150205.doc •64-201209050 carbonylamino)phenyl)-1-isopropyl-1Η-°bazol-4-yl)pyrimidin-2- at room temperature A solution of methyl propyl-2-aminocarbamate (1.15 g) in DCM (50 mL) The solvent was removed, followed by the addition of aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The combined organic extracts were then washed with sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and concentrated. The product is obtained by silica gel chromatography (60:1 to 40:1 DCM/nonanol as the eluent); MS m/z 462.1 (M+1) 0 Step 3: N-[(2S)-l-[(4) -{3-[5-chloro-2-fluoro-3-(propan-1-sulfonylamino)phenyl]-1-(propan-2-yl)-1Η-°bazol-4-yl}pyrimidine Ethyl 2-amino)amino]propan-2-yl]carbazate. Treatment of (S)-l-(4-(3-(3-Amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H with propane sulfonium (4 〇mg, 0.27 mmol) - oxazol-4-yl)pyrimidin-2-ylamino)propan-2-ylamino decanoate (4 j mg, 〇〇9 mmol), diethylamine (1 ml) and DCM (4 a mixture of ml). The mixture was searched for 16 hours at room temperature. The crude mixture was concentrated, and the residue was dissolved in a mixture of toluene (9 ml), ethanol (1 mi), sodium carbonate (2 g) and water (1 ml). The stirred mixture was heated at 85 C for 16 hours. The crude product was obtained by the title compound (yield: EtOAc: EtOAc: EtOAc: EtOAc) Example 4 N-[(2S)-l-({4-[3-(5-Gas-2-fluoro-3-methanesulfonylaminophenyl)"·(oxacyclo-2-yl) -1Η-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamic acid methyl ester (compound 33 in Table 1) and N_[(2S)-l-({4 -[3-(5-Gas-2-fluoro-3-methanesulfonylaminophenyl)_1H_吼150205.doc •65· 201209050 Az ex-4-yl]pyrimidin-2-yl}amino)propyl- Methyl 2-amino]carbamate (Compound 31 in Table i)

Step 1: 5-Gas-2-fluoro-3-(4-(2-(methylthio)pyrimidin-4-yl)(tetrahydro-2H-pyran-2-yl)-1Η-pyrazole-3 -yl) aniline. According to the procedure of Example 3, step i, the intermediate 4-(3-iodo-1-(tetrahydro-2H-pyran-2-ylpyrazole-4-yl)-2-(methylthio)pyrimidine and intermediate 5_Air fluorine_3_(4,4,5,5-tetramethyl-1,3,2-monoborate-2-yl)aniline was prepared as a starting material. Ms was 42〇〇 (M+ 1). Step 2. N-(5-Gas-2-fluoro-3-(4-(2.(Indolylthio)pyrimidin-4-yl)-indole_(tetrahydro-2H-pentan-2- Base)-1Η-pyrazol-3-yl) stupyl) methanesulfonamide) and 1^_(5_ gas-2-fluoro-3-(4-(2-(methylthio)pyrimidin-4-yl) ) - (tetrahydro-2H_pyran-2-yl)-1 Η-.bazol-3-yl)phenyl)-N-(indolylsulfonyl)methanesulfonamide. To 5-Chloro-2-fluoro-3-(4-(2-(methylthio)pyrimidine-'kesing^(tetrahydro-2H-pyran-2-yl)-1Η-0-salt-3-yl) Add decanesulfonium (〇 13 mL, 1.66 mmol) to a solution of the amine (233 mg, 0.55 mmol) and triethylamine (2 mL) in dioxane (1 mL). The mixture was stirred for 16 hours to give the title compound. MS w/z of salicylamine: 498.0 (M+1); ms m/z of disulfonamide: 576.0 150205.doc -66 · 201209050 (Μ+l) Step 3: N-[(2S)- L-({4-[3-(5-Gas-2-fluoro-3-decanesulfonylaminophenyl)-bu (oxacyclohexane-2-yl)-1Η-° ratio 吐-4 -Methoxy-methyl-2-amino]amino decanoate. The crude product mixture from Step 2 was dissolved in THF-H20 (1:1, 30 mL). Treated with 〇xone® (i.68 g, 2.75 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours, then ethyl acetate was added. The organic layer was washed with water and brine, then dried over sodium sulfate filtered and concentrated. The crude residue was dissolved in NMP (5 mL) with intermediate (5 &gt; 1-aminopropan-2-ylamino carboxylic acid Treatment with decyl ester (146 mg, 1 1 mmol) and sodium carbonate (233 mg, 2, 2 mmol). The mixture was stirred at 110 ° C for 16 hours with stirring. The cooled reaction mixture was diluted with ethyl acetate and then water. Washed with brine and dried over EtOAc EtOAc EtOAc (EtOAc) -l-({4-[3-(5-Gas-2-fluoro-3-methanesulfonylaminophenyl)-1Η-pyrazol-4-yl]pyrimidin-2-yl}amino)propyl- 2-yl]amino decanoate. To (2S)-l-(4-(3-(5-chloro-2-fluoro-3-(methylsulfonylamino)phenyl) (tetrahydro- 2Η-»Butan-2-yl)-1Η-.Phenyl-4-yl)methylene-2-ylamino)propan-2-ylcarbamate (94 mg '0.16 mmol) in MeOH ( Concentrated hydrochloric acid (0.5 mL) was added to the solution in 15 mL). The mixture was stirred at room temperature for 16 hours. The mixture was extracted to pH 9 and the mixture was extracted with ethyl acetate. The crude product was purified by silica gel chromatography (3::::::::::::::::: 150205.doc -67- 201209050 N-[(2 S)-1-( {4-[3-(5-Gas-2-1-3-甲炫) Continued amidinophenyl)_ι_(丙_2 -yl)-1 Η-&quot; 嗤-4-yl] 咬 bit-2-yl}amino)propan-2-yl]carbamic acid methyl vinegar (Compound 9 in Table 1)

To (S)-l-(4-(3-(3-Amino-5-ethane-2-|t phenyl)-1-isopropylpyrazol-4-yl)pyrimidin-2-ylamino a solution of decyl-2-ylaminocarbazate (55 〇 mg, i 2 mmol) in DCM (30 mL) and pyridine (i 〇 mL) with toluene (0.277 mL '3.57 mmol) 'And the mixture was stirred at room temperature for 16 hours. Aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate and washed with brine: The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (60:1 to 40:1 DCM / methanol) to give the title compound. An alternative synthesis is described in Example 6 below. Also isolated from the reaction mixture: ice [(28)_2_({4_[3_(5_气_2, fluoro-3- 3-decanesulfonylamino)-1-(propan-2-yl)· 1Η_pyrazolyl]pyrimidin-2-yl}amino)propyl]carbamic acid oxime ester (Compound 32 in Table 1); ν_{3_[4_(2-Aminopyrimidin-4-yl)-1- (Prop-2-yl)_ιη-pyrazole_3_yl]_5_chloro-2-fluorophenyl}methyl succinylamine (compound 3 in Table 1). Example 6

Substrate] Continued biting _2_yl}amino)propan-2-ylcarbamic acid methyl ketone 150205.doc -68 · 201209050 (Compound 9 in Table 1)

Step 1. 1-Benzimylene-2-isopropylindole. Isopropyl hydrazine hydrochloride (712 g, 6.43 mol), sodium acetate (528 g, 0.43 mol) and 50% were fed to a reactor equipped with a mechanical stirrer, thermometer and addition funnel under a nitrogen purge. Ethanol (4500 mL). The mixture was stirred at 20 ° C for 5 minutes. Benzoic acid (683 g, 6.43 mol) was added while maintaining the batch temperature below 23. (:. Stir the mixture for 20 hours at 20 C. Add toluene (65 〇〇 mL) and stir for 5 minutes. Separate the organic layer. Slowly add a saturated aqueous solution of sodium bicarbonate (4800 mL) to the vigorously stirred organic layer (Note: The pH of the aqueous layer was about 8.0. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate (3 mL). The organic layer was then separated and evaporated at 50 ° Torr)) Concentrate to give the title compound as a yellow oil (m.m.). Step 2: 2-((2-phenylhydrazinyl isopropyl decyl) fluorenylpropanonitrile. (Ethyloxyethylidene)malononitrile (755 g, 618 mol), DMAP (150 g, 1.23 mol) and ethanol were fed to a flask equipped with a mechanical stirrer, thermometer and addition funnel under a nitrogen purge. (6400 mL). The mixture was stirred to give a dark orange solution, and an endothermic process from 2 (rc to 12 〇c) was observed. 丨 Benzene fluorenyl 2 isopropyl hydrazine (u〇1) was slowly added over 15 minutes. g, coarse), exotherm to 3 2 C and give an orange suspension. Heat the orange suspension to 150205.doc •69- 201209050 50 C and kept at 50 ° C for 30 minutes' to obtain a dark brown suspension. Ethanol (3200 mL) was added to the mixture, and the mixture was cooled to 20. (: and kept at 20 ° C for 1 hour. The slurry was filtered and ethanol was used ( 3 〇〇〇 mL) The solid cake was washed with EtOAc (3 mL). Amino-1-isopropyl-iH-pyrazole-4-carbonitrile. Under a nitrogen purge, feed 2-((2) to a flask equipped with a mechanical stirrer, thermometer, condenser, and addition funnel. -benzylidene-1-isopropylindenyl)methylene)-malononitrile (632.6 g, 2.65 mol), MeOH (2.5 L) and concentrated (12 N) hydrochloric acid (329.0 mL ' 3.94 mol). The mixture was heated to 63 ° C and held at 63 ° C for 30 minutes to give an orange solution. The mixture was cooled to force. Heptane (4 L) and MTBE (1 L) were added and the mixture was stirred for 5 min. (: to 25. (: Water was added in the form of a stream over 30 minutes) (7. 5 L). After the water addition was completed, the mixture was stirred at 25 ° C for 10 minutes. The heptane/MTBE layer was separated. (: The aqueous layer was washed by stirring (4:1 v/v) heptane/MTBE mixture (2 x 5 L), and the primary washing was continued for 10 minutes. The layers were separated. Solid sodium carbonate (1 Kg) was added to the aqueous layer. A saturated aqueous solution of potassium carbonate was then slowly added to the aqueous layer to control the precipitation of CO 2 and adjust the pH to about 9.0. The aqueous layer was then extracted twice with CH2C12 (1 X 2.2 L, 1 x 800 mL). The combined CH2C12 layers were dried over MgSO 4 and filtered and concentrated under vacuum (200 Torr) at a bath temperature of 30 ° C until the residual weight was about 1 Kg. The heptane (6.0 L) was added slowly (after about 20 minutes) to the CH2C12 solution with stirring and a slurry formed. The mixture was concentrated under vacuum (60 Torr) at an internal temperature of 25 ° C until the residual volume was about 6.2 L. The slurry was cooled to 15 ° C and held at this temperature for 10 minutes. The product I50205.doc -70- 201209050 was filtered and washed with heptane (1 L). The title compound was obtained as a yellow solid. Hplc purity &gt;99% ° Step 4: 1-(3-Amino-1-isopropyl-lH-η ratio. Sit-heart group)-Ethyl ketone. 3-Amino-1-isopropyl was fed to a flask equipped with a mechanical stirrer, thermometer, reflux condenser, heating/cooling capacity, addition funnel and nitrogen inlet/outlet at 20 ° C under nitrogen. -1H- ° than saliva-4_indene nitrile (274 g, 1 82 mol) and cyclopentyl methyl ether (2600 mL). Cool the suspension to. An ether solution of l_5 Μmethyllithium/lithium bromide complex (6·0 L ' 9.00 mol) was added dropwise at -10 ° C to 〇 ° C over 2.5 hours. When the addition of the fluorenyllithium was completed, the reaction suspension was rapidly heated to 5 ° C to 1 Torr and maintained at this temperature for 1 hour. The mixture was cooled to 0 ° C and 2 N HCl (6.0 L) was added dropwise at 5-1 〇 °. The (upper) organic layer was separated and extracted with 2 n EtOAc (500 mL). The combined aqueous layers were searched for 16 hours at room temperature. The mixture was cooled to 15 ° C and tested with 50 〇 / 〇 NaOH (260.0 g) to give a pH of about ιι. The mixture was extracted with CH2C12 (1 x 2.0 L, 1×1 L). The combined CHsCh layer was dried <RTI ID=0.0> Heat to 65. (: After that, the solid was dissolved in EtOAc (750 mL). The solution was cooled to room temperature and a slurry was obtained. Glucose was slowly added at room temperature for 4 minutes (1500 mLp of cooled slurry to _1 Torr. The mixture was kept for 3 minutes at i 〇 ° c. The slurry was filtered and the filter cake was rinsed with heptane (300 mL). The solid was dried under vacuum (5 Torr) for 3 hours to give a pale brown solid. Title compound. HPLC purity &gt; 99%. Melting point: 136-139 X: Step 5: 1-(3-Iodo-i-isopropyl-1H-pyrazole-4-yl)-ethanone. Doc -71 · 201209050 Under a purge, feed 1-(3-amino-1-isopropyl-1H-pyrazol-4-yl)-B to a flask equipped with a mechanical stirrer, thermometer and addition funnel Ketone (250.0 g, 1.49 mol) and acetonitrile (3725 mL). Cool the mixture to -20 ° C. Add BF3.THF (313.1 g &lt;-10 ° C dropwise. Add isoamyl nitrite dropwise ( 227.5 g, 1.94 mol) while maintaining the internal temperature &lt;-10 ° C. The mixture was allowed to warm to 10 ° C and stirred at 10 ° C for 30 minutes. Stirring at 1 〇 -1 5 ° C Next, to contain I2 (28.5 g, 0.112 mol), KI (371. The mixture was added in a fine stream of a mixture of 9 g, 2.24 mol) and acetonitrile (116 (mL). The addition allowed nitrogen to evolve and slightly exothermic. The mixture was stirred at room temperature for 3 minutes. HPLC showed no residual diazonium. Then, add a solution of sodium hydrogen sulfite (157.1 g, 1.51 mol) in 8% sodium chloride solution (4360 mL) at 15-20. The mixture is alkalized to pH with saturated potassium carbonate.约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约约iPr〇Ac layer and concentrated to a residual volume of about l. A suspension is obtained. Heptane (55 l) is added to the suspension at 2 (TC) for 30 minutes. After the addition of the heptane, the suspension is mixed under the thief. 1 G min. Filter the liquid and rinse the solid with heptane (1 L), then dry under vacuum (5 Torr) for 16 hrs at 2 〇t to give the title compound. Hss: 90-92t. Step 6: 3_ (Dimethylamino) small (3_峨 small isopropyl out "ratio. sitting _4_!" two · 2 · dilute -1 · 嗣. Under a gas purge, a flask equipped with a mechanical stirrer, and an addition funnel was fed with H3 Winter 1 · Isopropyl. 吼... Heart Group &gt; Ethyl Ketone (64 Gg, 2.3 Gm. 丨) and dmf (6.4 l) ). Heat the obtained 150205.doc •71· 201209050 orange Loose solution to 120 °C. The Bradeneck's reagent (598 6 g, 3 '43 mol) was added in one portion. The addition causes the batch temperature to drop to 1丨4. Oh, and the color of the solution becomes darker. At 12 o'clock. (The mixture was stirred for 2 minutes. The mixture was cooled to room temperature, then concentrated at 5 mm Hg, 60. (:: to give an oily residue. The residue was dissolved in iPr 〇Ac by heating to 74 ° C ( 24 〇〇mL). The mixture was cooled to 35 ° C and stirred to obtain a slurry. At 35 ° t to room temperature, heptane (6000 mL) was added over 1 hour. The mixture was cooled to _ 15 π and over-considered, and The solid was dried under vacuum <RTIgt; </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; -pyrazole-4-yl)-pyrimidine-2-amine. Under a nitrogen purge, a flask equipped with a mechanical stirrer, thermometer, Dean-Stark trap and condenser Feeding (E) 3_didecylamino-1-(3-iodo-1-isopropyl-1H-pyrazole-4-yl)-propan-2-ene-1-indole (735 g, 2.2 mol), cesium carbonate (596 g, 3.3 mol) and NMP (5200 mL). Heat the mixture to 130 ° C and hold for 5 hours at i3 〇t. (Note. Collected by Dean-Stoker trap Any low boiling point.) Cool the mixture to 80 ° C, and at 8 CTC to 3 5^ under the condition of b], add 15% aqueous solution of sodium hydride (7500 mL). When about half of the sodium carbonated aqueous solution is added, the product begins to precipitate. The mixture is further cooled to room temperature for 3 minutes. The solid product was collected and dried under vacuum <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; -iodo-1-isopropyl-1H-pyrazole-4-yl)-pyrimidine-2-ol. Under a nitrogen purge, a flask equipped with a mechanical stirrer and a thermometer was fed 150205.doc •73- 201209050 TFA (748.8 mL). Add 4_(3 iodine)isopropyl-1H-pyrazol-4-yl)-pyrimidin-2-amine (300 g, 0.91 mol) as a solid, using a cold water bath Maintain the internal temperature below 30 ° C. Mix the mixture at room temperature for a few minutes to obtain a solution. Cool the mixture to 20. (:, and at 22-28 ° C, under rapid stirring: mixed with 5. Sodium arginine (79.7 g, 1 27 mol) was added portion by hour. (Note: some gas evolution was observed with mild exotherm, which is easy to control with a cold water bath.) Add DCM (12 L) The mixture was allowed to warm to 27 ° C. Water (4400 mL) was added (note: gas evolution started at the beginning). A saturated solution of potassium carbonate (about 15 〇〇 mL) was slowly added to the mixture to verify the pH to about 9 _0 (note : A large amount of gas is precipitated). A solution of sodium hydrogen sulfite (32 g, 0.30 mol) in water (1 mL) was added to the mixture. The mixture was stirred at 27 ° C for 15 minutes and the pH was adjusted again to about 9.0. The DCM layer was separated and concentrated under vacuum (200-1 〇〇 111111118) at a bath temperature of 40 ° until the residual weight was about 2300 g (about 1750 mL). Addition to the residue at 2 (TC) MTBE (1500 mL). The mixture was stirred at <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Hyun: 2 16 218 〇 C. Step 9. 2-Ga-4-(3-峨-1-isopropyl·ΐΗ-ηBizozol-4-yl)-pyrimidine. , a thermometer, a condenser, an addition funnel, and a nitrogen inlet/outlet flask were fed with 4-(3-Eth-1-isopropyl-1Η-pyrazol-4-yl)-pyrimidine 2-ol (311 g, 942). Add acetonitrile (2500 mL) to the solid at 2 ° C. Stir the mixture to give a suspension. Add DIPEA (246.2 mL, 1.41 m〇l), DMF (218.8 mL, 2) to the suspension. 83 150205.doc •74· 201209050 m〇l). Stir the resulting suspension for 5 minutes at 2°C. Add P〇Cl3 (217 g, 1.41 m〇 to the suspension at 2〇_4 (rc) i), an orange solution is obtained. The mixture is allowed to warm to 8 (TC and Hold at 8 (TC for 3 hours). Cool the mixture to 10 C and slowly add a solution of ammonium oxychloride (622, 28%) in deionized water (5550 mL) over 1.5 hours while maintaining the temperature below 2 Torr. 〇 After the addition of cesium hydroxide was completed, the resulting suspension was stirred at 1 〇 2 (Tc for 4 Torr. The solid product was collected by filtration, and dried under vacuum (5 Torr) overnight at 4 〇t: The title compound is obtained as a brown solid. HpLC purity &gt; 99% ° Step 10: (S)-2-(decyloxycarbonylamino)propyl phenyl carbamate. To (S)-l,2 Add potassium carbonate (119〇mm〇1) to a suspension of diaminopropane dihydrochloride (5〇g, 34〇mm〇1) in di-methane (500 mL). Stir the suspension and collect by filtration. The filtrate was cooled to 0-5T: and stirred while adding benzyl chloroformate (51 ml, 357 mm 〇l). After the addition was completed, the reaction mixture was stirred at 0-5 C for 3 hours, then It was warmed to the chamber and stirred overnight at ambient temperature. To this mixture was added dropwise triethylamine (71 ml ' 510 mmo丨) and the mixture was cooled to 〇^^c. _5C; invasive slowly added under gas Yue c acid methyl ester (28 ml, 357 mmol), the mixture was warmed to room temperature and stirred overnight The mixture was poured into water. The organic volatiles were removed under vacuum. The resulting aqueous slurry was filtered to give a solid, which was subsequently washed with ethyl acetate to afford a white solid (65 g, 92-94% HPLC purity). The title compound was obtained as a white solid (yield: 99.5%). Step 11. (S)_i_Aminopropyl-2-ylaminocarbamic acid methyl ester hydrochloride. Hydrogenation of (8)_2-(methoxybenzylamino)propylaminocarbamic acid benzoate over a 5%!e/C catalyst at 5 〇 150205.doc -75 - 201209050 6 〇 pS1T was applied to a solution in methanol. (iv) The reaction mixture was concentrated under vacuum to give a colourless oil. 60 g of a colorless oil was dissolved in 200 mL of anhydrous dichloromethane and the solution was cooled to 0-5 C in an ice-water bath. A solution of HC1 in methanol was added dropwise (about 75 melons until the pH of the solution was &lt;1. at 〇_5. (: the resulting suspension was stirred for 3 minutes, then the solid was collected via filtration. The title compound is obtained as a white solid. Step 12: 3-bromo-5-hexane-2-fluorobenzaldehyde. Under an argon atmosphere, 2,2,6,6·tetrazole A solution of the piperidine (327 g, 98%, 2.274 mol) and THF (1.9 L, HPLC grade) was cooled to _75t: (dry ice- decyl alcohol bath) over one hour at -67 ° C A 16 M n_BuLi/hexane solution (1.47 L, 2.35 mol) was slowly added to the mixture. The mixture was stirred at -72 ° C to -67 ° C for 30 minutes to give a pale yellow suspension. -72 ° C to -67 (: Slowly add 2-&gt; odor-4-gas-1-phenylene (435 g, 97%, 2.02 mol) to the mixture over 30 minutes, then at -72 ° C to -67 ° C The mixture was stirred for 30 minutes. Dimethyl decylamine (230 g, 99.5%, 3.14 mol) was slowly added to the mixture over 30 minutes at -70 ° C to -65 ° C, followed by _7 ° ° c to - Mix the mixture at 65 ° C for 30 minutes to get a light brown solution The cooling bath was removed, followed by the addition of a saturated solution of ammonium chloride (72 0 mL) to the batch over 15 minutes at -60t to -30 ° C to give a cloudy mixture at -3 0. (: to 10 ° C 6 N hydrochloric acid was quickly added to the mixture over 15 minutes to pH 1. Then ethyl acetate (2.0 L) was added at 1 ° C to 20 ° C. The layers were separated and extracted with ethyl acetate (1×300 mL) The organic extracts from the combined 150205.doc-76-201209050 were washed with water (1 x 800 mL) and brine (ix 500 mL), dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum (6 〇 _65 〇c). The title compound was obtained as a brown oily viscous oil which solidified after standing for several hours. 1H NMR (CDC13): δ 7.76-8.30 (m, 2H), 10-0-10.8 (br s, 1H); MS m/z 238.0 (M+l) Step 13: 3-bromo-5-gas-2-fluorobenzoic acid. 3-bromo-5-gas-2-fluorobenzaldehyde (415 g), tert-butanol (1.2) The mixture of L) and water (1.2 L) was heated to 30 ° C. Then potassium permanganate (335 g ' 2.12 mol) was added to the batch at 40-45 ° C for 1 hour (5 parts) Heat the dark purple inclusions in a stepwise manner as follows: 3 to 45 minutes at 45-50 °C , 50-55. (: Continue for 30 minutes and continue at 55-60 ° C for 30 minutes to obtain a purple-brown suspension. Cool the reaction mixture to 20 ° C, then at 22-27. (: Add saturated sodium sulfite solution until peroxide test After obtaining a negative value, warm water (2.5 L 'about 50 C) and saturated sodium carbonate solution (1 〇〇 mL) were added to the mixture in 15 minutes. The dark suspension was filtered through a 1 cm bed of earthworm. And the filter cake was washed with warm water (4 x 1 l, about 5 ° C). The combined filtrate was acidified to pH 1 ' with 6 N hydrochloric acid to give a yellow oily suspension. L) 'When the mixture was stirred for 1 hr. The organic layer was washed (upper) with water (1. 2 L), dried over magnesium sulfate <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The hexanes (700 mL) were added, and the suspension was cooled to 5-10 <RTI ID=0.0></RTI> <RTIgt; 150-152 ° C; HPLC purity (225 nm): 97.5%; 1H NMR (d6-DMSO): δ 7.82 (s, 1 H), 8.10 (s, 1H), 13.82 (br s, 1H) ; MS m/z 254 (M+H). 3 150205.doc -77· 201209050 Step 14: 3-Bromo-5-Ga-2- Tributyl fluorophenylamino decanoate. 3_Bromo-5-chloro-2-fluorobenzoic acid (243 g '97.5%, 0.935 mol), triethylamine (105 g, 99.5% '1.02 mol) And a mixture of tert-butanol (14 L) was heated to 74 ° C. Diphenyl fluorenyl azide (26 缓慢) was slowly added to the mixture at 75-79 ° C for 1 hour (slow reflux). g, 97%, 0.916 mol) in benzene (960 mL). The mixture was slowly heated to 83 over 30 minutes, and maintained at 83-84 ° C (slow reflux) for 1 hour. The contents were concentrated to a viscous oil at 65-70 ° C. Toluene (2 l) and water (1.5 L) were added sequentially to the batch, followed by stirring the mixture at 35 ° C for 15 minutes. The aqueous layer was discarded. The organic layer was washed with a saturated solution of sodium bicarbonate (400 mL) and water (400 mL). The organic layer was concentrated under vacuum (60-65 ° C) to about 350 mL of residue (about 94% purity) Add 1 〇% ethyl acetate / hexane (about l 2 l, v / v) to the batch, then heat mix at 50 ° C 15 minutes, a pale yellow homogeneous solution was obtained. The ethyl acetate / hexane solution was transferred to a 4 L Pyrex Biichner funnel (with a coarse sintered disc, 40-60 μηι, 16 cm diameter, Prefabricated silicone (18 kg, 7〇_2〇〇目) on the 18 cm height). The title compound was obtained as an off-white solid in the form of a butyl carbamic acid tributyl ester product, which was slowly dissolved (by gravity) from 3% to 5% (yield: 5 vol, v/v). Melting point: 87-88. (: ; HPLC purity (225 nm): 97-98%; ]H NMR (d6-DMSO): δ 1.48 (s, 9H), 7.48- 7.49 (m, 1H), 7.80-7.82 (m, 1H), 9.42 (s, 1H) ; MS m/z 325 (M+H) 〇 Step 15: (S)-l-(4-(3-iodo-l-isopropyl-iH-pyrazol-4-yl) Methyl sulfonate 2-methylamino)propan-2-ylamino decanoate. Under a nitrogen purge, a four-necked flask equipped with a 150205.doc -78· 201209050 mechanical stirrer, thermometer and condenser 2-Hydroxy-4_(3-峨-1-isopropyl-ΐΗ-α is more than sal-4-yl)-Mess (300.0 g), (s)-l-aminopropan-2-ylamine Methyl carbamate hydrochloride (174.3 g) 'Sodium carbonate (365.7 g) and DMSO (2400 mL). The mixture was heated under stirring at an internal temperature of 90 ° C for 18 hours. The mixture was cooled to 40. Add toluene (3870 mL) under stirring at 37-431. Add water (7200 mL) at 37-43. Separate the benzene layer at 37-43 ° C. Add to the benzene layer 15% aqueous sodium sulphate solution (3870 mL), and adjust the pH of the aqueous layer to a pH of about 5 _0 by adding 10% aqueous citric acid solution at 37-43 ° C. The pH adjustment requires about 20 mL of 10 % citric acid solution The ruthenium benzene layer was then washed with a saturated aqueous solution of sodium hydrogencarbonate (2 8 80 mL) at 37-43 ° C. The benzene layer containing the title compound was used as the feed in step 17. Step 16: 5-chloro- T-butyl 2-fluoro-3-(4,4,5,5-tetradecyl-1,3,2-dioxaboromid-2-yl)phenylcarbamic acid. Under nitrogen purge, Feeding a 3-butyl-5-fluoro-2-fluorophenylaminodecanoic acid tert-butyl ester (33.0 g) into a flask equipped with a mechanical crucible: a stirrer, a thermometer, a condenser and a heating mantle, double (frequency) Which alcohol base) diboron (447.0 g), potassium acetate (405.6 g) and toluene (2700 mL). The mixture was stirred at room temperature for 15 minutes, and PdCl 2 (dppf) (50.4 g) was added. The mixture was then heated to l. 8±2°C (Note: the mixture turns dark at 50-60 ° C.) Add 3-bromo-5-gas-2-fluorophenylamino decanoic acid at 70 ± 2 ° C for 70 minutes. A solution of tributyl ester (414 g) in toluene (1770 mL). The mixture was kept at 108 ± 2 ° C for 15 hours. The mixture was cooled to room temperature under a stream of nitrogen, then filtered over celite. The filtrate was used as the feed in step 17. 150205.doc 79· 201209050 Step 17: (S)-l-(4-(3-(5-Gas-2-fluoro-3-(T-butoxy))phenyl)-1-iso Propyl-1H-»bazol-4-yl)pyrimidin-2-ylamino)propan-2-ylaminodecanoate. Feeding (S)-l-(4-(3-magnetic-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylamino hydrazine into the flask Hydrate ester (3870 ml benzene solution, about 382 g, 0.861 mol) and 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron T-butyl phenyl) phenylamino decanoate (4470 ml benzene solution 'about 467.0 g ' 1.26 mol). A solution of sodium carbonate (349.8 g '3.30 mol) in water (1400 mL) was added to the obtained brown solution. To the mixture was added PdCl 2 (dppf) (34.5 g '0.047 mol). The mixture was warmed to 80 ° C with stirring and maintained at this temperature for 2 hours. The mixture was cooled to 4 ° C and filtered through celite. Separate the layers in the fluid. The benzene layer containing the title compound was used directly as the feed in step 18.

Step 18: (S)-1-(4-(3-(3-Amino-5-)-2-fluorophenyl)-1-isopropyl-1H-.Bizozol-4-yl)pyrimidine- 2-Aminoamino)propan-2-ylamino decanoate. The mixture was fed with 2^('(^^-gas-2-fluoro-3-(t-butoxycarbonylamino)phenyl)-indole-isopropyl at 2 ° C under a nitrogen atmosphere. Base Η π π ππβ-4-ylpyrimidin-2-ylamino)propan-2-ylamino decanoate (about 7.3 L benzene solution, about 483.3 g, 0.80 mol). 12 N HCl (574, 3 mL, 6.95 mol) was added to the solution over about 20 minutes while maintaining the temperature below 25 °C. Hydrochloric acid addition causes an exothermic process from 19 ° C to 24 ° C. At 2〇-23. (The mixture was stirred for 1 hour. Water (3 mL) was added to the reaction mixture. The mixture was stirred for 10 minutes under 2 hr. The aqueous layer was separated and washed with 2-diethyltetrahydrofuran (31 〇〇mL). A saturated aqueous solution of potassium carbonate (about 778 mL) was slowly added to the aqueous layer. The pH of the aqueous layer was about 8.5. The aqueous layer was extracted with 2-methyltetrahydrofuran (3825 mL) 150205.doc -80 - 201209050. Concentration of the 2-mercaptotetrahydrofuran layer under 〇mmHg, 40 ° C. The residue was diluted with 2-indyltetrahydrofuran (about 3800 mL) to give the title compound as a material. Hplc purity: 95%. Step 19: (S)-l-(4-(3-(5-chloro-2-fluoro-3-(N-(indolylsulfonyl) fluorenylphosphonium) Phenyl)-1_isopropyl_1Η-° ratio. Sodium-4-yl) mouth bite 2-amino-amino)propyl-2-ylaminocarbazate. At 2 °C, 'to the flask Medium feed (3-(3-amino-5-gas-2-1phenyl)-1-isopropyl-1 Η-° than 嗤4-yl) mouth. _ 2-aminol group) Propyl-2-ylamino decanoate (about 3.8 L mercapto tetrahydrogen. Fu B South solution 'about 396.5 g, 0.86 mol). Triethylamine (435 〇 g, 4.3 mol) was added to the solution. The solution was cooled to _5 °C. Methane sulfonium chloride (246 〇 g, 2.15 mol) was added dropwise to the solution over 20 minutes at -5 to -5 °C under a drop. The mixture was allowed to warm to 18-20 ° C and held at this temperature for 2 Torr. Water (2115 mL) was added to the reaction mixture over 30 minutes at 18-20 °C. After the addition was completed, the mixture was stirred at 20 ° C for 1 Torr. The pH was then adjusted to between 6.0 and 6.5 with 2 N HCl (about 1230 mL). The pH was then adjusted to 7-7.5 using a saturated aqueous solution of sodium bicarbonate. The mixture was searched for 10 minutes at 2 °C. Separate the layers. The 2_mercaptotetrahydrofuran layer containing the title compound was used directly in step 20. Step 20: N-[(2S)-l-({4-[3-(5-chloro-2-fluoro-3-decanesulfonylamino)-1-(propan-2-yl)- Methyl 1 -pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]amino decanoate. Feeding (S)-l-(4-(3-(5-chloro-2-fluoro_3-(Ν·(methylsulfonyl)methylsulfonyl)phenyl)4- to the flask Isopropyl guanidino-2-ylamino)propan-2-ylaminocarbamate (about 3 ·8 L decyl tetrahydroanthracene 150205.doc •81 201209050 turmeric solution, about 53 1.5 g, 0.86 mol) A 3 N aqueous solution of sodium hydroxide (1782.8 mL, 5.34 mol) was added to the solution under stirring at 15-20 ° C. The mixture was vigorously stirred at 20-23 ° C for 30 minutes and the mixing was stopped. The aqueous layer was discarded. 2 N HCl (about 410 mL) was added to the organic layer to adjust the pH to 6.0-6.5' and then a saturated aqueous solution of sodium hydrogencarbonate (about 3 〇〇mL) was added to adjust the pH to about 8.5. The aqueous layer was discarded. The organic layer was washed with a 5% aqueous solution of sodium carbonate (2000 mL). The organic layer was concentrated under vacuum (8 Torr) at a bath temperature of 45 ° C to give a brown solution (780 g). The solution was diluted with 2-mercaptotetrahydrofuran (3500 mL) and then the suspension of PICA HP 120N activated carbon (90 g 'CDH858) in 2-mercaptotetrahydrofuran (1 l) was added. The black suspension was warmed to 60 ° C and held at 60 ° C for 16 hours. After 16 hours, 'Pd The amount was 309 ppm. The mixture was cooled to 2 Torr and filtered through a pad of Celite (pre-wet with 2-Methyltetrahydrofuran). The reaction flask was rinsed with 2-methyltetrahydrofuran (500 mL). pICA/ Shiyoshizao soil filter cake. PL-TMT resin (90 g) was added to the filtrate. The resulting suspension was heated to 60 ° C with stirring and kept at this temperature for 4 hours. After 4 hours at 60 ° C The Pd content was 2.3 ppn^cooled to 2 〇. and stirred overnight at 20 C. The mixture was filtered through a diatomaceous earth pad (pre-wet with 2_mercaptotetrahydrofuran) at 40-45 ° C under vacuum The filtrate was concentrated (1 〇〇8 Torr) and evaporated to abr. EtOAc (EtOAc). The resulting clear orange solution was cooled to 2 (TC, and a precipitate formed, then the mixture was cooled to 0 ° C and kept at 0 ° C for 1 hour. The mixture was filtered and washed with ethanol (3 blush). The solid was dried under TC for 14 h to give the title compound: 150 205. doc: 82· 201209050 Melting point: 186-189 C. The above-mentioned example compound was prepared using the appropriate starting materials. The compound number structure A375 CP Ι〇 5〇 (μΜ) BRAFV600E biochemical Ι (: 50 (μΜ) physical data h NMR 400 MHz and / or MS (m/z) meaning

Ο NH

0.002 H NMR 400 MHz (CD3OD)5 8.41 (s, 1H), 8.06 (d, 1H), 7.57 (dd, 1H), 7.34 (dd, 1H), 6.64 (d, 1H), 4.63 (seven peaks, out ), 3_62-3.68 (m, 1H), 3.57(s, 3H), 3.40-3.44 (m, 1H), 3.32-3.36 (m, 1H), 3.05 (q, 2H), 1.88 (q, 2H), 1.58 (d, 6H), 1.02 (d, 3H), 0.97 (t, 3H); MS fli/z 568.2 (M+l).

0.018 0.0008 MS m/z 522.1 (M+l)

150205.doc -83 - 201209050 Compound No. Structure A375 CP Ι〇50(μΜ) BRAFV600E Biochemistry ICS0_) Physical data 'H NMR 400 MHz and / or MS (m/z) 4 . NH ηνύ, N-N J. NH °&quot;S-0 0.033 0.0023 MS m/z 506.1 (M+l) 5 , . People NH ,’s HNYN^ Cl N-N NH ' 〇》. 0.001 0.0002 MS w/z 550.1 (M+l) 6 . Person NH , , ' eight N-N J NH 〇 0.046 0.0039 MS m/z 524.2 (M+l) 84- 150205.doc 201209050 Compound Number

0.008 0.027 0.002 A375 CP Ι(:50(μΜ) BRAFV600E Biochemistry ΐε5〇(μΜ) 0.0007 0.0003 Physical Data 4 NMR 400 MHz and / or MS (m/z) MS m/z 552.2 (M+l) MS m/ z 588.2 (M+l) 'HNMR400 MHz (CD3〇D)5 8.41 (s, 1H), 8.08 (d, y=5.6 Hz, 1H), 7.57 (dd, J=6.4, 2.6 Hz, 1H), 7.34 (dd, 7=5.6, 2.6 Hz, 1H), 6.65 (brs, 1H), 4.63 (seven peaks, /=6.8 Hz, 1H), 3.62-3.68 (m, 1H), 3.57 (s, 3H), 3.40 -3.44 (m, 1H), 3.32-3.36 (m, 1H), 3.00 (s, 3H), 1.58 (d, J = 6.8 Hz, 6H), 1.02 (d, J = 4.8 Hz, 3H). MS τη /ζ 540.1 (M+l) 150205.doc 85- 201209050 Compound No. 10 11 12 13

0.003 0.003 0.004 0.006 A375 CP Ι〇:50(μΜ) BRAFV600E BiochemistryΙ&lt;:50(μΜ) 0.0006 0.0005 0.00095 0.0010 Physical Data NMR 400 MHz and / or MS (m/z) *HNMR400 MHz (CD3〇D) δ 8.41 (s, 1H), 8.08 (d, 1H), 7.37 (ddd, 1H), 7.08 (ddd, 1H), 6.62 (brs, 1H), 4_63 (seven peaks, 1H), 3.63 (s, 3H), 3.54-3.58 (m, 1H), 3.34-3.40 (m, 2H), 3.00 (s, 3H), 1.58 (d, 6H), 1.12 (d, 3H) ; MS m/z 524.1 (M+l) 0 HNMR 400 MHz (CD3OD) δ 8.34 (s, 1H), 8.09 (d, 1H), 7.57 (dd, 1H), 7.35 (dd, 1H), 6.65 (brs, 1H), 4.28 (q, 2H), 3.68 -3.71 (m, 1H), 3.57 (s, 3H), 3.32-3.36 (m, 2H), 3.00 (s, 3H), 1.54 (t, 3H), 1.02 (d, 3H) ; MS m/z 526.0 (M+l) 〇 (400 MHz, CDC13) δ 8.12 (s, 2H), 7.40 (d, 1H), 7.20 (d, 1H), 7.10 (m, 1H), 6.40 (s, 1H), 5.35 ( s,1H), 5.25 (d, 1H), 4.60 (m, 1H), 3.90 (s, 1H), 3.65 (s, 3H), 3.30 (s, 1H), 3.00 (s, 3H), 2.40 (s , 3H), 1.60 (d, 6H), 1.10 (d, 3H) ° MS (ESI) m/z: 521 (M+H)+. 'H (400 MHz, CDCI3) δ 10.10 (s51H), 8.60 (s, 1H), 7.75 (s, 1H), 7.60 (d, 1H), 7.15 (d, 1H), 7.05 (s, 1H), 6.30 (s, 1H), 4.95 (s, 1H), 4.65 (m, 1H), 3.95 (s, 1H), 3.65 (s, 3H), 3.45 (s, 1H), 3.30 (s, 1H), 3.05 ( s, 3H), 2.45 (s, 3H), 1.65 (d, 6H), 1.20 (d, 3H). MS (ESI) m/z: 537 (M+H)+. 150205.doc • 86 - 201209050 Compound number structure A375 CP icso_) BRAFV600E Biochemistry Ι〇 5〇 (μΜ) Physical data NMR 400 MHz and / or MS (m/z) 14 , NH人 NH ',, 彳ηνύ, Υ ^ λχχ Ν—N / ΝΗ 1 01 °7^〇0.079 MS »2/z 523.1 (M+l)1 15 , 0 person ΝΗ , , , , .s ΗΝΛ r Xr^yX NN / NH 1 Cl °7^ 〇0.004 0.0011 MS w/z 540.1 (M+l) 16 'CT^NH ',, 's ηνύ, Y ^ λΧκ NN J NH 1 F 〇,〇1.4 0.024 MS m/z 507.2 (M+l) 17 N ^l Hrv, Cl NN J NH 010 0 0.002 MS w/z 478.1 (M+l) 150205.doc 87 · 201209050 Compound number structure A375 CP IC50_) BRAFV600E Biochemistry Ι&lt;:50(μΜ) Physical data NMR 400 MHz And / or MS (m/z) 18,. Human NH,,,,,,,,,,,,,,,,, 6.57 (d,1H), 4.61 (seven peaks, 1H), 3.70-3.74 (m, 1H), 3.58 (s, 3H), 3.34-3.40 (m, 2H), 3.23 (q, 2H), 1.58 (d , 6H), 1.43 (t, 3H), 1.02 (d, 3H); MS, m/z 513 Λ (M+l). 19,. People NH ΗΝγ, N-N J NH ~~~\ 〇10. 0.093 0.0061 MS m/z 524.1 (M+l) 20 , 0 person NH Λ ηνλ □ NN "Factory NH 〇f〇0.007 0.0008 MS m/z 540.2 (M+l) 21 , 0 person NH ', 彳ΗΝβ Γ Λ^ΤΡ NN l NH 〇,0 0.045 'H (400 MHz, CDCI3) δ 7.95 (s, 2H), 7.30 (s, 1H), 6.40 (s, 1H), 5.15 (s, 1H), 4.50 (m , 1H), 3.70 (s, 1H), 3.52 (s, 3H), 3.20 (s, 1H), 3.05 (s, 3H), 1.50 (d, 6H), 1.05 (d, 3H). MS (ESI) m/z: 542 (M+H)+. 150205.doc -88 - 201209050 Compound Number 22 23

A375 CP Κ: 50 (μΜ) BRAFV600E Biochemical Ι (: 50 (μΜ) Physical data NMR 400 MHz and / or MS (m / z) 0.006 1.15 0.023 'Η (400 MHz, CDC13) δ 8.50 (s, 1H) , 7.85 (s, 1H), 7.80 (s, 1H), 7.30 (s, 1H), 6.40 (s, 1H), 5.0(s, 1H), 4.62 (m, 1H), 3.90 (s, 1H), 3.65 (s, 3H), 3.30 (s, 1H), 3.10 (s, 3H), 1.70 (d, 6H), 1.20 (d, 3H). MS (ESI) m/z: 557 (M+H)+ 〇MS m/z 488.2 (M+l) MS m/z 550.1 (M+l) 150205.doc 89- 201209050

150205.doc -90- 201209050 Compound numbering structure A375 CP IC50_) BRAF V600E Biochemical IC50_) Physical data 咕 NMR 400 MHz and / or MS (m/z) 29 Cl NN J NH 1 °7&quot;〇0.076 0.008 MS w/ z 439.0 (M+l) 30 H2N N NN J NH Λ F〇t. 0.069 0.0043 MS w/z 425.1 (M+l) 31 ,. NH &quot;'S HN丫, Cl ίφι HN-N J NH F °7^〇0.18 0.0008 MS w/z 497.9 (M+l) 32 ^O^NH V NN J NH 1 010 0 0.031 0.0029 MS w /z 540.1 (M+l) 150205.doc 91 - 201209050 Compound number structure Α375 CP Ι05〇(μΜ) BRAFV600E Biochemistry ICS0_) Physical data!ΗΝΜΚ400ΜΗζΑ/ or MS (m/z) 33,0 personΝΗ ΛHNYN&quot; 1 c. Ν-Ν Γ ΝΗ 〇, 0 0.007 MS m/z 582.1 (M+l) 34,. ΝΗ % % Mr Mr Ν Ν Ν Ν Ν 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 (d, 1H), 4.62 (seven bees, 1H), 3.71-3.74 (m, 1H), 3.58 (s, 3H), 3.34-3.40 (m, 2H), 3.05 (q, 2H), 1.88 (q, 2H), 1.58 (d, 6H), 1.02 (d, 3H), 0.97 (t, 3H); MS m/z 552.1 (M+l). Example 122

B-Raf V600E/Mek Enhanced Luminescence Proximity Assay (B-Raf V600E Biochemical Assay) Combine B-Raf (V600E; 4 pM) and biotinylated Mek (lethal kinase; 10 nM) at 2x final concentration In assay buffer (50 mM Tris (pH 7.5), 15 mM MgCl2, 0.01% BSA, and 1 mM DTT), and dispensed in assay plates containing 0.5 μl of the compound of the invention diluted in 100% DMSO ( Greiner 384-well white assay plate, No. 781207), 10 μM per well. The plates were incubated for 60 minutes at room temperature. The B-Raf kinase activity was initiated by adding 10 μΐ of the assay buffer diluted 2 μM (10 μΜ) 150205.doc -92- 201209050 per well. After 3 hours, 1 〇沁 terminating reagent (60 mM EDTA, 0.01% Tween 20) was added to terminate the reaction. Rabbit anti-p_ MEK (Cell Signaling ' No. 9121) antibody and Alpha Screen IgG (Protein A) detection kit (perkinElmer, No. 6760617R) were used, by adding 30 卟 containing antibody to the well (1:2000 dilution) The phosphorylated product was measured with a bead buffer (5 〇 Tns (pH 7.5), 0.01% Tween 20) which detected a mixture of beads (both beads diluted 1:1000). The addition is carried out under dark conditions to protect the beads from light. The lid was placed on top of the plate and the plate was incubated for 1 hour at room temperature. Luminescence was read on a PerkinElmer Envision instrument. The 5 〇% inhibitory concentration (ic5 〇) of each compound was calculated by nonlinear regression using XL Fit data analysis software. The compounds of the invention in free form or in a pharmaceutically acceptable salt form exhibit the pharmacological properties of the present value, for example, as indicated by the in vitro test described in this application. For example, the ICso exhibited by the uninvented compound for V6〇〇e B-Raf is preferably in the range of 1 X 1 〇 10 to 1 X 1 〇 5 μm, preferably less than 500 η Μ, 250 η Μ, 1〇〇ηΜ and 50 ηΜ. For example, ICso data for some of the compounds of the invention in the luminescent proximity homogenization assay are shown in the table above. Example 123 A375 Cell Proliferation Assay (A375 CP) A375 is a melanoma cell line with the B-Raf V600E mutation. A375-luc cells engineered to express luciferase were applied at 1,500 cells/50 μM/well in a 384-well white clear bottom plate containing 1 〇〇/. FBS in DMEM. The compound of the present invention dissolved in 100% DMSO at an appropriate concentration was transferred to the cells by a robotic needle tool (rob〇tic Pin T〇〇1) (1〇〇 nl) at 150205.doc -93 - 201209050. The cells were incubated for 2 days at 25 ° C, then 25 μL of BrightGloTM was added to each well, and the plate data was read via luminescence. Calculating 50% inhibitory concentration of each compound by non-linear regression using XL Fit data analysis software (IC50p free form or pharmaceutically acceptable salt form of the compound of the invention exhibits valuable pharmacological properties, eg, as Indications for the in vitro test described in the application. For example, the compounds of the invention exhibit preferred IC5(R) for wild-type B-Raf and V600E B-Raf below 500 nM, 250 nM, 100 nM and 50. For example, IC50 data for some of the compounds of the invention in the A375 cell proliferation assay are shown in the table below. Example 124 Immunoassay Cells were seeded at a density of 30 cells per well (96 wells) &lt; 103 cells. In tissue culture treated plates, 1640 RPMI + 10% FBS, followed by incubation for 24 hours at 37 ° C and 5% CO 2 prior to compound addition. Test compounds were serially diluted in DMSO and subsequently added to the cells (final The DMSO concentration was 0.1%) and was incubated for 3 hours at 37 ° C and 5% CO 2 . The pMEK and pERK levels were measured using a sandwich immunoassay kit (Meso Scale Discovery). The culture supernatant was removed and The cells were lysed by adding cold solubilization buffer (provided in the kit) over 30 minutes under buffering. To detect pMEKl/2 (Ser217/221) &amp; pERKl/2 (Thr/Tyr202/204, Thr/Tyrl85/187) Add lysate to the plate coated with the blocked antibody and have a set, and 150205.doc -94· 201209050 incubated overnight under shaking at 4 ° C. Wash the plate and use the provided labeled Antibody Detection of Phosphoproteins and Reading Data on a Sector 6000 Instrumentation Example 125 SW620 Cell Viability Assay SW620 cells were seeded at a density of 1,500 cells per well (96 wells) in tissue culture treated black wall clear In a bottom plate, 1640 RPMI + 10% FBS. Test compounds were serially diluted in DMSO, then added to the cells (final DMSO concentration 0.1%) and incubated for 4 days at 37t and 5% C02. Force the cell culture plate to room temperature, remove the medium' and add 200 μM Cell Titer-Glo reagent to each well (Promega, mix the kit components according to the manufacturer's protocol, then dilute 1:2 with growth medium) ) shake the plate for 5 minutes, then at room temperature Incubate for 5 minutes and measure the luminescence (Trilux, Perkin Elmer). Example 126

Rati Soft Agarose Assay Rati cells were suspended in 1% steose (Lonza) at a density of 1 cell per well (96 wells). The agarose/cell mixture is allowed to set. The test compound was serially diluted with dms, then added to the agarose cell mixture (final DMSO concentration of 0.2%)' and incubated at 37 ° C and 5% CO 2 . After π days, the community was determined by culturing the cells with alamarBlue (TREK Diagnostics) and measuring the metabolic activity with a Spectramax plate reader (Molecular Devices, Inc; measuring absorbance at 562 nm). growing situation. 150205.doc •95- 201209050 Example 127 Liver Microsomal Clearance Assay An in vitro microsomal clearance test was designed to assess the potential risks associated with the hepatic metabolic stability of the compound. Test compound (1 μΜ) with liver microsomes (〇5 mg/mL) of different species (mouse, rat, monkey, dog and human) and 100 mM containing NADPH (1 mM) at 37 °C Incubate with acid clock buffer. At a specific reaction time point (0, 5, 10 and 30 minutes), the reaction aliquot was removed and the reaction was terminated by the addition of ice-cold acetonitrile containing the internal standard for mass spectrometry. The sample was centrifuged and the supernatant was analyzed by LC-MS/MS. In vitro metabolic half-life (heart 2, min) and intrinsic clearance (CLint, pL/min/mg) are based on the metabolic rate and extent of the test compound, such as the parent compound self-reactive mixing. The condition of disappearance was measured. These values can be scaled to predict hepatic-induced beta removal (CLh, mL/min/kg) and extraction rate (ER, expressed as the ratio of predicted hepatic metabolic clearance to hepatic blood flow in the species) . It is generally accepted that compounds with higher CLint or ER levels predicted in vitro are at higher risk of expo exposure imiting metabolism in vivo. The following table gives the measured extraction rates for some of the compounds of the invention.

150205.doc •96· 201209050 7 . People NH, ', 彳 ηνύ, N-N J NH Λ F〇Y 0.65 0.91 4 , 〇 person NH, Λ ηνύ, N~N 1 NH Λ F〇,. &lt;0.31 0.40 6 . People NH, ', 彳 ηνύ, N-N J NH 1 °7&quot;〇 0.69 3 ,. NH &quot;'S ηνύ, N-N J NH 〇. 0.69 0.85 150205.doc -97- 201209050

A549 ρ38α MAP Kinase Bright-Glo Reporter Gene Assay A549 cells were stably transfected with the IL-8 promoter driven reporter pGL3-IL8-Luc. Cells were plated at 4χ105 cells/ml in 384-well solid white plates (40 μM per well, 5.0% CD-FBS, lxp/S, DMEM) and incubated at 37 ° C overnight (18-20 hours) ). The test compound was serially diluted with DMSO, and then 50 nl of the test solution was added to the culture (final DMS oxime concentration was 〇 1%). After incubation with the test compound for 30 minutes, the cells were stimulated with i ng/ml lL_ip (1 〇 μΐ 5 ng/ml solution per well). After 78 hours of stimulation, Bright-Gl was added. (25 μl per well) to measure luciferase performance. The table below gives the IC5() data for some of the compounds of the invention. 150205.doc 98- 201209050 Compound structure A549 p38 RGA ic50~m) A375 CP ic50_) (p38 RGA)/(A3 75) ratio 9 , 0 person NH , , , ' NN J NH ^ 0 10 0 2.2 0.002 1100 32 , . Human NH S'&quot; ΗΝΛ d NN J NH 1 0 0.69 0.031 91 29 I NN J NH 1 F〇t〇17 0.076 220 Example 129 In vivo pharmacokinetic assay Complete pharmacokinetic study: Male Balb/c mice (n=3, body weight 22-25 g) or male Wistar rat (n=3, body weight 250-300 g) administered intravenously via the lateral tail vein or by oral gavage Test compounds. The formulation is typically a solution of 2.5 mg/mL of the compound in 75% PEG 300 and 25% D5 W. After administration, six blood samples were continuously collected over 24 hours 150205.doc •99·201209050 (50 μM each. The blood samples were centrifuged to separate plasma. Plasma samples were analyzed and quantified by LC-MS/MS. Pharmacokinetic studies: Male Balb/c mice (η=3, body weight g) or male Wistar rats (η=3, body weight 250-300 g) were administered intravenously (IV) via the lateral tail vein or The test compound is administered orally (PO) via gavage. The formulation is typically a 2.5 mg/mL solution of the compound in 75% PEG 300 and 25% D5W. After administration, six blood samples are continuously collected over 24 hours (each 50 pL). The blood sample was centrifuged, and plasma was separated, and plasma was collected at each time point in each of the three animals. Plasma samples were analyzed and quantified by LC-MS/MS. For the study and rapid pharmacokinetic study, the following parameters were calculated by non-compartmental regression analysis using Winnonlin 5.0 software (Pharsight, Mountain View, CA, US A): plasma clearance (C1), maximum plasma concentration (Cmax), Plasma concentration-time curve area (AUC) 〇-inf) and oral bioavailability percentage (F%). The following table gives some pharmacokinetic parameters of the compounds of the invention in mice. 150205.doc -100- 201209050 Compound number structure dose (mg/kg) PO/ IV CI(mL/min/kg) PO AUC (h-μΜ) PO Cmax (μΜ) F(%) , 〇 and NH 9 ηνύ, Cl 10/2 4.3 ±0.4 30 Earth 4 27 ±4 43 ±6 τ r^\ fV \X NN / NH F〇f〇'CT^NH hnyS 7 nOf 10/2 99 0.24 0.15 8 IV\ ±13 ±0.21 ±0.07 ±7 &lt;hr \X NN Λ / NH F〇$〇 , 〇^NH , , '.k 4 ' 1 ηνύ, 10/2 41 3.0 2.0 36 ±9 ±0.5 ±0.5 ±6 fV Ol NN NH f〇7^〇150205.doc • 101 - 201209050 6 people NH , ',.SX NN _ 1 Q'h Strict 0 10/2 61 Soil 6 1.1 ±0.2 0.60 ±0.02 15 Earth 3 3 'Ο人 NH &quot;&quot;S ηνύν' X Ν-Ν Λ 5/2 51 (n =l) 0.20 (n=l) 0.07 (n=l) 6 (n=l) 1 , 〇人ΝΗ,, ',.S HfV, Cl 5/2 ------ 7.0 9.7 7.4 46 rr NN 1 ¢1 Q, h 严0 -~~-- (n=l) (n=l) (n=l) (n=l) free form or pharmaceutically acceptable 〗 Salt form of compound of formula by pharmacologically exhibit characteristic táng value, e.g., as the application of the present in vitro and in vivo tests indicated. For example, the ICso exhibited by the compound in the A375 cP cell proliferation assay is preferably in the range of 250 nM or better, and the car is less than 200 η Μ, 150 Μ Μ, 1 〇〇 Μ and 50 nM.

The 2-(methoxycarbonylamino)_ 1 propyl group at Ri provides a preferred level of activity and 150205.doc -102-201209050 outperforms the selectivity of other kinases, including p3 8 . For example, the activity between compounds 9 and 29 is increased by more than 3 fold, wherein A375 IC5 is 2 nM and 76 nM, respectively, and the phenyl substitution type of the formula is for metabolic stability (ER in mice and humans). Most preferably, wherein fluorine or chlorine is at the scale 5 position and the fluorine, gas or sulfhydryl group is at the R3 position. In contrast, for example, the ERs (humans) of Compounds 9 and 6 are &lt;〇.21 and &lt;〇.69, respectively. The combination of 2-(nonoxycarbonylamino)-hydrazine-propyl, sulphate-substituted, and methyl at the ampule at R! has a surprising effect on total drug exposure (AUC). See, for example Compound 9 (compared to compounds 1, 3, 4, 6 and 7), wherein the AUC was 30 ± 4 μλ/Ih at an oral dose of 10 mg/kg. Example 130 In vivo efficacy-14 days Α375 mouse xenograft model Under sterile conditions, the A375 cells were grown for 2 to 4 weeks in a 5% C02. (The cells were cultured in RPMI-1640 medium supplemented with 1% fbs twice a week. The cells were subcultured with % trypsin/EDTA. On the day of implantation, the cells were collected in HBSS (Hank's Balanced Salt Solution). On day 1, 2 mL of A3 75 cells were used. 50% matrigel subcutaneous (SQ) implanted in female Nu/Nu mice (Charles River, at the beginning of the study ι〇_ι 1 week) in the right abdomen '5 × 1 〇 6 A375 per mouse Cells: 19 days after implantation, mice were randomized into 6 groups (9 mice per group) with an average tumor volume of 2丨5 mm3 and an average body weight of 24 g. The test compound was administered twice daily for a dose of 〇·2 mL per dose for 14 days, in which the compound was formulated at a concentration of 150205.doc •103·201209050 to obtain the desired dose. Clinical observations were performed daily. Tumor volume and body weight were measured twice a week. End point: Any individual animal or group exhibited a body weight loss of more than 25% of the initial body weight and/or a tumor volume of more than 3000 mm3. According to the above protocol, Compound 9 was administered using the following course of administration ( Formulated in 20〇/〇 PEG300/3% ETPGS/77% water): Group 1: vehicle, once daily X14 Group 2: 1 mg/kg Compound 9, twice daily χ14 Group 3: 3 mg /kg of compound 9, twice daily χ14 Group 4: 1 〇mg/kg of compound 9, twice daily χ14 Group 5: 20 mg/kg of compound 9, twice per sputum 14 14 days after initial administration Tumor volume results. Tumor growth was determined as a partial response to 20-50°/❶ of the control tumor growth. The final tumor volume was determined to be stable within +/- 20°/ of the initial tumor size. The final tumor volume was less than the initial tumor volume. 80% of the tumor volume is determined to be partially resolved. Group 2: Part Reaction Group 3: Stable Disease Group 4: Partial Regression Group 5: Partial Regression It should be understood that the examples and examples described herein are for illustrative purposes only, and those skilled in the art will make various modifications accordingly. Or such changes, and such modifications or variations are included in the scope and scope of the application and the scope of the patent application. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety in their entirety herein BRIEF DESCRIPTION OF THE DRAWINGS 150205.doc •104·201209050 Figure 1 illustrates the inhibition produced by the addition of a MEK inhibitor to the compound of formula I of the present invention. 150205.doc 105-

Claims (1)

201209050 VII. Patent application scope: 1. A compound of formula la, R3 Wherein: Y is selected from N and CR6; R2, R3, 115 and R6 are independently selected from the group consisting of hydrogen, _ cyano, Ci 4 alkyl, substituted by dentate, c] 4 methoxy and Substituted by a dentate group C].4 methoxyl; the limiting condition is when &amp; is &lt;&amp;&gt; is selected from the group consisting of t. '-X^sa^-X, OX2R8a. -X,C(0)NR8aR8b -X)NR8aX2R8b ^ and _x]NR8aS(〇)〇2R8b when hydrogenation is not hydrogen; R4 is selected from -R9 and -NRl〇Rii; wherein r9 is selected from Ci 6 alkyl, C3 8 a cycloalkyl group, a c3-8 heterocycloalkyl group, an aryl group, and a heteroaryl group; wherein the alkyl group of the R9 of the alkyl group, the heterocyclic alkyl group, the aryl group or the heteroaryl group is optionally 1 to 3 independently Substituted from a group selected from the group consisting of a cyano group, a cyano group, a c alkyl group, a halogen group substituted Gw alkyl group, a Cm alkoxy group, and a dentate group substituted with a Ci4 alkoxy group; and the Rio and R&quot; are independently It is selected from the group consisting of hydrogen and R9; R7 is selected from the group consisting of hydrogen, Cl-4 alkyl, C3_5 cycloalkyl and c3_5 heterocycloalkyl; wherein the pendant, cycloalkyl or heterocycloalkyl group of R? 3 independently selected from halo, cyano, hydroxy, C _4 alkyl, substituted by halo 150205.doc 201209050 c!·4 alkyl, Cl_4 alkane The substituent group by halo and Cl4 alkoxy groups; or a mutually acceptable salts tautomers, prodrugs, stereoisomers or pharmaceutically. 2. The compound of claim 1, wherein R4 is -R9; wherein R9 is selected from the group consisting of Cw Hyun and C3-8 cycloalkyl; wherein the alkyl or cycloalkyl group of R9 is independently from 1 to 3 Substituted for a group selected from a benzyl group and a halogen-substituted Ci 4 alkyl group. 3. The compound of claim 2, wherein: r2 is selected from the group consisting of hydrogen and fluorine; & is selected from the group consisting of chlorine, fluorine, and methyl; R5 is selected from the group consisting of hydrogen, gas, and fluorine; and gamma is selected from the group consisting of N and CR6; Han 6 is selected from the group consisting of hydrogen and fluorine. 4. A compound according to claim 3, which is selected from the group consisting of: N-[(2S)-bu({4-[3-(3-gas·5·decanesulfonylamino)-1-(propyl) -2-yl)-1Η-»Bizozol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamic acid methyl ester; N-[(2S)-l-[(4 -{3-[2-Fluoro-3-(propan-1-sulfonylamino)phenyl]_ι_(prop-2-yl)_ih_pyrazol-4-yl}pyrimidin-2-yl)amino] Methyl propan-2-yl]amino decanoate; fluoro-3-decanesulfonylaminophenyl)-1-(propan-2-yl)-1Η-pyrazole-4-yl]pyrimidin-2- Methyl}amino)propan-2-yl]carbamic acid methyl ester; N-[(2S)-1-[(4-{3-[3-gas-5-(propan-1-one) Phenyl]-1-(propan-2-yl)-i 吼 _ 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 甲酯 甲酯 甲酯 甲酯 甲酯 甲酯 甲酯 甲酯 甲酯 甲酯 甲酯 甲酯 甲酯1-({4-[3-(2,6-difluoro-3-methanesulfonylamino)-1-(propan-2-yl)-1Η-pyrazol-4-yl]pyrimidine-2 -yl}amino)propan-2-yl]amino decanoate; N-[(2S)-l-[(4-{3-[2,6-difluoro-3.(propane-1-) Sulfonyl)phenyl]-1-(propan-2-yl)-1Η-.bazol-4-yl}pyrimidin-2-yl)amino]propyl-2-yl] carbamic acid carboxylate; N-[(2S)-l-{[4-(3-{2-Fluoro-3-[(3,3,3-trifluoropropene 150205.doc -2- 201209050) Amino acid] benzyl}-1-(propan-2-yl)-1Η-π than wow-4-yl) ° 密_2_2 yl]amino}propan-2-yl]amino decanoate ;&gt;^-[(23)-1-({4-[3-(3-chloro-2-nonanesulfonylaminopyridin-4-yl)-1-(propan-2-yl)-1Η) -pyrazolyl]. Methyl-2-amino}amino)propan-2-yl]amino decanoate; N-[(2S)-l-({4-[3-(3-fluoro-) 2-methanesulfonylaminopyridine_4-yl)-bu(propan-2-yl)-1 Η-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]amino Nitrate citrate; N-[(2S)-1-({4-[3-(2-chloro-3-ethanesulfonylamino)-4,5-difluorophenyl)-1-(propyl- 2-yl)_1Η-η ratio. 坐-4-yl]pyrimidin-2-yl}amino)propan-2-yl]amino decanoate; N-[(2S)-l-({4 -[3-(2,4-difluoro-3-methanesulfonylaminophenyl)-1_(prop-2-yl)-1Η-pyrazol-4-yl]pyrimidin-2-yl}amino) Propionate, &gt;1-[(28)-1-({4-[1-(propan-2-yl)-3-(2,4,5-three) Fluorine-3_甲院石黄醯 aminophenyl)-1Η-»Bizozol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]amino decanoate; N-[ (2S)-l-({4-[3-(3-decanesulfonylaminophenyl)_1_(propan-2-yl)-lH-. N-[(2S)-l-({4-[3-(3-ethane)] benzyl 4-amino]pyrimidin-2-yl}amino)propan-2-yl]amino decanoate Sulfonamide 2,4-difluorophenyl)-1-(propan-2-yl)-1Η-pyrazol-4-yl]pyrimidine-2-yl}amino)propan-2-yl]amine Methyl carbazate; N-[(2S)-2-({4-[3-(5-chloro-2-fluoro-3-decanesulfonylamino)-1-(propan-2-yl) )-1Η-pyrazol-4-yl]pyrimidin-2-yl}amino)propyl]aminocarbamic acid methyl ester; N-[(2S)-l-({4-[3-(5-gas- 2-fluoro-3·decanesulfonic acid basic group)-1 - (oxazepine-2-yl)-1H-. ratio. sit-4-yl]. 密定定_2~ base} Ethyl)propan-2-yl]carbamic acid decyl ester; n_[(2S)-1 -|χ4-·{3-[2,4-difluoro-3-(propan-1-indolyl) )phenyl]_丨_(propion-2-yl)_1Η_pyrazole_4_ base}.疋-2-yl)amino]propan-2-yl]amino decanoic acid; n_[(2s)-1_ ({4-[3-(3-cyclopropanesulfonylamino) 2,5- Difluorophenyl)_丨_(propen-2-yl 150205.doc 201209050 1 Η-.bazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamic acid oxime; N-[(2S)-l-({4-[3-(5-Gas-3-cyclopropanesulfonylamino-2-fluorophenyl)-1-(propan-2-yl)_1H-pyrazole) 4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamic acid oxime ester; and N-[(2S)-l-[(4-{3-[5-gas-2- Fluoro-3-(propane-1-sulfonylamino)benzyl]-1-(propan-2-yl)-1H- ° than 〇-4-yl} ° dense sigma-2-yl)amine Methyl propan-2-yl]carbamate. 5. A compound according to claim 1 which has the formula Ib: Wherein: R3 is selected from the group consisting of chlorine, fluorine and sulfhydryl; Rs is selected from the group consisting of fluorine and gas; and R7 is selected from the group consisting of ethyl and isopropyl. 6. The compound of claim 5, which is selected from the group consisting of: N-[(2S)-l-({4-[3-(5-虱-2-rat_3-曱 醯 醯 醯 ) ))) -1-(propan-2-yl)-1Η-η ratio π sitting _4_ yl] 密 定 -2- -2-yl}amino) propan-2-yl] carbamic acid 曱 g; ({4- [3-(2,5-Difluoro-3-methanesulfonylaminophenyl)_1-(propan-2-yl)-111_ ° than sal-4-yl]pyrimidin-2-yl}amino)propane- 2-yl]aminocarbamic acid tortoise; N_[(2S)-l-({4-[3-(5-Gas-2-fluoro-3-methanesulfonylamino)phenyl]-ethyl -°boxazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamic acid methyl ketone; 150205.doc • 4 - 201209050 N-[(2S)-l-({4- [3-(2-Fluoro-3-decanesulfonylamino-5-methylphenyl)]-(propan-2-yl)-1Η-pyrazol-4-yl]pyrimidin-2-yl}amine N-[(2S)-l-({4-[3-(2-chloro-3-indolesulfonylamino)-5-methylphenyl) )-1-(propan-2-yl)-1Η-°bizozol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]amino decanoate; N-[(2S)- L-({4-[3-(2-Ga-5-fluoro-3-methanesulfonylamino)-1-(propan-2-yl)-1Η-°bizozol-4-yl; Methyl-2-yl}amino)propan-2-yl]carbamate; N-[(2R)-l-({4-[3-(5-gas-) 2-fluoro-3-methyl-sinterdylaminophenyl)-1-(propan-2-ylpyrazol-4-yl)pyrimidin-2-yl}amino)propan-2-yl]carbamic acid Ester; N-[(2S)-l-({4-[3-(;2,5-diox-3-indole) decylphenyl)-l-(propan-2-yl)-lH -° 嗤-4-yl]°Midyl-2-yl}amino)propan-2-yl]amino decanoate, and n-[(2S)-1-({4-[3 -(5-Gas-2-fluoro-3-decanesulfonylamino)-1 Η-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]aminopurine An acid ester. 7. A compound selected from the group consisting of: Ν-[5-gas-3-(4-{2-[(2-cyanoethyl)amino]pyrimidin-4-yl}-1 -(propan-2-yl)-1Η-pyrazol-3-yl)-2-fluorophenyl]decanesulfonamide; N-{5-gas_3-[4-(2-{[2- (didecylamino)ethyl]amino}pyrimidin-4-yl)-1_(propan-2-yl)-1Η-pyrazol-3-yl]-2-fluorophenyl}methanesulfonamide; N-(5-Gas-2-fluoro-3-{4-[2-(indolyl)pyrimidin-4-yl]-1-(propan-2-yl)_ih-pyrazol-3-yl} Phenyl)nonanesulfonamide; and N-{3-[4-(2-aminopyrimidin-4-yl)-1-(propan-2-yl)-1Η-pyrazol-3-yl]- 5-Gas-2-fluorophenyl}decanesulfonamide. 8. A compound selected from the group consisting of: 3-bromo-5-aero-2-fluoroaniline; cyano-(2-indolyl-pyrimidin-4-yl)-acetic acid tert-butyl ester; 1-iso Propyl-4-(2-(methylthio)pyrimidin-4-yl)-lH-pyrazol-3-amine; 2-((2-benzylidene-1-ethylhydrazine 150205.doc 201209050 (indolyl)-malononitrile; i-O-aminoisopropyl-1H-pyrazole-4-yl) ethyl ketone; 1-(3-iodoisopropyl_1H-carbazole _4• group Ethyl ketone; iodine-ethyl 嗤·4_yl) ethyl ketone; 1-(3_iodo-1-indolyl-1H-pyrazole-4-yl) ethyl ketone, 3-(dimethylamino) 1-(3-iodo-1-isopropyl-1Η-pyrazole-4-yl)propan-2-en-1-one; 3-(dimethylamino)-1-(3-iodo-1 -ethyl_1H, pyrazole-4-yl)prop-2-ene_ι·ketone; 3-(dimethylamino)iodomethylpyrazol-4-yl)prop-2-en-1-one ; 4-(3-iodo-1-isopropyl-1 Η-pyrazole _4_yl) ° αα定-2-amine, 4-(3-E-1-ethyl·ιη·〇 ratio. Sit- 4-base) π dense. 1-2 amine; 4-(3·iodo-1-indolyl-1Η-pyrazol-4-yl)pyrimidine-2-amine; 4-(3-iodoisopropyl-1H-pyrazol-4-yl Pyrimidine-2-ol; 2-chloro-4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidine; isopropyl-1H-oxazol-4-yl)pyrazine Ethyl-2-ylamino)propan-2-ylamino decanoate; $)^(4-(3-Eth-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl Methylamino)propan-2-methyl carbazate; (S)-l-(4-(3-iodo-1-isopropyl-1-indole-pyrazol-4-yl)pyridin-2-ylamine Tert-butyl 3-propylaminocarbamate;, ('(i-iodo-^isopropyl-1Η-pyrazol-4-yl)pyrimidin-2-ylamino)propanenitrile; 4-( 3-iodo-1-isopropyl-1H-pyrazol-4-yl)-N-decylpyrimidin-2-amine;:^-(4-(3-iodo-1_isopropyl-1H-pyridyl) Zin-4-yl)pyrimidin-2-yl)-N2,N2-dimercaptoethane-1,2-diamine; N-(3-bromo-2,4-difluorophenyl)propane _1 _ indoleamine; 3_fluoro-4_iodine. Bis-2-amine; 3-ox-4-iodopyridin-2-amine; 3-bromo-2,5,6-trifluoroaniline; 2.4-dibromo-3,6-di-aniline; 3-bromo 2-ox-5-mercaptoaniline; 3-bromo-2.5-difluoroaniline; 3-bromo-5-gas-2-fluorobenzoic acid; 3-bromo-5-chloro-2-fluorophenylamine Tert-butyl carboxylic acid; tert-butyl 3-bromo-2-fluoro-5-nonylphenylamino decanoate; 5-chloro-2-fluoro-3-(4,4,5,5-four Mercapto-1,3,2-diboron-flavor-2-150205.doc -6 - 201209050 phenyl)phenylaminocarboxylic acid tert-butyl S| ; 2,6_H(4,4,5,5_tetraindole Base _ 1,3,2-dioxaboron-2-yl)phenylamino decanoic acid second---; N-(2,4-difluoro- 5,5-tetramethyl-(10)dioxo Butterfly. "· base" stupid base) propane " · sulfonamide; 2-(2-fluoro-3-nitrophenyl) _4,4,5,5_tetradecyl _132 two #: flavor; 2 , 5 · difluoride 5,5_tetradecyl ... with two L Peng :::) • gas · 3 · (Μ, 5,5 · tetramethyl cut.: oxygen end 2_ base) ^ ^ two gas Methyl-like dimethyl-dioxyl base), *, 2-indole-5-methyl-3-(4,4,5,5-tetramethylq 3 #yl)aniline H5-fluorenyl- 3, 5,5_tetradecyl 2 = taste I, taste-2-yl) tert-butyl phenylaminocarbamate; 3_fluoro-lactoboryl-I,3,2-dioxosole_2_ base). Bisidine a, amine ' '5 two \ four A (AA ^ r , 2,3,6-difluoro-5-, methyl-1,3,2 · dioxygrain) ° ratio ... ^ gas '' '5-Tetramethyl-1,3,2-dioxopurine_2-yl) strepamine; and 3_methoxy_2-methyl-5-(4,4,5,5-tetramethyl Base q 3 2_-oxygen 9. 10. - a medical doctor I ^ *, 2 - money taste_2_ base) stupid amine. A medicinal composition comprising as claimed in any one of claims (1) in admixture with at least one pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 9, wherein the excipient is selected from the group consisting of: corn house powder 'potato powder, wooden temple powder, rape: nano pregelatinized powder, sugar, gelatin, natural Glue, synthetic rubber, brown; Cannes, alginic acid, tragacanth, guar gum, cellulose, ethyl cellulose, ethyl cellulose, cellulose, methyl cellulose, methyl cellulose, methyl Cellulose, (tetra)methylcellulose, microcrystalline cellulose, magnesium alumite, polyvinylpyrrolidone, talc, calcium carbonate, powdered cellulose, Portuguese 150205.doc 201209050 glucose binder (dextrate), Kaolin, mannitol, citric acid, sorbitol, agar, sodium carbonate, croscarmellose sodium, crospovidone, p〇iacriiin p〇tassium, hydroxyl Acetic acid; sodium powder, clay, sodium stearate, stearic acid, stearic acid, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, Other diols, sodium lauryl sulfate, hydrogenated vegetable oil, peanut oil, cottonseed oil, sunflower oil Sesame oil, Han olive oil, corn oil, soybean oil, zinc stearate, sodium oleate, ethyl oleate, ethyl laureate, silicon dioxide, and combinations thereof. 11. 12. 13. 14. 15. 16. The pharmaceutical composition of claim 9, which additionally comprises another therapeutic agent. The pharmaceutical composition according to claim 11, wherein the other therapeutic agent is selected from the group consisting of an anticancer compound, an analgesic, an antiemetic, an antidepressant, and an anti-inflammatory agent. A compound according to any one of claims 1 to 7 for use in the treatment of cancer. The compound of claim 13, wherein the cancer to be treated is selected from the group consisting of lung cancer, pancreatic cancer, bladder cancer, colon cancer, bone marrow disorder, adenocarcinoma, squamous cell carcinoma, melanoma, gland Tumor, and cancer of the ovary, eyes, liver, biliary tract and nervous system. A use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to any one of claims 9 to 2 for the manufacture of a medicament for use in a home treatment or a disease. The use of claim 15, wherein the cancer is selected from the group consisting of:, lung cancer, pancreatic cancer, bladder cancer, colon cancer, bone marrow stenosis, prostate cancer, thyroid cancer, melanoma, adenoma, And the cancer of the nest, the liver, the biliary tract and the nervous system. 150205.doc 201209050 17. The use of claim 15 or 16, wherein the medicament additionally comprises another therapeutic agent. 18. The use of claim 17, wherein the additional therapeutic agent comprises an anticancer drug, a pain drug, an antiemetic, an antidepressant or an anti-inflammatory agent. 1 9. The use of claim 18, wherein the another therapeutic agent is a different Raf kinase inhibitor, or MEK, mTOR, HSP90, AKT, PI3K, CDK9, PAK, protein kinase C, MAP kinase, MAPK kinase or ERK Inhibitor. 20. The use of claim 19, wherein the MEK inhibitor is selected from the group consisting of: AS703026 'MSC1936369B, GSK1120212, AZD6244, PD-0325901, ARRY-438162, RDEA119, GDC0941, GDC0973, TAK-733, R05126766, and XL-518. 2 1. The use of claim 20, wherein the additional therapeutic agent is administered to the individual concurrently with the compound. 22. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to any one of claims 9 to 12 for the manufacture of a condition mediated by Raf kinase Drug. 23. The use of claim 22, wherein the Raf kinase is a mutant b-Raf kinase. 20. 24. The use of claim 23, wherein the mutant b-Raf kinase is b-Raf (V600E). 150205.doc