CN105473560A

CN105473560A - Therapeutically active compounds and use methods thereof

Info

Publication number: CN105473560A
Application number: CN201480046845.2A
Authority: CN
Inventors: Z·D·孔塔替斯; J·泊泊威次-马勒; J·M·特维斯; R·扎勒; 蔡振伟; 周鼎
Original assignee: Agios Pharmaceuticals Inc
Current assignee: Laboratoires Servier SAS
Priority date: 2013-07-11
Filing date: 2014-07-10
Publication date: 2016-04-06
Anticipated expiration: 2034-07-10
Also published as: CN105473560B; CN111087353B; CN111087353A

Abstract

Provided are compounds useful for treating cancer and methods of treating cancer comprising administering to a subject in need thereof a compound described herein.

Description

Therapeutical active compound and using method thereof

Priority request

This application claims the right of priority of the international application serial PCT/CN2013/079200 that on July 11st, 2013 submits to, this international application is combined in this in full with it by reference.

Background of invention

The decarboxylation of isocitric enzyme (IDH) catalysis isocitrate oxidation becomes 2-oxoglutaric acid (2-oxoglutarate) (that is, α-ketoglutaric acid).These enzymes belong to two kinds of different subclass, and one of them utilizes NAD (+) as electron acceptor(EA) and another kind utilizes NADP (+) as electron acceptor(EA).Reported five kinds of isocitric enzymes: three kinds of NAD (+) dependency isocitric enzymes, these enzymes are positioned at mitochondrial matrix; With two kinds of NADP (+) dependency isocitric enzymes, wherein a kind of is mitochondrial and another kind mainly kytoplasm.Often kind of NADP (+) dependency isozyme is all a kind of homodimer.

IDH1 (isocitric enzyme 1 (NADP+), kytoplasm) is also referred to as IDH; IDP; IDCD; IDPC or PICD.It is NADP (+) the dependency isocitric enzyme found in tenuigenin and peroxysome by the protein of this genes encoding.It comprises PTS-1 peroxysome target signal sequence.The existence of this enzyme in peroxysome indicates in the regeneration of the NADPH for reducing in peroxysome, as the conversion of 2,4-dienoyl-CoA to 3-enoyl--CoA; And consuming the peroxidase precursor reactant of 2-oxoglutaric acid, i.e. the effect of the 'alpha '-hydroxylation aspect of Phytanoic acid.Tenuigenin enzyme provides remarkable effect in tenuigenin NADPH production.

Mankind IDH1 genes encoding one has 414 amino acid whose protein.The Nucleotide of mankind IDH1 and aminoacid sequence can find with GenBank entry NM_005896.2 and NP_005887.2 accordingly.Described by the Nucleotide of IDH1 and aminoacid sequence also have in following each: the people such as the such as Tan Ke of resistance to Crewe (Nekrutenko), " molecular biology and evolution " (Mol.Biol.Evol.) 15:1674-1684 (1998); The people such as this mine-laying lucky uncommon special (Geisbrecht), " journal of biological chemistry " (J.Biol.Chem.) 274:30527-30533 (1999); The people such as Wei Man (Wiemann), " genome research " (GenomeRes.) 11:422-435 (2001); MGC project team, " genome research " 14:2121-2127 (2004); The people such as Lu Beike (Lubec), submit to (in December, 2008) to UniProt knowledge base; The people such as Coleman (Kullmann), submit to (in June, 1996) to EMBL/GenBank/DDBJ database; And the people such as Suo Qiaobulong (Sjoeblom), " science " (Science) 314:268-274 (2006).

The decarboxylation of non-mutant (such as, wild-type) IDH1 catalysis isocitrate oxidation becomes α-ketoglutaric acid, makes NAD thus ⁺(NADP ⁺) be reduced into NADH (NADPH), such as, in following positive reaction: isocitric acid+NAD ⁺(NADP ⁺) → α-KG+CO ₂+ NADH (NADPH)+H ⁺.

Have been found that the sudden change of the IDH1 be present in some cancer cells facilitates the new ability that this enzyme catalysis α-ketoglutaric acid NAPH dependency is reduced into R (-)-2-hydroxyl pentanedioic acid (2HG).The generation of 2HG is considered to the formation and the progress (red lattice, the people such as L (Dang, L), " nature " (Nature) 2009,462:739-44) that facilitate cancer.

IDH2 (isocitric enzyme 2 (NADP+), mitochondrial) is also referred to as IDH; IDP; IDHM; IDPM; ICD-M; Or mNADP-IDH.It is NADP (+) the dependency isocitric enzyme found in plastosome by the protein of this genes encoding.It works in intermediary metabolism and production capacity.This protein can closely be combined with pyruvate dehydrogenase complex or interact.Mankind IDH2 genes encoding one has 452 amino acid whose protein.The Nucleotide of IDH2 and aminoacid sequence can find with GenBank entry NM_002168.2 and NP_002159.2 accordingly.Described by the Nucleotide of mankind IDH2 and aminoacid sequence also have in following each: such as breathe out people such as (Huh), submit to (in November, 1992) to EMBL/GenBank/DDBJ database; With MGC project team, " genome research " 14:2121-2127 (2004).

The decarboxylation of non-mutant (such as, wild-type) IDH2 catalysis isocitrate oxidation becomes α-ketoglutaric acid (α-KG), makes NAD thus ⁺(NADP ⁺) be reduced into NADH (NADPH), such as, in following positive reaction:

Isocitric acid+NAD ⁺(NADP ⁺) → α-KG+CO ₂+ NADH (NADPH)+H ⁺.

Have been found that the sudden change of the IDH2 be present in some cancer cells facilitates the new ability that this enzyme catalysis α-ketoglutaric acid NAPH dependency is reduced into R (-)-2-hydroxyl pentanedioic acid (2HG).2HG is not formed by wild-type IDH2.The generation of 2HG is considered to the formation and the progress (red lattice, the people such as L, " nature " 2009,462:739-44) that facilitate cancer.

Therefore, mutation inhibiting type IDH1 and/or saltant type IDH2 and new activity thereof are a kind of potential therapeutic treatments for cancer.Therefore, there are the lasting needs to the inhibitor with new active IDH1 and/or the IDH2 mutant of α hydroxyl.

Summary of the invention

There is described herein the compound or its a kind of pharmacy acceptable salt or hydrate with Formula I:

wherein:

Ring A is the 5-6 unit's monocyclic aryl or bicyclic heteroaryl that are optionally substituted;

X is N, CH or C-halogen;

R ¹, R ³, R ⁴and R ⁶be selected from hydrogen, C independently of one another ₁-C ₄alkyl, C ₁-C ₄haloalkyl ,-O-C ₁-C ₄alkyl and CN, wherein R ¹, R ³, R ⁴and R ⁶each described moieties independently of one another optionally by-OH ,-NH ₂,-CN ,-O-C ₁-C ₄alkyl ,-NH (C ₁-C ₄alkyl) or-N (C ₁-C ₄alkyl) ₂replace;

R ²and R ⁵be selected from independently of one another :-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkyl)-C (O)-NH ₂,-(C ₁-C ₆alkyl)-CO ₂h ,-(C ₂-C ₆alkenyl or alkynyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶) (R ⁶) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-S (O) ₁- ₂-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-S (O) ₁- ₂-(C ₀-C ₆alkyl)-Q ,-(C ₁-C ₆alkylidene group)-S (O) ₁- ₂-N (R ⁶) (R ⁶) ,-(C ₁-C ₄alkylidene group)-S (O) ₁- ₂-N (R ⁶)-(C ₁-C ₆alkylidene group)-Q ,-C (O) N (R ⁶)-(C ₁-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-C (O) N (R ⁶)-(C ₁-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₀-C ₆alkyl)-Q ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶) C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶) C (O)-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-S (O) ₀- ₂-(C ₁-C ₆alkyl) _,-(C ₀-C ₆alkylidene group)-S (O) ₀- ₂-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-C (O)-N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-Q, wherein:

Be present in R ²and R ⁵in any alkyl or alkylene moiety optionally by one or more-OH ,-O (C ₁-C ₄alkyl) ,-CO ₂h or halogen replace;

Be present in R ²and R ⁵in any terminal methyl group moiety ground by-CH ₂oH, CF ₃,-CH ₂f ,-CH ₂cl, C (O) CH ₃, C (O) CF ₃, CN or CO ₂h replaces;

R ⁷and R ⁸be selected from hydrogen and C independently of one another ₁-C ₆alkyl; And

Q is selected from aryl, heteroaryl, carbocylic radical and heterocyclic radical, and wherein any one is optionally substituted; Wherein

R ¹and R ³optionally be attached to it together with carbon atom on it and form C (=O); Or

R ⁴and R ⁶optionally be attached to it together with carbon atom on it and form C (=O); Or

R ¹and R ²the heterocyclic radical optionally forming a carbocylic radical be optionally substituted together or be optionally substituted; Or

R ⁴and R ⁵optionally form the carbocylic radical be optionally substituted, the heterocyclic radical be optionally substituted, an aryl be optionally substituted or the heteroaryl be optionally substituted together;

Wherein:

(i) when X is N and A is the phenyl be optionally substituted, so (a) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NHCH ₂cH ₂oCH ₂cH ₂oCH ₂cH ₂nH ₂, 4-[[2-[2-(2-amino ethoxy) oxyethyl group] ethyl] amino] and (b) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all NHEt, NH (n-propyl), NH (normal-butyl), NH (dodecyl), NH-[(4-p-methoxy-phenyl) methyl], NHCH ₂cH ₂cHO, NHCH ₂cH ₂oCH ₃, NHCH ₂cH ₂oH, NHCH ₂cH (OH) CH ₃, NHCH ₂cH ₂oC (O) phenyl, NHCH ₂cH ₂cH ₂oH, NHCH ₂cH ₂cH ₂n (CH ₃) phenyl, NHCH ₂c (O) OCH ₃, NHCH ₂c (O) OCH ₂cH ₃, NHCH ₂phenyl, NHCH (CH ₃) CH ₂cH ₃or NHCH ₂cH ₂oC (O) CH ₃;

(ii) when X is CH or C-Cl and A is optionally by F, Cl or SO ₂cH ₃during the phenyl replaced, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all N (CH ₃) CH ₂c (O) NH-sec.-propyl, NHCH (CH ₃) (CH ₂) ₃n (CH ₂cH ₃) ₂, NHCH ₂cH ₂oH, NHCH ₂cH ₂oCH ₃, NHCH ₂cH ₂oSO ₃h, NHCH ₂cH ₂cH ₂oCH ₂cH ₂o-phenyl, NHCH ₂cH ₂cH ₂oH, NHCH ₂cH ₂cH ₂oCH ₃, NHCH ₂cH (OH) CH ₃, N (CH ₂cH ₃) ₂, NH-sec.-propyl, NHCH ₂cH ₂nHC (O) OCH ₃, NHCH ₂cH ₂nHC (O) CH ₃, NHCH ₂cH ₂nH ₂or NHCH ₂-phenyl;

(iii) when X is CH and A is the pyridyl be optionally substituted, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NHCH ₂-phenyl, NHCH ₂-(2,4 difluorobenzene base), N (CH ₃) CH ₂cH ₂c (O) OH, NHCH ₂cH ₂c (O) OH, NHCH ₂cH ₂c (O) OCH ₂cH ₃, NHCH ₂cH ₂c (O) the O-tertiary butyl, NHCH ₂cH ₂c (O) NH ₂, NHCH ₂cH ₂-phenyl, NHCH ₂cH ₂oH, NHCH ₂cH ₂nH ₂, NHCH ₂cH ₂n (CH ₃) ₂or NHCH ₂cH ₂cH ₃;

(iv) when X is CH and A be the 1-imidazolyl be optionally substituted, the 1-pyrryl be optionally substituted or be optionally substituted 1-pyrazolyl time, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NH (CH ₂) ₇cH ₃, NHCH ₂-(adjacent chloro-phenyl) or NHCH ₂cH ₂oH;

(v) when X be N and A be one be optionally substituted pyridyl time, so (A) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NHC (O)-[the chloro-4-of 2-(methyl sulphonyl)], N (CH ₃) ₂, NHCH ₂cH ₂cH ₂sO ₂cH ₂cH ₂cl, NHCH ₂cH ₂oCH ₂cH ₂sO ₂cH ₂cH ₂cl or NHCH ₂cH ₂sO ₂cH ₂cH ₂cl; (B) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all NHC (O) C (CH ₃) ₃, NHC (O) CH=CH ₂, NHC (O) C (CH ₃)=CH ₂, NHCH ₂cH ₂oH, NH-cyclohexyl, NHCH ₂-phenyl, NHC (O) phenyl, NHC (O) (CH ₂) ₅nH ₂, NHC (O) OCH ₃, NHC (O) CH ₃and the phenyl that NHC (O) NH-is optionally substituted; And (C) as N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) be NHC (CH ₃) ₃time, so N (R ⁸) C (R ¹) (R ²) (R ³) not NHCH ₂-phenyl or NH-CH ₂cH ₃;

(vi) when X is N and A is the heteroaryl be optionally substituted, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all N (CH ₂cH ₃) ₂, NHCH ₂cH ₂-sec.-propyl, NHCH ₂cH (CH ₃) ₂and NHC (O) CH ₃;

(vii) when X is CH and A is unsubstituted 2-pyridyl, so R is passed through ⁴and R ⁵the ring formed is not 5-methyl isophthalic acid H-pyrazole-3-yl;

(viii) when A is the 1-pyrazolyl be optionally substituted, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all N (CH ₃) ₂, NHCH ₃, NHAc, NH sec.-propyl, NHCH ₂cH ₃, NHCH ₂cH ₂sO ₃h or N (CH ₂cH ₃) ₂;

(ix) when X is N and A is the phenyl, thienyl or the pyridyl that are optionally substituted, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NH cyclohexyl C (O) NHCH ₂r, wherein R is by OCF ₃, OCH ₃, chlorine or CF ₃in the phenyl of one or more replacements or pyridyl;

X () is the phenyl and R that are optionally substituted when X is N, A ⁴and R ⁵when forming the phenyl be optionally substituted, so N (R ⁸) C (R ¹) (R ²) (R ³) not NHCH ₂(4-fluorophenyl), NHCH ₂cO ₂h, NHCH ₂c (O) Cl, NHCH (CO ₂h) (CH ₂sCH ₂phenyl), NHCH ₂c (O) NHC (O) NHR or NHCH ₂c (O) NHC (S) NHR, wherein R is the phenyl or naphthyl be optionally substituted;

(xi) when the X Yi oxadiazole that to be N, A replaced by a pyridyl be optionally substituted, so R ⁴and R ⁵do not form a phenyl be optionally substituted;

(xii) when A is the 1-pyrazolyl be substituted, so (A) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all NHC (CH ₃) ₃; And (B) A is not replaced by N=N-R, wherein R is ring;

(xiii) ring A is not the triazolyl, 3, the 5-dimethyl-1H-pyrazol-1-yls that are optionally substituted;

(xix) R is worked as ¹and R ²optionally form a unsubstituted cyclohexyl together, and R ⁴and R ⁵when optionally forming a unsubstituted cyclohexyl together, so A is not a dibasic 1-pyrazolyl or unsubstituted phenyl; And

(xx) this compound is not be selected from lower group:

(1) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-1H-indenes-2-base) is amino]-6-phenyl-1,3,5-triazines-2-base] is amino] methyl]-benzamide;

(2) the chloro-N-of 2-[4-(cyclopropylamino)-6-(2-pyridyl)-1,3,5-triazines-2-base]-4-(methyl sulphonyl)-benzamide;

(3) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazines-2-base]-1H-1,2,4-triazole-3-base] sulfenyl]-ethanamide;

(4) N ²-cyclopropyl-N ⁴-ethyl-6-[3-[(phenyl methyl) sulfenyl]-1H-1,2,4-triazol-1-yl]-1,3,5-triazines-2,4-diamines;

(5) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazines-2-base]-1H-1,2,4-triazole-3-base] sulfenyl]-methyl acetate;

(6) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridyl)-1,3,5-triazines-2-base] is amino] methyl] cyclohexyl] methyl] the fluoro-benzsulfamide of-4-;

(7) N ²-cyclopropyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)-N ⁴-phenyl-1,3,5-triazines-2,4-diamines;

(8) N ², N ⁴-dicyclohexyl-6-[3-(4-p-methoxy-phenyl)-5-(methylthio group)-1H-pyrazol-1-yl]-1,3,5-triazines-2,4-diamines;

(9) N ², N ⁴-dicyclohexyl-6-[3-(3,4-Dimethoxyphenyl)-5-(methylthio group)-1H-pyrazol-1-yl]-1,3,5-triazines-2,4-diamines;

(10) N ², N ⁴-dicyclohexyl-6-[5-(methylthio group)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-1-yl]-1,3,5-triazines-2,4-diamines;

(11) N ², N ⁴-dicyclohexyl-6-phenyl-1,3,5-triazines-2,4-diamines;

(12) 1,1'-[(6-phenyl-guanamine, 4-bis-base) diimino] two [ten dihydros-anthraquinone];

Two [two (1,1-the dimethyl ethyl)-phenol of 2,6-of (13) 4,4'-[(6-phenyl-1,3,5-triazines-2,4-bis-base) two (iminomethylene)];

(14) N-[4-[(4-aminobutyl) is amino]-6-[5-[[[[the chloro-3-of 4-(trifluoromethyl) phenyl] is amino] carbonyl] is amino]-2-aminomethyl phenyl]-1,3,5-triazine-2-base]-glycine;

(15) 4-[2-[[4-[(5-Aminopentyl) is amino]-6-(3-fluorophenyl)-1,3,5-triazines-2-base] is amino] ethyl]-phenol;

(16) 4-[2-[[4-[(5-Aminopentyl) is amino]-6-(4-fluorophenyl)-1,3,5-triazines-2-base] is amino] ethyl]-phenol;

(17) 6-(4-aminopyridine-3-base)-N ²-benzyl-N ⁴-(tertiary butyl)-1,3,5-triazines-2,4-diamines;

(18) N ², N ⁴-bis-(cyclohexyl methyl)-6-phenyl-1,3,5-triazines-2,4-diamines;

(19) 4,4'-[[6-[two (1,1-the dimethyl ethyl)-4-hydroxy phenyl of 3,5-]-1,3,5-triazine-2,4-bis-base] two (imino--3,1-propane two base)] two [two (1,1-dimethyl ethyl)-phenol of 2,6-;

Two [two (1,1-the dimethyl ethyl)-phenol of 2,6-of (20) 4,4'-[(6-phenyl-1,3,5-triazines-2,4-bis-base) two (imino--3,1-propane two base)];

(21) N-[6-[(2,3-dihydro-1H-indenes-2-base) is amino]-2-(2-pyridyl)-4-pyrimidyl]-beta Alanine;

(22) N ⁴-cyclopentyl-2-phenyl-N ⁶-(phenyl methyl)-4,6-pyrimidinediamine;

(23) 2-[[6-(dicyclo [2.2.1]-2-in heptan base is amino)-2-phenyl-4-pyrimidyl] is amino]-ethanol;

(24) N ²-sec.-propyl-6-phenyl-N4-(tetrahydrochysene-2H-pyrans-4-base)-1,3,5-triazines-2,4-diamines;

(25) the chloro-4-of 2-(methyl sulphonyl)-N-[4-[(phenyl methyl) is amino]-6-(2-pyridyl)-1,3,5-triazines-2-base]-benzamide;

(26) N-[[4-[[[4-(cyclopropyl)-6-(2-pyridyl)-1,3,5-triazines-2-base] is amino] methyl] cyclohexyl] methyl] the fluoro-benzsulfamide of-4-;

(27) [[4-[[[[[4-amino-6-(4-pyridyl)-1,3,5-triazine-2-base] amino] methoxyl group] methyl] amino]-6-(4-pyridyl)-1,3,5-triazines-2-base] imino-] two methyl alcohol;

(28) [[4-[[[[[4-[two (hydroxymethyl) is amino]-6-(4-pyridyl)-1,3,5-triazine-2-base] amino] methoxyl group] methyl] (hydroxymethyl) amino]-6-(4-pyridyl)-1,3,5-triazine-2-base] imino-] two methyl alcohol;

(29) 5-[two (diethylamino)-1,3,5-triazines-2-base of 4,6-]-2H-tetrazolium-2-ethyl acetate;

(30) N ², N ², N ⁴, N ⁴-tetraethyl--6-(2H-tetrazolium-5-base)-1,3,5-triazines-2,4-diamines;

(31) N, N'-[6-[4-(kharophen)-1,2,5-oxadiazole-3-base]-1,3,5-triazines-2,4-bis-base] bis-dimethylsilyl-acetamide;

(32) N-(the chloro-6-aminomethyl phenyl of 2-)-5-[[4-(dimethylamino)-6-(2-pyridyl)-1,3,5-triazines-2-base] is amino]-1,3,4-oxadiazole-2-methane amides;

(33) N4-(5-methyl isophthalic acid H-pyrazole-3-yl)-2-(2-pyridyl)-N6-(tetrahydrochysene-2H-pyrans-4-base)-4,6-pyrimidinediamines;

(34) 6-(4-chloro-phenyl-)-N2-[the chloro-3-of 4-(trifluoromethyl) phenyl]-N4-[3-(diethylamino) propyl group]-1,3,5-triazines-2,4-diamines;

(35) 6-(4-chloro-phenyl-)-N2-[the chloro-3-of 4-(trifluoromethyl) phenyl]-N4-[3-(dimethylamino) propyl group]-1,3,5-triazines-2,4-diamines;

(36) N2-[two (trifluoromethyl) phenyl of 3,5-]-6-(4-chloro-phenyl-)-N4-[3-(diethylamino) propyl group]-1,3,5-triazines-2,4-diamines;

(37) two [(4-p-methoxy-phenyl) methyl]-6-[4-(trifluoromethoxy) phenyl]-1,3,5-triazines-2,4-diamines of N2, N4-;

(38) N, N "-(6-phenyl-1,3,5-triazines-2,4-bis-base) two [N'-(2-chloroethyl)-urea;

(39) N-[the chloro-3-of 4-(trifluoromethyl) phenyl]-N'-[4-methyl-3-[[4-phenyl-6-(propylcarbamic)-1,3,5-triazines-2-base] is amino] phenyl]-urea;

(40) N-[4-[[5-[[[[the chloro-3-of 4-(trifluoromethyl) phenyl] is amino] carbonyl] is amino]-2-aminomethyl phenyl] is amino]-6-(4-pyridyl)-1,3,5-triazine-2-base]-glycine;

(41) N-[4-[[5-[[[[the chloro-3-of 4-(trifluoromethyl) phenyl] is amino] carbonyl] is amino]-2-aminomethyl phenyl] is amino]-6-(5-thiazolyl)-1,3,5-triazine-2-base]-Valine;

(42) 2-phenyl-4,6-two [[6-[[4-phenyl-6-[[6-[[4-phenyl-6-(trichloromethyl)-guanamine-Ji] is amino] hexyl] is amino]-guanamine-Ji] is amino] hexyl] is amino]-s-triazine;

(43) α, α '-[(6-phenyl-1,3,5-triazine-2,4-bis-base) two [imino-(1,1,2,2-tetra-fluoro-3-oxo-3,1-propane two base)]] two [ω-[tetrafluoro (trifluoromethyl) oxyethyl group]-poly-[oxygen base [trifluoro (trifluoromethyl)-1,2-ethane two base]];

(44) α-[[4-[[(3-chloro-phenyl-) methyl] is amino]-6-(1H-imidazoles-1-base)-1,3,5-triazine-2-base] amino]-N-[[4-(trifluoromethyl) phenyl] methyl]-, (α R)-hexanaphthene propionic acid amide;

(45) 6-(1H-imidazoles-1-base)-N ², N ⁴-bis-(1-methylethyl)-1,3,5-triazines-2,4-diamines; And

(46) N ², N ⁴-bis-(1-methyl-propyl)-6-phenyl-1,3,5-triazines-2,4-diamines.

Have Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc and IIId compound or as compound mutation inhibiting type IDH1 described in this any one embodiment or saltant type IDH2.Also describe at this pharmaceutical composition of compound comprising and there is Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc and IIId, and use such composition to treat the method that there is the cancer that saltant type IDH1 or saltant type IDH2 is feature.

Describe in detail

To illustrate in the following description or the structure of component illustrated in the accompanying drawings and the details of arrangement are not intended to be restrictive.For putting into practice in other embodiments of the present invention and different modes be expressly included.Equally, wording and term are all for purposes of illustration as used herein, and should not be considered to be restrictive.At this use of " comprising (including) ", " comprising (comprising) " or " having (having) ", " containing (containing) ", " relating to (involving) " and variant thereof represented and contain project listed after which and its equivalent and etceteras.

definition:

Term " halogen " or " halogen " refer to any group in fluorine, chlorine, bromine or iodine.

Term " alkyl " refers to that, containing the completely saturated of specified quantity carbon atom or undersaturated hydrocarbon chain, this hydrocarbon chain can be straight or branched.Such as, C ₁-C ₁₂alkyl represents in this group can have from 1 to 12 (comprising end value) carbon atoms.Term " haloalkyl " refers to the alkyl that wherein one or more hydrogen atoms are replaced by halogen, and comprises wherein all hydrogen by moieties (such as perfluoroalkyl) that halogen is replaced.Term " arylalkyl " or " aralkyl " refer to the moieties that wherein alkyl hydrogen atom is replaced by aryl.Aralkyl comprises one of them above hydrogen atom by group that aryl is replaced.The example of " arylalkyl " or " aralkyl " comprises benzyl, 2-styroyl, 3-hydrocinnamyl, 9-fluorenyl, diphenyl-methyl and trityl.Term " alkyl " comprises " thiazolinyl " and " alkynyl ".

Term " alkylidene group " refers to divalent alkyl, such as-CH ₂-,-CH ₂cH ₂-,-CH ₂cH ₂cH ₂-and-CH ₂cH (CH ₃) CH ₂-.

Term " thiazolinyl " refers to containing 2-12 carbon atom and has the straight or branched hydrocarbon chain of one or more double bond.The example of thiazolinyl includes but not limited to allyl group, propenyl, crotyl, 3-hexenyl and 3-octenyl.One of double key carbon can be optionally the tie point of alkenyl group.

Term " alkynyl " refers to containing 2-12 carbon atom and is characterised in that the straight or branched hydrocarbon chain with one or more triple bond.The example of alkynyl includes but not limited to ethynyl, propargyl and 3-hexin base.One of triple bond carbon can be optionally the tie point of alkynyl substituted base.

Term " alkoxyl group " refers to-O-alkyl.Term " halogenated alkoxy " refers to the alkoxyl group that wherein one or more hydrogen atoms are replaced by halogen, and comprises wherein all hydrogen by alkoxy portion (such as, perfluoro alkoxy) that halogen is replaced.

Unless otherwise indicated, otherwise term " aryl " refers to complete aromatic monocycle, dicyclo or tricyclic hydrocarbon loop systems.The example of aryl moiety is phenyl, naphthyl and anthryl.Unless otherwise indicated, any annular atoms otherwise in aryl can be replaced by one or more substituting group.Term " monocyclic aryl " means the complete aromatic hydrocarbons loop systems of monocycle, is optionally replaced by one or more substituting group that can not form condensed-bicyclic or three rings.

Term " carbocylic radical " refers to the monocycle of non-aromatic, dicyclo or tricyclic hydrocarbon loop systems.Carbocylic radical comprises completely saturated loop systems (such as, cycloalkyl) and the loop systems of fractional saturation.Carbocylic radical also comprises spirocyclic moiety.The example of spirocyclic moiety includes but not limited to dicyclo [3.1.0] hexyl, spiral shell [2.2] amyl group, spiral shell [3.3] heptyl, spiral shell [2.5] octyl group, spiral shell [3.5] nonyl, spiral shell [4.5] decyl and spiral shell [3.6] decyl.Unless otherwise indicated, any annular atoms otherwise in carbocylic radical can be replaced by one or more substituting group.

Wherein aryl-condensedly be regarded as carbocylic radical (such as, cycloalkyl) to the tie point of molecule rest part through the dicyclo of non-aromatic ring or three-loop system in carbocylic radical and from loop systems.The example of this type of carbocyclyl moieties includes but not limited to 2,3-dihydro-1H-indenes and 1,2,3,4-tetralin.

As this term " cycloalkyl " that adopts comprise saturated cyclic, dicyclo, three rings or the multi-ring alkyl with 3 to 12 carbon.Any annular atoms can be replaced by (such as, by one or more substituting group).The example of cycloalkyl moiety includes but not limited to cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl and norcamphyl.

Unless otherwise indicated, otherwise term " heteroaryl " refers to the loop systems with 1-3 heteroatoms (if monocycle), the complete aromatic 5-8 unit monocycle of a 1-6 heteroatoms (if dicyclo) or 1-9 heteroatoms (if three rings), 8-12 unit's dicyclo or 11-14 unit three rings, described heteroatoms is selected from O, N or S, and (or oxidised form, as N ⁺-O-, S (O) and S (O) ₂).Term " bicyclic heteroaryl " means to have 1-3 the complete aromatic ring system of heteroatomic monocycle, is optionally replaced by one or more substituting group that can not form condensed-bicyclic or three rings.

Term " heterocyclic radical " refers to the loop systems with 1-3 heteroatoms (if monocycle), the 3-10 unit monocycle of non-aromatic of a 1-6 heteroatoms (if dicyclo) or 1-9 heteroatoms (if three rings), 8-12 unit's dicyclo or 11-14 unit three rings, described heteroatoms is selected from O, N or S, and (or oxidised form, as N ⁺-O-, S (O) and S (O) ₂).This heteroatoms can be optionally the tie point of heterocyclyl substituent.The example of heterocyclic radical includes but not limited to tetrahydrofuran base, THP trtrahydropyranyl, piperidyl, morpholinyl, pyrrolinyl, pyrimidyl and pyrrolidyl.Heterocyclic radical comprises completely saturated loop systems and the loop systems of fractional saturation.

Heterocyclic radical or heteroaryl is all regarded as containing one or more heteroatomic dicyclo and three-loop system and aromatic series and non-aromatic ring.Wherein aryl or be heteroaryl-condensedly accordingly regarded as aryl or heteroaryl to the tie point of molecule rest part through the dicyclo of aromatic ring or three-loop system in carbocylic radical or heterocyclic radical and from loop systems.Wherein aryl or be heteroaryl-condensedly accordingly regarded as carbocylic radical (such as, cycloalkyl) or heterocyclic radical to the tie point of molecule rest part through the dicyclo of non-aromatic ring or three-loop system in carbocylic radical or heterocyclic radical and from loop systems.

Aryl, heteroaryl, carbocylic radical (comprising cycloalkyl) and heterocyclic radical or separately or as a group a part (such as, the aryl moiety of aralkyl) be optionally substituted with a substituent at one or more atom place that replaces, unless otherwise, otherwise these substituting groups independently selected from halogen ,-C ≡ N, C ₁-C ₄alkyl ,=O ,-OR ^b,-OR ^{b '},-SR ^b,-SR ^{b '},-(C ₁-C ₄alkyl)-N (R ^b) (R ^b) ,-(C ₁-C ₄alkyl)-N (R ^b) (R ^{b '}) ,-N (R ^b) (R ^b) ,-N (R ^b) (R ^{b '}) ,-O-(C ₁-C ₄alkyl)-N (R ^b) (R ^b) ,-O-(C ₁-C ₄alkyl)-N (R ^b) (R ^{b '}) ,-(C ₁-C ₄alkyl)-O-(C ₁-C ₄alkyl)-N (R ^b) (R ^b) ,-(C ₁-C ₄alkyl)-O-(C ₁-C ₄alkyl)-N (R ^b) (R ^{b '}) ,-C (O)-N (R ^b) (R ^b) ,-(C ₁-C ₄alkyl)-C (O)-N (R ^b) (R ^b) ,-(C ₁-C ₄alkyl)-C (O)-N (R ^b) (R ^{b '}) ,-OR ^{b '}, R ^{b '},-C (O) (C ₁-C ₄alkyl) ,-C (O) R ^{b '},-C (O) N (R ^{b '}) (R ^b) ,-N (R ^b) C (O) (R ^b) ,-N (R ^b) C (O) (R ^{b '}) ,-N (R ^b) SO ₂(R ^b) ,-SO ₂n (R ^b) (R ^b) ,-N (R ^b) SO ₂(R ^{b '}) and-SO ₂n (R ^b) (R ^{b '}), wherein any alkyl substituent is optionally further by-OH ,-O-(C ₁-C ₄alkyl), halogen ,-NH ₂,-NH (C ₁-C ₄alkyl) or-N (C ₁-C ₄alkyl) ₂in one or more replacements;

Each R ^ball independently selected from hydrogen and-C ₁-C ₄alkyl; Or

Two R ^bform 4-to a 8-unit heterocyclic radical together with the nitrogen-atoms of its bond, this heterocyclyl ground comprises the other heteroatoms that is selected from N, S and O; And

Each R ^{b '}all independently selected from C ₃-C ₇carbocylic radical, phenyl, heteroaryl and heterocyclic radical, the one or more commutable position on wherein said phenyl, cycloalkyl, heteroaryl or heterocyclic substituent is optionally further by-(C ₁-C ₄alkyl) ,-(C ₁-C ₄fluoroalkyl) ,-OH ,-O-(C ₁-C ₄alkyl) ,-O-(C ₁-C ₄fluoroalkyl), halogen ,-NH ₂,-NH (C ₁-C ₄alkyl) or-N (C ₁-C ₄alkyl) ₂in one or more replacements.

Heterocyclic radical or separately or as the part of a group on one or more any commutable nitrogen-atoms optionally by oxo ,-C ₁-C ₄the C of alkyl or fluoro-replacement ₁-C ₄alkyl replaces.

Term " is substituted " and refers to that hydrogen atom is by another group displacement.

Term " body fluid " comprise in the following one or more: around the amniotic fluid of fetus, aqueous humour, blood (such as, blood plasma), serum, cerebrospinal fluid, earwax, chyme, examine amber liquid, Female ejaculation, interstitial fluid, lymph, breast milk, mucus (such as, nasal cavity drainage or phlegm), Pleural fluid, purulence, saliva, sebum, seminal fluid, serum, sweat, tear, urine, vaginal secretions or vomitus.

As used herein, term " suppression " or " prevention " comprise completely and part suppresses and both prevention.Inhibitor completely or partially can suppress to expect target.

Term " treatment " means to reduce, suppress, weaken, weaken, stop or stablize a kind of disease/illness (such as, cancer) development or progress, alleviate this disease/illness (such as, cancer) severity or improve the symptom relevant with this disease/illness (such as, cancer).

As used herein, the amount effectively can treating a kind of illness of compound or " treatment significant quantity " refer to after giving single dose or multiple doses to experimenter, this compound exceedes to be expected when there is not such treatment, effectively can to treat the amount that cell or healing, mitigation, alleviation or improvement suffer from a kind of experimenter of illness.

As used herein, term " experimenter " is intended to comprise the mankind and non-human animal.Exemplary human experimenter comprises and suffers from a kind of illness, the human patients (being called patient) of such as illness described herein or normal subjects.The term " non-human animal " of one aspect of the present invention comprises all vertebratess, such as, nonmammalian (as chicken, Amphibians, Reptilia) and Mammals, as the animal of non-human primate, domestic and/or agriculturally useful, such as sheep, dog, cat, ox, pig etc.

compound

Provide a kind of compound or its a kind of pharmacy acceptable salt or the hydrate with Formula I:

wherein:

X is N, CH or C-halogen;

R ²and R ⁵be selected from independently of one another :-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkyl)-C (O)-NH ₂,-(C ₁-C ₆alkyl)-CO ₂h ,-(C ₂-C ₆alkenyl or alkynyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶) (R ⁶) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-S (O) ₁- ₂-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-S (O) ₁- ₂-(C ₀-C ₆alkyl)-Q ,-(C ₁-C ₆alkylidene group)-S (O) ₁- ₂-N (R ⁶) (R ⁶) ,-(C ₁-C ₄alkylidene group)-S (O) ₁- ₂-N (R ⁶)-(C ₁-C ₆alkylidene group)-Q ,-C (O) N (R ⁶)-(C ₁-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-C (O) N (R ⁶)-(C ₁-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₁-C ₆alkyl) _,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₀-C ₆alkyl)-Q ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶) C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶) C (O)-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-S (O) ₀- ₂-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-S (O) ₀- ₂-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-C (O)-N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-Q, wherein:

Wherein:

(vii) when X is CH and A is unsubstituted 2-pyridyl, so R is passed through ⁴and R ⁵the ring formed is not 5-methyl isophthalic acid H-pyrazole-3-yl,

(viii) when A is the 1-pyrazolyl be optionally substituted, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all N (CH ₃) ₂, NHCH ₃, NHAc, NH sec.-propyl, NHCH ₂cH ₃, NHCH ₂cH ₂sO ₃h or N (CH ₂cH ₃) ₂,

(ix) when X is N and A is the phenyl, thienyl or the pyridyl that are optionally substituted, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NH cyclohexyl C (O) NHCH ₂r, wherein R is by OCF ₃, OCH ₃, chlorine or CF ₃in the phenyl of one or more replacements or pyridyl,

X () is the phenyl and R that are optionally substituted when X is N, A ⁴and R ⁵when forming the phenyl be optionally substituted, so N (R ⁸) C (R ¹) (R ²) (R ³) not NHCH ₂(4-fluorophenyl), NHCH ₂cO ₂h, NHCH ₂c (O) Cl, NHCH (CO ₂h) (CH ₂sCH ₂phenyl), NHCH ₂c (O) NHC (O) NHR or NHCH ₂c (O) NHC (S) NHR, wherein R is the phenyl or naphthyl be optionally substituted,

(xi) when the X Yi oxadiazole that to be N, A replaced by a pyridyl be optionally substituted, so R ⁴and R ⁵do not form a phenyl be optionally substituted,

(xii) when A is the 1-pyrazolyl be substituted, so (A) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all NHC (CH ₃) ₃; And (B) A is not replaced by N=N-R, wherein R is ring,

(xiii) ring A is not the triazolyl, 3, the 5-dimethyl-1H-pyrazol-1-yls that are optionally substituted,

(xx) this compound is not be selected from lower group:

(1) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-1H-indenes-2-base) is amino]-6-phenyl-1,3,5-triazines-2-base] is amino] methyl]-benzamide,

(2) the chloro-N-of 2-[4-(cyclopropyl)-6-(2-pyridyl)-1,3,5-triazines-2-base]-4-(methyl sulphonyl)-benzamide,

(3) 2-[[1-[4-(cyclopropyl)-6-(ethylamino)-1,3,5-triazines-2-base]-1H-1,2,4-triazole-3-base] sulfenyl]-ethanamide,

(4) N ²-cyclopropyl-N ⁴-ethyl-6-[3-[(phenyl methyl) sulfenyl]-1H-1,2,4-triazol-1-yl]-1,3,5-triazines-2,4-diamines,

(5) 2-[[1-[4-(cyclopropyl)-6-(ethylamino)-1,3,5-triazines-2-base]-1H-1,2,4-triazole-3-base] sulfenyl]-methyl acetate,

(6) N-[[4-[[[4-(cyclopropyl)-6-(2-pyridyl)-1,3,5-triazines-2-base] is amino] methyl] cyclohexyl] methyl] the fluoro-benzsulfamide of-4-,

(7) N ²-cyclopropyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)-N ⁴-phenyl-1,3,5-triazines-2,4-diamines,

(8) N ², N ⁴-dicyclohexyl-6-[3-(4-p-methoxy-phenyl)-5-(methylthio group)-1H-pyrazol-1-yl]-1,3,5-triazines-2,4-diamines,

(9) N ², N ⁴-dicyclohexyl-6-[3-(3,4-Dimethoxyphenyl)-5-(methylthio group)-1H-pyrazol-1-yl]-1,3,5-triazines-2,4-diamines,

(10) N ², N ⁴-dicyclohexyl-6-[5-(methylthio group)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-1-yl]-1,3,5-triazines-2,4-diamines,

(11) N ², N ⁴-dicyclohexyl-6-phenyl-1,3,5-triazines-2,4-diamines,

(12) 1,1'-[(6-phenyl-guanamine, 4-bis-base) diimino] two [ten dihydros-anthraquinone],

(13) 4,4'-[(6-phenyl-1,3,5-triazines-2,4-bis-base) two (iminomethylene)] two [two (1,1-the dimethyl ethyl)-phenol of 2,6-,

(14) N-[4-[(4-aminobutyl) is amino]-6-[5-[[[[the chloro-3-of 4-(trifluoromethyl) phenyl] is amino] carbonyl] is amino]-2-aminomethyl phenyl]-1,3,5-triazine-2-base]-glycine

(15) 4-[2-[[4-[(5-Aminopentyl) is amino]-6-(3-fluorophenyl)-1,3,5-triazines-2-base] is amino] ethyl]-phenol,

(16) 4-[2-[[4-[(5-Aminopentyl) is amino]-6-(4-fluorophenyl)-1,3,5-triazines-2-base] is amino] ethyl]-phenol,

(17) 6-(4-aminopyridine-3-base)-N ²-benzyl-N ⁴-(tertiary butyl)-1,3,5-triazines-2,4-diamines,

(18) N ², N ⁴--two (cyclohexyl methyl)-6-phenyl-1,3,5-triazines-2,4-diamines,

(19) 4,4'-[[6-[two (1,1-the dimethyl ethyl)-4-hydroxy phenyl of 3,5-]-1,3,5-triazine-2,4-bis-base] two (imino--3,1-propane two base)] two [2, two (1,1-the dimethyl ethyl)-phenol of 6-

(20) 4,4'-[(6-phenyl-1,3,5-triazines-2,4-bis-base) two (imino--3,1-propane two base)] two [two (1,1-the dimethyl ethyl)-phenol of 2,6-,

(21) N-[6-[(2,3-dihydro-1H-indenes-2-base) is amino]-2-(2-pyridyl)-4-pyrimidyl]-beta Alanine,

(22) N ⁴-cyclopentyl-2-phenyl-N ⁶-(phenyl methyl)-4,6-pyrimidinediamine,

(23) 2-[[6-(dicyclo [2.2.1]-2-in heptan base is amino)-2-phenyl-4-pyrimidyl] is amino]-ethanol,

(24) N ²-sec.-propyl-6-phenyl-N4-(tetrahydrochysene-2H-pyrans-4-base)-1,3,5-triazines-2,4-diamines,

(25) the chloro-4-of 2-(methyl sulphonyl)-N-[4-[(phenyl methyl) is amino]-6-(2-pyridyl)-1,3,5-triazines-2-base]-benzamide,

(26) N-[[4-[[[4-(cyclopropyl)-6-(2-pyridyl)-1,3,5-triazines-2-base] is amino] methyl] cyclohexyl] methyl] the fluoro-benzsulfamide of-4-,

(27) [[4-[[[[[4-amino-6-(4-pyridyl)-1,3,5-triazine-2-base] amino] methoxyl group] methyl] amino]-6-(4-pyridyl)-1,3,5-triazine-2-base] imino-] two methyl alcohol

(28) [[4-[[[[[4-[two (hydroxymethyl) is amino]-6-(4-pyridyl)-1,3,5-triazine-2-base] amino] methoxyl group] methyl] (hydroxymethyl) amino]-6-(4-pyridyl)-1,3,5-triazine-2-base] imino-] two methyl alcohol

(29) 5-[two (diethylamino)-1,3,5-triazines-2-base of 4,6-]-2H-tetrazolium-2-ethyl acetate,

(30) N ², N ², N ⁴, N ⁴-tetraethyl--6-(2H-tetrazolium-5-base)-1,3,5-triazines-2,4-diamines,

(31) N, N'-[6-[4-(kharophen)-1,2,5-oxadiazole-3-base]-1,3,5-triazines-2,4-bis-base] bis-dimethylsilyl-acetamide,

(32) N-(the chloro-6-aminomethyl phenyl of 2-)-5-[[4-(dimethylamino)-6-(2-pyridyl)-1,3,5-triazines-2-base] is amino]-1,3,4-oxadiazole-2-methane amides,

(33) N4-(5-methyl isophthalic acid H-pyrazole-3-yl)-2-(2-pyridyl)-N6-(tetrahydrochysene-2H-pyrans-4-base)-4,6-pyrimidinediamines,

(34) 6-(4-chloro-phenyl-)-N2-[the chloro-3-of 4-(trifluoromethyl) phenyl]-N4-[3-(diethylamino) propyl group]-1,3,5-triazines-2,4-diamines,

(35) 6-(4-chloro-phenyl-)-N2-[the chloro-3-of 4-(trifluoromethyl) phenyl]-N4-[3-(dimethylamino) propyl group]-1,3,5-triazines-2,4-diamines,

(36) N2-[two (trifluoromethyl) phenyl of 3,5-]-6-(4-chloro-phenyl-)-N4-[3-(diethylamino) propyl group]-1,3,5-triazines-2,4-diamines,

(37) two [(4-p-methoxy-phenyl) methyl]-6-[4-(trifluoromethoxy) phenyl]-1,3,5-triazines-2,4-diamines of N2, N4-,

(38) N, N "-(6-phenyl-1,3,5-triazines-2,4-bis-base) two [N'-(2-chloroethyl)-urea,

(39) N-[the chloro-3-of 4-(trifluoromethyl) phenyl]-N'-[4-methyl-3-[[4-phenyl-6-(propylcarbamic)-1,3,5-triazines-2-base] is amino] phenyl]-urea,

(40) N-[4-[[5-[[[[the chloro-3-of 4-(trifluoromethyl) phenyl] is amino] carbonyl] is amino]-2-aminomethyl phenyl] is amino]-6-(4-pyridyl)-1,3,5-triazine-2-base]-glycine

(41) N-[4-[[5-[[[[the chloro-3-of 4-(trifluoromethyl) phenyl] is amino] carbonyl] is amino]-2-aminomethyl phenyl] is amino]-6-(5-thiazolyl)-1,3,5-triazine-2-base]-Valine

(42) 2-phenyl-4,6-two [[6-[[4-phenyl-6-[[6-[[4-phenyl-6-(trichloromethyl)-guanamine-Ji] is amino] hexyl] is amino]-guanamine-Ji] is amino] hexyl] is amino]-s-triazine

(43) α, α '-[(6-phenyl-1,3,5-triazine-2,4-bis-base) two [imino-(1,1,2,2-tetra-fluoro-3-oxo-3,1-propane two base)]] two [ω-[tetrafluoro (trifluoromethyl) oxyethyl group]-poly-[oxygen base [trifluoro (trifluoromethyl)-1,2-ethane two base]]

(44) α-[[4-[[(3-chloro-phenyl-) methyl] is amino]-6-(1H-imidazoles-1-base)-1,3,5-triazine-2-base] amino]-N-[[4-(trifluoromethyl) phenyl] methyl]-, (α R)-hexanaphthene propionic acid amide

(45) 6-(1H-imidazoles-1-base)-N ², N ⁴-bis-(1-methylethyl)-1,3,5-triazines-2,4-diamines, and

(46) N ², N ⁴-bis-(1-methyl-propyl)-6-phenyl-1,3,5-triazines-2,4-diamines.

wherein:

X is N, CH or C-halogen;

R ¹, R ³, R ⁴and R ⁶be selected from hydrogen, C independently of one another ₁-C ₄alkyl, C ₁-C ₄haloalkyl ,-O-C ₁-C ₄alkyl and CN, wherein R ¹, R ³, R ⁴and R ⁶any moieties independently of one another optionally by-OH ,-NH ₂,-CN ,-O-C ₁-C ₄alkyl ,-NH (C ₁-C ₄alkyl) or-N (C ₁-C ₄alkyl) ₂replace;

R ²and R ⁵be selected from independently of one another :-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkyl)-C (O)-NH ₂,-(C ₁-C ₆alkyl)-CO ₂h ,-(C ₂-C ₆alkenyl or alkynyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶) (R ⁶) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-S (O) ₁- ₂-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-S (O) ₁- ₂-(C ₀-C ₆alkyl)-Q ,-(C ₁-C ₆alkylidene group)-S (O) ₁- ₂-N (R ⁶) (R ⁶) ,-(C ₁-C ₄alkylidene group)-S (O) ₁- ₂-N (R ⁶)-(C ₁-C ₆alkylidene group)-Q ,-C (O) N (R ⁶)-(C ₁-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-C (O) N (R ⁶)-(C ₁-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₀-C ₆alkyl)-Q _,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶) C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶) C (O)-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-S (O) ₀- ₂-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-S (O) ₀- ₂-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-C (O)-N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-Q, wherein:

R ⁴and R ⁵the heterocyclic radical optionally forming a carbocylic radical be optionally substituted together or be optionally substituted;

Wherein:

(i) when X is N and A is the phenyl be optionally substituted, so (a) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all 4-[[2-[2-(2-amino ethoxy) oxyethyl group] ethyl] is amino] and (b) N (R7) C (R4) (R5) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all NHEt, NH (n-propyl), NH (normal-butyl), NH (dodecyl), NH-[(4-p-methoxy-phenyl) methyl], NHCH ₂cH ₂cHO, NHCH ₂cH ₂oCH ₃, NHCH ₂cH ₂oH, NHCH ₂cH (OH) CH ₃, NHCH ₂cH ₂oC (O) phenyl, NHCH ₂cH ₂cH ₂oH, NHCH ₂cH ₂cH ₂n (CH ₃) phenyl, NHCH ₂c (O) OCH ₃, NHCH ₂c (O) OCH ₂cH ₃, NHCH ₂phenyl, NHCH (CH ₃) CH ₂cH ₃or NHCH ₂cH ₂oC (O) CH ₃;

(v) when X be N and A be one be optionally substituted pyridyl time, so (A) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NHC (O)-[the chloro-4-of 2-(methyl sulphonyl)]; (B) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all NHC (O) C (CH ₃) ₃, NHC (O) CH=CH ₂, NHC (O) C (CH ₃)=CH ₂, NHCH ₂cH ₂oH, NH-cyclohexyl, NHCH ₂-phenyl, NHC (O) phenyl, NHC (O) (CH ₂) ₅nH ₂, NHC (O) OCH ₃, NHC (O) CH ₃and optionally by the phenyl of NHC (O) NH replacement; And (C) as N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) be NHC (CH ₃) ₃time, so N (R ⁸) C (R ¹) (R ²) (R ³) not NHCH ₂-phenyl or NH-CH ₂cH ₃;

(vii) this compound is not be selected from lower group:

(1) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N ⁴-cyclopentyl-6-phenyl-1,3,5-triazines-2,4-diamines,

(2) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N ⁴-cyclopentyl-6-(4-p-methoxy-phenyl)-1,3,5-triazines-2,4-diamines,

(3) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N ⁴-cyclopentyl-6-(3-nitrophenyl)-1,3,5-triazines-2,4-diamines,

(4) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N ⁴-cyclopentyl-6-(4-fluorophenyl)-1,3,5-triazines-2,4-diamines,

(5) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N ⁴-cyclopentyl-6-(4-trifluoromethoxy-phenyl)-1,3,5-triazines-2,4-diamines,

(6) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N ⁴-cyclopentyl-6-(4-tbutyl-phenyl)-1,3,5-triazines-2,4-diamines,

(7) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N ⁴-cyclopentyl-6-(2-thienyl)-1,3,5-triazines-2,4-diamines,

(8) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-1H-indenes-2-base) is amino]-6-phenyl-1,3,5-triazines-2-base] is amino] methyl]-benzamide,

(9) the chloro-N-of 2-[4-(cyclopropyl)-6-(2-pyridyl)-1,3,5-triazines-2-base]-4-(methyl sulphonyl)-benzamide,

(10) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N ⁴-cyclopropyl-6-(4-p-methoxy-phenyl)-1,3,5-triazines-2,4-diamines,

(11) 2-[[1-[4-(cyclopropyl)-6-(ethylamino)-1,3,5-triazines-2-base]-1H-1,2,4-triazole-3-base] sulfenyl]-ethanamide,

(12) N ²-cyclopropyl-N ⁴-ethyl-6-[3-[(phenyl methyl) sulfenyl]-1H-1,2,4-triazol-1-yl]-1,3,5-triazines-2,4-diamines,

(13) 2-[[1-[4-(cyclopropyl)-6-(ethylamino)-1,3,5-triazines-2-base]-1H-1,2,4-triazole-3-base] sulfenyl]-methyl acetate,

(14) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N ⁴-cyclopropyl-6-(2,4,6-trimethylphenyl)-1,3,5-triazines-2,4-diamines,

(15) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N ⁴-cyclopropyl-6-phenyl-1,3,5-triazines-2,4-diamines,

(16) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N ⁴-cyclopropyl-6-(4-aminomethyl phenyl)-1,3,5-triazines-2,4-diamines,

(17) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N ⁴-cyclopropyl-6-(4-chloro-phenyl-)-1,3,5-triazines-2,4-diamines,

(18) N-[[4-[[[4-(cyclopropyl)-6-(2-pyridyl)-1,3,5-triazines-2-base] is amino] methyl] cyclohexyl] methyl] the fluoro-benzsulfamide of-4-,

(19) N ²-cyclopropyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)-N ⁴-phenyl-1,3,5-triazines-2,4-diamines,

(20) N ², N ⁴-dicyclohexyl-6-[3-(4-p-methoxy-phenyl)-5-(methylthio group)-1H-pyrazol-1-yl]-1,3,5-triazines-2,4-diamines,

(21) N ², N ⁴-dicyclohexyl-6-[3-(3,4-Dimethoxyphenyl)-5-(methylthio group)-1H-pyrazol-1-yl]-1,3,5-triazines-2,4-diamines,

(22) N ², N ⁴-dicyclohexyl-6-[5-(methylthio group)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-1-yl]-1,3,5-triazines-2,4-diamines,

(23) N ², N ⁴-dicyclohexyl-6-phenyl-1,3,5-triazines-2,4-diamines,

(24) 1,1'-[(6-phenyl-guanamine, 4-bis-base) diimino] two [ten dihydros-anthraquinone],

(25) 4,4'-[(6-phenyl-1,3,5-triazines-2,4-bis-base) two (iminomethylene)] two [two (1,1-the dimethyl ethyl)-phenol of 2,6-,

(26) N-[4-[(4-aminobutyl) is amino]-6-[5-[[[[the chloro-3-of 4-(trifluoromethyl) phenyl] is amino] carbonyl] is amino]-2-aminomethyl phenyl]-1,3,5-triazine-2-base]-glycine

(27) 4-[2-[[4-[(5-Aminopentyl) is amino]-6-(3-fluorophenyl)-1,3,5-triazines-2-base] is amino] ethyl]-phenol,

(28) 4-[2-[[4-[(5-Aminopentyl) is amino]-6-(4-fluorophenyl)-1,3,5-triazines-2-base] is amino] ethyl]-phenol,

(29) 6-(4-aminopyridine-3-base)-N ²-benzyl-N ⁴-(tertiary butyl)-1,3,5-triazines-2,4-diamines,

(30) N ², N ⁴-bis-(cyclohexyl methyl)-6-phenyl-1,3,5-triazines-2,4-diamines,

(31) 4,4'-[[6-[two (1,1-the dimethyl ethyl)-4-hydroxy phenyl of 3,5-]-1,3,5-triazine-2,4-bis-base] two (imino--3,1-propane two base)] two [2, two (1,1-the dimethyl ethyl)-phenol of 6-

(32) 4,4'-[(6-phenyl-1,3,5-triazines-2,4-bis-base) two (imino--3,1-propane two base)] two [two (1,1-the dimethyl ethyl)-phenol of 2,6-,

(33) N-[6-[(2,3-dihydro-1H-indenes-2-base) is amino]-2-(2-pyridyl)-4-pyrimidyl]-beta Alanine,

(34) N4-cyclopentyl-2-phenyl-N6-(phenyl methyl)-4,6-pyrimidinediamine,

(35) 2-[[6-(dicyclo [2.2.1]-2-in heptan base is amino)-2-phenyl-4-pyrimidyl] is amino]-ethanol,

(36) N ²-sec.-propyl-6-phenyl-N4-(tetrahydrochysene-2H-pyrans-4-base)-1,3,5-triazines-2,4-diamines,

(37) the chloro-4-of 2-(methyl sulphonyl)-N-[4-[(phenyl methyl) is amino]-6-(2-pyridyl)-1,3,5-triazines-2-base]-benzamide,

(38) N-[[4-[[[4-(cyclopropyl)-6-(2-pyridyl)-1,3,5-triazines-2-base] is amino] methyl] cyclohexyl] methyl] the fluoro-benzsulfamide of-4-,

(39) [[4-[[[[[4-amino-6-(4-pyridyl)-1,3,5-triazine-2-base] amino] methoxyl group] methyl] amino]-6-(4-pyridyl)-1,3,5-triazine-2-base] imino-] two methyl alcohol

(40) [[4-[[[[[4-[two (hydroxymethyl) is amino]-6-(4-pyridyl)-1,3,5-triazine-2-base] amino] methoxyl group] methyl] (hydroxymethyl) amino]-6-(4-pyridyl)-1,3,5-triazine-2-base] imino-] two methyl alcohol

(41) 5-[two (diethylamino)-1,3,5-triazines-2-base of 4,6-]-2H-tetrazolium-2-ethyl acetate,

(42) N ², N ², N ⁴, N ⁴-tetraethyl--6-(2H-tetrazolium-5-base)-1,3,5-triazines-2,4-diamines, and

(43) N, N'-[6-[4-(kharophen)-1,2,5-oxadiazole-3-base]-1,3,5-triazines-2,4-bis-base] bis-dimethylsilyl-acetamide.

wherein:

X is N or CH;

R ²and R ⁵be selected from independently of one another :-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkyl)-C (O)-NH ₂,-(C ₁-C ₆alkyl)-CO ₂h ,-(C ₂-C ₆alkenyl or alkynyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶) (R ⁶) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-S (O) ₁- ₂-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-S (O) ₁- ₂-(C ₀-C ₆alkyl)-Q ,-(C ₁-C ₆alkylidene group)-S (O) ₁- ₂-N (R ⁶) (R ⁶) ,-(C ₁-C ₄alkylidene group)-S (O) ₁- ₂-N (R ⁶)-(C ₁-C ₆alkylidene group)-Q ,-C (O) N (R ⁶)-(C ₁-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-C (O) N (R ⁶)-(C ₁-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₀-C ₆alkyl)-Q ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₀-C ₆alkylidene group)-Q _,-(C ₁-C ₆alkylidene group)-N (R ⁶) C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶) C (O)-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-S (O) ₀- ₂-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-S (O) ₀- ₂-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-C (O)-N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-Q, wherein:

Wherein:

(vii) this compound is not be selected from lower group:

(12) N ²-cyclopropyl-N4-ethyl-6-[3-[(phenyl methyl) sulfenyl]-1H-1,2,4-triazol-1-yl]-1,3,5-triazines-2,4-diamines,

(14) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N4-cyclopropyl-6-(2,4,6-trimethylphenyl)-1,3,5-triazines-2,4-diamines,

(15) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N4-cyclopropyl-6-phenyl-1,3,5-triazines-2,4-diamines,

(16) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N4-cyclopropyl-6-(4-aminomethyl phenyl)-1,3,5-triazines-2,4-diamines,

(17) N ²-[2-[2-(2-amino ethoxy) oxyethyl group] ethyl]-N4-cyclopropyl-6-(4-chloro-phenyl-)-1,3,5-triazines-2,4-diamines,

(23) N ², N ⁴-dicyclohexyl-6-phenyl-1,3,5-triazines-2,4-diamines,

(30) N ², N ⁴-bis-(cyclohexyl methyl)-6-phenyl-1,3,5-triazines-2,4-diamines,

(34) N ⁴-cyclopentyl-2-phenyl-N6-(phenyl methyl)-4,6-pyrimidinediamine,

Additionally provide a kind of compound or its a kind of pharmacy acceptable salt or the hydrate with Formula I:

wherein:

X is N or CH;

R ²and R ⁵be selected from independently of one another :-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkyl)-C (O)-NH ₂,-(C ₁-C ₆alkyl)-CO ₂h ,-(C ₂-C ₆alkenyl or alkynyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶) (R ⁶) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-S (O) ₁- ₂-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-S (O) ₁- ₂-(C ₀-C ₆alkyl)-Q ,-(C ₁-C ₆alkylidene group)-S (O) ₁- ₂-N (R ⁶) (R ⁶) ,-(C ₁-C ₄alkylidene group)-S (O) ₁- ₂-N (R ⁶)-(C ₁-C ₆alkylidene group)-Q ,-C (O) N (R ⁶)-(C ₁-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-C (O) N (R ⁶)-(C ₁-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₀-C ₆alkyl)-Q ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶) C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶) C (O)-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-S (O) ₀- ₂-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-S (O) ₀- ₂-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-C (O)-N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-Q, wherein:

Wherein:

(xx) this compound is not be selected from lower group:

(7) N ²-cyclopropyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)-N4-phenyl-1,3,5-triazines-2,4-diamines,

(11) N ², N ⁴-dicyclohexyl-6-phenyl-1,3,5-triazines-2,4-diamines,

(18) N ², N ⁴-bis-(cyclohexyl methyl)-6-phenyl-1,3,5-triazines-2,4-diamines,

(22) N ⁴-cyclopentyl-2-phenyl-N6-(phenyl methyl)-4,6-pyrimidinediamine,

(45) two (1-methylethyl)-1,3,5-triazines-2, the 4-diamines of 6-(1H-imidazoles-1-base)-N2, N4-, and

(46) two (1-methyl-propyl)-6-phenyl-1,3,5-triazines-2, the 4-diamines of N2, N4-.

Additionally provide a kind of compound or its a kind of pharmacy acceptable salt or the hydrate with Formula I a:

wherein:

Wherein:

(i) when A is the phenyl be optionally substituted, so (a) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all 4-[[2-[2-(2-amino ethoxy) oxyethyl group] ethyl] is amino] and (b) N (R7) C (R4) (R5) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all NHEt, NH (n-propyl), NH (normal-butyl), NH (dodecyl), NH-[(4-p-methoxy-phenyl) methyl], NHCH ₂cH ₂cHO, NHCH ₂cH ₂oCH ₃, NHCH ₂cH ₂oH, NHCH ₂cH (OH) CH ₃, NHCH ₂cH ₂oC (O) phenyl, NHCH ₂cH ₂cH ₂oH, NHCH ₂cH ₂cH ₂n (CH ₃) phenyl, NHCH ₂c (O) OCH ₃, NHCH ₂c (O) OCH ₂cH ₃, NHCH ₂phenyl, NHCH (CH ₃) CH ₂cH ₃or NHCH ₂cH ₂oC (O) CH ₃;

(ii) when X is N and A be one be optionally substituted pyridyl time, so (A) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NHC (O)-[the chloro-4-of 2-(methyl sulphonyl)]; (B) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all NHC (O) C (CH ₃) ₃, NHC (O) CH=CH ₂, NHC (O) C (CH ₃)=CH ₂, NHCH ₂cH ₂oH, NH-cyclohexyl, NHCH ₂-phenyl, NHC (O) phenyl, NHC (O) (CH ₂) ₅nH ₂, NHC (O) OCH ₃, NHC (O) CH ₃and optionally by the phenyl of NHC (O) NH replacement; And (C) as N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) be NHC (CH ₃) ₃time, so N (R ⁸) C (R ¹) (R ²) (R ³) not NHCH ₂-phenyl or NH-CH ₂cH ₃;

(iii) when X is N and A is the heteroaryl be optionally substituted, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all N (CH ₂cH ₃) ₂, NHCH ₂cH ₂-sec.-propyl, NHCH ₂cH (CH ₃) ₂and NHC (O) CH ₃; And

(iv) this compound is not be selected from lower group:

(23) N ², N ⁴-dicyclohexyl-6-phenyl-1,3,5-triazines-2,4-diamines,

(30) N ², N ⁴-bis-(cyclohexyl methyl)-6-phenyl-1,3,5-triazines-2,4-diamines,

(33) N ²-sec.-propyl-6-phenyl-N4-(tetrahydrochysene-2H-pyrans-4-base)-1,3,5-triazines-2,4-diamines,

(34) the chloro-4-of 2-(methyl sulphonyl)-N-[4-[(phenyl methyl) is amino]-6-(2-pyridyl)-1,3,5-triazines-2-base]-benzamide,

(35) N-[[4-[[[4-(cyclopropyl)-6-(2-pyridyl)-1,3,5-triazines-2-base] is amino] methyl] cyclohexyl] methyl] the fluoro-benzsulfamide of-4-,

(36) [[4-[[[[[4-amino-6-(4-pyridyl)-1,3,5-triazine-2-base] amino] methoxyl group] methyl] amino]-6-(4-pyridyl)-1,3,5-triazine-2-base] imino-] two methyl alcohol

(37) [[4-[[[[[4-[two (hydroxymethyl) is amino]-6-(4-pyridyl)-1,3,5-triazine-2-base] amino] methoxyl group] methyl] (hydroxymethyl) amino]-6-(4-pyridyl)-1,3,5-triazine-2-base] imino-] two methyl alcohol

(38) 5-[two (diethylamino)-1,3,5-triazines-2-base of 4,6-]-2H-tetrazolium-2-ethyl acetate,

(39) N ², N ², N ⁴, N ⁴-tetraethyl--6-(2H-tetrazolium-5-base)-1,3,5-triazines-2,4-diamines, and

(40) N, N'-[6-[4-(kharophen)-1,2,5-oxadiazole-3-base]-1,3,5-triazines-2,4-bis-base] bis-dimethylsilyl-acetamide.

wherein:

Wherein:

(i) when A is the phenyl be optionally substituted, so (a) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NHCH ₂cH ₂oCH ₂cH ₂oCH ₂cH ₂nH ₂or 4-[[2-[2-(2-amino ethoxy) oxyethyl group] ethyl] amino] and (b) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all NHEt, NH (n-propyl), NH (normal-butyl), NH (dodecyl), NH-[(4-p-methoxy-phenyl) methyl], NHCH ₂cH ₂cHO, NHCH ₂cH ₂oCH ₃, NHCH ₂cH ₂oH, NHCH ₂cH (OH) CH ₃, NHCH ₂cH ₂oC (O) phenyl, NHCH ₂cH ₂cH ₂oH, NHCH ₂cH ₂cH ₂n (CH ₃) phenyl, NHCH ₂c (O) OCH ₃, NHCH ₂c (O) OCH ₂cH ₃, NHCH ₂phenyl, NHCH (CH ₃) CH ₂cH ₃or NHCH ₂cH ₂oC (O) CH ₃;

(ii) when A be one be optionally substituted pyridyl time, so (A) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NHC (O)-[the chloro-4-of 2-(methyl sulphonyl)], N (CH ₃) ₂, NHCH ₂cH ₂cH ₂sO ₂cH ₂cH ₂cl, NHCH ₂cH ₂oCH ₂cH ₂sO ₂cH ₂cH ₂cl or NHCH ₂cH ₂sO ₂cH ₂cH ₂cl; (B) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all NHC (O) C (CH ₃) ₃, NHC (O) CH=CH ₂, NHC (O) C (CH ₃)=CH ₂, NHCH ₂cH ₂oH, NH-cyclohexyl, NHCH ₂-phenyl, NHC (O) phenyl, NHC (O) (CH ₂) ₅nH ₂, NHC (O) OCH ₃, NHC (O) CH ₃and the phenyl that NHC (O) NH-is optionally substituted; And (C) as N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) be NHC (CH ₃) ₃time, so N (R ⁸) C (R ¹) (R ²) (R ³) not NHCH ₂-phenyl or NH-CH ₂cH ₃;

(iii) when A is the heteroaryl be optionally substituted, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all N (CH ₂cH ₃) ₂, NHCH ₂cH ₂-sec.-propyl, NHCH ₂cH (CH ₃) ₂and NHC (O) CH ₃;

(iv) when A is the 1-pyrazolyl be optionally substituted, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all N (CH ₃) ₂, NHCH ₃, NHAc, NH sec.-propyl, NHCH ₂cH ₃, NHCH ₂cH ₂sO ₃h or N (CH ₂cH ₃) ₂,

(v) when A is the phenyl, thienyl or the pyridyl that are optionally substituted, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NH cyclohexyl C (O) NHCH ₂r, wherein R is by OCF ₃, OCH ₃, chlorine or CF ₃in the phenyl of one or more replacements or pyridyl,

(vi) when A is the phenyl and R that are optionally substituted ⁴and R ⁵when forming the phenyl be optionally substituted, so N (R ⁸) C (R ¹) (R ²) (R ³) not NHCH ₂(4-fluorophenyl), NHCH ₂cO ₂h, NHCH ₂c (O) Cl, NHCH (CO ₂h) (CH ₂sCH ₂phenyl), NHCH ₂c (O) NHC (O) NHR or NHCH ₂c (O) NHC (S) NHR, wherein R is the phenyl or naphthyl be optionally substituted,

(vii) when the Yi oxadiazole that A is replaced by a pyridyl be optionally substituted, so R ⁴and R ⁵do not form a phenyl be optionally substituted,

(viii) when A is the 1-pyrazolyl be substituted, so (A) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all NHC (CH ₃) ₃; And (B) A is not replaced by N=N-R, wherein R is ring,

(ix) ring A is not the triazolyl, 3, the 5-dimethyl-1H-pyrazol-1-yls that are optionally substituted,

X () works as R ¹and R ²optionally form a unsubstituted cyclohexyl together, and R ⁴and R ⁵when optionally forming a unsubstituted cyclohexyl together, so A is not a dibasic 1-pyrazolyl or unsubstituted phenyl;

(xi) this compound is not be selected from lower group:

(11) N ², N ⁴-dicyclohexyl-6-phenyl-1,3,5-triazines-2,4-diamines,

(18) N ², N ⁴-bis-(cyclohexyl methyl)-6-phenyl-1,3,5-triazines-2,4-diamines,

(21) N ²-sec.-propyl-6-phenyl-N4-(tetrahydrochysene-2H-pyrans-4-base)-1,3,5-triazines-2,4-diamines,

(22) the chloro-4-of 2-(methyl sulphonyl)-N-[4-[(phenyl methyl) is amino]-6-(2-pyridyl)-1,3,5-triazines-2-base]-benzamide,

(23) N-[[4-[[[4-(cyclopropyl)-6-(2-pyridyl)-1,3,5-triazines-2-base] is amino] methyl] cyclohexyl] methyl] the fluoro-benzsulfamide of-4-,

(24) [[4-[[[[[4-amino-6-(4-pyridyl)-1,3,5-triazine-2-base] amino] methoxyl group] methyl] amino]-6-(4-pyridyl)-1,3,5-triazine-2-base] imino-] two methyl alcohol

(25) [[4-[[[[[4-[two (hydroxymethyl) is amino]-6-(4-pyridyl)-1,3,5-triazine-2-base] amino] methoxyl group] methyl] (hydroxymethyl) amino]-6-(4-pyridyl)-1,3,5-triazine-2-base] imino-] two methyl alcohol

(26) 5-[two (diethylamino)-1,3,5-triazines-2-base of 4,6-]-2H-tetrazolium-2-ethyl acetate,

(27) N ², N ², N ⁴, N ⁴-tetraethyl--6-(2H-tetrazolium-5-base)-1,3,5-triazines-2,4-diamines,

(28) N, N'-[6-[4-(kharophen)-1,2,5-oxadiazole-3-base]-1,3,5-triazines-2,4-bis-base] bis-dimethylsilyl-acetamide,

(29) N-(the chloro-6-aminomethyl phenyl of 2-)-5-[[4-(dimethylamino)-6-(2-pyridyl)-1,3,5-triazines-2-base] is amino]-1,3,4-oxadiazole-2-methane amides,

(30) 6-(4-chloro-phenyl-)-N2-[the chloro-3-of 4-(trifluoromethyl) phenyl]-N4-[3-(diethylamino) propyl group]-1,3,5-triazines-2,4-diamines,

(31) 6-(4-chloro-phenyl-)-N2-[the chloro-3-of 4-(trifluoromethyl) phenyl]-N4-[3-(dimethylamino) propyl group]-1,3,5-triazines-2,4-diamines,

(32) N2-[two (trifluoromethyl) phenyl of 3,5-]-6-(4-chloro-phenyl-)-N4-[3-(diethylamino) propyl group]-1,3,5-triazines-2,4-diamines,

(33) two [(4-p-methoxy-phenyl) methyl]-6-[4-(trifluoromethoxy) phenyl]-1,3,5-triazines-2,4-diamines of N2, N4-,

(34) N, N "-(6-phenyl-1,3,5-triazines-2,4-bis-base) two [N'-(2-chloroethyl)-urea,

(35) N-[the chloro-3-of 4-(trifluoromethyl) phenyl]-N'-[4-methyl-3-[[4-phenyl-6-(propylcarbamic)-1,3,5-triazines-2-base] is amino] phenyl]-urea,

(36) N-[4-[[5-[[[[the chloro-3-of 4-(trifluoromethyl) phenyl] is amino] carbonyl] is amino]-2-aminomethyl phenyl] is amino]-6-(4-pyridyl)-1,3,5-triazine-2-base]-glycine

(37) N-[4-[[5-[[[[the chloro-3-of 4-(trifluoromethyl) phenyl] is amino] carbonyl] is amino]-2-aminomethyl phenyl] is amino]-6-(5-thiazolyl)-1,3,5-triazine-2-base]-Valine

(38) 2-phenyl-4,6-two [[6-[[4-phenyl-6-[[6-[[4-phenyl-6-(trichloromethyl)-guanamine-Ji] is amino] hexyl] is amino]-guanamine-Ji] is amino] hexyl] is amino]-s-triazine

(39) α, α '-[(6-phenyl-1,3,5-triazine-2,4-bis-base) two [imino-(1,1,2,2-tetra-fluoro-3-oxo-3,1-propane two base)]] two [ω-[tetrafluoro (trifluoromethyl) oxyethyl group]-poly-[oxygen base [trifluoro (trifluoromethyl)-1,2-ethane two base]]

(40) α-[[4-[[(3-chloro-phenyl-) methyl] is amino]-6-(1H-imidazoles-1-base)-1,3,5-triazine-2-base] amino]-N-[[4-(trifluoromethyl) phenyl] methyl]-, (α R)-hexanaphthene propionic acid amide

(41) N, N'-[6-[4-(kharophen)-1,2,5-oxadiazole-3-base]-1,3,5-triazines-2,4-bis-base] bis-dimethylsilyl-acetamide,

(42) two (1-methylethyl)-1,3,5-triazines-2, the 4-diamines of 6-(1H-imidazoles-1-base)-N2, N4-, and

(43) two (1-methyl-propyl)-6-phenyl-1,3,5-triazines-2, the 4-diamines of N2, N4-.

In certain embodiments, R ¹and R ⁴be selected from hydrogen ,-CH independently of one another ₃,-CH ₂cH ₃,-CH ₂oH ,-CH (CH ₃) OH ,-C (CH ₃) ₂oH, CF ₃, CN; Or R ¹and R ³formation=O together; Or R ⁴and R ⁶optionally be attached to it together with carbon atom on it and form C (=O).

In certain embodiments, R ¹and R ²form carbocylic radical or heterocyclic radical together, wherein any one is optionally replaced by maximum 3 substituting groups, these substituting group independent selected from halo (such as fluorine), C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group ,-CN ,=O ,-OH and-C (O) C ₁-C ₄alkyl.In certain embodiments, R ¹and R ²form a carbocylic radical or heterocyclic radical together, wherein any one is optionally replaced by maximum 3 substituting groups, these substituting group independent selected from halo (such as fluorine), C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group ,-CN ,=O ,-OH, aryl, heteroaryl-SO ₂c ₁-C ₄alkyl ,-CO ₂c ₁-C ₄alkyl ,-C (O) aryl and-C (O) C ₁-C ₄alkyl.In certain embodiments, R ¹and R ²form a carbocylic radical or heterocyclic radical together, wherein any one is optionally optionally substituted aryl or heteroaryl, and this aryl or heteroaryl are optionally replaced by maximum 2 substituting groups, these substituting group independent selected from halo, C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group ,-CN and-OH.In certain embodiments, R ¹and R ²form a carbocylic radical or heterocyclic radical together, wherein any one is optionally replaced by phenyl, pyridyl or pyrimidyl, and this phenyl, pyridyl or pyrimidyl are optionally replaced by maximum 2 substituting groups, these substituting group independent selected from halo, C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group ,-CN and-OH.

In certain embodiments, R ⁴and R ⁵form carbocylic radical or heterocyclic radical together, wherein any one is optionally replaced by maximum 3 substituting groups, these substituting group independent selected from halo (such as fluorine), C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group ,-CN ,=O ,-OH and-C (O) C ₁-C ₄alkyl.In certain embodiments, R ⁴and R ⁵form a carbocylic radical or heterocyclic radical together, wherein any one is optionally replaced by maximum 3 substituting groups, these substituting group independent selected from halo (such as fluorine), C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group ,-CN ,=O ,-OH, aryl, heteroaryl-SO ₂c ₁-C ₄alkyl ,-CO ₂c ₁-C ₄alkyl ,-C (O) aryl and-C (O) C ₁-C ₄alkyl.In certain embodiments, R ¹and R ²form a carbocylic radical or heterocyclic radical together, wherein any one is optionally optionally substituted aryl or heteroaryl, and this aryl or heteroaryl are optionally replaced by maximum 2 substituting groups, these substituting group independent selected from halo, C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group ,-CN and-OH.In certain embodiments, R ¹and R ²form a carbocylic radical or heterocyclic radical together, wherein any one is optionally replaced by phenyl, pyridyl or pyrimidyl, and this phenyl, pyridyl or pyrimidyl are optionally replaced by maximum 2 substituting groups, these substituting group independent selected from halo, C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group ,-CN and-OH.

In certain embodiments, R ²and R ⁵be selected from independently of one another :-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkyl)-C (O)-NH ₂,-(C ₁-C ₆alkyl)-CO ₂h ,-(C ₂-C ₆alkenyl or alkynyl) ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₁-C ₆alkyl) and-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-Q, wherein Q is optionally replaced by maximum 3 substituting groups, and these substituting groups are independently selected from C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group ,=O ,-C (O)-C ₁-C ₄alkyl ,-CN and halogen.

In certain embodiments, R ²and R ⁵be selected from independently of one another: optionally by halogen (such as fluorine) or-OH replace-(C ₁-C ₄alkyl);-(C ₀-C ₄alkylidene group)-O-(C ₁-C ₄alkyl) ,-(C ₀-C ₂alkylidene group)-N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkyl)-C (O)-NH ₂,-(C ₀-C ₂alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₁-C ₆alkyl) and-O-(C ₀-C ₂alkylidene group)-Q, wherein Q is optionally replaced by maximum 3 substituting groups, and these substituting groups are independently selected from C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group ,=O ,-C (O)-C ₁-C ₄alkyl ,-CN and halogen.In in of these embodiments, Q is selected from pyridyl, tetrahydrofuran base, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl and oxetanyl, and wherein Q is optionally replaced by maximum 2 substituting groups, and these substituting groups are independently selected from C ₁-C ₄alkyl, C ₁-C ₄haloalkyl ,=O, fluorine, chlorine and bromine.These embodiments another in, Q is selected from pyridyl, tetrahydrofuran base, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl and oxetanyl, and wherein Q is optionally replaced by maximum 2 substituting groups, and these substituting groups are independently selected from-CH ₃with=O.

In certain embodiments, R ¹and R ²form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran base, THP trtrahydropyranyl, oxetanyl, dicyclo [2.2.1] heptyl, oxo dicyclo [3.1.0] hexyl, azetidinyl together, wherein any one is optionally replaced by maximum 2 substituting groups, and these substituting groups are independently selected from C ₁-C ₄alkyl, C ₁-C ₄alkoxyl group, C ₃-C ₆cycloalkyl ,-OH ,-C (O) CH ₃, fluorine and chlorine.

In certain embodiments, R ⁴and R ⁵form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran base, THP trtrahydropyranyl, oxetanyl, dicyclo [2.2.1] heptyl, oxo dicyclo [3.1.0] hexyl or azetidinyl together, wherein any one is optionally replaced by maximum 2 substituting groups, and these substituting groups are independently selected from C ₁-C ₄alkyl, C ₁-C ₄alkoxyl group, C ₃-C ₆cycloalkyl ,-OH ,-C (O) CH ₃, fluorine and chlorine.In certain embodiments, R ⁴and R ⁵form phenyl, pyrazolyl, imidazolyl, pyrrolidyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, triazinyl, thiazolyl, thiadiazolyl group or isothiazolyl together, wherein any one is optionally replaced by maximum 2 substituting groups, these substituting group independent selected from halo, CN, C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group, C ₃-C ₆cycloalkyl, phenyl ,-OH ,-C (O) CH ₃, wherein any alkyl, cycloalkyl or phenyl portion ground is by fluorine, chlorine ,-OH ,-NH ₂or-CN replaces.In certain embodiments, C ₃-C ₆cycloalkyl is

In certain embodiments, R ¹, R ³, R ⁴and R ⁶be selected from hydrogen, C independently of one another ₁-C ₄alkyl, C ₁-C ₄haloalkyl ,-O-C ₁-C ₄alkyl and CN, wherein R ¹, R ³, R ⁴and R ⁶each described moieties independently of one another optionally by-OH ,-NH ₂,-CN ,-O-C ₁-C ₄alkyl ,-NH (C ₁-C ₄alkyl) or-N (C ₁-C ₄alkyl) ₂replace; And R ²and R ⁵be selected from independently of one another :-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkyl)-C (O)-NH ₂,-(C ₁-C ₆alkyl)-CO ₂h ,-(C ₂-C ₆alkenyl or alkynyl) ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₁-C ₆alkyl) and-(C ₀-C ₆alkylidene group)-C (O)-(C ₁-C ₆alkyl), wherein: be present in R ²and R ⁵in any alkyl or alkylene moiety optionally by one or more-OH ,-O (C ₁-C ₄alkyl) ,-CO ₂h or halogen replace; And

Be present in R ²and R ⁵in any terminal methyl group moiety ground by-CH ₂oH, CF ₃,-CH ₂f ,-CH ₂cl, C (O) CH ₃, C (O) CF ₃, CN or CO ₂h replaces; Or R ¹and R ³optionally be attached to it together with carbon atom on it and form C (=O); Or

R ⁴and R ⁶optionally be attached to it together with carbon atom on it and form C (=O); Or R ¹and R ²optionally form a carbocylic radical be optionally substituted together; Or R ⁴and R ⁵optionally form a carbocylic radical be optionally substituted together, wherein, when A is a phenyl be optionally substituted, 2-pyrryl or 1-imidazolyl, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not identical, and this compound is not 2-(1,2-bis-bromotrifluoromethane)-4-phenyl-6-(1,1,2,2,3,3,4,4,5,5,6,6,6)-ten trifluoro hexyl-1,3,5-triazines.

In certain embodiments, ring A is the 6 yuan of monocyclic aryl be optionally substituted.In certain embodiments, ring A is the 5-6 unit heteroaryl be optionally substituted.In certain embodiments, ring A is the 5 yuan of heteroaryls be optionally substituted.

In certain embodiments, ring A is the 5-6 unit's monocyclic aryl or bicyclic heteroaryl that are substituted, and this monocyclic aryl or bicyclic heteroaryl are replaced by maximum two substituting groups, these substituting group independent selected from halo ,-C ₁-C ₄alkyl ,-C ₁-C ₄haloalkyl ,-C ₁-C ₄hydroxyalkyl ,-NH-S (O) ₂-(C ₁-C ₄alkyl) ,-S (O) ₂nH (C ₁-C ₄alkyl) ,-CN ,-S (O) ₂-(C ₁-C ₄alkyl), C ₁-C ₄alkoxyl group ,-NH (C ₁-C ₄alkyl) ,-OH ,-OCF ₃,-CN ,-NH ₂,-C (O) NH ₂,-C (O) NH (C ₁-C ₄alkyl) ,-C (O)-N (C ₁-C ₄alkyl) ₂,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl), azetidinyl, phenyl and optionally by cyclopropyl that OH replaces.In certain embodiments, ring A is the 5-6 unit's monocyclic aryl or bicyclic heteroaryl that are substituted, and this monocyclic aryl or bicyclic heteroaryl are replaced by maximum two substituting groups, and these substituting groups are independently selected from fluorine, chlorine, CF ₃, CF ₂,-OH ,-OCH ₃,-OCF ₃,-CN ,-NH ₂.In certain embodiments, ring A is the 6 yuan of monocyclic aryl be substituted.In certain embodiments, ring A is the 5-6 unit heteroaryl be substituted.In certain embodiments, ring A is the 5 yuan of heteroaryls be substituted.

In certain embodiments, ring A is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl and thiazolyl, and wherein ring A is optionally replaced by maximum two substituting groups, these substituting group independent selected from halo ,-C ₁-C ₄alkyl ,-C ₁-C ₄haloalkyl ,-C ₁-C ₄hydroxyalkyl ,-NH-S (O) ₂-(C ₁-C ₄alkyl) ,-S (O) ₂nH (C ₁-C ₄alkyl) ,-CN ,-S (O) ₂-(C ₁-C ₄alkyl), C ₁-C ₄alkoxyl group ,-NH (C ₁-C ₄alkyl) ,-OH ,-OCF ₃,-CN ,-NH ₂,-C (O) NH ₂,-C (O) NH (C ₁-C ₄alkyl) ,-C (O)-N (C ₁-C ₄alkyl) ₂and optionally by cyclopropyl that OH replaces.

In certain embodiments, ring A is selected from phenyl, pyrazolyl, imidazolyl, pyrrolidyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, triazinyl, thiazolyl, thiadiazolyl group and isothiazolyl, wherein ring A is optionally replaced by maximum two substituting groups, these substituting group independent selected from halo ,-C ₁-C ₄alkyl ,-C ₁-C ₄haloalkyl ,-C ₁-C ₄hydroxyalkyl ,-NH-S (O) ₂-(C ₁-C ₄alkyl) ,-S (O) ₂nH (C ₁-C ₄alkyl) ,-CN ,-S (O) ₂-(C ₁-C ₄alkyl), C ₁-C ₄alkoxyl group ,-NH (C ₁-C ₄alkyl) ,-OH ,-CN and-NH ₂.

In certain embodiments, ring A is optionally by halogen ,-C ₁-C ₄alkyl ,-C ₁-C ₄haloalkyl ,-O-C ₁-C ₄haloalkyl ,-OH ,-CN and-NH ₂the bicyclic heteroaryl replaced; R ¹, R ³, R ⁴and R ⁶be selected from hydrogen and C independently of one another ₁-C ₄alkyl; And R ²and R ⁵-(C independently of one another ₀-C ₆alkylidene group)-Q; Or R ¹and R ²optionally form the carbocylic radical be optionally substituted, a heterocyclic radical be optionally substituted or the heteroaryl be optionally substituted together; Or R ⁴and R ⁵optionally form the carbocylic radical be optionally substituted, a heterocyclic radical be optionally substituted or the heteroaryl be optionally substituted together.

In certain embodiments, ring A is optionally by halogen ,-C ₁-C ₄alkyl ,-C ₁-C ₄haloalkyl ,-O-C ₁-C ₄haloalkyl ,-OH ,-CN and-NH ₂the bicyclic heteroaryl replaced; R ¹, R ³, R ⁴and R ⁶be selected from hydrogen and C independently of one another ₁-C ₄alkyl; And R ²and R ⁵-(C independently of one another ₀-C ₆alkylidene group)-Q; Or R ¹and R ²optionally form a carbocylic radical be optionally substituted or a heterocyclic radical be optionally substituted together; Or R ⁴and R ⁵optionally form the carbocylic radical be optionally substituted, a heterocyclic radical be optionally substituted or the heteroaryl be optionally substituted together.

In certain embodiments, ring A is: wherein R ⁹be selected from hydrogen, halogen and-C ₁-C ₄haloalkyl; Each X ^an or C-R independently ^9a, its condition is as an X ^awhen being N, so another two X ^aall C-R ^9a; And R ^9abe selected from hydrogen, halogen and-C ₁-C ₄haloalkyl.

In certain embodiments, ring A is: wherein R ⁹be selected from hydrogen, halogen and-C ₁-C ₄haloalkyl.In certain embodiments, ring A is: wherein R ⁹be selected from hydrogen, halogen and-C ₁-C ₄haloalkyl.In certain embodiments, ring A is: wherein R ⁹be selected from hydrogen, halogen and-C ₁-C ₄haloalkyl.

In certain embodiments, ring A is optionally by halogen or-C ₁-C ₄the pyridyl that haloalkyl replaces.In certain embodiments, ring A is optionally by pyridyl that halogen (such as chlorine or fluorine) replaces.In certain embodiments, ring A is by-C ₁-C ₄haloalkyl (such as-CHF ₂and CF ₃) pyridine-2-base that replaces.In certain embodiments, ring A is: wherein R ⁹be selected from hydrogen, halogen and-C ₁-C ₄haloalkyl.In certain embodiments, ring A is: wherein each R ⁹independently selected from hydrogen, halogen and-C ₁-C ₄haloalkyl.In certain embodiments, R ⁹chlorine or fluorine.In certain embodiments, R ⁹-CHF ₂or CF ₃.In certain embodiments, R ⁹cF ₃or chlorine.In certain embodiments, R ⁹cF ₃.

In certain embodiments, ring A is: wherein R ^9bbe selected from hydrogen and-C ₁-C ₄alkyl, and wherein R ⁹be selected from hydrogen, halogen and-C ₁-C ₄haloalkyl.

In certain embodiments, ring A is: wherein R ⁹be selected from hydrogen, halogen and-C ₁-C ₄haloalkyl.In certain embodiments, ring A is optionally by halogen or-C ₁-C ₄the pyrazolyl that haloalkyl replaces.In certain embodiments, ring A is optionally by pyrazolyl that halogen (such as chlorine or fluorine) replaces.In certain embodiments, ring A is by-C ₁-C ₄haloalkyl (such as-CHF ₂and CF ₃) the 1H-pyrazol-1-yl that replaces.In certain embodiments, ring A is: wherein R ⁹be selected from hydrogen, halogen and-C ₁-C ₄haloalkyl.In certain embodiments, R ⁹chlorine or fluorine.In certain embodiments, R ⁹-CHF ₂or CF ₃.In certain embodiments, R ⁹cF ₃or chlorine.In certain embodiments, R ⁹cF ₃.

In certain embodiments, ring A is: wherein R ⁹be selected from hydrogen, halogen and-C ₁-C ₄haloalkyl.

In certain embodiments, ring A is optionally by halogen or-C ₁-C ₄the pyridyl that haloalkyl replaces.In certain embodiments, the pyridyl that replaced by halogen (such as chlorine or fluorine) of ring A.In certain embodiments, ring A is by-C ₁-C ₄haloalkyl (such as-CHF ₂and CF ₃) pyridyl that replaces.In certain embodiments, ring A is optionally by halogen or-C ₁-C ₄the pyrazinyl that haloalkyl replaces.In certain embodiments, the pyrazinyl that replaced by halogen (such as chlorine or fluorine) of ring A.In certain embodiments, ring A is by-C ₁-C ₄haloalkyl (such as-CHF ₂and CF ₃) pyrazinyl that replaces.In certain embodiments, ring A is optionally by halogen or-C ₁-C ₄the pyrimidyl that haloalkyl replaces.In certain embodiments, the pyrimidyl that replaced by halogen (such as chlorine or fluorine) of ring A.In certain embodiments, ring A is by-C ₁-C ₄haloalkyl (such as-CHF ₂and CF ₃) pyrimidyl that replaces.In certain embodiments, ring A is optionally by halogen or-C ₁-C ₄the pyrazolyl that haloalkyl replaces.In certain embodiments, the pyrazolyl that replaced by halogen (such as chlorine or fluorine) of ring A.In certain embodiments, ring A is by-C ₁-C ₄haloalkyl (such as-CHF ₂and CF ₃) pyrazolyl that replaces.

In certain embodiments, R ¹, R ³, R ⁴and R ⁶be selected from hydrogen and C independently of one another ₁-C ₄alkyl; A and R ²and R ⁵-(C independently of one another ₀-C ₆alkylidene group)-Q.In certain embodiments, R ¹and R ⁴each hydrogen naturally.In certain embodiments, R ³and R ⁶each C naturally ₁-C ₄alkyl.In certain embodiments, R ³and R ⁶each C naturally ₁-C ₄haloalkyl.In certain embodiments, Q is selected from aryl, heteroaryl, carbocylic radical and heterocyclic radical, and wherein any one is optionally substituted.In certain embodiments, Q is the carbocylic radical be optionally substituted.In certain embodiments, Q is the cyclopropyl be optionally substituted.In certain embodiments, Q is unsubstituted cyclopropyl.In certain embodiments, R ²and R ⁵unsubstituted cyclopropyl independently of one another.In certain embodiments, R ¹and R ⁴each hydrogen naturally, R ³and R ⁶each-CH naturally ₃, and R ²and R ⁵each unsubstituted cyclopropyl naturally.In certain embodiments, R ²-(C ₀-C ₆alkylidene group)-cyclopropyl and R ⁵-(C ₀-C ₆alkylidene group)-aryl, the phenyl be such as optionally substituted.In certain embodiments, R ²be cyclopropyl and R ⁵by the phenyl that halogen (such as fluorine) replaces.

In certain embodiments, R ³and R ⁶be selected from hydrogen and C independently of one another ₁-C ₄alkyl; R ¹and R ²form a carbocylic radical be optionally substituted together; And R ⁴and R ⁵form a carbocylic radical be optionally substituted together.In certain embodiments, R ¹and R ²form the cyclobutyl, cyclopentyl or the cyclohexyl that are optionally substituted separately together.In certain embodiments, R ¹and R ²form the cyclopentyl be optionally substituted separately or cyclohexyl together.In certain embodiments, R ⁴and R ⁵form the cyclobutyl, cyclopentyl or the cyclohexyl that are optionally substituted separately together.In certain embodiments, R ⁴and R ⁵form the cyclopentyl be optionally substituted separately or cyclohexyl together.In certain embodiments, R ¹and R ²form the cyclopentyl or cyclohexyl that are replaced by one or more halogen (such as fluorine) separately together; And R ⁴and R ⁵formed together separately by cyclobutyl, cyclopentyl or cyclohexyl that one or more halogen (such as fluorine) replaces.In certain embodiments, R ¹and R ²form dicyclo [3.1.0] hexyl together; And R ⁴and R ⁵form dicyclo [3.1.0] hexyl together.In certain embodiments, R ¹and R ²together, and R ⁴and R ⁵formed together: in certain embodiments, R ¹and R ²together, and R ⁴and R ⁵formed together: in certain embodiments, R ¹and R ²together, and R ⁴and R ⁵formed together: in certain embodiments, R ¹and R ²together, and R ⁴and R ⁵formed together: in certain embodiments, R ¹and R ²together; And R ⁴and R ⁵formed together: this compound is optionally replaced by cyano group or halogen (such as fluorine, chlorine or bromine).In certain embodiments, R ¹and R ²together, and R ⁴and R ⁵formed together: in certain embodiments, R ¹and R ²formed separately by cyclobutyl, cyclopentyl or cyclohexyl that one or more 6 yuan of monocyclic aryl (such as phenyl) replace together, this monocyclic aryl is optionally replaced by halogen (such as fluorine, chlorine or bromine); And R ⁴and R ⁵formed separately by cyclobutyl, cyclopentyl or cyclohexyl that one or more 6 yuan of monocyclic aryl (such as phenyl) replace together, this monocyclic aryl is optionally replaced by halogen (such as fluorine, chlorine or bromine).In certain embodiments, R ¹and R ²or R ⁴and R ⁵formed together: wherein ring C is phenyl, pyridyl or pyrimidyl, and this phenyl, pyridyl or pyrimidyl are optionally replaced by cyano group or halogen (such as fluorine, chlorine or bromine).In certain embodiments, R ¹and R ²or R ⁴and R ⁵formed together: wherein ring C is phenyl, pyridyl or pyrimidyl, and this phenyl, pyridyl or pyrimidyl are optionally replaced by cyano group or halogen (such as fluorine, chlorine or bromine).In certain embodiments, R ¹and R ²or R ⁴and R ⁵formed together: wherein ring C is phenyl, pyridyl or pyrimidyl, and this phenyl, pyridyl or pyrimidyl are optionally replaced by cyano group or halogen (such as fluorine, chlorine or bromine).

In certain embodiments, R ¹, R ³, R ⁴and R ⁶be selected from hydrogen, C independently of one another ₁-C ₄alkyl and-CN, wherein R ¹, R ³, R ⁴and R ⁶each described moieties independently of one another optionally by-OH ,-NH ₂,-CN ,-O-C ₁-C ₄alkyl replaces; A and R ²and R ⁵be selected from-(C independently of one another ₁-C ₆alkyl) and-(C ₀-C ₆alkylidene group)-Q.In certain embodiments, R ¹, R ³, R ⁴and R ⁶be selected from hydrogen, C independently of one another ₁-C ₄alkyl and-CN; A and R ²and R ⁵-(C independently of one another ₁-C ₆alkyl) and-(C ₀-C ₆alkylidene group)-Q.In certain embodiments, R ¹, R ³, R ⁴and R ⁶be selected from hydrogen, C independently of one another ₁-C ₄alkyl and-CN; R ²-(C ₁-C ₆alkyl); And R5 is-(C ₀-C ₆alkylidene group)-Q, wherein Q is the carbocylic radical be optionally substituted.In certain embodiments, Q is unsubstituted carbocylic radical.In certain embodiments, Q is cyclopropyl.

In certain embodiments, ring A is optionally by halogen or-C ₁-C ₄the pyridyl that haloalkyl replaces.In certain embodiments, ring A is by-C ₁-C ₄haloalkyl (such as-CHF ₂and CF ₃) pyridyl that replaces.In certain embodiments, ring A is optionally by halogen or-C ₁-C ₄the pyrazinyl that haloalkyl replaces.In certain embodiments, the pyrazinyl that replaced by halogen (such as chlorine or fluorine) of ring A.In certain embodiments, ring A is by-C ₁-C ₄haloalkyl (such as-CHF ₂and CF ₃) pyrazinyl that replaces.In certain embodiments, ring A is optionally by halogen or-C ₁-C ₄the pyrimidyl that haloalkyl replaces.In certain embodiments, the pyrimidyl that replaced by halogen (such as chlorine or fluorine) of ring A.In certain embodiments, ring A is by-C ₁-C ₄haloalkyl (such as-CHF ₂and CF ₃) pyrimidyl that replaces.In certain embodiments, ring A is optionally by halogen or-C ₁-C ₄the pyrazolyl that haloalkyl replaces.In certain embodiments, the pyrazolyl that replaced by halogen (such as chlorine or fluorine) of ring A.In certain embodiments, ring A is by-C ₁-C ₄haloalkyl (such as-CHF ₂and CF ₃) pyrazolyl that replaces.

In certain embodiments, R ¹, R ³and R ⁶be selected from hydrogen and C independently of one another ₁-C ₄alkyl, wherein R ¹, R ³and R ⁶each described moieties independently of one another optionally by-OH ,-NH ₂,-CN ,-O-C ₁-C ₄alkyl ,-NH (C ₁-C ₄alkyl) or-N (C ₁-C ₄alkyl) ₂replace; R ²-(C ₀-C ₆alkylidene group)-Q; And R ⁴and R ⁵the heteroaryl forming the carbocylic radical be optionally substituted, the heterocyclic radical be optionally substituted together or be optionally substituted.In certain embodiments, R ⁴and R ⁵form a carbocylic radical be optionally substituted together.In certain embodiments, this carbocylic radical is selected from optionally by-OH ,-O (C ₁-C ₄alkyl), CO ₂the cyclopentyl that H or halogen replace and cyclohexyl.In certain embodiments, R ⁴and R ⁵form one together optionally by-OH ,-O (C ₁-C ₄alkyl) ,-CO ₂the heterocyclic radical be optionally substituted that H or halogen replace.In certain embodiments, R ⁴and R ⁵form a tetrahydrofuran (THF) be optionally substituted together.In certain embodiments, R ¹, R ³and R ⁶be selected from hydrogen and C independently of one another ₁-C ₄alkyl, wherein R ¹, R ³and R ⁶each described moieties independently of one another optionally by-OH ,-NH ₂,-CN ,-O-C ₁-C ₄alkyl replaces; R ²-(C ₀-C ₆alkylidene group)-Q; And R ⁵c ₁-C ₄alkyl.In certain embodiments, R ¹, R ³and R ⁶be selected from hydrogen, C independently of one another ₁-C ₄alkyl or or carbocylic radical, wherein R ¹, R ³and R ⁶any alkyl or carbocyclyl moieties independently of one another optionally by-OH ,-NH ₂,-CN ,-O-C ₁-C ₄alkyl ,-SO ₂-C ₁-C ₄alkyl ,-C (O) NH ₂,-O-R ¹²,-CO ₂r ¹²or-C (O) R ¹²replace, wherein R ¹²morpholinyl, piperidyl, phenyl, pyridyl or pyrimidyl.In certain embodiments, R ¹, R ³and R ⁶be selected from hydrogen and C independently of one another ₁-C ₄alkyl, wherein R ¹, R ³and R ⁶each described moieties independently of one another optionally by-OH ,-NH ₂,-CN ,-O-C ₁-C ₄alkyl ,-O-R ¹²replace, wherein R ¹²phenyl, pyridyl or pyrimidyl; R ²-(C ₀-C ₆alkylidene group)-Q; And R ⁵c ₁-C ₄alkyl.

In certain embodiments, R ⁷h.In certain embodiments, R ⁸h.In certain embodiments, R ⁷and R ⁸both are all H.

In certain embodiments, ring A, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸be selected from any one in previous embodiment.

Additionally provide a kind of there is chemical formula B compound or its pharmacy acceptable salt or hydrate:

wherein:

X is N, CH or C-halogen;

X ^an or C-R ^9a, its condition is as an X ^awhen being N, so another two X ^aall C-R ^9a;

R ⁹halogen ,-C ₁-C ₄alkyl ,-C ₁-C ₄haloalkyl ,-C ₁-C ₄hydroxyalkyl ,-NH-S (O) ₂-(C ₁-C ₄alkyl) ,-S (O) ₂nH (C ₁-C ₄alkyl) ,-CN ,-S (O) ₂-(C ₁-C ₄alkyl), C ₁-C ₄alkoxyl group ,-NH (C ₁-C ₄alkyl) ,-N (C ₁-C ₄alkyl) ₂,-OH ,-OCF ₃,-CN ,-NH ₂,-C (O) NH ₂,-C (O) NH (C ₁-C ₄alkyl) ,-C (O)-N (C ₁-C ₄alkyl) ₂,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl), aryl and optionally by cyclopropyl that OH replaces;

Each R ^9aindependently selected from hydrogen, halogen ,-C ₁-C ₄alkyl ,-C ₁-C ₄haloalkyl ,-C ₁-C ₄hydroxyalkyl ,-NH-S (O) ₂-(C ₁-C ₄alkyl) ,-S (O) ₂nH (C ₁-C ₄alkyl) ,-CN ,-S (O) ₂-(C ₁-C ₄alkyl), C ₁-C ₄alkoxyl group ,-NH (C ₁-C ₄alkyl) ,-N (C ₁-C ₄alkyl) ₂,-OH ,-OCF ₃,-CN ,-NH ₂,-C (O) NH ₂,-C (O) NH (C ₁-C ₄alkyl) ,-C (O)-N (C ₁-C ₄alkyl) ₂,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl), aryl and optionally by cyclopropyl that OH replaces;

R ²and R ⁵be selected from independently of one another :-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkyl)-C (O)-NH ₂,-(C ₁-C ₆alkyl)-CO ₂h ,-(C ₂-C ₆alkenyl or alkynyl) ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₁-C ₆alkyl),

-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₁-C ₆alkyl) and-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-Q, wherein:

R ⁴and R ⁵optionally form a carbocylic radical be optionally substituted or the heterocyclic radical be optionally substituted, a 5-6 unit's monocyclic aryl be optionally substituted or a 5-6 unit bicyclic heteroaryl be optionally substituted together;

Wherein this compound is not be selected from lower group:

(1) 2-(6-methyl-2-pyridyl)-N4, N6-dipropyl-4,6-pyrimidinediamine;

(2) N4-ethyl-2-(6-methyl-2-pyridyl)-N6-propyl group-4,6-pyrimidinediamine;

(3) N4, N4-diethyl-2-(6-methyl-2-pyridyl)-N6-propyl group-4,6-pyrimidinediamine;

(4) N6-[2-(dimethylamino) ethyl]-N2', N2', N4, N4-tetramethyl--[2,4'-bis-pyrimidine]-2', 4,6-triamine; Or

(5) phosphoric acid N6-[2-(dimethylamino) ethyl]-N2', N2', N4, N4-tetramethyl--[2,4'-bis-pyrimidine]-2', 4,6-triamine.

In certain embodiments, R ⁴and R ⁵the heterocyclic radical optionally forming a carbocylic radical be optionally substituted together or be optionally substituted.

Additionally provide a kind of there is Formula I b compound or its pharmacy acceptable salt or hydrate:

wherein:

R ²and R ⁵be selected from independently of one another :-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkyl)-C (O)-NH ₂,-(C ₁-C ₆alkyl)-CO ₂h ,-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-Q, wherein:

R ⁷and R ⁸be selected from hydrogen and C independently of one another ₁-C ₆alkyl;

R ⁹be selected from hydrogen, halogen and-C ₁-C ₄haloalkyl; And

R ¹and R ²the heterocyclic radical optionally form a carbocylic radical be optionally substituted together, being optionally substituted; Or

R ⁴and R ⁵the heterocyclic radical optionally form a carbocylic radical be optionally substituted together, being optionally substituted;

Wherein:

(i) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NHC (O)-[the chloro-4-of 2-(methyl sulphonyl)] or N (CH ₃) ₂,

(ii) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all NHC (O) C (CH ₃) ₃, NHC (O) CH=CH ₂, NHC (O) C (CH ₃)=CH ₂, NHCH ₂cH ₂oH, NH-cyclohexyl, NHCH ₂-phenyl, NHC (O) phenyl, NHC (O) (CH ₂) ₅nH ₂, NHC (O) OCH ₃, NHC (O) CH ₃and optionally by the phenyl that NHC (O) NH replaces, and

(iii) as N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) be NHC (CH ₃) ₃time, so N (R ⁸) C (R ¹) (R ²) (R ³) not NHCH ₂-phenyl or NH-CH ₂cH ₃; And

Wherein this compound is not:

(1) the chloro-N-of 2-[4-(cyclopropyl)-6-(2-pyridyl)-1,3,5-triazines-2-base]-4-(methyl sulphonyl)-benzamide,

(2) N-[[4-[[[4-(cyclopropyl)-6-(2-pyridyl)-1,3,5-triazines-2-base] is amino] methyl] cyclohexyl] methyl] the fluoro-benzsulfamide of-4-,

(3) the chloro-4-of 2-(methyl sulphonyl)-N-[4-[(phenyl methyl) is amino]-6-(2-pyridyl)-1,3,5-triazines-2-base]-benzamide, or

(4) N-[[4-[[[4-(cyclopropyl)-6-(2-pyridyl)-1,3,5-triazines-2-base] is amino] methyl] cyclohexyl] methyl] the fluoro-benzsulfamide of-4-.

wherein:

R ³and R ⁶all hydrogen;

R ¹and R ⁴be selected from C independently of one another ₁-C ₄alkyl and C ₁-C ₄haloalkyl; And

R ²and R ⁵respectively naturally-(C ₁-C ₆alkyl); Or

R ¹and R ²optionally form a monocyclic carbocyclyl residues be optionally substituted together; Or

R ⁴and R ⁵optionally form a monocyclic carbocyclyl residues be optionally substituted together;

Wherein:

I () ring A is not the triazolyl, 3, the 5-dimethyl-1H-pyrazol-1-yls that are optionally substituted,

(ii) R is worked as ¹and R ²optionally form a unsubstituted cyclohexyl together, and R ⁴and R ⁵when optionally forming a unsubstituted cyclohexyl together, so A is not a dibasic 1-pyrazolyl or unsubstituted phenyl; And

(iii) this compound is not be selected from lower group:

(1) two (1-methylethyl)-1,3,5-triazines-2, the 4-diamines of 6-(1H-imidazoles-1-base)-N2, N4-, or

(2) two (1-methyl-propyl)-6-phenyl-1,3,5-triazines-2, the 4-diamines of N2, N4-.

Additionally provide a kind of formula C compound or its pharmacy acceptable salt or hydrate:

wherein:

X is N, CH or C-halogen;

Each X ^bn-R independently ^9b, O, S, C-H or C-R ^9c, its condition is at least one X ^bc-R ^9c, and as an X ^bc-H or C-R ⁹and another is C-R ^9ctime, so X ^cn; And as an X ^bn-R ^9b, O or S time, so X ^cc;

R ^9bhydrogen or-C ₁-C ₄alkyl;

R ^9chalogen ,-C ₁-C ₄alkyl ,-C ₁-C ₄haloalkyl ,-C ₁-C ₄hydroxyalkyl ,-NH-S (O) ₂-(C ₁-C ₄alkyl) ,-S (O) ₂nH (C ₁-C ₄alkyl) ,-CN ,-S (O) ₂-(C ₁-C ₄alkyl), C ₁-C ₄alkoxyl group ,-NH (C ₁-C ₄alkyl) ,-N (C ₁-C ₄alkyl) ₂,-OH ,-OCF ₃,-CN ,-NH ₂,-C (O) NH ₂,-C (O) NH (C ₁-C ₄alkyl) ,-C (O)-N (C ₁-C ₄alkyl) ₂,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl), aryl and optionally by cyclopropyl that OH replaces;

R ⁴and R ⁵optionally form a carbocylic radical be optionally substituted or the heterocyclic radical be optionally substituted, a 5-6 unit's monocyclic aryl or a heteroaryl be optionally substituted optionally be substituted together;

Wherein:

(i) when X be CH and A be the 1-imidazolyl be optionally substituted, the 1-pyrryl be optionally substituted or be optionally substituted 1-pyrazolyl time, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NH (CH ₂) ₇cH ₃, NHCH ₂-(adjacent chloro-phenyl) or NHCH ₂cH ₂oH; And

(ii) as X and X ^cwhen being all N, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all N (CH ₃) ₂, NHCH ₃or N (CH ₂cH ₃) ₂.

Additionally provide a kind of there is Formula I d compound or its pharmacy acceptable salt or hydrate:

wherein:

R ⁹halogen or-C ₁-C ₄haloalkyl; And

R ⁴and R ⁶optionally be attached to it together with carbon atom on it and form C (=O);

Wherein this compound is not:

(1) N2, N2, N4-trimethylammonium-6-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-1,3,5-triazines-2,4-diamines, or

(2) N4-ethyl-N2, N2-dimethyl-6-[3-(Trifluoromethyl-1 H-pyrazol-1-yl]-1,3,5-triazines-2,4-diamines.

A kind of there is Formula I e compound or its pharmacy acceptable salt or hydrate:

wherein

R ⁹be selected from hydrogen, halogen and-C ₁-C ₄haloalkyl; And

R ⁴and R ⁵the heterocyclic radical optionally forming a carbocylic radical be optionally substituted together or be optionally substituted.

A kind of there is Formula I f compound or its pharmacy acceptable salt or hydrate:

wherein

R ⁹be selected from hydrogen, halogen and-C ₁-C ₄haloalkyl; And

Additionally provide a kind of there is Formulae II compound or its pharmacy acceptable salt or hydrate:

wherein:

Wherein:

(i) when A be optionally by F, Cl or SO ₂cH ₃during the phenyl replaced, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all N (CH ₃) CH ₂c (O) NH-sec.-propyl, NHCH (CH ₃) (CH ₂) ₃n (CH ₂cH ₃) ₂, NHCH ₂cH ₂oH, NHCH ₂cH ₂oCH ₃, NHCH ₂cH ₂oSO ₃h, NHCH ₂cH ₂cH ₂oCH ₂cH ₂o-phenyl, NHCH ₂cH ₂cH ₂oH, NHCH ₂cH ₂cH ₂oCH ₃, NHCH ₂cH (OH) CH ₃, N (CH ₂cH ₃) ₂, NH-sec.-propyl, NHCH ₂cH ₂nHC (O) OCH ₃, NHCH ₂cH ₂nHC (O) CH ₃, NHCH ₂cH ₂nH ₂or NHCH ₂-phenyl;

(ii) when A is the pyridyl be optionally substituted, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NHCH ₂-phenyl, NHCH ₂-(2,4 difluorobenzene base), N (CH ₃) CH ₂cH ₂c (O) OH, NHCH ₂cH ₂c (O) OH, NHCH ₂cH ₂c (O) OCH ₂cH ₃, NHCH ₂cH ₂c (O) the O-tertiary butyl, NHCH ₂cH ₂c (O) NH ₂, NHCH ₂cH ₂-phenyl, NHCH ₂cH ₂oH, NHCH ₂cH ₂nH ₂, NHCH ₂cH ₂n (CH ₃) ₂or NHCH ₂cH ₂cH ₃;

(iii) when A be the 1-imidazolyl be optionally substituted, the 1-pyrryl be optionally substituted or be optionally substituted 1-pyrazolyl time, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NH (CH ₂) ₇cH ₃, NHCH ₂-(adjacent chloro-phenyl) or NHCH ₂cH ₂oH;

(iv) when A is unsubstituted 2-pyridyl, so R is passed through ⁴and R ⁵the ring formed is not 5-methyl isophthalic acid H-pyrazole-3-yl; And

(v) when A is the 1-pyrazolyl be optionally substituted, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all N (CH ₃) ₂, NHCH ₃, NHAc, NH sec.-propyl, NHCH ₂cH ₃, NHCH ₂cH ₂sO ₃h or N (CH ₂cH ₃) ₂,

(vi) ring A is not the triazolyl, 3, the 5-dimethyl-1H-pyrazol-1-yls that are optionally substituted,

(vii) R is worked as ¹and R ²optionally form a unsubstituted cyclohexyl together, and R ⁴and R ⁵when optionally forming a unsubstituted cyclohexyl together, so A is not a dibasic 1-pyrazolyl or unsubstituted phenyl; And

(viii) this compound is not be selected from lower group:

Additionally provide a kind of there is Formula I c compound or its pharmacy acceptable salt or hydrate:

wherein:

Each R ⁹independent selected from halo ,-C ₁-C ₄alkyl ,-C ₁-C ₄haloalkyl ,-C ₁-C ₄hydroxyalkyl ,-NH-S (O) ₂-(C ₁-C ₄alkyl) ,-S (O) ₂nH (C ₁-C ₄alkyl) ,-CN ,-S (O) ₂-(C ₁-C ₄alkyl), C ₁-C ₄alkoxyl group ,-NH (C ₁-C ₄alkyl) ,-N (C ₁-C ₄alkyl) ₂,-OH ,-OCF ₃,-CN ,-NH ₂,-C (O) NH ₂,-C (O) NH (C ₁-C ₄alkyl) ,-C (O)-N (C ₁-C ₄alkyl) ₂,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl), aryl and optionally by cyclopropyl that OH replaces;

N is 1 to 3;

Q is selected from carbocylic radical and heterocyclic radical, and wherein any one is optionally substituted; Wherein

R ¹and R ²optionally form a carbocylic radical be optionally substituted together; Or

R ⁴and R ⁵optionally form a carbocylic radical be optionally substituted together;

Wherein:

(i) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NHCH ₂cH ₂oCH ₂cH ₂oCH ₂cH ₂nH ₂or 4-[[2-[2-(2-amino ethoxy) oxyethyl group] ethyl] is amino],

(ii) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) both are not all NHEt, NH (n-propyl), NH (normal-butyl), NH (dodecyl), NH-[(4-p-methoxy-phenyl) methyl], NHCH ₂cH ₂cHO, NHCH ₂cH ₂oCH ₃, NHCH ₂cH ₂oH, NHCH ₂cH (OH) CH ₃, NHCH ₂cH ₂oC (O) phenyl, NHCH ₂cH ₂cH ₂oH, NHCH ₂cH ₂cH ₂n (CH ₃) phenyl, NHCH ₂c (O) OCH ₃, NHCH ₂c (O) OCH ₂cH ₃, NHCH ₂phenyl, NHCH (CH ₃) CH ₂cH ₃or NHCH ₂cH ₂oC (O) CH ₃; And

(iii) N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not all NH cyclohexyl C (O) NHCH ₂r, wherein R is by OCF ₃, OCH ₃, chlorine or CF ₃in the phenyl of one or more replacements or pyridyl.

Additionally provide a kind of there is Formulae II I compound or its pharmacy acceptable salt or hydrate:

wherein:

Ring A is a 5-6 unit bicyclic heteroaryl be optionally substituted;

Ring B is the 5-6 unit's monocyclic aryl or bicyclic heteroaryl that are optionally substituted;

R ¹and R ³be selected from hydrogen, C independently of one another ₁-C ₄alkyl, C ₁-C ₄haloalkyl ,-O-C ₁-C ₄alkyl and CN, wherein R ¹, R ³, R ⁴and R ⁶each described moieties independently of one another optionally by-OH ,-NH ₂,-CN ,-O-C ₁-C ₄alkyl ,-NH (C ₁-C ₄alkyl) or-N (C ₁-C ₄alkyl) ₂replace;

R ²be selected from :-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkyl)-C (O)-NH ₂,-(C ₁-C ₆alkyl)-CO ₂h ,-(C ₂-C ₆alkenyl or alkynyl) ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₁-C ₆alkyl) and-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-Q, wherein:

Be present in R ²in any alkyl or alkylene moiety optionally by one or more-OH ,-O (C ₁-C ₄alkyl) ,-CO ₂h or halogen replace;

Be present in R ²in any terminal methyl group moiety ground by-CH ₂oH, CF ₃,-CH ₂f ,-CH ₂cl, C (O) CH ₃, C (O) CF ₃, CN or CO ₂h replaces;

R ¹and R ²the heterocyclic radical optionally forming a carbocylic radical be optionally substituted together or be optionally substituted;

Wherein when the Yi oxadiazole that A is replaced by a pyridyl be optionally substituted, so G is not a phenyl be optionally substituted.

In certain embodiments, G is replaced by 1 or 2 substituting group, and these substituting groups are selected from halogen, C1-C4 alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group ,-CN ,=O ,-OH, aryl, heteroaryl-SO ₂c ₁-C ₄alkyl ,-CO ₂c ₁-C ₄alkyl ,-C (O) aryl and-C (O) C ₁-C ₄alkyl.

Additionally provide a kind of there is Formulae II Ia compound or its pharmacy acceptable salt or hydrate:

wherein:

Ring A is a 5-6 unit bicyclic heteroaryl be substituted;

X ^dc or N;

Each R ^bindependent selected from halo, CN, C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group, C ₃-C ₆cycloalkyl, phenyl ,-OH ,-C (O) CH ₃, wherein any alkyl, cycloalkyl or phenyl portion ground is by fluorine, chlorine ,-OH ,-NH ₂or-CN replaces;

P is 1 to 2;

R ²be selected from :-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkyl)-C (O)-NH ₂,-(C ₁-C ₆alkyl)-CO ₂h ,-(C ₂-C ₆alkenyl or alkynyl) ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₁-C ₆alkyl),

Wherein when the Yi oxadiazole that A is replaced by a pyridyl be optionally substituted, so X ^dnot C.

Additionally provide a kind of there is Formulae II Ib compound or its pharmacy acceptable salt or hydrate:

wherein:

Ring A is a 5-6 unit bicyclic heteroaryl be substituted;

P is 1 to 2; And

G is the carbocylic radical or heterocyclic radical that are optionally substituted,

Wherein A is not replaced oxadiazole by the pyridyl be optionally substituted.

Additionally provide a kind of there is Formulae II Ic compound or its pharmacy acceptable salt or hydrate:

wherein:

Ring A is a 5-6 unit bicyclic heteroaryl be substituted;

Each R ^bindependent selected from halo, CN, C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group, C ₃-C ₆cycloalkyl, phenyl ,-OH ,-C (O) CH ₃, wherein any alkyl, cycloalkyl or phenyl portion ground is by fluorine, chlorine ,-OH ,-NH ₂or-CN replaces; And

P is 1 to 2.

Additionally provide a kind of there is Formulae II Id compound or its pharmacy acceptable salt or hydrate:

wherein:

Ring A is a 5-6 unit bicyclic heteroaryl be substituted;

P is 1 to 2; And

G is the carbocylic radical or heterocyclic radical that are optionally substituted.

The one or more combination in above cited specific embodiment is comprised in these other embodiments provided.

In another embodiment, this compound is selected from any one in compound cited in following table 1.

Table 1. representative compound

Also comprise the method for the manufacture of the compound of any one had in the compound of Formula I or embodiment described herein at this, these methods comprise to be made with reaction.In certain embodiments, preceding method comprises step (1) and makes with reaction is to obtain make with step (2) with reaction.In other embodiments, preceding method comprises step (1) and makes with reaction is to obtain step (2) makes with reaction is to obtain make with step (3) with reaction.

Also comprise the method for the manufacture of the compound of any one had in the compound of Formula I or embodiment described herein, these methods comprise to be made with reaction.

Also comprise the method for the manufacture of the compound of any one had in the compound of Formula I or embodiment described herein, these methods comprise to be made with reaction.In certain embodiments, preceding method comprises step (1) and makes with reaction is to obtain make with step (2) with reaction.

Also comprise the method for the manufacture of the compound of any one had in the compound of Formula I or embodiment described herein, these methods comprise to be made with reaction.In other embodiments, preceding method comprises step (1) and uses in the basic conditions transform to obtain step (2) makes with PCl ₅, POCl ₃reaction is to obtain step (3) makes with reaction is to obtain make with step (4) with reaction.In other embodiments, preceding method comprises step (1) and uses in the basic conditions transform to obtain step (2) makes with PCl ₅, POCl ₃reaction is to obtain step (3) makes with reaction is to obtain make with step (4) with reaction.In other embodiments, preceding method comprises step (1) and uses in the basic conditions transform to obtain step (2) makes with PCl ₅, POCl ₃reaction is to obtain step (3) makes with reaction is to obtain make with step (4) with reaction.In other embodiments, the method comprises the following steps: make with react in the basic conditions to obtain wherein ring G is carbocylic radical or heterocyclic ring.In other embodiments, the method comprises the following steps: 1) make with reaction is to obtain with 2) make with reaction is to obtain wherein ring B is aryl or heteroaryl ring.In other embodiments, the method comprises the following steps: make with react in the basic conditions to obtain wherein ring B is aryl or heteroaryl ring, and ring G is carbocylic radical or heterocyclic ring.In other embodiments, the method comprises the following steps: make react to be formed with ring A

The compound of one aspect of the present invention can comprise one or more asymmetric center and thus occur in following form: racemic modification, racemic mixture, non-racemic mixture and non-enantiomer mixture, and does not contain in fact the single enantiomer of another kind of possible enantiomer or steric isomer or independent steric isomer.Term as used herein " in fact not containing other steric isomers " means to be rich in a kind of like this preparation of compound, and this compound has at least about the stereochemistry selected by 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% at one or more selected stereocenter place.It is the compound at one or more selected stereocenter place with selected stereochemistry that term " is rich in " preparation meaning at least prescribed percentage.To obtain or the method for the independent enantiomer or steric isomer of synthesizing given compound is as known in the art and as feasible, go for finalization compound or parent material or intermediate.

In certain embodiments, there is Formula I, the compound of Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId is rich in has selected stereochemical a kind of structure or various structures at one or more carbon atom place.Such as, this compound is rich in the particular stereoisomer at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%.

There is Formula I, the compound of Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId can also comprise one or more isotropic substances replace.Such as, H can be any isotope form, comprises ¹h, ²h (D or deuterium) and ³h (T or tritium); C can be any isotope form, comprises ¹¹c, ¹²c, ¹³c and ¹⁴c; ; N can be any isotope form, comprises ¹³n, ¹⁴n and ¹⁵n; O can be any isotope form, comprises ¹⁵o, ¹⁶o and ¹⁸o; F can be any isotope form, comprises ¹⁸f; Etc..Such as, this compound is rich in the specific isotope form of H, C, N, O and/or F at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%.

Except as otherwise noted, otherwise when disclosed compound is named by the structure not indicating stereochemistry or described and have one or more chiral centre, be interpreted as all possible steric isomer representing this compound.

The compound of one aspect of the present invention can also present with multiple tautomeric form, in such cases, one aspect of the present invention comprises all tautomeric forms of compound described herein clearly, although only single tautomeric form can be presented (such as, the alkylation of loop systems can produce alkylation in multiple site, and one aspect of the present invention comprises this type of reaction product all and keto-enol tautomerism body clearly).These type of isomeric form all of this compounds are included clearly at this.

Can easily or the preparation making us wishing, purifying and/or process active compound the salt of correspondence, such as pharmacy acceptable salt.The example of pharmacy acceptable salt is people such as uncles strange (Berge), 1977, " pharmacy acceptable salt (PharmaceuticallyAcceptableSalts.) " " Journal of Pharmaceutical Sciences " (J.Pharm.Sci.) the 66th volume, discusses in 1-19 page to some extent.

Such as, if compound is anionic, or to have can be functional group's (such as ,-COOH can be-COO-) of anionic, so can with a kind of suitable salt forming cation.The example of suitable inorganic cation includes but not limited to that alkalimetal ion is (as Na ⁺and K ⁺), alkaline earth metal cation is (as Ca ²⁺and Mg ²⁺) and other positively charged ions (as Al ³⁺).Suitable organic cations example includes but not limited to ammonium ion (that is, NH ₄ ⁺) and ammonium ion (such as, the NH that is substituted ₃r ⁺, NH ₂r ²⁺, NHR ³⁺, NR ⁴⁺).The example of some suitable ammonium ions be substituted derives from those of the following: ethamine, diethylamine, dicyclohexyl amine, triethylamine, butylamine, quadrol, thanomin, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and trometamol, together with amino acid, as Methionin and arginine.An example of common quaternary ammonium ion is N (CH ₃) ₄ ⁺.

If compound is cationic, or to have can be cationic functional group (such as ,-NH ₂can be-NH ₃ ⁺), so can form salt with a kind of suitable negatively charged ion.The example of suitable inorganic anion includes but not limited to derive from those of following mineral acid: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid and phosphorous acid.

The example of suitable organic anion include but not limited to derive from following organic acid those: Aspirin, acetic acid, xitix, aspartic acid, phenylformic acid, camphorsulfonic acid, styracin, citric acid, edetic acid, ethionic acid, ethyl sulfonic acid, FUMARIC ACID TECH GRADE, glucoheptonic acid, gluconic acid, L-glutamic acid, oxyacetic acid, hydroxy-maleic acid, hydroxynaphthoic acid, hydroxyethylsulfonic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, oxysuccinic acid, methylsulfonic acid, mucic acid, oleic acid, oxalic acid, palmitinic acid, pamoic acid, pantothenic acid, toluylic acid, Phenylsulfonic acid, propionic acid, pyruvic acid, Whitfield's ointment, stearic acid, succsinic acid, Sulphanilic Acid, tartrate, toluenesulphonic acids and valeric acid.The mesylate of often kind of compound in table 1 is included clearly at this.The example of suitable polymerization organic anion includes but not limited to derive from those of following polymeric acid: tannic acid, carboxymethyl cellulose.

If applicable, so therefore comprise these compounds itself together with its salt, hydrate and prodrug thereof at this compound provided.Can be modified and be changed into prodrug by additional appropriate functional group at this compound provided, thus the biological nature selected by strengthening, such as target particular organization.(namely this type of modify, prodrug) be as known in the art and comprise increase bio-osmosis in given biological compartment (such as, blood, lymphsystem, central nervous system), increase oral availability, increase solubleness with allows drug administration by injection, change metabolism and change discharge rate those modifications.The example of prodrug comprises ester (such as, phosphoric acid ester, amino acid (such as, α-amino-isovaleric acid) ester), carbamate and other pharmaceutically acceptable derivates, and these prodrugs can provide active compound after giving experimenter.If applicable, calcium phosphate and the sodium phosphate of often kind of compound so in table 1 are included clearly at this.If applicable, amino acid (such as, the α-amino-isovaleric acid) ester of often kind of compound so in table 1 is included clearly at this.

composition and route of administration

The compound adopted in method described herein can be mixed with pharmaceutically acceptable composition together with the pharmaceutically acceptable carrier of one or adjuvant, then gives experimenter.In another embodiment, this type of pharmaceutically acceptable composition comprises the other therapeutical agent of the amount of the adjustment that effectively can realize disease or disease symptoms (comprise described herein those) further.

Term " pharmaceutically acceptable carrier or adjuvant " refers to and can give experimenter together with the compound of one aspect of the present invention and not destroy its pharmacological activity and when being nontoxic carrier or adjuvant to be enough to when delivery treatments quantizes that the dosage of compound gives.

The pharmaceutically acceptable carrier of the pharmaceutical composition of an aspect used in the present invention, adjuvant and mediator include but not limited to ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, self-emulsifying drug delivery systems (SEDDS) (as d-alpha-tocopherol cetomacrogol 1000 succinate), for the tensio-active agent (as tween (Tween) or other similar polymeric delivery matrices) in pharmaceutical dosage form, serum protein (as human serum albumin), buffer substance (as phosphoric acid salt), glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, salt or ionogen are (as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloidal silica, Magnesium Trisilicate), Polyvinylpyrolidone (PVP), cellulose base materials, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, wax, polyethylene-polyoxypropylene block polymer, polyoxyethylene glycol and lanolin.The derivative of cyclodextrin (as alpha-cylodextrin, beta-cyclodextrin and γ-cyclodextrin) or chemically modified derivative (as hydroxyalkyl cyclodextrin, comprising 2-HP-BETA-CD and 3-hydroxypropyl-beta-cyclodextrin) or other dissolvings also can be advantageously used in strengthen has sending of the compound of chemical formula described herein.

The pharmaceutical composition of one aspect of the present invention can per os, without intestines, by sucking spraying, partly, per rectum, intranasal, through cheek, transvaginal or via implanted reservoir, giving preferably by oral administration or drug administration by injection.The pharmaceutical composition of one aspect of the present invention can comprise acceptable carrier, adjuvant or mediator on any conventional non-toxic pharmaceutical.In some cases, the pH of preparation can be regulated to strengthen the stability of institute's preparation compound or its delivery form with pharmaceutically acceptable acid, alkali or damping fluid.Term as used herein comprises in subcutaneous, intracutaneous, intravenously, intramuscular, intraarticular, intra-arterial, synovial membrane, in breastbone, in sheath without intestines, intralesional and intracranial injection or infusion techniques.

Pharmaceutical composition can be the form of sterile injectable preparation, such as, in the water-based of sterile injectable or the form of oily suspensions.This suspension can, according to technology as known in the art, use applicable dispersion or wetting agent (such as tween 80) and suspension agent to prepare.Sterile injectable preparation also can be nontoxic without the sterile injectable solution in the acceptable thinner of intestines or solvent or suspension, such as, in the solution form in 1,3 butylene glycol.The acceptable mediator that can adopt and solvent have N.F,USP MANNITOL, water, Ringer's solution (Ringer'ssolution) and isotonic sodium chlorrde solution.In addition, adopt aseptic fixed oil as solvent or suspension medium routinely.For this purpose, the fixed oil of any gentleness can be adopted, comprise direactive glyceride or two glyceryl ester of synthesis.Lipid acid (as oleic acid) and glyceride derivative thereof have for the preparation of injectable agent as natural pharmaceutically acceptable oil (as sweet oil or Viscotrol C, especially in its polyoxyethylated versions).These oil solutions or suspension can also contain long-chain alcohol diluents or dispersion agent, or carboxymethyl cellulose or be generally used for prepares the similar dispersion agent of pharmaceutically acceptable formulation (as emulsion and or suspension).For the object of preparation, other the conventional tensio-active agents being usually used in producing pharmaceutically acceptable solid, liquid or other formulations can also be used, as TWEEN Series or this dish series (Spans) and/or other similar emulsifying agents or bioavailability toughener.

The pharmaceutical composition of one aspect of the present invention can give with the acceptable formulation per os of any per os, and this formulation includes but not limited to capsule, tablet, emulsion and waterborne suspension, dispersion liquid and solution.In the situation of the tablet Gong orally using, conventional carrier comprises lactose and W-Gum.Typically also add lubricant, as Magnesium Stearate.Give for capsules per os, useful thinner comprises lactose and dry W-Gum.When per os gives waterborne suspension and/or emulsion, activeconstituents can be suspended or is dissolved in a kind of combination has in the oil phase of emulsifying agent and/or suspension agent.If desired, some sweeting agent and/or seasonings and/or tinting material can be added.

The pharmaceutical composition of one aspect of the present invention can also give in the suppository form for per rectum administration.These compositions can be prepared by the compound and a kind of suitable non-irritating excipient mixing one aspect of the present invention, this vehicle is at room temperature solid but under rectal temperature, is liquid and therefore will melts in the rectum, thus discharges active ingredient.This type of material includes but not limited to theobroma oil, beeswax and polyoxyethylene glycol.

The local of the pharmaceutical composition of one aspect of the present invention give desired treatment relate to by topical application easily accessibility region or organ time be useful.For application to skin partly, this pharmaceutical composition should be prepared with the ointment be applicable to comprising the active ingredient suspending or be dissolved in carrier.The carrier giving the compound of one aspect of the present invention for local includes but not limited to mineral oil, liquid petroleum, white oil, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternately, can prepare this pharmaceutical composition with the lotion be applicable to or emulsifiable paste comprising active compound, this active compound suspends with the emulsifying agent be applicable to or is dissolved in carrier.Suitable carrier includes but not limited to mineral oil, polysorbate60, spermaceti ester type waxes, cetostearyl alcohol, 2-Standamul G, benzylalcohol and water.The pharmaceutical composition of one aspect of the present invention or can also be that a kind of applicable enema preparation form topical application is to lower bowel by rectal suppository preparation.Topical transdermal patch is also included within one aspect of the present invention.

The pharmaceutical composition of one aspect of the present invention can be given by nose aerosol or suction.Such composition is according to technology preparation well-known in pharmaceutical-formulating art, and benzylalcohol or other suitable sanitass, the absorption enhancer strengthening biological usability, fluorocarbon and/or other solubilizing agent as known in the art or dispersion agent can be adopted, with the solution form preparation in normal saline solution.

When the composition of one aspect of the present invention comprises the combination of compound and one or more other therapeutical agents or the preventive with chemical formula described herein, this compound and this additive all should with between about 1% to 100% of given dosage usual in monotherapy scheme, and the dosage level more preferably between about 5% to 95% exists.As a part for multiple doses scheme, additive can give dividually with the compound of one aspect of the present invention.Alternately, those medicaments can be parts for single formulation, are mixed together in single composition with the compound of one aspect of the present invention.

Compound described herein such as can pass through injection, intravenously, intra-arterial, subcutaneous, intraperitoneal, intramuscular or subcutaneous; Or per os, through cheek, intranasal, through mucous membrane, locally, with a kind of ophthalmic preparation form or by suck, with from every kg body weight about 0.5 to the dosage within the scope of about 100mg, dosage alternately between every dosage 1mg and 1000mg, every 4 to 120 hours, or give according to the requirement of certain drug.These methods contemplated that the compound or compound composition that give significant quantity are to obtain effect that is desired or that state.Typically, the pharmaceutical composition of one aspect of the present invention will give from about 1 time to about 6 times every day, or alternately, give with continuous infusion form.Giving like this can be used as chronic or acute therapy.The amount that can combine the activeconstituents to produce single formulation with solid support material will depend on treated host and concrete mode of administration and changes.Typical preparation will comprise the active compound (w/w) of from about 5% to about 95%.Alternately, this type of preparation comprises the active compound of from about 20% to about 80%.

The dosage low or higher than those dosage mentioned above may be needed.To depend on many factors for the concrete dosage of any particular subject and treatment plan, these factors comprise the activity of particular compound used, the age, body weight, general health situation, sex, diet, give the time, discharge rate, drug regimen, the severity of this disease, symptom or symptom and process, experimenter easily suffers from this disease, symptom or symptom, and the judgement for the treatment of doctor.

After the symptom of experimenter is improved, the compound of one aspect of the present invention of maintenance dose, composition or combination can be given where necessary.Subsequently, according to symptom, the dosage of administration or frequency or both all can be reduced to certain level, at which level, when symptom has been alleviated to desired level, the symptom improved has been maintained.But experimenter can require Intermittent treatment based on the long-term consideration of any recurrence of disease symptoms.

The mentioned above pharmaceutical composition with Formula I, the compound of Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or the compound described in this embodiment any one that comprises can include the another kind of therapeutical agent being used for the treatment of cancer further.

using method

Provide a kind of method for mutation inhibiting type IDH1 activity, the method comprise make to its experimenter in need with there is the compound described in Formula I, the compound (comprising its tautomer and/or isotropic substance thing) of Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or in this embodiment any one, or its pharmacy acceptable salt contact.In one embodiment, have the feature of cancer to be treated to be a kind of mutant allele of IDH1, wherein IDH1 sudden change facilitates this enzyme catalysis α-ketoglutaric acid NAPH dependency in experimenter and is reduced into the new ability of R (-)-2-hydroxyl pentanedioic acid.In in of this embodiment, this saltant type IDH1 has R132X sudden change.In in of this embodiment, this R132X sudden change is selected from R132H, R132C, R132L, R132V, R132S and R132G.In one aspect of the method, this R132X sudden change is R132H or R132C.In again in another, this R132X sudden change is R132H.

Additionally provide treatment with the method that there is the cancer that the mutant allele of IDH1 is feature, these methods comprise the following steps: give (a) compound with Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId to its experimenter in need, or the compound described in this embodiment any one, or its pharmacy acceptable salt; Or (b) a kind of pharmaceutical composition, this pharmaceutical composition comprises (a) and pharmaceutically acceptable carrier.

In one embodiment, have the feature of cancer to be treated to be a kind of mutant allele of IDH1, wherein IDH1 sudden change facilitate this enzyme in patients catalysis α-ketoglutaric acid NAPH dependency be reduced into the new ability of R (-)-2-hydroxyl pentanedioic acid.In in of this embodiment, this IDH1 sudden change is R132X sudden change.This embodiment another in, this R132X sudden change be selected from R132H, R132C, R132L, R132V, R132S and R132G.In one aspect of the method, this R132X sudden change is R132H or R132C.Cancer can determine by checking order to cell sample that the existence of the sudden change (being such as present in this amino acid changed) at amino acid/11 32 place at IDH1 and special property are analyzed.

Not bound by theory, applicant believes the mutant allele (wherein IDH1 sudden change facilitates the new ability that this enzyme catalysis α-ketoglutaric acid NAPH dependency is reduced into R (-)-2-hydroxyl pentanedioic acid) of IDH1, and particularly the R132H sudden change of IDH1 describes the feature of all types cancer subgroup, do not consider its cellularity in vivo or position.Thus, Compounds and methods for of the present invention has the mutant allele that is used for the treatment of to exist the IDH1 giving such activity and particularly IDH1R132H or R132C sports the cancer of any type of feature.

In in of this embodiment, the curative effect of cancer therapy is monitored by the 2HG level measured in experimenter.Typically, measure 2HG level before treatment, the level wherein raised show to employ have in Formula I, the compound of Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or embodiment described herein any one described in compound carry out Therapeutic cancer.Once establish the level of rising, namely during stopped treatment is with the process determining curative effect and/or afterwards, measure 2HG level.In certain embodiments, 2HG level is only during the process of stopped treatment and/or measure afterwards.The decline instruction during therapeutic process and after the treatment of 2HG level is effective in cure.Similarly, the mensuration that 2HG level does not raise during therapeutic process or after treatment also indicates effective in cure.Typically, these 2HG measure and adopt together with other well-known measuring methods of the curative effect with cancer therapy, other well-known measuring methods such as the quantity of tumour and/or other cancer relevant diseases and size reduce, and the general health situation of experimenter is improved and the change of the other biological relevant to the effectiveness of cancer therapies mark.

The 2HG in sample can be detected by LC/MS.Sample is mixed with 80:20 with methyl alcohol, and at 4 DEG C, under 3,000rpm centrifugal 20 minutes.Gained supernatant liquor can be collected and at being stored in-80 DEG C, then carry out LC-MS/MS to evaluate 2-hydroxyl pentanedioic acid level.Multiple different liquid chromatography (LC) separation method can be used.Often kind of method can be ionized (ESI ,-3.0kV) and be coupled in the triple quadrupole mass spectrometer of multiple-reaction monitoring (MRM) pattern operation by negative electrospray, the metabolite standardized solution wherein about institute's infusion optimizes MS parameter.Metabolite can pass through reverse-phase chromatography, use 10mM Tributylamine as the ion pair reagent in water-based moving phase, according to previous report method (people's " chromatography magazine A collects " (JChromatogrA) 1147 such as sieve (Luo), 153-64,2007) variant is separated.One method allows to split TCA metabolite: t=0,50%B; T=5,95%B; T=7,95%B; T=8,0%B, wherein B refers to organic moving phase of 100% methyl alcohol.Another kind method has specificity to 2-hydroxyl pentanedioic acid, lasts the fast linear gradient run for 5 minutes from 50% to 95%B (damping fluid as hereinbefore defined).As mentioned above, can use SynergiHydro-RP, 100mm × 2mm, 2.1 μm of particle diameters (Féraud door company (Phenomonex)) are as tubing string.Metabolite can be undertaken quantitatively by the pure metabolite standard substance of comparison peak area and concentration known.Can as such as described in people " Nature Biotechnol " (NatBiotechnol) 26,1179-86,2008 such as awns lattice (Munger) from ¹³c-glutamine carries out metabolic flux research.

In one embodiment, directly 2HG is assessed.

In another embodiment, assess at the derivative carrying out the 2HG formed in the process of analytical procedure.By way of example, a kind of like this derivative can be the derivative formed in MS analyzes.Derivative can comprise salt adduct (such as, Na adducts), hydration variant or also be the hydration variant (such as, Na adducts) of salt adduct, such as in analyzing at MS formed.

In another embodiment, the metabolic derivative of 2HG is assessed.Example comprises existence accumulation due to 2HG or the material that raises or reduce, as with 2HG, such as, the glutarate that R-2HG is relevant or glutamate.

Exemplary 2HG derivative comprises anhydro derivatives, the compound or its salt adducts provided as following:

and

In one embodiment, cancer is wherein when diagnosing or treat, and the tumour cell of at least 30%, 40%, 50%, 60%, 70%, 80% or 90% carries IDH1 sudden change, and the tumour of particularly IDH1R132H or R132C sudden change.

In the known cancer appeared at as some type pointed in following table 2 of IDH1R132X sudden change.

the IDH that table 2. is relevant to some cancer suddenlys change

IDH1R132H sudden change has been differentiated to arrive in the following: glioblastoma, acute myelogenous leukemia, sarcoma, melanoma, nonsmall-cell lung cancer, cholangiocarcinoma, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative anything superfluous or useless (MPN), colorectal carcinoma and Angioimmunoblast non Hodgkin lymphom (angio-immunoblasticnon-Hodgkin'slymphoma; NHL).Therefore, in one embodiment, method described herein is used for the treatment of the neurospongioma (glioblastoma) of patient, acute myelogenous leukemia, sarcoma, melanoma, nonsmall-cell lung cancer (NSCLC), cholangiocarcinoma, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative anything superfluous or useless (MPN), colorectal carcinoma or Angioimmunoblast non Hodgkin lymphom (NHL).

In another embodiment, method described herein is used for the treatment of the neurospongioma (glioblastoma) of patient, acute myelogenous leukemia, sarcoma, melanoma, nonsmall-cell lung cancer (NSCLC), cholangiocarcinoma (such as, intrahepatic cholangiocarcinoma (IHCC)), chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative anything superfluous or useless (MPN), prostate cancer, chronic myelomonocytic leukemia (CMML), B-acute lymphoblastic leukemia (B-ALL), B-acute lymphoblastic leukemia (B-ALL), myelosarcoma, multiple myeloma, lymphoma colorectal carcinoma or Angioimmunoblast non Hodgkin lymphom (NHL).

In another embodiment, have Malignancy in late period to be treated be lymphoma (such as, non-Hodgkin lymphoma (NHL), as B cell lymphoma (such as, Burkitt lymphoma (Burkittlymphoma), lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B cell lymphoma, follicular lymphoma, immunoblast large celllymphoma, precursor B-LBL and lymphoma mantle cell) and T-cell lymphoma is (such as, mycosis fungoides, primary cutaneous type and precursor T-LBL).

Therefore, in one embodiment, this cancer is the cancer of any one be selected from the cancer types listed by table 2, and IDHR132X sudden change is for one or more in the IDH1R132X sudden change listed by particular cancers type in table 2.

Methods for the treatment of described herein can be included in addition with have in Formula I, the compound of Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or embodiment described herein any one described in compounds for treating before or after different appraisal procedures.

In one embodiment, with have in Formula I, the compound of Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or embodiment described herein any one described in compounds for treating before or after, the method comprises the step of the growth of this cancer of assessment, size, weight, aggressive, stage and/or other phenotypes further.

In one embodiment, with have in Formula I, the compound of Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or embodiment described herein any one described in compounds for treating before or after, the method comprises the genotypic step of IDH1 of assessment of cancer further.This can be obtained by the usual way in this area, as the existence of DNA sequencing, immunoassay and/or assessment 2HG, distribution or level.

In one embodiment, with have in Formula I, the compound of Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or embodiment described herein any one described in compounds for treating before or after, the method comprises the step of the 2HG level measured in experimenter further.This can be obtained by the following: spectroscopic analysis, such as, based on the analysis of mr, and such as MRI and/or MRS measuring method; The sample analysis of body fluid, as serum or spinal fluid analysis; Or by the analysis of surgical material, such as, pass through mass spectroscopy.

Additionally provide a kind of method for mutation inhibiting type IDH2 activity, the method comprise make to its experimenter in need with there is the compound described in Formula I, the compound of Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId, in this embodiment any one or its pharmacy acceptable salt contacts.In one embodiment, have the feature of cancer to be treated to be a kind of mutant allele of IDH2, wherein IDH2 sudden change facilitates this enzyme catalysis α-ketoglutaric acid NAPH dependency in experimenter and is reduced into the new ability of R (-) 2-hydroxyl pentanedioic acid.In in of this embodiment, this saltant type IDH2 has R140X sudden change.This embodiment another in, this R140X sudden change be R140Q sudden change.This embodiment another in, this R140X sudden change be R140W sudden change.This embodiment another in, this R140X sudden change be R140L sudden change.This embodiment another in, this mutant IDH2 have R172X sudden change.This embodiment another in, this R172X sudden change be R172K sudden change.This embodiment another in, this R172X sudden change be R172G sudden change.

Additionally provide treatment with the method that there is the cancer that the mutant allele of IDH2 is feature, these methods comprise the following steps: give (a) compound with Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId to its experimenter in need, or the compound described in this embodiment any one, or its pharmacy acceptable salt; Or (b) a kind of pharmaceutical composition, this pharmaceutical composition comprises (a) and pharmaceutically acceptable carrier.

In one embodiment, have the feature of cancer to be treated to be a kind of mutant allele of IDH2, wherein IDH2 sudden change facilitate this enzyme in patients catalysis α-ketoglutaric acid NAPH dependency be reduced into the new ability of R (-) 2-hydroxyl pentanedioic acid.In in of this embodiment, this saltant type IDH2 has R140X sudden change.This embodiment another in, this R140X sudden change be R140Q sudden change.This embodiment another in, this R140X sudden change be R140W sudden change.This embodiment another in, this R140X sudden change be R140L sudden change.This embodiment another in, this mutant IDH2 have R172X sudden change.This embodiment another in, this R172X sudden change be R172K sudden change.This embodiment another in, this R172X sudden change be R172G sudden change.Cancer can determine by checking order to cell sample that the existence of the sudden change (being such as present in this amino acid changed) at amino acid/11 40 and/or 172 place of IDH2 and special property are analyzed.

Not bound by theory, applicant believes the mutant allele (wherein IDH2 sudden change facilitates the new ability that this enzyme catalysis α-ketoglutaric acid NAPH dependency is reduced into R (-) 2-hydroxyl pentanedioic acid) of IDH2, and particularly R140Q and/or the R172K sudden change of IDH2 describes the feature of all types cancer subgroup, do not consider its cellularity in vivo or position.Thus, the Compounds and methods for of one aspect of the present invention has the mutant allele that is used for the treatment of to exist the IDH2 giving such activity and particularly IDH2R140Q and/or R172K sports the cancer of any type of feature.

As said, in of this embodiment, the curative effect of cancer therapy is monitored by measuring 2HG level.

In one embodiment, cancer is wherein when diagnosing or treat, the tumour cell of at least 30%, 40%, 50%, 60%, 70%, 80% or 90% carries IDH2 sudden change, and the tumour of particularly IDH2R140Q, R140W or R140L and/or R172K or R172G sudden change.

In another embodiment, one aspect of the present invention provide a kind of by give to patient can effectively Therapeutic cancer amount there is Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, the compound of IIIc or IIId treats the method for the cancer of this patient, this cancer is selected from glioblastoma (neurospongioma), myelodysplastic syndromes (MDS), myeloproliferative anything superfluous or useless (MPN), acute myelogenous leukemia (AML), sarcoma, melanoma, nonsmall-cell lung cancer, chondrosarcoma, cholangiocarcinoma or angioimmunoblastic lymphoma.In one more specifically embodiment, cancer to be treated is had to be neurospongioma, myelodysplastic syndromes (MDS), myeloproliferative anything superfluous or useless (MPN), acute myelogenous leukemia (AML), melanoma, chondrosarcoma or Angioimmunoblast non Hodgkin lymphom (NHL).

2HG is known to be gathered in inherited metabolic illness 2-hydroxyl glutaric aciduria.This disease is by lacking caused by enzyme 2-hydroxyl glutatate dehydrogenase, 2HG is changed into α-KG (Shi Telusi by this enzyme, E.A. (Struys, people " American Journal of Human Genetics " (AmJHumGenet) 76,358-60 (2005) such as E.A.)).As by MRI and CSF analyze evaluate, the patient lacking 2-hydroxyl glutatate dehydrogenase gathers 2HG in brain, suffer from leukoencephalopathy, and there is risk (A Jili, M. (Aghili, M.), the Zha Hedi of the increase suffering from cerebral tumor, F. (Zahedi, and draw phenanthrene (Rafiee), " neural tumor magazine " (JNeurooncol) 91,233-6 (2009) F.); Cole Ke Er, S. (Kolker, S.), Mayan are worn gram, E. (Mayatepek, E.) and Huffman, G.F. (Hoffmann, G.F.) " Child Neurology " (Neuropediatrics) 33,225-31 (2002); Wa Na, M. (Wajner, M.), La Dini, A. (Latini, A.), intelligence, A.T. (Wyse, and Du Telafei mechanical ohm A.T.), C.S. (Dutra-Filho, C.S.) " inherited metabolic disease magazine " (JInheritMetabDis) 27,427-48 (2004)).In addition, 2HG brain level raises and causes ROS level to increase (Cole Ke Er, the people such as S. " European Journal of Neuroscience " (EurJNeurosci) 16,21-8 (2002); The people such as La Dini, A. " European Journal of Neuroscience " 17,2017-22 (2003)), risk of cancer may be caused to increase.The ability that 2HG serves as nmda receptor agonist can promote this effect (Cole Ke Er, the people such as S. " European Journal of Neuroscience " 16,21-8 (2002)).2HG can also have toxicity by suppressing competitively to adopt the enzyme of L-glutamic acid and/or α KG to cell.These enzymes comprise and allow to adopt L-glutamic acid nitrogen for transaminase that is amino and Nucleic acid, and α KG dependency prolyl hydroxylase, as those of adjustment HIF1-alpha levels.

Thus, according to another embodiment, one aspect of the present invention provide a kind of by have to patient in Formula I, the compound of Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or embodiment described herein any one described in compound treat the 2-hydroxyl glutaric aciduria of this patient, the especially method of D-2-hydroxyl glutaric aciduria.

Additionally provide the method that treatment is selected from the disease of maffucci's syndrome (Maffuccisyndrome) and dyschondroplasia (Ollierdisease), the feature of this disease is the mutant allele that there is IDH1, these methods comprise the following steps: have the compound described in Formula I, the compound of Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or in this embodiment any one to giving (a) to its experimenter in need, or its pharmacy acceptable salt; Or (b) a kind of pharmaceutical composition, this pharmaceutical composition comprises (a) and pharmaceutically acceptable carrier.

In one embodiment, with have in Formula I, the compound of Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or embodiment described herein any one described in compounds for treating before or after, the method comprises the genotypic step of IDH2 of assessment of cancer further.This can be obtained by the usual way in this area, as the existence of DNA sequencing, immunoassay and/or assessment 2HG, distribution or level.

combination treatment

In certain embodiments, method described herein comprises the other step to giving the second therapy altogether to its experimenter in need, and this second therapy is such as other cancer therapeutic agent or other cancer therapy.Exemplary other cancer therapeutic agent comprises such as chemotherapy, targeted therapies, antibody therapy, immunotherapy and hormonotherapy.Other cancer therapy comprises such as: operation and radiotherapy.The example of each in these treatments is provided in hereinafter.

Can with a part of form of single formulation (as comprising the composition of the compound of one aspect of the present invention and one aspect of the present invention of the second therapeutical agent as above) or give with multiple dosage form of separating together with the compound of one aspect of the present invention as " given " to mean this other cancer therapeutic agent at this altogether relative to the term that other cancer therapeutic agent uses.Alternately, other cancer therapeutic agent can before giving the compound of one aspect of the present invention, give therewith continuously or after this.In such combination therapy to treat, compound and these one or more second therapeutical agent of one aspect of the present invention are all given by ordinary method.Another time during the composition comprising the compound of one aspect of the present invention and one aspect of the present invention of the second therapeutical agent to experimenter is not precluded within therapeutic process, give separately the compound of described identical treatment agent, any other second therapeutical agent or any one aspect of the present invention to described experimenter.Can before giving the compound of one aspect of the present invention, occur concurrently or after this continuously, therewith therewith as " given " to mean this other cancer therapy at this altogether relative to the term that other cancer therapy uses.

In certain embodiments, other cancer therapeutic agent is a kind of chemotherapeutics.Example for the chemotherapeutic of cancer therapy comprises such as that metabolic antagonist is (such as, folic acid, purine and pyrimidine derivatives), alkylating agent (such as, mustargen, nitrosourea, platinum, alkyl sulfonate esters, hydrazine, triazene, aziridine, spindle poison, cytotoxic agent, topoisomerase enzyme inhibitor etc.) and hypomethylation agent is (such as, Decitabine (5-azepine-Deoxyribose cytidine), Ze Bulaen (zebularine), lsothiocyanates, azacitidine (5-azacytidine), the fluoro-2'-Deoxyribose cytidine of 5-, 5, 6-dihydro-5-azacytidine etc.).Exemplary Agents comprises aclarubicin, actinomycin, alitretinoin, altretamine, aminopterin-induced syndrome, amino-laevulic acid, amrubicin, amsacrine, anagrelide, white arsenic, asparaginase, atrasentan, Belotecan, Bei Seluoting, bendamustine, bleomycin, Velcade, busulfan, camptothecine, capecitabine, carboplatin, carboquone, carmofur, carmustine, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-l-yl, Chlorambucil, mustargen, cis-platinum, CldAdo, Clofarex, Ke Lita enzyme, endoxan, cytosine arabinoside, Dacarbazine, gengshengmeisu, daunomycin, Decitabine, Omaine, docetaxel, Dx, Efaproxiral, Ai Li More, according to arenomycin, enocitabine, epirubicin, estramustine, Etoglucid, Etoposide, floxuridine, fludarabine, Fluracil (5FU), fotemustine, gemcitabine, Ge Li get implant (Gliadelimplant), hydroxycarbamide, hydroxyurea, Ida mycin, ifosfamide, irinotecan, Yi Luofufen, ipsapirone, La Luotasai, formyl tetrahydrofolic acid, liposomal doxorubicin, liposome daunomycin, lonidamine, lomustine, lucanthone, Mannosulfan, masoprocol, melphalan, purinethol, mesna, methotrexate, amino-laevulic acid methyl esters, mitobronitol, mitoguazone, mitotane, mitomycin, mitoxantrone, S 254, nimustine, Ao Limosen, Ao Mataxin, Ao Tasai, oxaliplatin, Paclitaxel, pegaspargase, pemetrexed, spray department statin, pirarubicin, pixantrone, Plicamycin, porfimer sodium, prednimustine, Procarbazine, thunder is for Qu Sai, ranomustine, Rubitecan, 1-(2-C-cyano-2-dioxy-BETA-D-arabino-pentofuranosyl)-N4-palmitoyl cytosine, semustine, adenovirus carrier alignment code gene injection agent (Sitimageneceradenovec), his platinum (Strataplatin) husky bent, streptozocin, talaporfin, Ftorafur-uridylic, temoporfin, Temozolomide, Vumon, for Si Tasai, testolactone, tetranitrate, thiophene is for group, tiazofurine, Tioguanine, for pyrrole method Buddhist nun, topotecan, ET-743, triaziquone, Tretamine, Te Ruilating, vitamin A acid, Treosulfan, trofosfamide, Uramustine, cut down and softly compare star, Visudyne, vinealeucoblastine(VLB), vincristine(VCR), vindesine, Vinflunine, vinorelbine, Vorinostat, left soft than star and other cytostatics described herein or cytotoxic agent.

Because some medicines are together than working better separately, usually give two or more medicines simultaneously.Usually, use two or more chemotherapeutics as combinatorial chemistry therapy.

In certain embodiments, other cancer therapeutic agent is a kind of differentiation agent.This type of differentiation agent comprises class xanthoplane (as all tra/s-retinoic acid (ATRA), 9CRA, 13CRA (13-cRA) and 4-hydroxy-pheny VAAE (4-HPR)); White arsenic; Histone deacetylase inhibitors HDAC (as azacytidine ((Vidaza) is pricked in Victor) and butyrates (such as, phenylbutyrate sodium)); Hybrid polar compound is (as HMBA ((HMBA)); Vitamins D; And cytokine (as G CFS, comprising G-CSF and GM-CSF and Interferon, rabbit).

In certain embodiments, other cancer therapeutic agent is a kind of targeted therapies medicament.Targeted therapies constitutes the use imbalance protein for cancer cells to specific medicament.The inhibitor of the enzyme domains of the sudden change of small molecules targeted therapies medicine normally in cancer cells, overexpression or protein crucial in other respects.Outstanding example is tyrosine kinase inhibitor, as Axitinib, Bosutinib, AZD2171, Dasatinib, erlotinib, imatinib, Gefitinib, lapatinibditosylate, lestaurtinib, nilotinib, SU5416, Xarelto, Sutent and ZD6474; And cyclin-dependent kinase inhibitor, as Ah former times's enlightening cloth and Sai Lixibu.Monoclonal antibody therapy is another kind of strategy, and wherein therapeutical agent is a kind of antibody of the protein be specifically bound on cancer cell surfaces.Example comprises typically for the anti-HER2/neu antibody trastuzumab of mammary cancer and typically for anti-CD20 antibodies Rituximab and the tositumomab of multiple B-cell malignancies.Other exemplary antibodies comprise Cetuximab, Victibix, Herceptin, alemtuzumab, rhuMAb-VEGF, Edrecolomab and lucky trastuzumab.Exemplary fusion proteins comprises VEGF Trap and denileukin.In certain embodiments, targeted therapies can combinationally use with one compound described herein (such as a kind of biguanides, as N1,N1-Dimethylbiguanide or phenformin, preferred phenformin).

Targeted therapies can also relate to little peptide as " device of going back to the nest (homingdevice) ", and described little peptide can be incorporated into the extracellular matrix be infected around cell surface receptor or tumour.If nucleic decays near cell, the radionuclide being so connected to these peptides (such as, RGD) finally kills cancer cells.An example of such therapy comprises

In certain embodiments, other cancer therapeutic agent is a kind of immunotherapy agents.Immunotherapy for cancer refers to and is designed to induce the immunity system of experimenter self to antineoplastic one group of various therapeutic strategy.For generation of BCG immunotherapy in the vesica that the contemporary methodologies of the immunne response for tumour comprises for superficial bladder cancer and the immunne response using Interferon, rabbit and other cytokine induction renal cell carcinomas and melanoma experimenter.

Allogeneic hematopoietic stem cell transplantation can be regarded as a kind of form of immunotherapy, because the immunocyte of donor will attack tumour with Graft-versus-tumor response usually.In certain embodiments, immunotherapy agents can use with one compound described herein or combination of compositions.

In certain embodiments, other cancer therapeutic agent is a kind of hormonotherapy medicament.The growth of certain cancers can by providing or block some hormone to suppress.The Common examples of hormone-sensitive tumour comprises mammary cancer and the prostate cancer of some type.Remove or block oestrogenic hormon or normally a kind of important additional treatment of testosterone.In some cancer, giving Hormone agonists (as progestogen) can be that treatment is useful.In certain embodiments, hormonotherapy medicament can use with one compound described herein or combination of compositions.

Other possible other Therapeutic mode comprise imatinib, gene therapy, peptide and dendritic cell vaccine, synthesis catilan and radiolabeled medicine and antibody.

Example

General experimental annotates:

In the following example; reagent (chemical) buys from commercial source (as alpha (Alfa), peace laughable this (Acros), Sigma-Aldrich (SigmaAldrich), TCI and Solution on Chemical Reagents in Shanghai company (ShanghaiChemicalReagentCompany)), and namely use without being further purified.Brooker (Brucker) AMX-400NMR (Brooker, Switzerland) obtains nucleus magnetic resonance (NMR) spectrum.Chemical shift is with the low format of field report of the PPM (ppm, δ) compared with tetramethylsilane.Mass spectrum by from this (Waters) LCTTOF mass spectrograph of water (water this, the U.S.) or the electron spray ionisation (ESI) of Shimadzu (Shimadzu) LC-MS-2020 mass spectrograph (Shimadzu, Japan) provide.Initiator2.5 microwave synthesizer (Bai Taiqi (Biotage), Sweden) carries out microwave reaction.

About the exemplary compounds disclosed in this part, steric isomer (such as, (R) or (S) steric isomer) detailed description show the preparation of described compound, make this compound sentence at least about 90%, 95%, 96%, 97%, 98% or 99% enrichment at appointment stereocenter like this.The chemical name of often kind in exemplary compounds as described below is produced by ChemDraw software.

Abbreviation inventory:

General

Anhy. anhydrous

Aq. the aqueous solution

Min minute

Hrs hour

ML milliliter

Mmol mmole

Mol mole

MS mass spectrum

Nuclear magnetic resonance

TLC thin-layer chromatography

HPLC high performance liquid chromatography

Satd. saturated

Spectrum

Hz hertz

δ chemical shift

J coupling constant

S is unimodal

D is bimodal

T triplet

Q quartet

M multiplet

Br broad peak

Qd quadruple is bimodal

Dual five peaks of dquin

Dd doublet of doublet

Dual three peaks of dt

Solvent and reagent

DAST diethylaminosulfur trifluoride

CHCl ₃chloroform

DCM methylene dichloride

DMF dimethyl formamide

Et ₂o diethyl ether

EtOH ethanol

EtOAc ethyl acetate

MeOH methyl alcohol

MeCN acetonitrile

PE sherwood oil

THF tetrahydrofuran (THF)

DMSO methyl-sulphoxide

AcOH acetic acid

HCl hydrochloric acid

H ₂sO ₄sulfuric acid

NH ₄cl ammonium chloride

KOH potassium hydroxide

NaOH sodium hydroxide

K ₂cO ₃salt of wormwood

Na ₂cO ₃sodium carbonate

TFA trifluoroacetic acid

Na ₂sO ₄sodium sulfate

NaBH ₄sodium borohydride

NaHCO ₃sodium bicarbonate

NaHMDS hexamethyldisilane base sodium amide

LiHMDS hexamethyldisilane base Lithamide

LAH lithium aluminium hydride

NaBH ₄sodium borohydride

LDA lithium diisopropylamine

Et ₃n triethylamine

Py pyridine

DMAP4-(dimethylamino) pyridine

DIPEAN, N-diisopropylethylamine

Xphos2-dicyclohexyl phosphino--2,4,6-tri isopropyl biphenyl

BINAP2,2'-two (diphenylphosphino)-1,1'-dinaphthalene

Two (diphenylphosphino) ferrocene of dppf1,1'-

TBTU Tetrafluoroboric acid 2-(1H-benzotriazole-1-base)-1,1,3,3-tetramethyl-urea

DPPA diphenyl phosphate azide

NH ₄oH ammonium hydroxide

EDCI1-ethyl-3-(3-dimethylaminopropyl) carbodiimide

HOBt1-hydroxybenzotriazole

Py pyridine

Two (diphenylphosphino) ferrocene of Dppf1,1'-

HATUO-(7-azepine benzo triazol-1-yl)-N, N, N', N'-tetramethyl-urea

BINAP2,2'-two (diphenylphosphino)-1,1'-dinaphthalene

Prepare intermediate

Preparation 1-benzyl ring propylamine.

At-70 DEG C, through 30 minutes, to benzonitrile (5g, 48mmol, 3 equivalents) and titanium tetraisopropylate (21.5mL, 73mmol, 1.5 equivalents) dropwise add ethylmagnesium bromide (48.5mL, 146mmol) in solution in dry THF (140mL).At room temperature stirred solution 1.5 hours, then dropwise added boron fluoride etherate (15mL, 121mmol, 2.5 equivalents) through 15 minutes.At room temperature stir the mixture again 1.5 hours, then add 1N water-based HCl and Et ₂o.Gained mixture to be poured in 10% water-based NaOH and to use Et ₂o extracts.Use anhydrous Na ₂sO ₄the dry organic layer merged is also concentrated.By column chromatography, use PE/EtOAc/NH ₃.H ₂o (4:1:0.1%) Purification, thus the product desired by obtaining.LC-MS:m/z134.1(M+H) ⁺。

Preparation 2-amino-2-methyl propionitrile

At room temperature, to NH ₄kCN (5g, 76.9mmol) is added in Cl (4.9g, 92.3mmol) and the mixture of acetone (7mL, 92.3mmol) in ammonium hydroxide (40mL, 230.7mmol).At room temperature stirred reaction mixture 3 days.Mixture is extracted with DCM (2x30mL).With the organic layer that salt water washing merges, use anhydrous Na ₂sO ₄drying is also concentrated, thus the product desired by obtaining, namely this product is directly used in next step without any being further purified.

Preparation 2-aminopropionitrile

At room temperature, to NH ₄kCN (1g, 15.4mmol) is added in Cl (981mg, 18.5mmol), acetaldehyde (1mL, the 18.5mmol) mixture in ammonium hydroxide (3mL).At room temperature stirred reaction mixture 2 days.Mixture is extracted with DCM (2x30mL).With the organic layer that salt water washing merges, use anhydrous Na ₂sO ₄drying is also concentrated, thus the product desired by obtaining, namely this product is directly used in next step without any being further purified.

Prepare Bicyclopropyl methylamine

Step 1. prepares Bicyclopropyl ketoxime.Hydroxylamine hydrochloride (469mg, 6.75mmol) is added in the mixture of Bicyclopropyl ketone (500mg, 4.5mmol) in pyridine (5mL).Stirred reaction mixture 4 hours at 100 DEG C cool to room temperature, then add EtOAc.With 1N water-based HCl and salt water washing gained mixture, use anhydrous Na ₂sO ₄drying, and under reduced pressure concentrate, thus obtaining desired product, namely this product is directly used in next step without any being further purified.

LC-MS:m/z124.1(M-H) ^-。

Step 2. prepares Bicyclopropyl methylamine.LiAlH is added in the cooling solution of Bicyclopropyl ketoxime (550mg, 4.4mmol) in THF (5mL) ₄(200mg, 5.3mmol).Then stir the mixture at 80 DEG C 6 hours and cool to room temperature.By 1N water-based NaOH quench mix until gas effusion stops and then filtering.Filtrate is extracted with EtOAc.Use anhydrous Na ₂sO ₄the organic layer that washing merges, and under reduced pressure concentrate, thus obtaining desired product, namely this product is directly used in next step without any being further purified.

LC-MS:m/z112.1(M+H) ⁺。

Prepare the own-3-amine of dicyclo [3.1.0]

Step 1: prepare ring penta-3-enylcarbamate.At room temperature, Et is added to ring penta-3-zinecarboxylic acid (5g, 44.6mmol, 1 equivalent) and DPPA (13.5g, 49mmol, 1.1 equivalents) in the solution in toluene (80mL) ₃n (7.4mL, 53.5mmol, 1.2 equivalents).Then stir the mixture under reflux 2 hours, separate out more substantial nitrogen during this period.After interpolation BnOH (7mL, 66.9mmol, 1.5 equivalents), at 100 DEG C, stir gained mixture overnight and cool to room temperature.With saturated water-based NaHCO ₃after cancellation, extract gained mixture with EtOAc.With the organic layer that salt water washing merges, use anhydrous Na ₂sO ₄drying, and under reduced pressure concentrate.By flash chromatography, use PE/EtOAc (5:1) to carry out Purification as eluent, thus obtain desired product.

LC-MS:m/z218.0(M+H) ⁺。

Step 2: prepare the own-3-aminocarbamic acid benzyl ester of dicyclo [3.1.0].At 0 DEG C, under nitrogen atmosphere, in the solution of ring penta-3-enylcarbamate (1g, 4.6mmol, 1 equivalent) in anhydrous DCM, ZnEt is added ₂(9.7mL, 9.7mmol, 2.1 equivalents), then dropwise add CH ₂i ₂(0.78mL, 9.7mmol, 2.1 equivalents).Reaction mixture is warmed up to room temperature and stirs 4 hours.With salt solution cancellation gained reaction mixture, and extract with DCM.Use anhydrous Na ₂sO ₄dry organic layer is also concentrated.By column chromatography, use PE/EtOAc (5:1) to carry out Purification as eluent, thus obtain desired product.

LC-MS:m/z232.1(M+H) ⁺。

Step 3: prepare the own-3-amine of dicyclo [3.1.0].At room temperature, under nitrogen atmosphere, to disposable interpolation Pd/C (0.2g) in the solution of oneself-3-aminocarbamic acid benzyl ester (2g) of dicyclo [3.1.0] in MeOH (20mL).Then under hydrogen balloon, gained mixture overnight is stirred.Filter reaction mixture and under reduced pressure concentrated filtrate, thus obtain desired product, namely this product is directly used in next step without any being further purified.

LC-MS:m/z98.1(M+H) ⁺。

Preparation 2-(1,1-bis-fluoro ethyl) pyridine-4-amine

Step 1: preparation 4-chloro-N-methoxy-N-methylpyridine acid amides.At 0 DEG C, to 4-chloropyridine formic acid (10g, TBTU (30.6g is added in solution 63.5mmol) in DMF (150mL), 95.2mmol), N, O-dimethyl hydroxylamine (9.3g, 95.2mmol) and DIPEA (24.6g, 190.4mmol).At room temperature stir the mixture and spend the night.With saturated water-based NH ₄cl diluted reaction mixture also extracts with EtOAc.Use Na ₂sO ₄dry organic layer is also concentrated.By purified by flash chromatography resistates, thus obtain desired product.

LC-MS:m/z201.0(M+H) ⁺。

Step 2: preparation 1-(4-chloropyridine-2-base) ethyl ketone.At 0 DEG C, in the solution of 4-chloro-N-methoxy-N-methylpyridine acid amides (11.25g, 56.08mmol) in THF (50mL), add MeMgBr (28.04mL, 84.12mmol).Then at room temperature stir the mixture and to spend the night and with saturated water-based NH ₄cl cancellation.Gained mixture is extracted with EtOAc.Use anhydrous Na ₂sO ₄dry organic layer is also concentrated.By purified by flash chromatography resistates, thus obtain desired product.

¹HNMR(400MHz,CDCl ₃):δ8.52(d,J＝5.2Hz,1H),7.96(s,1H),7.40(d,J＝5.2Hz,1H),2.64(s,3H)。LC-MS:m/z156.0(M+H) ⁺。

The chloro-2-of step 3:4-(1,1-bis-fluoro ethyl) pyridine.At 0 DEG C, in 1-(4-chloropyridine-2-base) solution of ethyl ketone (6.3g, 40.5mmol) in DCM (30mL), add DAST (65.2g, 405mmol).Then at room temperature stir the mixture and to spend the night and with saturated water-based NaHCO ₃cancellation.Gained mixture is extracted with DCM.Use anhydrous Na ₂sO ₄dry organic layer is also concentrated.By purified by flash chromatography resistates, thus obtain desired product.

¹HNMR(400MHz,CDCl ₃):δ8.48(d,J＝5.2Hz,1H),7.60(s,1H),7.31(d,J＝5.2Hz,1H),1.90-1.99(m,3H)。LC-MS:m/z178.0(M+H) ⁺。

Step 4: preparation (2-(1,1-bis-fluoro ethyl) pyridin-4-yl) t-butyl carbamate.At room temperature, in the solution of the chloro-2-of 4-(1,1-bis-fluoro ethyl) pyridine (6.0g, 33.8mmol) in diox (20mL), BocNH is added ₂(4.74g, 40.5mmol), X-phos (1.14g, 1.7mmol), CsCO ₃(16.5g, 50.7mmol) and Pd (OAc) ₂(1.32g, 2.7mmol).Then stir the mixture at 80 DEG C and spend the night and then cool to room temperature.With saturated water-based NH ₄cl diluted reaction mixture also extracts with EtOAc.Use anhydrous Na ₂sO ₄dry organic layer is also concentrated.By purified by flash chromatography resistates, thus obtain desired product.

LC-MS:m/z259.1(M+H) ⁺。

Step 5: preparation 2-(1,1-bis-fluoro ethyl) pyridine-4-amine.Under ice-water bath, cooling (2-(1,1-bis-fluoro ethyl) pyridin-4-yl) t-butyl carbamate (7.97g, 30.86mmol) solution in DCM (30mL).Then TFA (10mL) is dropwise added.At room temperature stirred reaction mixture 4 hours being monitored by TLC.Once react completely, namely dilute with water mixture is also by saturated water-based NaHCO ₃regulate pH>7.Gained mixture is extracted with DCM.Use anhydrous Na ₂sO ₄the dry organic layer merged is also concentrated, thus obtains desired product, and this product is without being further purified namely in next step.

LC-MS:m/z159.1(M+H) ⁺。

Preparation 1-(4-aminopyridine-2-base) cyclopropanecarbonitrile

Step 1: preparation 1-(4-bromopyridine-2-base) cyclopropanecarbonitrile.To 4-bromo-2-fluorine pyridine (1g, 5.7mmol), cyclopropanecarbonitrile (1.25mL, 17mmol, 3 equivalents) and 4AMS cold (-5 DEG C) mixture in toluene (20mL) in dropwise add LiHMDS (1M, in toluene, 17.6mL, 17.6mmol, 3.1 equivalents).Make reaction mixture be warmed up to room temperature and stir 16 hours.After being poured in water, filtering mixt.With EtOAc and H ₂o dilutes filtrate, and extracts with EtOAc.By water and salt water washing organic phase, use anhydrous Na ₂sO ₄drying, and concentrated.By column chromatography, use PE/EtOAc (9:1) to carry out Purification as eluent, thus obtain desired product.

LC-MS：m/z223.0(M+H) ⁺。

Step 2: preparation 1-(4-(diphenylmethylene is amino) pyridine-2-base) cyclopropanecarbonitrile.At room temperature, under nitrogen atmosphere, to 1-(4-bromopyridine-2-base) cyclopropanecarbonitrile (0.45g, 2.1mmol), BINAP (0.04g, 0.063mmol), Pd ₂(dba) ₃(0.019g, 0.021mmol) and NaO ^tdiphenylmethyl imines (0.45g, 2.51mmol) is added in the mixture of Bu (0.282g, 2.94mmol) in toluene (6mL).Stirred reaction mixture 2 hours and then cool to room temperature under reflux.Under reduced pressure enriched mixture and by column chromatography eluting resistates, thus obtain desired product.

LC-MS:m/z324.1(M+H) ⁺。

Step 3: preparation 1-(4-aminopyridine-2-base) cyclopropanecarbonitrile.At room temperature stir 1-(4-(diphenylmethylene is amino) pyridine-2-base) cyclopropanecarbonitrile (0.48g, 1.49mmol), the mixture 1 hour of THF (10mL) and water-based hydrochloric acid (2N, 2.0mL).Then mixture is allocated between EtOAc (15mL) and water (15mL).By EtOAc (2x25mL) aqueous phase extracted.Use anhydrous Na ₂sO ₄the dry organic layer merged is also concentrated.By column chromatography eluting resistates, thus obtain desired product.

LC-MS:m/z160.1(M+H) ⁺。

Example 1 preparation has two aliphatics triaizine compounds of chemical formula D, and wherein ring A is the pyridine-2-base or phenyl that are substituted.The compound of this example is prepared by following cited general scheme 1.

Scheme 1

Step 1: preparation 6-trifluoromethylpyridin-2-methyl-formiate (2).Under nitrogen atmosphere, in the solution of the chloro-6-trifluoromethylpyridin of 2-(2g, 11.1mmol, 1.0 equivalents) in MeOH (20mL), Pd (OAc) is added ₂(124mg, 0.05 equivalent) and dppf (600mg, 0.1 equivalent).Then in gained orange solution, Et is added ₃n (2.3mL, 1.5 equivalents).Then under carbon monoxide (40psi) atmosphere, at 60 DEG C, stirring reaction solution 22 hours.Once react completely, namely filtering mixt and in high vacuum concentrated filtrate.By column chromatography eluting resistates, thus the product desired by obtaining.

¹HNMR(400MHz,CDCl ₃):δ8.32(d,J＝8Hz,1H),8.06(t,J＝8Hz,1H),8.88(d,J＝8Hz,1H),4.04(s,3H)。LC-MS:m/z206(M+H) ⁺。

Step 2: preparation 6-(6-5-flumethiazine 2-yl)-1,3,5-triazines-2,4-diketone.To the NaOEt (3.84g from the fresh preparation of Na, 0.16mol, 3 equivalents) add 6-5-flumethiazine methyl-formiate (33g, 0.16mol in solution in ethanol (500mL), 3 equivalents) and biuret (5.3g, 0.052mol).Gained mixture is heated to backflow, continues 1 hour and then concentrate.Resistates to be poured into water and with saturated water-based NaHCO ₃process is to regulate pH to 7.Also dry under air by collected by filtration solid, thus obtain desired compound.

¹HNMR(400MHz,DMSO-d ₆):δ10.88(s,1H),8.46(d,J＝7.4Hz,1H),8.28(t,J＝7.3Hz,1H),8.11(d,J＝7.4Hz,1H)。LC-MS:m/z259(M+H) ⁺。

Step 3: preparation 2,4-bis-chloro-6-(6-trifluoromethylpyridin 2-yl)-1,3,5-triazines.To 6-(6-trifluoromethylpyridin-2-base)-1,3,5-triazines-2,4 (1H, 3H)-diketone (3.37g, 0.013mol) in POCl ₃(48mL) PCl is added in the solution in ₅(23g, 0.1mol).Stir the mixture at 100 DEG C 2 hours and then concentrate.Resistates to be dissolved in EtOAc and then with saturated water-based NaHCO ₃washing.Use anhydrous Na ₂sO ₄dry organic layer and then concentrating, thus obtain desired product.

¹HNMR(4400MHz,CDCl ₃):δ8.76(d,J＝7.9Hz,1H),8.19(t,J＝7.9Hz,1H),7.97(d,J＝7.8Hz,1H)。LC-MS:m/z294.9(M+H) ⁺。

Step 4: preparation N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(6-(trifluoromethyl)-pyridine-2-base)-1,3,5-triazines-2,4-diamines.At room temperature, to the chloro-6-of 2,4-bis-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine (600mg, 2.0mmol, 1.0 equivalents) and (R)-1-cyclopropylethyI amine hydrochloride (536mg, 4.4mmol, 2.2 equivalents) add CsF (1.2g, 8.0mmol, 2 equivalents) and DIPEA (1.4mL in mixture in THF (12mL), 8.0mmol, 4 equivalents).Stir the mixture at 60 DEG C and spend the night and then filter.Under reduced pressure concentrated filtrate and by standard method Purification, thus obtain desired product.

¹HNMR(400MHz,CD ₃OD):δ8.70-8.68(m,1H),8.34-8.32(m,1H),8.16-8.14(m,1H),3.61-3.57(m,2H),1.36-1.32(m,6H),1.06-1.01(m,2H),0.61-0.39(m,8H)。LC-MS:m/z393.2(M+H) ⁺。

Use program cited in example 1, use appropriate parent material to prepare following compound.

Compound N ², N ⁴-bis-((S)-1-cyclopropylethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.50(s,1H),7.99(t,J＝7.9Hz,1H),7.77(d,J＝7.7Hz,1H),5.44-5.18(m,2H),3.66-3.57(m,2H),1.27(d,J＝5.4Hz,6H),0.93-0.88(m,2H),0.52-0.27(m,8H)。LC-MS:m/z393.2(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-((S)-1-cyclopropylethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.51(s,1H),7.99(t,J＝7.9Hz,1H),7.77(d,J＝7.3Hz,1H),5.46-5.19(m,2H),3.67-3.54(m,2H),1.32-1.22(m,6H),0.95-0.83(m,2H),0.59-0.23(m,8H)。LC-MS:m/z393.2(M+H) ⁺。

Compound N ², N ⁴-bis-(1-cyclopropylethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CD ₃OD):δ8.6(m,1H),8.2-8.1(m,1H),8.0-7.9(m,1H),4.0-3.52(m,2H),1.4-1.2(m,6H),1.0(m,2H),0.6-0.35(m,6H),0.35-0.2(m,2H)。LC-MS:m/z393.2(M+H) ⁺。

Compound N ², N ⁴-bis-(cyclobutylmethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.54(m,1H),8.00(m,1H),7.78(d,J＝5.9Hz,1H),5.27(m,2H),3.69-3.32(m,4H),2.59(m,2H),2.10(m,4H),1.92(m,4H),1.84-1.62(m,4H)。LC-MS:m/z393.2(M+H) ⁺。

Compound N ², N ⁴-bis-((R)-1-CYCLOBUTYLETHYL)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.71-8.41(m,1H),7.99(d,J＝7.4Hz,1H),7.77(d,J＝7.7Hz,1H),5.34-4.84(m,2H),4.30-3.96(m,2H),2.44-2.28(m,2H),2.09-1.96(m,4H),1.93-1.78(m,8H),1.14(d,J＝5.9Hz,6H)。LC-MS:m/z421.2(M+H) ⁺。

Compound N ², N ⁴-bis-(2-methylcyclopropyl groups)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CD ₃OD):δ8.65-8.4(m,1H),8.1-7.75(m,2H),2.55-2.25(m,2H),1.2-1.0(m,6H),0.9-0.8(m,2H),0.7-0.6(m,2H),0.5-0.38(m,2H)。LC-MS:m/z365.3(M+H) ⁺。

Compound N ², N ⁴-bis-(Cvclopropvlmethvl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CD ₃OD):δ8.60-8.68(m,1H),8.21(t,J＝8.0Hz,1H),7.93-8.00(m,1H),3.26-3.42(m,4H),1.08-1.19(m,2H),0.51-0.58(m,4H),0.25-0.34(m,4H)。LC-MS:m/z365.2(M+H) ⁺。

Compound N ², N ⁴-bis-((1-methylcyclopropyl groups) methyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CD ₃OD):δ8.61-8.59(m,1H),8.17-8.15(m,1H),7.94-7.92(m,1H),3.43-3.33(m,4H),1.14(s,6H),0.55-0.53(m,4H),0.34-0.32(m,4H)。LC-MS:m/z393.2(M+H) ⁺。

Compound N ², N ⁴-two cyclobutyl-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.67-8.38(m,1H),7.99(d,J＝6.8Hz,1H),7.78(d,J＝7.5Hz,1H),5.52(m2H),4.80-4.32(m,2H),2.41(s,4H),2.20(s,1H),2.06-1.62(m,8H)。LC-MS:m/z365.2(M+H) ⁺。

Compound N ², N ⁴-two (own-3-base of dicyclo [3.1.0])-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CD ₃OD):δ8.66-8.57(m,1H),8.14(t,J＝8.0Hz,1H),7.92(d,J＝7.5Hz,1H),4.60-4.44(m,2H),2.44-2.21(m,4H),1.80-1.69(m,4H),1.35(d,J＝3.4Hz,4H),0.69-0.53(m,2H),0.32(d,J＝4.3Hz,2H)。LC-MS:m/z417.2(M+H) ⁺。

Compound N, N'-bicyclopentyl-6-(6-trifluoromethylpyridin-2-base)-[1,3,5] triazine-2,4-diamines

¹HNMR(400MHz,CD ₃OD):δ8.60-8.68(m,1H),8.20(t,J＝7.6Hz,1H),7.95-8.01(m,1H),4.29-4.55(m,2H),2.00-2.15(m,4H),1.75-1.84(m,4H),1.51-1.74(m,8H)。LC-MS:m/z393.5(M+H) ⁺。

Compound N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.53(m,1H),8.08-8.02(m,1H),7.85-7.80(m,1H),5.78-5.18(m,2H),4.82-4.38(m,2H),2.82-2.50(m,2H),2.31-2.05(m,8H),1.93-1.80(m,2H)。LC-MS:m/z465.2(M+H) ⁺。

Compound N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.64-8.42(m,1H),8.05(t,J＝7.8Hz,1H),7.84(d,J＝6.6Hz,1H),6.24-5.25(m,2H),4.18-4.01(m,2H),2.43-1.48(m,16H)。LC-MS:m/z493.2(M+H) ⁺。

Compound N, N'-pair-(ttetrahydro-pyran-4-base)-6-(6-trifluoromethylpyridin-2-base)-[1,3,5] triazine-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆):δ7.43-8.55(m,5H),3.82-4.15(m,6H),3.48-3.50(m,4H),1.75-1.87(m,4H),1.46-1.60(m,4H)。LC-MS:m/z425.1(M+H) ⁺。

Compound N ², N ⁴-di-isopropyl-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.67-8.41(m,1H),7.99(s,1H),7.77(d,J＝7.7Hz,1H),5.18(m,2H),4.45-4.03(m,2H),2.15(m,1H),1.26(d,J＝4.5Hz,12H)。LC-MS:m/z341.2(M+H) ⁺。

Compound N ², N ⁴-di-t-butyl-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆):δ8.44-8.31(m,1H),8.19-8.12(m,1H),7.93(d,J＝7.3Hz,1H),7.16-6.77(m,2H),1.35(s,18H)。LC-MS:m/z369.2(M+H) ⁺。

Compound N, N'-di-sec-butyl) 6-(6-trifluoromethylpyridin-2-base)-[1,3,5] triazine-2,4-diamines

¹HNMR(400MHz,CD ₃OD):δ8.42-8.68(m,1H),8.15-8.21(m,1H),7.94(d,J＝8.0Hz,1H),4.01-4.29(m,2H),1.55-1.69(m,4H),1.19-1.30(m,6H),0.95-1.05(m,6H)。LC-MS:m/z369.5(M+H) ⁺。

Compound N, N'-di-sec-butyl-6-(6-trifluoromethylpyridin-2-base)-[1,3,5] triazine-2,4-diamines

¹HNMR(400MHz,CD ₃OD):δ8.72-8.79(m,1H),8.38-8.43(m,1H),8.20-8.23(m,1H),4.13-4.45(m,2H),1.67-1.74(m,4H),1.29-1.33(m,6H),1.01-1.05(m,6H)。LC-MS:m/z369.2(M+H) ⁺。

Compound N ², N ⁴-di-sec-butyl) 6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，CD ₃OD):δ8.72-8.79(m，1H)，8.38-8.43(m，1H)，8.20-8.23(m,1H),4.13-4.45(m,2H),1.67-1.74(m,4H),1.29-1.33(m,6H),1.01-1.05(m,6H)。LC-MS:m/z369.2(M+H) ⁺。

Compound N ²-((R)-sec-butyl)-N ⁴-((S)-sec-butyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CD ₃OD):δ8.59-8.65(m,1H),8.15-8.19(m,1H),7.94-7.95(m,1H),4.06-4.24(m,2H),1.58-1.65(m,4H),1.21-1.26(m,6H),0.98-1.01(m,6H)。LC-MS:m/z369.2(M+H) ⁺。

Compound N ², N ⁴-bis-(3-methyl fourth-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.58-8.47(m,1H),7.99(t,J＝7.2Hz,1H),7.77(d,J＝7.7Hz,1H),5.30-5.03(m,2H),4.16-3.97(m,2H),1.93-1.75(m,2H),1.16(d,J＝6.6Hz,6H),0.97-0.93(m,12H)。LC-MS:m/z397.2(M+H) ⁺。

Compound N ², N ⁴-bis-((R)-3-methyl fourth-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆):δ8.46(m,1H),8.21(m,1H),8.00(d,J＝7.7Hz,1H),7.36(m,2H),3.90(m2H),1.79(m,2H),1.05(t,J＝7.6Hz,6H),0.87(t,J＝7.6Hz,12H)。LC-MS:m/z397.2(M+H) ⁺。

Compound N ², N ⁴-bis-((S)-3-methyl fourth-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆):δ8.46(d,J＝7.9Hz,1H),8.24(d,J＝6.9Hz,1H),8.03(d,J＝7.7Hz,1H),7.55(m,2H),4.25-3.78(m,1H),1.93-1.65(m,1H),1.15-1.00(m,6H),0.89(t,J＝7.8Hz,12H)。LC-MS:m/z397.2(M+H) ⁺。

Compound N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(4-(trifluoromethyl) pyrimidine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ9.20(s,1H),7.74(s,1H),5.46(m,2H),3.59(m,2H),1.26(m,8H),0.91(s,2H),0.65--0.27(m,8H)。LC-MS:m/z394.2(M+H) ⁺。

Compound N ²-((R)-1-phenylethyl)-N ⁴-((S)-1-phenylethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.52-8.33(m,1H),8.05-7.86(m,1H),7.76(d,J＝7.7Hz,1H),7.52-7.18(m,10H),5.82-5.40(m,2H),5.37-4.92(m,2H),1.65-1.39(m,6H)。LC-MS:m/z465.2(M+H) ⁺。

Compound 6-(6-chloropyridine-2-base)-N ², N ⁴-bis-((R)-1-cyclopropylethyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CD ₃OD):δ8.37(t,J＝7.8Hz,1H),8.02(t,J＝7.8Hz,1H),7.71-7.65(m,1H),3.74-3.54(m,2H),1.32(d,J＝6.6Hz,6H),1.08-0.94(m,2H),0.63-0.21(m,8H)。LC-MS:m/z359.2(M+H) ⁺。

Compound 6-(6-chloropyridine-2-base)-N ², N ⁴-di-isopropyl-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CD3OD):δ8.5-8.38(m,1H),8.0-7.9(m,1H),7.6-7.5(m,1H),3.35-3.16(m,4H),2.0-1.9(m,2H),1.0-0.9(m,12H)。LC-MS:m/z335.1(M+H) ⁺。

¹HNMR(400MHz,CD ₃OD):δ8.25-8.19(m,1H),7.81(brs,1H),7.46(d,J＝7.6Hz,1H),4.26-4.11(m,2H),1.15(d,J＝6.0Hz,12H)。LC-MS:m/z307.1(M+H) ⁺。

Compound N ², N ⁴-two (fourth-3-alkene-1-base)-6-phenyl-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CD ₃OD):δ8.19-8.13(m,2H),7.77-7.61(m,3H),5.95-5.85(m,2H),5.20-5.11(m,4H),3.72-3.59(m,4H),2.49-2.44(m,4H)。LC-MS:m/z296.3(M+H) ⁺。

Compound N ², N ⁴-two (own-6-base of 3-oxabicyclo [3.1.0])-6-phenyl-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，CD ₃OD):δ8.35-8.1(m,2H),8.3-8.2(m,1H),7.7-7.6(m,2H),4.1-4.0(m,4H),3.85-3.7(m,4H),2.9-2.55(m,2H),2.1-2.0(m,2H)。LC-MS:m/z352.2(M+H) ⁺。

Compound N ², N ⁴-bis-((1S, 3S)-3-(4-fluorophenyl) cyclobutyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1, 3, 5-triazine-2, 4-diamines at room temperature, to 2, the chloro-6-of 4-bis-(6-(trifluoromethyl) pyridine-2-base)-1, 3, 5-triazine (600mg, 2.0mmol, 1.0 equivalents) and (1s, 3s)-3-(4-fluorophenyl) ring butylamine (726mg, 4.4mmol, 2.2 equivalents) add CsF (0.6g in mixture in THF (12mL), 2.0mmol, 1 equivalent) and DIPEA (0.7mL, 4.0mmol, 2 equivalents).At 60 DEG C, stir gained mixture overnight and then filter.Concentrated filtrate via standard technique purifying, thus the product desired by obtaining.

¹HNMR(400MHz,CDCl ₃)δ8.48(m,1H),7.95(m,1H),7.75(d,J＝7.6Hz,1H),7.16-7.04(m,4H),6.93(t,J＝8.5Hz,4H),6.46-5.32(m,2H),4.47(m,2H),3.28-3.02(m,2H),2.81(d,J＝7.6Hz,4H),2.01(m,4H)。LC-MS:m/z553.2(M+H) ⁺。

Compound N ², N ⁴-bis-((1R, 3R)-3-(4-fluorophenyl) cyclobutyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.56(m,1H),8.01(s,1H),7.80(s,1H),7.25-6.93(m,8H),5.64(m,2H),4.82-4.37(m,2H),3.68(s,1H),3.24(s,1H),2.89(m,2H),2.54(m,4H),2.09-1.98(m,2H)。LC-MS:m/z553.2(M+H) ⁺。

Compound 6-(6-(trifluoromethyl) pyridine-2-base)-N ², N ⁴-bis-((R)-1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

1HNMR(400MHz,CDCl ₃)δ8.62(m,1H),8.03(d,J＝7.8Hz,1H),7.83(d,J＝7.7Hz,1H),5.59(d,J＝9.4Hz,1H),5.34(m,3H),1.42(m,6H)；LC-MS:m/z449(M+H) ⁺。

Compound N ², N ⁴-bis-((S)-1,1,1-trifluoro fourth-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.55(d,J＝8Hz,1H),8.06-8.02(m,1H),7.83(d,J＝8Hz,1H),5.64-5.15(m,2H),4.93-4.71(m,2H),2.0-1.94(m,2H),1.69-1.57(m,2H),1.08-1.02(m,6H)。LC-MS:m/z477(M+H) ⁺。

Compound N ², N ⁴-bis-((2,2-difluorocyclopropyl) methyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，CDCl ₃)δ8.59-8.51(m,1H),8.02(bs,1H),7.80(d,J＝7.6Hz,1H),5.70-5.38(m,2H),3.81-3.41(m,4H),2.04-1.92(m,2H),1.73-1.59(m,2H),1.28-1.23(m,2H)。LC-MS:m/z437(M+H) ⁺。

Compound N ², N ⁴-bis-((3,3-difluoro cyclobutyl) methyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.54(m,1H),8.02(m,1H),7.80(d,J＝7.2Hz,1H),5.84-5.11(m,2H),3.95-3.27(m,4H),2.94-1.99(m,10H)。LC-MS:m/z465(M+H) ⁺。

Compound N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.56-8.48(m,1H),8.04-8.02(m,1H),7.82-7.80(m,1H),5.76-5.41(m,2H),4.52-4.37(m,2H),3.06(bs,4H),2.63-2.61(m,4H)。LC-MS:m/z437.1(M+H) ⁺。

Compound N ², N ⁴-bis-((S)-3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.54-8.38(m,1H),7.95(m1H),7.73(m,1H),5.60-5.25(m,2H),4.63-4.42(m,2H),2.68-2.52(m,2H),2.16-1.77(m,10H)。LC-MS:m/z465.1(M+H) ⁺。

Compound N ², N ⁴-bis-((R)-3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ57-8.48(m,1H),8.02-8.01(m,1H),7.80(s,1H),5.66-5.32(m,2H),4.71-4.49(m,2H),2.64-2.61(m,2H),2.31-2.05(m,8H),1.86-1.79(m,2H)。LC-MS:m/z465(M+H) ⁺。

Compound N 2-((R)-3,3-Difluorocyclopentyl)-N4-((S)-3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.56-8.48(m,1H),8.02(d,J＝8Hz,1H),7.80-7.81(m,1H),5.66-5.32(m,2H),4.71-4.54(m,2H),2.65-2.60(m,2H),2.31-2.05(m,8H),1.86-1.81(m,2H)。LC-MS:m/z465(M+H) ⁺。

Compound N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(4-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，CDCl ₃)δ8.70-8.62(m，2H)，7.62(d，1H)，6.70-6.43(m1H),5.22-3.95(m,3H),2.11-1.69(m,16H)。LC-MS:m/z493(M+H) ⁺。

Compound N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(6-methoxypyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.18-7.65(m,2H),7.15-6.98(m,1H),6.34-5.67(m,2H),4.15(s,3H),3.71-3.48(m,2H),1.33-1.25(m,6H),0.98-0.86(m,2H),0.62-0.26(m,8H)。LC-MS:m/z355.2(M+H) ⁺。

Compound N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(6-(trifluoromethoxy) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.34-8.27(m,1H),7.96-7.92(m,1H),7.22(d,J＝8Hz,1H),5.83-5.41(m,2H),4.49-4.35(m,2H),3.05(d,J＝4Hz,4H),2.63-2.54(m,4H)。LC-MS:m/z453(M+H) ⁺。

Compound N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-6-(6-(trifluoromethoxy) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.33-8.26(m,1H),7.95-7.92(m,1H),7.22(d,J＝8Hz,1H),5.65-5.28(m,2H),4.67-4.52(m,2H),2.64-2.59(m,2H),2.30-1.79(m,10H)。LC-MS:m/z481(M+H) ⁺。

Compound N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(6-(trifluoromethoxy) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.31(d,J＝8Hz,1H),7.98-7.92(m,1H),7.24(d,J＝12Hz,1H),5.44-5.08(m,2H),4.16-3.98(m,2H),2.15-1.65(m,16H)。LC-MS:m/z509(M+H) ⁺。

Compound N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(the fluoro-6-methoxypyridine of 3--2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ7.45-7.41(t,1H),6.84(d,1H),5.43-5.07(m,2H),4.08-3.98(m,5H),2.11-2.01(m,8H),1.96-1.89(m,4H),1.87-1.83(m,4H)。

LC-MS:m/z473(M+H) ⁺。

Table 1: prepare following compound by following the program described in above scheme 1.

Example 2 preparation has the two aliphatics triaizine compounds of chemical formula E, and wherein ring A is the pyridine-2-base or phenyl that are substituted.The compound of this example is prepared by following cited general scheme 2.

Scheme 2

Step 1: preparation (R)-4-chloro-N-(1-cyclopropylethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-amine.At room temperature, to the chloro-6-of 2,4-bis-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine (600mg, 2.0mmol, 1.0 equivalents) and (R)-1-cyclopropylethyI amine hydrochloride (268mg, 2.2mmol, 1.1 equivalents) add CsF (608mg, 4.0mmol, 2 equivalents) and DIPEA (0.7mL in mixture in THF (6mL), 4.0mmol, 2 equivalents).Stir the mixture at 40 DEG C and spend the night and then filter.Under reduced pressure concentrated filtrate and by standard method Purification, thus obtain desired product.

LC-MS：m/z344.1(M+H) ⁺。

Step 2: preparation N ²-((R)-1-cyclopropylethyl)-N4-(penta-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines.At room temperature, to the chloro-N-of (R)-4-(1-cyclopropylethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-amine (80mg, 0.23mmol, 1.0 equivalents) and the mixture of penta-2-amine (25mg, 0.28mmol, 1.2 equivalents) in THF (2mL) in add CsF (70mg, 0.46mmol, 2 equivalents) and DIPEA (0.08mL, 0.46mmol, 2 equivalents).Stir the mixture at 60 DEG C and spend the night and filter.Under reduced pressure concentrated filtrate and then by standard method purifying, thus obtain desired product.

¹HNMR(400MHz,DMSO-d ₆):δ8.54-8.42(m,1H),8.23(t,J＝7.8Hz,1H),8.02(d,J＝7.7Hz,1H),7.65(d,J＝8.4Hz,1H),7.52(t,J＝9.5Hz,1H),4.27-3.96(m,1H),3.65-3.47(m,1H),1.60-1.46(m,1H),1.41-1.29(m,3H),1.22(d,6.5Hz,3H),1.12(d,J＝6.1Hz,3H),1.01-0.96(m,1H),0.88(t,J＝7.1Hz,3H),0.50-0.29(m,3H),0.26-0.07(m,1H)。LC-MS:m/z395.2(M+H) ⁺。

Be used in program cited in example 2, use appropriate parent material to prepare following compound.

¹HNMR(400MHz,CDCl ₃):δ8.52(m,1H),8.00(t,J＝7.6Hz,1H),7.78(d,J＝7.7Hz,1H),5.63(m,2H),3.73(m,9H),2.66(d,J＝5.9Hz,2H),1.29(m,3H),1.01-0.79(m,1H),0.60-0.17(m,4H)。LC-MS:m/z411.2(M+H) ⁺。

Compound (R)-N ²-(1-cyclopropylethyl)-N ⁴-(4,4-difiuorocyclohexyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.66-8.39(m,1H),8.02(t,J＝7.7Hz,1H),7.80(d,J＝7.7Hz,1H),5.34(m,2H),4.11(m,1H),3.63(m,1H),2.32-1.54(m,9H),1.29(m,3H),0.95(s,1H),0.70-0.16(m,4H)。LC-MS:m/z443.2(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-(6,6-difluoro spiral shell [3.3]-2-in heptan base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.54-8.49(m,1H),8.01(t,J＝7.3Hz,1H),7.78(d,J＝7.7Hz,1H),5.60-5.27(m,2H),4.57-4.37(m,1H),3.67-3.57(m,1H),2.70-2.65(m,2H),2.57(m,3H),2.22-1.92(m,4H),1.30(d,J＝5.8Hz,2H),0.93(s,1H),0.54-0.29(m,4H)。LC-MS:m/z455.2(M+H) ⁺。

Compound N ²-((1R, 3R, 5R, 7R)-diamantane-2-base)-N ⁴-((R)-1-cyclopropylethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.63-8.34(m,1H),8.00(t,J＝7.8Hz,1H),7.78(d,J＝7.7Hz,1H),5.57(m,2H),4.21(m,1H),3.85-3.32(m,1H),2.22-1.57(m,15H),1.25(m,4H),0.90(m,1H),0.66-0.24(m,4H)。LC-MS:m/z459.2(M+H) ⁺。

Compound (R)-N ²-(1-cyclopropylethyl)-N ⁴-(bicyclic methyl propyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.49(d,J＝7.5Hz,1H),7.99(t,J＝7.9Hz,1H),7.77(d,J＝7.7Hz,1H),5.71-5.05(m,2H),3.59(m,2H),1.25(m,3H),1.07-0.80(m,3H),0.64-0.19(m,12H)。LC-MS:m/z419.2(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.53(s,1H),8.01(s,1H),7.80(d,J＝7.6Hz,1H),5.91-4.65(m,3H),3.67(m,1H),1.51-1.15(m,6H),0.93(s,1H),0.74-0.10(m,4H)。LC-MS:m/z421.1(M+H) ⁺。

Compound (R)-N ²-(1-cyclopropylethyl)-N ⁴-(2,3-dihydro-1H-indenes-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.61-8.46(m,1H),7.99(t,J＝8.1Hz,1H),7.77(d,J＝7.7Hz,1H),7.26-7.17(m,4H),5.75-5.30(m,2H),5.11-4.75(m,1H),3.78-3.54(m,1H),3.46-3.31(m,2H),2.94-2.88(m,2H),1.32(d,J＝6.4Hz,3H),1.24-1.19(m,1H),0.98-0.86(m,1H),0.52-043(m,3H),0.29(s,1H)。LC-MS:m/z441.2(M+H) ⁺。

Compound (R)-N ²-(1-cyclopropylethyl)-N ⁴-(the third-2-alkynes-1-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.55(m,1H),8.01(t,J＝7.8Hz,1H),7.79(d,J＝7.7Hz,1H),5.94-5.12(m,2H),4.30(m2H),3.59(m,1H),2.23(s,1H),2.01(s,3H),0.90(m,1H),0.59-0.16(m,4H)。LC-MS:m/z363.1(M+H) ⁺。

Compound (R)-N ²-(1-cyclopropylethyl)-N ⁴-(2-Phenoxyethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.43(d,J＝8.0Hz,1H),7.93(t,J＝7.6Hz,1H),7.71(d,J＝7.7Hz,1H),7.34-7.18(m,2H),7.00-6.69(m,3H),6.03-5.08(m,2H),4.07(s,2H),3.94-3.71(m,2H),3.53(d,J＝6.8Hz,1H),1.34-1.04(m,4H),0.35(m,4H)。LC-MS:m/z445.2(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-(1-methoxy propyl-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.51(m,1H),7.99(t,J＝7.9Hz,1H),7.77(d,J＝7.7Hz,1H),5.55-5.33(m,2H),4.45-4.29(m,2H),3.68-3.39(m,4H),1.85(s,3H),1.28-0.93(m,6H),0.60-0.27(m,3H)。LC-MS:m/z397.2(M+H) ⁺。

Compound (R)-N ²-(1-cyclopropylethyl)-N ⁴-(1,3-dimethoxy third-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，CDCl ₃):8.47(m,1H),8.05-7.80(m,1H),7.71(d,J＝7.7Hz,1H),5.90-5.06(m,2H),4.57-4.05(m,1H),3.65-3.38(m,4H),3.33(m,6H),1.23(m,4H),0.84(m,1H),0.61-0.05(m,4H)。LC-MS:m/z427.2(M+H) ⁺。

Compound 2-((4-(((R)-1-cyclopropylethyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) propionitrile

¹HNMR(400MHz,CDCl ₃):δ8.56(m,1H),8.03(t,J＝7.8Hz,1H),7.81(d,J＝7.7Hz,1H),5.52(m,2H),5.16-4.85(m,1H),3.76-3.44(m,1H),1.72-1.55(m,3H),1.39-1.21(m,3H),0.95(s,1H),0.65-0.16(m,4H)。LC-MS:m/z378.2(M+H) ⁺。

Compound (R)-2-(4-(1-cyclopropylethyl is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base is amino)-2-methyl propionitrile

¹HNMR(400MHz,CDCl ₃):δ8.56(d,J＝8.2Hz,1H),8.03(t,J＝7.7Hz,1H),7.80(d,J＝7.7Hz,1H),5.71-5.54(m,2H),3.70(m,1H),1.82(s,6H),1.36-1.25(m,4H),0.97(d,J＝7.7Hz,1H),0.62-0.26(m,4H)。LC-MS:m/z392(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-(tetrahydrofuran (THF)-3-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.57-8.47(m,1H),7.99(t,J＝7.2Hz,1H),7.78(d,J＝7.6Hz,1H),5.73-5.32(m,2H),4.79-4.60(m,1H),3.99-3.49(m,5H),2.29(m,2H),1.91(m,1H),1.30(m,3H),0.56-0.23(m,4H)。LC-MS:m/z395.2(M+H) ⁺。

Compound (1S, 2S)-2-(4-((R)-1-cyclopropylethyl is amino)-6-(6-(TRIFLUORO-METHYL) pyridine-2-base)-1,3,5-triazines-2-base is amino) hexalin

¹HNMR(400MHz,CDCl ₃):δ8.48(d,J＝7.4Hz,1H),8.01(t,J＝7.8Hz,1H),7.79(d,J＝7.7Hz,1H),5.67-5.28(m,2H),3.65(m,4H),2.09(s,3H),1.47-1.23(m,8H),0.92(s,1H),0.62-0.40(m,3H),0.30(s,1H)。LC-MS:m/z423.2(M+H) ⁺。

Compound (1R, 2S)-2-(4-((R)-1-cyclopropylethyl is amino)-6-(6-(trifluoromethyl)-pyridine-2-base)-1,3,5-triazines-2-base is amino) cyclopentanol

¹HNMR(400MHz,CDCl ₃):δ8.51(m,1H),8.01(t,J＝7.6Hz,1H),7.80(t,J＝6.4Hz,1H),5.40-5.31(m,1H),4.10-3.97(m,2H),3.69-3.52(m,1H),2.25-2.09(m,2H),1.95-1.55(m,7H),1.29(d,J＝6.0Hz,2H),0.93(d,J＝7.5Hz,1H),0.66-0.16(m,4H)。LC-MS:m/z409.2(M+H) ⁺。

Compound (R)-N ²-benzyl-N ⁴-(1-cyclopropylethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.49(d,J＝7.2Hz,1H),7.98(t,J＝7.7Hz,1H),7.77(d,J＝7.7Hz,1H),7.31(m,5H),5.51(m,2H),4.67(m,2H),3.63(m,1H),1.27(m,3H),0.91(s,1H),0.38(m,4H)。LC-MS:m/z415.2(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-((S)-1-phenylethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.45(t,J＝10.4Hz,1H),7.98(t,J＝7.7Hz,1H),7.77(d,J＝7.7Hz,1H),7.54-7.03(m,5H),5.70(d,J＝6.9Hz,1H),5.45(m,1H),5.15(m,1H),3.50(m,1H),1.55(m,3H),1.28(m,1H),0.96(m,3H),0.64-0.18(m,4H)。LC-MS:m/z429.2(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-((R)-1-phenylethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.47(d,J＝8.3Hz,1H),7.98(t,J＝7.7Hz,1H),7.76(d,J＝7.7Hz,1H),7.50-7.02(m,5H),5.78-5.07(m,3H),3.55(m,1H),1.72(m,1H),1.56(d,J＝6.7Hz,3H),0.97(m,3H),0.58-0.15(m,4H)。LC-MS:m/z429.2(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-(1-(3-fluorophenyl) ethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.55-8.36(m,1H),8.00(t,J＝7.7Hz,1H),7.78(d,J＝7.7Hz,1H),7.27(d,J＝7.8Hz,2H),7.18-6.90(m,3H),5.71-5.06(m,3H),3.78-3.32(m,1H),1.54(d,J＝6.8Hz,3H),1.34-1.22(m,3H),1.00(d,J＝6.3Hz,1H),0.94-0.72(m,1H),0.54-0.37(m,2H),0.31-0.20(m,1H)。LC-MS:m/z447.2(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-(1-(3-(trifluoromethyl) phenyl) ethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.42(m,1H),8.08-7.93(m,1H),7.79(d,J＝7.6Hz,1H),7.67-7.38(m,4H),5.84-5.49(m,1H),5.49-5.03(m,2H),3.72-3.16(m,1H),1.57(d,J＝6.9Hz,3H),1.26(d,J＝6.3Hz,3H),0.92(d,J＝6.4Hz,1H),0.73(m,1H),0.53-0.41(m,1H),0.37(m,1H),0.25(m,1H)。LC-MS:m/z497.2(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-((1R, 2S)-2-phenycyclopropyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.47(d,J＝8.3Hz,1H),7.98(t,J＝7.7Hz,1H),7.76(d,J＝7.7Hz,1H),7.37(m,4H),7.23(m,1H),5.81-5.05(m,3H),3.55(m1H),1.72(s,1H),1.56(d,J＝6.7Hz,3H),0.97(m3H),0.63-0.18(m,4H)。LC-MS:m/z441.2(M+H) ⁺。

Compound (R)-N ²-(1-cyclopropylethyl)-N ⁴-(1-phenycyclopropyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆):δ8.53-8.13(m,3H),7.99(m,1H),7.70(m,1H),7.45-7.04(m,5H),3.30-3.19(m,1H),1.38-1.09(m,5H),1.07-0.75(m,3H),0.43--0.09(m,4H)。LC-MS:m/z441.2(M+H) ⁺。

Compound (R)-6-(6-chloropyridine-2-base)-N ²-(1-cyclopropylethyl)-N ⁴, N ⁴-diethyl-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.32(d,J＝6.6Hz,1H),7.75(s,1H),7.42(s,1H),5.51(s,1H),3.62(m,5H),1.42-1.03(m,9H),0.92(d,J＝7.7Hz,1H),0.63-0.17(m,4H)。LC-MS:m/z347.2(M+H) ⁺。

Compound (R)-3-((4-((1-cyclopropylethyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) methyl propionate

Compound (1R, 2S)-2-((4-(clopentylamino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) cyclopentanol

¹HNMR(400MHz,CD ₃OD):δ8.63-8.57(m,1H),8.17-8.14(m,1H),7.94-7.92(m,1H),4.48-4.23(m,3H),2.05-1.91(m,5H),1.78-1.59(m,9H)。LC-MS:m/z409.3(M+H)。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(tetrahydrofuran (THF)-3-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CD ₃OD):δ8.68-8.56(m,1H),8.15(t,J＝8.3Hz,1H),7.93(d,J＝7.5Hz,1H),4.81-4.43(m,2H),4.11-3.92(m,2H),3.86(m,1H),3.78-3.66(m,1H),2.74-2.50(m,1H),2.38-1.75(m,7H)。LC-MS:m/z431.2(M+H) ⁺。

Compound 3-((4-((3,3-Difluorocyclopentyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) tetramethyleneimine-1-t-butyl formate

¹HNMR(400MHz,CDCl ₃):δ8.62-8.46(m,1H),8.03(d,J＝6.9Hz,1H),7.81(d,J＝7.7Hz,1H),5.91-5.19(m,2H),4.61(m,2H),3.82-3.59(m,1H),3.50(s,1H),3.29(m,1H),2.65(m,1H),2.43-2.06(m,5H),1.97(s,1H),1.47(s,9H)。LC-MS:m/z530.2(M+H) ⁺。

Compound N ²-isobutyl--N ⁴-(tetrahydrochysene-2H-pyrans-4-base)-6-(6-(trifluoromethyl)-pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CD ₃OD):δ8.7-8.6(m,1H),8.25-8.15(m,1H),8.0-7.9(m,1H),4.4-4.1(m,1H),4.05-3.96(m,2H),3.3-3.2(m,2H),2.1-1.9(m,3H),1.63-1.5(m,2H),1.05-0.9(m,6H)。LC-MS:m/z397.3(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-(1-(2-methoxy ethoxy) third-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.61-8.42(m,1H),7.99(t,J＝7.9Hz,1H),7.77(d,J＝7.7Hz,1H),5.78-5.37(m,2H),4.52-4.22(m,1H),3.79-3.47(m,7H),3.40(s,3H),1.29(d,J＝5.7Hz,6H),0.99-0.80(m,1H),0.61-0.21(m,4H)。LC-MS:m/z441(M+H) ⁺。

Compound 2-((4-(((R)-1-cyclopropylethyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) the third-1-alcohol

¹HNMR(400MHz,CDCl ₃)δ8.57-8.47(m,1H),8.01(t,J＝7.6Hz,1H),7.79(d,J＝7.6Hz,1H),5.62-5.20(m,2H),4.23(m,1H),3.82-3.49(m,3H),1.35-1.22(m,6H),0.93(m,1H),0.58-0.29(m,4H)。LC-MS:m/z383.2(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-(1-isopropoxy third-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.65-8.42(m,1H),7.99(t,J＝7.9Hz,1H),7.78(d,J＝7.3Hz,1H),5.92-5.08(m,2H),4.44-4.13(m,1H),3.73-3.27(m,4H),1.27(m,6H),1.17(d,J＝6.1Hz,6H),1.04-0.84(m,1H),0.63-0.16(m,4H)。LC-MS:m/z425(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-(4-methoxyl group fourth-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.63-8.48(m,1H),8.01-7.97(m,1H),7.77(d,J＝7.6Hz,1H),5.54-5.25(m,2H),4.44-4.22(m,1H),3.64-3.49(m,3H),3.33(d,J＝2.4Hz,3H),1.89-1.78(m,2H),1.30-1.25(m,5H),0.93-0.83(m,2H),0.53-0.28(m,4H)。LC-MS:m/z411(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-(1-phenyl third-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.41(d,J＝7.6Hz,1H),7.92(t,J＝7.8Hz,1H),7.70(d,J＝7.6Hz,1H),7.25-7.14(m,5H),5.50-4.92(m,2H),4.25(m,1H),3.68-3.39(m,1H),2.99(m,1H),2.61(m,1H),1.26-1.06(m,8H),0.52-0.28(m,3H)。LC-MS:m/z443(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-(1-morpholinyl third-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.51-8.50(m,1H),8.22(s,1H),8.03-7.99(m,1H),7.83-7.79(m,1H),6.39-5.86(m,2H),4.44(m,7H),3.79-3.52(m,5H),3.25-2.53(m,5H),0.95(s,1H),0.54-0.26(m,4H)。LC-MS:m/z452(M+H) ⁺。

Compound N ²-((R)-1-cyclopropylethyl)-N ⁴-(1-(piperidin-1-yl) third-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.54-8.51(m,2H),8.01-7.98(m,1H),7.77(d,J＝7.6Hz,1H),6.66-6.17(m,1H),5.72-5.54(m,1H),4.84-4.44(m,1H),4.21(s,5H),3.67-2.63(m,7H),1.77(d,J＝5.2Hz,4H),1.53(s,2H),0.93(d,J＝4Hz,1H),0.52-0.27(m,4H)。LC-MS:m/z450(M+H) ⁺。

Compound (R)-3-((4-((1-cyclopropylethyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino)-2,2-dimethylpropionamide

¹HNMR(400MHz,CDCl ₃)δ8.52-8.37(m,1H),8.00-7.96(m,1H),7.87-7.75(m,1H),6.01-5.22(m,2H),4.26-3.53(m,3H),2.32-1.45(m,2H),1.41-1.29(m,8H),1.23-1.21(m,1H),0.97-0.28(m,5H)。LC-MS:m/z424(M+H) ⁺。

Compound 3-((4-(((R)-1-cyclopropylethyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) butyronitrile

¹HNMR(400MHz,CDCl ₃)δ8.50(d,J＝7.6Hz,1H),8.03-7.99(m,1H),7.80(d,J＝7.6Hz,1H),5.64-5.17(m,2H),4.55-4.32(m,1H),3.70-3.51(m,1H),2.87-2.69(m,2H),1.46(d,J＝6.8Hz,3H),1.33-1.25(m,3H),0.96-0.89(m,1H),0.55-0.30(m,4H)。LC-MS:m/z392(M+H) ⁺。

Compound (R)-3-((4-((1-cyclopropylethyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino)-2,2-dimethyl propionitrile

¹HNMR(400MHz,CDCl ₃)δ8.55(s,1H),8.11(s,1H),7.91(d,J＝8Hz,1H),3.73-3.62(m,4H),1.47-1.42(m,7H),1.37-1.35(m,3H),0.75-0.69(m,1H),0.58(m,2H),0.40-0.34(m,2H)。LC-MS:m/z406(M+H) ⁺。

Compound 1-((4-((3,3-Difluorocyclopentyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino)-2-methyl propan-2-ol

¹HNMR(400MHz，CDCl3 ₃)δ8.50(s,1H),8.03(d,J＝7.3Hz,1H),7.80(d,J＝7.4Hz,1H),5.68(m,2H),4.60(m,1H),3.83-3.03(m,3H),2.74-2.56(m,1H),2.31(s,2H),2.19-1.97(m,2H),1.83(m,1H),1.30(s,6H)。LC-MS:m/z433(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(1-(4-fluorophenyl) azetidin-3-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ10.05-8.37(m,1H),8.31-7.54(m,2H),7.60-6.68(m,4H),5.49-4.41(m,4H),3.80-3.35(m,2H),2.55-2.12(m,6H)。LC-MS:m/z510(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(1-(pyridine-2-base) azetidin-3-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.50(s,1H),8.09(m,2H),7.80(s,1H),7.49(s,1H),6.66(s,1H),6.26(m,2H),5.77(m,1H),4.99-4.34(m,4H),3.96(m,2H),2.42-1.71(m,6H)。LC-MS:m/z493(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(1-(pyridin-3-yl) azetidin-3-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃):δ8.50(d,J＝8Hz,1H),8.07-8.01(m,2H),7.92(s,1H),7.80(d,J＝8Hz,1H),7.17-7.14(m,1H),6.80-6.79(m,1H),6.15-5.34(m,2H),5.14-4.51(m,2H),4.39-4.35(m,2H),3.89-3.78(m,2H),2.62-2.57(m,1H),2.30-2.11(m,5H)。LC-MS:m/z493(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-((1r, 3r)-3-(4-fluorophenyl) cyclobutyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.55(d,J＝7.6Hz,1H),8.21-8.01(m,1H),7.88(m,1H),7.26-7.15(m,2H),7.04(t,J＝8.4Hz,2H),4.89-4.35(m,2H),3.88-3.40(m,1H),3.00-1.75(m,11H)。LC-MS:m/z509(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-((1s, 3s)-3-(4-fluorophenyl) cyclobutyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.65-8.42(m,1H),8.02(t,J＝7.3Hz,1H),7.80(d,J＝7.6Hz,1H),7.20-7.12(m,2H),7.01(t,J＝8.6Hz,2H),5.82-5.20(m,2H),4.83-4.37(m,2H),3.40-3.11(m,1H),3.00-1.75(m,10H)。LC-MS:m/z509(M+H) ⁺。

Compound N 2-(3,3-Difluorocyclopentyl)-N4-(3-phenylcyclobutyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.65-8.42(m,1H),8.01(t,J＝7.8Hz,1H),7.80(d,J＝7.4Hz,1H),7.42-7.29(m,3H),7.23(t,J＝6.4Hz,1H),6.07-5.20(m,2H),4.90-4.40(m,2H),4.13-3.56(m,1H),2.75-1.75(m,10H)。LC-MS:m/z491(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(1-methylpyrrolidin-3-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，，CDCl ₃)δ8.62-8.48(m,1H),8.09-7.94(m,1H),7.80(t,J＝7.4Hz,1H),4.91-4.27(m,2H),3.42-2.56(m,9H),2.44-2.22(m,4H),2.00-1.57(m,4H)。LC-MS:m/z444(M+H) ⁺。

Compound (3-((4-((3,3-Difluorocyclopentyl) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino) pyrrolidin-1-yl) (phenyl) ketone

¹HNMR(400MHz,CDCl ₃)δ8.76-8.35(m,1H),8.10-7.91(m,1H),7.84(s,1H),7.53(d,J＝7.4Hz,2H),7.43(d,J＝6.5Hz,3H),5.75-5.29(m,2H),4.86-3.77(m,4H),3.70-3.23(m,2H),2.79-1.74(m,8H)。LC-MS:m/z534(M+H) ⁺。

Compound N ²-(1-benzyl-pyrrole alkane-3-base)-N ⁴-(3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ:8.62-8.40(m,1H),8.12-7.93(m,1H),7.79(d,J＝7.3Hz,1H),7.57-7.28(m,5H),6.23-5.45(m,2H),5.07-3.75(m,4H),3.06-2.40(m,4H),2.38-1.60(m,8H)。LC-MS:m/z520(M+H) ⁺。

Compound (4S)-4-((4-((3,3-Difluorocyclopentyl) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino)-1-(pyridine-2-base) pyrrolidin-2-one

¹HNMR(400MHz,CDCl ₃)δ8.66-8.29(m,3H),8.00(s,1H),7.73(m,2H),7.12-7.01(m,1H),5.73(m,2H),5.00-4.40(m,3H),4.24-4.05(m,1H),3.15(m,6.3Hz,1H),2.85-2.51(m,2H),2.21(m,5H)。LC-MS:m/z521(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(3-phenylcyclopentyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.59-8.48(m,1H),8.03-7.99(m,1H),7.80(d,J＝4Hz,1H),7.34-7.30(m,3H),7.23-7.19(m,2H),5.63-5.31(m,2H),4.70-4.56(m,2H),3.29-3.17(m,1H),2.65-2.04(m,9H),1.81(m,3H)。LC-MS:m/z505(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(2,3-dihydro-1H-indenes-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

1HNMR(400MHz,CDCl ₃)：δ8.64-8.46(m,1H),8.01(d,J＝12.8Hz,1H),7.78(d,J＝7.6Hz,1H),7.21(m,3H),5.76-5.31(m,2H),5.02-4.44(m,2H),3.45-3.36(m,2H),2.97-2.91(m,2H),2.68-2.58(m,1H),2.31-2.09(m,4H),1.85-1.84(m,1H),1.25(m,1H)。LC-MS:m/z477(M+H) ⁺。

Compound N ²-(chloro-2, the 3-dihydro-1H-indenes-2-bases of 5-)-N ⁴-(3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.57-8.48(m,1H),8.01(d,J＝8Hz,1H),7.81(d,J＝8Hz,1H),7.26-7.18(m,3H),6.02-5.36(m,2H),5.05-4.43(m,2H),3.48-3.32(m,2H),3.04-2.87(m,2H),2.70-2.58(m,1H),2.36-2.10(m,4H),1.99-1.82(m,1H)。LC-MS:m/z511(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(fluoro-2, the 3-dihydro-1H-indenes-2-bases of 5-)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.59-8.47(m,1H),8.04-7.97(m,1H),7.79(d,J＝7.2Hz,1H),7.26-7.17(m,1H),6.96-6.87(m,2H),5.75-5.30(m,2H),5.06-4.44(m,2H),3.39-3.32(m,2H),2.95-2.62(m,3H),2.33-2.05(m,4H),1.87-1.82(m,1H)。LC-MS:m/z495(M+H) ⁺。

Compound N ²-(bromo-2, the 3-dihydro-1H-indenes-2-bases of 5-)-N ⁴-(3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.57-8.47(m,1H),8.04-7.99(m,1H),7.82-7.78(m,1H),7.52-7.29(m,2H),7.18-7.00(m,1H),5.70-5.30(m,2H),5.03-4.48(m,2H),3.40-3.30(m,2H),2.96-2.63(m,3H),2.35-2.07(m,4H),1.87-1.25(m,1H)。LC-MS:m/z556(M+H) ⁺。

Compound 2-((4-((3,3-Difluorocyclopentyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino)-2,3-dihydro-1H-indenes-5-formonitrile HCNs

¹HNMR(400MHz,CDCl ₃)δ8.57-8.47(m,1H),8.01(d,J＝8Hz,1H),7.80(d,J＝4Hz,1H),7.54-7.50(m,2H),7.37-7.33(m,1H),5.77-5.34(m,2H),5.07-4.56(m,2H),3.43(m,2H),3.03-2.99(m,2H),2.70-2.58(m,1H),2.32-2.04(m,5H)。LC-MS:m/z502(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(5-methoxyl group-2,3-dihydro-1H-indenes-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.69-8.46(m,1H),8.00(d,J＝8Hz,1H),7.79-7.74(m,1H),7.14(s,1H),6.81-6.75(m,2H),5.76-5.33(m,2H),5.02-4.78(m,1H),4.58-4.47(m,1H),3.80(s,3H),3.39-3.33(m,2H),2.93-2.62(m,4H),2.31-2.10(m,4H)。LC-MS:m/z507(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(6,7-dihydro-5H-cyclopenta [b] pyridine-6-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ:8.64-8.35(m,2H),8.07-7.76(m,2H),7.53(m,1H),7.11(m,1H),5.86-5.30(m,2H),5.01-4.54(m,2H),3.62-2.60(m,5H),2.40-1.86(m,5H)。LC-MS:m/z478.2(M+H) ⁺。

Compound N ²-(bromo-2, the 3-dihydro-1H-indenes-2-bases of 4,6-bis-)-N ⁴-(3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.55-8.46(m,1H),8.07-7.99(m,1H),7.80(d,J＝8Hz,1H),7.51-7.44(m,2H),7.09-7.04(m,2H),6.03-5.38(m,2H),5.03-4.43(m,2H),3.48-3.25(m,2H),3.06-2.88(m,2H),2.69-2.58(m,1H),2.31-2.29(d,J＝8Hz,2H),2.17-2.01(m,2H),1.90-1.77(m,1H)。LC-MS:m/z635(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(1-Phenylpyrrolidine-3-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.61-8.49(m,1H),8.04-7.98(m,1H),7.80-7.78(m,1H),7.27-7.23(m,2H),6.74-6.70(t,1H),6.59(d,2H),5.73-5.33(m,2H),4.91-4.48(m,2H),3.75-3.28(m,4H),2.62-1.87(m,8H)。LC-MS:m/z506(M+H)+。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(1-(pyridine-2-base) pyrrolidin-3-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.67-8.44(m,1H),8.17(s,1H),8.01(d,J＝8.8Hz,1H),7.79(d,J＝6.4Hz,1H),7.48(t,J＝7.7Hz,1H),6.59(t,J＝5.9Hz,1H),6.39(d,J＝8.1Hz,1H),5.84-4.30(m,4H),4.07-3.51(m,4H),2.83-1.97(m,8H)。LC-MS:m/z507(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(1-(pyrimidine-2-base) pyrrolidin-3-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.64-8.48(m,1H),8.34-8.33(m,2H),8.04-7.38(m,1H),7.80-7.79(m,1H),6.54-6.52(m,1H),5.73-5.35(m,2H),4.61-4.58(m,2H),4.00-3.93(m,1H),3.79-3.58(m,3H),2.90-2.61(m,1H),2.38-2.12(m,6H),1.88-1.82(m,1H)。LC-MS:m/z508(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(6,6-difluoro spiral shell [3.3]-2-in heptan base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.66-8.39(m,1H),8.02(d,J＝7.2Hz,1H),7.80(d,J＝6.6Hz,1H),5.73-5.20(m,2H),4.80-4.30(m,2H),2.83-1.78(m,14H)。LC-MS:m/z491(M+H) ⁺。

Compound 1-((4-((4,4-difiuorocyclohexyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino)-2-methyl propan-2-ol

¹HNMR(400MHz，DMSO-d ₆)δ8.63-8.45(m,1H),8.24(t,J＝7.7Hz,1H),8.03(d,J＝7.5Hz,1H),7.83(d,J＝7.2Hz,1H),7.57-7.10(m,1H),4.62(m,1H),4.03-4.04(m,1H),3.37(s,2H),2.08(s,2H),1.93-1.85(m,4H),1.62(d,J＝12.2Hz,2H),1.12(s,6H)。LC-MS:m/z447(M+H) ⁺。

Compound N ²-(4,4-difiuorocyclohexyl)-N ⁴-(tetrahydrochysene-2H-pyrans-4-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl3)δ8.55-8.48(m,1H),8.05-7.99(m,1H),7.80(d,J＝7.6Hz,1H),5.44-5.12(m,2H),4.26-4.01(m,4H),3.74-3.52(m,2H),2.20-1.83(m,8H),1.73-1.50(m,4H)；LC-MS:m/z459.2(M+H) ⁺。

Compound 4-((4-((4,4-difiuorocyclohexyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) piperidines-1-t-butyl formate

¹HNMR(400MHz，，CDCl ₃)δ8.48-8.40(m,1H),7.97-7.91(m,1H),7.74-7.69(m,1H),5.56-5.15(m,2H),4.18-3.85(m,4H),2.95-2.82(m,2H),2.10-1.54(m,9H),1.40(m,12H)。LC-MS:m/z558.3(M+H) ⁺。

Compound 1-(4-((4-((4,4-difiuorocyclohexyl) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino) piperidin-1-yl) ethyl ketone

¹HNMR(400MHz,CDCl ₃)δ8.54-8.48(m,1H),8.06-7.97(m,1H),7.81(d,J＝7.2Hz,1H),5.57-5.14(m,2H),4.54-3.83(m,4H),3.25-2.83(m,4H),2.24-2.05(m,7H),1.77-1.44(m,6H)。LC-MS:m/z500.2(M+H) ⁺。

Compound N ²-(4,4-difiuorocyclohexyl)-N ⁴-(1-(methyl sulphonyl) piperidin-4-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

1HNMR(400MHzz,CDCl ₃)δ8.58-8.48(m,1H),8.05-7.96(m,1H),7.80(d,J＝6.8Hz,1H),5.56-5.18(m2H),4.25-3.95(m,4H),3.64-3.45(m,2H),2.26-1.55(m,15H)。LC-MS:m/z536.2(M+H) ⁺。

Compound N ²-(4,4-difiuorocyclohexyl)-N ⁴-(6,6-difluoro spiral shell [3.3]-2-in heptan base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.66-8.39(m,1H),8.14-7.94(m,1H),7.81(d,J＝7.7Hz,1H),6.04-5.01(m,2H),4.74-3.74(m,2H),2.79-2.42(m,6H),2.31-1.96(m,6H),1.85-1.50(m,4H)。LC-MS:m/z505(M+H) ⁺。

Compound N ²-(3,3-difluoro cyclobutyl)-N ⁴-(4,4-difiuorocyclohexyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.54-8.48(m,1H),8.02(d,J＝8Hz,1H),7.81(d,J＝4Hz,1H),5.77-5.14(m,2H),4.53-3.96(m,2H),3.11-3.03(m,2H),2.70-2.54(m,2H),2.15-2.09(m,4H),1.93(m,2H),1.69(m,2H)。LC-MS:m/z465(M+H) ⁺。

Compound N ²-(4,4-difiuorocyclohexyl)-N ⁴-(3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.48-8.56(m,1H),8.01(d,J＝4Hz,1H),7.80(d,J＝4Hz,1H),5.63-5.13(m,2H),4.72-3.97(m,2H),2.62(m,1H),2.31(m,2H),2.14-1.86(m,9H),1.74(m,2H)。LC-MS:m/z479(M+H) ⁺。

Compound (R)-6-(6-chloropyridine-2-base)-N ²-(1,1,1,3,3,3-hexafluoro third-2-base)-N ⁴-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.40-8.34(m,1H),7.87-7.84(m,1H),7.53(d,J＝8Hz,1H),-6.15-5.83(m,1H),5.77-5.31(m,2H),5.17-4.76(m,1H),1.51-1.43(m,3H)；LC-MS:m/z469(M+H) ⁺。

Compound (R)-6-(6-chloropyridine-2-base)-N ²-(4,4-difiuorocyclohexyl)-N ⁴-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆)δ8.33(m,2H),8.13-7.92(m,2H),7.78-7.59(m,1H),5.21-4.76(m,1H),4.06(m,1H),2.23-1.45(m,8H),1.42-1.25(m,3H)。LC-MS:m/z437(M+H) ⁺。

Table 2: prepare following target by the program described in above scheme 2.

Example 3 preparation has the two aliphatics triaizine compounds of chemical formula F.The compound of this example is prepared by following cited general scheme 3.

Step 1: the chloro-N of preparation 6- ², N ⁴-bis-((R)-1-cyclopropylethyl)-1,3,5-triazines-2,4-diamines.To 2,4,6-tri-chloro-1,3,5-triazine (2g, 10.9mmol, 1 equivalent) and (R)-1-cyclopropylethyI amine hydrochloride (2.7g, 22.8mmol, 2.1 equivalents) add DIPEA (4.5mL, 27.3mmol, 2.5 equivalents) and CsF (3.3g in mixture in acetone (50mL), 21.8mmol, 2.0 equivalents).Stir the mixture at 40 DEG C 3 hours and then at 50 DEG C, continue 3 hours again.Filtering mixt under reduced pressure concentrated filtrate.By standard method Purification, thus the product desired by obtaining.

LC-MS：m/z282.1(M+H) ⁺。

Step 2: preparation N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(pyridin-4-yl)-1,3,5-triazines-2,4-diamines.At room temperature stir, under nitrogen atmosphere, to the chloro-N of 6- ², N ⁴-bis-((R)-1-cyclopropylethyl)-1,3,5-triazines-2,4-diamines (100mg, 0.36mmol), pyridin-4-yl boric acid (66mg, 0.52mmol) and K ₂cO ₃disposable interpolation Pd (PPh in (99mg, 0.72mmol) mixture in Isosorbide-5-Nitrae-diox (3mL) and water (1mL) ₃) ₄(42mg, 0.036mmol).At 80 DEG C, stirred reaction mixture spends the night.Mixture is allocated between water and EtOAc.Use anhydrous Na ₂sO ₄dry organic layer is also concentrated.By standard method Purification, thus obtain desired product.

¹HNMR(400MHz,DMSO-d ₆):δ7.61-7.28(m,6H),3.58-3.39(m,2H),1.23-1.10(m,3H),1.02-0.89(m,2H),0.48-0.26(m,6H),0.20-0.10(m,2H)。LC-MS:m/z325.2(M+H) ⁺。

Use above cited program, use appropriate parent material to prepare following compound.

Compound 6-(3-chloro-phenyl-)-N ², N ⁴-bis-((R)-1-cyclopropylethyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆):δ8.30-8.14(m,2H),7.58(d,J＝7.7Hz,1H),7.52(t,J＝7.8Hz,1H),7.41(d,J＝8.2Hz,1H),7.35-7.26(m,1H),3.70-3.43(m,2H),1.26-1.15(m,6H),1.02-0.92(m,2H),0.49-0.30(m,6H),0.26-0.11(m,2H).LC-MS:m/z358.2(M+H) ⁺。

Compound 3-(4,6-two ((R)-1-cyclopropylethyl is amino)-1,3,5-triazines-2-base) phenol

¹HNMR(400MHz,CDCl ₃):δ7.99-7.64(m,2H),7.29(d,J＝7.9Hz,1H),6.96(d,J＝7.8Hz,1H),5.78-5.04(m,2H),4.07(s,1H),3.60(m,2H),1.27(d,J＝4.3Hz,6H),0.89(d,J＝3.6Hz,2H),0.43(m,8H)。LC-MS:m/z340.2(M+H) ⁺。

Table 3: prepare following target by the program described in above scheme 3.

Example 4 preparation has the two aliphatics triaizine compounds of chemical formula G.The compound of this example is prepared by following cited general scheme 4.

Scheme 4

Step 1. prepares N ²-(3,3-Difluorocyclopentyl)-N ⁴-(pyrrolidin-3-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines.At 0 DEG C, to 3-(4-(3,3-Difluorocyclopentyl is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base is amino) add TFA (1mL) in the solution of tetramethyleneimine-1-t-butyl formate (160mg, 0.3mmol) in DCM (3mL).At room temperature stir the mixture 2 hours and then concentrate.Use EtOAc extracted residues.With saturated water-based NaHCO ₃with the organic layer that salt water washing merges, use anhydrous Na ₂sO ₄dry and then concentrate, thus the product desired by obtaining, this product is further purified namely in next step without any.

LC-MS:m/z430.2(M+H) ⁺。

Step 2. prepares N ²-(3,3-Difluorocyclopentyl)-N ⁴-(1-(methyl sulphonyl) pyrrolidin-3-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines.At room temperature stir N ²-(3,3-Difluorocyclopentyl)-N ⁴-(pyrrolidin-3-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines (20mg, 0.05mmol), Et ₃n (9.4mg, 0.09mmol), MsCl (6mg, the 0.06mmol) mixture overnight in DCM (2mL).Enriched mixture and by standard method Purification, thus the product desired by obtaining.

¹HNMR(400MHzz,CDCl ₃):δ8.62-8.46(m,1H),8.04(d,J＝7.5Hz,1H),7.81(d,J＝7.6Hz,1H),5.79-5.38(m,2H),4.80-4.53(m,2H),3.76-3.52(m,2H),3.39-3.23(m,1H),2.91(s,3H),2.69-2.57(m,1H),2.45-2.25(m,3H),2.20-1.98(m,3H),1.95-1.81(m,1H),1.22-1.18(m,1H)。LC-MS:m/z508.1(M+H) ⁺。

Compound 3-((4-((3,3-Difluorocyclopentyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) tetramethyleneimine-1-methyl-formiate.

¹HNMR(400MHz,CDCl ₃):δ8.58-8.48(m,1H),8.02(d,J＝7.5Hz,1H),7.81(d,J＝7.5Hz,1H),5.94-5.18(m,2H),4.72-4.47(m,2H),3.83-3.74(m,1H),3.72(s,3H),3.65-3.51(m,2H),3.44-3.28(m,1H),2.45-1.80(m,7H)。LC-MS:m/z488.2(M+H) ⁺。

Compound 1-(3-((4-((3,3-Difluorocyclopentyl) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino) pyrrolidin-1-yl) ethyl ketone

¹HNMR(400MHzz,CDCl ₃):δ8.55(m,1H),8.07(d,J＝6.8Hz,1H),7.85(t,J＝6.7Hz,1H),4.84-4.30(m,2H),3.97-3.52(m,4H),2.62(m,1H),2.50-2.22(m,3H),2.22-1.98(m,3H),1.25(s,3H)。LC-MS:m/z472.2(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(1-methylpyrrolidin-3-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines.At 0 DEG C, to 3-(4-(3,3-Difluorocyclopentyl is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base is amino) add LiAlH in the solution of tetramethyleneimine-1-t-butyl formate (25mg, 0.05mmol) in THF (3mL) ₄(5mg, 0.14mmol).Stir the mixture at 0 DEG C 2 hours, then at room temperature stir 30 minutes, and finally stir 2 hours at 60 DEG C.To go out reaction mixture being extracted by EtOAc with shrend.With the organic layer that salt water washing merges, use anhydrous Na ₂sO ₄drying, and concentrated.By standard method Purification, thus obtain desired product.

¹HNMR(400MHzz,CDCl ₃):δ8.55(m,1H),8.08-7.93(m,1H),7.80(t,J＝7.4Hz,1H),4.63(m,2H),3.47-2.87(m,3H),2.69(m,6H),2.28(m,4H),1.84(m,4H)。LC-MS:m/z444.2(M+H) ⁺。

Example 5 prepares two aliphatics triaizine compounds.The compound of this example is prepared by following cited general scheme 5.

Scheme 5

Step 1: preparation 6-(6-(azetidin-1-base) pyridine-2-base)-N ², N ⁴-bis-((R)-1-cyclopropyl) ethyl)-1,3,5-triazines-2,4-diamines.At 100 DEG C, under nitrogen atmosphere, 6-(6-chloropyridine-2-base)-N is stirred ², N ⁴-bis-((R)-1-cyclopropylethyl)-1,3,5-triazine-2,4-diamines (40mg, 0.11mmol), azetidine (7.6mg, 0.13mmol), 2,2'-pair-(diphenylphosphino)-1,1'-dinaphthalene (6.9mg, 0.01mmol), sodium tert-butoxide (15mg, 0.16mmol) and the mixture overnight of three (dibenzalacetone)-two palladiums (10.2mg, 0.01mmol) in toluene (3mL).Mixture cool to room temperature is filtered.Under reduced pressure concentrated filtrate and by standard method Purification, thus the product desired by obtaining.

¹HNMR(400MHz,CD ₃OD):δ8.49(s,1H),7.72-7.53(m,2H),6.56(d,J＝7.4,1H),4.11(t,J＝7.4,4H),3.59(m,2H),2.42(p,J＝7.4,2H),1.30(d,J＝6.5,6H),0.98(s,2H),0.67-0.13(m,8H)。LC-MS:m/z380.2(M+H) ⁺。

Step 2: preparation N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(pyridine-2-base)-1,3,5-triazines-2,4-diamines.Under nitrogen atmosphere, to 6-(6-chloropyridine-2-base)-N ², N ⁴pd/C (2mg) is added in-bis-((the R)-1-cyclopropylethyl) solution of-1,3,5-triazines-2,4-diamines (20mg, 0.05mmol) in methyl alcohol (2mL).Then at room temperature stir the mixture under hydrogen balloon and spend the night.Filtering mixt concentrated filtrate.By standard method Purification, thus the product desired by obtaining.

¹HNMR(400MHz,DMSO-d ₆):δ8.82-8.03(m,4H),7.75(m,2H),3.79-3.45(m,2H),1.21(d,J＝6.3Hz,6H),1.07-0.84(m,2H),0.55-0.05(m,8H)。LC-MS:m/z325.2(M+H) ⁺。

Example 6 preparation has the two aliphatics triaizine compounds of chemical formula H.The compound of this example is prepared by following cited general scheme 6.

Step 1: preparation 2-((4-(the fluoro-5-hydroxy phenyl of 2-)-6-(isopropylamino)-1,3,5-triazines-2-base) is amino)-2-methyl propionitrile.At-65 DEG C, to 2-((4-(the fluoro-5-p-methoxy-phenyl of 2-)-6-(isopropylamino)-1,3,5-triazine-2-base) amino) dropwise add BBr in the solution of-2-methyl propionitrile (200mg, 0.6mmol) in anhydrous DCM (3mL) ₃(0.6mL) and at this temperature stirred reaction mixture 20 minutes.Mixture be warmed up to 0 DEG C lentamente and stir 10 minutes, and then at room temperature stirring 1 hour.With the saturated water-based NaHCO of ice ₃cancellation reaction is until pH=8.Gained mixture is extracted with EtOAc (2x10mL).With the organic layer that salt water washing merges, use anhydrous Na ₂sO ₄drying, and under reduced pressure concentrate.By standard method Purification, thus the product desired by obtaining.

¹HNMR(400MHz,CDCl ₃):δ7.20(s,1H),6.96(t,J＝9.6Hz,1H),6.83(d,J＝8.6Hz,1H),5.72(m,2H),4.26(s,1H),1.79(s,6H),1.26(d,J＝6.1Hz,6H)。LC-MS:m/z331.2(M+H) ⁺。

Example 7 preparation has the two aliphatics pyrimidine compounds of chemical formula J.The compound of this example is prepared by following cited general scheme 7.

Scheme 7

Step 1: preparation 6-(trifluoromethyl) picolyl ether.At 0 DEG C, in the solution of 6-(trifluoromethyl) pyridine carbonitrile (50mg, 0.3mmol, 1 equivalent) in EtOH (3mL), add NaOMe (1.6mg, 0.03mmol, 0.1 equivalent).At room temperature stir the mixture 1 hour, then add NH ₄cl (21mg, 0.39mmol, 13 equivalents).Gained mixture is stirred 1 hour and cool to room temperature at 90 DEG C.With saturated water-based NaHCO ₃regulate mixture pH to 9 and then extract with EtOAc.With the organic layer that salt water washing merges, use anhydrous Na ₂sO ₄drying, and concentrated.By standard method Purification, thus the product desired by obtaining.

LC-MS：m/z190.1(M+H) ⁺。

Step 2: preparation 2-(6-(trifluoromethyl) pyridine-2-base) pyrimidine-4,6-glycol.6-(trifluoromethyl) picolyl ether (600mg, the 3.2mmol) solution in EtOH is dropwise added in the solution of sodium (366mg, 15.9mmol, 5.0 equivalents) in anhydrous EtOH (6mL).At room temperature stirred reaction mixture 1 hour, then adds diethyl malonate (1mL, 6.4mmol, 2.0 equivalents).Stir the mixture under reflux and spend the night and then cool to room temperature.Regulate gained mixture pH to 7 by the 1NHCl aqueous solution.Filtering suspension liquid also washes filter cake with water.Solid suspension to be filtered in MeOH.Under reduced pressure concentrated filtrate, thus obtain desired product, namely this product is directly used in next step without any being further purified.

LC-MS:m/z256.0(M-H) ^-。

Step 3: preparation 4,6-bis-chloro-2-(6-(trifluoromethyl) pyridine-2-base) pyrimidine.2-(6-(trifluoromethyl) pyridine-2-base) pyrimidine-4,6-glycol (1g, 3.9mmol) is stirred in POCl at 90 DEG C ₃(6mL) solutions overnight in and then concentrated to remove volatile matter.By standard method Purification, thus the product desired by obtaining.

LC-MS:m/z294.0(M+H) ⁺。

Step 4: preparation (R)-6-chloro-N-(1-cyclopropylethyl)-2-(6-(trifluoromethyl)-pyridine-2-base) pyrimidine-4-amine.To 4, the chloro-2-of 6-bis-(6-(trifluoromethyl) pyridine-2-base) pyrimidine (80mg, 0.27mmol, 1 equivalent) add (R)-1--cyclopropylethyI amine (0.06mL in solution in THF (3mL), 0.6mmol, 2.2 equivalents) and Et ₃n (0.07mL, 0.54mmol, 2 equivalents).At room temperature stirred reaction mixture spends the night and concentrates.By standard method Purification, thus obtain desired product.

LC-MS:m/z343.1(M+H) ⁺。

Step 5: preparation N ⁴, N ⁶-bis-((R)-1-cyclopropylethyl)-2-(6-(trifluoromethyl) pyridine-2-base) pyrimidine-4,6-diamines.To the chloro-N-of (R)-6-(1-cyclopropylethyl)-2-(6-(trifluoromethyl)-pyridine-2-base) pyrimidine-4-amine (50mg, 0.15mmol, 1 equivalent) add (R)-1-cyclopropylethyI amine hydrochloride (22mg in solution in DMSO (2mL), 0.18mmol, 1.2 equivalents) and DIPEA (0.08mL, 0.45mmol, 3 equivalents).Under microwave, at 160 DEG C, irradiate mixture 1.5 hours.After interpolation (R)-1-cyclopropylethyI amine (0.18mmol, 1.2 equivalents), stir gained mixture and at 160 DEG C, irradiate 2 hours again under microwave.Then mixture cool to room temperature is allocated between EtOAc and water.With water and salt water washing organic layer, use anhydrous Na ₂sO ₄drying, and concentrated.By standard method Purification, thus obtain desired product.

¹HNMR(400MHz,CDCl ₃):δ8.40(d,J＝7.9Hz,1H),7.87(t,J＝7.9Hz,1H),7.62(d,J＝7.8Hz,1H),5.19(m,3H),3.13(d,J＝6.3Hz,2H),1.19(d,J＝6.4Hz,6H),0.96-0.72(m,2H),0.52-0.33(m,4H),0.33-0.10(m,4H)。LC-MS:m/z392.2(M+H) ⁺。

Compound N ⁴, N ⁶-bis-((S)-1-cyclopropylethyl)-2-(6-(trifluoromethyl) pyridine-2-base) pyrimidine-4,6-diamines

¹HNMR(400MHz,CDCl ₃):δ8.49(d,J＝7.8Hz,1H),7.95(t,J＝7.9Hz,1H),7.71(d,J＝7.8Hz,1H),5.22(m,3H),3.22(d,J＝6.5Hz,2H),1.40-1.15(m,6H),0.95(m,2H),0.61-0.44(m,4H),0.31(m,4H)。LC-MS:m/z392.2(M+H) ⁺。

Compound N ⁴-((R)-1-cyclopropylethyl)-N ⁶-((S)-1-cyclopropylethyl)-2-(6-(trifluoromethyl) pyridine-2-base) pyrimidine-4,6-diamines

¹HNMR(400MHz，CDCl ₃):δ8.49(d,J＝7.8Hz,1H),7.97(t,J＝7.9Hz,1H),7.72(d,J＝7.8Hz,1H),5.22(m,3H),3.22(d,J＝6.5Hz,2H),1.68-1.25(m,6H),0.97(m2H),0.61-0.44(m,4H),0.31(m,4H)。LC-MS:m/z392.2(M+H) ⁺。

Table 7: prepare following compound by the program described in above scheme 7.

Example 9. preparation has the symmetry two aliphatics triaizine compounds of chemical formula K.The compound of this example is prepared by following cited general scheme 9.

Scheme 9

Step 1: preparation 2-bromo-6-(1,1-bis-fluoro ethyl) pyridine.

At 0 DEG C, through 30 minutes, in 1-(6-bromopyridine-2-base) solution of ethyl ketone (26g, 130mmol) in dry DCM (150mL), dropwise add DAST (84mL, 650mmol).Then make reaction mixture be warmed up to room temperature lentamente, and stir until react completely.Gained mixture is poured into lentamente in ice (300g) also with DCM (2x50mL) extraction.Wash the organic layer of merging with water, use anhydrous Na ₂sO ₄drying also under reduced pressure concentrates.By standard method Purification, thus obtain 2-bromo-6-(1,1-bis-fluoro ethyl) pyridine.LC-MS:m/z222.0(M+H) ⁺。

Step 2: preparation 6-(1,1-bis-fluoro ethyl) pyridine carboxylic acid methyl esters.

To the bromo-6-(1 of 2-, 1-bis-fluoro ethyl) pyridine (30.2g, 1 is added in solution 136mmol) in MeOH (300mL), two (diphenylphosphino)-ferrocene (7.5g of 1'-, 13.6mmol), triethylamine (28.4mL, 204mmol) and Pd (OAc) ₂(1.52g, 6.7mmol).At 60 DEG C, under CO atmosphere (60psi), stir the mixture 16 hours.Filter gained mixture and under reduced pressure concentrate.By standard method Purification, thus obtain 6-(1,1-bis-fluoro ethyl) pyridine carboxylic acid methyl esters.LC-MS:m/z202.2(M+H) ⁺。

Step 3: preparation 6-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-1,3,5-triazines-2,4 (1H, 3H)-diketone.To the solution of NaOEt in EtOH (from sodium (1.9g, 82.6mmol) with EtOH (150mL) fresh preparation) middle interpolation 6-(1,1-bis-fluoro ethyl) pyridine carboxylic acid methyl esters (2.8g, 28mmol) with biuret (14.0g, 70mmol).Stir the mixture at 90 DEG C 16 hours and under reduced pressure concentrate.Water (50mL) is added in resistates.Regulate gained mixture pH to 7 with 1NHCl, and then filter.Wash filter cake with water, and dry under a high vacuum, thus obtain 6-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-1,3,5-triazines-2,4 (1H, 3H)-diketone.LC-MS:m/z255.1(M+H) ⁺。

Step 4: preparation 2,4-bis-chloro-6-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-1,3,5-triazines.

To 6-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-1,3,5-triazines-2,4 (1H, 3H)-diketone (6g, 25mmol) in POCl ₃(60mL) PCl is added in the solution in ₅(26g, 125mmol).Stir the mixture at 100 DEG C 16 hours and under reduced pressure concentrate.By standard method Purification, thus obtain 2,4-bis-chloro-6-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-1,3,5-triazines. ¹HNMR(400MHz,CDCl ₃)δ8.62(d,1H),8.07(t,1H),7.94(d,1H),2.16(q,3H)。LC-MS:m/z292.1(M+H) ⁺。

Step 5: preparation N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-1,3,5-triazine-2,4-diamines at room temperature, to the chloro-6-of 2,4-bis-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-1,3,5-triazine (582mg, 2.0mmol, 1.0 equivalents) and 4, CsF (1.2g is added in the mixture of 4-difluorocyclohex amine hydrochlorate (752mg, 4.4mmol, 2.2 equivalents) in THF (12mL), 8.0mmol, 2 equivalents) and DIPEA (1.4mL, 8.0mmol, 4 equivalents).Stir the mixture at 60 DEG C and spend the night and then filter.Under reduced pressure concentrated filtrate and by standard method Purification, thus obtain desired product.

¹HNMR(400MHz，CDCl ₃)δ8.32-8.40(m,1H),7.94(bs,1H),7.78(bs,1H),5.07-5.46(m,2H),3.99-4.18(m,2H),1.71-2.17(m,19H)。LC-MS:m/z489.2(M+H) ⁺。

Be used in program cited in example 9, use appropriate parent material to prepare following compound.

Compound N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-6-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.32-8.43(m,1H),7.93-7.95(m,1H),7.78(bs,1H),5.28-5.70(m,2H),4.54-4.71(m,2H),1.72-2.65(m,15H)。LC-MS:m/z461.2(M+H) ⁺。

Compound N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.35-8.42(m,1H),7.95(bs,1H),7.80(bs,1H),5.42-5.85(m,2H),4.35-4.52(m,2H),3.04(bs,4H),2.62(bs,4H),2.04-2.16(m,3H)。LC-MS:m/z433.2(M+H) ⁺。

Example 10. preparation has the symmetry two aliphatics triaizine compounds of chemical formula L.The compound of this example is prepared by following cited general scheme 10.

Scheme 10

Step 1: preparation 6-(6-chloropyridine-2-base)-1,3,5-triazines-2,4 (1H, 3H)-diketone.Biuret (14.8g, 0.14mol), 6-chloropyridine methyl-formiate (21g, 0.12mol) and EtOH (250mL) is added in three neck round-bottomed flasks of drying.Use N ₂make mixture degassed three times and then at 25 DEG C stir 20 minutes.Then make temperature rise to 50 DEG C, then add HC (OMe) ₃(17mL, 0.14mol) and TFA (1.37g, 0.01mol).Stirred reaction mixture (light yellow slurry) 30 minutes at this temperature, then dropwise adds the solution of NaOEt in EtOH (20%wt, 163g, 0.48mol).The thick slurry of micro-for gained yellow is heated to backflow and continues 2 hours, until react completely.Mixture cool to room temperature is also under reduced pressure concentrated.Process resistates with water (200mL) and under reduced pressure concentrate, to remove residual ethanol.Then in resistates, (while stirring) water (300mL) is added to form transparent brown solution.Solution be cooled to 10 DEG C and be adjusted to pH1 lentamente by 6NHCl.Stir gained mixture again 2 hours and filter.Use HCl (pH=1) washing leaching cake, collects and is suspended in DCM (300mL).At room temperature stirred suspension 2 hours, filters and drying, thus the product desired by obtaining.LC-MS:m/z225.0(M+H) ⁺。

Step 2: preparation 2,4-bis-chloro-6-(6-chloropyridine-2-base)-1,3,5-triazines.This program is identical with example 1 step 3 mentioned above.LC-MS:m/z260.9(M+H) ⁺。

Step 3: preparation 6-(6-chloropyridine-2-base)-N ², N ⁴-bis-((R)-1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines.At N ₂under atmosphere, at 50 DEG C, stir 2, the chloro-6-of 4-bis-(the chloro-pyridine of 6--2-base)-1,3,5-triazines (0.27g, 1.04mol), (R)-1,1,1-trifluoropropyl-2-amine hydrochlorate (0.39g, 2.6mol) and salt of wormwood (0.43g, 3.1mol) in dry 1, mixture in 4-diox (2.5mL) 36 hours, then stirs 36 hours again at 100 DEG C, until react completely.Also EtOAc washing leaching cake is used by diatomite filtration gained mixture.Concentrated filtrate also passes through standard method Purification, thus obtains desired product.

¹HNMR(400MHz,CDCl ₃)δ8.32(m,1H),7.80(m,1H),7.48(d,J＝7.9Hz,1H),5.61(m,1.5H),5.25(m,0.5H),5.09(m,0.5H),4.88(m,1.5H),1.54-1.26(m,6H)。LC-MS:m/z415(M+H) ⁺。

Be used in program cited in example 10, use appropriate parent material to prepare following compound.

Compound 6-(6-chloropyridine-2-base)-N ², N ⁴-bis-((S)-1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.29-8.16(m,1H),7.72(d,J＝7.6Hz,1H),7.41(d,J＝7.9Hz,1H),5.70-5.13(m,2H),5.09-4.71(m,2H),1.34(m,6H)。LC-MS:m/z415(M+H) ⁺。

Compound 6-(6-chloropyridine-2-base)-N ²-((R)-1,1,1-trifluoropropyl-2-base)-N ⁴-((S)-1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.41-8.23(m,1H),7.83(s,1H),7.51(d,J＝6.2Hz,1H),5.68-5.20(m,2H),5.18-4.81(m,2H),1.48-1.39(m,6H)。LC-MS:m/z415(M+H) ⁺。

Compound 6-(6-chloropyridine-2-base)-N ², N ⁴-bis-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

Compound 6-(6-chloropyridine-2-base)-N ², N ⁴-bis-(1,1,1-trifluoro fourth-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.39-8.31(m,1H),7.86-7.79(m,1H),7.50(d,J＝7.8Hz,1H),5.67-5.12(m,2H),4.98-4.65(m,2H),2.07-1.91(m,2H),1.70-1.55(m,2H),1.06(dd,J＝8.6,6.0Hz,6H)。LC-MS:m/z443(M+H) ⁺。

Compound 6-(6-chloropyridine-2-base)-N ², N ⁴-bis-((S)-1,1,1-trifluoro fourth-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.30-8.35(t,1H),7.78-7.82(t,1H),7.47-7.52(m,1H),5.49-5.63(m,2H),4.72-4.89(m,2H),1.95-1.99(m,2H),1.59(m,2H),1.02-1.08(t,6H)。LC-MS:m/z443(M+H) ⁺。

Compound 6-(6-chloropyridine-2-base)-N ², N ⁴-bis-((R)-1,1,1-trifluoro fourth-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.31-8.35(t,1H),7.78-7.82(t,1H),7.47-7.49(m,1H),5.16-5.71(m,2H),4.72-4.74(m,2H),1.94-2.01(m,2H),1.62-1.64(m,2H),1.02-1.08(t,6H)。LC-MS:m/z443(M+H) ⁺。

Compound 6-(6-chloropyridine-2-base)-N ²-((R)-1,1,1-trifluoro fourth-2-base)-N ⁴-((S)-1,1,1-trifluoro fourth-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.30-8.35(m,1H),7.81(s,1H),7.47-7.49(d,1H),5.35-5.66(m,2H),4.91-5.13(d,1H),4.72(s,1H),2.00-2.23(d,3H),1.31-1.42(d,1H),1.03-1.07(m,6H)。LC-MS:m/z443(M+H) ⁺。

Compound 3,3'-((6-(6-chloropyridine-2-base)-1,3,5-triazines-2,4-bis-base) two (nitrogen two base)) dibutyronitrile

¹HNMR(400MHz,CDCl ₃)δ8.21(s,1H),7.73(t,J＝7.6Hz,1H),7.41(d,J＝7.8Hz,1H),5.61-5.18(m,2H),4.59-4.20(m,2H),2.85-2.60(m,4H),1.44-1.36(m,6H)。LC-MS:m/z357(M+H) ⁺。

Compound 6-(6-chloropyridine-2-base)-N ², N ⁴-bis-(1-Cyclopropylpropyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.26(d,J＝7.3Hz,1H),7.76(t,J＝7.8Hz,1H),7.43(d,J＝7.8Hz,1H),5.37-5.08(m,2H),3.48-3.37(m,2H),1.73-1.56(m,4H),0.98(t,J＝7.3Hz,6H),0.92-0.80(m,2H),0.66-0.20(m,8H)。LC-MS(m/z):387.2(M+H) ⁺。

Compound 6-(6-chloropyridine-2-base)-N ², N ⁴-bis-(bicyclic methyl propyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.18(d,J＝7.6Hz,1H),7.69(t,J＝7.8Hz,1H),7.36(d,J＝7.8Hz,1H),5.50-5.01(m,2H),3.30(s,2H),0.89(m,4H),0.50-0.21(m,16H)。LC-MS:m/z411.2(M+H) ⁺。

Compound 6-(6-chloropyridine-2-base)-N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.28(d,J＝8.2Hz,1H),7.80(t,J＝7.5Hz,1H),7.44(d,J＝8.0Hz,1H),6.64-6.12(m,2H),4.17-3.98(m,2H),2.17-1.70(m,16H)。LC-MS:m/z459(M+H) ⁺。

Compound 6-(6-chloropyridine-2-base)-N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-1,3,5-triazines-2,4-diamines

1HNMR(400MHz,CDCl ₃)δ8.41-8.25(m,1H),7.85(t,J＝7.6Hz,1H),7.53(d,J＝7.6Hz,1H),5.78-5.37(m,2H),4.69-4.53(m,2H),2.65-2.55(m,2H),2.51-1.98(m,8H),1.85-1.76(m,2H)。LC-MS:m/z431.1(M+H) ⁺。

Compound 6-(6-chloropyridine-2-base)-N ², N ⁴-bis-(2,2-Difluorocyclopentyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.48-8.26(m,1H),7.82(s,1H),7.49(s,1H),5.63(m,2H),4.70(m,2H),2.41-2.08(m,6H),1.83(m,4H),1.66(s,2H)。LC-MS:m/z431(M+H) ⁺。

Compound 2,2'-((6-(6-chloropyridine-2-base)-1,3,5-triazines-2,4-bis-base) two (nitrogen two base)) two cyclopentanol

¹HNMR(400MHz,CDCl ₃)δ8.27-8.17(m,1H),7.77(t,J＝7.8Hz,1H),7.45(d,J＝7.9Hz,1H),6.30-5.83(m,1H),5.52(m,2H),5.00(m,1H),4.05-3.88(m,2H),2.32-2.17(m,2H),2.10(m,1H),2.01(s,1H),1.88-1.65(m,6H),1.51(m,2H)。LC-MS:m/z391(M+H) ⁺。

Compound 6-(6-chloropyridine-2-base)-N ², N ⁴-bis-(6,6-difluoro spiral shell [3.3]-2-in heptan base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.25-7.78(m,4H),7.64(m,1H),4.45-4.24(m,2H),2.72-2.66(m,4H),2.61-2.50(m,4H),2.46-2.41(m,4H),2.22-2.19(m,4H)。LC-MS:m/z483(M+H) ⁺。

Two (4,4-difiuorocyclohexyl)-1,3,5-triazines-2, the 4-diamines of compound 6-(4-chloropyridine-2-base)-N2, N4-

¹HNMR(400MHz，CDCl ₃)δ8.68(d,J＝8.0Hz,1H),8.48(s,1H),7.62(d,J＝8.0Hz,1H),5.28(d,J＝8.0Hz,2H),4.20-4.02(m,2H),1.98-1.61(m,16H)。LC-MS:m/z459.1(M+H) ⁺。

Compound 6-(5-chloropyridine-3-base)-N ², N ⁴-bis-((R)-1-cyclopropylethyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.36(m,1H),8.65(d,J＝2.1Hz,1H),8.54(t,J＝1.9Hz,1H),5.46-5.06(m,2H),3.78-3.40(m,2H),1.29(s,6H),0.95-0.87(m,2H),0.56-0.38(m,6H),0.29(s,2H)。LC-MS:m/z359(M+H) ⁺。

The compound of this example of example 11 is prepared by following cited general scheme 11.

Scheme 11

Step 1. prepares N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(6-((4-methoxy-benzyl) is amino) pyridine-2-base)-1,3,5-triazines-2,4-diamines.At room temperature, at N ₂under atmosphere, to 6-(6-chloropyridine-2-base)-N2, two ((the R)-1-cyclopropylethyl)-1 of N4-, 3,5-triazine-2,4-diamines (120mg, 0.33mmol), (4-p-methoxy-phenyl) methylamine (69mg, 0.51mmol), BINAP (42mg, 0.66mmol) and t-BuONa (63mg, 0.66mmol) disposable interpolation Pd in the solution in Shui diox (2mL) ₂(dba) ₃(30mg, 0.033mmol).Then at 100 DEG C, stirred reaction mixture spends the night, and then under reduced pressure concentrates, thus the product desired by obtaining.

LC-MS：m/z460(M+H) ⁺。

Step 2. prepares 6-(6-aminopyridine-2-base)-N ², N ⁴-bis-((R)-1-cyclopropylethyl)-1,3,5-triazines-2,4-diamines.At N ₂under atmosphere, by N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(6-(4-methoxYbenzylamino) pyridine-2-base)-1,3,5-triazine-2,4-diamines (80mg, 0.17mmol) is dissolved in TFA (0.5mL).Then at room temperature stirred solution mixture overnight, then under reduced pressure concentrates.By standard method Purification, thus the product desired by obtaining.

1HNMR(400MHz,CDCl ₃)δ7.71-7.54(m,2H),6.74-6.69(m,1H),6.24-5.30(m,2H),3.70-3.54(m,2H),1.29-1.25(m,6H),0.95-0.90(m,2H),0.58-0.26(m,8H)。LC-MS:m/z340.2(M+H) ⁺。

The compound of this example of example 12 is prepared by following cited general scheme 12.

Scheme 12

Step 1. prepares 6-(4,6-two ((R)-1-cyclopropylethyl is amino)-1,3,5-triazines-2-base) pyridine-2-alcohol.At room temperature, to N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(6-methoxypyridine-2-base)-1,3,5-triazines-2,4-diamines (50mg, 0.14mmol) and NaI (63mg, 0.42mmol) are in anhydrous CH ₃disposable interpolation TMSCl (46mg, 0.42mmol) in mixture in CN (1mL).At 80 DEG C, stirred reaction mixture 6 hours, then under reduced pressure concentrates.By standard method Purification, thus the product desired by obtaining. ¹HNMR(400MHz,CDCl ₃)δ10.24(brs,1H),7.51(t,J＝8.0Hz,1H),7.29-7.20(m,1H),6.71(d,J＝8.0Hz,1H),5.42-5.31(m,2H),3.63-3.52(m,2H),1.30-1.25(m,6H),0.98-0.87(m,2H),0.62-0.21(m,8H)。LC-MS:m/z341.2(M+H) ⁺。

The compound of this example of example 13 is prepared by following cited general scheme 13.

Scheme 13

Step 1. prepares N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(6-vinyl pyridine-2-base)-1,3,5-triazines-2,4-diamines.At N ₂under atmosphere, to two ((the R)-1-cyclopropylethyl)-1 of 6-(6-chloropyridine-2-base)-N2, N4-, 3,5-triazine-2,4-diamines (200mg, 0.56mmol), 2,4,6-trivinyl-1,3,5,2,4,6-trioxa three boron azacyclohexane (135mg, 0.84mmol) and K ₂cO ₃(154mg, 1.11mmol) Yu diox (2mL) and H ₂disposable interpolation Pd (dppf) Cl in suspension in O (0.8mL) ₂(41mg, 0.06mmol).At 100 DEG C, stirred reaction mixture spends the night, then cool to room temperature going out with shrend.Gained mixture is extracted with EtOAc (20mLx2).With the organic layer that water and salt water washing merge, use anhydrous Na ₂sO ₄drying, and under reduced pressure concentrate.By standard method Purification, thus the product desired by obtaining. ¹HNMR(400MHz,CDCl ₃)δ8.28-8.15(m,1H),7.77(t,J＝7.6Hz,1H),7.58(d,J＝7.6Hz,1H),7.05-6.99(m,1H),6.15(d,J＝17.6Hz,1H),5.42(d,J＝17.6Hz,1H),5.44-5.16(m,2H),3.72-3.52(m,2H),1.35-1.22(m,6H),0.98-0.86(m,2H),0.58-0.21(m,8H)。LC-MS:m/z351.1(M+H) ⁺。

The compound of this example of example 14 is prepared by following cited general scheme 14.

Scheme 14

Step 1. prepares 6-(4,6-two (((R)-1-cyclopropylethyl) is amino)-1,3,5-triazines-2-base) pyridylaldehyde.At-78 DEG C, ozone is sparging into N ², N ⁴1 hour is continued in-bis-((R)-1-cyclopropylethyl)-6-(6-vinyl pyridine-2-base) solution of-1,3,5-triazines-2,4-diamines (120mg, 0.34mmol) in DCM (2mL).Passing through N ₂after purification excessive ozone, at 0 DEG C, by Me ₂s (0.2mL) adds in reaction mixture.Concentrate gained mixture and pass through standard method Purification, thus the product desired by obtaining.LC-MS:m/z353(M+H) ⁺。

Step 2. prepares N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(6-(difluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines.At 0 DEG C, to 6-(4, two ((R)-1-cyclopropylethyl is amino)-1 of 6-, 3,5-triazine-2-base) pyridylaldehyde (50mg, DAST (68mg, 0.43mmol) is dropwise added in solution 0.14mmol) in anhydrous DCM (2mL).At room temperature stirred reaction mixture spends the night.At 0 DEG C, with saturated water-based NaHCO ₃(5mL) cancellation gained mixture lentamente, then uses DCM (40mL) to extract.With the organic layer that water and salt water washing merge, use anhydrous Na ₂sO ₄drying, concentrated, and by standard method purifying, thus the product desired by obtaining. ¹HNMR(400MHz,CDCl ₃)δ8.46(s,1H),7.97(t,J＝7.6Hz,1H),7.77(d,J＝7.6Hz,1H),6.98-6.70(m,1H),5.47-5.21(m,2H),3.67-3.50(m,2H),1.32-1.25(m,6H),0.92-0.86(m,2H),0.58-0.21(m,8H)。LC-MS:m/z375(M+H) ⁺。

Be used in program cited in example 14, use appropriate parent material to prepare following compound.

Compound N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(6-(difluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.48(,1H),8.01(brs.,1H),7.81(d,J＝8.0Hz,1H),6.67-7.01(m,1H),5.02-5.55(m,2H),3.95-4.20(m,2H),2.14(m,8H),1.86-1.98(m,4H),1.77(m,4H)。LC-MS:m/z475(M+H) ⁺。

Compound N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(6-(difluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.64-8.35(m,1H),8.10-7.92(m,1H),7.81(d,J＝7.7Hz,1H),6.82(m,1H),5.98-5.29(m,2H),4.70-4.16(m,2H),3.24-2.92(m,4H),2.79-2.44(m,4H)。LC-MS:m/z419(M+H) ⁺。

The compound of this example of example 15 is prepared by following cited general scheme 15.

Scheme 15

Step 1: preparation 6-(4,6-two ((R)-1-cyclopropylethyl is amino)-1,3,5-triazines-2-base) pyridine carboxylic acid methyl esters.To 6-(6-chloropyridine-2-base)-N ², N ⁴-bis-((R)-1-cyclopropylethyl)-1,3,5-triazine-2,4-diamines (0.25g, dppf (80mg, 0.15mmol), Pd (OAc) is added in mixture 0.7mmol) in MeOH (10mL) ₂(60mg, 27mmol) and Et ₃n (150mg, 1.5mmol).Make reaction mixture degassed and backfill three times with CO and then under CO (60psi) atmosphere, stir 12 hours at 70 DEG C.Gained mixture cool to room temperature is also under reduced pressure concentrated.Filter by EtOAc (100mL) grinding residues.Concentrated filtrate also passes through standard method purifying, thus obtains 6-(4,6-two ((R)-1-cyclopropylethyl is amino)-1,3,5-triazines-2-base) pyridine carboxylic acid methyl esters. ¹HNMR(400MHz,CDCl ₃)δ8.50(m,1H),8.24-8.22(dd,1H),7.99-7.95(t,1H),5.49(m,2H),4.02(s,3H),3.57(m,2H),1.92(s,6H),0.96-0.87(m,2H),0.52-0.26(m,8H)。LC-MS:m/z383(M+H) ⁺。

Step 2: preparation 6-(4,6-two (((R)-1-cyclopropylethyl) is amino)-1,3,5-triazines-2-base) pyridine carboxylic acid.To 6-(4, two ((R)-1-cyclopropylethyl is amino)-1 of 6-, 3,5-triazine-2-base) pyridine carboxylic acid methyl esters (150mg, lithium hydroxide (47mg, 2.0mmol) is added in mixture 0.40mmol) in water (2.0mL) and THF (3.0mL).At room temperature stirred reaction mixture spends the night, and then use HCl (1N) is acidified to pH5-6 and extracts with EtOAc.Use anhydrous Na ₂sO ₄the dry organic layer merged, and under reduced pressure concentrate, thus obtain desired product.LC-MS:m/z367(M-H)-。

Step 3: preparation 6-(4,6-two ((R)-1-cyclopropylethyl is amino)-1,3,5-triazines-2-base) picolinamide.To 6-(4, two (((R)-1-cyclopropylethyl) is amino)-1 of 6-, 3,5-triazine-2-base) pyridine carboxylic acid (120mg, oxalyl chloride (65mg, 0.5mmol) is dropwise added in ice cold mixture 0.32mmol) in dry DCM (5.0mL) and DMF (0.1mL).At room temperature stirred reaction mixture 2 hours, then uses ammonia treatment.At 0 DEG C, stir gained mixture 10 minutes, and then concentrate and pass through standard method purifying, thus obtain 6-(4,6-two ((R)-1-cyclopropylethyl is amino)-1,3,5-triazines-2-base) picolinamide. ¹HNMR(400MHz,CDCl ₃)δ13.59(s,1H),9.30-9.14(m,3H),8.58-8.30(m,3H),7.95(s,1H),3.77-3.54(m,2H),1.29(d,6H),1.02(m,2H),0.50-0.30(m,8H)。LC-MS:m/z368(M+H) ⁺。

Step 4: preparation 6-(4,6-two ((R)-1-cyclopropylethyl is amino)-1,3,5-triazines-2-base) pyridine carbonitrile.To 6-(4, two ((R)-1-cyclopropylethyl is amino)-1 of 6-, 3,5-triazine-2-base) add phosphorus trichloride (0.1mL) in the mixture of picolinamide (36mg, 0.1mmol) in dry pyridine (3.0mL).At room temperature stirred reaction mixture 2 hours, then under reduced pressure concentrates.By standard method Purification, thus obtain 6-(4,6-two ((R)-1-cyclopropylethyl is amino)-1,3,5-triazines-2-base) pyridine carbonitrile. ¹HNMR(400MHz,CDCl ₃)δ8.50-8.48(m,1H),8.24-8.22(t,1H),7.73-7.71(dd,1H),5.46-5.14(m,2H),3.62-3.50(m,2H),1.22-1.18(m,6H),0.89-0.84(m,2H),0.46-0.20(m,8H)。LC-MS:m/z350(M+H) ⁺。

The compound of this example of example 16 is prepared by following cited general scheme 16.

Scheme 16

Step 1: the fluoro-2-hydrazino pyridine of preparation 3,6-bis-.Hydrazine hydrate (0.75g, 15.0mmol) is added in the ice cold solution of 2,3,6-trifluoromethyl pyridine (1.0g, 7.5mmol) in ethanol (10mL).Reaction mixture is warmed up to room temperature and then heats 2 hours under reflux.After by its cool to room temperature, with water (10mL) diluted reaction mixture also with DCM (2x20mL) extraction.Use anhydrous Na ₂sO ₄the dry organic layer merged also under reduced pressure concentrates, thus obtains the fluoro-2-hydrazino pyridine of 3,6-bis-.LC-MS(m/z):146(M+H) ⁺。

Step 2: bromo-3, the 6-difluoro pyridines of preparation 2-.At room temperature, in the stirred solution of the fluoro-2-hydrazino pyridine (1.1g, 7.0mmol) of 3,6-bis-in chloroform (20mL), bromine (1.8g, 11.2mmol) is dropwise added.Reaction mixture is heated to 60 DEG C, continues 1.5 hours.By gained mixture cool to room temperature, with saturated water-based NaHCO ₃cancellation, and extract with methylene dichloride (2x20mL).Use anhydrous Na ₂sO ₄the dry organic layer merged is also concentrated, and by standard method purifying, thus obtain bromo-3, the 6-difluoro pyridines of 2-.LC-MS:m/z194(M+H) ⁺。

Step 3: preparation 3,6-difluoro pyridine methyl-formiate.Dppf (0.3g, 0.56mmol), Pd (OAc) is added in the solution of bromo-3, the 6-difluoro pyridines (0.8g, 4.1mmol) of 2-in MeOH (10mL) ₂(0.1g, 0.45mmol) and Et ₃n (1.6mL, 8.2mmol).Make suspension degassed and backfill three times by CO atmosphere.Under CO atmosphere (60psi), stir gained mixture 12 hours at 70 DEG C, then cool to room temperature also under reduced pressure concentrates.Filter by EtOAc (150mL) grinding residues.Concentrated filtrate also passes through standard method purifying, thus obtains 3,6-difluoro pyridine methyl-formiate.LC-MS:m/z174(M+H) ⁺。

Step 4: preparation N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(3,6-difluoro pyridine-2-base)-1,3,5-triazines-2,4-diamines.To N ¹, N ⁵-bis-(4,4-difiuorocyclohexyl)-biguanides (167mg, 0.50mmol) and 3,6-difluoro pyridine methyl-formiate (130mg, NaOMe (81mg, 1.5mmol) is added in suspension 0.75mmol) in MeOH (5mL).At room temperature stirred reaction mixture spends the night, and is then poured into water, and extracts with EtOAc.Use anhydrous Na ₂sO ₄the dry organic extract merged, and under reduced pressure concentrate.By standard method Purification, thus obtain N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(3,6-difluoro pyridine-2-base)-1,3,5-triazines-2,4-diamines. ¹HNMR(400MHz,CDCl ₃)δ7.67-7.61(m,1H),7.07-7.03(m,1H),5.46-5.10(m,2H),4.08-3.97(m,2H),2.17-2.09(m,8H),1.96-1.83(m,4H),1.73-1.63(m,4H)。LC-MS:m/z461(M+H) ⁺。

The compound of this example of example 17 is prepared by following cited general scheme 17.

Scheme 17

Step 1: preparation N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(the fluoro-6-hydrazino pyridine of 3--2-base)-1,3,5-triazines-2,4-diamines.To N ², N ⁴-bis-(4,4-Difluoro-cyclohexyl)-6-(3,6-difluoro pyridine-2-base)-1,3,5-triazine-2,4-diamines (230mg, hydrazine hydrate (150mg, 3.0mmol) is added in solution 0.50mmol) in THF (20mL).Stirred reaction mixture 2.5 hours at 60 DEG C.After cooling to room temperature, wash with water with DCM diluted reaction mixture.Be separated organic phase, use anhydrous Na ₂sO ₄drying, and under reduced pressure concentrate, thus obtain desired product.LC-MS(m/z):473.2(M+H) ⁺。

Step 2: preparation 6-(6-amino-3-fluorine pyridine-2-base)-N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-1,3,5-triazines-2,4-diamines.To N ², N ⁴-bis-(4,4-Difluoro-cyclohexyl)-6-(the fluoro-6-hydrazino pyridine of 3--2-base)-1,3,5-triazines-2, Raney's nickel (100mg) is added in the solution of 4-diamines (47mg, 0.1mmol) in methyl alcohol (5.0mL).At H ₂under atmosphere, at room temperature, stirred reaction mixture spends the night, and then filters.Concentrated filtrate also passes through standard method purifying, thus the product desired by obtaining. ¹HNMR(400MHz,CDCl ₃)δ7.43-7.39(m,1H),7.03-7.01(m,1H),4.59(s,2H),4.10-4.05(m,2H),2.09-1.93(m,12H),1.76-1.68(m,4H)。LC-MS:m/z458.2(M+H) ⁺。

The compound of this example of example 18 is prepared by following cited general scheme 18.

Scheme 18

Step 1: preparation 6-(4,6-two ((4,4-difiuorocyclohexyl) is amino)-1,3,5-triazines-2-base)-5-fluorine pyridine-2-alcohol.At 100 DEG C, stir N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(3, the 6-difluoro pyridine-2-base) mixture overnight of-1,3,5-triazines-2,4-diamines (100mg, 0.22mmol) in dense HCl (5.0mL).Concentrated gained mixture also passes through standard method purifying, thus the product desired by obtaining. ¹HNMR(400MHz,CDCl ₃)δ9.96(m,1H),7.40-7.27(m,2H),6.73-6.67(m,1H),5.47-5.17(m,2H),4.02-3.92(m,2H),2.11-1.66(m,16H)。LC-MS:m/z459(M+H) ⁺。

The compound of this example of example 19 is prepared by following cited general scheme 19.

Scheme 19

Step 1: preparation N ¹, N ⁵-bis-(3,3-Difluorocyclopentyl)-biguanides.At 160 DEG C, heat 3,3-difluoro cyclopentamine hydrochloride (3g, 19.1mmol) and Dyhard RU 100 receive the mixture 1 hour of (1.7g, 19.1mmol).Products therefrom is dissolved in MeOH, then filters.Concentrated filtrate, thus the product desired by obtaining.LC-MS:m/z310.2(M+H) ⁺。

Step 2: preparation 6-cyclopropyl pyridine ethyl formate.K is added in mixture in toluene (15mL) to 6-Bromopicolinic acid ethyl ester (200mg, 0.87mmol) and cyclopropylboronic acid (149mg, 1.74mmol) ₃pO ₄(369mg, 1.74mmol) and dichloro (diphenylphosphino ferrocene) palladium (11mg, 0.017mmol).At N ₂under atmosphere, at 100 DEG C, stir gained mixture overnight, then cool to room temperature filtering.Concentrated filtrate also passes through standard method purifying, thus the product desired by obtaining.LC-MS:m/z192.1(M+H) ⁺。

Step 3:6-(6-cyclopropyl pyridine-2-base)-N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-1,3,5-triazines-2,4-diamines.To N ¹, N ⁵-bis-(3,3-Difluorocyclopentyl)-biguanides (50mg, 0.16mmol) He in the mixture of 6-cyclopropyl pyridine ethyl formate (62mg, 0.33mmol) in methyl alcohol (5mL) add NaOMe (44mg, 0.80mmol).At room temperature stirred reaction mixture spends the night, and then under reduced pressure concentrates.Resistates is allocated between EtOAc and water.Be separated organic layer, use salt water washing, and use anhydrous Na ₂sO ₄drying, concentrated, and by standard method purifying, thus the product desired by obtaining. ¹HNMR(400MHz,CDCl ₃)δ8.43-8.33(m,1H),8.06-7.99(m,1H),7.25-7.23(d,J＝8Hz,1H),6.66-6.52(m,1H),5.90-5.79(m,1H),4.74-4.45(m,2H),2.66-2.54(m,2H),2.38-2.16(m,8H),1.90-1.88(m,2H),1.42-1.40(m,2H),1.29-1.25(m,1H),1.25-1.01(m,2H)。LC-MS:m/z437.2(M+H) ⁺。

Be used in program cited in example 19, use appropriate parent material to prepare following compound.

Compound 6-(6-cyclopropyl pyridine-2-base)-N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.21(s,1H),7.87(s,1H),7.14(s,1H),5.16(s,1H),4.17-4.01(m,2H),2.43(s,1H),2.16-1.74(m,16H),1.25(s,2H),1.02(s,2H),0.87(m,1H)。LC-MS:m/z465(M+H) ⁺。

Compound N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(6-picoline-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，，CDCl ₃)δ8.181-8.11(m,1H),7.71(s,1H),7.29(s,1H),5.46-5.07(m,2H),4.19-3.99(m,2H),2.69(s,3H),2.17-2.12(m,9H),1.97-1.84(m,4H),1.63-1.55(m,3H)。LC-MS:m/z439(M+H) ⁺。

Example 20 preparation has the symmetry two aliphatics triaizine compounds of chemical formula M.The compound of this example is prepared by following cited general scheme 20.

Scheme 20

Step 1: preparation 6-(trifluoromethyl) pyrazine-2-methyl-formiate.Dppf (0.16g, 0.29mmol), Pd (OAc) is added in the mixture of the chloro-6-of 2-(trifluoromethyl) pyrazine (1g, 5.5mol) in MeOH (5.5mL) ₂(0.1g, 0.44mmol) and Et ₃n (0.12mL, 8.2mmol).Make suspension degassed in a vacuum and then backfill three times with CO.Under CO atmosphere (80psi), at 70 DEG C, stir gained mixture 2 days, until react completely.Mixture cool to room temperature is also under reduced pressure concentrated at 30 DEG C.EtOAc (150mL) is added in resistates.Filtering suspension liquid concentrated filtrate, and by standard method purifying, thus the product desired by obtaining.LC-MS:m/z207(M+H) ⁺。

Step 2: preparation 6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4 (1H, 3H)-diketone.This program is identical with example 1 step 2 mentioned above.LC-MS:m/z260(M+H) ⁺。

Step 3: preparation 2,4-bis-chloro-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazines.To 6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4 (1H, 3H)-diketone (2.8g, 0.011mol) in POCl ₃(30mL) Et is added in the solution in ₃n (0.3mL).Stir the mixture at 100 DEG C 16 hours, until react completely.Concentrated gained mixture also passes through standard method purifying, thus the product desired by obtaining.LC-MS:m/z296(M+H) ⁺。

Step 4: preparation N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines.This program is identical with example 1 step 4.

¹HNMR(400MHz,CDCl ₃)δ9.73(m,1H),9.07(s,1H),5.49-5.15(m,2H),4.17-3.99(m,2H),2.17-1.58(m,16H)。LC-MS:m/z494(M+H) ⁺。

Be used in program cited in above example 20, use appropriate parent material to prepare following compound.

N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.74(m,1H),9.07(d,J＝3.2Hz,1H),5.68-5.37(m,2H),4.71-4.53(m,2H),2.66-2.61(m,2H),2.32-1.85(m,10H)。LC-MS:m/z466(M+H) ⁺。

N ², N ⁴-bis-((R)-3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，CDCl ₃)δ9.77-9.71(m,1H),9.06(s,1H),5.68-5.37(m,2H),5.54-4.72(m,2H),3.12(m,1H),2.64(m,1H),2.32(m,3H),2.17-2.13(m,6H)。LC-MS:m/z466(M+H) ⁺。

N ², N ⁴-bis-((S)-3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.74(m,1H),9.07(d,J＝3.6Hz,1H),5.70-5.38(m,2H),4.83-4.38(m,2H),2.80-1.76(m,12H)。LC-MS:m/z466(M+H) ⁺。

N ²-((R)-3,3-Difluorocyclopentyl)-N ⁴-((S)-3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.74(m,1H),9.07(d,J＝3.3Hz,1H),5.68-5.37(m,2H),4.81-4.40(m,2H),2.79-1.73(m,12H)。LC-MS:m/z466(M+H) ⁺。

N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.74(m,1H),9.08(s,1H),5.84-5.49(m,2H),4.53-4.37(m,2H),3.12-3.02(m,4H),2.70-2.57(m,4H)。LC-MS:m/z438(M+H) ⁺。

6-(6-(trifluoromethyl) pyrazine-2-base)-N ², N ⁴-bis-((R)-1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

1HNMR(400MHz,CD ₃OD)δ9.80(s,1H),9.17(s,1H),5.22-4.88(m,2H),1.43-1.38(m,6H)。LC-MS:m/z450.1(M+H) ⁺。

N ², N ⁴-bis-((S)-1,1,1-trifluoro fourth-2-base)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆)δ9.86-9.69(m,1H),9.37(d,1H),8.68-8.28(m,2H),5.04-4.71(m,2H),1.81-1.68(m,4H),0.97-0.90,6H)。LC-MS:m/z478.1(M+H) ⁺。

Example 21 preparation has the symmetry two aliphatics triaizine compounds of chemical formula N.The compound of this example is prepared by following cited general scheme 21.

Scheme 21

Step 1: preparation 1-(6-chloropyrazine-2-base) ethanol.At-5 DEG C, in the solution of 6-formyl radical pyrazine-2-methyl-formiate (590mg, 4.15mmol) in anhydrous THF (5mL), dropwise add CH ₃mgB (2.1mL, 6.2mmol).At room temperature stirred reaction mixture 1 hour, then at 0 DEG C with saturated water-based NH ₄cl cancellation also extracts with DCM (3x10mL).With the organic layer that salt water washing merges, use anhydrous Na ₂sO ₄drying is also concentrated, thus the product desired by obtaining.LC-MS:m/z159.0(M+H) ⁺。

Step 2: preparation 1-(6-chloropyrazine-2-base) ethyl ketone.At room temperature, in 1-(6-chloropyrazine-2-base) solution of ethanol (370mg, 2.3mmol) in DCM (5mL), DMP (1.5g, 3.5mmol) is added.At room temperature stirred reaction mixture 3 hours, then filters.Concentrated filtrate also passes through standard method purifying, thus the product desired by obtaining. ¹HNMR(400MHz,CDCl ₃)δ9.12(s,1H),8.78(s,1H),2.72(s,3H)。LC-MS:m/z157.1(M+H) ⁺。

Step 3: preparation 6-ethanoyl pyrazine-2-methyl-formiate.Dppf (94.0mg, 0.17mmol), Pd (OAc) is added in 1-(6-chloropyrazine-2-base) solution of ethyl ketone (260.0mg, 1.7mmol) in MeOH (3mL) ₂(20mg, 0.1mmol) and Et ₃n (0.4mL, 2.6mmol).At 60 DEG C, under CO (60psi) atmosphere, stir the mixture and spend the night.Gained mixture cool to room temperature is filtered.Concentrated filtrate also passes through standard method purifying, thus the product desired by obtaining.LC-MS:m/z181.0(M+H) ⁺。

Step 4: preparation 6-(1,1-bis-fluoro ethyl) pyrazine-2-methyl-formiate.At 0 DEG C, in the solution of 6-ethanoyl pyrazine-2-methyl-formiate (240mg, 1.3mmol) in anhydrous DCM (3mL), add DAST (0.86mL, 6.5mmol) lentamente.At room temperature stirred reaction mixture 3 hours, then at 0 DEG C with cold saturated water-based NaHCO ₃cancellation also extracts with DCM (3x10mL).Use anhydrous Na ₂sO ₄the dry organic layer merged is also concentrated, thus the product desired by obtaining.LC-MS:m/z203.1(M+H) ⁺。

Step 5: preparation 6-(6-(1,1-bis-fluoro ethyl) pyrazine-2-base)-1,3,5-triazines-2,4 (1H, 3H)-diketone.This program is identical with example 1 step 2 mentioned above.LC-MS:m/z256.1(M+H) ⁺。

Step 6: preparation 2,4-bis-chloro-6-(6-(1,1-bis-fluoro ethyl) pyrazine-2-base)-1,3,5-triazines.This program is identical with example 1 step 3 mentioned above.LC-MS:m/z292.0(M+H) ⁺。

Step 7: preparation N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(6-(1,1-bis-fluoro ethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines.This program is identical with example 1 step 4 mentioned above.

¹HNMR(400MHz,CDCl ₃)δ9.59(m,1H),9.05(s,1H),5.46(s,1H),5.06(m,1H),4.07(m,2H),2.17(s,3H),2.09(s,4H),1.93(m,4H),1.79-1.55(m,8H)。LC-MS:m/z490.2(M+H) ⁺。

Be used in program cited in example 21, use appropriate parent material to prepare following compound.

N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-6-(6-(1,1-bis-fluoro ethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.60(m,1H),9.04(d,J＝6.0Hz,1H),5.66-5.34(m,2H),4.70-4.52(m,2H),2.65-2.60(m,2H),2.32-2.08(m,10H),1.90-1.74(m,3H)。LC-MS:m/z462.2(M+H) ⁺。

N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(6-(1,1-bis-fluoro ethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.62-9.57(m,1H),9.05(s,1H),5.75-5.44(m,2H),4.51-4.37(m,2H),3.07(s,4H),2.65-2.61(m,4H),2.17-2.08(m,3H)。LC-MS:m/z434.2(M+H) ⁺。

Example 22 preparation has the symmetry two aliphatics triaizine compounds of chemical formula O.The compound of this example is prepared by following cited general scheme 22.

Scheme 22

Step 1: preparation 2-(methoxycarbonyl) pyrazine 1-oxide compound.3-chloroperoxybenzoic acid (25.0g, 140mmol) is added in the solution of pyrazine-2-methyl-formiate (10.0g, 70mmol) in 1,2-ethylene dichloride (120mL).At 60 DEG C, stirred reaction mixture spends the night.Gained mixture cool to room temperature is filtered.Use anhydrous K ₂cO ₃dried filtrate also under reduced pressure concentrates.Also filter and drying with hexanes trituration resistates, thus obtain 2-(methoxycarbonyl) pyrazine 1-oxide compound.LC-MS:m/z155.0(M+H) ⁺。

Step 2: preparation 6-chloropyrazine-2-methyl-formiate.2-(methoxycarbonyl) pyrazine 1-oxide compound (4.8g, 30mmol) is stirred in SOCl at 85 DEG C ₂(50mL) mixture overnight in.Mixture cool to room temperature is also under reduced pressure concentrated.By saturated water-based NaHCO ₃in and resistates and with DCM (3x20mL) extraction.With the organic layer that salt water washing merges, use anhydrous Na ₂sO ₄drying is also concentrated, and by standard method purifying, thus obtain 6-chloropyrazine-2-methyl-formiate. ¹HNMR(600MHz,CDCl ₃)δ8.59(s,1H),8.53(s,1H),4.84(s,2H),3.01(s,1H)。LC-MS:m/z173.0(M+H) ⁺。

Step 3: preparation (6-chlorine pyrrole base) 2-yl) methyl alcohol.At 0 DEG C, in the solution of 6-chloropyrazine-2-methyl-formiate (2.0g, 11.6mmol) in water (20mL), add NaBH by part ₄(2.3g, 58.0mmol).Make reaction mixture be warmed up to room temperature and stir 30 minutes, then adding saturated water-based K ₂cO ₃(40mL) with EtOH (20mL).Stir gained mixture again 1 hour and extract with EA (2x20mL).Use anhydrous Na ₂sO ₄the dry organic layer merged is also concentrated, and by standard method purifying, thus obtain (6-chloropyrazine-2-base) methyl alcohol.LC-MS:m/z145.0(M+H) ⁺。

Step 4: preparation 6-chloropyrazine-2-formaldehyde.Dai Si-Martin reagent (2.6g, 6.3mmol) is added in (6-chloropyrazine-2-base) methyl alcohol (600mg, 4.2mmol) solution in DCM (10mL).At room temperature stirred reaction mixture 3 hours, and then filter.Concentrated filtrate also passes through standard method purifying, thus obtains 6-chloropyrazine-2-formaldehyde.LC-MS:m/z143.0(M+H) ⁺。

Step 5: preparation 6-formyl radical pyrazine-2-methyl-formiate.Dppf (388mg, 0.7mmol), Pd (OAc) is added in the mixture of 6-chloropyrazine-2-formaldehyde (1.0g, 7.0mmol) in MeOH (10mL) ₂(90mg, 0.4mmol) and Et ₃n (1.5mL, 10.5mmol).Under CO atmosphere (60psi), at 60 DEG C, stirred suspension spends the night.Gained mixture cool to room temperature is filtered.Concentrated filtrate also passes through standard method purifying, thus obtains 6-formyl radical pyrazine-2-methyl-formiate.LC-MS:m/z167.0(M+H) ⁺。

Step 6: preparation 6-(difluoromethyl) pyrazine-2-methyl-formiate.At 0 DEG C, in the mixture of 6-formyl radical pyrazine-2-methyl-formiate (4.1g, 24.7mmol) in anhydrous DCM (40mL), add DAST (16.3mL, 123.5mmol) lentamente.At room temperature stirred reaction mixture 3 hours, then at 0 DEG C with cold saturated water-based NaHCO ₃cancellation also extracts with DCM (2x20mL).Use anhydrous Na ₂sO ₄the dry organic layer merged is also concentrated, thus the product desired by obtaining.LC-MS:m/z189.0(M+H) ⁺。

Step 7: preparation 6-(6-(difluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4 (1H, 3H)-diketone.In flame-dried three neck round-bottomed flasks, add biuret (659mg, 6.4mmol) and 6-(difluoromethyl) pyrazine-2-methyl-formiate (1.0g, 5.3mmol), then add EtOH (12mL).Make mixture degassed and use N ₂backfill three times.Stir the mixture at 25 DEG C 20 minutes, and be then heated to 50 DEG C.Then in above mixture, HC (OMe) is added ₃(0.7mL, 6.4mmol) and TFA (0.04mL, 0.53mmol).Stir the mixture (light yellow slurry) 30 minutes at this temperature, then dropwise adds the solution of NaOEt in EtOH (20%wt, 7.2g, 21.2mmol).Heat gained mixture 2 hours under reflux, then cool to room temperature also under reduced pressure concentrates.Process resistates with water (10mL) and again concentrate to remove residual ethanol.Final residual thing is suspended in water (30mL), is cooled to 10 DEG C when acidity is adjusted to pH=1 by interpolation 6NHCl (being settled out solid) of slowing down, and then stirs 2 hours.Filtering mixt use HCl (pH=1) washing leaching cake.Collect solid and be suspended in DCM (30mL).At room temperature stirred suspension 2 hours and and then filter.Collect filter cake and drying, thus the product desired by obtaining.LC-MS:m/z242.0(M+H) ⁺。

Step 8: preparation 2,4-bis-chloro-6-(6-(difluoromethyl) pyrazine-2-base)-1,3,5-triazines.This program is identical with example 1 step 3 mentioned above.LC-MS:m/z2782.0(M+H) ⁺。

Step 8: preparation N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(6-(difluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines.This program is identical with example 1 step 4 mentioned above.

¹HNMR(400MHz，CDCl ₃)δ9.69(m,1H),9.07(s,1H),6.89(m,1H),5.53-5.12(m,2H),4.08(m,2H),2.23-1.67(m,16H)。LC-MS:m/z476.2(M+H) ⁺。

Be used in program cited in example 22, use appropriate parent material to prepare following compound.

N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-6-(6-(difluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.73-9.67(m,1H),9.07(s,1H),7.03-6.76(m,1H),5.63-5.35(m,2H),4.73-4.55(m,2H),2.66-2.61(m,2H),2.32(s,4H),2.13-1.57(m,6H)。LC-MS:m/z448.2(M+H) ⁺。

N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(6-(difluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.72-9.67(m,1H),9.07(s,1H),6.85(d,1H),5.76-5.48(m,2H),4.54-4.38(m,2H),3.08(s,4H),2.66-2.61(m,4H)。LC-MS:m/z420.1(M+H) ⁺。

N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(4-(difluoromethyl) pyrimidine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.17(d,J＝4.9Hz,1H),7.77(d,J＝4.9Hz,1H),6.77(m,1H),5.76(m,2H),4.55(m,2H),3.07m,4H),2.61(m,4H)。LC-MS:m/z420(M+H) ⁺。

N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-6-(4-(difluoromethyl) pyrimidine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆)δ9.19(m,1H),8.16(m,1H),7.88(m,1H),7.04(m,1H),4.47(m,2H),2.63(m,1H),2.25(m,9H),1.83(m,2H)。LC-MS:m/z448(M+H) ⁺。

N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(4-(difluoromethyl) pyrimidine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ(m,1H),7.79-7.78(m,1H),6.91-6.64(m,1H),5.72-5.20(m,2H),4.26-4.02(m,2H),2.13-2.10(m,8H),1.98-1.87(m,4H),1.76-1.73(m,4H)。LC-MS:m/z476(M+H) ⁺。

The compound of this example of example 23 is prepared by following cited general scheme 23.

Scheme 23

Step 1: preparation 6-(6-chloropyrazine-2-base)-N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-1,3,5-triazines-2,4-diamines.To 6-chloropyrazine-2-methyl-formiate (300mg, 1.74mmol) and N ¹, N ⁵meONa (340mg, 6.28mmol) is added in the mixture of-two-(4,4-difluorocyclohex amine)-biguanides (700mg, 2.10mmol) in MeOH (8mL).At room temperature stirred reaction mixture spends the night, and is then allocated in EtOAc (30mL) and H ₂between O (30mL).Be separated organic layer, with salt solution (30mL) washing, use anhydrous Na ₂sO ₄drying is also concentrated, and by standard method purifying, thus the product desired by obtaining. ¹HNMR(400MHz,DMSO-d ₆)δ9.48-9.32(m,1H),8.93(d,J＝8Hz,1H),7.92-7.59(m,2H),4.15-3.95(m,2H),2.08-1.60(m,16H)。LC-MS:m/z460(M+H) ⁺。

Be used in program cited in example 23, use appropriate parent material to prepare following compound.

6-(6-chloropyrazine-2-base)-N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.45(d,1H),8.72(s,1H),5.65(d,2H),4.53-4.37(m,2H),3.07-2.60(m,8H)。LC-MS:m/z432(M+H) ⁺。

6-(6-chloropyrazine-2-base)-N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.45(d,1H),8.71(s,1H),5.69-5.36(m,2H),4.70-4.52(m,2H),2.65-2.05(m,12H)。LC-MS:m/z404(M+H) ⁺。

Two (1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2, the 4-diamines of 6-(6-chloropyrazine-2-base)-N2, N4-

¹HNMR(400MHz,CDCl ₃)δ9.42(d,1H),8.66(s,1H),5.61-5.24(m,2H),5.01-4.78(m,2H),1.41-1.34(m,6H)。LC-MS:m/z416(M+H) ⁺。

Example 24 preparation has the symmetry two aliphatics triaizine compounds of chemical formula P.The compound of this example is prepared by following cited general scheme 24.

Scheme 24

Step 1: preparation 2-(trifluoromethyl) pyrimidine-4-methyl-formiate.Dppf (3.0g, 5.5mmol), Pd (OAc) is added in the solution of the chloro-2-of 4-(trifluoromethyl) pyrimidine (10g, 54.9mmol) in MeOH (60mL) ₂(630mg, 2.8mmol) and Et ₃n (11.4mL, 41.2mmol).Stir the mixture at 60 DEG C under CO atmosphere (60psi) and spend the night.Gained mixture cool to room temperature is filtered.Concentrated filtrate also passes through standard method purifying, thus the product desired by obtaining.LC-MS:m/z207.0(M+H) ⁺。

Step 2: preparation 6-(2-(trifluoromethyl) pyrimidine-4-yl)-1,3,5-triazines-2,4 (1H, 3H)-diketone.This program is identical with example 1 step 2 mentioned above.LC-MS:m/z260.0(M+H) ⁺。

Step 3: preparation 2,4-bis-chloro-6-(2-(trifluoromethyl) pyrimidine-4-yl)-1,3,5-triazines.This program is identical with example 1 step 3 mentioned above.LC-MS:m/z296.0(M+H) ⁺。

Step 4: preparation N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(2-(trifluoromethyl) pyrimidine-4-yl)-1,3,5-triazines-2,4-diamines.This program is identical with example 1 step 4 mentioned above.

¹HNMR(4400MHz,CDCl ₃)δ9.08(m,1H),8.42(m,1H),5.54-5.19(m,2H),4.16-3.99(m,2H),2.29-1.73(m,16H)。LC-MS:m/z494.2(M+H) ⁺。

Be used in program cited in example 24, use appropriate parent material to prepare following compound.

N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-6-(2-(trifluoromethyl) pyrimidine-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.06-9.10(m,1H),8.39-8.45(m,1H),5.66-5.68(d,J＝8.0Hz,2H),4.52-4.70(m,2H),2.60-2.65(m,2H),2.13-2.32(m,8H),1.67-1.87(m,2H)。LC-MS:m/z466.2(M+H) ⁺。

N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(2-(trifluoromethyl) pyrimidine-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.10(m,1H),8.51-8.37(m,1H),5.93-5.48(m,2H),4.44(m,2H),3.07(m,4H),2.75-2.49(m,4H)。LC-MS:m/z438.1(M+H) ⁺。

6-(2-(trifluoromethyl) pyrimidine-4-yl)-N ², N ⁴-bis-((R)-1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.11(m,1H),8.45(t,J＝5.6Hz,1H),5.74-5.32(m,2H),5.16-4.79(m,2H),1.43(m,6H)。LC-MS:m/z450.1(M+H) ⁺。

N ², N ⁴-bis-((S)-1,1,1-trifluoro fourth-2-base)-6-(2-(trifluoromethyl) pyrimidine-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.11(m,1H),8.46(d,J＝5.0Hz,1H),5.78-5.22(m,2H),4.97-4.63(m,2H),2.12-1.90(m,2H),1.61-1.69(m,2H),1.05(t,J＝7.5Hz,6H)。LC-MS:m/z478.1(M+H) ⁺。

N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(4-(trifluoromethyl) pyrimidine-2-base)-1,3,5-triazines-2,4-diamines.

¹HNMR(400MHz,CDCl ₃)δ9.22(d,J＝4.9Hz,1H),7.77(d,J＝4.9Hz,1H),5.64-5.16(m,2H),4.21-4.01(m,2H),2.28-1.52(m,16H)。LC-MS:m/z494.2(M+H) ⁺。

N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-6-(4-(trifluoromethyl) pyrimidine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.22(d,1H),7.77(d,1H),5.87(d,2H),4.58-4.53(m,2H),2.69-2.56(m,2H),2.31-2.29(m,4H),2.17-2.08(m,4H),1.87-1.68(m,2H)。LC-MS:m/z466.2(M+H) ⁺。

N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(4-(trifluoromethyl) pyrimidine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆)δ9.34(m,1H),8.64-8.00(m,3H),4.46-4.10(m,2H),3.07-2.83(m,4H),2.74-2.62(m,4H)。LC-MS:m/z438.1(M+H) ⁺。

N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(4-(trifluoromethyl) pyrimidine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.19(s,0.6H),7.74-7.73(m,0.6H),5.63-5.43(m,2H),3.61-3.58(m,2H),1.27-1.26(m,8H),0.90(m,2H),0.50-0.26(m,8H)。LC-MS:m/z394(M+H) ⁺。

N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(4-(2-methoxy ethyl) pyrimidine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，CDCl ₃)δ8.83-8.82(m,1H),7.40-7.39(m,1H),5.60-5.58(m,2H),4.26-4.01(m,2H),3.81-3.77(t,J＝8Hz,2H),3.35(s,3H),3.21-3.18(m,J＝8Hz,2H),2.11-2.05(m,8H),1.94-1.86(m,4H),1.74-1.69(m,4H)。LC-MS:m/z484(M+H) ⁺。

The compound of this example of example 25 is prepared by following cited general scheme 25.

Scheme 25

Step 1: preparation 2-(trifluoromethyl) 4-thiazolecarboxylic acid ethyl ester.Lloyd's's reagent (3.06g, 7.56mmol) is added in the solution of 2,2,2-trifluoroacetamide (1.42g, 12.6mmol) in dry THF (60mL).Reacting by heating mixture 18 hours and then cooling under reflux, then adds the bromo-ethyl 2-oxopropanoate (1.6mL, 12.6mmol) of 3-.Mixture is refluxed 18 hours again and then cool to room temperature.Gained mixture is allocated between EtOAc and water.Be separated organic layer, use anhydrous Na ₂sO ₄drying is also concentrated, and by standard method purifying, thus obtain 2-(trifluoromethyl) 4-thiazolecarboxylic acid ethyl ester. ¹HNMR(400MH _Z,CDCl ₃)δ8.42(s,1H)4.47( _q,J＝7.1Hz,2H),1.45(t,J＝7.2Hz,3H)。LC-MS:m/z226(M+H) ⁺。

Step 2: preparation N ¹, N ⁵-bis-(3,3-difluoro cyclobutyl)-biguanides.Vigorous stirring 3,3-difluoro ring butylamine hydrochloride (3.024g, 0.021mol) and NaN (CN) at 160 DEG C ₂the mixture of (890mg, 0.01mol) 2 hours, then cool to room temperature.Gained mixture to be dissolved in MeOH and to filter.Concentrated filtrate, thus the product desired by obtaining.LC-MS:m/z282(M+H) ⁺。

Step 3: preparation N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(4-(trifluoromethyl) thiazol-2-yl)-1,3,5-triazines-2,4-diamines.To N ¹, N ⁵-bis-(3,3-difluoro cyclobutyl)-biguanides (60mg, 2-(trifluoromethyl) 4-thiazolecarboxylic acid ethyl ester (58.5mg is added in mixture 0.22mmol) in MeOH (5mL), 0.26mmol) with NaOMe (23.7mg, 0.44mmol).Then at room temperature stirred reaction mixture 48 hours, is then allocated in EtOAc and H ₂between O.Be separated organic layer, use salt water washing, use anhydrous Na ₂sO ₄drying, and concentrate and pass through standard method purifying, thus obtain N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(4-(trifluoromethyl) thiazol-2-yl)-1,3,5-triazines-2,4-diamines.

¹HNMR(400MHz,CDCl ₃)δ7.83(d,J＝5.2Hz,1H),7.01-6.74(m,1H),5.74-5.43(m,2H),4.45-4.32(m,2H),3.11-3.04(m,4H),2.63-2.48(m,4H)。LC-MS:m/z443(M+H) ⁺。

Be used in program cited in example 25, use appropriate parent material to prepare following compound.

N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(4-(trifluoromethyl) thiazol-2-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ7.84(s,1H),5.42-5.07(m,2H),3.89-3.79(m,2H),2.06-1.79(m,13H),1.67-1.57(m,3H)。LC-MS:m/z499(M+H) ⁺。

N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-6-(4-(trifluoromethyl) thiazol-2-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ7.91(d,J＝4Hz,1H),5.66-5.34(m,2H),4.64-4.51(m,2H),2.69-2.59(m,2H),2.31-2.04(m,8H),1.86-1.80(m,2H)。LC-MS:m/z471(M+H) ⁺。

6-(4-(trifluoromethyl) thiazol-2-yl)-N ², N ⁴-bis-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ7.94(s,1H),5.81-5.31(m,2H),5.01-4.83(m,2H),1.47-1.39(m,6H)。LC-MS:m/z455(M+H) ⁺。

N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(2-(trifluoromethyl) thiazole-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，CDCl ₃)δ8.48(m,1H),5.41-5.09(m,2H),4.16-3.99(m,2H),2.28-1.66(m,16H)。LC-MS:m/z499(M+H) ⁺。

N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(2-(trifluoromethyl) thiazole-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.50(m,1H),6.73-6.38(m,2H),4.46-4.36(m,2H),3.06(s,4H),2.61(s,4H)。LC-MS:m/z443(M+H) ⁺。

6-(2-(trifluoromethyl) thiazole-4-yl)-N ², N ⁴-bis-((R)-1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，CDCl ₃)δ8.49(d,1H),5.57-5.12(m,2H),4.97-4.49(m,2H),1.36-1.25(m,6H)。LC-MS:m/z455(M+H) ⁺。

N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(2-Jia Ji oxazole-4-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.11(s,1H),5.27-4.92(m,2H),4.02-3.81(m,2H),2.47(s,3H),2.03-1.79(m,12H),1.63-1.54(m,4H)。LC-MS:m/z429(M+H) ⁺。

N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(2-Jia Ji oxazole-4-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.24(m,1H),5.66(m,2H),4.31(s,2H),3.13-2.95(m,4H),2.60(m,7H)。LC-MS:m/z373(M+H) ⁺。

N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(5-methyl-isoxazole-3-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ6.52-6.48(m,1H),5.44-5.09(m,2H),4.15-3.96(m,2H),2.49(s,3H),2.11-1.89(m,13H),1.70-1.63(m,3H)。LC-MS:m/z429(M+H) ⁺。

N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(5-methyl-isoxazole-3-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆)δ6.51(m,1H),5.86-5.33(m,2H),4.65-4.13(m,2H),3.04(dd,J＝6.2,5.4Hz,4H),2.70-2.55(m,4H),2.50(s,3H)。LC-MS:m/z373(M+H) ⁺。

The compound of this example of example 26 is prepared by following cited general scheme 26.

Scheme 26

Step 1: preparation 2-bromo thiazole-4-ethyl formate.Isopentyl nitrite (24.5g, 209mmol) and CuBr is added in the solution of thiazolamine-4-ethyl formate (15.0g, 87.1mmol) in MeCN (100mL) ₂(27.5g, 122mmol).Stir the mixture at 70 DEG C and spend the night, then cool to room temperature, with water (200mL) dilution, and extract with EtOAc (2x200mL).Use anhydrous Na ₂sO ₄the dry organic layer merged is also concentrated, and by standard method purifying, thus obtain 2-bromo thiazole-4-ethyl formate.LC-MS:m/z236(M+H) ⁺。

Step 2: preparation 2-bromo thiazole-4-formic acid.To 2-bromo thiazole-4-ethyl formate (18.0g, 76.0mmol) in THF (90mL) and H ₂liOH (4.8g, 114mmol) is added in solution in O (90mL).At room temperature stir the mixture 3 hours and extract with EtOAc (2x150mL).Separate aqueous layer, with saturated water-based NH ₄cl is adjusted to pH2-3, and filters.Collect solid and drying under a high vacuum, thus obtain 2-bromo thiazole-4-formic acid.LC-MS:m/z206(M-H) ^-。

Step 3: preparation 2-bromo-N-methoxy-. N-methyl thiazole-4-carboxamide.To 2-bromo thiazole-4-formic acid (11.4g, N is added in solution 55.0mmol) in DCM (100mL), O-dimethyl hydroxylamine (6.9g, 71.0mmol), HATU (27.0g, 71.0mmol) and DIPEA (21.2g, 164.0mmol).At room temperature stir the mixture and spend the night, then use water (200mL) cancellation and extract with DCM (2x200mL).Use anhydrous Na ₂sO ₄the dry organic layer merged, and concentrate and pass through standard method purifying, thus obtain 2-bromo-N-methoxy-. N-methyl thiazole-4-carboxamide.LC-MS:m/z251(M+H) ⁺。

Step 4: preparation 1-(2-bromo thiazole-4-base) ethyl ketone.At N ₂under atmosphere, at 0 DEG C, to 2-bromo-N-methoxy-. N-methyl thiazole-4-carboxamide (6.8g, MeMgBr (9.9mL is dropwise added lentamente in solution 27.0mmol) in THF (60mL), 29.7mmol, 3M, in THF).Make mixture be warmed up to room temperature lentamente and stir 30 minutes at this temperature.With saturated water-based NH ₄cl (100mL) cancellation reaction mixture also extracts with EtOAc (2x100mL).Use anhydrous Na ₂sO ₄the dry organic layer merged is also concentrated, and by standard method purifying, thus obtain 1-(2-bromo thiazole-4-base) ethyl ketone.LC-MS:m/z206(M+H) ⁺。

Step 5: preparation 4-acetylthiazole-2-methyl-formiate.Pd (OAc) is added in 1-(2-bromo thiazole-4-base) solution of ethyl ketone (340mg, 1.65mmol) in MeOH (10mL) ₂(20.0mg, 0.08mmol), dppf (95.0mg, 0.16mmol) and Et ₃n (250mg, 2.5mmol).At 60 DEG C, under CO atmosphere (0.4mPa), heated mixt spends the night.Gained mixture cool to room temperature is filtered.Concentrated filtrate also passes through standard method Purification, thus obtains 4-acetylthiazole-2-methyl-formiate.LC-MS:m/z186(M+H) ⁺。

Step 6: preparation 4-(1,1-bis-fluoro ethyl) thiazole-2-methyl-formiate.At 0 DEG C, in the solution of 4-acetylthiazole-2-manthanoate (200mg, 1.07mmol) in DCM (10mL), dropwise add DAST (1.64g, 10.2mmol) lentamente.Then mixture is warmed up to room temperature and at room temperature stirs and spend the night.With saturated water-based NaHCO ₃(20mL) quench mix also extracts with DCM (2x20mL) lentamente.Use anhydrous Na ₂sO ₄the dry organic layer merged, and concentrate and pass through standard method purifying, thus obtain 4-(1,1-bis-fluoro ethyl) thiazole-2-methyl-formiate.LC-MS:m/z208(M+H) ⁺。

Step 7: preparation N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(4-(1,1-bis-fluoro ethyl) thiazol-2-yl)-1,3,5-triazines-2,4-diamines.To N ¹, N ⁵-bis-(3,3-difluoro cyclobutyl)-biguanides (60mg, 4-(1 is added in mixture 0.22mmol) in MeOH (5mL), 1-bis-fluoro ethyl) thiazole-2-ethyl formate (50mg, 0.26mmol) with NaOMe (23.7mg, 0.44mmol).Then at room temperature stirred reaction mixture 48 hours, and be then allocated in EtOAc and H ₂between O.Be separated organic layer, use salt water washing, use anhydrous Na ₂sO ₄drying, concentrates and passes through standard method purifying, thus obtaining N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(4-(1,1-bis-fluoro ethyl) thiazol-2-yl)-1,3,5-triazines-2,4-diamines.

¹HNMR(400MHz,CDCl ₃)δ7.75(d,J＝3.7Hz,1H),5.30(m,2H),4.05(d,J＝49.4Hz,2H),2.30-2.01(m,11H),1.94(d,J＝9.2Hz,4H),1.81-1.68(m,3H)。LC-MS:m/z495(M+H) ⁺。

Be used in program cited in example 26, use appropriate parent material to prepare following compound.

N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(2-(1,1-bis-fluoro ethyl) thiazole-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆)δ8.59(d,1H),7.52(m,2H),4.09(m,2H),3.25(m,3H),2.34(m,1H),1.58(m,16H)。LC-MS:m/z494(M+H) ⁺。

N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-6-(2-(1,1-bis-fluoro ethyl) thiazole-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.44-8.36(m,1H),5.54-5.24(m,2H),4.67-4.53(m,2H),2.63-2.60(m,2H),2.31-2.02(m,11H),1.82-1.75(m,2H)。LC-MS:m/z467(M+H) ⁺。

N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(2-(1,1-bis-fluoro ethyl) thiazole-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.45-8.36(m,1H),5.71-5.36(m,2H),4.47-4.35(m,2H),3.05(s,4H),3.61(s,4H),2.24-2.03(m,3H)。LC-MS:m/z439(M+H) ⁺。

The compound of this example of example 27 is prepared by following cited general scheme 27.

Scheme 27

Step 1: preparation 2-bromo thiazole-4-formaldehyde.At-78 DEG C, in the mixture of 2-bromo-N-methoxy-. N-methyl thiazole-4-carboxamide (10g, 0.04mol) in THF (80mL), add DIBAL-H (7.35g, 0.052mol) lentamente.Stirred reaction mixture 2 hours at-78 DEG C, then regulates pH to 5-6.Mixture is allocated in EtOAc (80mL) and H ₂between O (60mL).Be separated organic layer, with salt solution (40mL) washing, use anhydrous Na ₂sO ₄drying, concentrates and passes through standard method purifying, thus the product desired by obtaining.LC-MS:m/z192(M+H) ⁺。

Step 2: preparation 2-bromo-4-(difluoromethyl) thiazole.At 0 DEG C, in the mixture of 2-bromo thiazole-4-formaldehyde (0.764g, 0.004mol) in DCM (7mL), dropwise add DAST (3.22g, 0.02mol).Stir the mixture at 25 DEG C 48 hours, then with saturated water-based NaHCO ₃cancellation also regulates pH to 8-10.Gained mixture is extracted with DCM (2x40mL).With the organic layer that salt solution (30mL) washing merges, use anhydrous Na ₂sO ₄drying is also concentrated, and by standard method purifying, thus the product desired by obtaining.LC-MS:m/z214(M+H) ⁺。

Step 3: preparation 4-(difluoromethyl) thiazole-2-methyl-formiate.At 60 DEG C, under CO atmosphere, stir 2-bromo-4-(difluoromethyl) thiazole (0.6g, 2.82mmol), dppf (0.14g, 0.28mmol), Et ₃n (0.43g, 4.23mmol) and Pd (OAc) ₂(0.13g, 0.56mmol) mixture in MeOH (10mL) 16 hours.Filter gained mixture, resistates is also allocated in DCM (30mL) and H by concentrated filtrate ₂between O.Be separated organic layer, with salt solution (30mL) washing, use anhydrous Na ₂sO ₄drying is also concentrated, and by standard method purifying, thus the product desired by obtaining.LC-MS:m/z194(M+H) ⁺。

Step 4: preparation N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(4-(difluoromethyl) thiazol-2-yl)-1,3,5-triazines-2,4-diamines.To N ¹, N ⁵-bis-(3,3-difluoro cyclobutyl)-biguanides (45mg, 13.3mmol) with 4-(difluoromethyl) thiazole-2-methyl-formiate (40mg, NaOMe (20mg, 37.0mmol) is added in suspension 20.7mmol) in MeOH (10mL).At room temperature stirred reaction mixture spends the night, and is then poured into water, and extracts with EtOAc.Use anhydrous Na ₂sO ₄the dry organic layer merged, concentrates and passes through standard method purifying, thus the product desired by obtaining.

¹HNMR(400MHz,CDCl ₃)δ7.75(s,1H),6.94-6.67(t,1H),5.40-5.08(m,2H),4.04-3.90(m,2H),2.05-1.84(m,8H),1.79-1.64(m,4H),1.62-1.54(m,4H)。LC-MS:m/z481(M+H) ⁺。

Be used in program cited in example 27, use appropriate parent material to prepare following compound.

N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(4-(difluoromethyl) thiazol-2-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ7.84(d,J＝8Hz,1H),7.02-6.74(m,1H),5.74-5.44(m,2H),4.46-4.36(m,2H),3.06(d,J＝8Hz,4H),2.63-2.59(m,4H)。LC-MS:m/z425(M+H) ⁺。

N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-6-(4-(difluoromethyl) thiazol-2-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，，CDCl ₃)δ7.84(s,1H),7.04-6.76(m,1H),5.65-5.36(m,2H),4.66-4.55(m,2H),2.66-1.85(m,12H)。LC-MS:m/z453(M+H) ⁺。

The compound of this example of example 28 is prepared by following cited general scheme 28.

Scheme 28

Step 1: preparation 5-phenyl-1,3,4-oxa-thiazole-2-ketone.At N ₂under atmosphere, in the solution of benzamide (200mg, 1.65mmol) in toluene (2mL), add dicarbonyl chloride sulfo-hypochlorite (0.16mL, 1.98mmol).Stir the mixture at 120 DEG C 3 hours.By gained mixture cool to room temperature, then use H ₂o cancellation also extracts with EtOAc (2x10mL).With the organic layer that salt water washing merges, use anhydrous Na ₂sO ₄drying, concentrates and passes through standard method purifying, thus the product desired by obtaining.LC-MS:m/z180(M+H) ⁺。

Step 2: preparation 3-phenyl-1,2,4-thiadiazoles-5-manthanoate.In a sealed vial, under microwave irradiation, at 160 DEG C, stir 5-phenyl-1,3,4-oxa-thiazole-2-ketone (270mg, 1.5mmol) and the mixture of ethyl cyanoformate (790mg, 6.0mmol) in DCE (2mL) 0.5 hour.Concentrated gained mixture also passes through standard method purifying, thus the product desired by obtaining.LC-MS:m/z235(M+H) ⁺。

Step 3: preparation N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(3-phenyl-1,2,4-thiadiazoles-5-base)-1,3,5-triazines-2,4-diamines.To N ¹, N ⁵-bis-(4,4-difiuorocyclohexyl)-biguanides (90mg, 0.27mmol) and 3-phenyl-1,2, NaOMe (43mg, 0.8mmol) is added in the mixture of 4-thiadiazoles-5-ethyl formate (75mg, 0.32mmol) in MeOH (2mL).Then at room temperature stirred reaction mixture spends the night.Gained mixture is poured into water and extracts with EtOAc.Use anhydrous Na ₂sO ₄the dry organic layer merged is also concentrated, and by standard method purifying, thus the product desired by obtaining.

¹HNMR(400MHz,CDCl ₃)δ8.40(d,J＝3.3Hz,2H),7.48(s,3H),5.68-5.01(m,2H),4.27-3.87(m,2H),2.26-1.63(m,8H)。LC-MS:m/z508.2(M+H) ⁺。

Be used in program cited in example 28, use appropriate parent material to prepare following compound.

N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(3-methyl isophthalic acid, 2,4-thiadiazoles-5-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ5.58-5.10(m,2H),4.20-3.84(m,2H),2.77(s,3H),2.23-1.63(m,16H)。LC-MS:m/z446(M+H) ⁺。

The compound of this example of example 29 is prepared by following cited general scheme 29.

Scheme 29

Step 1. prepares the chloro-N of 6- ², N ⁴-bis-((R)-1-cyclopropylethyl)-1,3,5-triazines-2,4-diamines.To 2,4,6-tri-chloro-1,3, (S)-1-cyclopropylethyI amine hydrochloride (2.7mg, 22.8mmol), DIPEA (3.5mg is added in the solution of 5-triazine (2g, 10.9mmol) in acetone (35mL), 27mmol) and CsF (3.3mg, 21.8mmol).Stir the mixture at 50 DEG C and spend the night, and then filter.Concentrated filtrate also passes through standard method purifying, thus obtains desired product.LC-MS:m/z282(M+H) ⁺。

Step B. prepares N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(4-methyl isophthalic acid H-pyrazol-1-yl)-1,3,5-triazines-2,4-diamines.In the ice cold solution of 4-methyl isophthalic acid H-pyrazoles (207mg, 1.07mmol) in dry THF (5mL), add NaH (34mg, 1.42mmol) lentamente through 30 minutes, then add the chloro-N of 6- ², N ⁴-bis-((the R)-1-cyclopropylethyl) solution of-1,3,5-triazines-2,4-diamines (200mg, 0.71mmol) in THF (3mL).At room temperature stirred reaction mixture spends the night, and then concentrates and pass through standard method purifying, thus obtains N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(4-methyl isophthalic acid H-pyrazol-1-yl)-1,3,5-triazines-2,4-diamines.

¹HNMR(400MHz,CDCl ₃)δ8.17(s,1H),7.56(s,1H),5.50-5.12(m,2H),3.56(d,J＝6.0Hz,2H),2.12(s,3H),1.25(s,6H),0.94-0.84(m,2H),0.54-0.32(m,6H),0.26(d,J＝4.1Hz,2H)。LC-MS:m/z328(M+H) ⁺。

Be used in program cited in example 29, use appropriate parent material to prepare following compound.

Compound N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(the iodo-1H-pyrazol-1-yl of 4-)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.51(s,1H),7.73(s,1H),5.49-5.20(m,2H),3.56(d,J＝6.8Hz,2H),1.26(d,J＝6.5Hz,6H),0.90(s,2H),0.55-0.24(m,8H)。LC-MS:m/z440(M+H) ⁺。

Compound 6-(the chloro-1H-pyrazol-1-yl of 4-)-N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.43-8.38(m,1H),7.68(d,J＝9.2Hz,1H),5.41-5.18(m,2H),4.10-3.98(m,2H),2.14-1.91(m,13H),1.86-1.73(m,1.2H),1.68-1.61(m,1.8H)。LC-MS:m/z448(M+H) ⁺。

Compound N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.53(d,J＝10.0Hz,1H),6.66(d,J＝2.5Hz,1H),5.63-5.23(m,2H),3.63-3.45(m,2H),1.27(d,J＝6.5Hz,6H),0.91(d,J＝7.6Hz,2H),0.58-0.26(m,8H)。LC-MS:m/z382(M+H) ⁺。

Compound 6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-N ², N ⁴-bis-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.55(m,1H),6.70(d,J＝2.7Hz,1H),5.77-5.30(m,2H),5.05-4.78(m,2H),1.49-1.37(m,6H)。LC-MS:m/z438.1(M+H) ⁺。

Compound N ², N ⁴-bis-((S)-1,1,1-trifluoro fourth-2-base)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.60-8.57(m,1H),7.80-5.29(m,3H),4.76-4.69(m,2H),2.03-1.95(m,2H),1.72-1.63(m,2H),1.09-1.02(m,6H)。LC-MS:m/z466(M+H) ⁺。

Compound N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.57-8.50(m,1H),6.68(d,J＝4Hz,1H),5.74-5.44(m,2H),4.76-4.47(m,2H),2.66-2.57(m,2H),2.08-2.31(m,8H),1.81-1.86(m,2H)。LC-MS:m/z454(M+H) ⁺。

Compound N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，DMSO-d ₆)δ8.86-8.50(m,1H),8.13-7.76(m,2H),7.00(d,J＝9.7Hz,1H),4.18-3.92(m,2H),2.14-1.82(m,12H),1.62(s,4H)。LC-MS:m/z482(M+H) ⁺。

Compound N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.56-8.50(m,1H),6.69(d,J＝6Hz,1H),5.85-5.52(m,2H),4.37(m,2H),3.05-3.12(m,4H),2.50-2.67(m,4H)。LC-MS:m/z426(M+H) ⁺。

The compound of this example of example 30 is prepared by following cited general scheme 30.

Scheme 30

Step 1: preparation 1-methyl isophthalic acid H-pyrazoles-3-methyl-formiate.At 0 DEG C, in the solution of 1-methyl isophthalic acid H-pyrazoles-3-formic acid (504mg, 4mmol) in MeOH (5mL), add SOCl2 (1.4mL, 20mmol).At room temperature stir the mixture and spend the night, then under reduced pressure concentrate.Resistates is dissolved in EtOAc, with saturated water-based NaHCO ₃wash and concentrate, thus obtaining 1-methyl isophthalic acid H-pyrazoles-3-methyl-formiate.LC-MS:m/z141(M+H) ⁺。

Step 2: preparation N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(1-methyl isophthalic acid H-pyrazole-3-yl)-1,3,5-triazines-2,4-diamines.To N ¹, N ⁵-bis-(4,4-difiuorocyclohexyl)-biguanides (120mg, 0.36mmol) He in the solution of 1-methyl isophthalic acid H-pyrazoles-3-methyl-formiate (60mg, 0.43mmol) in MeOH (2mL) add NaOMe (28mg, 1.07mmol).At room temperature stirred reaction mixture spends the night, and is then poured into water, and extracts with EtOAc.Use anhydrous Na ₂sO ₄the dry organic layer merged, and concentrate and pass through standard method purifying, thus obtain N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(1-methyl isophthalic acid H-pyrazole-3-yl)-1,3,5-triazines-2,4-diamines.

¹HNMR(400MHz,CDCl ₃)δ7.40(d,J＝2.1Hz,1H),6.92(s,1H),5.75-4.94(m,2H),4.28-3.85(m,5H),2.26-1.54(m,16H)。LC-MS:m/z428(M+H) ⁺。

Be used in program cited in example 30, use appropriate parent material to prepare following compound.

Compound N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(1H-pyrazole-3-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，CDCl ₃)δ7.57(s,1H),6.89(s,1H),5.55-4.84(m,2H),4.15-3.80(m,2H),2.05-1.56(m,16H)。LC-MS:m/z414(M+H) ⁺。

Compound N ², N ⁴-bis-(3,3-Difluorocyclopentyl)-6-(2-methyl isophthalic acid H-imidazol-4 yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ7.71(s,1H),5.65-5.07(m,2H),4.63-4.61(m,2H),2.61-2.49(m,3H),2.29(s,3H),2.09-1.92(m,9H)。LC-MS:m/z400.1(M+H) ⁺。

Compound N ², N ⁴-bis-(3,3-difluoro cyclobutyl)-6-(2-methyl isophthalic acid H-imidazol-4 yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ7.62(s,1H),6.49-6.34(m,2H),4.36-4.33(m,2H),3.04(s,3H),2.69-2.49(m,8H)。LC-MS:m/z372(M+H) ⁺。

Compound N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(2-methyl isophthalic acid H-imidazol-4 yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.67-7.66(m,1H),6.26-5.84(m,1H),5.11-4.81(m,1H),3.49-3.11(m,7H),2.48(s,2H),2.10-1.66(m,12H)。LC-MS:m/z428.3(M+H) ⁺。

The compound of this example of example 31 is prepared by following cited general scheme 31.

Scheme 31

Step 1: preparation 4-iodo-3-(trifluoromethyl)-1H-pyrazoles.At 0 DEG C, to 3-(trifluoromethyl)-1H-pyrazoles (500mg, 3.7mmol) in 50%H ₂sO ₄in solution in add NIS (992mg, 4.4mmol).Stirred suspension 10 minutes at 0 DEG C and then at room temperature stir 3 hours.With water (50mL) cancellation gained mixture, and then stirring is spent the night.Also dry by collected by filtration, thus obtain 4-iodo-3-(trifluoromethyl)-1H-pyrazoles.LC-MS:m/z263(M+H) ⁺。

Step 2: preparation 4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base)-3-(trifluoromethyl)-1H-pyrazoles.To the iodo-3-of 4-(trifluoromethyl)-1H-pyrazoles (100mg, 0.38mmol) with (4,4,4', 4', 5,5,5', 5'-prestox-2, two (1,3,2-the dioxaborolanes) (397mg of 2'-, 1 is added in mixture 0.57mmol) in DMF (3mL), 1'-pair-(diphenylphosphino) ferrocene-palladium chloride (II) dichloromethane complex (31mg, 0.04mmol) and potassium acetate (509mg, 0.76).Stirred reaction mixture 2 hours at 90 DEG C, then goes out with shrend and uses Et ₂o extracts.With the organic layer that salt water washing merges, use anhydrous Na ₂sO ₄drying, and concentrated, thus obtain 4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base)-3-(trifluoromethyl)-1H-pyrazoles.LC-MS:m/z263(M+H) ⁺。

Step 3: preparation N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(3-(trifluoromethyl)-1H-pyrazoles-4-base)-1,3,5-triazines-2,4-diamines.At N ₂under atmosphere, to the chloro-N of 6- ², N ⁴-bis-(4,4-difiuorocyclohexyl)-1,3,5-triazines-2,4-diamines (145mg, 0.38mmol) with 4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolanes-2-base)-3-(trifluoromethyl)-1H-pyrazoles (100mg, 0.38mmol) is in DME (3mL) and H ₂k is added in solution in O (1mL) ₂cO ₃(158mg, 1.15mmol) and Pd (PPh ₃) ₄(44mg, 0.04mmol).Stir the mixture at 90 DEG C 16 hours, and then filter.By filtrate distribution in EtOAc and H ₂between O.Separate aqueous layer also extracts with EtOAc.With the organic layer that salt water washing merges, use anhydrous Na ₂sO ₄drying, and concentrate and pass through standard method purifying, thus obtain N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(3-(trifluoromethyl)-1H-pyrazoles-4-base)-1,3,5-triazines-2,4-diamines.

¹HNMR(400MHz，DMSO-d ₆)δ8.09-7.47(m,3H),7.29-7.00(m,1H),4.11-3.76(m,2H),2.19-1.46(m,16H)。LC-MS:m/z482(M+H) ⁺。

Program cited by use-case 31, uses appropriate parent material to prepare following compound.

Compound N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-N ²-methyl-6-(3-(trifluoromethyl)-1H-pyrazoles-4-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，CDCl ₃)δ7.75(s,1H),6.90(s,1H),5.45(d,J＝7.1Hz,1H),4.94-4.44(m,1H),4.09-3.84(m,1H),3.07(d,J＝11.0Hz,3H),2.35-2.02(m,6H),2.03-1.66(m,10H)。LC-MS:m/z496(M+H) ⁺。

Compound N ², N ⁴-bis-(4,4-difiuorocyclohexyl)-6-(1-methyl-3-(trifluoromethyl)-1H-pyrazoles-4-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，CDCl ₃)δ7.57-7.37(m,1H),5.18-4.88(m,2H),4.01-3.79(m,5H),2.21-1.46(m,16H)。LC-MS:m/z496(M+H) ⁺。

Compound N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(5-(trifluoromethyl) pyridin-3-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆)δ9.60(s,1H),9.13(s,1H),8.75(s,1H),7.60(s,1H),7.46(s,1H),3.64-3.50(m,2H),1.21(d,J＝4Hz,6H),0.96(s,2H),0.43-0.33(m,6H),0.14(s,2H)。LC-MS:m/z393(M+H) ⁺。

Compound N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.04-8.82(m,1H),8.68-8.28(m,2H),3.83-3.64(m,1H),3.60-3.51(m,1H),1.36(m,6H),0.91-0.85(m,2H),0.67-0.48(m,4H),0.34(m,4H)。LC-MS:m/z393(M+H) ⁺。

Compound N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(2,5-difluorophenyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ7.76-7.55(m,1H),7.08(dd,J＝7.6,5.8Hz,2H),5.43-5.02(m,2H),3.55(s,2H),1.27(d,J＝5.8Hz,6H),0.90(d,J＝7.4Hz,2H),0.55-0.37(m,6H),0.30-0.23(m,2H)。LC-MS:m/z360(M+H) ⁺。

Compound N ², N ⁴-bis-((R)-1-cyclopropylethyl)-6-(3-(trifluoromethoxy) phenyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)：δ8.25-8.18(m,2H),7.46-7.42(m,1H),7.32-7.26(m,1H),5.28-5.13(m,2H),3.68-3.55(m,2H),1.29-1.25(m,6H),0.95-0.88(m,2H),0.56-0.41(m,6H),0.28(s,2H)。LC-MS:m/z408(M+H) ⁺。

Compound 3-(4,6-two (((R)-1-cyclopropylethyl) is amino)-1,3,5-triazines-2-base) benzonitrile

¹HNMR(400MHz,CDCl3)δ8.63-8.55(m,2H),7.75(d,J＝8Hz,1H),7.57-7.53(m,1H),5.53-5.21(m,2H),3.69-3.55(m,2H),1.25(s,2H),0.90-8.86(m,2H),0.57-0.30(m,1H)。LC-MS:m/z349(M+H) ⁺。

Example 32. preparation has the aromatic-aliphatic triaizine compounds of formula Q.The compound of this example is prepared by following cited general scheme 32.

Scheme 32

Step 1: preparation 4-chloro-N-(6-(1,1-bis-fluoro ethyl) pyridin-3-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-amine.Under nitrogen atmosphere, to 2, the chloro-6-of 4-bis-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine (188mg, 0.64mmol) and 2-(1,1-bis-fluoro ethyl) pyridine-4-amine (50mg, add in mixture 0.32mmol) in Isosorbide-5-Nitrae-diox (4mL) ^tbuONa (61mg, 0.64mmol) and Pd (dppf) Cl ₂(22mg, 0.03mmol).Then at 80 DEG C, stirred reaction mixture spends the night, and then filters.Concentrated filtrate also passes through standard method purifying, thus the product desired by obtaining.

LC-MS：m/z417.1(M+H) ⁺。

Step 2: preparation N ²-(3,3-Difluorocyclopentyl)-N ⁴-(2-(1,1-bis-fluoro ethyl) pyridin-4-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2,4-diamines is to the chloro-N-of 4-(6-(1,1-bis-fluoro ethyl) pyridin-3-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-amine (35mg, 0.08mmol) He in the mixture of 3,3-difluoro cyclopentamine (16mg, 0.13mmol) in THF (2mL) add CsF (24mg, 0.16mmol) with DIPEA (0.03mL, 0.16mmol).Then at 50 DEG C, stirred reaction mixture spends the night.Filtering mixt concentrated filtrate and by standard method purifying, thus the product desired by obtaining.

¹HNMR(400MHz,CDCl ₃)δ8.61(m,1H),8.52(d,J＝5.4Hz,1H),8.43(s,1H),8.08(d,J＝7.7Hz,1H),8.03-7.73(m,2H),7.73-7.34(m,1H),6.08-5.52(m,1H),4.88-4.55(m,1H),2.82-2.64(m,1H),2.46-2.12(m,4H),2.11-1.98(m,3H),1.94-1.81(m,1H)。LC-MS:m/z502(M+H) ⁺。

Be used in program cited in example 32, use appropriate parent material to prepare following compound.

(S)-N ²-(3,3-Difluorocyclopentyl)-N ⁴-(2-(1,1-bis-fluoro ethyl) pyridin-4-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.61(m,1H),8.53(d,J＝5.4Hz,1H),8.46-7.94(m,2H),7.91-7.32(m,3H),5.77(m,1H),4.70(m,1H),2.79-2.60(m,1H),2.50-2.11(m,4H),2.04(m,3H),1.87(m,1H)。LC-MS:m/z502(M+H) ⁺。

(R)-N ²-(3,3-Difluorocyclopentyl)-N ⁴-(2-(1,1-bis-fluoro ethyl) pyridin-4-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.62(m,1H),8.53(d,J＝5.4Hz,1H),8.47-7.94(m,2H),7.93-7.33(m,3H),5.90-5.60(m,1H),4.96-4.46(m,1H),2.80-2.61(m,1H),2.50-2.10(m,4H),2.04(m,3H),1.87(m,1H)。LC-MS:m/z502(M+H) ⁺。

N ²-(4,4-difiuorocyclohexyl)-N ⁴-(2-(1,1-bis-fluoro ethyl) pyridin-4-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.69-8.43(m,3H),8.07(t,J＝7.8Hz,1H),8.01-7.73(m,2H),7.49(m,1H),5.61(m,1H),4.19(m,1H),2.24-2.13(m,4H),2.12-1.93(m,5H),1.76-1.65(m,2H)。LC-MS:m/z516(M+H) ⁺。

N ²-(3,3-difluoro cyclobutyl)-N ⁴-(2-(1,1-bis-fluoro ethyl) pyridin-4-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.72-8.26(m,3H),8.18-7.75(m,3H),7.72-7.33(m,1H),6.03(m,1H),4.53(m,1H),3.16(d,J＝8.2Hz,2H),2.59(m,2H),2.05(m,3H)。LC-MS:m/z488(M+H) ⁺。

2-((4-((2-(1,1-bis-fluoro ethyl) pyridin-4-yl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) propionitrile

¹HNMR(400MHz,DMSO-d ₆)δ11.25-10.25(m,1H),9.16-8.47(m,3H),8.41-8.19(m,2H),8.15-7.80(m,2H),5.40-4.80(m,1H),2.00(t,J＝19.0Hz,3H),1.63(d,J＝7.2Hz,3H)。LC-MS:m/z451(M+H) ⁺。

2-((4-((2-(1,1-bis-fluoro ethyl) pyridin-4-yl) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino)-2-methyl propionitrile

¹HNMR(400MHz,CDCl ₃)δ8.88-8.43(m,2H),8.03(m,4H),7.67(s,1H),5.97(m,1H),2.02(m,3H),1.86(s,6H)。LC-MS:m/z465(M+H) ⁺。

3-((4-((2-(1,1-bis-fluoro ethyl) pyridin-4-yl) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino)-2,2-dimethyl propionitrile

¹HNMR(400MHz,DMSO-d ₆)δ10.65(s,1H),8.91-8.38(m,4H),8.33(t,J＝7.9Hz,1H),8.21-7.51(m,2H),3.80-3.60(m,2H),2.00(m,3H),1.40(d,J＝3.9Hz,6H)。LC-MS:m/z479(M+H) ⁺。

3-((4-((2-(1,1-bis-fluoro ethyl) pyridin-4-yl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) butyronitrile

¹HNMR(400MHz,DMSO-d ₆)δ:10.90-10.25(m,1H),8.75-8.52(m,2H),8.52-8.20(m,3H),8.18-7.75(m,2H),4.67-4.26(m,1H),3.09-2.72(m,2H),2.00(m,3H),1.35(t,J＝5.5Hz,3H)。LC-MS:m/z465(M+H) ⁺。

3-((4-((2-(1,1-bis-fluoro ethyl) pyridin-4-yl) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino)-3-methylbutyronitrile

¹HNMR(400MHz,DMSO-d ₆)δ8.65-8.44(m,2H),8.42-7.96(m,3H),7.92-7.35(m,2H),6.00-5.60(m,1H),3.40-3.10(m,2H),2.10-1.90(m,3H),1.75-1.50(m,6H)。LC-MS:m/z479(M+H) ⁺。

N ²-(3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.67-8.57(m,2H),8.53(d,J＝1.7Hz,1H),8.19-7.38(m,4H),6.03-5.53(m,1H),4.85-4.55(m,1H),2.81-2.58(m,1H),2.51-2.07(m,4H),1.98-1.81(m,1H),1.32-1.16(m,1H)。LC-MS:m/z506(M+H) ⁺。

(R)-N ²-(3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.65-8.52(m,3H),8.10-8.06(m,2H),7.86-7.85(m,1H),7.48-7.42(m,1H),6.00-5.86(m,1H),4.81-4.60(m,1H),2.77-2.62(m,1H),2.41-2.32(m,2H),2.12-2.19(m,2H),1.93-1.86(m,1H)。LC-MS:m/z506(M+H) ⁺。

(S)-N ²-(3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.67-8.56(m,2H),8.53(d,J＝1.8Hz,1H),8.20-7.82(m,3H),7.77-7.40(m,1H),6.09-5.51(m,1H),4.92-4.46(m,1H),2.80-2.59(m,1H),2.46-2.29(m,2H),2.29-2.08(m,2H),1.97-1.85(m,1H)。LC-MS:m/z506(M+H) ⁺。

N ²-(4,4-difiuorocyclohexyl)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

1HNMR(400MHz,CDCl ₃)δ8.57-8.62(m,3H),7.85-8.17(m,3H),7.37-7.72(m,1H),5.45-5.82(m,1H),4.10-4.26(m,1H),2.17-2.19(d,J＝9.2Hz,4H),1.88-2.04(m,2H),1.66-1.81(m,2H)；LC-MS:m/z520(M+H) ⁺。

N ²-(3,3-difluoro cyclobutyl)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.65-8.55(m,2H),8.51-8.32(m,1H)8.11-8.04(m,1H),7.86-7.83(m,1H),7.68-7.47(m,1H),6.33-6.06(m,1H),4.58-4.42(m,1H),3.17-3.10(m,2H),2.75-2.53(m,2H),2.29(s,1H)。LC-MS:m/z492(M+H) ⁺。

N ²-(6,6-difluoro spiral shell [3.3]-2-in heptan base)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

1HNMR(400MHz,CDCl ₃)δ8.55-8.70(m,3H),7.84-8.20(m,3H),7.31-7.66(m,1H),5.68-6.00(m,1H),4.49-4.55(m,1H),2.57-2.76(m,6H),1.83-2.27(m,2H)。LC-MS:m/z532(M+H) ⁺。

6-(6-(trifluoromethyl) pyridine-2-base)-N ²-(2-(trifluoromethyl) pyridin-4-yl)-N ⁴-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.62-8.59(m,1H),8.44(s,1H),8.16-8.07(m,1H),7.87(d,J＝8Hz,1H),7.75-7.50(m,1H),1.53-1.49(m,3H)。LC-MS:m/z498(M+H) ⁺。

N ²-(2,2,2-trifluoroethyl)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆)δ10.91(s,1H),8.75-8.71(m,2H),8.61-8.57(m,2H),8.36-8.33(m,1H),8.21-7.83(m,2H),4.41-4.24(m,2H)。LC-MS:m/z484(M+H) ⁺。

N ²-((3,3-difluoro cyclobutyl) methyl)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.70-8.41(m,3H),7.96(m,4H),7.52(m,1H),5.95-5.58(m,1H),3.67(m,2H),2.77-2.13(m,5H)。LC-MS:m/z506(M+H) ⁺。

N ²-((2,2-difluorocyclopropyl) methyl)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆)δ10.76-10.69(m,1H),8.74-8.66(m,2H),8.58-8.55(m,2H),8.34-8.30(m,1H),8.11(d,J＝8Hz,1H),7.96-7.86(m,1H),3.61-3.43(m,2H),2.17-2.09(m,1H),1.67-1.32(m,2H)。LC-MS:m/z492(M+H) ⁺。

N ²-(3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(5-(trifluoromethyl) pyridin-3-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.86(t,J＝6.0Hz,1H),8.83-8.73(m,1H),8.64-8.55(m,2H),8.09-8.03(m,1H),7.89-7.83(m,1H),6.00-5.88(m,1H),4.80-4.55(m,1H),2.74-2.57(m,1H),2.47-2.05(m,4H),1.94-1.82(m,1H)。LC-MS:m/z506(M+H) ⁺。

1-(4-((4-((3,3-Difluorocyclopentyl) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(600MHz,CDCl ₃)δ8.67(s,2H),8.29(t,J＝5.9Hz,1H),8.07(t,J＝7.6Hz,1H),7.91-7.79(m,2H),7.05(s,1H),5.97(d,J＝7.9Hz,1H),5.06-4.61(m,1H),2.81-2.66(m,1H),2.43-1.36(m,1H),2.34-2.18(m,2H),2.14-2.04(m,1H),1.87-1.77(m,3H),1.72(m,2H)。LC-MS:m/z503(M+H) ⁺

(R)-1-(4-((4-((3,3-Difluorocyclopentyl) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,DMSO-d ₆)δ10.47(s,1H),8.77-8.59(m,2H),8.49(s,1H),8.36-8.20(m,2H),8.11(d,J＝7.8Hz,1H),7.55(d,J＝4.6Hz,1H),4.86-4.47(m,1H),2.75-2.57(m,1H),2.29-2.06(m,4H),1.97-1.82(m,1H),1.80-1.74(m,2H),1.71-1.63(m,2H)。LC-MS:m/z503(M+H) ⁺。

(S)-1-(4-((4-((3,3-Difluorocyclopentyl) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz，DMSO-d ₆)δ10.47(s，1H)，8.79-8.60(m，2H)，8.49(s1H),8.38-8.19(m,2H),8.11(d,J＝7.7Hz,1H),7.55(d,J＝4.4Hz,1H),4.80-4.54(m,1H),2.75-2.55(m,1H),2.37-2.06(m,4H),1.96-1.82(m,1H),1.76-1.67(m,4H)。LC-MS:m/z503(M+H) ⁺。

1-(4-((4-((4,4-difiuorocyclohexyl) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.83-8.65(m,1H),8.58(m,1H),8.32(d,J＝5.4Hz,1H),8.10(t,J＝7.8Hz,1H),7.86(d,J＝7.7Hz,1H),7.62(m,1H),7.09(s,1H),5.65(m,1H),4.29(s,1H),2.12(m,6H),1.89-1.91(m,2H),1.82-1.63(m,4H)。LC-MS:m/z517(M+H) ⁺。

1-(4-((4-((3,3-difluoro cyclobutyl) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,DMSO-d ₆)δ10.48(brs,1H),8.89(d,J＝6.5Hz,1H),8.78-8.56(m,1H),8.42(s,1H),8.37-8.24(m,2H),8.10(d,J＝7.8Hz,1H),7.58(d,J＝4.1Hz,1H),4.45(s,1H),3.13-2.97(m,2H),2.71-2.56(m,2H),1.83-1.59(m,4H)。LC-MS:m/z489(M+H) ⁺。

1-(4-((4-((6,6-difluoro spiral shell [3.3]-2-in heptan base) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.70-8.53(m,2H),8.31-8.28(m,1H),8.10-8.06(m,1H),7.85-7.83(d,J＝8Hz,1H),7.66-7.52(m,1H),7.20-7.07(m,1H),5.94-5.66(m,1H),4.67-4.63(m,1H),2.75-2.55(m,6H),2.25-2.10(m,2H),1.89-1.83(m,2H),1.74-1.71(m,2H)。LC-MS:m/z529(M+H) ⁺。

1-(4-((4-(((2,2-difluorocyclopropyl) methyl) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.72(m,2H),8.31(d,J＝5.5Hz,1H),8.09(d,J＝7.8Hz,1H),7.85(d,J＝7.8Hz,1H),7.58(m,1H),7.05(m,1H),5.92(m,1H),4.00(s,1H),3.61(m,1H),2.08(m,1H),1.83(m,2H),1.72(m,2H),1.52(m,2H)。LC-MS:m/z489(M+H) ⁺。

1-(4-((4-((2,2,2-trifluoroethyl) amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.93-8.42(m,2H),8.34-8.29(m,1H),8.10(t,J＝7.8Hz,1H),8.03-7.58(m,2H),7.13(d,J＝4.2Hz,1H),6.34-6.03(m,1H),4.36-4.29(m,2H),1.74(s,4H)。LC-MS:m/z481.2(M+H) ⁺。

1-(4-((4-((2-hydroxy-2-methyl propyl group) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.77-8.44(m,2H),8.29(d,J＝5.5Hz,1H),8.07(t,J＝7.7Hz,1H),7.77(m,2H),6.96(s,1H),6.14(m,1H),3.79-3.55(m,2H),1.91-1.84(m,2H),1.73-1.69(m,2H),1.35(s,6H)。LC-MS:m/z471(M+H) ⁺。

(R)-1-(4-((4-(6-(trifluoromethyl) pyridine-2-base)-6-((1,1,1-trifluoropropyl-2-base) amino)-1,3,5-triazines-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.73(m,2H),8.36(m,1H),8.11(d,J＝7.3Hz,1H),7.87(d,J＝7.8Hz,1H),7.52(s,1H),7.07(m,1H),5.82(m,1H),5.09(s,1H),4.81(m,4H),1.50(m,J＝8.5Hz,3H)。LC-MS:m/z495(M+H) ⁺。

(S)-1-(4-((4-(6-(trifluoromethyl) pyridine-2-base)-6-((1,1,1-trifluoropropyl-2-base) amino)-1,3,5-triazines-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.77(d,J＝9.2Hz,2H),8.66(m,J＝8Hz,1H),8.57(s,1H),8.10(m,1H),7.52(m,1H),7..10(d,J＝4Hz,1H),5.86(m,1H),5.05(m,1H),1.8(m,4H),1.62(m,3H)。LC-MS:m/z495(M+H) ⁺。

4-((4-(tert-butylamino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) pyridine carbonitrile

¹HNMR(400MHz,DMSO-d ₆)δ8.66-8.41(m,3H),8.12-8.00(m,1H),7.91-7.80(m,1H),7.65-7.55(m,1H),5.80-5.20(m,1H),1.58(m,9H)。LC-MS:m/z415(M+H) ⁺。

4-((4-((3,3-difluoro cyclobutyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) pyridine carbonitrile

¹HNMR(400MHz,DMSO-d ₆)δ10.78(s,1H),8.97-8.52(m,4H),8.38-8.25(m,1H),8.13(d,J＝7.8Hz,1H),8.01-7.80(m,1H),4.56-4.24(m,1H),3.17-2.95(m,2H),2.80-2.60(m,2H)。LC-MS:m/z449(M+H) ⁺。

4-((4-((3,3-Difluorocyclopentyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) pyridine carbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.07-8.66(m,4H),7.86(d,J＝8.0Hz,2H),7.53-7.68(m,1H),5.85-6.03(m,1H),4.58-4.79(m,1H),2.66-2.75(m,1H),1.95-2.47(m,1H),1.88-1.93(m,1H)。LC-MS:m/z463(M+H) ⁺。

4-((4-((4,4-difiuorocyclohexyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) pyridine carbonitrile

¹HNMR(400MHz,DMSO-d ₆)δ10.72-10.76(m,1H),7.93-8.72(m,5H),4.03-4.23(m,1H),1.94-2.16(m,6H),1.64-1.73(m,2H)。LC-MS:m/z477(M+H) ⁺。

4-((4-((2-hydroxy-2-methyl propyl group) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) pyridine carbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.57-8.50(m,2H),8.43-8.36(m,1H),8.22-8.02(m,2H),7.85(m,1H),7.60(s,1H),6.32-6.23(m,1H),3.74-3.58(m,2H),1.37(s,6H)。LC-MS:m/z431(M+H) ⁺。

3-((4-((3,3-Difluorocyclopentyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino)-5-fluorine benzonitrile

¹HNMR(400MHz,CDCl ₃)δ8.64-8.55(m,1H),8.16-7.74(m,5H),7.08-7.02(m,1H),5.97-5.71(m,1H),4.79-4.55(m,1H),2.69-2.64(m,1H),2.41-2.14(m,4H),2.01(s,1H)。LC-MS:m/z480(M+H) ⁺。

3-((4-((4,4-difiuorocyclohexyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino)-5-fluorine benzonitrile

¹HNMR(400MHz,CDCl ₃)：δ8.60-8.54(m,1H),8.08-8.07(m,1H),7.85-7.81(m,4H),7.08-7.03(m,1H),5.76-5.48(m,1H),4.22-4.04(m,1H),2.21-2.18(m,4H),2.02-1.92(m,2H),1.78-1.71(m,2H)。LC-MS:m/z494(M+H) ⁺。

3-((4-((3,3-difluoro cyclobutyl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino)-5-fluorine benzonitrile

¹HNMR(400MHz,DMSO-d ₆)δ10.50(s,1H),8.81-8.67(m,1H),8.55(d,J＝8Hz,1H),8.24-8.09(m,3H),7.46-7.42(m,1H),4.45-4.28(m,2H),3.05-3.01(m,2H),2.77(d,J＝8Hz,2H)。LC-MS:m/z466(M+H) ⁺。

3-((4-((Cvclopropvlmethvl) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino)-5-fluorine benzonitrile

¹HNMR(400MHz,CDCl ₃)δ8.59-8.49(m,1H),8.01-7.97(m,1H),7.83-7.74(m,3H),7.56(s,1H),6.99-6.96(m,1H),5.83-5.62(m,1H),3.43-3.30(m,2H),1.07(d,J＝4Hz,1H),0.57-0.52(m,2H),0.29-0.24(m,2H)。LC-MS:m/z430(M+H) ⁺。

The fluoro-5-of 3-((4-((2-hydroxy-2-methyl propyl group) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) benzonitrile

¹HNMR(400MHz,DMSO-d ₆)δ10.44(s,1H),8.61(m,1H),8.24(m,5H),7.43(t,J＝8.8Hz,1H),4.61(m,1H),3.45(m,2H),1.18(d,J＝4.4Hz,6H)。LC-MS:m/z448(M+H) ⁺。

1-((4-((3-chloro-phenyl-) is amino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino)-2-methyl propan-2-ol

¹HNMR(400MHz,DMSO-d ₆)δ10.11(m1H),8.67-8.52(m,1H),8.40-8.20(m,2H),8.09(d,J＝7.8Hz,1H),7.90(s,1H),7.67(d,J＝7.7Hz,1H),7.40-7.22(m,1H),7.05(t,J＝7.2Hz,1H),4.75-4.40(m,1H),3.44(m2H),1.17(d,J＝6.4Hz,6H)。LC-MS:m/z439(M+H) ⁺。

3-((4-(tert-butylamino)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino) benzonitrile

¹HNMR(400MHz,DMSO-d ₆)δ10.80-10.20(m,1H),9.50-9.25(m,1H),8.36-7.96(m,4H),7.50-7.40(m,1H),1.47(s,9H)。LC-MS:m/z414(M+H) ⁺。

N ²-(3,3-Difluorocyclopentyl)-N ⁴-(3,5-difluorophenyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，CDCl ₃)δ8.59(m,1H),8.06(t,J＝7.8Hz,1H),7.84(d,J＝7.7Hz,1H),7.41(m,3H),6.56(t,J＝8.8Hz,1H),5.74(m,1H),4.83-4.53(m,1H),2.79-2.60(m,1H),2.46-2.06(m,4H),1.95-1.81(m,1H)。LC-MS:m/z473(M+H) ⁺。

N ²-(4,4-difiuorocyclohexyl)-N ⁴-(3,5-difluorophenyl)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.50(d,J＝10.5Hz,1H),7.98(t,J＝7.7Hz,1H),7.76(d,J＝7.7Hz,1H),7.25(d,J＝7.6Hz,2H),6.48(t,J＝8.9Hz,1H),5.67-5.34(m,1H),4.14-3.96(m,1H),2.13-2.11(m,4H),2.00-1.74(m,5H)。LC-MS:m/z487.2(M+H) ⁺。

N ²-(4,4-difiuorocyclohexyl)-N ⁴-(2-phenylpyridine-4-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.59-8.58(m,2H),8.30(s,1H),8.08-7.81(m,5H),7.50-7.42(m,4H),5.87-5.85(m,1H),4.22-4.10(m,1H),2.15-1.68(m,8H)。LC-MS:m/z528(M+H) ⁺。

N ²-(3,3-Difluorocyclopentyl)-N ⁴-(2-phenylpyridine-4-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.61(m,2H),8.31-7.69(m,6H),7.69-7.40(m,4H),5.87(m,1H),4.72(m,1H),2.69(m,1H),2.34(m,2H),2.14(m,2H),1.86-1.80(m,1H)。LC-MS:m/z514(M+H) ⁺。

N ²-(2-phenylpyridine-4-base)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.63(m,2H),8.04(m,6H),7.62-7.30(m,5H),5.81(d,J＝9.1Hz,1H),5.39(m,1H),5.00(m,1H),1.50(d,J＝7.0Hz,3H)。LC-MS:m/z506(M+H) ⁺。

(R)-N ²-(2-phenylpyridine-4-base)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.67-8.58(m,2H),8.14(m,2H),8.01(d,J＝7.0Hz,2H),7.88(d,J＝7.6Hz,1H),7.71-7.34(m,5H),5.69(m,1H),5.22-4.92(m,1H),1.49(d,J＝7.1Hz,3H)。LC-MS:m/z506(M+H) ⁺。

(R)-4-(4-((4-(6-(trifluoromethyl) pyridine-2-base)-6-((1,1,1-trifluoropropyl-2-base) amino)-1,3,5-triazines-2-base) amino) pyridine-2-base) benzonitrile

¹HNMR(400MHz,CDCl ₃)δ8.87-8.53(m,2H),8.42(s,1H),8.11(d,J＝8.0Hz,3H),7.96-7.76(m,4H),7.40(s,1H),5.86-5.67(m,1H),5.18-4.91(m,1H),1.62-1.47(m,3H)。LC-MS:m/z531(M+H) ⁺。

(R)-N ²-(2-(4-fluorophenyl) pyridin-4-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.61(d,J＝8.0Hz,2H),8.27(s,1H),8.13-7.64(m,5H),7.36(s,1H),7.17(t,J＝8.6Hz,2H),6.83-6.64(m,1H),6.16-4.96(m,1H),1.50(d,J＝7.5Hz,3H)。LC-MS:m/z524.1(M+H) ⁺。

(R)-N ²-(2-(4-chloro-phenyl-) pyridin-4-yl)-6-(6-(trifluoromethyl) pyridine-2-base)-N ⁴-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.61(t,J＝6.4Hz,2H),8.31-8.05(m,2H),7.95(d,J＝8.5Hz,2H),7.89(d,J＝7.8Hz,1H),7.46(d,J＝8.4Hz,2H),6.10-5.91(m,1H),5.22-4.91(m,1H),1.51(t,J＝7.7Hz,3H)。LC-MS:m/z540(M+H) ⁺。

N ²-(3,3-Difluorocyclopentyl)-N ⁴-(1H-indoles-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆)δ10.76(s,1H),8.82-8.55(m,1H),8.16(m,4H),7.68(m,2H),7.02(m,3H),4.98(m,1H),2.68(s,1H),2.23(m,4H),1.97(m,1H)。LC-MS:m/z476(M+H) ⁺。

N ²-(3,3-Difluorocyclopentyl)-N ⁴-(1-Methyl-1H-indole-2-base)-6-(6-(trifluoromethyl) pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.54(s,1H),8.35(d,J＝6.8Hz,1H),8.10(s,1H),7.81(d,J＝7.5Hz,1H),7.17(m,4H),5.57(m,1H),4.83(m,1H),3.59(s,3H),2.94-2.06(m,7H)。LC-MS:m/z490(M+H) ⁺。

1-(4-((4-((4,4-difiuorocyclohexyl) amino)-6-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-1,3,5-triazines-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.54(m,2H),8.32(d,J＝5.5Hz,1H),8.02(d,J＝7.8Hz,1H),7.84(d,J＝8.0Hz,1H),7.59(m,1H),7.20(s,1H),5.71(d,J＝7.9Hz,1H),4.34(m,1H),2.15(m,9H),1.85(m,2H),1.23(m,1H)。LC-MS:m/z513(M+H) ⁺。

1-(4-((4-((3,3-Difluorocyclopentyl) amino)-6-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-1,3,5-triazines-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.61(s,1H),8.53(s,1H),8.30(d,J＝4Hz,1H),8.02-7.98(m,1H),7.82(d,J＝8Hz,1H),7.52-7.10(m,2H),5.93-5.60(m,1H),4.87-4.75(m,1H),2.74-2.71(m,1H),2.44(m,1H),2.18-2.04(m,5H),1.89-1.85(m,3H),1.72(m,3H)。LC-MS:m/z499(M+H) ⁺。

1-(4-((4-((3,3-difluoro cyclobutyl) amino)-6-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-1,3,5-triazines-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ10.43(m,1H),8.78(d,J＝4.1Hz,1H),8.61(d,J＝7.8Hz,1H),8.32(d,J＝5.6Hz,2H),8.12(m,1H),7.9(m,1H),7.88(m,1H),4.45(s,1H),3.03(m,2H),2.78(m,2H),2.13(m,3H),1.43(m,4H)。LC-MS:m/z485(M+H) ⁺。

(R)-1-(4-((4-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-6-((1,1,1-trifluoropropyl-2-base) is amino)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.59-8.52(m,1H),8.46-8.45(d,J＝4Hz,1H),8.32-8.25(m,1H),8.02-7.98(m,1H),7.82(d,J＝8Hz,1H),7.69-7.50(m,1H),7.21-7.00(m,1H),5.83-5.56(m,1H),5.18-5.07(m,1H),2.18-2.07(m,3H),1.87-1.85(m,2H),1.73-1.71(m,2H),1.50-1.46(m,3H)。LC-MS:m/z491(M+H) ⁺。

(S)-1-(4-((4-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-6-((1,1,1-trifluoropropyl-2-base) is amino)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.59-8.52(m,1H),8.46(s,1H),8.33-8.32(d,J＝4Hz,1H)8.03-7.99(m,1H),7.92-7.84(m,1H),7.52(s,1H),7.26-7.22(d,J＝16Hz,1H),5.85-5.59(m,1H),5.18-5.09(m,1H),2.18-2.09(m,3H),1.88-1.85(m,4H),1.51-1.48(m,3H)。LC-MS:m/z491(M+H) ⁺。

1-((4-((the chloro-5-fluorophenyl of 3-) is amino)-6-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-1,3,5-triazines-2-base) is amino)-2-methyl propan-2-ol

¹HNMR(400MHz,DMSO-d ₆)δ10.19(s,1H),8.43(m,1H),8.17(m,1H),7.88(m,3H),7.00(d,J＝7.9Hz,1H),4.54(s,1H),3.45(m,2H),2.10(m,3H),1.17(m,J＝7.0Hz,6H)。LC-MS:m/z453(M+H) ⁺。

3-((4-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-6-((2-hydroxy-2-methyl propyl group) is amino)-1,3,5-triazines-2-base) is amino)-5-fluorine benzonitrile

1HNMR(400MHz,CDCl ₃)δ8.40-8.42(d,J＝8Hz,1H),7.74-7.99(m,5H),7.03(m,1H),6.16-6.25(m,1H),3.49-3.64(m,2H),2.05-2.21(m,3H),1.33(s,6H)；LC-MS:m/z444(M+H) ⁺。

1-((4-(6-(1,1-bis-fluoro ethyl) pyridine-2-base)-6-((the fluoro-5-of 3-(trifluoromethyl) phenyl) is amino)-1,3,5-triazine-2-base) amino)-2-methyl propan-2-ol

¹HNMR(400MHz,CDCl ₃)δ8.42(bs,1H),7.57-7.96(m,5H),6.99-7.03(m,1H),6.16-6.28(m,1H),3.54-3.62(m,2H),2.00-2.21(m,3H),2.07-2.22(m,3H),1.28(s,6H)。LC-MS:m/z487(M+H) ⁺。

1-(4-((4-(6-chloropyridine-2-base)-6-((3,3-Difluorocyclopentyl) is amino)-1,3,5-triazines-2-base) is amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.68(s,1H),8.53-8.43(m,1H),8.30(d,J＝4Hz,1H),7.86-7.72(m,1H),7.59-7.49(m,2H),7.27-6.99(m,1H),5.96-5.71(m,1H),4.96-4.88(m,1H),2.76-2.70(m,1H),2.43-2.07(m,4H),1.89-1.79(m,3H),1.75-1.72(m,2H)。LC-MS:m/z469(M+H) ⁺。

(R)-1-(4-((4-(6-chloropyridine-2-base)-6-((1-cyclopropylethyl) is amino)-1,3,5-triazines-2-base) is amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.43(s,2H),8.23(d,J＝8Hz,1H),7.80-7.76(m,1H),7.43(d,J＝8Hz,2H),7.05-7.03(m,1H),5.79-5.50(m,1H),3.70-3.67(m,1H),1.80-1.77(m,2H),1.66-1.59(m,2H),1.29-1.18(m,4H),0.93-0.78(m,1H),0.48-0.33(m,4H)。LC-MS:m/z433(M+H) ⁺。

1-(4-((4-(6-chloropyridine-2-base)-6-((2,2,2-trifluoroethyl) is amino)-1,3,5-triazines-2-base) is amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.54-8.42(m,2H),8.33-8.29(m,1H),7.88-7.50(m,3H),7.14-7.08(m,1H),6.19-5.99(m,1H),4.31(s,2H),1.88-1.71(m,4H)。LC-MS:m/z447(M+H) ⁺。

1-(4-((4-(6-chloropyridine-2-base)-6-((1,1,1-trifluoropropyl-2-base) is amino)-1,3,5-triazines-2-base) is amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.56-8.43(m,2H),8.32(d,J＝4Hz,1H),7.88-7.84(m,1H),7.73-7.50(m,2H),7.07-7.00(m,1H),5.85-5.57(m,1H),5.30-5.07(m,1H),1.90-1.73(m,4H),1.50-1.46(m,3H)。LC-MS:m/z461(M+H) ⁺。

6-(6-chloropyridine-2-base)-N ²-(3,3-Difluorocyclopentyl)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.61-8.53(m,2H),8.41-8.33(m,1H),8.13-7.78(m,2H),7.68-7.27(m,2H),5.95-5.61(m,1H),4.79-4.60(m,1H),2.74-2.65(m,1H),2.44-2.29(m,2H),2.25-2.09(m,2H),1.92-1.83(m,1H)。LC-MS:m/z472(M+H) ⁺。

6-(6-chloropyridine-2-base)-N2-(Cvclopropvlmethvl)-N4-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.60-8.57(m,1H),8.52-8.42(m,1H),8.36-8.19(m,1H),7.86-7.68(m,2H),7.51(d,J＝8Hz,2H),5.96-5.65(m,1H),3.51-3.39(m,2H),1.16(d,J＝8Hz,1H),0.63-0.60(m,2H),0.35-0.30(m,2H)。LC-MS:m/z422(M+H) ⁺。

1-(4-((4-((3,3-difluoro cyclobutyl) amino)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHZz,CDCl ₃)δ9.84(s,1H),9.12(s,1H),8.49-8.31(m,2H),7.78-7.68(m,1H),7.15(s,1H),6.16-5.98(m,1H),4.73-4.58(m,1H),3.22(d,J＝8Hz,2H),2.62-2.54(m,2H),1.89-1.79(m,4H)。LC-MS:m/z490(M+H) ⁺。

1-(4-((4-((4,4-difiuorocyclohexyl) amino)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ9.84(d,J＝4Hz,1H),9.12(s,1H),8.49(s,1H),8.34-8.31(m,1H),7.72-7.63(m,1H),7.27-7.13(m,1H),5.79-5.58(m,1H),4.36-4.26(m,1H),2.20-2.13(m,4H),1.90-1.72(m,8H)。LC-MS:m/z518(M+H) ⁺。

1-(4-((4-((6,6-difluoro spiral shell [3.3]-2-in heptan base) amino)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,DMSO-d ₆)δ10.53(s,1H),9.84-9.75(m,1H),9.39(d,J＝8Hz,1H),8.80(d,J＝8Hz,1H),8.41-8.21(m,2H),7.83-7.56(m,1H),4.57(d,J＝8Hz,1H),2.71-2.57(m,6H),2.27-2.22(m,2H),1.81-1.67(m,4H)。LC-MS:m/z530(M+H) ⁺。

(R)-1-(4-((4-((3,3-Difluorocyclopentyl) amino)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,DMSO-d ₆)δ10.58(s,1H),9.87-9.77(m,1H),9.39(d,J＝4Hz,1H),8.77(d,J＝4Hz,1H),8.42-8.32(m,2H),7.82-7.57(m,1H),4.67(m,1H),2.67-1.69(m,10H)。LC-MS:m/z504(M+H) ⁺。

(S)-1-(4-((4-((3,3-Difluorocyclopentyl) amino)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ9.85(s,1H),9.12(s,1H),8.61-8.44(m,1H),8.33(d,J＝8Hz,1H),7.52(s,1H),7.00(s,1H),5.97-5.75(m,1H),4.94-4.75(m,1H),2.75-1.73(m,10H)。LC-MS:m/z504(M+H) ⁺。

(R)-1-(4-((4-(6-(trifluoromethyl) pyrazine-2-base)-6-((1,1,1-trifluoropropyl-2-base) amino)-1,3,5-triazines-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ9.90-9.84(m,1H),9.14(s,1H),8.43-8.35(m,2H),7.52-7.15(m,2H),5.86-5.60(m,1H),5.14-4.80(m,1H),1.87(d,J＝8Hz,2H),1.74(m,2H),1.50-1.57(m,3H)。LC-MS:m/z496(M+H) ⁺。

(R)-N ²-(3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyrazine-2-base)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.81(m1H),9.14(d,J＝3.6Hz,1H),8.81-8.14(m,2H),8.07-7.37(m,2H),6.30-5.59(m,1H),4.82-4.62(m,1H),2.70(m,1H),2.57-2.09(m,4H),2.01-1.84(m,1H)。LC-MS:m/z507(M+H) ⁺。

(S)-N ²-(3,3-Difluorocyclopentyl)-6-(6-(trifluoromethyl) pyrazine-2-base)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.81(m,1H),9.14(d,J＝3.1Hz,1H),8.74-8.08(m,2H),8.06-7.29(m,2H),6.22-5.58(m,1H),4.85-4.50(m,1H),2.70(m,1H),2.52-2.09(m,4H),2.01-1.82(m,1H)。LC-MS:m/z507(M+H) ⁺。

N ²-(3,3-difluoro cyclobutyl)-6-(6-(trifluoromethyl) pyrazine-2-base)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.81(d,J＝13.8Hz,1H),9.14(d,J＝3.5Hz,1H),8.80-8.19(m,2H),7.99-7.41(m,2H),6.31-5.71(m,1H),4.70-4.39(m,1H),3.29-3.06(m,2H),2.88-2.47(m,2H)。LC-MS:m/z493(M+H) ⁺。

N ²-(4,4-difiuorocyclohexyl)-6-(6-(trifluoromethyl) pyrazine-2-base)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.80(d,J＝8.8Hz,1H),9.14(d,J＝3.4Hz,1H),8.62(d,J＝5.5Hz,1H),8.59-8.20(m,1H),5.83-5.49(m,1H),4.25-4.11(m,1H),2.33-1.71(m,6H)。LC-MS:m/z521(M+H) ⁺。

N ²-(Cvclopropvlmethvl)-6-(6-(trifluoromethyl) pyrazine-2-base)-N4-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆)82(s,4H),9.20(s,4H),8.73(s,3H),8.49(t,J＝6.2Hz,4H),8.37(s,1H),8.13(s,1H),7.79(d,J＝4.4Hz,3H),3.45-3.30(m,8H),1.29-1.16(m,5H),0.57(m8H),0.39-0.30(m,8H)。LC-MS:m/z457(M+H) ⁺。

N ²-(6,6-difluoro spiral shell [3.3]-2-in heptan base)-6-(6-(trifluoromethyl) pyrazine-2-base)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CD ₃OD)δ9.84(d,J＝9.0Hz,1H),9.22(d,J＝5.1Hz,1H),8.93-8.35(m,2H),8.14-7.72(m,2H),4.77-4.35(m,1H),2.67(m,6H),2.43-2.15(m,2H)。LC-MS:m/z533(M+H) ⁺。

(S)-N ²-(3,3-Difluorocyclopentyl)-N ⁴-(3,5-difluorophenyl)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.80(m,1H),9.12(d,J＝3.1Hz,1H),7.71-7.27(m,3H),6.73-6.44(m,1H),5.98-5.48(m,1H),4.68(m,1H),2.81-2.59(m,1H),2.50-2.02(m,4H),1.97-1.78(m,1H)。LC-MS:m/z474(M+H) ⁺。

(R)-N ²-(3,3-Difluorocyclopentyl)-N ⁴-(3,5-difluorophenyl)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines

N ²-(4,4-difiuorocyclohexyl)-N ⁴-(3,5-difluorophenyl)-6-(6-(trifluoromethyl) pyrazine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.78(d,J＝7.6Hz,1H),9.11(s,1H),7.39(m,3H),6.58(t,J＝8.8Hz,1H),5.76-5.39(m,1H),4.22-4.06(m,1H),2.21(m,4H),1.95(m,2H),1.80-1.68(m,2H)。LC-MS:m/z488(M+H) ⁺。

1-(4-((4-((4,4-difiuorocyclohexyl) amino)-6-(6-(difluoromethyl) pyrazine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

1HNMR(400MHz,CDCl ₃)δ9.79(d,J＝7.0Hz,1H),9.12(s,1H),8.54(m,1H),8.32(d,J＝6.0Hz,1H),7.52(d,J＝6.1Hz,1H),7.14(m,1H),6.85(m,1H),5.68(m,1H),4.30(m,1H),2.18(m,6H),1.85(m,2H),1.73(m,4H)。LC-MS:m/z500(M+H) ⁺。

(S)-1-(4-((4-(6-(difluoromethyl) pyrazine-2-base)-6-((1,1,1-trifluoropropyl-2-base) amino)-1,3,5-triazines-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ9.83(m,1H),9.16(s,1H),8.42(m,2H),7.60(s,1H),7.13(m,1H),6.88(m,1H),5.88(m,J＝9.5Hz,1H),5.16(s,1H),1.89(m,J＝4.5Hz,2H),1.76(s,2H),1.52(d,J＝7.0Hz,3H)。LC-MS:m/z478(M+H) ⁺。

(R)-1-(4-((4-(6-(difluoromethyl) pyrazine-2-base)-6-((1,1,1-trifluoropropyl-2-base) amino)-1,3,5-triazines-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ9.81(m,1H),9.12(d,J＝10.5Hz,1H),8.34(m,2H),7.54(d,J＝13.1Hz,1H),7.08(m,1H),6.86(m,1H),5.85(d,J＝9.8Hz,1H),5.14(s,1H),1.92(m,2H),1.71(m,2H),1.51(m,J＝7.7Hz,3H)。LC-MS:m/z478(M+H) ⁺。

6-(6-chloropyrazine-2-base)-N ²-(3,3-Difluorocyclopentyl)-N ⁴-(3,5-difluorophenyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.51(d,J＝17.3Hz,1H),8.76(s,1H),7.64-7.11(m,3H),6.57(t,J＝8.8Hz,1H),5.95-5.50(m,1H),4.86-4.50(m,1H),2.85-1.80(m,6H)。LC-MS:m/z440(M+H) ⁺。

6-(6-chloropyrazine-2-base)-N ²-(3,3-difluoro cyclobutyl)-N ⁴-(3,5-difluorophenyl)-1,3,5-triazines-2,4-diamines

¹HNMR(4400MHz,CDCl ₃)δ9.53-9.49(m,1H),8.76(s,1H),7.60-7.50(m,1H),7.29(s,1H),7.26(s,1H),6.61-6.56(m,1H),6.01-5.74(m,1H),4.59-4.42(m,1H),3.16(s,2H),3.16-2.55(m,2H)。LC-MS:m/z426(M+H) ⁺。

(S)-N ²-(3,3-Difluorocyclopentyl)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-6-(2-(trifluoromethyl) pyrimidine-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.16(t,J＝6.1Hz,1H),8.68-7.76(m,4H),7.72-7.45(m,1H),5.86(m,1H),4.70(m,1H),2.86-1.84(m,6H)。LC-MS:m/z507(M+H) ⁺。

(R)-N ²-(3,3-Difluorocyclopentyl)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-6-(2-(trifluoromethyl) pyrimidine-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.18-9.15(m,1H),8.64-8.61(m,1H),8.53-8.51(m,1H),8.48(d,J＝4Hz,1H),8.17-7.80(m,1H)7.72-7.48(m,1H),6.02-5.71(m,1H),4.80-4.61(m,1H),2.76-2.63(m,4H),1.95-1.88(m,1H)。LC-MS:m/z507(M+H) ⁺。

(S)-1-(4-((4-((3,3-Difluorocyclopentyl) amino)-6-(2-(trifluoromethyl) pyrimidine-4-yl)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

1HNMR(400MHz,CDCl ₃)δ9.15(d,J＝5.4Hz,1H),7.62(m,2H),8.33(d,J＝5.5Hz,1H),7.57(s,1H),7.00(s,1H),6.00(d,J＝8.0Hz,1H),4.76(d,J＝8.6Hz,1H),2.71(s,1H),2.32(m,4H),1.83(m,5H)。LC-MS:m/z504(M+H) ⁺。

(R)-1-(4-((4-((3,3-Difluorocyclopentyl) amino)-6-(2-(trifluoromethyl) pyrimidine-4-yl)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ9.14(d,J＝5.1Hz,1H),8.35(m,2H),8.33(d,J＝5.5Hz,1H),7.56(s,1H),7.00(s,1H),5.99(d,J＝8.0Hz,1H),4.76(d,J＝7.1Hz,1H),2.73(m,1H),2.23(m,4H),1.78(m,5H)。LC-MS:m/z504(M+H) ⁺。

1-(4-((4-((3,3-Difluorocyclopentyl) amino)-6-(4-(trifluoromethyl) pyrimidine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ9.27(d,J＝4.8Hz,1H),8.67(s,1H),8.29(d,J＝5.2Hz,1H),8.06(s,1H),7.81(d,J＝5.2Hz,1H),6.97(s,1H),6.19(d,J＝7.6Hz,1H),2.85-2.69(m,1H),2.53-2.05(m,5H),1.92-1.68(m,5H)。LC-MS:m/z504(M+H) ⁺。

(S)-1-(4-((4-((3,3-Difluorocyclopentyl) amino)-6-(4-(trifluoromethyl) pyrimidine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ9.29(d,J＝4.9Hz,1H),8.58(m,1H),8.33(d,J＝5.5Hz,1H),7.82(t,J＝14.2Hz,2H),7.00(d,J＝13.0Hz,1H),6.14(d,J＝8.0Hz,1H),4.94(m,1H),2.89-2.69(m,1H),2.51(m,1H),2.34-2.07(m,3H),1.94-1.72(m,5H)。LC-MS:m/z504(M+H) ⁺。

(R)-1-(4-((4-((3,3-Difluorocyclopentyl) amino)-6-(4-(trifluoromethyl) pyrimidine-2-base)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ9.27(d,J＝4.9Hz,1H),8.68(s,1H),8.31(d,J＝5.5Hz,1H),7.80(dd,J＝20.2,12.7Hz,2H),6.95(s,1H),6.12(d,J＝8.1Hz,1H),5.02(s,1H),2.77(m,1H),2.56-2.41(m,1H),2.32-2.05(m,3H),1.95-1.69(m,5H)。LC-MS:m/z504(M+H) ⁺。

N ²-(tertiary butyl)-N ⁴-(2-(1,1-bis-fluoro ethyl) pyridin-4-yl)-6-(4-(trifluoromethyl) pyrimidine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.24(d,J＝5.0Hz,1H),8.50(d,J＝5.5Hz,1H),8.38(d,J＝1.4Hz,1H),7.97(s,1H),7.80(d,J＝5.0Hz,1H),7.37(s,1H),6.05(s,1H),2.04(d,J＝18.6Hz,3H),1.55(s,9H)。LC-MS:m/z455(M+H) ⁺。

N ²-(2-(1,1-bis-fluoro ethyl) pyridin-4-yl)-N ⁴-sec.-propyl-6-(4-(trifluoromethyl) pyrimidine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ9.26(d,J＝5.0Hz,1H),8.52(d,J＝5.5Hz,1H),8.41(d,J＝1.5Hz,1H),7.84(m,2H),7.41(s,1H),5.86(d,J＝7.5Hz,1H),4.32(m,1H),2.04(m,3H),1.36(d,J＝6.5Hz,6H)。LC-MS:m/z441(M+H) ⁺。

3-((4-(tert-butylamino)-6-(4-(trifluoromethyl) pyrimidine-2-base)-1,3,5-triazines-2-base) is amino)-5-fluorine benzonitrile

¹HNMR(400MHz,DDMSO-d ₆)δ10.80-10.20(m,1H),9.50-9.25(m,1H),8.36-7.96(m,4H),7.50-7.40(m,1H),1.47(s,9H)。LC-MS:m/z433(M+1) ⁺。

1-((4-((3,5-difluorophenyl) is amino)-6-(4-(trifluoromethyl) pyrimidine-2-base)-1,3,5-triazines-2-base) is amino)-2-methyl propan-2-ol

¹HNMR(400MHz，DMSO-d ₆)δ10.70-10.20(m,1H),9.50-9.27(m,1H),8.37-7.94(m,2H),7.80-7.50(m,2H),6.98-6.71(m,1H),4.75-4.48(m,1H),3.47-3.38(m,2H),1.14(s,6H)。LC-MS:m/z442(M+H) ⁺。

Example 33. prepares aromatic-aliphatic triaizine compounds.The compound of this example is prepared by following cited general scheme 33.

Scheme 33

Step 1: preparation N ¹-(3,5-difluorophenyl)-N ³-nitrile-guanidine.At 80 DEG C, to NaN (CN) ₂the solution of 3,5-difluoroaniline (3g, 23.2mmol) in the mixed solvent of water and dense HCl (2M, 2mL) is added in (4.1g, 46.5mmol) solution in water (34mL).Then stirred reaction mixture 16 hours at 90 DEG C.By gained mixture cool to room temperature and by saturated water-based NaHCO ₃cancellation and be adjusted to pH7-8.Filtering mixt also collects filter cake and drying, thus the product desired by obtaining.LC-MS:m/z197(M+H) ⁺。

Step 2: preparation N ¹-(3,5-difluorophenyl)-N ⁵-(4,4-difiuorocyclohexyl)-guanidine.By N ¹-(3,5-difluorophenyl)-N ³the mixture of-nitrile-guanidine (300mg, 1.53mmol) and 4,4-difluorocyclohex amine hydrochlorate (262mg, 1.53mmol) fully mixes and then stirs 1 hour at 160 DEG C.Then gained mixture cool to room temperature is ground with the mixed solvent of EtOAc and PE.Also dry by solid collected by filtration, thus the product desired by obtaining.LC-MS:m/z332(M+H) ⁺。

Step 3: the fluoro-2-hydrazino pyridine of preparation 3,6-bis-.Hydrazine hydrate (0.75g, 15.0mmol) is added in the ice cold mixture of 2,3,6-trifluoromethyl pyridine (1.0g, 7.5mmol) in ethanol (10mL).Reaction mixture is warmed up to room temperature, is then heated to backflow, continue 2 hours.After cooling to room temperature, also extract with DCM (2x20mL) with water (10mL) diluted reaction mixture.Use anhydrous Na ₂sO ₄the dry organic layer merged also under reduced pressure concentrates, thus obtains the fluoro-2-hydrazino pyridine of 3,6-bis-.LC-MS:m/z146(M+H) ⁺。

Step 4: bromo-3, the 6-difluoro pyridines of preparation 2-.At room temperature, in the stirred solution of the fluoro-2-hydrazino pyridine (1.1g, 7.0mmol) of 3,6-bis-in chloroform (20mL), bromine (1.8g, 11.2mmol) is dropwise added.Then stirred reaction mixture 1.5 hours at 60 DEG C.By gained mixture cool to room temperature, then with saturated water-based NaHCO ₃cancellation, and extract with methylene dichloride (2x20mL).Use anhydrous Na ₂sO ₄the dry organic layer merged is also concentrated, and by standard method purifying, thus obtain bromo-3, the 6-difluoro pyridines of 2-.LC-MS:m/z194(M+H) ⁺。

Step 5: preparation 3,6-difluoro pyridine methyl-formiate.Dppf (0.3g, 0.56mmol), Pd (OAc) is added in the solution of bromo-3, the 6-difluoro pyridines (0.8g, 4.1mmol) of 2-in MeOH (10mL) ₂(0.1g, 0.45mmol) and Et ₃n (1.6mL, 8.2mmol).Make suspension degassed and backfill three times by CO atmosphere.Then, under CO atmosphere (60psi), at 70 DEG C, stir the mixture 12 hours.Gained mixture cool to room temperature is also under reduced pressure concentrated.By EtOAc (150mL) grinding residues.Filters solid concentrated filtrate, and by standard method purifying, thus obtain 3,6-difluoro pyridine methyl-formiate.LC-MS:m/z174(M+H) ⁺。

Step 6: preparation N ²-(4,4-difiuorocyclohexyl)-N ⁴-(3,5-difluorophenyl)-6-(3,6-difluoro pyridine-2-base)-1,3,5-triazines-2,4-diamines.To N ¹-(3,5-difluorophenyl)-N ⁵-(4,4-difiuorocyclohexyl)-guanidine (191mg, 0.58mmol) and 3,6-difluoro pyridine methyl-formiate (100mg, NaOMe (94mg, 1.73mmol) is added in suspension 0.58mmol) in MeOH (3mL).At room temperature stirred reaction mixture spends the night, and is then poured into water, and extracts with EtOAc.Use anhydrous Na ₂sO ₄the dry organic layer merged, and concentrate and pass through standard method purifying, thus obtain N ²-(4,4-difiuorocyclohexyl)-N ⁴-(3,5-difluorophenyl)-6-(3,6-difluoro pyridine-2-base)-1,3,5-triazines-2,4-diamines.

¹HNMR(400MHz,CDCl ₃)δ7.70(td,J＝8.8,5.8Hz,1H),7.49-7.38(m,1H),7.37-7.17(m,2H),7.17-7.05(m,1H),6.55(t,J＝8.9Hz,1H),5.67-5.37(m,1H),4.13-4.02(m,1H),2.18(d,J＝8.3Hz,4H),2.03-1.87(m,2H),1.73-1.70(d,J＝11.2Hz,2H)。LC-MS:m/z455(M+H) ⁺。

Be used in program cited in example 33, use appropriate parent material to prepare following compound.

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(3,5-difluorophenyl)-6-(3,6-difluoro pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz，CDCl ₃)δ7.77-7.62(m,1H),7.47-7.27(m,2H),7.24(d,J＝7.7Hz,1H),7.11(ddd,J＝8.8,3.9,2.7Hz,1H),6.55(t,J＝8.7Hz,1H),5.94-5.29(m,1H),4.76-4.48(m,1H),2.90-1.72(m,6H)。LC-MS:m/z441(M+H) ⁺。

Compound N ²-(3,3-difluoro cyclobutyl)-N ⁴-(3,5-difluorophenyl)-6-(3,6-difluoro pyridine-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ7.70(m,1H),7.58-7.28(m,2H),7.25-7.19(m,1H),7.16-7.06(m,1H),6.73-6.30(m,1H),6.18-5.37(m,1H),4.63-4.31(m,1H),3.40-2.93(m,2H),2.88-2.19(m,2H)。LC-MS:m/z427(M+H) ⁺。

The compound of this example of example 34. is prepared by following cited general scheme 34.

Scheme 34

Step 1: preparation N ²-(4,4-difiuorocyclohexyl)-N ⁴-(3,5-difluorophenyl)-6-(the fluoro-6-hydrazino pyridine of 3--2-base)-1,3,5-triazines-2,4-diamines.To N ²-(4,4-difiuorocyclohexyl)-N ⁴-(3,5-difluorophenyl)-6-(3,6-difluoro pyridine-2-base)-1,3,5-triazine-2,4-diamines (225mg, hydrazine hydrate (150mg, 3.0mmol) is added in solution 0.49mmol) in THF (20mL).Then stirred reaction mixture 2.5 hours at 60 DEG C.After cooling to room temperature, also wash with salt solution (2x10mL) with DCM (20mL) diluted reaction mixture.Be separated organic phase, use anhydrous Na ₂sO ₄drying also under reduced pressure concentrates, thus obtains desired product.

LC-MS:m/z467(M+H) ⁺。

Step 2: preparation 6-(6-amino-3-fluorine pyridine-2-base)-N ²-(4,4-difiuorocyclohexyl)-N ⁴-(3,5-difluorophenyl)-1,3,5-triazines-2,4-diamines.To N ²-(4,4-difiuorocyclohexyl)-N ⁴-(3,5-difluorophenyl)-6-(the fluoro-6-hydrazino pyridine of 3--2-base)-1,3,5-triazines-2, Raney's nickel (100mg) is added in the solution of 4-diamines (46mg, 0.1mmol) in methyl alcohol (5.0mL).At room temperature at H ₂stir the mixture under atmosphere and spend the night.Filter gained mixture and concentrated filtrate, and by standard method purifying, thus obtain 6-(6-amino-3-fluorine pyridine-2-base)-N ²-(4,4-difiuorocyclohexyl)-N ⁴-(3,5-difluorophenyl)-1,3,5-triazines-2,4-diamines.

¹HNMR(400MHz,CDCl ₃)δ7.52-7.50(m,2H),7.45-7.39(m,1H),7.02-6.97(m,1H),6.63-6.54(m,1H),4.60(s,1H),4.26-4.05(m,1H),1.73-2.21(m,8H)。LC-MS:m/z452(M+H) ⁺。

Be used in program cited in example 34, use appropriate parent material to prepare following compound.

Compound 6-(6-amino-3-fluorine pyridine-2-base)-N ²-(3,3-Difluorocyclopentyl)-N ⁴-(3,5-difluorophenyl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ7.50-7.36(m,3H),6.96-6.95(m,1H),6.59-6.53(m,1H),4.89-4.51(m,2H),2.66-2.60(m,1H),2.35-2.11(m,4H),1.92-1.58(m,2H)。LC-MS:m/z438(M+H) ⁺。

Example 35: preparation N ⁴, N ⁶-bis-(4,4-difiuorocyclohexyl)-2-(6-(trifluoromethyl) pyrazine-2-base) pyrimidine-4,6-diamines

Scheme 35

Steps A: 6-(trifluoromethyl) pyrazine-2-methane amide.NH is added in the solution of 6-(trifluoromethyl) pyrazine-2-methyl-formiate (15g, 72.8mmol) in EtOH (20mL) ₄oH (6mL, 156mmol).At room temperature stirred reaction mixture 4 hours, then under reduced pressure concentrates.Use H ₂o (10mL) grinding residues and then filtering, thus obtain 6-(trifluoromethyl) pyrazine-2-methane amide.LC-MS:m/z192(M+H) ⁺。

Step B:6-(trifluoromethyl) pyrazine-2-formonitrile HCN.6-(trifluoromethyl) pyrazine-2-methane amide (10g, 52mmol) is stirred in POCl at 100 DEG C ₃(80mL) mixture overnight in.Reaction mixture cool to room temperature is also under reduced pressure concentrated.Resistates is allocated between DCM and frozen water.Be separated organic layer, use salt water washing, use anhydrous Na ₂sO ₄drying, concentrated, and by standard method purifying, thus obtain 6-(trifluoromethyl) pyrazine-2-formonitrile HCN.LC-MS:m/z174(M+H) ⁺。

Step C:6-(trifluoromethyl) pyrazine-2-amitraz hydrochloride.The solution of sodium metal (35mg, 1.5mmol) in MeOH is added in the solution of 6-(trifluoromethyl) pyrazine-2-formonitrile HCN (3.4g, 15mmol) in MeOH (5mL).At room temperature stirred reaction mixture 12 hours, then adds NH ₄cl (1.5g, 30mmol).Stir the mixture at 70 DEG C 3 hours, then cool to room temperature also under reduced pressure concentrates.Dilute resistates with EtOH (10mL) and stir 0.5 hour under reflux.Gained mixture cool to room temperature is filtered.Under reduced pressure concentrated filtrate, thus obtain 6-(trifluoromethyl) pyrazine-2-amitraz hydrochloride.LC-MS:m/z191(M+H) ⁺。

Step D:2-(6-(trifluoromethyl) pyrazine-2-base) pyrimidine-4,6 (1H, 5H)-diketone.Salt of wormwood (3.0g, 21.2mmol) is added in the mixture of 6-(trifluoromethyl) pyrazine-2-amitraz hydrochloride (1.6g, 7.0mmol) in diethyl malonate (3.2g, 21.2mmol).Stirred reaction mixture 8 hours at 120 DEG C.Gained mixture cool to room temperature is ground with sherwood oil.By solid collected by filtration, by petroleum ether, then with MeOH process, thus form suspension.Filtering suspension liquid under reduced pressure concentrated filtrate, thus obtain 2-(6-(trifluoromethyl) pyrazine-2-base) pyrimidine-4,6-(1H, 5H)-diketone.LC-MS:m/z259(M+H) ⁺。

The chloro-2-of step e: 4,6-bis-(6-(trifluoromethyl) pyrazine-2-base) pyrimidine.2-(6-(trifluoromethyl) pyrazine-2-base) pyrimidine-4,6 (1H, 5H)-diketone (1.4g, 5.4mmol) is stirred in POCl at 100 DEG C ₃(10mL) mixture overnight in, then cool to room temperature also under reduced pressure concentrates.By column chromatography (PE/EA=20/1 is to 10/1) Purification, thus obtain 4,6-bis-chloro-2-(6-(trifluoromethyl) pyrazine-2-base) pyrimidine.LC-MS:m/z295(M+H) ⁺。

Step F: N ⁴, N ⁶-bis-(4,4-difiuorocyclohexyl)-2-(6-(trifluoromethyl) pyrazine-2-base) pyrimidine-4,6-diamines.To 4, the chloro-2-of 6-bis-(6-(trifluoromethyl) pyrazine-2-base) pyrimidine (100mg, 0.34mmol), CsF (103mg, 0.68mmol) and 4,4-difluorocyclohex amine hydrochlorate (116mg, DIPEA (220mg, 0.17mmol) is added in mixture 0.68mmol) in DMSO (1mL).Stirred reaction mixture 4 hours under a nitrogen at 80 DEG C, and then stir 6 hours under microwave irradiation at 150 DEG C.By gained mixture cool to room temperature, go out with shrend, and extract with EtOAc.With the organic layer that salt water washing merges, use anhydrous Na ₂sO ₄drying also under reduced pressure concentrates.By standard method Purification, thus obtain N ⁴, N ⁶-bis-(4,4-difiuorocyclohexyl)-2-(6-(trifluoromethyl) pyrazine-2-base) pyrimidine-4,6-diamines.

¹HNMR(400MHz，CDCl ₃)δ9.73(s,1H),9.00(s,1H),5.31(s,1H),4.95(m,2H),3.76(m,2H),2.20-2.09(m,8H),1.98-1.85(m,4H),1.72-1.63(m,4H)。LC-MS:m/z493(M+H) ⁺。

Example 36. prepares aromatic-aliphatic triaizine compounds.The compound of this example is prepared by following cited general scheme 36.

Scheme 36

Step 1: preparation 1-(4-bromopyridine-2-base) cyclopropanecarbonitrile.Lower than-10 DEG C, to 4-bromo-2-fluorine pyridine (30g, 170.47mmol) He in the solution of cyclopropanecarbonitrile (22.9g, 340.94mmol) in THF (400mL) dropwise add LiHMDS (1.2mmol/L, 284mL) lentamente.Then at room temperature stirred reaction mixture 12 hours.Gained mixture is cooled to 0 DEG C, then uses salt solution (200mL) cancellation.Under reduced pressure enriched mixture.By EtOAc (3x200mL) extracted residues.Use anhydrous Na ₂sO ₄dry amalgamation layer is also concentrated, and by standard method purifying, thus the product desired by obtaining.LC-MS:m/z223(M+H) ⁺。

Step 2: preparation 1-(4-(diphenylmethylene is amino) pyridine-2-base) cyclopropanecarbonitrile.To 1-(4-bromopyridine-2-base) cyclopropanecarbonitrile (30g, 134.48mmol) with diphenylmethyl imines (29.3g, t-BuONa (19.4g is added in solution 161.38mmol) in Yu diox (150mL), 201.73mmol), Binap (5.0g, 8.1mmol) and Pd ₂(dba) ₃(2.5g, 2.69mmol).At N ₂under atmosphere, mixture is heated to 100 DEG C, continues 1 hour, then cool and filter.Concentrated filtrate, thus obtain desired product.LC-MS:m/z324(M+H) ⁺。

Step 3: preparation 1-(4-aminopyridine-2-base) cyclopropanecarbonitrile.At room temperature stir 1-(4-(diphenylmethylene is amino) pyridine-2-base) cyclopropanecarbonitrile (42.1g crude product, 130mmol) with THF/ water-based HCl (2N) (200mL, V:V=2:1) 1 hour, and under reduced pressure concentrate.By PE (3x100mL) aqueous layer extracted, then with saturated water-based Na ₂cO ₃be adjusted to pH8-9, and extract with EtOAc (3x100mL).Use anhydrous Na ₂sO ₄the dry organic layer merged is also concentrated, and by standard method purifying, thus the product desired by obtaining. ¹HNMR(CDCl ₃)δ8.04-8.05(d,J＝4Hz,1H),6.95-6.96(d,J＝4Hz),6.37-6.39(m,1H),4.23(br,2H),1.17-1.80(m,2H),1.61-1.63(m,2H)。LC-MS:m/z160(M+H) ⁺。

Step 4: preparation 1-(4-(4,6-bis-chloro-1,3,5-triazines-2-base is amino) pyridine-2-base) cyclopropanecarbonitrile.NaHCO is added in 1-(4-aminopyridine-2-base) cyclopropanecarbonitrile (2.5g, 15.7mmol), the solution of 2,4,6-tri-chloro-1,3,5-triazines (3.5g, 18.8mmol) in THF (40mL) ₃(2.64g, 31.4mmol).At room temperature stirred reaction mixture spends the night, and then filters.Concentrated filtrate also passes through standard method purifying, thus the product desired by obtaining.LC-MS:m/z307(M+H) ⁺。

Step 5: preparation 1-(4-(the chloro-6-of 4-(3,3-Difluorocyclopentyl is amino)-1,3,5-triazines-2-base is amino) pyridine-2-base) cyclopropanecarbonitrile.At 0 DEG C, to 1-(4-(4,6-bis-chloro-1,3,5-triazine-2-base is amino) pyridine-2-base) cyclopropanecarbonitrile (0.75g, 2.44mmol) and 3,3-difluoro cyclopentamine hydrochloride (0.39g, DIPEA (0.63g, 4.88mmol) is dropwise added lentamente in solution 2.44mmol) in THF (10mL).At room temperature stirred reaction mixture 8 hours, and then under reduced pressure concentrate.Resistates is allocated between EtOAc (20mL) and HCl solution (10%wt, 3mL).Separate aqueous layer also extracts with EtOAc (2x5mL).Use anhydrous Na ₂sO ₄the dry organic layer merged is also concentrated, and by standard method purifying, thus the product desired by obtaining.LC-MS:m/z392(M+H) ⁺。

Step 6: preparation 1-(4-(4-(3,3-Difluorocyclopentyl is amino)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazines-2-base is amino) pyridine-2-base) cyclopropanecarbonitrile.To 1-(4-(the chloro-6-(3 of 4-, 3-Difluorocyclopentyl is amino)-1,3,5-triazine-2-base is amino) pyridine-2-base) cyclopropanecarbonitrile (0.6g, 3-(trifluoromethyl)-1H-pyrazoles (0.2g, 1.53mmol) and K is added in solution 1.53mmol) in DMF (600mL) ₂cO ₃(0.42g, 3.06mmol).Stir the mixture at 35 DEG C and spend the night, then under reduced pressure concentrate.Resistates is dissolved in EtOAc (20mL), then uses the 10%LiCl aqueous solution (2x5mL), 5%HCl solution (2x5mL) and saturated water-based NaHCO successively ₃(2x5mL) wash.Be separated organic layer, use anhydrous Na ₂sO ₄drying, and concentrate and pass through standard method purifying, thus the product desired by obtaining. ¹HNMR(400MHz,CDCl ₃)δ8.81-8.21(m,3H),7.75-7.43(m,1H),7.17-6.88(m,1H),6.74(d,J＝2.7Hz,1H),6.05-5.76(m,1H),5.12-4.41(m,1H),2.86-2.61(m,1H),2.57-2.00(m,4H),1.97-1.78(m,3H),1.76-1.68(m,2H)。LC-MS:m/z492(M+H) ⁺。

Be used in program cited in example 36, use appropriate parent material to prepare following compound.

Compound (S)-1-(4-(4-(3,3-Difluorocyclopentyl is amino)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazine-2-base is amino) pyridine-2-base) cyclopropanecarbonitrile.

¹HNMR(400MHz,CDCl ₃)δ8.51-8.64(m,2H),8.30-8.32(m,1H),7.70-7.87(m,1H),7.96-7.14(m,1H),6.66-6.75(m,1H),5.86-6.07(m,1H),4.64-4.93(m,1H),2.44-2.76(m,1H),2.04-2.30(m,4H),1.72-1.94(m,5H)。LC-MS:m/z492(M+H) ⁺。

Compound (R)-1-(4-(4-(3,3-Difluorocyclopentyl is amino)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazine-2-base is amino) pyridine-2-base) cyclopropanecarbonitrile.

¹HNMR(400MHz,CDCl ₃)δ8.59(m,2H),8.32(d,J＝5.5Hz,1H),7.52(s,1H),6.95(m,1H),6.74(d,J＝2.7Hz,1H),5.91(m,1H),4.83(m,1H),2.69(m,1H),2.31(m,4H),1.76(m,5H)。LC-MS:m/z492(M+H) ⁺。

Compound 1-(4-((4-((4,4-difiuorocyclohexyl) amino)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.80-8.11(m,3H),7.63(m,1H),7.17-6.97(m,1H),6.76(t,J＝3.4Hz,1H),5.75(m,1H),4.21(m,1H),2.14(m,6H),1.93-1.83(m,2H),1.77-1.61(m,4H)。LC-MS:m/z506(M+H) ⁺。

Compound 1-(4-((4-((3,3-difluoro cyclobutyl) amino)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ:8.78-8.50(M,2H),8.32(m,1H),7.86-7.56(m,1H),7.13-6.98(M,1H),6.74(t,J＝3.9Hz,1H),6.18(d,J＝6.9Hz,1H),4.85-4.42(M,1H),3.28-3.05(m,2H),2.83-2.47(m,2H),1.91-1.85(m,2H),1.76-1.69(m,2H)。LC-MS:m/z478(M+H) ⁺。

Compound 1-(4-((4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-6-((1,1,1-trifluoropropyl-2-base) amino)-1,3,5-triazines-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.84-8.27(m,3H),7.71(m,1H),7.11(m,1H),6.76(d,J＝2.6Hz,1H),5.91(d,J＝9.6Hz,1H),5.03(s,1H),1.87(m,2H),1.76-1.72(m,2H),1.49(t,J＝8.4Hz,3H)。LC-MS:m/z484(M+H) ⁺。

Compound (R)-1-(4-((4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-6-((1,1,1-trifluoropropyl-2-base) amino)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.65(s,1H),8.48(d,J＝1.7Hz,1H),8.35(d,J＝5.5Hz,1H),7.59(m,1H),7.14(m,1H),6.76(d,J＝2.7Hz,1H),5.75(m,1H),5.02(s,1H),1.93-1.76(m,2H),1.69(m,2H),1.49(t,J＝8.7Hz,3H)。LC-MS:m/z484(M+H) ⁺。

Compound (S)-1-(4-((4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-6-((1,1,1-trifluoropropyl-2-base) amino)-1,3,5-triazine-2-base) amino) pyridine-2-base) cyclopropanecarbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.67(s,1H),8.50(d,J＝1.4Hz,1H),8.38(m,1H),7.64(m,1H),7.07(s,1H),6.77(d,J＝2.6Hz,1H),5.82(m,1H),5.34-4.85(m,1H),1.97-1.85(m,2H),1.77(m,2H),1.57-1.44(m,3H)。LC-MS:m/z484(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.52(m,3H),8.01-7.37(m,2H),6.76(t,J＝3.7Hz,1H),5.92(m,1H),4.79-4.53(m,1H),2.67(m,1H),2.47-2.09(m,4H),1.93-1.86(m,1H)。LC-MS:m/z495(M+H) ⁺。

Compound (S)-N ²-(3,3-Difluorocyclopentyl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.64-8.55(m,2H),8.48-8.11(m,1H),7.75-7.41(m,2H),6.77-6.75(m,1H),5.97-5.73(m,1H),4.71-4.61(m,1H),2.74-2.61(m,1H),2.42-2.36(m,2H),2.30-2.16(m,2H),1.93-1.86(m,1H)。LC-MS:m/z495(M+H) ⁺。

Compound N ²-(3,3-difluoro cyclobutyl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CD ₃OD)δ8.69-8.62(m,1H),8.51-7.67(m,3H),6.84-6.834(m,1H),4.51-4.29(m,1H),3.09-3.02(m,2H),2.68-2.64(m,2H)。LC-MS:m/z481(M+H) ⁺。

Compound N ²-(Cvclopropvlmethvl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.87-8.36(m,3H),8.27-7.44(m,2H),7.01-6.54(m,1H),6.17-5.80(m,1H),3.43(m,2H),1.35-1.01(m,1H),0.75-0.56(m,2H),0.43-0.24(m,2H)。LC-MS:m/z445(M+H) ⁺。

Compound 6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-N ²-(2-(trifluoromethyl) pyridin-4-yl)-N ⁴-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.69-8.08(m,3H),7.68(m,2H),6.77(d,J＝2.7Hz,1H),5.86(m,1H),4.93(m,1H),1.52(dd,J＝7.1Hz,3H)。LC-MS:m/z487(M+H) ⁺。

Compound (R)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-N ²-(2-(trifluoromethyl) pyridin-4-yl)-N ⁴-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.74-8.48(m,2H),8.46-7.74(m,2H),7.72-7.34(m,1H),6.77(d,J＝2.7Hz,1H),6.08-5.53(m,1H),5.11-4.77(m,1H),1.52(m,3H)。LC-MS:m/z487(M+H) ⁺。

Compound (S)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-N ²-(2-(trifluoromethyl) pyridin-4-yl)-N ⁴-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.65-8.61(m,1H),8.56(d,J＝4Hz,1H)，8.37(m,1H),8.08-7.81(m,1H),7.70-7.44(m,1H),6.76-6.68(m,1H),5.97-5.78(m,1H),5.05-4.82(m,1H),1.53-1.49(m,3H)。LC-MS:m/z487(M+H) ⁺。

Compound 3-((4-((3,3-difluoro cyclobutyl) is amino)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazines-2-base) is amino)-5-fluorine benzonitrile

¹HNMR(400MHz，CDCl ₃)δ8.61-8.54(m,1H),7.86-7.78(m,1H),7.69(s,1H)7.60(d,J＝8Hz,1H),7.13-7.08(m,1H),6.76-6.74(m,1H),6.01-5.94(m,1H),4.58-4.42(m,1H),3.20-3.10(m,2H),2.80-2.54(m,2H)。LC-MS:m/z455(M+H) ⁺。

The fluoro-5-of compound 3-((4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-6-((1,1,1-trifluoropropyl-2-base) is amino)-1,3,5-triazines-2-base) is amino) benzonitrile

¹HNMR(400MHz,CDCl ₃)δ8.60-8.53(m,1H),7.99-7.62(m,3H),7.14-7.09(m,1H),6.76(d,J＝4Hz,1H),5.90-5.82(m,1H),5.04-4.98(m,1H),4.87-4.81(m,3H)。LC-MS:m/z461(M+H) ⁺。

Compound 3-((4-((3,3-Difluorocyclopentyl) is amino)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazines-2-base) is amino)-5-fluorine benzonitrile

¹HNMR(400MHz，CDCl ₃)δ8.63-8.55(m,1H),7.83-7.66(m,3H),7.12-7.08(m,1H),6.77-6.75(m,1H),6.68(d,J＝4Hz,1H),6.21-5.79(m,1H),5.56-4.69(m,1H),2.74-2.50(m,1H),2.40-2.15(m,4H),1.94-1.89(m,1H)。LC-MS:m/z469(M+H) ⁺。

Compound 4-((4-((3,3-Difluorocyclopentyl) is amino)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazines-2-base) is amino) pyridine carbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.74-8.31(m,4H),7.83-7.51(m,1H),6.76-6.67(m,1H),6.24-6.19(m,1H),4.70-4.55(m,1H),2.78-2.62(m,1H),2.45-2.13(m,4H),1.98-1.91(m,1H)。LC-MS:m/z452(M+H) ⁺。

Compound (S)-4-((4-((3,3-Difluorocyclopentyl) amino)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazine-2-base) amino) pyridine carbonitrile

¹HNMR(400MHz,DMSO-d ₆)δ10.89(s,1H),8.90(d,J＝8Hz,1H),8.70-8.66(m,1H),8.58-8.42(m,2H),8.00-7.95(m,1H),7.09(s,1H),4.65-4.43(m,1H),2.69-2.57(m,1H),2.36-2.08(m,4H),1.91-1.80(m,1H)。LC-MS:m/z452(M+H) ⁺。

Compound 4-((4-((3,3-difluoro cyclobutyl) is amino)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazines-2-base) is amino) pyridine carbonitrile

¹HNMR(400MHz,CDCl)δ10.12(s,1H),8.28-7.58(m,4H),7.09-7.14(m,1H),6.25(s,1H),3.61-3.48(m,1H),2.29-1.88(m,4H)。LC-MS:m/z438(M+H) ⁺。

Compound (R)-4-((4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-6-((1,1,1-trifluoropropyl-2-base) amino)-1,3,5-triazines-2-base) amino) pyridine carbonitrile

¹HNMR(400MHz,CDCl ₃)δ8.64(d,J＝8Hz,1H),8.61-8.57(m,1H),8.45-8.32(m,1H),8.14-7.84(m,1H),7.78-7.48(m,1H),6.78-6.68(m,1H),6.05-5.96(m,1H),5.26-4.70(m,1H),1.57-1.51(m,3H)。LC-MS:m/z444(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(3,5-difluorophenyl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.65-8.51(m,1H),7.65-7.40(m,1H),7.23(m,2H),6.78-6.69(m,1H),6.64-6.50(m,1H),5.95-5.70(m,1H),4.74-4.51(m,1H),2.78-2.58(m,1H),2.44-2.06(m,4H),1.87(d,J＝3.8Hz,1H)。LC-MS:m/z462(M+H) ⁺。

Compound N ²-(3,3-difluoro cyclobutyl)-N ⁴-(3,5-difluorophenyl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(4400MHz,CDCl ₃)δ8.73-8.40(m,1H),7.61(m,1H),7.22(m,2H),6.73(dd,J＝6.7,2.7Hz,1H),6.61-6.43(m,1H),6.00(m,1H),4.44(m,1H),3.29-3.02(m,2H),2.85-2.38(m,2H)。LC-MS:m/z448(M+H) ⁺。

Compound N ²-(3,5-difluorophenyl)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-N ⁴-(1,1,1-trifluoropropyl-2-base)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.62-8.51(m,1H),7.78-7.35(m,1H),7.25-7.12(m,2H),6.74(d,J＝2.0Hz,1H),6.65-6.52(m,1H),5.85-5.62(m,1H),5.06-4.80(m,1H),1.48(m,3H)。LC-MS:m/z454(M+H) ⁺。

Compound 1-((4-((3,5-difluorophenyl) is amino)-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1,3,5-triazines-2-base) is amino)-2-methyl propan-2-ol

¹HNMR(400MHz,CDCl ₃)δ8.53(d,J＝4Hz,1H),7.70-7.53(m,1H),7.23-7.19(m,2H),6.71-6.67(m,1H),6.57-6.51(m,1H),6.28-6.08(m,1H),3.73-3.56(m,2H),2.46-1.49(m,6H),1.24(m,1H)。LC-MS:m/z430(M+H) ⁺。

Example 37. preparation has the aromatic-aliphatic triaizine compounds of Formula I c.The compound of this example is prepared by following cited general scheme 37.

Scheme 37

Step 1: the preparation chloro-N-of 4,6-bis-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2-amine.NaHCO is added in solution in THF (40mL) to 2-(trifluoromethyl) pyridine-4-amine (3g, 18.7mmol) and 2,4,6-tri-chloro-1,3,5-triazines (3.6g, 19.5mmol) ₃(3.1g, 37.5mmol).At room temperature stirred reaction mixture 16 hours filtering.Concentrated filtrate also passes through standard method purifying, thus the product desired by obtaining.LC-MS:m/z310(M+H) ⁺。

Step 2: the chloro-N of preparation 6- ²-(3,3-difluoro cyclobutyl)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazines-2,4-diamines.To 4, the chloro-N-of 6-bis-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazine-2-amine (4g, 12.9mmol) He 3, DIPEA (4.8g, 37.2mmol) is added in the solution of 3-difluoro ring butylamine hydrochloride (1.9g, 13.5mmol) in THF (40mL).At room temperature stirred reaction mixture 15 hours, then under reduced pressure concentrates.Resistates is allocated between EtOAc (200mL) and water-based HCl (10%wt, 50mL).Separate aqueous layer also extracts with EtOAc (2x100mL).With the organic layer that anhydrous Na 2SO4 drying merges, concentrate and pass through standard method purifying, thus the product desired by obtaining.

LC-MS:m/z381(M+H) ⁺。

Step 3: preparation 4-(3,3-difluoro Cyclobutylamino)-6-(2-(trifluoromethyl) pyridin-4-yl is amino)-1,3,5-triazines-2-formonitrile HCN.At room temperature, to the chloro-N of 6- ²-(3,3-difluoro cyclobutyl)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-1,3,5-triazine-2,4-diamines (2.2g, NaCN (2.9g, 60mmol) is added in solution 5.77mmol) in MeCN (30mL) and DMSO (10mL).At 60 DEG C, stirred reaction mixture spends the night, and is then allocated in EtOAc (50mL) and H ₂between O (20mL).Be separated organic layer, use salt water washing, use anhydrous Na ₂sO ₄drying, concentrates and passes through standard method purifying, thus the product desired by obtaining.LC-MS:m/z372(M+H) ⁺。

Step 4: preparation 4-(3,3-difluoro Cyclobutylamino)-6-(2-(trifluoromethyl) pyridin-4-yl is amino)-1,3,5-triazines-2-carbon thioamides.To 4-(3,3-difluoro Cyclobutylamino)-6-(2-(trifluoromethyl) pyridin-4-yl is amino)-1,3,5-triazine-2-formonitrile HCN (0.7g, NaHS (0.5g, 9.0mmol) and MgCl is added in solution 1.88mmol) in DMF (15mL) ₂(0.85g, 9.0mmol).At room temperature stirred reaction mixture 0.5 hour, is then allocated in EtOAc (30mL) and H ₂between O (10mL).Be separated organic layer, use salt water washing, use anhydrous Na ₂sO ₄drying, and concentrate and pass through standard method purifying, thus the product desired by obtaining.LC-MS:m/z406(M+H) ⁺。

Step 5: preparation 2-(4-(3,3-difluoro Cyclobutylamino)-6-(2-(trifluoromethyl) pyridin-4-yl is amino)-1,3,5-triazine-2-base)-4-(trifluoromethyl)-4,5-thiazoline-4-alcohol.4-(3 is stirred at 60 DEG C, 3-difluoro Cyclobutylamino)-6-(2-(trifluoromethyl) pyridin-4-yl is amino)-1,3,5-triazine-2-thioformamide (350mg, 0.86mmol) with bromo-1,1, the 1-trifluoropropyl-2-ketone (180mg of 3-, mixture 0.95mmol) in MeCN (10mL) 2 hours, is then allocated in EtOAc (20mL) and H ₂between O (10mL).Be separated organic layer, use salt water washing, use anhydrous Na ₂sO ₄drying, and concentrate and pass through standard method purifying, thus the product desired by obtaining.

¹HNMR(400MHz,DMSO-d ₆)δ10.94-10.86(m,1H),9.08(d,J＝6.0Hz,1H),8.69-8.48(m,2H),7.86-7.78(m,2H),4.30-4.21(m,1H),3.76-3.71(m,1H),3.53-3.41(m,1H),3.11-2.93(m,2H),2.87-2.66(m,2H)。LC-MS:m/z516(M+H) ⁺。

Step 6: preparation N ²-(3,3-difluoro cyclobutyl)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-6-(4-(trifluoromethyl) thiazol-2-yl)-1,3,5-triazines-2,4-diamines.At 0 DEG C, to 2-(4-(3,3-difluoro Cyclobutylamino)-6-(2-(trifluoromethyl) pyridin-4-yl is amino)-1,3,5-triazine-2-base)-4-(trifluoromethyl)-4,5-thiazoline-4-alcohol (250mg, 0.48mmol) with TEA (0.4mL, the solution of triphosgene (290mg, 0.96mmol) in DCM (5mL) is dropwise added in solution 2.4mmol) in DCM (20mL).Stirred reaction mixture 0.5 hour at 0 DEG C, and be then allocated in DCM (20mL) and H ₂between O (10mL).Be separated organic layer, use salt water washing, use anhydrous Na ₂sO ₄drying, and concentrate and pass through standard method purifying, thus the product desired by obtaining. ¹HNMR(400MHz,DMSO-d ₆)δ11..05-10.94(m,1H),9.10(d,J＝6.1Hz,1H),8.82(s,1H),8.70(s,1H),8.64(t,J＝5.4Hz,1H),7.83(d,J＝5.4Hz,1H),4.52-4.22(m,1H),3.18-2.99(m,2H),2.82(dt,J＝32.2,14.2Hz,2H)。LC-MS:m/z498(M+H) ⁺。

Be used in program cited in above example 37, use appropriate parent material to prepare following compound.

Compound N ²-(Cvclopropvlmethvl)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-6-(4-(trifluoromethyl) thiazol-2-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ8.61(t,J＝5.7Hz,1H),8.52-8.15(m,1H),7.99(s,1H),7.77-7.41(m,2H),6.09-5.70(m,1H),3.50-3.34(m,2H),1.20-1.11(m,1H),0.67-0.57(m,2H),0.40-0.28(m,2H)。LC-MS:m/z462(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(2-(trifluoromethyl) pyridin-4-yl)-6-(4-(trifluoromethyl) thiazol-2-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,DMSO-d ₆)δ10.88(s,1H),8.83(d,J＝6.9Hz,1H),8.75(s,1H),8.62(s,1H),8.57(d,J＝5.5Hz,1H),7.79(d,J＝5.5Hz,1H),4.61-4.32(m,1H),2.59-2.51(m,1H),2.41-1.99(m,4H),1.95-1.74(m,1H)。LC-MS:m/z512(M+H) ⁺。

Compound N ²-(3,3-Difluorocyclopentyl)-N ⁴-(3,5-difluorophenyl)-6-(4-(trifluoromethyl) thiazol-2-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,，CDCl ₃)δ7.97(s,1H),7.45-7.26(m,4H),7.25-7.23(m,1H),6.60-6.56(m,1H),5.92-5.34(m,1H),4.68-4.57(m,1H),2.70-2.64(m,1H),2.37-2.16(m,4H),1.87(s,1H)。LC-MS:m/z479(M+H) ⁺。

Compound N ²-(3,3-difluoro cyclobutyl)-N ⁴-(3,5-difluorophenyl)-6-(4-(trifluoromethyl) thiazol-2-yl)-1,3,5-triazines-2,4-diamines

¹HNMR(400MHz,CDCl ₃)δ7.97(d,J＝4Hz,1H),7.60-7.47(m,1H),7.26(m,1H),7.26-7.22(m,1H),6.61-6.53(m,1H),6.00-5.74(m,1H),4.52-4.41(m,1H),3.15(s,2H),2.70-2.57(m,2H)。LC-MS:m/z465(M+H) ⁺。

Compound 3-((4-((3,3-difluoro cyclobutyl) is amino)-6-(4-(trifluoromethyl) thiazol-2-yl)-1,3,5-triazines-2-base) is amino)-5-fluorine benzonitrile

¹HNMR(400MHz,CDCl ₃)δ8.01(s,1H),7.87-7.797(m,2H),7.66(d,J＝8Hz,1H),7.14-7.10(m,1H),5.99-5.75(m,1H),4.72-4.58(m,1H),2.79-2.65(m,1H),2.40-2.18(m,3H)。LC-MS:m/z472(M+H) ⁺。

Compound 3-((4-((3,3-Difluorocyclopentyl) is amino)-6-(4-(trifluoromethyl) thiazol-2-yl)-1,3,5-triazines-2-base) is amino)-5-fluorine benzonitrile

¹HNMR(400MHz,CDCl ₃)δ8.00(s,1H),7.28-7.02(m,3H),6.61(s,1H),6.01-5.76(m,1H),4.51-4.44(m,1H),3.18(s,1H),2.63(m,2H),1.60-1.50(m,1H),1.27-1.10(m,2H)。LC-MS:m/z486(M+H) ⁺。

Example 38. preparation has the two aliphatics pyrimidine compounds of chemical formula S.The compound of this example is prepared by following cited general scheme 32.

Scheme 32

Step 1: preparation 6-chloropyridine first methyl ester imidate.In the solution of 6-chloropyridine formonitrile HCN (3g, 22mmol) in MeOH (25mL), add fresh in MeOH (5mL) of sodium metal (55mg, 2.4mol) prepare solution.At room temperature stirred reaction mixture 16 hours, and then under reduced pressure concentrate, thus the product desired by obtaining.LC-MS:m/z171(M+H) ⁺。

Step 2: preparation 6-chloropyridine carbonamidine.Ammonium chloride (2.18g, 40mmol) and the mixture of 6-chloropyridine first methyl ester imidate (3.5g, 20mmol) in MeOH (30mL) 3 hours is stirred, then cool to room temperature under reduced pressure concentrating at 70 DEG C.Dilute resistates with EtOH (40mL) and stir 0.5 hour under reflux.Cooling gained mixture also filters.Under reduced pressure concentrated filtrate, thus obtain desired product.LC-MS:m/z156(M+H) ⁺。

Step 3: preparation 2-(6-chloropyridine-2-base) pyrimidine-4,6-glycol.6-chloropyridine amidine (2g, 13mmol) and dimethyl malonate (1.7g, 13mmol) is added in the solution of sodium metal (0.9g, 40mmol) in MeOH (10mL).At 85 DEG C, stirred reaction mixture spends the night, and then under reduced pressure concentrates.Filter by EtOAc (30mL) grinding residues.Collect solid and drying under a high vacuum, thus obtain desired product.LC-MS:m/z224(M+H) ⁺。

Step 4: preparation 4,6-bis-chloro-2-(6-chloropyridine-2-base) pyrimidine.2-(6-chloropyridine-2-base) pyrimidine-4,6-glycol (2g, 9mmol) is stirred in POCl at 90 DEG C ₃(20mL) mixture overnight in, then under reduced pressure concentrates.At 0 DEG C, pour resistates into saturated water-based NaHCO lentamente ₃in.Gained mixture is extracted with EtOAc (2x30mL).With the organic layer that water (30mL) and salt solution (30mL) washing merge, use anhydrous Na ₂sO ₄drying also under reduced pressure concentrates.By standard method Purification, thus obtain desired product.LC-MS:m/z260(M+H) ⁺。

Step 5: preparation (R)-6-chloro-2-(6-chloropyridine-2-base)-N-(1,1,1-trifluoropropyl-2-base) pyrimidine-4-amine.4 are stirred at 100 DEG C, the chloro-2-of 6-bis-(6-chloropyridine-2-base) pyrimidine (200mg, 0.77mmol), 1,1,1-trifluoropropyl-2-amine hydrochlorate (255mg, 1.7mmol), the mixture overnight of CsF (258mg, 1.7mmol) and DIPEA (497mg, 3.85mmol) in DMSO (3mL).Use H ₂o (30mL) cancellation gained mixture also extracts with EtOAc (2x30mL).With the organic layer that salt solution (30mL) washing merges, use anhydrous Na ₂sO ₄drying also under reduced pressure concentrates.By standard method Purification, thus obtain desired product. ¹HNMR(400MHz,DMSO-d ₆)δ8.37(m,2H),8.04(m,1H),7.68(d,J＝8Hz,1H),6.89(m,1H),5.02(m,1H),1.38(d,J＝8Hz,3H)。LC-MS:m/z337(M+H) ⁺。

Step 6: preparation (R)-2-(6-chloropyridine-2-base)-N ⁴-(4,4-difiuorocyclohexyl)-N ⁶-(1,1,1-trifluoropropyl-2-base) pyrimidine-4,6-diamines.(R)-6-chloro-2-(6-chloropyridine-2-base)-N-(1 is stirred at 100 DEG C, 1,1-trifluoropropyl-2-base) pyrimidine-4-amine (100mg, 0.3mmol), 4,4-difluorocyclohex amine hydrochlorate (114mg, 0.66mmol), the mixture overnight of CsF (100mg, 0.66mmol) and DIPEA (194mg, 1.5mmol) in DMSO (3mL).Use H ₂o (30mL) cancellation gained mixture also extracts with EtOAc (2x30mL).With the organic layer that salt solution (30mL) washing merges, use anhydrous Na ₂sO ₄drying, concentrated, and by standard method purifying, thus the product desired by obtaining.

¹HNMR(400MHz,DMSO-d ₆)δ8.25(d,J＝8Hz,1H),8.15(s,1H),7.96(m,1H),7.56(d,J＝8Hz,1H),7.31(m,1H),7.06(d,J＝8Hz,1H),5.62(m,1H),5.30-4.84(m,1H),2.33(m,1H),2.14-1.90(m,5H),1.65(m,2H),1.32(d,J＝8Hz,3H)。LC-MS:m/z436(M+H) ⁺

Example 8. enzyme and raji cell assay Raji

The external test of IDH1m (R132H or R132C) inhibitor

Described below is the experimental arrangement of the data on the 2nd row of the 2nd row and the 4th row and the table 5 that may be used for acquisition table 4.

In primary reaction, α-KG acid is reduced into 2-HG and is oxidized to NADP along with NADPH with property.In diaphorase/resazurin secondary reaction, measure the amount of remaining NADPH at the end of the reaction times, wherein consume NADPH with 1:1 mol ratio, and resazurin changes into high fluorescence resorufin.Uncontrolled reaction mensuration at the end of show low Poison, and wherein NADPH by R132HIDH1 consume be subject to small molecules suppress reaction and display go out high fluorescence.

Primary reaction is at 1X damping fluid (150mMNaCl, 20mMTris7.5,10mMMgCl of 50 μ L volumes ₂, 0.05% (w/v) bovine serum albumin) in carry out, this damping fluid comprise 0.25 μ g/mL (2.7nM) IDH1wt/IDH1R132H heterodimer, 0.3mM α-ketoglutaric acid, 4 μMs of NADPH and or 300 μMs of NADP (saturated) or 30 μMs of NADP (unsaturated) and 1 μ L50X compound in DMSO.The mixture of compound, enzyme and cofactor at room temperature preincubate 1 hour, then adds α-ketoglutaric acid.In order to carry out secondary reaction, in primary reaction, adding the 10 μ L1X damping fluids containing 36 μ g/ml diaphorases and 30mM resazurin and hatch 5 minutes again at 25 DEG C.Read plate instrument reads fluorescence under Ex544Em590 at Spectramax.In 100%DMSO concentration, prepare multiple or a kind of diluted chemical compound liquid and be diluted to end reaction thing with 1:50.Measure IDH1wt/IDH1R132C under similar conditions, only 1X damping fluid is 50mMK ₂hPO ₄, pH6.5; 10mMMgCl ₂; 10% glycerine; 0.03% (w/v) bovine serum albumin and ultimate density are 0.4 μ g/mL (4.3nM) IDH1wt/IDH1R132C heterodimer, 0.02mM α-ketoglutaric acid, 4 μMs of NADPH and or 300 μMs of NADP (saturated) or 30 μMs of NADP (unsaturated).Measure IC50.

IDH1 or IDH2 wild-type (wt) and saltant type heterodimer are by method expression and purification as known in the art.Such as, also purifying is as follows for the expression of IDH1wt/R132m heterodimer.The coexpression of IDH1wt-his and IDH1R132C-label is carried out in sf9 insect cell.At 4 DEG C, when stirring, make cell (25g) settling flux in 250ml50mMTirs, 500mMNaCl, in pH7.4.Cell is made to pass through to be set to the M-Y110 microfluidization device (microfluid (Microfluidics)) 4 times of 500psi and be destroyed, and then 22, under 000rcf at 4 DEG C centrifugal 20 minutes.Collect supernatant liquor and be loaded on HistrapFF5*1ml tubing string (GE) by it with 15cm/h, this tubing string 50mMTirs, 500mMNaCl, pH7.4 balances.By in succession removing host cell contaminants, to reach baseline with the level pad containing 20mM imidazoles and the equilibration buffer solution tubing string containing 60mM imidazoles.By the level pad wash-out IDH1wt-his homodimer containing 250mM imidazoles and IDH1wt-his/IDH1R132C-label.Fraction by 250mM imidazoles wash-out is pooled together and is loaded into 15cm/h and uses 10ml on the tubing string that M2 affinity gel (Sigma (Sigma)) is pre-filled, this tubing string 50mMTris, 500mMNaCl, pH7.4 balances.After with equilibration buffer solution, by the level pad wash-out IDH1wt-his/IDH1R132C-label heterodimer containing labelled peptide (0.2mg/ml).By the aliquots containig IQF of IDH1wt-his/IDH1R132C-label at liquid N ₂in and at being stored in-80 DEG C.The same terms is used to carry out purifying IDH1wt-his/IDH1R132H-label.

The external test of IDH1m (R132H or R132C) inhibitor

Described below is the experimental arrangement of data that the 3rd row and the 6th that may be used for acquisition table 4 arrange.

In DMSO, prepare test compounds with 10mM stock solution and it is diluted to 50X ultimate density in DMSO, obtaining 50 μ l reaction mixtures.Use NADPH to exhaust mensuration and measure IDH enzymic activity α-ketoglutaric acid being changed into 2-hydroxyl pentanedioic acid.In this mensuration, at the end of reaction, the diaphorase excessive by interpolation catalysis and resazurin measure residue cofactor to produce the fluorescent signal proportional with NADPH residual content.Damping fluid (150mMNaCl, 20mMTris-ClpH7.5,10mMMgCl is measured at 40 μ l ₂, 0.05%BSA, 2mM beta-mercaptoethanol) in IDH1-R132 homodimer enzyme is diluted to 0.125 μ g/ml; Add the test compounds diluent of 1 μ l in DMSO and at room temperature mixtures incubated 60 minutes.React and start and at room temperature mixtures incubated 90 minutes to add 10 μ l substrate mixture (20 μ lNADPH, 5mM α-ketoglutaric acids, in mensuration damping fluid).React and detect damping fluids (36 μ g/ml diaphorases, 30mM resazurin measure in damping fluid at 1X) stop adding 25 μ l, and hatch 1 minute, then to read on plate instrument reading under Ex544/Em590 at SpectraMax.

Follow mensuration same as above but carry out following amendment to measure the activity of the anti-IDH1R132C of these compounds: measuring damping fluid is (50mM potassiumphosphate, pH6.5; 40mM sodium carbonate, 5mMMgCl ₂, 10% glycerine, 2mM beta-mercaptoethanol and 0.03%BSA).NADPH in substrate buffer solution and the concentration of α-ketoglutaric acid are 20 μMs and 1mM accordingly.

The external test of IDH1m (R132H or R132C) inhibitor

Described below is the experimental arrangement of data that the 3rd row and the 5th that may be used for acquisition table 5 arrange.

In DMSO, prepare test compounds with 10mM stock solution and it is diluted to 50X ultimate density in DMSO, obtaining 50 μ l reaction mixtures.Use NADPH to exhaust mensuration and measure IDH enzymic activity α-ketoglutaric acid being changed into 2-hydroxyl pentanedioic acid.In this mensuration, at the end of reaction, the diaphorase excessive by interpolation catalysis and resazurin measure residue cofactor to produce the fluorescent signal proportional with NADPH residual content.Damping fluid (150mMNaCl, 20mMTris-ClpH7.5,10mMMgCl is measured at the 40 μ l containing 5 μMs of NADPH and 37.5 μM NADP ₂, 0.05%BSA, 2mM beta-mercaptoethanol) in IDH1-R132H homodimer enzyme is diluted to 0.125 μ g/ml; Add the test compounds diluent of 1 μ l in DMSO and at room temperature mixtures incubated 60 minutes.React and start and at room temperature mixtures incubated 60 minutes to add 10 μ l substrate mixture (20 μ lNADPH, 5mM α-ketoglutaric acids, in mensuration damping fluid).React and detect damping fluids (36 μ g/ml diaphorases, 30mM resazurin measure in damping fluid at 1X) stop adding 25 μ l, and hatch 1 minute, then to read on plate instrument reading under Ex544/Em590 at SpectraMax.

Follow with mensuration identical above but carry out following amendment to measure the activity of the anti-IDH1R132C of these compounds: measuring damping fluid (50mM potassiumphosphate, pH6.5 at the 40 μ l containing 5 μMs of NADPH and 28.75 μM NADP; 40mM sodium carbonate, 5mMMgCl ₂, 10% glycerine, 2mM beta-mercaptoethanol and 0.03%BSA) in IDH1-R132C homodimer enzyme is diluted to 0.1875 μ g/ml.The concentration of the α-ketoglutaric acid in substrate buffer solution is 1mM.

The external test of IDH2mR140Q inhibitor

Described below is the experimental arrangement of the data that may be used on the 7th row of acquisition table 4.

The IDH2R140Q inhibit activities measuring and measure these compounds is exhausted by cofactor.With enzyme preincubate compound, then start reaction by adding NADPH and α-KG, and allow previously confirming to carry out 60 minutes under the elapsed time condition linearly about cofactor and substrate.By adding second enzyme diaphorase and corresponding substrate resazurin stopped reaction.Resazurin reduction is become high fluorescence resorufin by diaphorase, and NADPH is oxidized to NADP with property, both all interrupt IDH2 reaction by exhausting obtainable cofactor pond and promote the quantitative generation of fluorophore by easily detecting, and carry out quantitatively the amount of remaining cofactor after a specific amount of time.

Exactly, in each in 12 holes of 384 orifice plates, put 1 μ l100x diluted chemical compound liquid series, then add the 40 μ l damping fluid (50mM potassiumphosphate (K containing 0.25 μ g/mlIDH2R140Q albumen ₂hPO ₄), pH7.5; 150mMNaCl; 10mMMgCl ₂, 10% glycerine, 0.05% bovine serum albumin, 2mM beta-mercaptoethanol).Then at room temperature test compounds is hatched one hour together with enzyme; Then IDH2 reaction is started by the 10 μ l substrate mixture containing 4 μMs of NADPH and 1.6mM α-KG be added in damping fluid mentioned above.After at room temperature hatching again 16 hours, interrupt reacting and passing through interpolation 25 μ l termination mix (36 μ g/ml diaphorases and 60 μMs of resazurins; In damping fluid) resazurin is changed into resorufin to measure residue NADPH.After hatching one minute, reading plate instrument reads this plate under Ex544/Em590.

In order to measure the suppression usefulness of the anti-IDH2R140Q of these compounds with the mensuration form be similar to above, carry out a similar program, only final test enriched material is 0.25 μ g/mlIDH2R140Q albumen, 4 μMs of NADPH and 1.6mM α-KG.

In order to measure the suppression usefulness of the anti-IDH2R140Q of these compounds with high flux screening form, carry out a similar program, in pre-incubation step, only adopt 0.25 μ g/mlIDH2R140Q albumen, and this reaction starts to add 4 μMs of NADPH and 8 μM α-KG.

The external test of IDH2mR140Q inhibitor

Described below is the experimental arrangement of the data that may be used on the 6th row of acquisition table 5.

The IDH2R140Q inhibit activities measuring and measure these compounds is exhausted by cofactor.Making these compounds and enzyme preincubate together with cofactor, then starting reaction by adding α-KG, and allow to carry out 60 minutes under the condition that previously confirmation is linear.By adding second enzyme diaphorase and corresponding substrate resazurin stopped reaction.Resazurin reduction is become high fluorescence resorufin by diaphorase, and NADPH is oxidized to NADP with property, both all interrupt IDH2 reaction by exhausting obtainable cofactor pond and promote the quantitative generation of fluorophore by easily detecting, and carry out quantitatively the amount of remaining cofactor after a specific amount of time.

Exactly, in each in 12 holes of 384 orifice plates, put 1 μ l50x diluted chemical compound liquid series, then add the 40 μ l damping fluid (50mM potassiumphosphate (K containing 0.39 μ g/mlIDH2R140Q albumen, 5 μMs of NADPH and 750 μM NADP ₂hPO ₄), pH7.5; 150mMNaCl; 10mMMgCl ₂, 10% glycerine, 0.05% bovine serum albumin, 2mM beta-mercaptoethanol).Then at room temperature hatch test compounds with enzyme 16 hours together with cofactor, then start IDH2 reaction by the 10 μ l substrate mixture containing 8mM α-KG (ultimate density 1.6mM) be added in damping fluid mentioned above.After at room temperature hatching again 1 hour, interrupt reacting and passing through interpolation 25 μ l termination mix (36 μ g/ml diaphorases and 60 μMs of resazurins; In damping fluid) resazurin is changed into resorufin to measure residue NADPH.After hatching one minute, reading plate instrument reads this plate under Ex544/Em590.

The raji cell assay Raji of IDH1m (R132H or R132C) inhibitor

Described below is the experimental arrangement of the data that may be used on the 5th row of acquisition table 4.

Cell (HT1080 or U87MG) is grown in T125 flask in the DMEM containing 10%FBS, 1x penicillin/streptomycin and 500 μ g/mLG418 (existing only in U87MG cell).Collect them by trypsinase and it is inoculated in 96 hole white background plates containing in the DMEM of 10%FBS with 100 μ L/ holes with the density of 5000 cells/well.Cell is not put in the 1st row and the 12nd row.At 5%CO at 37 DEG C ₂middle incubated cell spends the night.Second day, make the test compounds of 2x ultimate density and add 100 μ l in each cell hole.The ultimate density of DMSO is 0.2% and is coated with DMSO control wells in G is capable.Then these plates are placed in incubator and continue 48 hours.At 48 hours, shift out 100 μ l substratum from each hole and analyze 2-HG concentration by LC-MS.Cell plate are put back in incubator and continue 24 hours again.After compound adds 72 hours, thaw and mix Pu Luomaige (Promega) the CellTiterGlo reagent of 10mL/ plate.Emigrated cells plate from incubator also allows to equilibrate to room temperature.Then in the substratum in each hole, add 100 μ l Pu Luomaige CellTiterGlo reagent.Then cell plate are placed on orbital shaker and continue 10 minutes and then allow at room temperature to leave standstill 20 minutes.Then the luminescence of this plate within 500ms integral time is read.

Based on the mensuration of U87MGpLVX-IDH2R140Q-neo and HT1080 cell

Described below is the experimental arrangement of the data on the 8th row for obtaining table 4.

U87MGpLVX-IDH2R140Q-neo cell is maintained in the DMEM containing 10%FBS, 1x penicillin/streptomycin and 500 μ g/ μ LG418.HT1080 cell is maintained in the RPMI containing 10%FBS, 1x penicillin/streptomycin.With 5, cell to be inoculated in 96 hole microtiter plates and at 37 DEG C and 5%CO by the density of 000 (U87MGR140Q) or 2,500 (HT1080) individual cells/well ₂lower overnight incubation.Second day, in 100%DMSO, prepare compound and then dilute in the medium, obtaining the ultimate density of 0.2%DMSO.From cell plate, remove substratum and add 200 μ L diluted chemical compound liquid to each hole.Hatch compound 48 hours at 37 DEG C after, from each hole, remove 100 μ L substratum and as red lattice, L. (Dang, L.) etc. people " nature " (Nature), by LC-MS analysis 2-HG concentration described in 2009,462,739-744.Then cell plate are allowed to hatch 24 hours again.After compound adds 72 hours, add Pu Luomaige CellTiterGlo reagent to each hole and the luminescence of reading these plates to measure any compound to growth inhibiting effect (GI ₅₀).

The raji cell assay Raji of IDH1mR132H inhibitor.

Described below is the experimental arrangement of the data that may be used on the 4th row of acquisition table 5.

Make neurosphere cell (TS603) at 37 DEG C at 5%CO ₂in at the stem cells technology NeuroCult being supplemented with 1%Primocin, 1%Normocin, 0.0002% heparin, 20ng/mLEGF and 10ng/mLbFGF ^tMgrow in NS-A substratum.Collecting cell, make it become spherolite and settling flux in A Maisi (Accumax) so that cell dissociation and counting.Cell is counted and then by its with 400 ten thousand cells/10mL substratum settling flux in containing 2x heparin, EGF and bFGF NeuroCult substratum in.100 μ l cell solutions are coated in each hole in 96 holes except the 1st row and the 12nd row.1st row and the 12nd row comprise 200 μ LPBS.Compound agent quantitative response is set up with 2x concentration in the Neurocult substratum not containing heparin, EGF and bFGF.The ultimate density of DMSO is 0.25%.Only the control wells of DMSO be coated on H capable in.Then these plates are placed in incubator and continue 48 hours.At 48 hours, shift out 100 μ l substratum from each hole and analyze 2-HG concentration by LC-MS.Cell plate are put back in incubator and continue 24 hours again.After compound adds 72 hours, thaw and mix the Pu Luomaige CellTiterGlo reagent of 10mL/ plate.Emigrated cells plate from incubator also allows to equilibrate to room temperature.Then in the substratum in each hole, add 100 μ l Pu Luomaige CellTiterGlo reagent.Then cell plate are placed on orbital shaker and continue 10 minutes and then allow at room temperature to leave standstill 20 minutes.Then the luminescence of this plate within 500ms integral time is read.

The data of different compounds in R132H enzymatic determination as above, R132C enzymatic determination, R140Q enzymatic determination, the mensuration based on R132C cell and the mensuration based on R140Q cell or similar mensuration of one aspect of the present invention are presented in following table 2 and 3.About each mensuration, the value being designated as " A " represents the IC50 being less than 50nM; The value being designated as " B " represents the IC50 between 50nM and 100nM; The value being designated as " C " represents and is greater than 100nM and the IC50 being less than 1 μM; The value being designated as " D " represents the IC50 being more than or equal to 1 μM; The value being designated as " being not suitable for " be non-activity and blank value represent this compound or non-activity or test in described concrete mensuration.

Table 4. representativeness has the inhibit activities of the compound of Formula I

Table 5. representativeness has the inhibit activities of the compound of Formula I

Be thus described some aspects of some embodiments of the present invention, it should be understood that those skilled in the art easily should expect different change, modify and improve.This type of changes, amendment and improve and be intended to be the part of this disclosure, and is intended in the spirit and scope of the present invention.Therefore, above explanation and accompanying drawing are just in order to illustrate.

Claims

1. one kind has compound or its a kind of pharmacy acceptable salt or the hydrate of Formula I:

wherein:

X is N, CH or C-halogen;

Wherein:

(xiii) this compound is not be selected from lower group:

(11) N ², N ⁴-dicyclohexyl-6-phenyl-1,3,5-triazines-2,4-diamines,

(12) 1,1 '-[(6-phenyl-guanamine, 4-bis-base) diimino] two [ten dihydros-anthraquinone],

(13) 4,4 '-[(6-phenyl-1,3,5-triazines-2,4-bis-base) two (iminomethylene)] two [two (1,1-the dimethyl ethyl)-phenol of 2,6-,

(18) N ², N ⁴-bis-(cyclohexyl methyl)-6-phenyl-1,3,5-triazines-2,4-diamines,

(19) 4,4 '-[[6-[two (1,1-the dimethyl ethyl)-4-hydroxy phenyl of 3,5-]-1,3,5-triazine-2,4-bis-base] two (imino--3,1-propane two base)] two [2, two (1,1-the dimethyl ethyl)-phenol of 6-

(20) 4,4 '-[(6-phenyl-1,3,5-triazines-2,4-bis-base) two (imino--3,1-propane two base)] two [two (1,1-the dimethyl ethyl)-phenol of 2,6-,

(22) N ⁴-cyclopentyl-2-phenyl-N ⁶-(phenyl methyl)-4,6-pyrimidinediamine,

(31) N, N '-[6-[4-(kharophen)-1,2,5-oxadiazole-3-base]-1,3,5-triazines-2,4-bis-base] bis-dimethylsilyl-acetamide,

(38) N, N "-(6-phenyl-1,3,5-triazines-2,4-bis-base) two [N '-(2-chloroethyl)-urea,

(39) N-[the chloro-3-of 4-(trifluoromethyl) phenyl]-N '-[4-methyl-3-[[4-phenyl-6-(propylcarbamic)-1,3,5-triazines-2-base] is amino] phenyl]-urea,

(43) α, α '-[(6-phenyl-1,3,5-triazine-2,4-bis-base) two [imino-(1,1,2,2-tetra-fluoro-3-oxo-3,1-propane two base)]] two [ω-[tetrafluoro (trifluoromethyl) oxyethyl group]-poly-[oxygen base [trifluoro (trifluoromethyl)-1,2-ethane two base]], and

(44) α-[[4-[[(3-chloro-phenyl-) methyl] is amino]-6-(1H-imidazoles-1-base)-1,3,5-triazine-2-base] amino]-N-[[4-(trifluoromethyl) phenyl] methyl]-, (α R)-hexanaphthene propionic acid amide.

2. one kind has compound or its a kind of pharmacy acceptable salt or the hydrate of Formula I a:

wherein:

R ²and R ⁵be selected from independently of one another :-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkyl)-C (O)-NH ₂,-(C ₁-C ₆alkyl)-CO ₂h ,-(C ₂-C ₆alkenyl or alkynyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶) (R ⁶) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-S (O) ₁- ₂-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-S (O) ₁- ₂-(C ₀-C ₆alkyl)-Q ,-(C ₁-C ₆alkylidene group)-S (O) ₁- ₂-N (R ⁶) (R ⁶) ,-(C ₁-C ₄alkylidene group)-S (O) ₁- ₂-N (R ⁶)-(C ₁-C ₆alkylidene group)-Q ,-C (O) N (R ⁶)-(C ₁-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-C (O) N (R ⁶)-(C ₁-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₀-C ₆alkyl)-Q ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-O-(C ₁-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-O-C (O)-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶) C (O)-(C ₁-C ₆alkyl) ,-(C ₁-C ₆alkylidene group)-N (R ⁶) C (O)-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-S (O) ₀- ₂-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-S (O) ₀-2-(C ₀-C ₆alkylidene group)-Q ,-(C ₁-C ₆alkylidene group)-N (R ⁶)-C (O)-N (R ⁶)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-Q ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O)-(C ₀-C ₆alkylidene group)-Q, wherein:

Wherein:

(ix) this compound is not be selected from lower group:

(11) N ², N ⁴-dicyclohexyl-6-phenyl-1,3,5-triazines-2,4-diamines,

(18) N ², N ⁴-bis-(cyclohexyl methyl)-6-phenyl-1,3,5-triazines-2,4-diamines,

(28) N, N '-[6-[4-(kharophen)-1,2,5-oxadiazole-3-base]-1,3,5-triazines-2,4-bis-base] bis-dimethylsilyl-acetamide,

(34) N, N "-(6-phenyl-1,3,5-triazines-2,4-bis-base) two [N '-(2-chloroethyl)-urea,

(35) N-[the chloro-3-of 4-(trifluoromethyl) phenyl]-N '-[4-methyl-3-[[4-phenyl-6-(propylcarbamic)-1,3,5-triazines-2-base] is amino] phenyl]-urea,

(39) α, α '-[(6-phenyl-1,3,5-triazine-2,4-bis-base) two [imino-(1,1,2,2-tetra-fluoro-3-oxo-3,1-propane two base)]] two [ω-[tetrafluoro (trifluoromethyl) oxyethyl group]-poly-[oxygen base [trifluoro (trifluoromethyl)-1,2-ethane two base]], and

(40) α-[[4-[[(3-chloro-phenyl-) methyl] is amino]-6-(1H-imidazoles-1-base)-1,3,5-triazine-2-base] amino]-N-[[4-(trifluoromethyl) phenyl] methyl]-, (α R)-hexanaphthene propionic acid amide.

3. compound as claimed in claim 2, wherein

R ¹, R ³, R ⁴and R ⁶be selected from hydrogen, C independently of one another ₁-C ₄alkyl, C ₁-C ₄haloalkyl ,-O-C ₁-C ₄alkyl and CN, wherein R ¹, R ³, R ⁴and R ⁶each described moieties independently of one another optionally by-OH ,-NH ₂,-CN ,-O-C ₁-C ₄alkyl ,-NH (C ₁-C ₄alkyl) or-N (C ₁-C ₄alkyl) ₂replace; And

R ²and R ⁵be selected from independently of one another :-C ₁-C ₆alkyl) ,-(C ₁-C ₆alkyl)-C (O)-NH ₂,-(C ₁-C ₆alkyl)-CO ₂h ,-(C ₂-C ₆alkenyl or alkynyl) ,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl) ,-(C ₀-C ₆alkylidene group)-C (O) N (R ⁶)-(C ₁-C ₆alkyl) and-(C ₀-C ₆alkylidene group)-C (O)-(C ₁-C ₆alkyl), wherein:

Be present in R ²and R ⁵in any alkyl or alkylene moiety optionally by one or more-OH ,-O (C ₁-C ₄alkyl) ,-CO ₂h or halogen replace; And

R ⁴and R ⁵optionally form a carbocylic radical be optionally substituted together,

Wherein, when A is a phenyl be optionally substituted, 2-pyrryl or 1-imidazolyl, so N (R ⁷) C (R ⁴) (R ⁵) (R ⁶) and N (R ⁸) C (R ¹) (R ²) (R ³) not identical, and this compound is not 2-(1,2-bis-bromotrifluoromethane)-4-phenyl-6-(1,1,2,2,3,3,4,4,5,5,6,6,6-ten trifluoro hexyl-1,3,5-triazines.

4. compound as claimed in claim 2, wherein A is the 5-6 unit's monocyclic aryl or bicyclic heteroaryl that are substituted, and this monocyclic aryl or bicyclic heteroaryl are replaced by maximum two substituting groups, these substituting group independent selected from halo ,-C ₁-C ₄alkyl ,-C ₁-C ₄haloalkyl ,-C ₁-C ₄hydroxyalkyl ,-NH-S (O) ₂-(C ₁-C ₄alkyl) ,-S (O) ₂nH (C ₁-C ₄alkyl) ,-CN ,-S (O) ₂-(C ₁-C ₄alkyl), C ₁-C ₄alkoxyl group ,-NH (C ₁-C ₄alkyl) ,-OH ,-OCF ₃,-CN ,-NH ₂,-C (O) NH ₂,-C (O) NH (C ₁-C ₄alkyl) ,-C (O)-N (C ₁-C ₄alkyl) ₂,-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl), azetidinyl, phenyl and optionally by cyclopropyl that OH replaces.

5. there is a compound of chemical formula B, or its pharmacy acceptable salt or hydrate:

wherein:

X is N, CH or C-halogen;

Q is selected from aryl, heteroaryl, carbocylic radical and heterocyclic radical, and wherein any one is optionally substituted;

Wherein

Wherein this compound is not be selected from lower group:

(1) 2-(6-methyl-2-pyridyl)-N4, N6-dipropyl-4,6-pyrimidinediamine;

(2) N4-ethyl-2-(6-methyl-2-pyridyl)-N6-propyl group-4,6-pyrimidinediamine;

(4) N6-[2-(dimethylamino) ethyl]-N2 ', N2 ', N4, N4-tetramethyl--[2,4 '-two pyrimidine]-2 ', 4,6-triamine; Or

(5) phosphoric acid N6-[2-(dimethylamino) ethyl]-N2 ', N2 ', N4, N4-tetramethyl--[2,4 '-two pyrimidine]-2 ', 4,6-triamine.

6. compound, wherein R as claimed in claim 5 ⁴and R ⁵the heterocyclic radical optionally forming a carbocylic radical be optionally substituted together or be optionally substituted.

7. there is a compound of chemical formula C, or its pharmacy acceptable salt or hydrate:

wherein:

X is N, CH or C-halogen;

Each X ^bn-R independently ^9b, O, S, C-H or C-R ^9c, its condition is at least one X ^bc-R ^9c, and as an X ^bc-H or C-R ^9cand another is C-R ^9ctime, so X ^cn; And as an X ^bn-R ^9b, O or S time, so X ^cc;

R ^9bhydrogen or-C ₁-C ₄alkyl;

Wherein:

8. compound as claimed in claim 7, wherein:

R ^9chalogen ,-OH, CN ,-NH ₂,-O-C ₁-C ₄alkyl ,-NH (C ₁-C ₄alkyl) ,-N (C ₁-C ₄alkyl) ₂,-C ₁-C ₄alkyl ,-C ₁-C ₄haloalkyl and-(C ₁-C ₆alkylidene group)-O-(C ₁-C ₆alkyl);

R ¹and R ⁴each hydrogen naturally;

R ³and R ⁶be selected from C independently of one another ₁-C ₄alkyl, C ₁-C ₄haloalkyl ,-O-C ₁-C ₄alkyl and CN; And

R ²and R ⁵respectively naturally-(C ₁-C ₆alkyl), wherein:

Be present in R ²and R ⁵in this moieties optionally by one or more-OH ,-O (C ₁-C ₄alkyl) ,-CO ₂h or halogen replace; And be present in R ²and R ⁵in any terminal methyl group moiety ground by-CH ₂oH, CF ₃,-CH ₂f ,-CH ₂cl, C (O) CH ₃, C (O) CF ₃, CN or CO ₂h replaces.

9. compound, wherein R as claimed in claim 7 ¹and R ⁴be selected from C independently of one another ₁-C ₄alkyl and C ₁-C ₄haloalkyl, and R ²and R ⁵respectively naturally-(C ₁-C ₆alkyl).

10. as the compound that claim 1 or 2 is stated, wherein R ³and R ⁶all hydrogen, R ¹and R ⁴be selected from C independently of one another ₁-C ₄alkyl and C ₁-C ₄haloalkyl, and R ²and R ⁵respectively naturally-(C ₁-C ₆alkyl).

11. 1 kinds of compounds with Formulae II I, or its pharmacy acceptable salt or hydrate:

wherein:

Ring A is a 5-6 unit bicyclic heteroaryl be optionally substituted;

12. compounds as claimed in claim 11, wherein G is replaced by 1 or 2 substituting group, and these substituting groups are selected from halogen, C ₁-C ₄alkyl, C ₁-C ₄haloalkyl, C ₁-C ₄alkoxyl group ,-CN ,=O ,-OH, aryl, heteroaryl-SO ₂c ₁-C ₄alkyl ,-CO ₂c ₁-C ₄alkyl ,-C (O) aryl and-C (O) C ₁-C ₄alkyl.

13. 1 kinds of pharmaceutical compositions, comprise a kind of compound as claimed in claim 1 and the pharmaceutically acceptable carrier of one.

14. compositions as claimed in claim 13, comprise a kind of the second therapeutical agent having treatment for cancer further.

There is the method that IDH1 sports the cancer of feature in 15. 1 kinds of treatments, wherein this IDH1 sudden change facilitate this enzyme in patients catalysis α-ketoglutaric acid NAPH dependency be reduced into the new ability of one of R (-)-2-hydroxyl pentanedioic acid, the method comprises the step to giving a kind of composition as claimed in claim 13 to its this patient in need.

16. methods as claimed in claim 15, wherein this IDH1 sudden change is that a kind of IDH1R132H or R132C suddenlys change.

17. methods as claimed in claim 16, wherein in patients, this cancer is selected from neurospongioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, nonsmall-cell lung cancer (NSCLC), cholangiocarcinoma, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative anything superfluous or useless (MPN), colorectal carcinoma or Angioimmunoblast non Hodgkin lymphom (NHL).

18. methods as claimed in claim 16, comprise further to its this patient in need being given to a kind of the second therapeutical agent having treatment for cancer.