CN105473560B

CN105473560B - Therapeutically active compounds and methods of use thereof

Info

Publication number: CN105473560B
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: 2020-01-17
Anticipated expiration: 2034-07-10
Also published as: CN111087353B; CN111087353A; CN105473560A

Abstract

Compounds useful for treating cancer and methods of treating cancer are provided, the methods comprising administering to a subject in need thereof one of the compounds described herein.

Description

Therapeutically active compounds and methods of use thereof

Priority requirement

This application claims priority to international application serial No. PCT/CN 2013/079200 filed on 11/7/2013, which is incorporated herein by reference in its entirety.

Background

Isocitrate Dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., alpha-ketoglutarate). These enzymes belong to two different subclasses, one of which utilizes NAD (+) as an electron acceptor and the other utilizes NADP (+) as an electron acceptor. Five isocitrate dehydrogenases have been reported: three NAD (+) dependent isocitrate dehydrogenases, which are located on the mitochondrial matrix; and two NADP (+) dependent isocitrate dehydrogenases, one of which is mitochondrial and the other is predominantly cytosolic. Each NADP (+) dependent isozyme is a homodimer.

IDH1 (isocitrate dehydrogenase 1(NADP +), cytosolic) is also known as IDH; an IDP; IDCD; IDPC or PICD. The protein encoded by this gene is NADP (+) dependent isocitrate dehydrogenase found in cytoplasm and peroxisome. It contains a PTS-1 peroxisome targeting signal sequence. The presence of this enzyme in peroxisomes is indicated in terms of the regeneration of NADPH for reduction in peroxisomes, such as the conversion of 2, 4-dienoyl-CoA to 3-enoyl-CoA; and in peroxisome reactions that consume 2-oxoglutarate, i.e. alpha-hydroxylation of phytanic acid. Cytoplasmic enzymes provide a significant role in cytoplasmic NADPH production.

The human IDH1 gene encodes a protein of 414 amino acids. The nucleotide and amino acid sequences of human IDH1 can be found in GenBank entries NM _005896.2 and NP _005887.2, respectively. The nucleotide and amino acid sequence of IDH1 is also described in each of: for example, Kruenttan Kong (Nekruetenko) et al, molecular biology and evolution (mol. biol. Evol.)15: 1674-; gisbrexhlet (Geisbrecht), et al, J.Biol.chem., 274:30527-30533 (1999); wiemann (Wiemann), et al, genome research (genome Res.)11: 422-; MGC project set, genome research 14:2121-2127 (2004); lubeck (lube), et al, submitted (12 months 2008) to UniProt knowledge base; kullmann et al, filed (6.1996) on the EMBL/GenBank/DDBJ database; and Sorbulon (Sjoeblom) et al, Science 314: 268-.

Non-mutant (e.g., wild-type) IDH1 catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, thereby enabling NAD⁺(NADP⁺) Reduction to NADH (NADPH), for example in the following positive reactions: isocitric acid + NAD⁺(NADP⁺)→α-KG+CO₂+NADH(NADPH)+H⁺。

It has been found that mutations in IDH1 present in certain cancer cells contribute to the novel ability of the enzyme to catalyze NADPH-dependent reduction of alpha-ketoglutarate to R (-) -2-hydroxyglutarate (2 HG). The production of 2HG is thought to promote the development and progression of cancer (Dange, L (Dang, L) et al, Nature 2009,462: 739-44).

IDH2 (isocitrate dehydrogenase 2(NADP +), mitochondrial) is also known as IDH; an IDP; IDHM; IDPM; ICD-M; or mNADP-IDH. The protein encoded by this gene is NADP (+) dependent isocitrate dehydrogenase found in mitochondria. It plays a role in intermediate metabolism and energy production. Such proteins can bind or interact tightly with the pyruvate dehydrogenase complex. The human IDH2 gene encodes a protein of 452 amino acids. The nucleotide and amino acid sequences of IDH2 can be found in GenBank entries NM _002168.2 and NP _002159.2, respectively. The nucleotide and amino acid sequence of human IDH2 is also described in each of: for example, Ha (Huh) et al, filed (11.1992) on the EMBL/GenBank/DDBJ database; and the MGC project group, genome research 14:2121-2127 (2004).

Non-mutant (e.g., wild-type) IDH2 catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (alpha-KG), thereby mobilizing NAD⁺(NADP⁺) Reduction to NADH (NADPH), for example in the following positive reactions:

isocitric acid + NAD⁺(NADP⁺)→α-KG+CO₂+NADH(NADPH)+H⁺。

It has been found that mutations in IDH2 present in certain cancer cells contribute to the novel ability of the enzyme to catalyze NADPH-dependent reduction of alpha-ketoglutarate to R (-) -2-hydroxyglutarate (2 HG). 2HG was not formed by wild-type IDH 2. The production of 2HG is thought to promote the development and progression of cancer (Dange, L et al, Nature 2009,462: 739-44).

Thus, inhibition of mutant IDH1 and/or mutant IDH2 and novel activities thereof is a potential therapeutic treatment for cancer. Thus, there is a continuing need for inhibitors of IDH1 and/or IDH2 mutants that have alpha hydroxyl novel activity.

Summary of The Invention

Described herein are compounds of formula I or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

ring a is an optionally substituted 5-6 membered monocyclic aryl or monocyclic heteroaryl;

x is N, CH or C-halo;

R¹、R³、R⁴and R⁶Each independently selected from hydrogen and C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -O-C₁-C₄Alkyl and CN, wherein R¹、R³、R⁴And R⁶Each of said alkyl moieties of (a) is independently optionally substituted with-OH, -NH₂、-CN、-O-C₁-C₄Alkyl, -NH (C)₁-C₄Alkyl) or-N (C)₁-C₄Alkyl radical)₂Substitution;

R²and R⁵Each independently selected from: - (C)₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₁-C₆Alkyl) -CO₂H、-(C₂-C₆Alkenyl or alkynyl), -C₁-C₆Alkylene) -N (R)⁶)-(C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -N (R)⁶)-(C₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -N (R)⁶)(R⁶)、-(C₁-C₆Alkylene) -N (R)⁶)-S(O)_1-2-(C₁-C₆Alkyl), - (C)₁-C₆Alkylene) -N (R)⁶)-S(O)_1-2-(C₀-C₆Alkyl) -Q, - (C)₁-C₆Alkylene) -S (O)_1-2-N(R⁶)(R⁶)、-(C₁-C₄Alkylene) -S (O)_1-2-N(R⁶)-(C₁-C₆Alkylene) -Q, -C (O) N (R)⁶)-(C₁-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₁-C₆Alkyl), -C (O) N (R)⁶)-(C₁-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -O-C (O) - (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -O-C (O) - (C)₀-C₆Alkyl) -Q, - (C)₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -O- (C)₁-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₁-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -O-C (O) - (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -O-C (O) - (C)₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -N (R)⁶)C(O)-(C₁-C₆Alkyl), - (C)₁-C₆Alkylene) -N (R)⁶)C(O)-(C₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -S (O)_0-2-(C₁-C₆Alkyl), - (C)₀-C₆Alkylene) -S (O)_0-2-(C₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -N (R)⁶)-C(O)-N(R⁶)-(C₁-C₆Alkyl), - (C)₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) - (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -Q, wherein:

present in R²And R⁵Any alkyl or alkylene moiety of (a) is optionally substituted by one or more-OH, -O (C)₁-C₄Alkyl), -CO₂H or halo;

present in R²And R⁵Any terminal methyl moiety in (a) is optionally substituted with-CH₂OH、CF₃、-CH₂F、-CH₂Cl、C(O)CH₃、C(O)CF₃、CNOr CO₂H replacement;

R⁷and R⁸Each independently selected from hydrogen and C₁-C₆An alkyl group; and is

Q is selected from aryl, heteroaryl, carbocyclyl, and heterocyclyl, any of which is optionally substituted; wherein

R¹And R³Optionally together with the carbon atom to which it is attached to form C (═ O); or

R⁴And R⁶Optionally together with the carbon atom to which it is attached to form C (═ O); or

R¹And R²Optionally together forming an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

R⁴And R⁵Optionally together forming an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl;

wherein:

(i) when X is N and A is optionally substituted phenyl, then (a) N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NHCH₂CH₂OCH₂CH₂OCH₂CH₂NH₂4- [ [2- [2- (2-aminoethoxy) ethoxy ] ethoxy]Ethyl radical]Amino group]And (b) N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not NHEt, NH (n-propyl), NH (n-butyl), NH (n-dodecyl), NH- [ (4-methoxyphenyl) methyl]、NHCH₂CH₂CHO、NHCH₂CH₂OCH₃、NHCH₂CH₂OH、NHCH₂CH(OH)CH₃、NHCH₂CH₂OC (O) phenyl, NHCH₂CH₂CH₂OH、NHCH₂CH₂CH₂N(CH₃) Phenyl, NHCH₂C(O)OCH₃、NHCH₂C(O)OCH₂CH₃、NHCH₂Phenyl, NHCH (CH)₃)CH₂CH₃Or NHCH₂CH₂OC(O)CH₃；

(ii) When X is CH or C-Cl and A is optionally substituted with F, Cl or SO₂CH₃Substituted phenyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not all N (CH)₃)CH₂C (O) NH-isopropyl, NHCH (CH)₃)(CH₂)₃N(CH₂CH₃)₂、NHCH₂CH₂OH、NHCH₂CH₂OCH₃、NHCH₂CH₂OSO₃H、NHCH₂CH₂CH₂OCH₂CH₂O-phenyl, NHCH₂CH₂CH₂OH、NHCH₂CH₂CH₂OCH₃、NHCH₂CH(OH)CH₃、N(CH₂CH₃)₂NH-isopropyl, NHCH₂CH₂NHC(O)OCH₃、NHCH₂CH₂NHC(O)CH₃、NHCH₂CH₂NH₂Or NHCH₂-a phenyl group;

(iii) when X is CH and A is optionally substituted pyridyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NHCH₂-phenyl, NHCH₂- (2, 4-difluorophenyl), N (CH)₃)CH₂CH₂C(O)OH、NHCH₂CH₂C(O)OH、NHCH₂CH₂C(O)OCH₂CH₃、NHCH₂CH₂C (O) O-tert-butyl, NHCH₂CH₂C(O)NH₂、NHCH₂CH₂-phenyl, NHCH₂CH₂OH、NHCH₂CH₂NH₂、NHCH₂CH₂N(CH₃)₂Or NHCH₂CH₂CH₃；

(iv) When X is CH and A is optionally substituted 1-imidazolyl, orOptionally substituted 1-pyrrolyl or optionally substituted 1-pyrazolyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NH (CH)₂)₇CH₃、NHCH₂- (o-chloro-phenyl) or NHCH₂CH₂OH；

(v) When X is N and A is an optionally substituted pyridyl group, then (A) N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NHC (O) - [ 2-chloro-4- (methylsulfonyl)]、N(CH₃)₂、NHCH₂CH₂CH₂SO₂CH₂CH₂Cl、NHCH₂CH₂OCH₂CH₂SO₂CH₂CH₂Cl or NHCH₂CH₂SO₂CH₂CH₂Cl；(B)N(R⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not NHC (O) C (CH)₃)₃、NHC(O)CH＝CH₂、NHC(O)C(CH₃)＝CH₂、NHCH₂CH₂OH, NH-cyclohexyl, NHCH₂Phenyl, NHC (O) (CH)₂)₅NH₂、NHC(O)OCH₃、NHC(O)CH₃And NHC (O) NH-optionally substituted phenyl; and (C) when N (R)⁷)C(R⁴)(R⁵)(R⁶) Is NHC (CH)₃)₃Then N (R)⁸)C(R¹)(R²)(R³) Is not NHCH₂-phenyl or NH-CH₂CH₃；

(vi) When X is N and A is optionally substituted heteroaryl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not being N (CH)₂CH₃)₂、NHCH₂CH₂-isopropyl, NHCH₂CH(CH₃)₂And NHC (O) CH₃；

(vii) When X is CH and A is unsubstituted 2-pyridyl, then⁴And R⁵The ring formed is not 5-methyl-1H-pyrazol-3-yl;

(viii) when A is optionally substituted 1-pyrazolyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not all N (CH)₃)₂、NHCH₃NHAc, NH isopropyl, NHCH₂CH₃、NHCH₂CH₂SO₃H or N (CH)₂CH₃)₂；

(ix) When X is N and A is optionally substituted phenyl, thienyl or pyridyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) None of NH cyclohexyl C (O) NHCH₂R, wherein R is OCF₃、OCH₃Chlorine or CF₃One or more substituted phenyl or pyridyl groups of (a);

(x) When X is N, A is optionally substituted phenyl and R⁴And R⁵When an optionally substituted phenyl group is formed, then N (R)⁸)C(R¹)(R²)(R³) Is not NHCH₂(4-fluorophenyl), NHCH₂CO₂H、NHCH₂C(O)Cl、NHCH(CO₂H)(CH₂SCH₂Phenyl), NHCH₂C (O) NHC (O) NHR or NHCH₂C (O) NHC (S) NHR, wherein R is optionally substituted phenyl or naphthyl;

(xi) When X is N, A is an oxadiazole substituted by an optionally substituted pyridyl group, then R is⁴And R⁵Does not form an optionally substituted phenyl group;

(xii) When A is substituted 1-pyrazolyl, then (A) N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both are not NHC (CH)₃)₃(ii) a And (B) a is not substituted with N ═ N-R, wherein R is a ring;

(xiii) Ring a is not optionally substituted triazolyl, 3, 5-dimethyl-1H-pyrazol-1-yl;

(xix) When R is¹And R²Optionally together form an unsubstituted cyclohexyl group, and R⁴And R⁵Optionally together forming an unsubstituted cyclohexyl group, then a is not a disubstituted 1-pyrazolyl or unsubstituted phenyl; and is

(xx) The compound is not selected from the group consisting of:

(1) n- (2-aminophenyl) -4- [ [ [4- [ (2, 3-dihydro-1H-inden-2-yl) amino ] -6-phenyl-1, 3, 5-triazin-2-yl ] amino ] methyl ] -benzamide;

(2) 2-chloro-N- [4- (cyclopropylamino) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] -4- (methylsulfonyl) -benzamide;

(3)2- [ [1- [4- (cyclopropylamino) -6- (ethylamino) -1,3, 5-triazin-2-yl ] -1H-1,2, 4-triazol-3-yl ] thio ] -acetamide;

(4)N²-cyclopropyl-N⁴-ethyl-6- [3- [ (phenylmethyl) thio]-1H-1,2, 4-triazol-1-yl]-1,3, 5-triazine-2, 4-diamine;

(5)2- [ [1- [4- (cyclopropylamino) -6- (ethylamino) -1,3, 5-triazin-2-yl ] -1H-1,2, 4-triazol-3-yl ] thio ] -acetic acid methyl ester;

(6) n- [ [4- [ [ [4- (cyclopropylamino) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methyl ] cyclohexyl ] methyl ] -4-fluoro-benzenesulfonamide;

(7)N²-cyclopropyl-6- (3, 5-dimethyl-1H-pyrazol-1-yl) -N⁴-phenyl-1, 3, 5-triazine-2, 4-diamine;

(8)N²,N⁴-dicyclohexyl-6- [3- (4-methoxyphenyl) -5- (methylthio) -1H-pyrazol-1-yl]-1,3, 5-triazine-2, 4-diamine;

(9)N²,N⁴-dicyclohexyl-6- [3- (3, 4-dimethoxyphenyl) -5- (methylthio) -1H-pyrazol-1-yl]-1,3, 5-triazine-2, 4-diamine;

(10)N²,N⁴-dicyclohexyl-6- [5- (methylthio) -3- (3,4, 5-trimethoxyphenyl) -1H-pyrazol-1-yl]-1,3, 5-triazine-2, 4-diamine;

(11)N²,N⁴-dicyclohexyl-6-phenyl-1, 3, 5-triazine-2, 4-diamine;

(12)1,1' - [ (6-phenyl-s-triazine-2, 4-diyl) diimino ] bis [ dodecahydro-anthraquinone ];

(13)4,4' - [ (6-phenyl-1, 3, 5-triazine-2, 4-diyl) bis (iminomethylene) ] bis [2, 6-bis (1, 1-dimethylethyl) -phenol;

(14) n- [4- [ (4-aminobutyl) amino ] -6- [5- [ [ [ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino ] carbonyl ] amino ] -2-methylphenyl ] -1,3, 5-triazin-2-yl ] -glycine;

(15)4- [2- [ [4- [ (5-aminopentyl) amino ] -6- (3-fluorophenyl) -1,3, 5-triazin-2-yl ] amino ] ethyl ] -phenol;

(16)4- [2- [ [4- [ (5-aminopentyl) amino ] -6- (4-fluorophenyl) -1,3, 5-triazin-2-yl ] amino ] ethyl ] -phenol;

(17)6- (4-Aminopyridin-3-yl) -N²-benzyl-N⁴- (tert-butyl) -1,3, 5-triazine-2, 4-diamine;

(18)N²,N⁴-bis (cyclohexylmethyl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine;

(19)4,4' - [ [6- [3, 5-bis (1, 1-dimethylethyl) -4-hydroxyphenyl ] -1,3, 5-triazine-2, 4-diyl ] bis (imino-3, 1-propanediyl) ] bis [2, 6-bis (1, 1-dimethylethyl) -phenol;

(20)4,4' - [ (6-phenyl-1, 3, 5-triazine-2, 4-diyl) bis (imino-3, 1-propanediyl) ] bis [2, 6-bis (1, 1-dimethylethyl) -phenol;

(21) n- [6- [ (2, 3-dihydro-1H-inden-2-yl) amino ] -2- (2-pyridyl) -4-pyrimidinyl ] -beta alanine;

(22)N⁴-cyclopentyl-2-phenyl-N⁶- (phenylmethyl) -4, 6-pyrimidinediamine;

(23)2- [ [6- (bicyclo [2.2.1] hept-2-ylamino) -2-phenyl-4-pyrimidinyl ] amino ] -ethanol;

(24)N²-isopropyl-6-phenyl-N4- (tetrahydro-2H-pyran-4-yl) -1,3, 5-triazine-2, 4-diamine;

(25) 2-chloro-4- (methylsulfonyl) -N- [4- [ (phenylmethyl) amino ] -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] -benzamide;

(26) n- [ [4- [ [ [4- (cyclopropylamino) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methyl ] cyclohexyl ] methyl ] -4-fluoro-benzenesulfonamide;

(27) [ [4- [ [ [ [ [ [ 4-amino-6- (4-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methoxy ] methyl ] amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] imino ] biscresol;

(28) [ [4- [ [ [ [ [ [4- [ bis (hydroxymethyl) amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methoxy ] methyl ] (hydroxymethyl) amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] imino ] biscresol;

(29) ethyl 5- [4, 6-bis (diethylamino) -1,3, 5-triazin-2-yl ] -2H-tetrazole-2-acetate;

(30)N²,N²,N⁴,N⁴-tetraethyl-6- (2H-tetrazol-5-yl) -1,3, 5-triazine-2, 4-diamine;

(31) n, N' - [6- [4- (acetylamino) -1,2, 5-oxadiazol-3-yl ] -1,3, 5-triazine-2, 4-diyl ] diacetamide;

(32) n- (2-chloro-6-methylphenyl) -5- [ [4- (dimethylamino) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] amino ] -1,3, 4-oxadiazole-2-carboxamide;

(33) n4- (5-methyl-1H-pyrazol-3-yl) -2- (2-pyridinyl) -N6- (tetrahydro-2H-pyran-4-yl) -4, 6-pyrimidinediamine;

(34)6- (4-chlorophenyl) -N2- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N4- [3- (diethylamino) propyl ] -1,3, 5-triazine-2, 4-diamine;

(35)6- (4-chlorophenyl) -N2- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N4- [3- (dimethylamino) propyl ] -1,3, 5-triazine-2, 4-diamine;

(36) n2- [3, 5-bis (trifluoromethyl) phenyl ] -6- (4-chlorophenyl) -N4- [3- (diethylamino) propyl ] -1,3, 5-triazine-2, 4-diamine;

(37) n2, N4-bis [ (4-methoxyphenyl) methyl ] -6- [4- (trifluoromethoxy) phenyl ] -1,3, 5-triazine-2, 4-diamine;

(38) n, N "- (6-phenyl-1, 3, 5-triazine-2, 4-diyl) bis [ N' - (2-chloroethyl) -urea;

(39) n- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - [ 4-methyl-3- [ [ 4-phenyl-6- (propylamino) -1,3, 5-triazin-2-yl ] amino ] phenyl ] -urea;

(40) n- [4- [ [5- [ [ [ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino ] carbonyl ] amino ] -2-methylphenyl ] amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] -glycine;

(41) n- [4- [ [5- [ [ [ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino ] carbonyl ] amino ] -2-methylphenyl ] amino ] -6- (5-thiazolyl) -1,3, 5-triazin-2-yl ] -L-valine;

(42) 2-phenyl-4, 6-bis [ [6- [ [ 4-phenyl-6- (trichloromethyl) -s-triazin-2-yl ] amino ] hexyl ] amino ] -s-triazine;

(43) α, α' - [ (6-phenyl-1, 3, 5-triazine-2, 4-diyl) bis [ imino (1,1,2, 2-tetrafluoro-3-oxo-3, 1-propanediyl) ] ] bis [ ω - [ tetrafluoro (trifluoromethyl) ethoxy ] -poly [ oxy [ trifluoro (trifluoromethyl) -1, 2-ethanediyl ] ];

(44) α - [ [4- [ [ (3-chlorophenyl) methyl ] amino ] -6- (1H-imidazol-1-yl) -1,3, 5-triazin-2-yl ] amino ] -N- [ [4- (trifluoromethyl) phenyl ] methyl ] -, (α R) -cyclohexanepropionamide;

(45)6- (1H-imidazol-1-yl) -N²,N⁴-bis (1-methylethyl) -1,3, 5-triazine-2, 4-diamine; and

(46)N²,N⁴bis (1-methylpropyl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine.

A compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, and IIId or a compound as described in any one of the embodiments herein inhibits mutant IDH1 or mutant IDH 2. Also described herein are pharmaceutical compositions comprising compounds of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, and IIId, and methods of using such compositions to treat cancers characterized by the presence of mutant IDH1 or mutant IDH 2.

Detailed Description

The details of the construction and arrangement of the components set forth in the following description are not intended to be limiting. Other embodiments and different ways of practicing the invention are explicitly included. Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having," "containing," "involving," and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

Defining:

the term "halo" or "halogen" refers to any of fluorine, chlorine, bromine, or iodine.

The term "alkyl" refers to a fully saturated or unsaturated hydrocarbon chain containing the specified number of carbon atoms, which hydrocarbon chain may be straight or branched. E.g. C₁-C₁₂Alkyl means that the group may have from 1 to 12 (inclusive) carbon atoms in the group. The term "haloalkyl" refers to an alkyl group wherein one or more hydrogen atoms are replaced with a halo group, and includes alkyl moieties wherein all hydrogens have been replaced with halo groups (e.g., perfluoroalkyl groups). The term "arylalkyl" or "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced with an aryl group. Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of "arylalkyl" or "aralkyl" groups include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl. The term "alkyl" includes "alkenyl" and "alkynyl".

The term "alkylene" refers to a divalent alkyl group, such as-CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-and-CH₂CH(CH₃)CH₂-。

The term "alkenyl" refers to a straight or branched hydrocarbon chain containing 2 to 12 carbon atoms and having one or more double bonds. Examples of alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl, and 3-octenyl. One of the double bond carbons may optionally be the point of attachment for the alkenyl substituent.

The term "alkynyl" refers to a straight or branched hydrocarbon chain containing 2 to 12 carbon atoms and characterized by having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of an alkynyl substituent.

The term "alkoxy" refers to-O-alkyl. The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms have been replaced with halo, and includes alkoxy moieties in which all hydrogens have been replaced with halo (e.g., perfluoroalkoxy).

Unless otherwise indicated, the term "aryl" refers to a fully aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring system. Examples of aryl moieties are phenyl, naphthyl and anthracenyl. Unless otherwise specified, any ring atom in an aryl group may be substituted with one or more substituents. The term "monocyclic aryl" means a monocyclic, fully aromatic hydrocarbon ring system, optionally substituted with one or more substituents that do not form a fused bicyclic or tricyclic ring.

The term "carbocyclyl" refers to a non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system. Carbocyclyl groups include fully saturated ring systems (e.g., cycloalkyl) and partially saturated ring systems. Carbocyclyl also includes spiro moieties. Examples of spiro moieties include, but are not limited to, bicyclo [3.1.0] hexyl, spiro [2.2] pentyl, spiro [3.3] heptyl, spiro [2.5] octyl, spiro [3.5] nonyl, spiro [4.5] decyl, and spiro [3.6] decyl. Unless otherwise specified, any ring atom in a carbocyclyl group may be substituted with one or more substituents.

Bicyclic or tricyclic ring systems in which an aryl group is fused to a carbocyclic group and the point of attachment from the ring system to the rest of the molecule passes through a non-aromatic ring are considered carbocyclic groups (e.g., cycloalkyl). Examples of such carbocyclyl moieties include, but are not limited to, 2, 3-dihydro-1H-indene and 1,2,3, 4-tetrahydronaphthalene.

The term "cycloalkyl" as used herein includes saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having from 3 to 12 carbons. Any ring atom may be substituted (e.g., with one or more substituents). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.

Unless otherwise indicated, the term "heteroaryl" refers to a group having 1-3 heteroatoms (if monocyclic), 1-6 heteroatomsA fully aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system of heteroatoms (if bicyclic) or 1-9 heteroatoms (if tricyclic) selected from O, N or S (or oxidized forms, such as N⁺-O-, S (O) and S (O)₂). The term "monocyclic heteroaryl" means a monocyclic fully aromatic ring system having 1-3 heteroatoms, optionally substituted with one or more substituents that do not form a fused bicyclic or tricyclic ring.

The term "heterocyclyl" refers to a non-aromatic 3-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic), or 1-9 heteroatoms (if tricyclic), selected from O, N or S (or oxidized forms, such as N⁺-O-, S (O) and S (O)₂). The heteroatom may optionally be the point of attachment of a heterocyclyl substituent. Examples of heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, pyrrolinyl, pyrimidinyl, and pyrrolidinyl. Heterocyclyl includes fully saturated ring systems and partially saturated ring systems.

Both bicyclic and tricyclic systems and aromatic and non-aromatic rings containing one or more heteroatoms are considered heterocyclyl or heteroaryl. Bicyclic or tricyclic ring systems in which the aryl or heteroaryl group is fused to a carbocyclic or heterocyclic group and the point of attachment from the ring system to the rest of the molecule passes through the aromatic ring are correspondingly considered as aryl or heteroaryl. Bicyclic or tricyclic ring systems in which the aryl or heteroaryl group is fused to the carbocyclic or heterocyclic group and the point of attachment from the ring system to the rest of the molecule passes through a non-aromatic ring are correspondingly considered carbocyclic (e.g., cycloalkyl) or heterocyclic groups.

Aryl, heteroaryl, carbocyclyl (including cycloalkyl), and heterocyclyl, either alone or as part of a group (e.g., the aryl portion of an aralkyl), are optionally substituted at one or more substitutable atoms with substituents independently selected from: halo, -C ≡ N, C₁-C₄Alkyl, ═ O, -OR^b、-OR^b’、-SR^b、-SR^b’、-(C₁-C₄Alkyl) -N (R)^b)(R^b)、-(C₁-C₄Alkyl) -N (R)^b)(R^b’)、-N(R^b)(R^b)、-N(R^b)(R^b’)、-O-(C₁-C₄Alkyl) -N (R)^b)(R^b)、-O-(C₁-C₄Alkyl) -N (R)^b)(R^b’)、-(C₁-C₄Alkyl) -O- (C₁-C₄Alkyl) -N (R)^b)(R^b)、-(C₁-C₄Alkyl) -O- (C₁-C₄Alkyl) -N (R)^b)(R^b’)、-C(O)-N(R^b)(R^b)、-(C₁-C₄Alkyl) -C (O) -N (R)^b)(R^b)、-(C₁-C₄Alkyl) -C (O) -N (R)^b)(R^b’)、-OR^b’、R^b’、-C(O)(C₁-C₄Alkyl), -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)SO₂(R^b)、-SO₂N(R^b)(R^b)、-N(R^b)SO₂(R^b’) and-SO₂N(R^b)(R^b’) Wherein any alkyl substituent is optionally further substituted by-OH, -O- (C)₁-C₄Alkyl), halo, -NH₂、-NH(C₁-C₄Alkyl) or-N (C)₁-C₄Alkyl radical)₂One or more substitutions of (a);

each R^bAre all independently selected from hydrogen and-C₁-C₄An alkyl group; or

Two R^bTogether with the nitrogen atom to which it is bound, form a 4-to 8-membered heterocyclyl, which optionally contains an additional heteroatom selected from N, S and O; and is

Each R^b’Are all independently selected from C₃-C₇Carbocyclyl, phenyl, heteroaryl and heterocyclyl wherein one or more substitutable positions on said phenyl, cycloalkyl, heteroaryl or heterocyclic substituent are optionally further substituted by- (C)₁-C₄Alkyl), - (C)₁-C₄Fluoroalkyl), -OH, -O- (C)₁-C₄Alkyl), -O- (C)₁-C₄Fluoroalkyl), halo, -NH₂、-NH(C₁-C₄Alkyl) or-N (C)₁-C₄Alkyl radical)₂One or more substitutions of (a).

Heterocyclyl is optionally oxo, -C on one or more of any substitutable nitrogen atom, either alone or as part of a group₁-C₄Alkyl or fluoro-substituted C₁-C₄Alkyl substitution.

The term "substituted" means that a hydrogen atom is replaced with another group.

The term "bodily fluid" includes one or more of the following: amniotic fluid surrounding the fetus, aqueous fluid, blood (e.g., plasma), serum, cerebrospinal fluid, cerumen, chyme, cowper's fluid, female ejaculatory fluid, interstitial fluid, lymph, breast milk, mucus (e.g., nasal drainage or sputum), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal secretions, or vomit.

As used herein, the term "inhibit" or "prevent" includes both complete and partial inhibition as well as prevention. The inhibitor may inhibit the intended target, in whole or in part.

The term "treating" means reducing, inhibiting, attenuating, impairing, preventing or stabilizing the development or progression of a disease/disorder (e.g., cancer), lessening the severity of the disease/disorder (e.g., cancer) or ameliorating the symptoms associated with the disease/disorder (e.g., cancer).

As used herein, an amount of a compound that is effective to treat a condition or a "therapeutically effective amount" refers to an amount of the compound that, after a single or multiple doses are administered to a subject, is more effective than would be expected in the absence of such treatment to treat cells or to cure, alleviate, or ameliorate a subject suffering from a condition.

As used herein, the term "subject" is intended to include humans as well as non-human animals. Exemplary human subjects include human patients (referred to as patients) or normal subjects suffering from a disorder, e.g., a disorder described herein. The term "non-human animal" in one aspect of the invention includes all vertebrates, e.g., non-mammals (e.g., chickens, amphibians, reptiles) and mammals, e.g., non-human primates, domestic and/or agriculturally useful animals, e.g., sheep, dogs, cats, cattle, pigs, etc.

Compound (I)

There is provided a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

x is N, CH or C-halo;

present in R²And R⁵Any terminal methyl moiety in (a) is optionally substituted with-CH₂OH、CF₃、-CH₂F、-CH₂Cl、C(O)CH₃、C(O)CF₃CN or CO₂H replacement;

wherein:

(iii) when X is CH and A is optionalWhen substituted pyridyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NHCH₂-phenyl, NHCH₂- (2, 4-difluorophenyl), N (CH)₃)CH₂CH₂C(O)OH、NHCH₂CH₂C(O)OH、NHCH₂CH₂C(O)OCH₂CH₃、NHCH₂CH₂C (O) O-tert-butyl, NHCH₂CH₂C(O)NH₂、NHCH₂CH₂-phenyl, NHCH₂CH₂OH、NHCH₂CH₂NH₂、NHCH₂CH₂N(CH₃)₂Or NHCH₂CH₂CH₃；

(iv) When X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1-pyrrolyl or optionally substituted 1-pyrazolyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NH (CH)₂)₇CH₃、NHCH₂- (o-chloro-phenyl) or NHCH₂CH₂OH；

(vii) When X is CH and A is unsubstituted 2-pyridyl, then⁴And R⁵The ring formed is not 5-methyl-1H-pyrazol-3-yl,

(viii) when A is optionally substituted 1-pyrazolyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not all N (CH)₃)₂、NHCH₃NHAc, NH isopropyl, NHCH₂CH₃、NHCH₂CH₂SO₃H or N (CH)₂CH₃)₂，

(ix) When X is N and A is optionally substituted phenyl, thienyl or pyridyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) None of NH cyclohexyl C (O) NHCH₂R, wherein R is OCF₃、OCH₃Chlorine or CF₃One or more substituted phenyl or pyridyl groups of (a),

(x) When X is N, A is optionally substituted phenyl and R⁴And R⁵When an optionally substituted phenyl group is formed, then N (R)⁸)C(R¹)(R²)(R³) Is not NHCH₂(4-fluorophenyl), NHCH₂CO₂H、NHCH₂C(O)Cl、NHCH(CO₂H)(CH₂SCH₂Phenyl), NHCH₂C (O) NHC (O) NHR or NHCH₂C (O) NHC (S) NHR, wherein R is optionally substituted phenyl or naphthyl,

(xi) When X is N, A is an oxadiazole substituted by an optionally substituted pyridyl group, then R is⁴And R⁵Does not form an optionally substituted phenyl group,

(xii) When A is substituted 1-pyrazolyl, then (A) N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both are not NHC (CH)₃)₃(ii) a And (B) A is not substituted by N ═ N-R, where R is a ring,

(xiii) Ring A is not optionally substituted triazolyl, 3, 5-dimethyl-1H-pyrazol-1-yl,

(xx) The compound is not selected from the group consisting of:

(1) n- (2-aminophenyl) -4- [ [ [4- [ (2, 3-dihydro-1H-inden-2-yl) amino ] -6-phenyl-1, 3, 5-triazin-2-yl ] amino ] methyl ] -benzamide,

(2) 2-chloro-N- [4- (cyclopropyl) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] -4- (methylsulfonyl) -benzamide,

(3)2- [ [1- [4- (cyclopropyl) -6- (ethylamino) -1,3, 5-triazin-2-yl ] -1H-1,2, 4-triazol-3-yl ] sulfanyl ] -acetamide,

(4)N²-cyclopropyl-N⁴-ethyl-6- [3- [ (phenylmethyl) thio]-1H-1,2, 4-triazol-1-yl]1,3, 5-triazine-2, 4-diamine,

(5)2- [ [1- [4- (cyclopropyl) -6- (ethylamino) -1,3, 5-triazin-2-yl ] -1H-1,2, 4-triazol-3-yl ] sulfanyl ] -acetic acid methyl ester,

(6) n- [ [4- [ [ [4- (cyclopropylamino) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methyl ] cyclohexyl ] methyl ] -4-fluoro-benzenesulfonamide,

(7)N²-cyclopropyl-6- (3, 5-dimethyl-1H-pyrazol-1-yl) -N⁴Phenyl-1, 3, 5-triazine-2, 4-diamine,

(8)N²,N⁴-dicyclohexyl-6- [3- (4-methoxyphenyl) -5- (methylthio) -1H-pyrazol-1-yl]1,3, 5-triazine-2, 4-diamine,

(9)N²,N⁴-dicyclohexyl-6- [3- (3, 4-dimethoxyphenyl) -5- (methylthio) -1H-pyrazol-1-yl]1,3, 5-triazine-2, 4-diamine,

(10)N²,N⁴-dicyclohexyl-6- [5- (methylthio) -3- (3,4, 5-trimethoxyphenyl) -1H-pyrazol-1-yl]1,3, 5-triazine-2, 4-diamine,

(11)N²,N⁴-dicyclohexyl-6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(12)1,1' - [ (6-phenyl-s-triazine-2, 4-diyl) diimino ] bis [ dodecahydro-anthraquinone ],

(13)4,4' - [ (6-phenyl-1, 3, 5-triazine-2, 4-diyl) bis (iminomethylene) ] bis [2, 6-bis (1, 1-dimethylethyl) -phenol,

(14) n- [4- [ (4-aminobutyl) amino ] -6- [5- [ [ [ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino ] carbonyl ] amino ] -2-methylphenyl ] -1,3, 5-triazin-2-yl ] -glycine,

(15)4- [2- [ [4- [ (5-aminopentyl) amino ] -6- (3-fluorophenyl) -1,3, 5-triazin-2-yl ] amino ] ethyl ] -phenol,

(16)4- [2- [ [4- [ (5-aminopentyl) amino ] -6- (4-fluorophenyl) -1,3, 5-triazin-2-yl ] amino ] ethyl ] -phenol,

(17)6- (4-Aminopyridin-3-yl) -N²-benzyl-N⁴- (tert-butyl) -1,3, 5-triazine-2, 4-diamine,

(18)N²,N⁴bis (cyclohexylmethyl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(19)4,4' - [ [6- [3, 5-bis (1, 1-dimethylethyl) -4-hydroxyphenyl ] -1,3, 5-triazine-2, 4-diyl ] bis (imino-3, 1-propanediyl) ] bis [2, 6-bis (1, 1-dimethylethyl) -phenol,

(20)4,4' - [ (6-phenyl-1, 3, 5-triazine-2, 4-diyl) bis (imino-3, 1-propanediyl) ] bis [2, 6-bis (1, 1-dimethylethyl) -phenol,

(21) n- [6- [ (2, 3-dihydro-1H-inden-2-yl) amino ] -2- (2-pyridyl) -4-pyrimidinyl ] -beta-alanine,

(22)N⁴-cyclopentyl-2-phenyl-N⁶- (phenylmethyl) -4, 6-pyrimidinediamine,

(23)2- [ [6- (bicyclo [2.2.1] hept-2-ylamino) -2-phenyl-4-pyrimidinyl ] amino ] -ethanol,

(24)N²-isopropyl-6-phenyl-N4- (tetrahydro-2H-pyran-4-yl) -1,3, 5-triazine-2, 4-diamine,

(25) 2-chloro-4- (methylsulfonyl) -N- [4- [ (phenylmethyl) amino ] -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] -benzamide,

(26) n- [ [4- [ [ [4- (cyclopropylamino) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methyl ] cyclohexyl ] methyl ] -4-fluoro-benzenesulfonamide,

(27) [ [4- [ [ [ [ [ [ 4-amino-6- (4-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methoxy ] methyl ] amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] imino ] biscresol,

(28) [ [4- [ [ [ [ [ [4- [ bis (hydroxymethyl) amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methoxy ] methyl ] (hydroxymethyl) amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] imino ] biscresol,

(29) ethyl 5- [4, 6-bis (diethylamino) -1,3, 5-triazin-2-yl ] -2H-tetrazole-2-acetate,

(30)N²,N²,N⁴,N⁴-tetraethyl-6- (2H-tetrazol-5-yl) -1,3, 5-triazine-2, 4-diamine,

(31) n, N' - [6- [4- (acetylamino) -1,2, 5-oxadiazol-3-yl ] -1,3, 5-triazine-2, 4-diyl ] diacetic acid amide,

(32) n- (2-chloro-6-methylphenyl) -5- [ [4- (dimethylamino) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] amino ] -1,3, 4-oxadiazole-2-carboxamide,

(33) n4- (5-methyl-1H-pyrazol-3-yl) -2- (2-pyridinyl) -N6- (tetrahydro-2H-pyran-4-yl) -4, 6-pyrimidinediamine,

(34)6- (4-chlorophenyl) -N2- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N4- [3- (diethylamino) propyl ] -1,3, 5-triazine-2, 4-diamine,

(35)6- (4-chlorophenyl) -N2- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N4- [3- (dimethylamino) propyl ] -1,3, 5-triazine-2, 4-diamine,

(36) n2- [3, 5-bis (trifluoromethyl) phenyl ] -6- (4-chlorophenyl) -N4- [3- (diethylamino) propyl ] -1,3, 5-triazine-2, 4-diamine,

(37) n2, N4-bis [ (4-methoxyphenyl) methyl ] -6- [4- (trifluoromethoxy) phenyl ] -1,3, 5-triazine-2, 4-diamine,

(38) n, N '- (6-phenyl-1, 3, 5-triazine-2, 4-diyl) bis [ N' - (2-chloroethyl) -urea,

(39) n- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - [ 4-methyl-3- [ [ 4-phenyl-6- (propylamino) -1,3, 5-triazin-2-yl ] amino ] phenyl ] -urea,

(40) n- [4- [ [5- [ [ [ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino ] carbonyl ] amino ] -2-methylphenyl ] amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] -glycine,

(41) n- [4- [ [5- [ [ [ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino ] carbonyl ] amino ] -2-methylphenyl ] amino ] -6- (5-thiazolyl) -1,3, 5-triazin-2-yl ] -L-valine,

(42) 2-phenyl-4, 6-bis [ [6- [ [ 4-phenyl-6- (trichloromethyl) -s-triazin-2-yl ] amino ] hexyl ] amino ] -s-triazine,

(43) α, α' - [ (6-phenyl-1, 3, 5-triazine-2, 4-diyl) bis [ imino (1,1,2, 2-tetrafluoro-3-oxo-3, 1-propanediyl) ] ] bis [ ω - [ tetrafluoro (trifluoromethyl) ethoxy ] -poly [ oxy [ trifluoro (trifluoromethyl) -1, 2-ethanediyl ] ],

(44) alpha- [ [4- [ [ (3-chlorophenyl) methyl ] amino ] -6- (1H-imidazol-1-yl) -1,3, 5-triazin-2-yl ] amino ] -N- [ [4- (trifluoromethyl) phenyl ] methyl ] -, (alpha R) -cyclohexanepropionamide,

(45)6- (1H-imidazol-1-yl) -N²,N⁴Bis (1-methylethyl) -1,3, 5-triazine-2, 4-diamine, and

(46)N²,N⁴bis (1-methylpropyl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine。

wherein:

x is N, CH or C-halo;

R¹、R³、R⁴and R⁶Each independently selected from hydrogen and C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -O-C₁-C₄Alkyl and CN, wherein R¹、R³、R⁴And R⁶Each independently of the other, is optionally substituted by-OH, -NH₂、-CN、-O-C₁-C₄Alkyl, -NH (C)₁-C₄Alkyl) or-N (C)₁-C₄Alkyl radical)₂Substitution;

R²and R⁵Each independently selected from: - (C)₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₁-C₆Alkyl) -CO₂H、-(C₂-C₆Alkenyl or alkynyl), -C₁-C₆Alkylene) -N (R)⁶)-(C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -N (R)⁶)-(C₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -N (R)⁶)(R⁶)、-(C₁-C₆Alkylene) -N (R)⁶)-S(O)_1-2-(C₁-C₆Alkyl), - (C)₁-C₆Alkylene) -N (R)⁶)-S(O)_1-2-(C₀-C₆Alkyl) -Q, - (C)₁-C₆Alkylene) -S (O)_1-2-N(R⁶)(R⁶)、-(C₁-C₄Alkylene) -S (O)_1-2-N(R⁶)-(C₁-C₆Alkylene radical)-Q、-C(O)N(R⁶)-(C₁-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₁-C₆Alkyl), -C (O) N (R)⁶)-(C₁-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -O-C (O) - (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -O-C (O) - (C)₀-C₆Alkyl) -Q, - (C)₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -O- (C)₁-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₁-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -O-C (O) - (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -O-C (O) - (C)₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -N (R)⁶)C(O)-(C₁-C₆Alkyl), - (C)₁-C₆Alkylene) -N (R)⁶)C(O)-(C₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -S (O)_0-2-(C₁-C₆Alkyl), - (C)₀-C₆Alkylene) -S (O)_0-2-(C₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -N (R)⁶)-C(O)-N(R⁶)-(C₁-C₆Alkyl), - (C)₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) - (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -Q, wherein:

R⁴And R⁵Optionally together forming an optionally substituted carbocyclyl or optionally substituted heterocyclyl;

wherein:

(i) when X is N and A is optionally substituted phenyl, then (a) N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not 4- [ [2- [2- (2-aminoethoxy) ethoxy ] ethoxy]Ethyl radical]Amino group]And (b) N (R7) C (R4) (R5) (R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not NHEt, NH (n-propyl), NH (n-butyl), NH (n-dodecyl), NH- [ (4-methoxyphenyl) methyl]、NHCH₂CH₂CHO、NHCH₂CH₂OCH₃、NHCH₂CH₂OH、NHCH₂CH(OH)CH₃、NHCH₂CH₂OC (O) phenyl, NHCH₂CH₂CH₂OH、NHCH₂CH₂CH₂N(CH₃) Phenyl, NHCH₂C(O)OCH₃、NHCH₂C(O)OCH₂CH₃、NHCH₂Phenyl, NHCH (CH)₃)CH₂CH₃Or NHCH₂CH₂OC(O)CH₃；

(v) When X is N and A is an optionally substituted pyridyl group, then (A) N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NHC (O) - [ 2-chloro-4- (methylsulfonyl)]；(B)N(R⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not NHC (O) C (CH)₃)₃、NHC(O)CH＝CH₂、NHC(O)C(CH₃)＝CH₂、NHCH₂CH₂OH, NH-cyclohexyl, NHCH₂Phenyl, NHC (O) (CH)₂)₅NH₂、NHC(O)OCH₃、NHC(O)CH₃And phenyl optionally substituted with nhc (o) NH; and (C) when N (R)⁷)C(R⁴)(R⁵)(R⁶) Is NHC (CH)₃)₃Then N (R)⁸)C(R¹)(R²)(R³) Is not NHCH₂-phenyl or NH-CH₂CH₃；

(vii) The compound is not selected from the group consisting of:

(1)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N⁴-cyclopentyl-6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(2)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N⁴-cyclopentyl-6- (4-methoxyphenyl) -1,3, 5-triazine-2, 4-diamine,

(3)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N⁴-cyclopentyl-6- (3-nitrophenyl) -1,3, 5-triazine-2, 4-diamine,

(4)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N⁴-cyclopentyl-6- (4-fluorophenyl) -1,3, 5-triazine-2, 4-diamine,

(5)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N⁴-cyclopentyl-6- (4-trifluoromethoxy-phenyl) -1,3, 5-triazine-2, 4-diamine,

(6)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N⁴-cyclopentyl-6- (4-tert-butyl-phenyl) -1,3, 5-triazine-2, 4-diamine,

(7)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N⁴-cyclopentyl-6- (2-thienyl) -1,3, 5-triazine-2, 4-diamine,

(8) n- (2-aminophenyl) -4- [ [ [4- [ (2, 3-dihydro-1H-inden-2-yl) amino ] -6-phenyl-1, 3, 5-triazin-2-yl ] amino ] methyl ] -benzamide,

(9) 2-chloro-N- [4- (cyclopropyl) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] -4- (methylsulfonyl) -benzamide,

(10)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N⁴-cyclopropyl-6- (4-methoxyphenyl) -1,3, 5-triazine-2, 4-diamine,

(11)2- [ [1- [4- (cyclopropyl) -6- (ethylamino) -1,3, 5-triazin-2-yl ] -1H-1,2, 4-triazol-3-yl ] sulfanyl ] -acetamide,

(12)N²-cyclopropyl-N⁴-ethyl-6- [3- [ (phenylmethyl) thio]-1H-1,2, 4-triazol-1-yl]1,3, 5-triazine-2, 4-diamine,

(13)2- [ [1- [4- (cyclopropyl) -6- (ethylamino) -1,3, 5-triazin-2-yl ] -1H-1,2, 4-triazol-3-yl ] sulfanyl ] -acetic acid methyl ester,

(14)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N⁴-cyclopropyl-6- (2,4, 6-trimethylphenyl) -1,3, 5-triazine-2, 4-diamine,

(15)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N⁴-cyclopropyl-6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(16)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N⁴-cyclopropyl-6- (4-methylphenyl) -1,3, 5-triazine-2, 4-diamine,

(17)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N⁴-cyclopropyl-6- (4-chlorophenyl) -1,3, 5-triazine-2, 4-diamine,

(18) n- [ [4- [ [ [4- (cyclopropylamino) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methyl ] cyclohexyl ] methyl ] -4-fluoro-benzenesulfonamide,

(19)N²-cyclopropyl-6- (3, 5-dimethyl-1H-pyrazol-1-yl) -N⁴Phenyl-1, 3, 5-triazine-2, 4-diamine,

(20)N²,N⁴-dicyclohexyl-6- [3- (4-methoxyphenyl) -5- (methylthio) -1H-pyrazol-1-yl]1,3, 5-triazine-2, 4-diamine,

(21)N²,N⁴-dicyclohexyl-6- [3- (3, 4-dimethoxyphenyl) -5- (methylthio) -1H-pyrazol-1-yl]1,3, 5-triazine-2, 4-diamine,

(22)N²,N⁴-dicyclohexyl-6- [5- (methylthio) -3- (3,4, 5-trimethoxyphenyl) -1H-pyrazol-1-yl]1,3, 5-triazine-2, 4-diamine,

(23)N²,N⁴-dicyclohexyl-6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(24)1,1' - [ (6-phenyl-s-triazine-2, 4-diyl) diimino ] bis [ dodecahydro-anthraquinone ],

(25)4,4' - [ (6-phenyl-1, 3, 5-triazine-2, 4-diyl) bis (iminomethylene) ] bis [2, 6-bis (1, 1-dimethylethyl) -phenol,

(26) n- [4- [ (4-aminobutyl) amino ] -6- [5- [ [ [ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino ] carbonyl ] amino ] -2-methylphenyl ] -1,3, 5-triazin-2-yl ] -glycine,

(27)4- [2- [ [4- [ (5-aminopentyl) amino ] -6- (3-fluorophenyl) -1,3, 5-triazin-2-yl ] amino ] ethyl ] -phenol,

(28)4- [2- [ [4- [ (5-aminopentyl) amino ] -6- (4-fluorophenyl) -1,3, 5-triazin-2-yl ] amino ] ethyl ] -phenol,

(29)6- (4-Aminopyridin-3-yl) -N²-benzyl-N⁴- (tert-butyl) -1,3, 5-triazine-2, 4-diamine,

(30)N²,N⁴bis (cyclohexylmethyl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(31)4,4' - [ [6- [3, 5-bis (1, 1-dimethylethyl) -4-hydroxyphenyl ] -1,3, 5-triazine-2, 4-diyl ] bis (imino-3, 1-propanediyl) ] bis [2, 6-bis (1, 1-dimethylethyl) -phenol,

(32)4,4' - [ (6-phenyl-1, 3, 5-triazine-2, 4-diyl) bis (imino-3, 1-propanediyl) ] bis [2, 6-bis (1, 1-dimethylethyl) -phenol,

(33) n- [6- [ (2, 3-dihydro-1H-inden-2-yl) amino ] -2- (2-pyridyl) -4-pyrimidinyl ] -beta-alanine,

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

(35)2- [ [6- (bicyclo [2.2.1] hept-2-ylamino) -2-phenyl-4-pyrimidinyl ] amino ] -ethanol,

(36)N²-isopropyl-6-phenyl-N4- (tetrahydro-2H-pyran-4-yl) -1,3, 5-triazine-2, 4-diamine,

(37) 2-chloro-4- (methylsulfonyl) -N- [4- [ (phenylmethyl) amino ] -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] -benzamide,

(38) n- [ [4- [ [ [4- (cyclopropylamino) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methyl ] cyclohexyl ] methyl ] -4-fluoro-benzenesulfonamide,

(39) [ [4- [ [ [ [ [ [ 4-amino-6- (4-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methoxy ] methyl ] amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] imino ] biscresol,

(40) [ [4- [ [ [ [ [ [4- [ bis (hydroxymethyl) amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methoxy ] methyl ] (hydroxymethyl) amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] imino ] biscresol,

(41) ethyl 5- [4, 6-bis (diethylamino) -1,3, 5-triazin-2-yl ] -2H-tetrazole-2-acetate,

(42)N²,N²,N⁴,N⁴-tetraethyl-6- (2H-tetrazol-5-yl) -1,3, 5-triazine-2, 4-diamine, and

(43) n, N' - [6- [4- (acetylamino) -1,2, 5-oxadiazol-3-yl ] -1,3, 5-triazine-2, 4-diyl ] bisacetamide.

wherein:

x is N or CH;

wherein:

(vii) The compound is not selected from the group consisting of:

(12)N²-cyclopropyl-N4-ethyl-6- [3- [ (phenylmethyl) thio]-1H-1,2, 4-triazol-1-yl]1,3, 5-triazine-2, 4-diamine,

(14)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N4-cyclopropyl-6- (2,4, 6-trimethylphenyl) -1,3, 5-triazine-2, 4-diamine,

(15)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N4-cyclopropyl-6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(16)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N4-cyclopropyl-6- (4-methylphenyl) -1,3, 5-triazine-2, 4-diamine,

(17)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N4-cyclopropyl-6- (4-chlorophenyl) -1,3, 5-triazine-2, 4-diamine,

(23)N²,N⁴-dicyclohexyl-6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(30)N²,N⁴bis (cyclohexylmethyl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine,

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

Also provided is a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

x is N or CH;

wherein:

(ix) When X is N and A is optionally substituted phenyl, thienyl or pyridyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) None of NH cyclohexyl C (O) NHCH₂R, wherein R is OCF₃、OCH₃Chlorine or CF₃Is taken by one or more ofA substituted phenyl group or a pyridyl group,

(xx) The compound is not selected from the group consisting of:

(4)N²-cyclopropyl-N⁴-ethyl-6- [3- [ (phenylmethyl) methyl ] carbonylRadical) thio radical]-1H-1,2, 4-triazol-1-yl]1,3, 5-triazine-2, 4-diamine,

(6) n- [ [4- [ [ [4- (cyclopropyl) -6- (2-pyridinyl) -1,3, 5-triazin-2-yl ] amino ] methyl ] cyclohexyl ] methyl ] -4-fluoro-benzenesulfonamide,

(7)N²-cyclopropyl-6- (3, 5-dimethyl-1H-pyrazol-1-yl) -N4-phenyl-1, 3, 5-triazine-2, 4-diamine,

(11)N²,N⁴-dicyclohexyl-6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(18)N²,N⁴-bis (cyclohexylmethyl) -6-phenyl-1, 3, 5-trisAn oxazine-2, 4-diamine,

(22)N⁴-cyclopentyl-2-phenyl-N6- (phenylmethyl) -4, 6-pyrimidinediamine,

(45)6- (1H-imidazol-1-yl) -N2, N4-bis (1-methylethyl) -1,3, 5-triazine-2, 4-diamine, and

(46) n2, N4-bis (1-methylpropyl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine.

Also provided is a compound of formula Ia or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

R²and R⁵Each independently selected from: - (C)₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₁-C₆Alkyl) -CO₂H、-(C₂-C₆Alkenyl or alkynyl), -C₁-C₆Alkylene) -N (R)⁶)-(C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -N (R)⁶)-(C₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -N (R)⁶)(R⁶)、-(C₁-C₆Alkylene) -N (R)⁶)-S(O)_1-2-(C₁-C₆Alkyl), - (C)₁-C₆Alkylene) -N (R)⁶)-S(O)_1-2-(C₀-C₆Alkyl) -Q, - (C)₁-C₆Alkylene) -S (O)_1-2-N(R⁶)(R⁶)、-(C₁-C₄Alkylene) -S (O)_1-2-N(R⁶)-(C₁-C₆Alkylene) -Q, -C (O) N (R)⁶)-(C₁-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₁-C₆Alkyl), -C (O) N (R)⁶)-(C₁-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -O-C (O) - (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -O-C (O) - (C)₀-C₆Alkyl) -Q_、-(C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -O- (C)₁-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₁-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -O-C (O) - (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -O-C (O) - (C)₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -N (R)⁶)C(O)-(C₁-C₆Alkyl), - (C)₁-C₆Alkylene) -N (R)⁶)C(O)-(C₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -S (O)_0-2-(C₁-C₆Alkyl), - (C)₀-C₆Alkylene) -S (O)_0-2-(C₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -N (R)⁶)-C(O)-N(R⁶)-(C₁-C₆Alkyl), - (C)₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) - (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene oxideRadical) -C (O) - (C)₀-C₆Alkylene) -Q, wherein:

wherein:

(i) when A is optionally substituted phenyl, then (a) N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not 4- [ [2- [2- (2-aminoethoxy) ethoxy ] ethoxy]Ethyl radical]Amino group]And (b) N (R7) C (R4) (R5) (R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not NHEt, NH (n-propyl), NH (n-butyl), NH (n-dodecyl), NH- [ (4-methoxyphenyl) methyl]、NHCH₂CH₂CHO、NHCH₂CH₂OCH₃、NHCH₂CH₂OH、NHCH₂CH(OH)CH₃、NHCH₂CH₂OC (O) phenyl, NHCH₂CH₂CH₂OH、NHCH₂CH₂CH₂N(CH₃) Phenyl, NHCH₂C(O)OCH₃、NHCH₂C(O)OCH₂CH₃、NHCH₂Phenyl, NHCH (CH)₃)CH₂CH₃Or NHCH₂CH₂OC(O)CH₃；

(ii) When X is N and A is an optionally substituted pyridyl group, then (A) N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NHC (O) - [ 2-chloro-4- (methylsulfonyl)]；(B)N(R⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not NHC (O) C (CH)₃)₃、NHC(O)CH＝CH₂、NHC(O)C(CH₃)＝CH₂、NHCH₂CH₂OH, NH-cyclohexyl, NHCH₂Phenyl, NHC (O) (CH)₂)₅NH₂、NHC(O)OCH₃、NHC(O)CH₃And phenyl optionally substituted with nhc (o) NH; and (C) when N (R)⁷)C(R⁴)(R⁵)(R⁶) Is NHC (CH)₃)₃Then N (R)⁸)C(R¹)(R²)(R³) Is not NHCH₂-phenyl or NH-CH₂CH₃；

(iii) When X is N and A is optionally substituted heteroaryl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not being N (CH)₂CH₃)₂、NHCH₂CH₂-isopropyl, NHCH₂CH(CH₃)₂And NHC (O) CH₃(ii) a And is

(iv) The compound is not selected from the group consisting of:

(1)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N⁴-cyclopentyl-6-phenyl1,3, 5-triazine-2, 4-diamine,

(14)N²- [2- [2- (2-aminoethoxy) ethoxy group]Ethyl radical]-N⁴-cyclopropyl-6- (2, 4)6-trimethylphenyl) -1,3, 5-triazine-2, 4-diamine,

(23)N²,N⁴-dicyclohexyl-6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(30)N²,N⁴bis (cyclohexylmethyl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(33)N²-isopropyl-6-phenyl-N4- (tetrahydro-2H-pyran-4-yl) -1,3, 5-triazine-2, 4-diamine,

(34) 2-chloro-4- (methylsulfonyl) -N- [4- [ (phenylmethyl) amino ] -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] -benzamide,

(35) n- [ [4- [ [ [4- (cyclopropylamino) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methyl ] cyclohexyl ] methyl ] -4-fluoro-benzenesulfonamide,

(36) [ [4- [ [ [ [ [ [ 4-amino-6- (4-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methoxy ] methyl ] amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] imino ] biscresol,

(37) [ [4- [ [ [ [ [ [4- [ bis (hydroxymethyl) amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methoxy ] methyl ] (hydroxymethyl) amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] imino ] biscresol,

(38) ethyl 5- [4, 6-bis (diethylamino) -1,3, 5-triazin-2-yl ] -2H-tetrazole-2-acetate,

(39)N²,N²,N⁴,N⁴-tetraethyl-6- (2H-tetrazol-5-yl) -1,3, 5-triazine-2, 4-diamine, and

(40) n, N' - [6- [4- (acetylamino) -1,2, 5-oxadiazol-3-yl ] -1,3, 5-triazine-2, 4-diyl ] bisacetamide.

wherein:

R²and R⁵Each independently selected from: - (C)₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₁-C₆Alkyl) -CO₂H、-(C₂-C₆Alkenyl or alkynyl), -C₁-C₆Alkylene) -N (R)⁶)-(C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -N (R)⁶)-(C₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -N (R)⁶)(R⁶)、-(C₁-C₆Alkylene) -N (R)⁶)-S(O)_1-2-(C₁-C₆Alkyl), - (C)₁-C₆Alkylene) -N (R)⁶)-S(O)_1-2-(C₀-C₆Alkyl) -Q, - (C)₁-C₆Alkylene) -S (O)_1-2-N(R⁶)(R⁶)、-(C₁-C₄Alkylene) -S (O)_1-2-N(R⁶)-(C₁-C₆Alkylene) -Q, -C (O) N (R)⁶)-(C₁-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₁-C₆Alkyl), -C (O) N (O)R⁶)-(C₁-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -O-C (O) - (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -O-C (O) - (C)₀-C₆Alkyl) -Q, - (C)₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -O- (C)₁-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -O- (C)₁-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -O-C (O) - (C)₁-C₆Alkyl), - (C)₁-C₆Alkylene) -O-C (O) - (C)₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -N (R)⁶)C(O)-(C₁-C₆Alkyl), - (C)₁-C₆Alkylene) -N (R)⁶)C(O)-(C₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -S (O)_0-2-(C₁-C₆Alkyl), - (C)₀-C₆Alkylene) -S (O)_0-2-(C₀-C₆Alkylene) -Q, - (C)₁-C₆Alkylene) -N (R)⁶)-C(O)-N(R⁶)-(C₁-C₆Alkyl), - (C)₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) - (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -Q, wherein:

wherein:

(i) when A is optionally substituted phenyl, then (a) N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NHCH₂CH₂OCH₂CH₂OCH₂CH₂NH₂Or 4- [ [2- [2- (2-aminoethoxy) ethoxy ] ethoxy]Ethyl radical]Amino group]And (b) N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not NHEt, NH (n-propyl), NH (n-butyl), NH (n-dodecyl), NH- [ (4-methoxyphenyl) methyl]、NHCH₂CH₂CHO、NHCH₂CH₂OCH₃、NHCH₂CH₂OH、NHCH₂CH(OH)CH₃、NHCH₂CH₂OC (O) phenyl, NHCH₂CH₂CH₂OH、NHCH₂CH₂CH₂N(CH₃) Phenyl, NHCH₂C(O)OCH₃、NHCH₂C(O)OCH₂CH₃、NHCH₂Phenyl, NHCH (CH)₃)CH₂CH₃Or NHCH₂CH₂OC(O)CH₃；

(ii) When A is an optionally substituted pyridyl group, then (A) N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NHC (O) - [ 2-chloro-4- (methylsulfonyl)]、N(CH₃)₂、NHCH₂CH₂CH₂SO₂CH₂CH₂Cl、NHCH₂CH₂OCH₂CH₂SO₂CH₂CH₂Cl or NHCH₂CH₂SO₂CH₂CH₂Cl；(B)N(R⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not NHC (O) C (CH)₃)₃、NHC(O)CH＝CH₂、NHC(O)C(CH₃)＝CH₂、NHCH₂CH₂OH, NH-cyclohexyl, NHCH₂Phenyl, NHC (O) (CH)₂)₅NH₂、NHC(O)OCH₃、NHC(O)CH₃And NHC (O) NH-optionally substituted phenyl; and (C) when N (R)⁷)C(R⁴)(R⁵)(R⁶) Is NHC (CH)₃)₃Then N (R)⁸)C(R¹)(R²)(R³) Is not NHCH₂-phenyl or NH-CH₂CH₃；

(iii) When A is optionally substituted heteroaryl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not being N (CH)₂CH₃)₂、NHCH₂CH₂-isopropyl, NHCH₂CH(CH₃)₂And NHC (O) CH₃；

(iv) When A is optionally substituted 1-pyrazolyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not all N (CH)₃)₂、NHCH₃NHAc, NH isopropyl, NHCH₂CH₃、NHCH₂CH₂SO₃H or N (CH)₂CH₃)₂，

(v) When A is optionally substituted phenyl, thienyl or pyridyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) None of NH cyclohexyl C (O) NHCH₂R, wherein R is OCF₃、OCH₃Chlorine or CF₃One or more substituted phenyl or pyridyl groups of (a),

(vi) when A is optionally substituted phenyl and R⁴And R⁵When an optionally substituted phenyl group is formed, then N (R)⁸)C(R¹)(R²)(R³) Is not NHCH₂(4-fluorophenyl), NHCH₂CO₂H、NHCH₂C(O)Cl、NHCH(CO₂H)(CH₂SCH₂Phenyl), NHCH₂C (O) NHC (O) NHR or NHCH₂C (O) NHC (S) NHR, wherein R is optionally substituted phenyl or naphthyl,

(vii) when A is an oxadiazole substituted by an optionally substituted pyridyl group, then R⁴And R⁵Does not form an optionally substituted phenyl group,

(viii) when A is substituted 1-pyrazolyl, then (A) N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both are not NHC (CH)₃)₃(ii) a And (B) A is not substituted by N ═ N-R, where R is a ring,

(ix) ring A is not optionally substituted triazolyl, 3, 5-dimethyl-1H-pyrazol-1-yl,

(x) When R is¹And R²Optionally together form an unsubstituted cyclohexyl group, and R⁴And R⁵Optionally together forming an unsubstituted cyclohexyl group, then a is not a disubstituted 1-pyrazolyl or unsubstituted phenyl;

(xi) The compound is not selected from the group consisting of:

(11)N²,N⁴-dicyclohexyl-6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(18)N²,N⁴bis (cyclohexylmethyl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(21)N²-isopropyl-6-phenyl-N4- (tetrahydro-2H-pyran-4-yl) -1,3, 5-triazine-2, 4-diamine,

(22) 2-chloro-4- (methylsulfonyl) -N- [4- [ (phenylmethyl) amino ] -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] -benzamide,

(23) n- [ [4- [ [ [4- (cyclopropylamino) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methyl ] cyclohexyl ] methyl ] -4-fluoro-benzenesulfonamide,

(24) [ [4- [ [ [ [ [ [ 4-amino-6- (4-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methoxy ] methyl ] amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] imino ] biscresol,

(25) [ [4- [ [ [ [ [ [4- [ bis (hydroxymethyl) amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methoxy ] methyl ] (hydroxymethyl) amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] imino ] biscresol,

(26) ethyl 5- [4, 6-bis (diethylamino) -1,3, 5-triazin-2-yl ] -2H-tetrazole-2-acetate,

(27)N²,N²,N⁴,N⁴-tetraethyl-6- (2H-tetrazol-5-yl) -1,3, 5-triazine-2, 4-diamine,

(28) n, N' - [6- [4- (acetylamino) -1,2, 5-oxadiazol-3-yl ] -1,3, 5-triazine-2, 4-diyl ] diacetic acid amide,

(29) n- (2-chloro-6-methylphenyl) -5- [ [4- (dimethylamino) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] amino ] -1,3, 4-oxadiazole-2-carboxamide,

(30)6- (4-chlorophenyl) -N2- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N4- [3- (diethylamino) propyl ] -1,3, 5-triazine-2, 4-diamine,

(31)6- (4-chlorophenyl) -N2- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N4- [3- (dimethylamino) propyl ] -1,3, 5-triazine-2, 4-diamine,

(32) n2- [3, 5-bis (trifluoromethyl) phenyl ] -6- (4-chlorophenyl) -N4- [3- (diethylamino) propyl ] -1,3, 5-triazine-2, 4-diamine,

(33) n2, N4-bis [ (4-methoxyphenyl) methyl ] -6- [4- (trifluoromethoxy) phenyl ] -1,3, 5-triazine-2, 4-diamine,

(34) n, N '- (6-phenyl-1, 3, 5-triazine-2, 4-diyl) bis [ N' - (2-chloroethyl) -urea,

(35) n- [ 4-chloro-3- (trifluoromethyl) phenyl ] -N' - [ 4-methyl-3- [ [ 4-phenyl-6- (propylamino) -1,3, 5-triazin-2-yl ] amino ] phenyl ] -urea,

(36) n- [4- [ [5- [ [ [ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino ] carbonyl ] amino ] -2-methylphenyl ] amino ] -6- (4-pyridyl) -1,3, 5-triazin-2-yl ] -glycine,

(37) n- [4- [ [5- [ [ [ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino ] carbonyl ] amino ] -2-methylphenyl ] amino ] -6- (5-thiazolyl) -1,3, 5-triazin-2-yl ] -L-valine,

(38) 2-phenyl-4, 6-bis [ [6- [ [ 4-phenyl-6- (trichloromethyl) -s-triazin-2-yl ] amino ] hexyl ] amino ] -s-triazine,

(39) α, α' - [ (6-phenyl-1, 3, 5-triazine-2, 4-diyl) bis [ imino (1,1,2, 2-tetrafluoro-3-oxo-3, 1-propanediyl) ] ] bis [ ω - [ tetrafluoro (trifluoromethyl) ethoxy ] -poly [ oxy [ trifluoro (trifluoromethyl) -1, 2-ethanediyl ] ],

(40) alpha- [ [4- [ [ (3-chlorophenyl) methyl ] amino ] -6- (1H-imidazol-1-yl) -1,3, 5-triazin-2-yl ] amino ] -N- [ [4- (trifluoromethyl) phenyl ] methyl ] -, (alpha R) -cyclohexanepropionamide,

(41) n, N' - [6- [4- (acetylamino) -1,2, 5-oxadiazol-3-yl ] -1,3, 5-triazine-2, 4-diyl ] diacetic acid amide,

(42)6- (1H-imidazol-1-yl) -N2, N4-bis (1-methylethyl) -1,3, 5-triazine-2, 4-diamine, and

(43) n2, N4-bis (1-methylpropyl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine.

In some embodiments, R¹And R⁴Each independently selected from hydrogen, -CH₃、-CH₂CH₃,-CH₂OH、-CH(CH₃)OH、-C(CH₃)₂OH、CF₃CN; or R¹And R³Together form ═ O; or R⁴And R⁶Optionally together with the carbon atom to which it is attached to form C (═ O).

In some embodiments, R¹And R²Together form a carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 substituents independently selected from halo (e.g. fluoro), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN, ═ O, -OH and-C (O) C₁-C₄An alkyl group. In some embodiments, R¹And R²Together form a carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 substituents independently selected from halo (e.g. fluoro), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN, ═ O, -OH, aryl, heteroaryl-SO₂C₁-C₄Alkyl, -CO₂C₁-C₄Alkyl, -C (O) aryl and-C (O) C₁-C₄An alkyl group. In some embodiments, R¹And R²Together forming a carbocyclic groupOr heterocyclyl, either of which is optionally substituted with aryl or heteroaryl, which aryl or heteroaryl is optionally substituted with up to 2 substituents independently selected from halo, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN and-OH. In some embodiments, R¹And R²Together form a carbocyclyl or heterocyclyl, any of which is optionally substituted with phenyl, pyridyl or pyrimidinyl, the phenyl, pyridyl or pyrimidinyl being optionally substituted with up to 2 substituents independently selected from halo, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN and-OH.

In some embodiments, R⁴And R⁵Together form a carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 substituents independently selected from halo (e.g. fluoro), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN, ═ O, -OH and-C (O) C₁-C₄An alkyl group. In some embodiments, R⁴And R⁵Together form a carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 substituents independently selected from halo (e.g. fluoro), C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN, ═ O, -OH, aryl, heteroaryl-SO₂C₁-C₄Alkyl, -CO₂C₁-C₄Alkyl, -C (O) aryl and-C (O) C₁-C₄An alkyl group. In some embodiments, R¹And R²Together form a carbocyclyl or heterocyclyl, either of which is optionally substituted with aryl or heteroaryl, which are optionally substituted with up to 2 substituents independently selected from halo, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN and-OH. In some embodiments, R¹And R²Together form a carbocyclyl or heterocyclyl, any of which is optionally substituted with phenyl, pyridyl or pyrimidinyl, the phenyl, pyridyl or pyrimidinyl being optionally substituted with up to 2 substituents independently selected from halo, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN and-OH.

In some embodiments, R²And R⁵Each independently selected from: - (C)₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₁-C₆Alkyl) -CO₂H_、-(C₂-C₆Alkenyl or alkynyl), -C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₁-C₆Alkyl), - (C)₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) - (C)₁-C₆Alkyl) and- (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, ═ O, -C (O) -C₁-C₄Alkyl, -CN, and halo.

In some embodiments, R²And R⁵Each independently selected from: - (C) optionally substituted by halo (e.g. fluoro) or-OH₁-C₄Alkyl groups); - (C)₀-C₄Alkylene) -O- (C)₁-C₄Alkyl), - (C)₀-C₂Alkylene) -N (R)⁶)-(C₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₀-C₂Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) - (C)₁-C₆Alkyl) and-O- (C)₀-C₂Alkylene) -Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, ═ O, -C (O) -C₁-C₄Alkyl, -CN, and halo. In one aspect of these embodiments, Q is selected from pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl, and oxetanyl, wherein Q is optionally substituted with up to 2 substituents independently selected from C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, ═ O, fluorine, chlorine, and bromine. In another aspect of these embodiments, Q is selected from pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl, and oxetanyl, wherein Q is optionally substituted with up to 2 substituents independently selected from-CH₃And ═ O.

In some embodiments, R¹And R²Together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuryl, tetrahydropyranyl, oxetanyl, bicyclo [2.2.1]Heptyl, oxo-bicyclo [3.1.0]Hexyl, azetidinyl, any of which is optionally substituted with up to 2 substituents independently selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy radical, C₃-C₆Cycloalkyl, -OH, -C (O) CH₃Fluorine and chlorine.

In some embodiments, R⁴And R⁵Together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuryl, tetrahydropyranyl, oxetanyl, bicyclo [2.2.1]Heptyl, oxo-bicyclo [3.1.0]Hexyl or azetidinyl, either of which is optionally substituted with up to 2 substituents independently selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy radical, C₃-C₆Cycloalkyl, -OH, -C (O) CH₃Fluorine and chlorine. In some embodiments, R⁴And R⁵Together form a phenyl, pyrazolyl, imidazolyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, thiadiazolyl or isothiazolyl group, any of whichOne is optionally substituted with up to 2 substituents independently selected from halo, CN, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₃-C₆Cycloalkyl, phenyl, -OH, -C (O) CH₃Wherein any alkyl, cycloalkyl or phenyl moiety is optionally substituted by fluorine, chlorine, -OH, -NH₂or-CN substitution. In some embodiments, C₃-C₆Cycloalkyl is

In some embodiments, R¹、R³、R⁴And R⁶Each independently selected from hydrogen and C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -O-C₁-C₄Alkyl and CN, wherein R¹、R³、R⁴And R⁶Each of said alkyl moieties of (a) is independently optionally substituted with-OH, -NH₂、-CN、-O-C₁-C₄Alkyl, -NH (C)₁-C₄Alkyl) or-N (C)₁-C₄Alkyl radical)₂Substitution; and R is²And R⁵Each independently selected from: - (C)₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₁-C₆Alkyl) -CO₂H、-(C₂-C₆Alkenyl or alkynyl), -C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₁-C₆Alkyl) and- (C)₀-C₆Alkylene) -C (O) - (C)₁-C₆Alkyl), wherein: present in R²And R⁵Any alkyl or alkylene moiety of (a) is optionally substituted by one or more-OH, -O (C)₁-C₄Alkyl), -CO₂H or halo; and is

Present in R²And R⁵Any terminal methyl moiety in (a) is optionally substituted with-CH₂OH、CF₃、-CH₂F、-CH₂Cl、C(O)CH₃、C(O)CF₃CN or CO₂H replacement; or R¹And R³Optionally together with the carbon atom to which it is attached to form C (═ O); or

R⁴And R⁶Optionally together with the carbon atom to which it is attached to form C (═ O); or R¹And R²Optionally together forming an optionally substituted carbocyclyl; or R⁴And R⁵Optionally together form an optionally substituted carbocyclyl, wherein when A is an optionally substituted phenyl, 2-pyrrolyl or 1-imidazolyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Is not the same, and the compound is not 2- (1, 2-dibromoethyl) -4-phenyl-6- (1,1,2,2,3,3,4,4,5,5,6,6,6) -tridecafluorohexyl-1, 3, 5-triazine.

In some embodiments, ring a is an optionally substituted 6-membered monocyclic aryl. In some embodiments, ring a is an optionally substituted 5-6 membered heteroaryl. In some embodiments, ring a is an optionally substituted 5-membered heteroaryl.

In some embodiments, ring a is a substituted 5-6 membered monocyclic aryl or monocyclic heteroaryl, which is substituted with up to two substituents independently selected from halo, -C₁-C₄Alkyl, -C₁-C₄Haloalkyl, -C₁-C₄Hydroxyalkyl, -NH-S (O)₂-(C₁-C₄Alkyl), -S (O)₂NH(C₁-C₄Alkyl), -CN, -S (O)₂-(C₁-C₄Alkyl group), C₁-C₄Alkoxy, -NH (C)₁-C₄Alkyl), -OH, -OCF₃、-CN、-NH₂、-C(O)NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) -N (C)₁-C₄Alkyl radical)₂、-(C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), azetidinyl, phenyl and cyclopropyl optionally substituted with OH. In some embodiments, ring a is a substituted 5-6 membered monocyclic aryl or monocyclic heteroaryl, which is substituted with up to two substituents independently selected from fluoro, chloro, CF₃、CF₂、-OH、-OCH₃、-OCF₃、-CN、-NH₂. In some embodiments, ring a is a substituted 6-membered monocyclic aryl. In some embodiments, ring a is a substituted 5-6 membered heteroaryl. In some embodiments, ring a is a substituted 5-membered heteroaryl.

In some embodiments, ring a is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, wherein ring a is optionally substituted with up to two substituents independently selected from halo, -C₁-C₄Alkyl, -C₁-C₄Haloalkyl, -C₁-C₄Hydroxyalkyl, -NH-S (O)₂-(C₁-C₄Alkyl), -S (O)₂NH(C₁-C₄Alkyl), -CN, -S (O)₂-(C₁-C₄Alkyl group), C₁-C₄Alkoxy, -NH (C)₁-C₄Alkyl), -OH, -OCF₃、-CN、-NH₂、-C(O)NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) -N (C)₁-C₄Alkyl radical)₂And cyclopropyl optionally substituted with OH.

In some embodiments, ring a is selected from phenyl, pyrazolyl, imidazolyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, thiadiazolyl, and isothiazolyl, wherein ring a is optionally substituted with up to two substituents independently selected from halo, -C₁-C₄Alkyl, -C₁-C₄Haloalkyl, -C₁-C₄Hydroxyalkyl, -NH-S (O)₂-(C₁-C₄Alkyl), -S (O)₂NH(C₁-C₄Alkyl), -CN, -S (O)₂-(C₁-C₄Alkyl radicals),C₁-C₄Alkoxy, -NH (C)₁-C₄Alkyl), -OH, -CN and-NH₂。

In some embodiments, ring a is optionally halo, -C₁-C₄Alkyl, -C₁-C₄Haloalkyl, -O-C₁-C₄Haloalkyl, -OH, -CN and-NH₂A substituted monocyclic heteroaryl; r¹、R³、R⁴And R⁶Each independently selected from hydrogen and C₁-C₄An alkyl group; and R is²And R⁵Each independently is- (C)₀-C₆Alkylene) -Q; or R¹And R²Optionally together forming an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl; or R⁴And R⁵Optionally together form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

In some embodiments, ring a is optionally halo, -C₁-C₄Alkyl, -C₁-C₄Haloalkyl, -O-C₁-C₄Haloalkyl, -OH, -CN and-NH₂A substituted monocyclic heteroaryl; r¹、R³、R⁴And R⁶Each independently selected from hydrogen and C₁-C₄An alkyl group; and R is²And R⁵Each independently is- (C)₀-C₆Alkylene) -Q; or R¹And R²Optionally together forming an optionally substituted carbocyclyl or an optionally substituted heterocyclyl; or R⁴And R⁵Optionally together form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

In some embodiments, ring a is:

wherein R is⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group; each X^aIndependent of each otherGround is N or C-R^9aWith the proviso that when an X is present^aWhen N is present, then the other two X^aAre all C-R^9a(ii) a And R is^9aSelected from hydrogen, halo and-C₁-C₄A haloalkyl group.

In some embodiments, ring a is:

wherein R is⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group. In some embodiments, ring a is:

wherein R is⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group.

In some embodiments, ring a is optionally substituted with halo or-C₁-C₄Haloalkyl substituted pyridyl. In some embodiments, ring a is pyridyl optionally substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is-C₁-C₄Haloalkyl (e.g., -CHF)₂And CF₃) Substituted pyridin-2-yl. In some embodiments, ring a is:

wherein R is⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group. In some embodiments, ring a is:wherein each R⁹Independently selected from hydrogen, halo and-C₁-C₄A haloalkyl group. In some embodiments, R⁹Is chlorine or fluorine. In some embodiments, R⁹is-CHF₂Or CF₃. In some embodiments，R⁹Is CF₃Or chlorine. In some embodiments, R⁹Is CF₃。

In some embodiments, ring a is:

wherein R is^9bSelected from hydrogen and-C₁-C₄Alkyl, and wherein R⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group.

In some embodiments, ring a is:

In some embodiments, ring a is:wherein R is^9bSelected from hydrogen and-C₁-C₄Alkyl, and wherein R⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group.

In some embodiments, ring a is:

wherein R is⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group. In some embodiments, ring a is optionally substituted with halo or-C₁-C₄Haloalkyl-substituted pyrazolyl. In some embodiments, ring a is pyrazolyl optionally substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is-C₁-C₄Haloalkyl (e.g., -CHF)₂And CF₃) Substituted 1H-pyrazol-1-yl. In some embodiments, ring a is:

wherein R is⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group. In some embodiments, R⁹Is chlorine or fluorine. In some embodiments, R⁹is-CHF₂Or CF₃. In some embodiments, R⁹Is CF₃Or chlorine. In some embodiments, R⁹Is CF₃。

In some embodiments, ring a is:wherein R is⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group.

In some embodiments, ring a is:

wherein R is⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group.

In some embodiments, ring a is:

wherein R is⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group.

In some embodiments, ring a is:

wherein R is⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group.

In some embodiments, ring a is:

wherein R is⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group.

In some embodiments, ring a is:

wherein R is⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group.

In some implementationsIn the examples, ring a is:wherein R is⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group.

In some embodiments, ring a is optionally substituted with halo or-C₁-C₄Haloalkyl substituted pyridyl. In some embodiments, ring a is pyridyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is-C₁-C₄Haloalkyl (e.g., -CHF)₂And CF₃) A substituted pyridyl group. In some embodiments, ring a is optionally substituted with halo or-C₁-C₄Haloalkyl substituted pyrazinyl. In some embodiments, ring a is pyrazinyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is-C₁-C₄Haloalkyl (e.g., -CHF)₂And CF₃) A substituted pyrazinyl group. In some embodiments, ring a is optionally substituted with halo or-C₁-C₄A haloalkyl substituted pyrimidinyl group. In some embodiments, ring a is pyrimidinyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is-C₁-C₄Haloalkyl (e.g., -CHF)₂And CF₃) A substituted pyrimidinyl group. In some embodiments, ring a is optionally substituted with halo or-C₁-C₄Haloalkyl-substituted pyrazolyl. In some embodiments, ring a is pyrazolyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is-C₁-C₄Haloalkyl (e.g., -CHF)₂And CF₃) A substituted pyrazolyl group.

In some embodiments, R¹、R³、R⁴And R⁶Each independently selected from hydrogen and C₁-C₄An alkyl group; a and R²And R⁵Each independently is- (C)₀-C₆Alkylene) -Q. In some embodiments, R¹And R⁴Each is hydrogen. In some embodiments, R³And R⁶Each is C₁-C₄An alkyl group. In some embodiments，R³And R⁶Each is C₁-C₄A haloalkyl group. In some embodiments, Q is selected from aryl, heteroaryl, carbocyclyl, and heterocyclyl, any of which is optionally substituted. In some embodiments, Q is optionally substituted carbocyclyl. In some embodiments, Q is optionally substituted cyclopropyl. In some embodiments, Q is unsubstituted cyclopropyl. In some embodiments, R²And R⁵Each independently is an unsubstituted cyclopropyl group. In some embodiments, R¹And R⁴Each is hydrogen, R³And R⁶Each is-CH₃And R is²And R⁵Each is unsubstituted cyclopropyl. In some embodiments, R²Is- (C)₀-C₆Alkylene) -cyclopropyl and R⁵Is- (C)₀-C₆Alkylene) -aryl, for example optionally substituted phenyl. In some embodiments, R²Is cyclopropyl and R⁵Is phenyl substituted by halo (e.g., fluoro).

In some embodiments, ring a is optionally substituted with halo or-C₁-C₄Haloalkyl substituted pyridyl. In some embodiments, ring a is pyridyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is-C₁-C₄Haloalkyl (e.g., -CHF)₂And CF₃) A substituted pyridyl group. In some embodiments, ring a is optionally substituted with halo or-C₁-C₄Haloalkyl substituted pyrazinyl. In some embodiments, ring a is pyrazinyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is-C₁-C₄Haloalkyl (e.g., -CHF)₂And CF₃) A substituted pyrazinyl group. In some embodiments, ring a is optionally substituted with halo or-C₁-C₄A haloalkyl substituted pyrimidinyl group. In some embodiments, ring a is pyrimidinyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is-C₁-C₄Haloalkyl (e.g., -CHF)₂And CF₃) A substituted pyrimidinyl group. In some embodiments, ring a is optionally halo or-C₁-C₄Haloalkyl-substituted pyrazolyl. In some embodiments, ring a is pyrazolyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is-C₁-C₄Haloalkyl (e.g., -CHF)₂And CF₃) A substituted pyrazolyl group.

In some embodiments, R³And R⁶Each independently selected from hydrogen and C₁-C₄An alkyl group; r¹And R²Together form an optionally substituted carbocyclyl; and R is⁴And R⁵Together form an optionally substituted carbocyclyl. In some embodiments, R¹And R²Together form a cyclobutyl, cyclopentyl or cyclohexyl group, each of which is optionally substituted. In some embodiments, R¹And R²Together form a cyclopentyl or cyclohexyl group, each optionally substituted. In some embodiments, R⁴And R⁵Together form a cyclobutyl, cyclopentyl or cyclohexyl group, each of which is optionally substituted. In some embodiments, R⁴And R⁵Together form a cyclopentyl or cyclohexyl group, each optionally substituted. In some embodiments, R¹And R²Together form a cyclopentyl or cyclohexyl group, each substituted with one or more halo (e.g., fluoro); and R is⁴And R⁵Together form a cyclobutyl, cyclopentyl or cyclohexyl group, each substituted by one or more halo groups (e.g. fluoro). In some embodiments, R¹And R²Together form a bicyclo [3.1.0]]Hexyl; and R is⁴And R⁵Together form a bicyclo [3.1.0]]And hexyl. In some embodiments, R¹And R²Together, and R⁴And R⁵Together form:

in some embodiments, R¹And R²Together, and R⁴And R⁵Together form:

in some embodiments, R¹And R²Together, and R⁴And R⁵Together form:

in some embodiments, R¹And R²Together, and R⁴And R⁵Together form:

in some embodiments, R¹And R²Together; and R is⁴And R⁵Together form:

the compound is optionally substituted with cyano or halo (e.g., fluoro, chloro, or bromo). In some embodiments, R¹And R²Together, and R⁴And R⁵Together form:

in some embodiments, R¹And R²Together form a cyclobutyl, cyclopentyl or cyclohexyl group each substituted by one or more 6-membered monocyclic aryl groups (e.g. phenyl) optionally substituted by halo (e.g. fluoro, chloro or bromo); and R is⁴And R⁵Together form a cyclobutyl, cyclopentyl or cyclohexyl group each substituted by one or more 6-membered monocyclic aryl groups (e.g. phenyl) optionally substituted by halo (e.g. fluoro, chloro or bromo). In some embodiments, R¹And R²Or R⁴And R⁵Together form:

wherein ring C is phenyl, pyridyl or pyrimidinyl, optionally substituted with cyano or halo (e.g., fluoro, chloro or bromo). In some embodiments, R¹And R²Or R⁴And R⁵Together form:

wherein ring C is phenyl, pyridyl or pyrimidinyl, optionally substituted with cyano or halo (e.g., fluoro, chloro or bromo).

In some embodiments, R¹、R³、R⁴And R⁶Each independently selected from hydrogen and C₁-C₄Alkyl and-CN, wherein R¹、R³、R⁴And R⁶Each of said alkyl moieties of (a) is independently optionally substituted with-OH, -NH₂、-CN、-O-C₁-C₄Alkyl substitution; a and R²And R⁵Each independently selected from- (C)₁-C₆Alkyl) and- (C)₀-C₆Alkylene) -Q. In some embodiments, R¹、R³、R⁴And R⁶Each independently selected from hydrogen and C₁-C₄Alkyl and-CN; a and R²And R⁵Each independently is- (C)₁-C₆Alkyl) and- (C)₀-C₆Alkylene) -Q. In some embodiments, R¹、R³、R⁴And R⁶Each independently selected from hydrogen and C₁-C₄Alkyl and-CN; r²Is- (C)₁-C₆Alkyl groups); and R5 is- (C)₀-C₆Alkylene) -Q, wherein Q is an optionally substituted carbocyclyl. In some embodiments, Q is unsubstituted carbocyclyl. In some embodiments, Q is cyclopropyl.

In some embodiments, ring a is optionally substituted with halo or-C₁-C₄Haloalkyl substituted pyridyl. In some embodiments, ring A is-C₁-C₄Haloalkyl (e.g., -CHF)₂And CF₃) A substituted pyridyl group. In some embodiments, ring a is optionally substituted with halo or-C₁-C₄Haloalkyl substituted pyrazinyl. In some embodiments, ring a is pyrazinyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is-C₁-C₄Haloalkyl (e.g., -CHF)₂And CF₃) A substituted pyrazinyl group. In some embodiments, ring a is optionally substituted with halo or-C₁-C₄A haloalkyl substituted pyrimidinyl group. In some embodiments, ring a is pyrimidinyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is-C₁-C₄Haloalkyl (e.g., -CHF)₂And CF₃) A substituted pyrimidinyl group. In some embodiments, ring a is optionally substituted with halo or-C₁-C₄Haloalkyl-substituted pyrazolyl. In some embodiments, ring a is pyrazolyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is-C₁-C₄Haloalkyl (e.g., -CHF)₂And CF₃) A substituted pyrazolyl group.

In some embodiments, R¹、R³And R⁶Each independently selected from hydrogen and C₁-C₄Alkyl radical, wherein R¹、R³And R⁶Each of said alkyl moieties of (a) is independently optionally substituted with-OH, -NH₂、-CN、-O-C₁-C₄Alkyl, -NH (C)₁-C₄Alkyl) or-N (C)₁-C₄Alkyl radical)₂Substitution; r²Is- (C)₀-C₆Alkylene) -Q; and R is⁴And R⁵Together form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl. In some embodiments, R⁴And R⁵Together form an optionally substituted carbocyclyl. In some embodiments, the carbocyclyl is selected from optionally substituted with-OH, -O (C)₁-C₄Alkyl), CO₂H or halo-substituted cyclopentyl and cyclohexyl. In some embodiments, R⁴And R⁵Together form an optionally substituted-OH, -O (C)₁-C₄Alkyl), -CO₂H or halo substituted optionally substituted heterocyclyl. In some embodiments, R⁴And R⁵Together form an optionally substituted tetrahydrofuran. In some embodiments, R¹、R³And R⁶Each independently selected from hydrogen and C₁-C₄Alkyl radical, wherein R¹、R³And R⁶Each of said alkyl moieties of (a) is independently optionally substituted with-OH, -NH₂、-CN、-O-C₁-C₄Alkyl substitution; r²Is- (C)₀-C₆Alkylene) -Q; and R is⁵Is C₁-C₄An alkyl group. In some embodiments of the present invention, the,R¹、R³and R⁶Each independently selected from hydrogen and C₁-C₄Alkyl or carbocyclyl, wherein R¹、R³And R⁶Any alkyl or carbocyclyl moiety of (a) is independently optionally substituted by-OH, -NH₂、-CN、-O-C₁-C₄Alkyl, -SO₂-C₁-C₄Alkyl, -C (O) NH₂、-O-R¹²、-CO₂R¹²or-C (O) R¹²Is substituted in which R¹²Is morpholinyl, piperidinyl, phenyl, pyridinyl or pyrimidinyl. In some embodiments, R¹、R³And R⁶Each independently selected from hydrogen and C₁-C₄Alkyl radical, wherein R¹、R³And R⁶Each of said alkyl moieties of (a) is independently optionally substituted with-OH, -NH₂、-CN、-O-C₁-C₄Alkyl, -O-R¹²Is substituted in which R¹²Is phenyl, pyridyl or pyrimidinyl; r²Is- (C)₀-C₆Alkylene) -Q; and R is⁵Is C₁-C₄An alkyl group.

In some embodiments, R⁷Is H. In some embodiments, R⁸Is H. In some embodiments, R⁷And R⁸Both are H.

In some embodiments, ring A, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸Selected from any of the preceding embodiments.

Also provided is a compound of formula B or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

x is N, CH or C-halo;

X^ais N or C-R^9aWith the proviso that when an X is present^aWhen N is present, then the other two X^aAre all C-R^9a；

R⁹Is halo, -C₁-C₄Alkyl, -C₁-C₄Haloalkyl, -C₁-C₄Hydroxyalkyl, -NH-S (O)₂-(C₁-C₄Alkyl), -S (O)₂NH(C₁-C₄Alkyl), -CN, -S (O)₂-(C₁-C₄Alkyl group), C₁-C₄Alkoxy, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OH、-OCF₃、-CN、-NH₂、-C(O)NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) -N (C)₁-C₄Alkyl radical)₂、-(C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), aryl and cyclopropyl optionally substituted with OH;

each R^9aIndependently selected from hydrogen, halo, -C₁-C₄Alkyl, -C₁-C₄Haloalkyl, -C₁-C₄Hydroxyalkyl, -NH-S (O)₂-(C₁-C₄Alkyl), -S (O)₂NH(C₁-C₄Alkyl), -CN, -S (O)₂-(C₁-C₄Alkyl group), C₁-C₄Alkoxy, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OH、-OCF₃、-CN、-NH₂、-C(O)NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) -N (C)₁-C₄Alkyl radical)₂、-(C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), aryl and cyclopropyl optionally substituted with OH;

R¹、R³、R⁴and R⁶Each independently selected from hydrogen and C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -O-C₁-C₄Alkyl and CN, wherein R¹、R³、R⁴And R⁶Each of said alkyl moieties of (a) is independently optionally substituted with-OH, -NH₂、-CN、-O-C₁-C₄Alkyl, -NH (C)₁-C₄Alkyl) or-N(C₁-C₄Alkyl radical)₂Substitution;

R²and R⁵Each independently selected from: - (C)₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₁-C₆Alkyl) -CO₂H_、-(C₂-C₆Alkenyl or alkynyl), -C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₁-C₆Alkyl radicals),

-(C₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) - (C)₁-C₆Alkyl) and- (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -Q, wherein:

R⁴And R⁵Optionally, theTogether form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, an optionally substituted 5-6 membered monocyclic aryl or an optionally substituted 5-6 membered monocyclic heteroaryl;

wherein the compound is not selected from the group consisting of:

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

(2) n4-ethyl-2- (6-methyl-2-pyridyl) -N6-propyl-4, 6-pyrimidinediamine;

(3) n4, N4-diethyl-2- (6-methyl-2-pyridyl) -N6-propyl-4, 6-pyrimidinediamine;

(4) n6- [2- (dimethylamino) ethyl ] -N2', N2', N4, N4-tetramethyl- [2,4 '-bipyrimidine ] -2',4, 6-triamine; or

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

In some embodiments, R⁴And R⁵Optionally together form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.

Also provided is a compound of formula Ib or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

R²and R⁵Each independently selected from: - (C)₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₁-C₆Alkyl) -CO₂H、-(C₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) - (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -Q, wherein:

R⁷and R⁸Each independently selected from hydrogen and C₁-C₆An alkyl group;

R⁹selected from hydrogen, halo and-C₁-C₄A haloalkyl group; and is

R¹And R²Optionally together forming an optionally substituted carbocyclyl, optionally substituted heterocyclyl; or

R⁴And R⁵Optionally together forming an optionally substituted carbocyclyl, optionally substituted heterocyclyl;

wherein:

(i)N(R⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NHC (O) - [ 2-chloro-4- (methylsulfonyl)]Or N (CH)₃)₂，

(ii)N(R⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not NHC (O) C (CH)₃)₃、NHC(O)CH＝CH₂、NHC(O)C(CH₃)＝CH₂、NHCH₂CH₂OH, NH-cyclohexyl, NHCH₂Phenyl, NHC (O) (CH)₂)₅NH₂、NHC(O)OCH₃、NHC(O)CH₃And phenyl optionally substituted with NHC (O) NH, and

(iii) when N (R)⁷)C(R⁴)(R⁵)(R⁶) Is NHC (CH)₃)₃Then N (R)⁸)C(R¹)(R²)(R³) Is not NHCH₂-phenyl or NH-CH₂CH₃(ii) a And is

Wherein the compound is not:

(1) 2-chloro-N- [4- (cyclopropyl) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] -4- (methylsulfonyl) -benzamide,

(2) n- [ [4- [ [ [4- (cyclopropylamino) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methyl ] cyclohexyl ] methyl ] -4-fluoro-benzenesulfonamide,

(3) 2-chloro-4- (methylsulfonyl) -N- [4- [ (phenylmethyl) amino ] -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] -benzamide, or

(4) N- [ [4- [ [ [4- (cyclopropylamino) -6- (2-pyridyl) -1,3, 5-triazin-2-yl ] amino ] methyl ] cyclohexyl ] methyl ] -4-fluoro-benzenesulfonamide.

wherein:

R³and R⁶Are both hydrogen;

R¹and R⁴Each independently selected from C₁-C₄Alkyl and C₁-C₄A haloalkyl group; and is

R²And R⁵Each is- (C)₁-C₆Alkyl groups); or

R¹And R²Optionally together forming an optionally substituted monocyclic carbocyclic group; or

R⁴And R⁵Optionally together forming an optionally substituted monocyclic carbocyclic group;

wherein:

(i) ring A is not optionally substituted triazolyl, 3, 5-dimethyl-1H-pyrazol-1-yl,

(ii) when R is¹And R²Optionally together form an unsubstituted cyclohexyl group, and R⁴And R⁵Optionally together forming an unsubstituted cyclohexyl group, then a is not a disubstituted 1-pyrazolyl or unsubstituted phenyl; and is

(iii) The compound is not selected from the group consisting of:

(1)6- (1H-imidazol-1-yl) -N2, N4-bis (1-methylethyl) -1,3, 5-triazine-2, 4-diamine, or

(2) N2, N4-bis (1-methylpropyl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine.

Also provided is a compound of formula C or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

x is N, CH or C-halo;

each X^bIndependently is N-R^9bO, S, C-H or C-R^9cWith the proviso that at least one X^bIs C-R^9cAnd when an X is present^bIs C-H or C-R⁹And the other is C-R^9cThen X^cIs N; and when an X^bIs N-R^9bO or S, then X^cIs C;

R^9bis hydrogen or-C₁-C₄An alkyl group;

R^9cis halo, -C₁-C₄Alkyl, -C₁-C₄Haloalkyl, -C₁-C₄Hydroxyalkyl, -NH-S (O)₂-(C₁-C₄Alkyl), -S (O)₂NH(C₁-C₄Alkyl), -CN, -S (O)₂-(C₁-C₄Alkyl group), C₁-C₄Alkoxy, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OH、-OCF₃、-CN、-NH₂、-C(O)NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) -N (C)₁-C₄Alkyl radical)₂、-(C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), aryl and cyclopropyl optionally substituted with OH;

R⁴And R⁵Optionally together form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, an optionally substituted 5-6 membered monocyclic aryl or an optionally substituted heteroaryl;

wherein:

(i) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1-pyrrolyl or optionally substituted 1-pyrazolyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NH (CH)₂)₇CH₃、NHCH₂- (o-chloro-phenyl) or NHCH₂CH₂OH; and is

(ii) When X and X^cWhen both are N, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not all N (CH)₃)₂、NHCH₃Or N (CH)₂CH₃)₂。

Also provided is a compound of formula Id or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

R⁹is halo or-C₁-C₄A haloalkyl group; and is

R⁴And R⁶Optionally together with the carbon atom to which it is attached to form C (═ O);

wherein the compound is not:

(1) n2, N2, N4-trimethyl-6- [3- (trifluoromethyl) -1H-pyrazol-1-yl ] -1,3, 5-triazine-2, 4-diamine, or

(2) N4-ethyl-N2, N2-dimethyl-6- [3- (trifluoromethyl-1H-pyrazol-1-yl ] -1,3, 5-triazine-2, 4-diamine.

A compound of formula Ie or a pharmaceutically acceptable salt or hydrate thereof:

wherein

R⁹selected from hydrogen, halo and-C₁-C₄A haloalkyl group; and is

R⁴And R⁵Optionally together form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.

A compound of formula If, or a pharmaceutically acceptable salt or hydrate thereof:

wherein

R⁹selected from hydrogen, halo and-C₁-C₄A haloalkyl group; and is

Also provided is a compound of formula II or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

(i) when A is optionally F, Cl or SO₂CH₃Substituted phenyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not all N (CH)₃)CH₂C (O) NH-isopropyl, NHCH (CH)₃)(CH₂)₃N(CH₂CH₃)₂、NHCH₂CH₂OH、NHCH₂CH₂OCH₃、NHCH₂CH₂OSO₃H、NHCH₂CH₂CH₂OCH₂CH₂O-phenyl, NHCH₂CH₂CH₂OH、NHCH₂CH₂CH₂OCH₃、NHCH₂CH(OH)CH₃、N(CH₂CH₃)₂NH-isopropyl, NHCH₂CH₂NHC(O)OCH₃、NHCH₂CH₂NHC(O)CH₃、NHCH₂CH₂NH₂Or NHCH₂-a phenyl group;

(ii) when A is optionally substituted pyridyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NHCH₂-phenyl, NHCH₂- (2, 4-difluorophenyl), N (CH)₃)CH₂CH₂C(O)OH、NHCH₂CH₂C(O)OH、NHCH₂CH₂C(O)OCH₂CH₃、NHCH₂CH₂C (O) O-tert-butyl, NHCH₂CH₂C(O)NH₂、NHCH₂CH₂-phenyl, NHCH₂CH₂OH、NHCH₂CH₂NH₂、NHCH₂CH₂N(CH₃)₂Or NHCH₂CH₂CH₃；

(iii) When A is optionally substituted 1-imidazolyl, optionally substituted 1-pyrrolyl or optionally substituted 1-pyrazolyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NH (CH)₂)₇CH₃、NHCH₂- (o-chloro-phenyl) or NHCH₂CH₂OH；

(iv) When A is unsubstituted 2-pyridyl, then⁴And R⁵The ring formed is not 5-methyl-1H-pyrazol-3-yl; and is

(v) When A is optionalWhen substituted 1-pyrazolyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not all N (CH)₃)₂、NHCH₃NHAc, NH isopropyl, NHCH₂CH₃、NHCH₂CH₂SO₃H or N (CH)₂CH₃)₂，

(vi) Ring A is not optionally substituted triazolyl, 3, 5-dimethyl-1H-pyrazol-1-yl,

(vii) when R is¹And R²Optionally together form an unsubstituted cyclohexyl group, and R⁴And R⁵Optionally together forming an unsubstituted cyclohexyl group, then a is not a disubstituted 1-pyrazolyl or unsubstituted phenyl; and is

(viii) The compound is not selected from the group consisting of:

(2) N2, N4-bis (1-methylpropyl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine.

Also provided is a compound of formula Ic or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

each R⁹Independently selected from halo, -C₁-C₄Alkyl, -C₁-C₄Haloalkyl, -C₁-C₄Hydroxyalkyl, -NH-S (O)₂-(C₁-C₄Alkyl), -S (O)₂NH(C₁-C₄Alkyl), -CN, -S (O)₂-(C₁-C₄Alkyl group), C₁-C₄Alkoxy, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OH、-OCF₃、-CN、-NH₂、-C(O)NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) -N (C)₁-C₄Alkyl radical)₂、-(C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), aryl and cyclopropyl optionally substituted with OH;

n is 1 to 3;

R²and R⁵Each independently selected from: - (C)₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₁-C₆Alkyl) -CO₂H、-(C₂-C₆Alkenyl or alkynyl), -C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₁-C₆Alkyl radicals),

Q is selected from carbocyclyl and heterocyclyl, either of which is optionally substituted; wherein

R¹And R²Optionally together forming an optionally substituted carbocyclyl; or

R⁴And R⁵Optionally together forming an optionally substituted carbocyclyl;

wherein:

(i)N(R⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NHCH₂CH₂OCH₂CH₂OCH₂CH₂NH₂Or 4- [ [2- [2- (2-aminoethoxy) ethoxy ] ethoxy]Ethyl radical]Amino group]，

(ii)N(R⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not NHEt, NH (n-propyl), NH (n-butyl), NH (n-dodecyl), NH- [ (4-methoxyphenyl) methyl]、NHCH₂CH₂CHO、NHCH₂CH₂OCH₃、NHCH₂CH₂OH、NHCH₂CH(OH)CH₃、NHCH₂CH₂OC (O) phenyl, NHCH₂CH₂CH₂OH、NHCH₂CH₂CH₂N(CH₃) Phenyl, NHCH₂C(O)OCH₃、NHCH₂C(O)OCH₂CH₃、NHCH₂Phenyl, NHCH (CH)₃)CH₂CH₃Or NHCH₂CH₂OC(O)CH₃(ii) a And is

(iii)N(R⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not all NH cyclohexyl C(O)NHCH₂R, wherein R is OCF₃、OCH₃Chlorine or CF₃One or more substituted phenyl or pyridyl groups.

Also provided is a compound of formula III or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

ring a is an optionally substituted 5-6 membered monocyclic heteroaryl;

ring B is an optionally substituted 5-6 membered monocyclic aryl or monocyclic heteroaryl;

R¹and R³Each independently selected from hydrogen and C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -O-C₁-C₄Alkyl and CN, wherein R¹、R³、R⁴And R⁶Each of said alkyl moieties of (a) is independently optionally substituted with-OH, -NH₂、-CN、-O-C₁-C₄Alkyl, -NH (C)₁-C₄Alkyl) or-N (C)₁-C₄Alkyl radical)₂Substitution;

R²selected from: - (C)₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₁-C₆Alkyl) -CO₂H、-(C₂-C₆Alkenyl or alkynyl), -C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₁-C₆Alkyl radical)_、-(C₀-C₆Alkylene) -Q, - (C)₀-C₆Alkylene) -C (O) - (C)₁-C₆Alkyl) and- (C)₀-C₆Alkylene) -C (O) - (C)₀-C₆Alkylene) -Q, wherein:

present in R²Any alkyl or alkylene moiety of (a) is optionally substituted by one or more-OH, -O (C)₁-C₄Alkyl), -CO₂H or halo;

present in R²Any terminal methyl moiety in (a) is optionally substituted with-CH₂OH、CF₃、-CH₂F、-CH₂Cl、C(O)CH₃、C(O)CF₃CN or CO₂H replacement;

R¹And R²Optionally together forming an optionally substituted carbocyclyl or optionally substituted heterocyclyl;

wherein when a is an oxadiazole substituted with an optionally substituted pyridyl group, then G is not an optionally substituted phenyl.

In some embodiments, G is substituted with 1 or 2 substituents selected from halo, C1-C4 alkyl, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN, ═ O, -OH, aryl, heteroaryl-SO₂C₁-C₄Alkyl, -CO₂C₁-C₄Alkyl, -C (O) aryl and-C (O) C₁-C₄An alkyl group.

Also provided is a compound of formula IIIa or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

ring a is a substituted 5-6 membered monocyclic heteroaryl;

X^dis C or N;

each R^bIndependently selected from halo, CN, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₃-C₆Cycloalkyl, phenyl, -OH, -C (O) CH₃Wherein any alkyl, cycloalkyl or phenyl moiety is optionally substituted by fluorine, chlorine, -OH, -NH₂or-CN substitution;

p is 1 to 2;

R²selected from: - (C)₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₁-C₆Alkyl) -CO₂H、-(C₂-C₆Alkenyl or alkynyl), -C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₁-C₆Alkyl radicals),

wherein when A is an oxadiazole substituted by an optionally substituted pyridyl group, then X^dIs not C.

Also provided is a compound of formula IIIb or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

ring a is a substituted 5-6 membered monocyclic heteroaryl;

p is 1 to 2; and is

G is an optionally substituted carbocyclic or heterocyclic group,

wherein a is other than oxadiazole substituted with optionally substituted pyridyl.

Also provided is a compound of formula IIIc or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

ring a is a substituted 5-6 membered monocyclic heteroaryl;

R¹And R³Optionally with a carbon atom to which it is attachedTogether, the subgroups form C (═ O); or

each R^bIndependently selected from halo, CN, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy radical, C₃-C₆Cycloalkyl, phenyl, -OH, -C (O) CH₃Wherein any alkyl, cycloalkyl or phenyl moiety is optionally substituted by fluorine, chlorine, -OH, -NH₂or-CN substitution; and is

p is 1 to 2.

Also provided is a compound of formula IIId or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

ring a is a substituted 5-6 membered monocyclic heteroaryl;

p is 1 to 2; and is

G is an optionally substituted carbocyclyl or heterocyclyl.

Other embodiments provided herein include combinations of one or more of the specific embodiments listed above.

In another embodiment, the compound is selected from any one of the compounds listed in table 1 below.

TABLE 1 representative Compounds

Also included herein are implementations for making compounds of formula I or as described hereinA method of preparing a compound of any one of the examples, which method comprises reactingAnd

and (4) reacting. In some embodiments, the foregoing method comprises the step of (1) contacting

Andreacting to obtain

And step (2) of

And

and (4) reacting. In other embodiments, the aforementioned method comprises the step of (1) contacting

Andreacting to obtainStep (2) of

And

reacting to obtainAnd step (3) of

And

and (4) reacting.

Also included are methods for making compounds of formula I or any of the embodiments described herein, comprising contacting

And

and (4) reacting.

Also included are methods for making compounds of formula I or any of the embodiments described herein, comprising contactingAnd

And

reacting to obtain

And step (2) of

And

and (4) reacting.

Also included are methods for making a compound of formula I or a compound of any of the embodiments described herein,these methods comprise reacting

And

and (4) reacting. In other embodiments, the foregoing method comprises the step of (1) treating the substrate with a solution of a compound of formula (I) and (II)Transformation of

To obtain

Step (2) of

And PCl₅、POCl₃Reacting to obtain

Step (3) of

Andreacting to obtain

And step (4) of

Andand (4) reacting. In other embodiments, the foregoing method comprises the step of (1) treating the substrate with a solution of a compound of formula (I) and (II)

Transformation of

To obtain

Step (2) of

And PCl₅、POCl₃Reacting to obtain

Step (3) of

And

reacting to obtain

And step (4) of

And

and (4) reacting. In other embodiments, the foregoing method comprises the step of (1) treating the substrate with a solution of a compound of formula (I) and (II)

Transformation ofTo obtainStep (2) of

And PCl₅、POCl₃Reacting to obtain

Step (3) of

And

reacting to obtain

And step (4) of

And

and (4) reacting. In other embodiments, the method comprises the steps of: make itAnd

under alkaline conditions to obtain

Wherein ring G is a carbocyclyl or heterocyclyl ring. In other embodiments, the method comprises the steps of: 1) make itAnd

reacting to obtain

And 2) makingAndreacting to obtainWherein ring B is an aryl or heteroaryl ring. In other embodiments, the method comprises the steps of: make it

And

under alkaline conditions to obtain

Wherein ring B is an aryl or heteroaryl ring and ring G is a carbocyclyl or heterocyclyl ring. In other embodiments, the method comprises the steps of: make itWith ring A to form

The compounds of one aspect of the invention may contain one or more asymmetric centers and thus occur in the form of: racemates, racemic mixtures, non-racemic mixtures and diastereomeric mixtures, and individual enantiomers or individual stereoisomers substantially free of another possible enantiomer or stereoisomer. The term "substantially free of other stereoisomers" as used herein means a preparation enriched in a compound having at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of a selected stereochemistry at one or more selected stereocenters. The term "enriched" means that at least a specified percentage of the formulation is a compound having a selected stereochemistry at one or more selected stereocenters. Methods of obtaining or synthesizing individual enantiomers or stereoisomers of a given compound are known in the art and, as applicable, may be applied to the final compound or starting material or intermediate.

In certain embodiments, the compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId is enriched in a structure or structures having a selected stereochemistry at one or more carbon atoms. For example, the compound is enriched in at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of a particular stereoisomer.

The compounds of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId may also include one or more isotopic substitutions. For example, H may be in any isotopic form, including¹H、²H (D or deuterium) and³h (T or tritium); c may be in any isotopic form, including¹¹C、¹²C、¹³C and¹⁴c; (ii) a N may be in any isotopic form, including¹³N、¹⁴N and¹⁵n; o may be in any isotopic form, including¹⁵O、¹⁶O and¹⁸o; f may be in any isotopic form, including¹⁸F; and so on. For example, the compound is enriched in at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the particular isotopic form of H, C, N, O and/or F.

Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without indicating stereochemistry and has one or more chiral centers, it is understood to mean all possible stereoisomers of the compound.

The compounds of one aspect of the invention can also be present in multiple tautomeric forms, in such cases, one aspect of the invention expressly includes all tautomeric forms of the compounds described herein, although only a single tautomeric form may be present (e.g., alkylation of a ring system may result in alkylation at multiple sites, one aspect of the invention expressly includes all such reaction products and keto-enol tautomers). All such isomeric forms of such compounds are expressly included herein.

Corresponding salts, e.g. pharmaceutically acceptable salts, of the active compounds may be conveniently prepared, purified and/or worked up. Examples of Pharmaceutically Acceptable Salts are discussed in birch (Berge) et al, 1977, "Pharmaceutically Acceptable Salts" (journal of pharmaceutical sciences), vol 66, pages 1-19.

For example, if the compound is anionic, or has a functional group that may be anionic (e.g., -COOH may be-COO-), a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions (e.g., Na)⁺And K⁺) Alkaline earth metal cations (e.g. Ca)²⁺And Mg²⁺) And other cations (e.g. Al)³⁺). Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH)₄ ⁺) And substituted ammonium ions (e.g., NH)₃R⁺、NH₂R²⁺、NHR³⁺、NR⁴⁺). Some examples of suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N (CH)₃)₄ ⁺。

If the compound is cationic, or has a functional group which may be cationic (e.g., -NH)₂May be-NH₃ ⁺) Then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid.

Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxycitric acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, mucic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, benzenesulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, and valeric acid. The mesylate salt of each compound in table 1 is specifically included herein. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

The compounds provided herein thus include the compounds themselves, as well as salts, hydrates, and prodrugs thereof, if applicable. The compounds provided herein can be modified by the addition of appropriate functional groups and converted to prodrugs to enhance selected biological properties, e.g., targeting to specific tissues. Such modifications (i.e., prodrugs) are known in the art and include those that increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and alter rate of excretion. Examples of prodrugs include esters (e.g., phosphate esters, amino acid (e.g., valine) esters), carbamates and other pharmaceutically acceptable derivatives, which prodrugs are capable of providing the active compound after administration to a subject. Calcium phosphate and sodium phosphate for each of the compounds in table 1 are specifically included herein, if applicable. Amino acid (e.g., valine) esters of each of the compounds in table 1 are expressly included herein, if applicable.

Compositions and routes of administration

The compounds employed in the methods described herein may be formulated into pharmaceutically acceptable compositions with a pharmaceutically acceptable carrier or adjuvant and then administered to a subject. In another embodiment, such pharmaceutically acceptable compositions further comprise an additional therapeutic agent in an amount effective to effect modulation of a disease or disease symptoms (including those described herein).

The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a subject with a compound of one aspect of the invention and which does not destroy its pharmacological activity and is non-toxic when administered in a dosage sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of one aspect of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (e.g., d-alpha-tocopheryl polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (e.g., Tween (Tween) or other similar polymeric delivery matrices), serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphate salts), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate), polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, sodium, Polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycols and lanolin. Cyclodextrins (such as alpha-, beta-, and gamma-cyclodextrins) or chemically modified derivatives (such as hydroxyalkyl cyclodextrins, including 2-hydroxypropyl-beta-cyclodextrin and 3-hydroxypropyl-beta-cyclodextrin) or other solubilized derivatives may also be advantageously used to enhance delivery of compounds having the formulas described herein.

The pharmaceutical composition of one aspect of the invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or injection administration. The pharmaceutical composition of one aspect of the invention may comprise any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, in the form of a sterile injectable aqueous or oleaginous suspension. Such suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents such as, for example, tween 80 and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids (such as oleic acid) and glyceride derivatives thereof are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils (such as olive oil or castor oil, especially in their polyoxyethylated forms). These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms, such as the tween series or span series (Spans) and/or other similar emulsifying agents or bioavailability enhancers may also be used for formulation purposes.

The pharmaceutical composition of one aspect of the invention can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oil phase combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

The pharmaceutical composition of one aspect of the invention may also be administered in the form of suppositories for rectal administration. These compositions may be prepared by mixing a compound of one aspect of the invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

Topical administration of a pharmaceutical composition of one aspect of the invention is useful when the desired treatment involves an area or organ that is readily accessible by topical administration. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of one aspect of the present invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutical compositions may be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in the carrier with a suitable emulsifier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical composition of one aspect of the invention may also be administered topically to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topical transdermal patches are also included in one aspect of the present invention.

The pharmaceutical composition of one aspect of the invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

When the composition of one aspect of the invention comprises a combination of a compound of the formula described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additive should be present at dosage levels of between about 1% and 100%, and more preferably between about 5% and 95%, of the dosage normally administered in a monotherapy regimen. The additive may be administered separately from the compound of one aspect of the invention as part of a multiple dose regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of one aspect of the invention in a single composition.

The compounds described herein can be administered, for example, by injection, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic formulation or by inhalation, at a dose ranging from about 0.5 to about 100mg per kilogram of body weight, alternatively a dose between 1mg and 1000mg per dose, every 4 to 120 hours, or as required by the particular drug. The methods herein contemplate administration of an effective amount of a compound or compound composition to achieve a desired or stated effect. Typically, the pharmaceutical composition of one aspect of the invention will be administered from about 1 to about 6 times per day, or alternatively, in the form of a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Typical formulations will contain from about 5% to about 95% active compound (w/w). Alternatively, such formulations comprise from about 20% to about 80% of the active compound.

Lower or higher doses than those described above may be required. The specific dose and treatment regimen for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptom, the predisposition of the subject to the disease, condition or symptom, and the judgment of the treating physician.

After the condition of the subject is improved, a maintenance dose of a compound, composition or combination of one aspect of the invention may be administered as necessary. Subsequently, depending on the symptoms, the dose or frequency of administration, or both, may be reduced to a level at which the improved condition is maintained when the symptoms have been alleviated to a desired level. However, the subject may require intermittent treatment based on long-term consideration of any recurrence of disease symptoms.

The pharmaceutical composition described above comprising a compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or a compound described in any of this example can further comprise another therapeutic agent for the treatment of cancer.

Application method

A method for inhibiting activity of mutant IDH1 is provided, the method comprising contacting a subject in need thereof with a compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId (including tautomers and/or isotopologues thereof) or a compound described in any of this embodiments, or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer to be treated is characterized by a mutant allele of IDH1, wherein the IDH1 mutation contributes to the novel ability of the enzyme to catalyze NADPH-dependent reduction of α -ketoglutarate to R (-) -2-hydroxyglutarate in a subject. In one aspect of this embodiment, the mutant IDH1 has the R132X mutation. In one aspect of this embodiment, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S, and R132G. In another aspect, the R132X mutation is R132H or R132C. In yet another aspect, the R132X mutation is R132H.

Also provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1, comprising the steps of: administering to a subject in need thereof (a) a compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId, or a compound described in any of this example, or a pharmaceutically acceptable salt thereof; or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.

In one embodiment, the cancer to be treated is characterized by a mutant allele of IDH1, wherein the IDH1 mutation contributes to the novel ability of the enzyme to catalyze NADPH-dependent reduction of α -ketoglutarate to R (-) -2-hydroxyglutarate in a patient. In one aspect of this embodiment, the IDH1 mutation is an R132X mutation. In another aspect of this embodiment, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S, and R132G. In another aspect, the R132X mutation is R132H or R132C. Cancer can be analyzed by sequencing cell samples to determine the presence and specific nature of the mutation at amino acid 132 of IDH1 (e.g., the altered amino acid present therein).

Without being bound by theory, applicants believe that the mutant allele of IDH1 (where the IDH1 mutation contributes to the novel ability of the enzyme to catalyze NADPH-dependent reduction of α -ketoglutarate to R (-) -2-hydroxyglutarate) and in particular the R132H mutation of IDH1 characterizes a subset of all types of cancers regardless of their cellular nature or location in vivo. Thus, the compounds and methods of the invention are useful for treating any type of cancer characterized by the presence of a mutant allele of IDH1, and in particular, an IDH1R132H or R132C mutation, that confers such activity.

In one aspect of this embodiment, the efficacy of the cancer treatment is monitored by measuring the level of 2HG in the subject. Typically, the 2HG level is measured prior to treatment, wherein an elevated level indicates that a compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId, or a compound described in any of the embodiments described herein, is used to treat cancer. Once the elevated level is established, the 2HG level is determined during and/or after the course of terminating treatment to determine efficacy. In certain embodiments, the 2HG level is determined only during and/or after the course of terminating treatment. A decrease in 2HG levels during the course of treatment and after treatment is indicative of efficacy. Similarly, a determination that the level of 2HG is not elevated during the course of treatment or after treatment is also indicative of efficacy. Typically, these 2HG measurements will be employed with other well-known assays of efficacy of cancer treatment, such as a reduction in the number and size of tumors and/or other cancer-related lesions, an improvement in the general health of the subject, and other biomarker changes associated with efficacy of cancer treatment.

The 2HG in the sample may be detected by LC/MS. The sample was mixed with methanol at 80:20 and centrifuged at 3,000rpm for 20 minutes at 4 ℃. The resulting supernatant can be collected and stored at-80 ℃ before LC-MS/MS to assess 2-hydroxyglutarate levels. A variety of different Liquid Chromatography (LC) separation methods may be used. Each method can be coupled by negative electrospray ionization (ESI, -3.0kV) to a triple quadrupole mass spectrometer operating in multi-reaction monitoring (MRM) mode, in which MS parameters are optimized with respect to the infused metabolite standard solution. Metabolites can be isolated by reverse phase chromatography using 10mM tributylamine as the ion-pair reagent in an aqueous mobile phase according to a variant of the previously reported method (Roo et al, J.chromatographie. A. section A. 1147,153-64, 2007). One method allows the resolution of TCA metabolites: t is 0, 50% B; t is 5, 95% B; t is 7, 95% B; t-8, 0% B, where B refers to 100% methanol in organic mobile phase. Another method is specific for 2-hydroxyglutarate, running a rapid linear gradient from 50% to 95% B (buffer as defined above) over 5 minutes. As described above, Synergi Hydro-RP, 100 mm. times.2 mm, 2.1 μm particle size (Phenomonex) was used as a column. Metabolites can be quantified by comparing peak areas to pure metabolite standards of known concentration. Can be prepared from, for example, Misger (Munger) et al Nature Biotech (Nat Biotechnol)26,1179-86,2008¹³C-Glutamine was subjected to metabolic flux studies.

In one embodiment, 2HG is directly evaluated.

In another embodiment, derivatives of 2HG formed during the performance of the assay method are assessed. By way of example, such a derivative may be a derivative formed in an MS analysis. Derivatives may include salt adducts (e.g., Na adducts), hydrated variants, or hydrated variants that are also salt adducts (e.g., Na adducts), e.g., as formed in MS assays.

In another embodiment, metabolic derivatives of 2HG are evaluated. Examples include materials that accumulate or increase or decrease due to the presence of 2HG, such as glutarates or glutamates associated with 2HG, e.g., R-2 HG.

Exemplary 2HG derivatives include dehydrated derivatives, such as the compounds provided below or their salt adducts:

in one embodiment, the cancer is a tumor in which at least 30%, 40%, 50%, 60%, 70%, 80% or 90% of the tumor cells carry an IDH1 mutation, and in particular an IDH1R132H or R132C mutation, at the time of diagnosis or treatment.

The IDH1R 132X mutation is known to occur in certain types of cancer as indicated in table 2 below.

TABLE 2 IDH mutations associated with certain cancers

The IDH1R132H mutation has been identified in: glioblastoma, acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer, cholangiocarcinoma, chondrosarcoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), colon cancer, and angioimmunoblastic non-Hodgkin's lymphoma (NHL). Thus, in one embodiment, the methods described herein are used to treat glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinoma, chondrosarcoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), colon cancer, or angioimmunoblastic non-hodgkin's lymphoma (NHL) in a patient.

In another embodiment, the methods described herein are used to treat a glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinoma (e.g., intrahepatic cholangiocarcinoma (IHCC)), chondrosarcoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), prostate cancer, chronic myelomonocytic leukemia (CMML), B-acute lymphoblastic leukemia (B-ALL), myelosarcoma, multiple myeloma, lymphoma colon cancer, or angioimmunoblastic non-hodgkin's lymphoma (NHL) in a patient.

In another embodiment, the advanced hematologic malignancy to be treated is a lymphoma (e.g., non-hodgkin's lymphoma (NHL), such as B-cell lymphoma (e.g., Burkitt's lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma) and T-cell lymphoma (e.g., mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma).

Thus, in one embodiment, the cancer is a cancer selected from any one of the cancer types listed in table 2, and the IDH R132X mutation is one or more of the IDH1R 132X mutations listed in table 2 for the particular cancer type.

The methods of treatment described herein can additionally include various evaluation steps before and/or after treatment with a compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId or a compound described in any of the examples described herein.

In one embodiment, the method further comprises the step of assessing the growth, size, weight, aggressiveness, stage and/or other phenotype of the cancer before and/or after treatment with a compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or a compound described in any of the embodiments described herein.

In one embodiment, the method further comprises the step of assessing the IDH1 genotype of the cancer before and/or after treatment with a compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or a compound described in any of the embodiments described herein. This may be achieved by methods common in the art, such as DNA sequencing, immunoassay and/or assessing the presence, distribution or level of 2 HG.

In one embodiment, the method further comprises the step of determining the level of 2HG in the subject before and/or after treatment with a compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or a compound described in any of the embodiments described herein. This can be obtained by: spectroscopic analysis, e.g. magnetic resonance based analysis, e.g. MRI and/or MRS measurement methods; sample analysis of body fluids, such as serum or spinal fluid analysis; or by analysis of the surgical material, e.g., by mass spectrometry.

Also provided is a method for inhibiting activity of mutant IDH2, the method comprising contacting a subject in need thereof with a compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId, a compound described in any of the embodiments, or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer to be treated is characterized by a mutant allele of IDH2, wherein the IDH2 mutation contributes to the novel ability of the enzyme to catalyze NADPH-dependent reduction of α -ketoglutarate to R (-) 2-hydroxyglutarate in a subject. In one aspect of this embodiment, the mutant IDH2 has the R140X mutation. In another aspect of this embodiment, the R140X mutation is an R140Q mutation. In another aspect of this embodiment, the R140X mutation is an R140W mutation. In another aspect of this embodiment, the R140X mutation is an R140L mutation. In another aspect of this embodiment, the mutant IDH2 has the R172X mutation. In another aspect of this embodiment, the R172X mutation is a R172K mutation. In another aspect of this embodiment, the R172X mutation is a R172G mutation.

Also provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH2, comprising the steps of: administering to a subject in need thereof (a) a compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId, or a compound described in any of this example, or a pharmaceutically acceptable salt thereof; or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.

In one embodiment, the cancer to be treated is characterized by a mutant allele of IDH2, wherein the IDH2 mutation contributes to the novel ability of the enzyme to catalyze NADPH-dependent reduction of α -ketoglutarate to R (-) 2-hydroxyglutarate in a patient. In one aspect of this embodiment, the mutant IDH2 has the R140X mutation. In another aspect of this embodiment, the R140X mutation is an R140Q mutation. In another aspect of this embodiment, the R140X mutation is an R140W mutation. In another aspect of this embodiment, the R140X mutation is an R140L mutation. In another aspect of this embodiment, the mutant IDH2 has the R172X mutation. In another aspect of this embodiment, the R172X mutation is a R172K mutation. In another aspect of this embodiment, the R172X mutation is a R172G mutation. Cancer can be analyzed by sequencing cell samples to determine the presence and specific nature of mutations at amino acids 140 and/or 172 of IDH2 (e.g., altered amino acids present therein).

Without being bound by theory, applicants believe that the mutant allele of IDH2 (where the IDH2 mutation contributes to the novel ability of the enzyme to catalyze NADPH-dependent reduction of α -ketoglutarate to R (-) 2-hydroxyglutarate), and in particular the R140Q and/or R172K mutations of IDH2, characterize a subset of all types of cancers regardless of their cellular nature or location in vivo. Thus, the compounds and methods of one aspect of the invention are useful for treating any type of cancer characterized by the presence of a mutant allele of IDH2, and in particular, an IDH 2R 140Q and/or R172K mutation, that confers such activity.

As described herein, in one aspect of this embodiment, the efficacy of a cancer treatment is monitored by measuring the 2HG level.

In one embodiment, the cancer is a tumor in which at least 30%, 40%, 50%, 60%, 70%, 80% or 90% of the tumor cells carry an IDH2 mutation, and in particular an IDH 2R 140Q, R140W or R140L and/or R172K or R172G mutation, at the time of diagnosis or treatment.

In another embodiment, one aspect of the invention provides a method of treating a cancer selected from glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), Acute Myelogenous Leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma, or angioimmunoblastic lymphoma in a patient by administering to the patient an amount of a compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId effective to treat the cancer. In a more specific embodiment, the cancer to be treated is glioma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), Acute Myelogenous Leukemia (AML), melanoma, chondrosarcoma, or angioimmunoblastic non-hodgkin's lymphoma (NHL).

2HG is known to accumulate in the inherited metabolic disorder 2-hydroxyglutarate uremia. This disease is caused by the absence of the enzyme 2-hydroxyglutarate dehydrogenase, which converts 2HG to α -KG (Struys, E.A.) et al, J.Nature of human genetics (Am J Hum Genet)76,358-60 (2005)). Patients lacking 2-hydroxyglutarate dehydrogenase accumulate 2HG in the brain, suffer from leukoencephalopathy, and have an increased risk of developing brain tumors as assessed by MRI and CSF analyses (argrie, M. (aghli, M.), zahidi, F. (Zahedi, F.), and rafie (rafie), "journal of neural tumors" (J neuroool) 91,233-6(2009), "cole, S. (Kolker, S.), malayan dack, E. (Mayatepek, E.), and hofmann, g.f. (Hoffmann, g.f.)" pediatric neurology (neuropatriciatrics) 33,225-31(2002), varna, M. (warner, M., ladie., a., Latini., a., lasitini, a. (lekul., l.) (lekuchikutakura, k.) (3656, wucherenkola.) (wu-34, wucherie, wu.) (wucherie, p.) (wu.) (wurtly, p.) (3648, and (wurtly). Furthermore, increased brain levels of 2HG cause increased levels of ROS (Coreckle, S. et al, J. European neuroscience (Eur J Neurosci)16,21-8 (2002); Latinib, A. et al, J. European neuroscience 17,2017-22(2003)), possibly leading to increased risk of cancer. The ability of 2HG to act as an NMDA receptor agonist may contribute to this effect (Colrker, S. et al, J. European neuroscience 16,21-8 (2002)). 2HG can also be toxic to cells by competitively inhibiting enzymes that employ glutamate and/or alpha KG. These enzymes include transaminases, which allow the use of glutamate nitrogen for amino and nucleic acid biosynthesis, and α KG-dependent prolyl hydroxylases, such as those which regulate HIF1- α levels.

Thus, according to another embodiment, one aspect of the invention provides a method of treating 2-hydroxyglutarate uropathy, in particular D-2-hydroxyglutarate uropathy, in a patient by administering to the patient a compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or a compound described in any of the embodiments described herein.

Also provided are methods of treating a disease selected from Maffucci syndrome and orlistat disease (Ollierdisease) characterized by the presence of a mutant allele of IDH1, comprising the steps of: administering to a subject in need thereof (a) a compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId or a compound described in any of this embodiment, or a pharmaceutically acceptable salt thereof; or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.

In one embodiment, the method further comprises the step of assessing the IDH2 genotype of the cancer before and/or after treatment with a compound of formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc or IIId or a compound described in any of the embodiments described herein. This may be achieved by methods common in the art, such as DNA sequencing, immunoassay and/or assessing the presence, distribution or level of 2 HG.

Combination therapy

In some embodiments, the methods described herein comprise the additional step of co-administering to a subject in need thereof a second therapy, e.g., an additional cancer therapeutic or an additional cancer treatment. Exemplary additional cancer therapeutic agents include, for example, chemotherapy, targeted therapy, antibody therapy, immunotherapy, and hormone therapy. Additional cancer treatments include, for example: surgery and radiation therapy. Examples of each of these treatments are provided below.

The term "co-administration" as used herein with respect to a further cancer therapeutic means that the further cancer therapeutic may be administered with a compound of one aspect of the invention in a portion of a single dosage form (e.g., a composition of one aspect of the invention comprising a compound of one aspect of the invention and a second therapeutic as described above) or in separate multiple dosage forms. Alternatively, the additional cancer therapeutic agent may be administered prior to, sequentially with, or after administration of the compound of one aspect of the invention. In such combination therapy treatment, the compound of one aspect of the invention and the one or more second therapeutic agents are both administered by conventional methods. Administration of a composition of one aspect of the invention comprising both a compound of one aspect of the invention and a second therapeutic agent to a subject does not preclude administration of the same therapeutic agent, any other second therapeutic agent, or any compound of one aspect of the invention alone to the subject at another time during the course of treatment. The term "co-administration" as used herein with respect to an additional cancer treatment means that the additional cancer treatment may occur prior to, sequentially with, concurrently with, or after administration of a compound of one aspect of the invention.

In some embodiments, the additional cancer therapeutic agent is a chemotherapeutic agent. Examples of chemotherapeutic agents for cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives), alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazine, triazenes, aziridines, spindle poisons, cytotoxic agents, topoisomerase inhibitors, and the like), and hypomethylating agents (e.g., decitabine (5-aza-deoxycytidine), zebularine (zebularine), isothiocyanates, azacytidine (5-azacytidine), 5-fluoro-2' -deoxycytidine, 5, 6-dihydro-5-azacytidine, and the like). Exemplary agents include doxorubicin, actinomycin, alitretinol, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bepotrotene, bendamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carboquinone, carmofur, carmustine, celecoxib, chlorambucil, nitrogen mustard, cisplatin, cladribine, clofarabine, clinitase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunomycin, decitabine, colchicine, docetaxel, doxorubicin, ethacryloxide, elimotocel, ethacrycin, enocitabine, epirubicin, estramustine, etoposide, floxuridine, fludarabine, FU (5FU), fluorouracil, Fotemustine, gemcitabine, Grignard implants (Gliadel implant), hydroxyurea, idamycin, ifosfamide, irinotecan, iloufen, ixabepilone, larotaxel, leucovorin, liposomal doxorubicin, liposomal daunomycin, lonidamine, lomustine, methioninone, gansulvan, maxolone, melphalan, mercaptopurine, sodium mercaptoethanesulfonate, methotrexate, methyl aminoacetonate, dibromomannitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, orimoemerson, omastatin, otaxel, oxaliplatin, paclitaxel, pemetrexed, pentastatin, pirrubicin, picoxystrobin, porphine sodium, poultitussine, procarbazine, rivastigmine, ranitidine, irinotecan, bixib, Sapatitabine, semustine, adenoviral vector niche gene injection (sitemaradonovec), sarutaplatin (stratapidin), streptozocin, talaporfin, tegafur-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate, thiotepa, thiazolelline, thioguanine, tipifarnine, topotecan, trabectedin, triimiquinone, trittamine, teriratine, tretinoin, trooshusuofane, trofosfamide, uramustine, vatuofin, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, levoflexixin, and other cytostatics or cytotoxic agents described herein.

Because some drugs work better together than individually, two or more drugs are usually administered simultaneously. Typically, two or more chemotherapeutic agents are used as a combination chemotherapy.

In some embodiments, the additional cancer therapeutic agent is a differentiating agent. Such differentiating agents include retinoids (e.g., all trans-retinoic acid (ATRA), 9-cis-retinoic acid, 13-cis-retinoic acid (13-cRA), and 4-hydroxy-phenyl-retinoic acid amide (4-HPR)); arsenic trioxide; histone deacetylase inhibitors HDACs (such as azacytidine (Vidaza) and butyrate (e.g., sodium phenylbutyrate)); mixed polar compounds (e.g., hexamethylene-bis-acetamide ((HMBA)); vitamin D; and cytokines (e.g., colony stimulating factors, including G-CSF and GM-CSF, and interferon).

In some embodiments, the additional cancer therapeutic agent is a targeted therapy agent. Targeted therapy constitutes the use of agents specific for dysregulated proteins directed against cancer cells. Small molecule targeted therapy drugs are often inhibitors of the enzyme domain of mutated, overexpressed, or otherwise critical proteins within cancer cells. Prominent examples are tyrosine kinase inhibitors such as axitinib, bosutinib, cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, lestatinib, nilotinib, semaxanib, sorafenib, sunitinib and vandetanib; and cyclin-dependent kinase inhibitors such as axidizib and celecoxib. Monoclonal antibody therapy is another strategy, in which the therapeutic agent is an antibody that specifically binds to a protein on the surface of the cancer cell. Examples include the anti-HER 2/neu antibody trastuzumab that is typically used for breast cancer

And the anti-CD 20 antibodies rituximab and tositumomab, which are typically used for a variety of B-cell malignancies. Other exemplary antibodies include cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, and gemtuzumab. Exemplary fusion protein packagesIncluding aflibercept and dinil interleukins. In some embodiments, targeted therapy may be used in combination with a compound described herein (e.g., a biguanide, such as metformin or phenformin, preferably phenformin).

Targeted therapies may also involve small peptides as "homing devices", which may bind to cell surface receptors or the infected extracellular matrix surrounding the tumor. Radionuclides attached to these peptides (e.g., RGD) eventually kill cancer cells if the nuclide decays near the cell. One example of such a therapy includes

In some embodiments, the additional cancer therapeutic agent is an immunotherapy agent. Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the subject's own immune system against tumors. Contemporary methods for generating an immune response against tumors include intravesicular BCG immunotherapy for superficial bladder cancer and the use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma subjects.

Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, as the immune cells of the donor will typically attack the tumor with a graft-versus-tumor effect. In some embodiments, an immunotherapy agent may be used in combination with one of the compounds or compositions described herein.

In some embodiments, the additional cancer therapeutic agent is a hormone therapy agent. The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone sensitive tumors include certain types of breast and prostate cancer. Removal or blockade of estrogen or testosterone is often an important additional treatment. In certain cancers, administration of a hormonal agonist (e.g., a progestin) may be therapeutically beneficial. In some embodiments, a hormone therapy agent can be used in combination with one of the compounds or compositions described herein.

Other possible additional therapeutic modalities include imatinib, gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxin, and radiolabeled drugs and antibodies.

Examples of the invention

General experimental comments:

in the following examples, reagents (chemicals) were purchased from commercial sources such as alpha (Alfa), ancao (Acros), Sigma-Aldrich (Sigma Aldrich), TCI, and Shanghai chemical reagent Company (Shanghai chemical reagent Company) and used without further purification. Nuclear Magnetic Resonance (NMR) spectra were obtained on Brucker AMX-400NMR (Brucker, Switzerland). Chemical shifts are reported in parts per million (ppm, δ) low field format compared to tetramethylsilane. Mass spectra were given by electrospray ionization (ESI) from either a Waters (Waters) LCT TOF mass spectrometer (Waters, usa) or Shimadzu (Shimadzu) LC-MS-2020 mass spectrometer (Shimadzu, japan). The microwave reaction was performed on an Initiator 2.5 microwave synthesizer (Biotage, sweden).

With respect to the exemplary compounds disclosed in this section, a detailed description of a stereoisomer (e.g., the (R) or (S) stereoisomer) indicates the preparation of the compound such that the compound is enriched at the indicated stereocenter by at least about 90%, 95%, 96%, 97%, 98%, or 99%. The chemical name of each of the exemplary compounds described below was generated by ChemDraw software.

List of abbreviations:

general purpose

anhy. anhydrous

aq. aqueous solution

min for

hrs hour

mL of

mmol millimole

mol mole of

MS Mass Spectrometry

NMR nuclear magnetic resonance

TLC thin layer chromatography

HPLC high performance liquid chromatography

saturation of satd

Optical spectrum

Hz

Chemical shift of delta

J coupling constant

s single peak

d double peak

t triplet peak

q quartet peak

m multiplet

br broad peak

qd quadruple doublet

double quinan of dquin

dd double doublet

dt double trimodal

Solvents and reagents

DAST diethylaminosulfur trifluoride

CHCl₃Chloroform

DCM dichloromethane

DMF dimethyl formamide

Et₂O diethyl ether

EtOH ethanol

EtOAc ethyl acetate

MeOH methanol

MeCN acetonitrile

PE Petroleum Ether

THF tetrahydrofuran

DMSO dimethyl sulfoxide

AcOH acetic acid

HCl hydrochloric acid

H₂SO₄Sulfuric acid

NH₄Cl ammonium chloride

KOH potassium hydroxide

NaOH sodium hydroxide

K₂CO₃Potassium carbonate

Na₂CO₃Sodium carbonate

TFA trifluoroacetic acid

Na₂SO₄Sodium sulfate

NaBH₄Sodium borohydride

NaHCO₃Sodium bicarbonate

Sodium NaHMDS hexamethyldisilazane

LiHMDS lithium hexamethyldisilazide

LAH lithium aluminum hydride

NaBH₄Sodium borohydride

LDA lithium diisopropylamide

Et₃N-Triethylamine

Py pyridine

DMAP 4- (dimethylamino) pyridine

DIPEA N, N-diisopropylethylamine

Xphos 2-dicyclohexylphosphino-2, 4, 6-triisopropylbiphenyl

BINAP 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl

dppf 1,1' -bis (diphenylphosphino) ferrocene

TBTU 2- (1H-benzotriazol-1-yl) -1,1,3, 3-tetramethylurea tetrafluoroborate

DPPA Azidophosphoric acid Diphenyl ester

NH₄OH ammonium hydroxide

EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide

HOBt 1-hydroxybenzotriazole

Py pyridine

Dppf 1,1' -bis (diphenylphosphino) ferrocene

HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea

BINAP 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl

Preparation of intermediates

Preparation of 1-phenylcyclopropylamine.

To a solution of benzonitrile (5g, 48mmol, 3 equivalents) and titanium tetraisopropoxide (21.5mL, 73mmol, 1.5 equivalents) in dry THF (140mL) at-70 deg.C over 30 min was added ethylmagnesium bromide (48.5mL, 146mmol) dropwise. The solution was stirred at room temperature for 1.5 hours, followed by dropwise addition of boron trifluoride etherate (15mL, 121mmol, 2.5 equiv.) over 15 minutes. The mixture was stirred at room temperature for a further 1.5 h, followed by addition of 1N aqueous HCl and Et₂And O. The resulting mixture was poured into 10% aqueous NaOH and Et₂And (4) extracting. With anhydrous Na₂SO₄The combined organic layers were dried and concentrated. By column chromatography using PE/EtOAc/NH₃.H₂The residue was purified O (4:1: 0.1%) to obtain the desired product. LC-MS M/z 134.1(M + H)⁺。

Preparation of 2-amino-2-methylpropanenitrile

At room temperature to NH₄To a mixture of Cl (4.9g, 92.3mmol) and acetone (7mL, 92.3mmol) in ammonium hydroxide (40mL, 230.7mmol) was added KCN (5g, 76.9 mmol). The reaction mixture was stirred at room temperature for 3 days. The mixture was extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Dried and concentrated to give the desired product, which was used directly in the next step without any further purification.

Preparation of 2-aminopropionitrile

At room temperature to NH₄KCN (1g, 15.4mmol) was added to a mixture of Cl (981mg, 18.5mmol) and acetaldehyde (1mL, 18.5mmol) in ammonium hydroxide (3 mL). The reaction mixture was stirred at room temperature for 2 days. The mixture was extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Drying and concentrating to obtain the desired productThe product, which was used directly in the next step without any further purification.

Preparation of dicyclopropylmethylamine

Step 1, preparing the dicyclopropyl methyl ketoxime. To a mixture of dicyclopropylmethanone (500mg, 4.5mmol) in pyridine (5mL) was added hydroxylamine hydrochloride (469mg, 6.75 mmol). The reaction mixture was stirred at 100 ℃ for 4 h and cooled to room temperature, followed by addition of EtOAc. The resulting mixture was washed with 1N aqueous HCl and brine, and anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give the desired product, which was used directly in the next step without any further purification.

LC-MS:m/z 124.1(M-H)^-。

And 2, preparing dicyclopropylmethylamine. To a cooled solution of dicyclopropylmethylketoxime (550mg, 4.4mmol) in THF (5mL) was added LiAlH₄(200mg, 5.3 mmol). The mixture was then stirred at 80 ℃ for 6 hours and cooled to room temperature. The mixture was quenched by 1N aqueous NaOH until gas evolution ceased and then filtered. The filtrate was extracted with EtOAc. With anhydrous Na₂SO₄The combined organic layers were washed and concentrated under reduced pressure to give the desired product, which was used directly in the next step without any further purification.

LC-MS:m/z 112.1(M+H)⁺。

Preparation of bicyclo [3.1.0] hex-3-amine

Step 1: to prepare benzyl cyclopent-3-enylcarbamate. To a solution of cyclopent-3-enecarboxylic acid (5g, 44.6mmol, 1 eq.) and DPPA (13.5g, 49mmol, 1.1 eq.) in toluene (80mL) at room temperature was added Et₃N (7.4mL, 53.5mmol, 1.2 equiv.). The mixture was then stirred at reflux for 2 hours, during which time a greater amount of nitrogen gas evolved. After addition of BnOH (7mL, 66.9mmol, 1.5 equiv.), the resulting mixture was stirred at 100 ℃ overnight and cooled to room temperature. After the reaction with saturated aqueous NaHCO₃After quenching, the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by flash chromatography using PE/EtOAc (5:1) as eluent to give the desired product.

LC-MS:m/z 218.0(M+H)⁺。

Step 2: preparation of bicyclo [3.1.0]Hex-3-ylcarbamic acid benzyl ester. To a solution of benzyl cyclopent-3-enylcarbamate (1g, 4.6mmol, 1 eq) in anhydrous DCM at 0 deg.C under a nitrogen atmosphere was added ZnEt₂(9.7mL, 9.7mmol, 2.1 equiv.) followed by dropwise addition of CH₂I₂(0.78mL, 9.7mmol, 2.1 equiv.). The reaction mixture was warmed to room temperature and stirred for 4 hours. The resulting reaction mixture was quenched with brine and extracted with DCM. With anhydrous Na₂SO₄The organic layer was dried and concentrated. The residue was purified by column chromatography using PE/EtOAc (5:1) as eluent to give the desired product.

LC-MS:m/z 232.1(M+H)⁺。

And step 3: preparation of bicyclo [3.1.0] hex-3-amine. To a solution of benzyl bicyclo [3.1.0] hex-3-ylcarbamate (2g) in MeOH (20mL) at room temperature under a nitrogen atmosphere was added Pd/C (0.2g) in one portion. The resulting mixture was then stirred under a hydrogen balloon overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the desired product, which was used directly in the next step without any further purification.

LC-MS:m/z 98.1(M+H)⁺。

Preparation of 2- (1, 1-difluoroethyl) pyridin-4-amine

Step 1: preparation of 4-chloro-N-methoxy-N-picolinamide. To a solution of 4-chloropicolinic acid (10g, 63.5mmol) in DMF (150mL) at 0 deg.C was added TBTU (30.6g, 95.2mmol), N, O-dimethylhydroxylamine (9.3g, 95.2mmol) and DIPEA (24.6g, 190.4 mmol). The mixture was stirred at room temperature overnight. With saturated aqueous NH₄The reaction mixture was diluted with Cl and extracted with EtOAc. With Na₂SO₄The organic layer was dried and concentrated. The residue was purified by flash chromatography to give the desired product.

LC-MS:m/z 201.0(M+H)⁺。

Step 2: preparation of 1- (4-chloropyridin-2-yl) ethanone. To a solution of 4-chloro-N-methoxy-N-picolinamide (11.25g, 56.08mmol) in THF (50mL) at 0 deg.C was added MeMgBr (28.04mL, 84.12 mmol). The mixture was then stirred at room temperature overnight and saturated aqueous NH₄And (4) quenching by Cl. The resulting mixture was extracted with EtOAc. With anhydrous Na₂SO₄The organic layer was dried and concentrated. The residue was purified by flash chromatography to give the desired product.

¹H NMR(400MHz,CDCl₃):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/z 156.0(M+H)⁺。

And step 3: 4-chloro-2- (1, 1-difluoroethyl) pyridine. To a solution of 1- (4-chloropyridin-2-yl) ethanone (6.3g, 40.5mmol) in DCM (30mL) was added DAST (65.2g, 405mmol) at 0 ℃. The mixture was then stirred at room temperature overnight and saturated aqueous NaHCO was used₃And (4) quenching. The resulting mixture was extracted with DCM. With anhydrous Na₂SO₄The organic layer was dried and concentrated. The residue was purified by flash chromatography to give the desired product.

¹H NMR(400MHz,CDCl₃):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/z 178.0(M+H)⁺。

And 4, step 4: preparation of tert-butyl (2- (1, 1-difluoroethyl) pyridin-4-yl) carbamate. To a solution of 4-chloro-2- (1, 1-difluoroethyl) pyridine (6.0g, 33.8mmol) in dioxane (20mL) was added BocNH at room temperature₂(4.74g，40.5mmol)、X-phos(1.14g，1.7mmol)、CsCO₃(16.5g, 50.7mmol) and Pd (OAc)₂(1.32g, 2.7 mmol). The mixture was then stirred at 80 ℃ overnight and then cooled to room temperature. With saturated aqueous NH₄The reaction mixture was diluted with Cl and extracted with EtOAc. With anhydrous Na₂SO₄The organic layer was dried and concentrated. The residue was purified by flash chromatography to give the desired product.

LC-MS:m/z 259.1(M+H)⁺。

And 5: preparation of 2- (1, 1-difluoroethyl) pyridin-4-amine. (2- (1, 1-Difluoroethyl) pyridine was cooled in an ice water bath-4-yl) carbamic acid tert-butyl ester (7.97g, 30.86mmol) in DCM (30 mL). TFA (10mL) was then added dropwise. The reaction mixture was stirred at room temperature for 4 hours and monitored by TLC. Once the reaction is complete, the mixture is diluted with water and passed through saturated aqueous NaHCO₃Adjusting the pH>7. The resulting mixture was extracted with DCM. With anhydrous Na₂SO₄The combined organic layers were dried and concentrated to give the desired product, which was used in the next step without further purification.

LC-MS:m/z 159.1(M+H)⁺。

Preparation of 1- (4-aminopyridin-2-yl) cyclopropanecarbonitrile

Step 1: preparation of 1- (4-bromopyridin-2-yl) cyclopropanecarbonitrile. To a cold (-5 ℃) mixture of 4-bromo-2-fluoropyridine (1g, 5.7mmol), cyclopropanecarbonitrile (1.25mL, 17mmol, 3 equiv.) and 4A MS in toluene (20mL) was added LiHMDS (1M in toluene, 17.6mL, 17.6mmol, 3.1 equiv.) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After pouring it into water, the mixture was filtered. With EtOAc and H₂The filtrate was diluted with EtOAc and extracted. The organic phase was washed with water and brine, and anhydrous Na₂SO₄Dried and concentrated. The residue was purified by column chromatography using PE/EtOAc (9:1) as eluent to give the desired product.

LC-MS:m/z 223.0(M+H)⁺。

Step 2: preparation of 1- (4- (diphenylmethyleneamino) pyridin-2-yl) cyclopropanecarbonitrile. To 1- (4-bromopyridin-2-yl) cyclopropanecarbonitrile (0.45g, 2.1mmol) at room temperature under a nitrogen atmosphere,BINAP(0.04g，0.063mmol)、Pd₂(dba)₃(0.019g, 0.021mmol) and NaO^tTo a mixture of Bu (0.282g, 2.94mmol) in toluene (6mL) was added diphenylazomethine (0.45g, 2.51 mmol). The reaction mixture was stirred at reflux for 2 hours and then cooled to room temperature. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography to give the desired product.

LC-MS:m/z 324.1(M+H)⁺。

And step 3: preparation of 1- (4-aminopyridin-2-yl) cyclopropanecarbonitrile. A mixture of 1- (4- (diphenylmethyleneamino) pyridin-2-yl) cyclopropanecarbonitrile (0.48g, 1.49mmol), THF (10mL), and aqueous hydrochloric acid (2N, 2.0mL) was stirred at room temperature for 1 hour. The mixture was then partitioned between EtOAc (15mL) and water (15 mL). The aqueous phase was extracted with EtOAc (2 × 25 mL). With anhydrous Na₂SO₄The combined organic layers were dried and concentrated. The residue was purified by column chromatography to give the desired product.

LC-MS:m/z 160.1(M+H)⁺。

Example 1 a dialiphatic triazine compound of formula D is prepared, wherein ring a is a substituted pyridin-2-yl or phenyl group. The compounds of this example were prepared by general scheme 1, listed below.

Scheme 1

Step 1: preparation of methyl 6-trifluoromethyl-pyridine-2-carboxylate (2). To a solution of 2-chloro-6-trifluoromethyl-pyridine (2g, 11.1mmol, 1.0 eq) in MeOH (20mL) under nitrogen was added Pd (OAc)₂(124mg, 0.05 eq.) and dppf (600mg, 0.1 eq.). Then adding the obtained orangeEt was added to the color solution₃N (2.3mL, 1.5 equiv). The reaction solution was then stirred under an atmosphere of carbon monoxide (40psi) at 60 ℃ for 22 hours. Once the reaction was complete, the mixture was filtered and the filtrate was concentrated in high vacuum. The residue was purified by column chromatography to obtain the desired product.

¹HNMR(400MHz,CDCl₃):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/z 206(M+H)⁺。

Step 2: preparation of 6- (6-trifluoromethylpyridine 2-yl) -1,3, 5-triazine-2, 4-dione. To a solution of fresh NaOEt (3.84g, 0.16mol, 3 equiv.) prepared from Na in ethanol (500mL) was added methyl 6-trifluoromethylpicolinate (33g, 0.16mol, 3 equiv.) and biuret (5.3g, 0.052 mol). The resulting mixture was heated to reflux for 1 hour and then concentrated. The residue was poured into water and saturated aqueous NaHCO was used₃Treated to adjust the pH to 7. The precipitated solid was collected by filtration and dried under air to give the desired compound.

¹H NMR(400MHz,DMSO-d₆):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/z 259(M+H)⁺。

And step 3: preparation of 2, 4-dichloro-6- (6-trifluoromethyl-pyridin-2-yl) -1,3, 5-triazine. To 6- (6-trifluoromethyl-pyridin-2-yl) -1,3, 5-triazine-2, 4(1H,3H) -dione (3.37g, 0.013mol) in POCl₃(48mL) to the solution was added PCl₅(23g, 0.1 mol). The mixture was stirred at 100 ℃ for 2 hours and then concentrated. The residue was dissolved in EtOAc and then saturated aqueous NaHCO₃And (6) washing. With anhydrous Na₂SO₄The organic layer was dried and then concentrated to give the desired product.

¹H NMR(400MHz,CDCl₃):δ8.76(d,J＝7.9Hz,1H),8.19(t,J＝7.9Hz,1H),7.97(d,J＝7.8Hz,1H)。LC-MS:m/z 294.9(M+H)⁺。

And 4, step 4: preparation of N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (6- (trifluoromethyl) -pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. To a mixture of 2, 4-dichloro-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine (600mg, 2.0mmol, 1.0 equiv.) and (R) -1-cyclopropylethylamine hydrochloride (536mg, 4.4mmol, 2.2 equiv.) in THF (12mL) was added CsF (1.2g, 8.0mmol, 2 equiv.) and DIPEA (1.4mL, 8.0mmol, 4 equiv.) at room temperature. The mixture was stirred at 60 ℃ overnight and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by standard methods to give the desired product.

¹H NMR(400MHz,CD₃OD):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)⁺。

Using the procedure set forth in example 1, the following compounds were prepared using the appropriate starting materials.

Compound N²,N⁴-bis ((S) -1-cyclopropylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 393.2(M+H)⁺。

Compound N²- ((R) -1-cyclopropylethyl) -N⁴- ((S) -1-Cyclopropylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 393.2(M+H)⁺。

Compound N²,N⁴-bis (1-cyclopropylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹HNMR(400MHz,CD₃OD):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/z 393.2(M+H)⁺。

Compound N²,N⁴-bis (cyclobutylmethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 393.2(M+H)⁺。

Compound N²,N⁴Bis ((R) -1-cyclobutylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 421.2(M+H)⁺。

Compound N²,N⁴-bis (2-methylcyclopropyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹HNMR(400MHz,CD₃OD):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/z 365.3(M+H)⁺。

Compound N²,N⁴Bis (cyclopropylmethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CD₃OD):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 N²,N⁴Bis ((1-methylcyclopropyl) methyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹HNMR(400MHz,CD₃OD):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/z 393.2(M+H)⁺。

Compound N²,N⁴-dicyclobutyl-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):δ8.67-8.38(m,1H),7.99(d,J＝6.8Hz,1H),7.78(d,J＝7.5Hz,1H),5.52(m 2H),4.80-4.32(m,2H),2.41(s,4H),2.20(s,1H),2.06-1.62(m,8H)。LC-MS:m/z 365.2(M+H)⁺。

Compound N²,N⁴Bis (bicyclo [ 3.1.0)]Hex-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CD₃OD):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/z 417.2(M+H)⁺。

The compound N, N' -dicyclopentyl-6- (6-trifluoromethyl-pyridin-2-yl) - [1,3,5] triazine-2, 4-diamine

¹HNMR(400MHz,CD₃OD):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 N²,N⁴-bis (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 465.2(M+H)⁺。

Compound N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 493.2(M+H)⁺。

The compound N, N' -bis- (tetrahydro-pyran-4-yl) -6- (6-trifluoromethyl-pyridin-2-yl) - [1,3,5] triazine-2, 4-diamine

¹HNMR(400MHz,DMSO-d₆):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/z 425.1(M+H)⁺。

Compound N²,N⁴-diisopropyl-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl3):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/z 341.2(M+H)⁺。

Compound N²,N⁴Di-tert-butyl-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆):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/z 369.2(M+H)⁺。

The compound N, N' -di-sec-butyl-6- (6-trifluoromethyl-pyridin-2-yl) - [1,3,5] triazine-2, 4-diamine

¹HNMR(400MHz，CD₃OD):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)⁺。

¹HNMR(400 MHz,CD₃OD):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 N²,N⁴Di-sec-butyl-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹HNMR(400 MHz,CD₃OD):δ8.72-8.79(m,1H),8.38-8.43(m,1 H),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 N²- ((R) -sec-butyl) -N⁴- ((S) -sec-butyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400 MHz,CD₃OD):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 N²,N⁴Bis (3-methylbut-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 397.2(M+H)⁺。

Compound N²,N⁴-bis ((R) -3-methylbut-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆):δ8.46(m,1H),8.21(m,1H),8.00(d,J＝7.7Hz,1H),7.36(m,2H),3.90(m 2H),1.79(m,2H),1.05(t,J＝7.6Hz,6H),0.87(t,J＝7.6Hz,12H)。LC-MS:m/z 397.2(M+H)⁺。

Compound N²,N⁴-bis ((S) -3-methylbut-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆):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/z 397.2(M+H)⁺。

Compound N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 394.2(M+H)⁺。

Compound N²- ((R) -1-phenylethyl) -N⁴- ((S) -1-phenylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 465.2(M+H)⁺。

Compound 6- (6-chloropyridin-2-yl) -N²,N⁴Bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CD₃OD):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/z 359.2(M+H)⁺。

Compound 6- (6-chloropyridin-2-yl) -N²,N⁴Diisopropyl-1, 3, 5-triazine-2, 4-diamine

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/z 335.1(M+H)⁺。

Compound 6- (6-chloropyridine)-2-yl) -N²,N⁴Diisopropyl-1, 3, 5-triazine-2, 4-diamine

¹HNMR(400MHz,CD₃OD):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/z 307.1(M+H)⁺。

Compound N²,N⁴Bis (but-3-en-1-yl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine

¹HNMR(400MHz,CD₃OD):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/z 296.3(M+H)⁺。

Compound N²,N⁴Bis (3-oxabicyclo [3.1.0]]Hex-6-yl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine

¹HNMR(400MHz,CD₃OD):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/z 352.2(M+H)⁺。

Compound N²,N⁴-bis ((1S,3S) -3- (4-fluorophenyl) cyclobutyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine to a mixture of 2, 4-dichloro-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine (600mg, 2.0mmol, 1.0 equiv.) and (1S,3S) -3- (4-fluorophenyl) cyclobutylamine (726mg, 4.4mmol, 2.2 equiv.) in THF (12mL) at room temperature were added CsF (0.6g, 2.0mmol, 1 equiv.) and DIPEA (0.7mL, 4.0mmol, 2 equiv.). The resulting mixture was stirred at 60 ℃ overnight and then filtered. The filtrate is concentrated and purified via standard techniques to obtain the desired product.

¹H NMR(400MHz,CDCl₃)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/z 553.2(M+H)⁺。

Compound N²,N⁴-bis ((1R,3R) -3- (4-fluorophenyl) cyclobutyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 553.2(M+H)⁺。

The compound 6- (6- (trifluoromethyl) pyridin-2-yl) -N²,N⁴Bis ((R) -1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

1H NMR(400MHz,CDCl₃)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 N²,N⁴-bis ((S) -1,1, 1-trifluorobutan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz，CDCl₃)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/z 477(M+H)⁺。

Compound N²,N⁴-bis ((2, 2-difluorocyclopropyl) methyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,，CDCl₃)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/z 437(M+H)⁺。

Compound N²,N⁴-bis ((3, 3-difluorocyclobutyl) methyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹HNMR(400MHz,CDCl₃)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 N²,N⁴-bis (3, 3-difluorocyclobutyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 437.1(M+H)⁺。

Compound N²,N⁴-bis ((S) -3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)δ8.54-8.38(m,1H),7.95(m 1H),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/z 465.1(M+H)⁺。

Compound N²,N⁴-bis ((R) -3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400 MHz,，CDCl₃)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/z 465(M+H)⁺。

The compound N2- ((R) -3, 3-difluorocyclopentyl) -N4- ((S) -3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR((400MHz,CDCl₃)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/z 465(M+H)⁺。

Compound N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (4- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)δ8.70-8.62(m,2H),7.62(d,1H),6.70-6.43(m,1H),5.22-3.95(m,3H),2.11-1.69(m,16H)。LC-MS:m/z 493(M+H)⁺。

Compound N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (6-methoxypyridin-2-yl) -1,3, 5-triazine2, 4-diamines

¹H NMR(400MHz,CDCl₃)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/z 355.2(M+H)⁺。

Compound N²,N⁴-bis (3, 3-difluorocyclobutyl) -6- (6- (trifluoromethoxy) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 453(M+H)⁺。

Compound N²,N⁴-bis (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethoxy) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 481(M+H)⁺。

Compound N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (6- (trifluoromethoxy) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 509(M+H)⁺。

Compound N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (3-fluoro-6-methoxypyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 473(M+H)⁺。

Table 3: the following compounds were prepared by following the procedure described in scheme 1 above.

Example 2 a dialiphatic triazine compound of formula E is prepared, wherein ring a is a substituted pyridin-2-yl or phenyl group. The compounds of this example were prepared by general scheme 2, listed below.

Scheme 2

Step 1: preparation of (R) -4-chloro-N- (1-cyclopropylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-amine. To a mixture of 2, 4-dichloro-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine (600mg, 2.0mmol, 1.0 equiv.) and (R) -1-cyclopropylethylamine hydrochloride (268mg, 2.2mmol, 1.1 equiv.) in THF (6mL) was added CsF (608mg, 4.0mmol, 2 equiv.) and DIPEA (0.7mL, 4.0mmol, 2 equiv.) at room temperature. The mixture was stirred at 40 ℃ overnight and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by standard methods to give the desired product.

LC-MS:m/z 344.1(M+H)⁺。

Step 2: preparation of N²- ((R) -1-Cyclopropylethyl) -N4- (pent-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. To a mixture of (R) -4-chloro-N- (1-cyclopropylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-amine (80mg, 0.23mmol, 1.0 equiv.) and pentan-2-amine (25mg, 0.28mmol, 1.2 equiv.) in THF (2mL) was added CsF (70mg, 0.46mmol, 2 equiv.) and DIPEA (0.08mL, 0.46mmol, 2 equiv.) at room temperature. The mixture was stirred at 60 ℃ overnight and filtered. The filtrate was concentrated under reduced pressure and then purified by standard methods to give the desired product.

¹H NMR(400MHz,DMSO-d₆):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)⁺。

The following compounds were prepared using the procedure set forth in example 2, using the appropriate starting materials.

¹H NMR(400MHz,CDCl₃):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/z 411.2(M+H)⁺。

Compound (R) -N²- (1-cyclopropylethyl) -N⁴- (4, 4-difluorocyclohexyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 443.2(M+H)⁺。

Compound N ²- ((R) -1-cyclopropylethyl) -N⁴- (6, 6-Difluorospiro [3.3]]Hept-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 455.2(M+H)⁺。

Compound N²- ((1R,3R,5R,7R) -adamantan-2-yl) -N⁴- ((R) -1-Cyclopropylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 459.2(M+H)⁺。

Compound (R) -N²- (1-cyclopropylethyl) -N⁴- (dicyclopropylmethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 419.2(M+H)⁺。

Compound N²- ((R) -1-Cyclopropylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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) -N²- (1-cyclopropylethyl) -N⁴- (2, 3-dihydro-1H-inden-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 441.2(M+H)⁺。

Compound (R) -N²- (1-cyclopropylethyl) -N⁴- (prop-2-yn-1-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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(m 2H),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/z 363.1(M+H)⁺。

Compound (R) -N²- (1-cyclopropylethyl) -N⁴- (2-phenoxyethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 445.2(M+H)⁺。

Compound N²- ((R) -1-cyclopropylethyl) -N⁴- (1-methoxypropan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 397.2(M+H)⁺。

Compound (R) -N²- (1-cyclopropylethyl) -N⁴- (1, 3-Dimethoxypropan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 427.2(M+H)⁺。

The compound 2- ((4- (((R) -1-cyclopropylethyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) propionitrile

¹H NMR(400MHz,CDCl₃):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/z 378.2(M+H)⁺。

The compound (R) -2- (4- (1-cyclopropylethylamino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-ylamino) -2-methylpropanenitrile

¹H NMR(400MHz,CDCl₃):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/z 392(M+H)⁺。

Compound N²- ((R) -1-cyclopropylethyl) -N⁴- (tetrahydrofuran-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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)⁺。

The compound (1S,2S) -2- (4- ((R) -1-cyclopropylethylamino) -6- (6- (trifluoro-methyl) pyridin-2-yl) -1,3, 5-triazin-2-ylamino) cyclohexanol

¹H NMR(400MHz,CDCl₃):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/z 423.2(M+H)⁺。

The compound (1R,2S) -2- (4- ((R) -1-cyclopropylethylamino) -6- (6- (trifluoromethyl) -pyridin-2-yl) -1,3, 5-triazin-2-ylamino) cyclopentanol

¹H NMR(400MHz,CDCl₃):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) -N²-benzyl-N⁴- (1-cyclopropylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 415.2(M+H)⁺。

Compound N²- ((R) -1-cyclopropylethyl) -N⁴- ((S) -1-phenylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 429.2(M+H)⁺。

Compound N²- ((R) -1-cyclopropylethyl) -N⁴- ((R) -1-phenylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 429.2(M+H)⁺。

Compound N²- ((R) -1-cyclopropylethyl) -N⁴- (1- (3-fluorophenyl) ethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 447.2(M+H)⁺。

Compound N²- ((R) -1-cyclopropylethyl) -N⁴- (1- (3- (trifluoromethyl) phenyl) ethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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 N²- ((R) -1-cyclopropylethyl) -N⁴- ((1R,2S) -2-phenylcyclopropyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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(m 1H),1.72(s,1H),1.56(d,J＝6.7Hz,3H),0.97(m 3H),0.63-0.18(m,4H)。LC-MS:m/z 441.2(M+H)⁺。

Compound (R) -N²- (1-cyclopropylethyl) -N⁴- (1-phenylcyclopropyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆):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/z 441.2(M+H)⁺。

Compound (R) -6- (6-chloropyridin-2-yl) -N²- (1-cyclopropylethyl) -N⁴,N⁴Diethyl-1, 3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 347.2(M+H)⁺。

The compound (R) -methyl 3- ((4- ((1-cyclopropylethyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) propionate

The compound (1R,2S) -2- ((4- (cyclopentylamino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) cyclopentanol

¹HNMR(400MHz,CD₃OD):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/z 409.3(M+H)。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (tetrahydrofuran-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CD₃OD):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/z 431.2(M+H)⁺。

The compound tert-butyl 3- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyrrolidine-1-carboxylate

¹H NMR(400MHz,CDCl₃):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/z 530.2(M+H)⁺。

Compound N²-isobutyl-N⁴- (tetrahydro-2H-pyran-4-yl) -6- (6- (trifluoromethyl) -pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹HNMR(400MHz,CD₃OD):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/z 397.3(M+H)⁺。

Compound N²- ((R) -1-cyclopropylethyl) -N⁴- (1- (2-methoxyethoxy) propan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 441(M+H)⁺。

The compound 2- ((4- (((R) -1-cyclopropylethyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) propan-1-ol

¹H NMR(400MHz,CDCl₃)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/z 383.2(M+H)⁺。

Compound N²- ((R) -1-cyclopropylethyl) -N⁴- (1-Isopropoxypropan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 425(M+H)⁺。

Compound N²- ((R) -1-cyclopropylethyl) -N⁴- (4-methoxybut-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 411(M+H)⁺。

Compound N²- ((R) -1-cyclopropylethyl) -N⁴- (1-phenylpropan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 443(M+H)⁺。

Compound N²- ((R) -1-cyclopropylethyl) -N⁴- (1-morpholinylpropan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 452(M+H)⁺。

Compound N²- ((R) -1-cyclopropylethyl) -N⁴- (1- (piperidin-1-yl) propan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 450(M+H)⁺。

The compound (R) -3- ((4- ((1-cyclopropylethyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -2, 2-dimethylpropionamide

¹H NMR(400MHz,CDCl₃)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/z 424(M+H)⁺。

The compound 3- ((4- (((R) -1-cyclopropylethyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) butanenitrile

¹H NMR(400MHz,CDCl₃)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)⁺。

The compound (R) -3- ((4- ((1-cyclopropylethyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -2, 2-dimethylpropionitrile

¹H NMR(400MHz,CDCl₃)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/z 406(M+H)⁺。

The compound 1- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -2-methylpropan-2-ol

¹H NMR(400MHz,CDCl₃)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/z 433(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (1- (4-fluorophenyl) azacyclesButan-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 510(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (1- (pyridin-2-yl) azetidin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 493(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (1- (pyridin-3-yl) azetidin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃):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/z 493(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- ((1r,3r) -3- (4-fluorophenyl) cyclobutyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 509(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- ((1s,3s) -3- (4-fluorophenyl) cyclobutyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 509(M+H)⁺。

The compound N2- (3, 3-difluorocyclopentyl) -N4- (3-phenylcyclobutyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 491(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (1-methylpyrrolidin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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)⁺。

The compound (3- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyrrolidin-1-yl) (phenyl) methanone

¹H NMR(400MHz,CDCl₃)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/z 534(M+H)⁺。

Compound N²- (1-benzylpyrrolidin-3-yl) -N⁴- (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 520(M+H)⁺。

The compound (4S) -4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -1- (pyridin-2-yl) pyrrolidin-2-one

¹H NMR(400MHz,CDCl₃)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/z 521(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (3-phenylcyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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 N²- (3, 3-difluorocyclopentyl) -N⁴- (2, 3-dihydro-1H-inden-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

1H NMR(400MHz,CDCl₃)：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/z 477(M+H)⁺。

Compound N²- (5-chloro-2, 3-dihydro-1H-inden-2-yl) -N⁴- (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 511(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (5-fluoro-2, 3-dihydro-1H-inden-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 495(M+H)⁺。

Compound N²- (5-bromo-2, 3-dihydro-1H-inden-2-yl) -N⁴- (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 556(M+H)⁺。

The compound 2- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -2, 3-dihydro-1H-indene-5-carbonitrile

¹H NMR(400MHz,CDCl₃)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/z 502(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (5-methoxy-2, 3-dihydro-1H-inden-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 507(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (6, 7-dihydro-5H-cyclopenta [ b)]Pyridin-6-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 478.2(M+H)⁺。

Compound N²- (4, 6-dibromo-2, 3-dihydro-1H-inden-2-yl) -N⁴- (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 635(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (1-phenylpyrrolidin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 506(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (1- (pyridin-2-yl) pyrrolidin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 507(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (1- (pyrimidin-2-yl) pyrrolidin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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 N²- (3, 3-difluorocyclopentyl) -N⁴- (6, 6-Difluorospiro [3.3]]Hept-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 491(M+H)⁺。

The compound 1- ((4- ((4, 4-difluorocyclohexyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -2-methylpropan-2-ol

¹H NMR(400MHz,DMSO-d₆)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 N²- (4, 4-difluorocyclohexyl) -N⁴- (tetrahydro-2H-pyran-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(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/z 459.2(M+H)⁺。

The compound tert-butyl 4- ((4- ((4, 4-difluorocyclohexyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) piperidine-1-carboxylate

¹H NMR(400MHz,CDCl₃)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/z 558.3(M+H)⁺。

The compound 1- (4- ((4- ((4, 4-difluorocyclohexyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) piperidin-1-yl) ethanone

¹H NMR(400MHz,CDCl₃)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/z 500.2(M+H)⁺。

Compound N²- (4, 4-difluorocyclohexyl) -N⁴- (1- (methylsulfonyl) piperidin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

1H NMR(400MHz,CDCl₃)δ8.58-8.48(m,1H),8.05-7.96(m,1H),7.80(d,J＝6.8Hz,1H),5.56-5.18(m 2H),4.25-3.95(m,4H),3.64-3.45(m,2H),2.26-1.55(m,15H)。LC-MS:m/z 536.2(M+H)⁺。

Compound N²- (4, 4-difluorocyclohexyl) -N⁴- (6, 6-Difluorospiro [3.3]]Hept-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 505(M+H)⁺。

Compound N²- (3, 3-difluorocyclobutyl) -N⁴- (4, 4-difluorocyclohexyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 465(M+H)⁺。

Compound N²- (4, 4-difluorocyclohexyl) -N⁴- (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 479(M+H)⁺。

Compound (R) -6- (6-chloropyridin-2-yl) -N²- (1,1,1,3,3, 3-hexafluoropropan-2-yl) -N⁴- (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 469(M+H)⁺。

Compound (R) -6- (6-chloropyridin-2-yl) -N²- (4, 4-difluorocyclohexyl) -N⁴- (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆)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/z 437(M+H)⁺。

Table 4: the following targets were prepared by the procedure described in scheme 2 above.

Example 3 a dialiphatic triazine compound of formula F is prepared. The compounds of this example were prepared by general scheme 3, listed below.

Scheme 3

Step 1: preparation of 6-chloro-N²,N⁴Bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine. To a mixture of 2,4, 6-trichloro-1, 3, 5-triazine (2g, 10.9mmol, 1 equiv.) and (R) -1-cyclopropylethylamine hydrochloride salt (2.7g, 22.8mmol, 2.1 equiv.) in acetone (50mL) was added DIPEA (4.5mL, 27.3mmol, 2.5 equiv.) and CsF (3.3g, 21.8mmol, 2.0 equiv.). The mixture was stirred at 40 ℃ for 3 hours and then at 50 ℃ for another 3 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by standard methods to obtain the desired product.

LC-MS:m/z 282.1(M+H)⁺。

Step 2: preparation of N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine. Stirring at room temperature under nitrogen atmosphere to obtain 6-chloro-N²,N⁴Bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine (100mg, 0.36mmol), pyridin-4-ylboronic acid (66mg, 0.52mmol) and K₂CO₃(99mg, 0.72mmol) to a mixture of 1, 4-dioxane (3mL) and water (1mL) was added Pd (PPh) in one portion₃)₄(42mg, 0.036 mmol). The reaction mixture was stirred at 80 ℃ overnight. The mixture was partitioned between water and EtOAc. With anhydrous Na₂SO₄The organic layer was dried and concentrated. The residue was purified by standard methods to give the desired product.

¹H NMR(400MHz,DMSO-d₆):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/z 325.2(M+H)⁺。

The following compounds were prepared using the procedures listed above, using the appropriate starting materials.

The compound 6- (3-chlorophenyl) -N²,N⁴Bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆):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/z 358.2(M+H)⁺。

The compound 3- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) phenol

¹H NMR(400MHz,CDCl₃):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/z 340.2(M+H)⁺。

Table 5: the following targets were prepared by the procedure described in scheme 3 above.

Example 4 a dialiphatic triazine compound having the formula G is prepared. The compounds of this example were prepared by general scheme 4, listed below.

Scheme 4

Step 1. preparation of N²- (3, 3-difluorocyclopentyl) -N⁴- (pyrrolidin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. To a solution of tert-butyl 3- (4- (3, 3-difluorocyclopentylamino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-ylamino) pyrrolidine-1-carboxylate (160mg, 0.3mmol) in DCM (3mL) was added TFA (1mL) at 0 ℃. The mixture was stirred at room temperature for 2 hours and then concentrated. The residue was extracted with EtOAc. With saturated aqueous NaHCO₃The combined organic layers were washed with brine and anhydrous Na₂SO₄Dried and then concentrated to obtain the desired product, which was used in the next step without any further purification.

LC-MS:m/z 430.2(M+H)⁺。

Step 2. preparation of N²- (3, 3-difluorocyclopentyl) -N⁴- (1- (methylsulfonyl) pyrrolidin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. Stirring N at room temperature²- (3, 3-difluorocyclopentyl) -N⁴- (pyrrolidin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (20mg, 0.05mmol), Et₃A mixture of N (9.4mg, 0.09mmol), MsCl (6mg, 0.06mmol) in DCM (2mL) was left overnight. The mixture was concentrated and the residue was purified by standard methods to obtain the desired product.

¹H NMR(400MHz,CDCl₃):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/z 508.1(M+H)⁺。

The compound methyl 3- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyrrolidine-1-carboxylate.

¹H NMR(400MHz,CDCl₃):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/z 488.2(M+H)⁺。

The compound 1- (3- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyrrolidin-1-yl) ethanone

¹H NMR(400MHz,CDCl₃):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/z 472.2(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (1-methylpyrrolidin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. To a solution of tert-butyl 3- (4- (3, 3-difluorocyclopentylamino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-ylamino) pyrrolidine-1-carboxylate (25mg, 0.05mmol) in THF (3mL) at 0 deg.C was added LiAlH₄(5mg, 0.14 mmol). The mixture was stirred at 0 ℃ for 2 hours, then at room temperature for 30 minutes, and finally at 60 ℃ for 2 hours. Quenching with waterThe mixture was washed and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Dried and concentrated. The residue was purified by standard methods to give the desired product.

¹H NMR(400MHz,CDCl₃):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/z 444.2(M+H)⁺。

Example 5 preparation of a dialiphatic triazine compound. The compounds of this example were prepared by general scheme 5, listed below.

Scheme 5

Step 1: preparation of 6- (6- (azetidin-1-yl) pyridin-2-yl) -N²,N⁴Bis ((R) -1-cyclopropyl-ethyl) -1,3, 5-triazine-2, 4-diamine. Stirring 6- (6-chloropyridin-2-yl) -N at 100 ℃ under a nitrogen atmosphere²,N⁴A mixture of-bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine (40mg, 0.11mmol), azetidine (7.6mg, 0.13mmol), 2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (6.9mg, 0.01mmol), sodium tert-butoxide (15mg, 0.16mmol) and tris (dibenzylideneacetone) -dipalladium (10.2mg, 0.01mmol) in toluene (3mL) overnight. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by standard methods to obtain the desired product.

¹H NMR(400MHz,CD₃OD):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/z 380.2(M+H)⁺。

Step 2: preparation of N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. Under nitrogen atmosphere, to 6- (6-chloropyridin-2-yl) -N²,N⁴To a solution of (E) -bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine (20mg, 0.05mmol) in methanol (2mL) was added Pd/C (2 mg). The mixture was then stirred under a hydrogen balloon at room temperature overnight. The mixture was filtered and the filtrate was concentrated. The residue was purified by standard methods to obtain the desired product.

¹H NMR(400MHz,DMSO-d₆):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/z 325.2(M+H)⁺。

Example 6 a dialiphatic triazine compound of formula H is prepared. The compounds of this example were prepared by general scheme 6, listed below.

Scheme 6

Step 1: preparation of 2- ((4- (2-fluoro-5-hydroxyphenyl) -6- (isopropylamino) -1,3, 5-triazin-2-yl) amino) -2-methylpropanenitrile. To a solution of 2- ((4- (2-fluoro-5-methoxyphenyl) -6- (isopropylamino) -1,3, 5-triazin-2-yl) amino) -2-methylpropanenitrile (200mg, 0.6mmol) in anhydrous DCM (3mL) at-65 deg.C was added BBr dropwise₃(0.6mL) and the reaction mixture was stirred at this temperature for 20 minutes. The mixture was slowly warmed to 0 ℃ and stirred for 10 minutes, and then stirred at room temperature for 1 hour. Saturated aqueous NaHCO with Ice₃The reaction was quenched until pH 8. The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by standard methods to obtain the desired product.

¹H NMR(400MHz,CDCl₃):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/z 331.2(M+H)⁺。

Example 7 preparation of a dialiphatic pyrimidine compound of formula J. The compounds of this example were prepared by general scheme 7, listed below.

Scheme 7

Step 1: preparation of 6- (trifluoromethyl) pyridine carboxamidine. To a solution of 6- (trifluoromethyl) pyridinecarbonitrile (50mg, 0.3mmol, 1 equiv) in EtOH (3mL) was added NaOMe (1.6mg, 0.03mmol, 0.1 equiv) at 0 ℃. The mixture was stirred at room temperature for 1 hour, followed by addition of NH₄Cl (21mg, 0.39mmol, 13 equivalents). The resulting mixture was stirred at 90 ℃ for 1 hour and cooled to room temperature. With saturated aqueous NaHCO₃The mixture pH was adjusted to 9 and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Dried and concentrated. The residue was purified by standard methods to obtain the desired product.

LC-MS:m/z 190.1(M+H)⁺。

Step 2: preparation of 2- (6- (trifluoromethyl) pyridin-2-yl) pyrimidine-4, 6-diol. To a solution of sodium (366mg, 15.9mmol, 5.0 equiv) in anhydrous EtOH (6mL) was added dropwise a solution of 6- (trifluoromethyl) pyridine carboxamidine (600mg, 3.2mmol) in EtOH. The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of diethyl malonate (1mL, 6.4mmol, 2.0 equiv.). The mixture was stirred under reflux overnight and then cooled to room temperature. The pH of the resulting mixture was adjusted to 7 by 1N aqueous HCl. The suspension was filtered and the filter cake was washed with water. The solid was suspended in MeOH and filtered. The filtrate was concentrated under reduced pressure to give the desired product, which was used directly in the next step without any further purification.

LC-MS:m/z 256.0(M-H)^-。

And step 3: preparation of 4, 6-dichloro-2- (6- (trifluoromethyl) pyridin-2-yl) pyrimidine. 2- (6- (trifluoromethyl) pyridin-2-yl) pyrimidine-4, 6-diol (1g, 3.9mmol) was stirred in POCl at 90 deg.C₃(6mL) overnight and then concentrated to remove volatiles. The residue was purified by standard methods to obtain the desired product.

LC-MS:m/z 294.0(M+H)⁺。

And 4, step 4: preparation of (R) -6-chloro-N- (1-cyclopropylethyl) -2- (6- (trifluoromethyl) -pyridin-2-yl) pyrimidin-4-amine. To a solution of 4, 6-dichloro-2- (6- (trifluoromethyl) pyridin-2-yl) pyrimidine (80mg, 0.27mmol, 1 eq) in THF (3mL) was added (R) -1-cyclopropylethylamine (0.06mL, 0.6mmol, 2.2 eq) and Et₃N (0.07mL, 0.54mmol, 2 equiv.). The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified by standard methods to give the desired product.

LC-MS:m/z 343.1(M+H)⁺。

And 5: preparation of N⁴,N⁶-bis ((R) -1-cyclopropylethyl) -2- (6- (trifluoromethyl) pyridin-2-yl) pyrimidine-4, 6-diamine. To (R) -6-chloro-N- (1-cyclopropylethyl) -2- (6- (trifluoromethyl) -pyridin-2-yl) pyrimidin-4-amine (50mg, 0.15mmol, 1 eq) in DMSO (2mL)To the solution were added (R) -1-cyclopropylethylamine hydrochloride (22mg, 0.18mmol, 1.2 equiv.) and DIPEA (0.08mL, 0.45mmol, 3 equiv.). The mixture was irradiated under microwave at 160 ℃ for 1.5 hours. After addition of (R) -1-cyclopropylethylamine (0.18mmol, 1.2 eq.) the resulting mixture was stirred and irradiated under microwave at 160 ℃ for a further 2 h. The mixture was cooled to room temperature and then partitioned between EtOAc and water. The organic layer was washed with water and brine, and anhydrous Na₂SO₄Dried and concentrated. The residue was purified by standard methods to give the desired product.

¹H NMR(400MHz,CDCl₃):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/z 392.2(M+H)⁺。

Compound N⁴,N⁶-bis ((S) -1-cyclopropylethyl) -2- (6- (trifluoromethyl) pyridin-2-yl) pyrimidine-4, 6-diamine

¹H NMR(400MHz,CDCl₃):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/z 392.2(M+H)⁺。

Compound N⁴- ((R) -1-cyclopropylethyl) -N⁶- ((S) -1-Cyclopropylethyl) -2- (6- (trifluoromethyl) pyridin-2-yl) pyrimidine-4, 6-diamine

¹H NMR(400MHz,CDCl₃):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(m 2H),0.61-0.44(m,4H),0.31(m,4H)。LC-MS:m/z 392.2(M+H)⁺。

Table 6: the following compounds were prepared by the procedure described in scheme 7 above.

Example 9 preparation of a symmetric dialiphatic triazine compound having formula K. The compounds of this example were prepared by general scheme 9, listed below.

Scheme 9

Step 1: preparation of 2-bromo-6- (1, 1-difluoroethyl) pyridine.

To a solution of 1- (6-bromopyridin-2-yl) ethanone (26g, 130mmol) in dry DCM (150mL) was added DAST (84mL, 650mmol) dropwise over 30 min at 0 ℃. The reaction mixture was then allowed to warm slowly to room temperature and stirred until the reaction was complete. The resulting mixture was poured slowly into ice (300g) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with water and anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by standard methods to obtain 2-bromo-6- (1, 1-difluoroethyl) pyridine. LC-MS M/z 222.0(M + H)⁺。

Step 2: preparation of methyl 6- (1, 1-difluoroethyl) picolinate.

To a solution of 2-bromo-6- (1, 1-difluoroethyl) pyridine (30.2g, 136mmol) in MeOH (300mL) was added 1,1' -bis (diphenylphosphino) -ferrocene (7.5g, 13.6mmol), triethylamine (28.4mL, 204mmol), and Pd (OAc)₂(1.52g, 6.7 mmol). The mixture was stirred at 60 ℃ under CO atmosphere (60psi) for 16 hours. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by standard procedures to give 6- (1, 1-difluoro)Ethyl) picolinic acid methyl ester. LC-MS M/z 202.2(M + H)⁺。

And step 3: preparation of 6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4(1H,3H) -dione. To a solution of NaOEt in EtOH (freshly prepared from sodium (1.9g, 82.6mmol) and EtOH (150 mL)) was added methyl 6- (1, 1-difluoroethyl) picolinate (2.8g, 28mmol) and biuret (14.0g, 70 mmol). The mixture was stirred at 90 ℃ for 16 hours and concentrated under reduced pressure. To the residue was added water (50 mL). The resulting mixture was adjusted to pH7 with 1N HCl and then filtered. The filter cake is washed with water and dried under high vacuum to obtain 6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4(1H,3H) -dione. LC-MS M/z 255.1(M + H)⁺。

And 4, step 4: preparation of 2, 4-dichloro-6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazine.

To 6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4(1H,3H) -dione (6g, 25mmol) in POCl₃(60mL) to the solution was added PCl₅(26g, 125 mmol). The mixture was stirred at 100 ℃ for 16 hours and concentrated under reduced pressure. The residue was purified by standard methods to obtain 2, 4-dichloro-6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazine.¹H NMR(400MHz,CDCl₃)δ8.62(d,1H),8.07(t,1H),7.94(d,1H),2.16(q,3H)。LC-MS:m/z 292.1(M+H)⁺。

And 5: preparation of N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine to a mixture of 2, 4-dichloro-6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazine (582mg, 2.0mmol, 1.0 equiv.) and 4, 4-difluorocyclohexylamine hydrochloride (752mg, 4.4mmol, 2.2 equiv.) in THF (12mL) at room temperature was added CsF (1.2g, 8.0mmol, 2 equiv.) and DIPEA (1.4mL, 8.0mmol, 4 equiv.). The mixture was stirred at 60 ℃ overnight and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by standard methods to give the desired product.

¹H NMR(400MHz,CDCl₃)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/z 489.2(M+H)⁺。

The following compounds were prepared using the procedure set forth in example 9, using the appropriate starting materials.

Compound N²,N⁴Bis (3, 3-difluorocyclopentyl) -6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 461.2(M+H)⁺。

Compound N²,N⁴Bis (3, 3-difluorocyclobutyl) -6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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 of a symmetric dialiphatic triazine compound having formula L. The compounds of this example were prepared by general scheme 10, listed below.

Scheme 10

Step 1: preparation of 6- (6-chloropyridin-2-yl) -1,3, 5-triazine-2, 4(1H,3H) -dione. To a dry three-neck round bottom flask were added biuret (14.8g, 0.14mol), methyl 6-chloropicolinate (21g, 0.12mol), and EtOH (250 mL). With N₂The mixture was degassed three times and then stirred at 25 ℃ for 20 minutes. The temperature was then raised to 50 ℃ and HC (OMe) was added₃(17mL, 0.14mol) and TFA (1.37g, 0.01 mol). The reaction mixture (pale yellow slurry) was stirred at this temperature for 30 minutes, followed by dropwise addition of a solution of NaOEt in EtOH (20% wt, 163g, 0.48 mol). The resulting yellowish thick slurry was heated to reflux for 2 hours until the reaction was complete. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with water (200mL) and concentrated under reduced pressure to remove residual ethanol. Water (300mL) was then added (while stirring) to the residue to form a clear brown solution. The solution was cooled to 10 ℃ and slowly adjusted to pH 1 by 6N HCl. The resulting mixture was stirred for an additional 2 hours and filtered. The filter cake was washed with aqueous HCl (pH 1), collected and suspended in DCM (300 mL). The suspension was stirred at room temperature for 2 hours, filtered and dried to obtain the desired product. LC-MS M/z 225.0(M + H)⁺。

Step 2: preparation of 2, 4-dichloro-6- (6-chloropyridin-2-yl) -1,3, 5-triazine. The procedure was the same as described above for example 1, step 3. LC-MS M/z 260.9(M + H)⁺。

And step 3: preparation of 6- (6-chloropyridin-2-yl) -N²,N⁴-bis ((R) -1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine. In N₂A mixture of 2, 4-dichloro-6- (6-chloro-pyridin-2-yl) -1,3, 5-triazine (0.27g, 1.04mol), (R) -1,1, 1-trifluoropropan-2-amine hydrochloride (0.39g, 2.6mol), and potassium carbonate (0.43g, 3.1mol) in dry 1, 4-dioxane (2.5mL) was stirred at 50 ℃ for 36 hours under ambient conditions, then at 100 ℃ for an additional 36 hours until the reaction was complete. The resulting mixture was filtered through celite and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by standard methods to give the desired product.

¹H NMR(400MHz,CDCl₃)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/z 415(M+H)⁺。

The following compounds were prepared using the procedure set forth in example 10, using the appropriate starting materials.

Compound 6- (6-chloropyridin-2-yl) -N²,N⁴Bis ((S) -1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 415(M+H)⁺。

Compound 6- (6-chloropyridin-2-yl) -N²- ((R) -1,1, 1-trifluoropropan-2-yl) -N⁴- ((S) -1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 415(M+H)⁺。

Compound 6- (6-chloropyridin-2-yl) -N²,N⁴Bis (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

Compound 6- (6-chloropyridin-2-yl) -N²,N⁴Bis (1,1, 1-trifluorobutan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 443(M+H)⁺。

Compound 6- (6-chloropyridin-2-yl) -N²,N⁴Bis ((S) -1,1, 1-trifluorobutan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 443(M+H)⁺。

Compound 6- (6-chloropyridin-2-yl) -N²,N⁴Bis ((R) -1,1, 1-trifluorobutan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 443(M+H)⁺。

Compound 6- (6-chloropyridin-2-yl) -N²- ((R) -1,1, 1-trifluorobutan-2-yl) -N⁴- ((S) -1,1, 1-trifluorobutan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹HNMR(400MHz,CDCl₃)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/z 443(M+H)⁺。

The compound 3,3' - ((6- (6-chloropyridin-2-yl) -1,3, 5-triazine-2, 4-diyl) bis (azepinyl)) dibutyrronitrile

¹H NMR(400MHz,CDCl₃)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-chloropyridin-2-yl) -N²,N⁴Bis (1-cyclopropyl-propyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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-chloropyridin-2-yl) -N²,N⁴Bis (dicyclopropylmethyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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-chloropyridin-2-yl) -N²,N⁴Bis (4, 4-difluorocyclohexyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 459(M+H)⁺。

Compound 6- (6-chloropyridin-2-yl) -N²,N⁴Bis (3, 3-difluorocyclopentyl) -1,3, 5-triazine-2, 4-diamine

1H NMR(400MHz,CDCl₃)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/z 431.1(M+H)⁺。

Compound 6- (6-chloropyridin-2-yl) -N²,N⁴Bis (2, 2-difluorocyclopentyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 431(M+H)⁺。

The compound 2,2' - ((6- (6-chloropyridin-2-yl) -1,3, 5-triazine-2, 4-diyl) bis (azepinyl)) dicyclopentanol

¹H NMR(400MHz,CDCl₃)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/z 391(M+H)⁺。

Compound 6- (6-chloropyridin-2-yl) -N²,N⁴-bis (6, 6-difluorospiro [3.3]]Hept-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 483(M+H)⁺。

The compound 6- (4-chloropyridin-2-yl) -N2, N4-bis (4, 4-difluorocyclohexyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 459.1(M+H)⁺。

Compound 6- (5-chloropyridin-3-yl) -N²,N⁴Bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 359(M+H)⁺。

Example 11 the compounds of this example were prepared by general scheme 11, listed below.

Scheme 11

Step 1. preparation of N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (6- ((4-methoxybenzyl) amino) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. At room temperature, in N₂To 6- (6-chloropyridin-2-yl) -N2, N4-bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine (120mg, 0.33mmol), (4-methoxyphenyl) methylamine under an atmosphereTo a solution of (69mg, 0.51mmol), BINAP (42mg, 0.66mmol) and t-BuONa (63mg, 0.66mmol) in anhydrous dioxane (2mL) was added Pd in one portion₂(dba)₃(30mg, 0.033 mmol). The reaction mixture was then stirred at 100 ℃ overnight and then concentrated under reduced pressure to obtain the desired product.

LC-MS:m/z 460(M+H)⁺。

Step 2. preparation of 6- (6-aminopyridin-2-yl) -N²,N⁴Bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine. In N₂Under the atmosphere, adding N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (6- (4-methoxybenzylamino) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (80mg, 0.17mmol) was dissolved in TFA (0.5 mL). The solution mixture was then stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified by standard methods to obtain the desired product.

1H NMR(400MHz,CDCl₃)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)⁺。

Example 12 the compounds of this example were prepared by general scheme 12, listed below.

Scheme 12

Step 1. preparation of 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) pyridin-2-ol. At room temperature to N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (6-methoxypyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (50mg, 0.14mmol) and NaI (63mg, 0.42mmol) in anhydrous CH₃In CN (1mL)TMSCl (46mg, 0.42mmol) was added to the mixture in one portion. The reaction mixture was stirred at 80 ℃ for 6 hours and then concentrated under reduced pressure. The residue was purified by standard methods to obtain the desired product.¹H NMR(400MHz,CDCl₃)δ10.24(br s,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/z 341.2(M+H)⁺。

Example 13 the compounds of this example were prepared by general scheme 13, listed below.

Scheme 13

Step 1. preparation of N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (6-vinylpyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. In N₂To 6- (6-chloropyridin-2-yl) -N2, N4-bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine (200mg, 0.56mmol), 2,4, 6-trivinyl-1, 3,5,2,4, 6-trioxatriboran (135mg, 0.84mmol) and K under an atmosphere₂CO₃(154mg, 1.11mmol) in dioxane (2mL) and H₂Suspension in O (0.8mL) was added Pd (dppf) Cl in one portion₂(41mg, 0.06 mmol). The reaction mixture was stirred at 100 ℃ overnight, then cooled to room temperature and quenched with water. The resulting mixture was extracted with EtOAc (20mL x 2). The combined organic layers were washed with water and brine, and anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by standard methods to obtain the desired product.¹H NMR(400MHz,CDCl₃)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/z 351.1(M+H)⁺。

Example 14 the compounds of this example were prepared by general scheme 14, listed below.

Scheme 14

Step 1. preparation of 6- (4, 6-bis (((R) -1-cyclopropylethyl) amino) -1,3, 5-triazin-2-yl) pyridinecarboxaldehyde. Bubbling ozone into N at-78 deg.C²,N⁴A solution of bis ((R) -1-cyclopropylethyl) -6- (6-vinylpyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (120mg, 0.34mmol) in DCM (2mL) for 1 hour. In the passage of N₂After purification of the excess ozone, Me is reacted at 0 DEG C₂S (0.2mL) was added to the reaction mixture. The resulting mixture was concentrated and the residue was purified by standard methods to obtain the desired product. LC-MS M/z 353(M + H)⁺。

Step 2. preparation of N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (6- (difluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. To a solution of 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) pyridylaldehyde (50mg, 0.14mmol) in anhydrous DCM (2mL) at 0 deg.C was added DAST (68mg, 0.43mmol) dropwise. The reaction mixture was stirred at room temperature overnight. At 0 deg.C, with saturated aqueous NaHCO₃The resulting mixture was quenched slowly (5mL) and then extracted with DCM (40 mL). The combined organic layers were washed with water and brine, and anhydrous Na₂SO₄Dried, concentrated, and purified by standard methods to obtain the desired product.¹H NMR(400MHz,CDCl₃)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/z 375(M+H)⁺。

The following compounds were prepared using the procedure set forth in example 14, using the appropriate starting materials.

Compound N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (6- (difluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)δ8.48(,1H),8.01(br s.,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/z 475(M+H)⁺。

Compound N²,N⁴Bis (3, 3-difluorocyclobutyl) -6- (6- (difluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 419(M+H)⁺。

Example 15 the compounds of this example were prepared by general scheme 15, listed below.

Scheme 15

Step 1: preparation of methyl 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) picolinate. To 6- (6-chloropyridin-2-yl) -N²,N⁴(iii) -bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine (0.25g, 0.7mmol) in MeOH (10mL) was added dppf (80mg, 0.15mmol), Pd (OAc)₂(60mg, 27mmol) and Et₃N (150mg, 1.5 mmol). The reaction mixture was degassed and backfilled with CO three times and then stirred under an atmosphere of CO (60psi) at 70 ℃ for 12 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with EtOAc (100mL) and filtered. The filtrate was concentrated and purified by a standard method to obtain methyl 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) picolinate.¹H NMR(400MHz,CDCl₃)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/z 383(M+H)⁺。

Step 2: preparation of 6- (4, 6-bis (((R) -1-cyclopropylethyl) amino) -1,3, 5-triazin-2-yl) picolinic acid. To a mixture of methyl 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) picolinate (150mg, 0.40mmol) in water (2.0mL) and THF (3.0mL) was added lithium hydroxide (47mg, 2.0 mmol). The reaction mixture was stirred at room temperature overnight, then acidified to pH 5-6 with aqueous HCl (1N) and extracted with EtOAc. With anhydrous Na₂SO₄The combined organic layers were dried and concentrated under reduced pressure to give the desired product. LC-MS M/z 367(M-H)^-。

And step 3: preparation of 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) picolinamide. To an ice-cold mixture of 6- (4, 6-bis (((R) -1-cyclopropylethyl) amino) -1,3, 5-triazin-2-yl) picolinic acid (120mg, 0.32mmol) in dry DCM (5.0mL) and DMF (0.1mL) was added oxalyl chloride (65mg, 0.5mmol) dropwise. The reaction mixture was stirred at room temperature for 2 hours and then treated with ammonia. The resulting mixture was stirred at 0 ℃ for 10 minutes, and then concentrated and purified by standard methods to give 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) picolinamide.¹H NMR(400MHz,CDCl₃)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/z 368(M+H)⁺。

And 4, step 4: preparation of 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) pyridinecarbonitrile. To a mixture of 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) picolinamide (36mg, 0.1mmol) in dry pyridine (3.0mL) was added phosphorus trichloride (0.1 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by standard methods to give 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) pyridinecarbonitrile.¹H NMR(400MHz,CDCl₃)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/z 350(M+H)⁺。

Example 16 the compounds of this example were prepared by general scheme 16, listed below.

Scheme 16

Step 1: preparation of 3, 6-difluoro-2-hydrazinopyridine. To an ice-cooled solution of 2,3, 6-trifluoropyridine (1.0g, 7.5mmol) in ethanol (10mL) was added hydrazine hydrate (0.75g, 15.0 mmol). The reaction mixture was warmed to room temperature and then heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (10mL) and extracted with DCM (2 × 20 mL). With anhydrous Na₂SO₄The combined organic layers were dried and concentrated under reduced pressure to obtain 3, 6-difluoro-2-hydrazinopyridine. LC-MS (M/z):146(M + H)⁺。

Step 2: preparation of 2-bromo-3, 6-difluoropyridine. To a stirred solution of 3, 6-difluoro-2-hydrazinopyridine (1.1g, 7.0mmol) in chloroform (20mL) was added dropwise bromine (1.8g, 11.2mmol) at room temperature. The reaction mixture was heated to 60 ℃ for 1.5 hours. The resulting mixture was cooled to room temperature and quenched with saturated aqueous NaHCO₃Quenched and extracted with dichloromethane (2 × 20 mL). With anhydrous Na₂SO₄The combined organic layers were dried and concentrated, and purified by standard methods to obtain 2-bromo-3, 6-difluoropyridine. LC-MS M/z 194(M + H)⁺。

And step 3: preparation of methyl 3, 6-difluoropicolinate. To a solution of 2-bromo-3, 6-difluoropyridine (0.8g, 4.1mmol) in MeOH (10mL) was added dppf (0.3g, 0.56mmol), Pd (OAc)₂(0.1g, 0.45mmol) and Et₃N (1.6mL, 8.2 mmol). The suspension was degassed and backfilled three times with a CO atmosphere. The resulting mixture was stirred at 70 ℃ for 12 hours under a CO atmosphere (60psi), then cooled to room temperature and concentrated under reduced pressure. The residue was triturated with EtOAc (150mL) and filtered. The filtrate was concentrated and purified by a standard method, thereby obtaining methyl 3, 6-difluoropicolinate. LC-MS M/z 174(M + H)⁺。

And 4, step 4: preparation of N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (3, 6-difluoropyridin-2-yl) -1,3,5Triazine-2, 4-diamine. To N¹,N⁵To a suspension of-bis (4, 4-difluorocyclohexyl) -biguanide (167mg, 0.50mmol) and methyl 3, 6-difluoropicolinate (130mg, 0.75mmol) in MeOH (5mL) was added NaOMe (81mg, 1.5 mmol). The reaction mixture was stirred at room temperature overnight, then poured into water and extracted with EtOAc. With anhydrous Na₂SO₄The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by standard methods to obtain N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine.¹H NMR(400MHz,CDCl₃)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/z 461(M+H)⁺。

Example 17 the compounds of this example were prepared by general scheme 17, listed below.

Scheme 17

Step 1: preparation of N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (3-fluoro-6-hydrazinopyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. To N²,N⁴To a solution of-bis (4, 4-difluoro-cyclohexyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (230mg, 0.50mmol) in THF (20mL) was added hydrazine hydrate (150mg, 3.0 mmol). The reaction mixture was stirred at 60 ℃ for 2.5 hours. After cooling to room temperature, the reaction mixture was diluted with DCM and washed with water. Separating the organic phase with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give the desired product. LC-MS (M/z):473.2(M + H)⁺。

Step 2: preparation of 6- (6-amino-3-fluoropyridin-2-yl) -N²,N⁴Bis (4, 4-difluorocyclohexyl) -1,3, 5-triazine-2, 4-diamine. To N²,N⁴To a solution of-bis (4, 4-difluoro-cyclohexyl) -6- (3-fluoro-6-hydrazinopyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (47mg, 0.1mmol) in methanol (5.0mL) was added raney nickel (100 mg). At H₂In the atmosphereThe reaction mixture was stirred at room temperature overnight and then filtered. The filtrate was concentrated and purified by standard methods to obtain the desired product.¹H NMR(400MHz,CDCl₃)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/z 458.2(M+H)⁺。

Example 18 the compounds of this example were prepared by general scheme 18, listed below.

Scheme 18

Step 1: preparation of 6- (4, 6-bis ((4, 4-difluorocyclohexyl) amino) -1,3, 5-triazin-2-yl) -5-fluoropyridin-2-ol. Stirring N at 100 deg.C²,N⁴A mixture of bis (4, 4-difluorocyclohexyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (100mg, 0.22mmol) in concentrated HCl (5.0mL) overnight. The resulting mixture was concentrated and purified by standard methods to obtain the desired product.¹H NMR(400MHz,CDCl₃)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)⁺。

Example 19 the compounds of this example were prepared by general scheme 19, listed below.

Scheme 19

Step 1: preparation of N¹,N⁵-bis (3, 3-difluorocyclopentyl) -biguanide. A mixture of 3, 3-difluorocyclopentylamine hydrochloride (3g, 19.1mmol) and sodium dicyandiamide (1.7g, 19.1mmol) was heated at 160 ℃ for 1 hour. The resulting product was dissolved in MeOH and then filtered. The filtrate was concentrated to obtain the desired product. LC-MS M/z 310.2(M + H)⁺。

Step 2: preparation of 6-cyclopropylpicolinic acid ethyl ester. To 6-bromopicolinic acid ethyl ester (200mg, 0.87mmol) and cyclopropylboronic acid (149mg, 1.74 m)mol) to a mixture in toluene (15mL) K was added₃PO₄(369mg, 1.74mmol) and dichloro (diphenylphosphino ferrocene) palladium (11mg, 0.017 mmol). In N₂The resulting mixture was stirred at 100 ℃ under ambient conditions overnight, then cooled to room temperature and filtered. The filtrate was concentrated and purified by standard methods to obtain the desired product. LC-MS M/z 192.1(M + H)⁺。

And step 3: 6- (6-Cyclopropylpyridin-2-yl) -N²,N⁴Bis (3, 3-difluorocyclopentyl) -1,3, 5-triazine-2, 4-diamine. To N¹,N⁵To a mixture of-bis (3, 3-difluorocyclopentyl) -biguanide (50mg, 0.16mmol) and ethyl 6-cyclopropylpicolinate (62mg, 0.33mmol) in methanol (5mL) was added NaOMe (44mg, 0.80 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was separated, washed with brine and dried over anhydrous Na₂SO₄Dried, concentrated, and purified by standard methods to obtain the desired product.¹H NMR(400MHz,CDCl₃)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)⁺。

Using the procedure set forth in example 19, the following compounds were prepared using the appropriate starting materials.

Compound 6- (6-cyclopropylpyridin-2-yl) -N²,N⁴Bis (4, 4-difluorocyclohexyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 465(M+H)⁺。

Compound N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (6-methyl-cyclohexanePyridopyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 439(M+H)⁺。

Example 20 a symmetric dialiphatic triazine compound having the formula M is prepared. The compounds of this example were prepared by general scheme 20, listed below.

Scheme 20

Step 1: preparing 6- (trifluoromethyl) pyrazine-2-methyl formate. To a mixture of 2-chloro-6- (trifluoromethyl) pyrazine (1g, 5.5mol) in MeOH (5.5mL) was added dppf (0.16g, 0.29mmol), Pd (OAc)₂(0.1g, 0.44mmol) and Et₃N (0.12mL, 8.2 mmol). The suspension was degassed in vacuo and then backfilled with CO three times. The resulting mixture was stirred at 70 ℃ for 2 days under CO atmosphere (80psi) until the reaction was complete. The mixture was cooled to room temperature and concentrated under reduced pressure at 30 ℃. To the residue was added EtOAc (150 mL). The suspension was filtered and the filtrate was concentrated and purified by standard methods to obtain the desired product. LC-MS M/z207 (M + H)⁺。

Step 2: preparation of 6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4(1H,3H) -dione. The procedure was the same as described above for example 1, step 2. LC-MS M/z 260(M + H)⁺。

And step 3: preparation of 2, 4-dichloro-6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine. To 6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4(1H,3H) -dione (2.8g, 0.011mol) in POCl₃Et (30mL) was added to the solution₃N (0.3 mL). The mixture was stirred at 100 ℃ for 16 hours until the reaction was complete. Concentrating the resulting mixtureAnd purified by standard methods to obtain the desired product. LC-MS M/z 296(M + H)⁺。

And 4, step 4: preparation of N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine. The procedure was the same as in example 1, step 4.

¹H NMR(400MHz,CDCl₃)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/z 494(M+H)⁺。

Using the procedure outlined in example 20 above, the following compounds were prepared using the appropriate starting materials.

N²,N⁴-bis (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 466(M+H)⁺。

N²,N⁴-bis ((R) -3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 466(M+H)⁺。

N²,N⁴-bis ((S) -3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 466(M+H)⁺。

N²- ((R) -3, 3-difluorocyclopentyl) -N⁴- ((S) -3, 3-Difluorocyclopentyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 466(M+H)⁺。

N²,N⁴Bis (3, 3-difluorocyclobutyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 438(M+H)⁺。

6- (6- (trifluoromethyl) pyrazin-2-yl) -N²,N⁴Bis ((R) -1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

1H NMR(400MHz,CD₃OD)δ9.80(s,1H),9.17(s,1H),5.22-4.88(m,2H),1.43-1.38(m,6H)。LC-MS:m/z 450.1(M+H)⁺。

N²,N⁴-bis ((S) -1,1, 1-trifluorobutan-2-yl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆)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/z 478.1(M+H)⁺。

Example 21 a symmetric dialiphatic triazine compound having the formula N is prepared. The compounds of this example were prepared by general scheme 21, listed below.

Scheme 21

Step 1: preparation of 1- (6-chloropyrazin-2-yl) ethanol. To a solution of methyl 6-formylpyrazine-2-carboxylate (590mg, 4.15mmol) in anhydrous THF (5mL) at-5 deg.C was added CH dropwise₃MgB (2.1mL, 6.2 mmol). The reaction mixture was stirred at room temperature for 1 hour and then saturated with aqueous NH at 0 deg.C₄Quenched with Cl and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Dried and concentrated to obtain the desired product. LC-MS M/z 159.0(M + H)⁺。

Step 2: preparing 1- (6-chloropyrazin-2-yl) ethanone. To a solution of 1- (6-chloropyrazin-2-yl) ethanol (370mg, 2.3mmol) in DCM (5mL) was added DMP (1.5g, 3.5mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then filtered. The filtrate was concentrated and purified by standard methods to obtain the desired product.¹H NMR(400MHz,CDCl₃)δ9.12(s,1H),8.78(s,1H),2.72(s,3H)。LC-MS:m/z 157.1(M+H)⁺。

And step 3: preparing 6-acetylpyrazine-2-methyl formate. To a solution of 1- (6-chloropyrazin-2-yl) ethanone (260.0mg, 1.7mmol) in MeOH (3mL) was added dppf (94.0mg, 0.17mmol), Pd (OAc)₂(20mg, 0.1mmol) and Et₃N (0.4mL, 2.6 mmol). The mixture was stirred overnight at 60 ℃ under an atmosphere of CO (60 psi). The resulting mixture was cooled to room temperature and filtered. ConcentrationThe filtrate is condensed and purified by standard methods to obtain the desired product. LC-MS M/z181.0(M + H)⁺。

And 4, step 4: preparation of methyl 6- (1, 1-difluoroethyl) pyrazine-2-carboxylate. To a solution of methyl 6-acetylpyrazine-2-carboxylate (240mg, 1.3mmol) in anhydrous DCM (3mL) was slowly added DAST (0.86mL, 6.5mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 3 hours and then saturated with cold aqueous NaHCO at 0 deg.C₃Quenched and extracted with DCM (3 × 10 mL). With anhydrous Na₂SO₄The combined organic layers were dried and concentrated to obtain the desired product. LC-MS M/z203.1(M + H)⁺。

And 5: preparation of 6- (6- (1, 1-difluoroethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4(1H,3H) -dione. The procedure was the same as described above for example 1, step 2. LC-MS M/z 256.1(M + H)⁺。

Step 6: preparation of 2, 4-dichloro-6- (6- (1, 1-difluoroethyl) pyrazin-2-yl) -1,3, 5-triazine. The procedure was the same as described above for example 1, step 3. LC-MS M/z 292.0(M + H)⁺。

And 7: preparation of N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (6- (1, 1-difluoroethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine. The procedure was the same as described above for example 1, step 4.

¹H NMR(400MHz,CDCl₃)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/z 490.2(M+H)⁺。

The following compounds were prepared using the procedure set forth in example 21, using the appropriate starting materials.

N²,N⁴Bis (3, 3-difluorocyclopentyl) -6- (6- (1, 1-difluoroethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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)⁺。

N²,N⁴Bis (3, 3-difluorocyclobutyl) -6- (6- (1, 1-difluoroethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 434.2(M+H)⁺。

Example 22 a symmetrical dialiphatic triazine compound having the formula O is prepared. The compounds of this example were prepared by general scheme 22, listed below.

Scheme 22

Step 1: preparing 2- (methoxycarbonyl) pyrazine 1-oxide. To a solution of pyrazine-2-carboxylic acid methyl ester (10.0g, 70mmol) in 1, 2-dichloroethane (120mL) was added 3-chloroperoxybenzoic acid (25.0g, 140 mmol). The reaction mixture was stirred at 60 ℃ overnight. The resulting mixture was cooled to room temperature and filtered. By anhydrous K₂CO₃The filtrate was dried and concentrated under reduced pressure. The residue was triturated with hexane and filtered and dried to obtain 2- (methoxycarbonyl) pyrazine 1-oxide. LC-MS M/z 155.0(M + H)⁺。

Step 2: preparing 6-chloropyrazine-2-methyl formate. 2- (methoxycarbonyl) pyrazine 1-oxide (4.8g, 30mmol) was stirred in SOCl at 85 deg.C₂(50mL) overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. By saturated aqueous NaHCO₃The residue was neutralized and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Dried and concentrated, and purified by standard methods to obtain methyl 6-chloropyrazine-2-carboxylate.¹H NMR(600MHz,CDCl₃)δ8.59(s,1H),8.53(s,1H),4.84(s,2H),3.01(s,1H)。LC-MS:m/z 173.0(M+H)⁺。

And step 3: preparation of (6-chloropyrazin-2-yl) methanol. To a solution of methyl 6-chloropyrazine-2-carboxylate (2.0g, 11.6mmol) in water (20mL) at 0 deg.C was added NaBH portionwise₄(2.3g, 58.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes, followed by addition of saturated aqueous K₂CO₃(40mL) and EtOH (20 mL). The resulting mixture was stirred for an additional 1 hour and extracted with EA (2 × 20 mL). With anhydrous Na₂SO₄The combined organic layers were dried and concentrated, and purified by standard methods to obtain (6-chloropyrazin-2-yl) methanol. LC-MS M/z 145.0(M + H)⁺。

And 4, step 4: preparing 6-chloropyrazine-2-formaldehyde. To a solution of (6-chloropyrazin-2-yl) methanol (600mg, 4.2mmol) in DCM (10mL) was added dess-martin reagent (2.6g, 6.3 mmol). The reaction mixture was stirred at room temperature for 3 hours, and then filtered. The filtrate was concentrated and purified by standard methods to obtain 6-chloropyrazine-2-carbaldehyde. LC-MS M/z143.0(M + H)⁺。

And 5: preparing 6-formyl pyrazine-2-methyl formate. To a mixture of 6-chloropyrazine-2-carbaldehyde (1.0g, 7.0mmol) in MeOH (10mL) was added dppf (388mg, 0.7mmol), Pd (OAc)₂(90mg, 0.4mmol) and Et₃N (1.5mL, 10.5 mmol). The suspension was stirred under CO atmosphere (60psi) at 60 ℃ overnight. The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by a standard method to obtain methyl 6-formylpyrazine-2-carboxylate. LC-MS M/z167.0(M + H)⁺。

Step 6: preparation of methyl 6- (difluoromethyl) pyrazine-2-carboxylate. To a mixture of methyl 6-formylpyrazine-2-carboxylate (4.1g, 24.7mmol) in anhydrous DCM (40mL) was slowly added DAST (16.3mL, 123.5mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 3 hours and then saturated with cold aqueous NaHCO at 0 deg.C₃Quenched and extracted with DCM (2 × 20 mL). With anhydrous Na₂SO₄The combined organic layers were dried and concentrated to obtain the desired product. LC-MS M/z 189.0(M + H)⁺。

And 7: preparation of 6- (6- (difluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4(1H,3H) -dione. To a flame-dried three-necked round bottom flask was added biuret (659mg, 6.4mmol) and methyl 6- (difluoromethyl) pyrazine-2-carboxylate (1.0g, 5.3mmol), followed by EtOH (12 mL). Degassing the mixture and applying N₂Backfilling for three times. The mixture was stirred at 25 ℃ for 20 minutes and then heated to 50 ℃. Then adding HC (OMe)₃(0.7mL, 6.4mmol) and TFA (0.04mL, 0.53 mmol). The mixture (pale yellow slurry) was stirred at this temperature for 30 minutes, followed by dropwise addition of a solution of NaOEt in EtOH (20% wt, 7.2g, 21.2 mmol). The resulting mixture was heated at reflux for 2 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was treated with water (10mL) and concentrated again to remove residual ethanol. The final residue was suspended in water (30mL), cooled to 10 ℃ when the acidity was adjusted to pH 1 by slow addition of 6N HCl (precipitating out solid), and then stirred for 2 hours. The mixture was filtered and the filter cake was washed with aqueous HCl (pH 1). The solid was collected and suspended in DCM (30 mL). The suspension was stirred at room temperature for 2 hours and then filtered again. The filter cake is collected and dried to obtain the desired product. LC-MS M/z 242.0(M + H)⁺。

And 8: preparation of 2, 4-dichloro-6- (6- (difluoromethyl) pyrazin-2-yl) -1,3, 5-triazine. The procedure was the same as described above for example 1, step 3. LC-MS M/z 2782.0(M + H)⁺。

And 8: preparation of N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (6- (difluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine. The procedure was the same as described above for example 1, step 4.

¹H NMR(400MHz,CDCl₃)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/z 476.2(M+H)⁺。

Using the procedure set forth in example 22, the following compounds were prepared using the appropriate starting materials.

N²,N⁴-bis (3, 3-difluorocyclopentyl) -6- (6- (difluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 448.2(M+H)⁺。

N²,N⁴Bis (3, 3-difluorocyclobutyl) -6- (6- (difluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 420.1(M+H)⁺。

N²,N⁴Bis (3, 3-difluorocyclobutyl) -6- (4- (difluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 420(M+H)⁺。

N²,N⁴-bis (3, 3-difluorocyclopentyl) -6- (4- (difluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆)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/z 448(M+H)⁺。

N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (4- (difluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 476(M+H)⁺。

Example 23 the compounds of this example were prepared by general scheme 23, listed below.

Scheme 23

Step 1: preparation of 6- (6-chloropyrazin-2-yl) -N²,N⁴Bis (4, 4-difluorocyclohexyl) -1,3, 5-triazine-2, 4-diamine. To 6-chloropyrazine-2-carboxylic acid methyl ester (300mg, 1.74mmol) and N¹,N⁵To a mixture of-bis- (4, 4-difluorocyclohexylamine) -biguanide (700mg, 2.10mmol) in MeOH (8mL) was added MeONa (340mg, 6.28 mmol). The reaction mixture was stirred at room temperature overnight and then partitioned between EtOAc (30mL) and H₂O (30 mL). The organic layer was separated, washed with brine (30mL), and dried over anhydrous Na₂SO₄Dried and concentrated and purified by standard methods to obtain the desired product.¹HNMR(400MHz,DMSO-d₆)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/z 460(M+H)⁺。

The following compounds were prepared using the procedure set forth in example 23, using the appropriate starting materials.

6- (6-chloropyrazine)-2-yl) -N²,N⁴Bis (3, 3-difluorocyclopentyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 432(M+H)⁺。

6- (6-chloropyrazin-2-yl) -N²,N⁴Bis (3, 3-difluorocyclobutyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 404(M+H)⁺。

6- (6-Chloropyrazin-2-yl) -N2, N4-bis (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 416(M+H)⁺。

Example 24 a symmetrical dialiphatic triazine compound having the formula P is prepared. The compounds of this example were prepared by general scheme 24, listed below.

Scheme 24

Step 1: preparation of methyl 2- (trifluoromethyl) pyrimidine-4-carboxylate. To a solution of 4-chloro-2- (trifluoromethyl) pyrimidine (10g, 54.9mmol) in MeOH (60mL) was added dppf (3.0g, 5.5mmol), Pd (OAc)₂(630mg, 2.8mmol) and Et₃N (11.4mL, 41.2 mmol). In thatThe mixture was stirred overnight at 60 ℃ under CO atmosphere (60 psi). The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by standard methods to obtain the desired product. LC-MS M/z207.0(M + H)⁺。

Step 2: preparation of 6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazine-2, 4(1H,3H) -dione. The procedure was the same as described above for example 1, step 2. LC-MS M/z 260.0(M + H)⁺。

And step 3: preparation of 2, 4-dichloro-6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazine. The procedure was the same as described above for example 1, step 3. LC-MS M/z 296.0(M + H)⁺。

And 4, step 4: preparation of N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazine-2, 4-diamine. The procedure was the same as described above for example 1, step 4.

¹H NMR(400MHz,CDCl₃)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/z 494.2(M+H)⁺。

The following compounds were prepared using the procedure set forth in example 24, using the appropriate starting materials.

N²,N⁴-bis (3, 3-difluorocyclopentyl) -6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 466.2(M+H)⁺。

N²,N⁴Bis (3, 3-difluorocyclobutyl) -6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 438.1(M+H)⁺。

6- (2- (trifluoromethyl) pyrimidin-4-yl) -N²,N⁴Bis ((R) -1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 450.1(M+H)⁺。

N²,N⁴-bis ((S) -1,1, 1-trifluorobutan-2-yl) -6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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)⁺。

N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine.

¹H NMR(400MHz,CDCl₃)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/z 494.2(M+H)⁺。

N²,N⁴-bis (3, 3-difluorocyclopentyl) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-24-diamines

¹H NMR(400MHz,CDCl₃)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)⁺。

N²,N⁴Bis (3, 3-difluorocyclobutyl) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆)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/z 438.1(M+H)⁺。

N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 394(M+H)⁺。

N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (4- (2-methoxyethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 484(M+H)⁺。

Example 25 the compounds of this example were prepared by general scheme 25, listed below.

Scheme 25

Step 1: preparation of ethyl 2- (trifluoromethyl) thiazole-4-carboxylate. To a solution of 2,2, 2-trifluoroacetamide (1.42g, 12.6mmol) in dry THF (60mL) was added thionine (3.06g, 7.56 mmol). The reaction mixture was heated at reflux for 18 hours and then cooled, followed by the addition of ethyl 3-bromo-2-oxopropanoate (1.6mL, 12.6 mmol). The mixture was refluxed for another 18 hours and then cooled to room temperature. The resulting mixture was partitioned between EtOAc and water. Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated, and purified by standard methods to obtain ethyl 2- (trifluoromethyl) thiazole-4-carboxylate.¹HNMR(400MH_Z,CDCl₃)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 of N¹,N⁵-bis (3, 3-difluorocyclobutyl) -biguanide. 3, 3-Difluorocyclobutylamine hydrochloride (3.024g, 0.021mol) and NaN (CN) were vigorously stirred at 160 deg.C₂(890mg, 0.01mol) for 2 hours, and then cooled to room temperature. The resulting mixture was dissolved in MeOH and filtered. The filtrate was concentrated to obtain the desired product. LC-MS M/z282(M + H)⁺。

And step 3: preparation of N²,N⁴-bis (3, 3-difluorocyclobutyl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine. To N¹,N⁵To a mixture of-bis (3, 3-difluorocyclobutyl) -biguanide (60mg, 0.22mmol) in MeOH (5mL) was added ethyl 2- (trifluoromethyl) thiazole-4-carboxylate (58.5mg, 0.26mmol) and NaOMe (23.7mg, 0.44 mmol). The reaction mixture was then stirred at room temperature for 48 hours, then partitioned between EtOAc and H₂And O is between. The organic layer was separated, washed with brine, and dried over anhydrous Na₂SO₄Dried, concentrated and purified by standard methods to obtainTo obtain N²,N⁴-bis (3, 3-difluorocyclobutyl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine.

¹H NMR(400MHz,CDCl₃)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/z 443(M+H)⁺。

Using the procedure set forth in example 25, the following compounds were prepared using the appropriate starting materials.

N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 499(M+H)⁺。

N²,N⁴-bis (3, 3-difluorocyclopentyl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 471(M+H)⁺。

6- (4- (trifluoromethyl) thiazol-2-yl) -N²,N⁴Bis (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 455(M+H)⁺。

N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (2- (trifluoromethyl) thiazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 499(M+H)⁺。

N²,N⁴Bis (3, 3-difluorocyclobutyl) -6- (2- (trifluoromethyl) thiazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 443(M+H)⁺。

6- (2- (trifluoromethyl) thiazol-4-yl) -N²,N⁴Bis ((R) -1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 455(M+H)⁺。

N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (2-methyloxazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 429(M+H)⁺。

N²,N⁴Bis (3, 3-difluorocyclobutyl) -6- (2-methyloxazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 373(M+H)⁺。

N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (5-methylisoxazol-3-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 429(M+H)⁺。

N²,N⁴Bis (3, 3-difluorocyclobutyl) -6- (5-methylisoxazol-3-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆)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/z 373(M+H)⁺。

Example 26 the compounds of this example were prepared by general scheme 26, listed below.

Scheme 26

Step 1: preparation of ethyl 2-bromothiazole-4-carboxylate. To a solution of ethyl 2-aminothiazole-4-carboxylate (15.0g, 87.1mmol) in MeCN (100mL) was added nitrous acidIsoamyl ester (24.5g, 209mmol) and CuBr₂(27.5g, 122 mmol). The mixture was stirred at 70 ℃ overnight, then cooled to room temperature, diluted with water (200mL), and extracted with EtOAc (2 × 200 mL). With anhydrous Na₂SO₄The combined organic layers were dried and concentrated, and purified by standard methods to obtain ethyl 2-bromothiazole-4-carboxylate. LC-MS M/z 236(M + H)⁺。

Step 2: preparing the 2-bromothiazole-4-formic acid. To ethyl 2-bromothiazole-4-carboxylate (18.0g, 76.0mmol) in THF (90mL) and H₂To a solution in O (90mL) was added LiOH (4.8g, 114 mmol). The mixture was stirred at room temperature for 3h and extracted with EtOAc (2 × 150 mL). Separating the aqueous layer with saturated aqueous NH₄Cl was adjusted to pH 2-3 and filtered. The solid was collected and dried under high vacuum to obtain 2-bromothiazole-4-carboxylic acid. LC-MS M/z206 (M-H)^-。

And step 3: preparation of 2-bromo-N-methoxy-N-methylthiazole-4-carboxamide. To a solution of 2-bromothiazole-4-carboxylic acid (11.4g, 55.0mmol) in DCM (100mL) was added N, O-dimethylhydroxylamine (6.9g, 71.0mmol), HATU (27.0g, 71.0mmol) and DIPEA (21.2g, 164.0 mmol). The mixture was stirred at room temperature overnight, then quenched with water (200mL) and extracted with DCM (2 × 200 mL). With anhydrous Na₂SO₄The combined organic layers were dried, concentrated and purified by standard methods to obtain 2-bromo-N-methoxy-N-methylthiazole-4-carboxamide. LC-MS M/z 251(M + H)⁺。

And 4, step 4: preparation of 1- (2-bromothiazol-4-yl) ethanone. In N₂To a solution of 2-bromo-N-methoxy-N-methylthiazole-4-carboxamide (6.8g, 27.0mmol) in THF (60mL) at 0 ℃ under an atmosphere was slowly added dropwise MeMgBr (9.9mL, 29.7mmol, 3M in THF). The mixture was slowly warmed to room temperature and stirred at this temperature for 30 minutes. With saturated aqueous NH₄The reaction mixture was quenched with Cl (100mL) and extracted with EtOAc (2 × 100 mL). With anhydrous Na₂SO₄The combined organic layers were dried and concentrated, and purified by standard methods to give 1- (2-bromothiazol-4-yl) ethanone. LC-MS M/z206(M + H)⁺。

And 5: preparation of 4-acetylthiazole-2-Carboxylic acid methyl ester. To a solution of 1- (2-bromothiazol-4-yl) ethanone (340mg, 1.65mmol) in MeOH (10mL) was added Pd (OAc)₂(20.0mg, 0.08mmol), dppf (95.0mg, 0.16mmol) and Et₃N (250mg, 2.5 mmol). The mixture was heated at 60 ℃ under CO atmosphere (0.4mPa) overnight. The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by standard methods to obtain 4-acetylthiazole-2-carboxylic acid methyl ester. LC-MS M/z 186(M + H)⁺。

Step 6: preparation of methyl 4- (1, 1-difluoroethyl) thiazole-2-carboxylate. To a solution of 4-acetylthiazole-2-carboxylate (200mg, 1.07mmol) in DCM (10mL) at 0 deg.C was slowly added DAST (1.64g, 10.2mmol) dropwise. The mixture was then warmed to room temperature and stirred at room temperature overnight. With saturated aqueous NaHCO₃The mixture was quenched slowly (20mL) and extracted with DCM (2 × 20 mL). With anhydrous Na₂SO₄The combined organic layers were dried, concentrated and purified by standard methods to obtain methyl 4- (1, 1-difluoroethyl) thiazole-2-carboxylate. LC-MS M/z 208(M + H)⁺。

And 7: preparation of N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (4- (1, 1-difluoroethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine. To N¹,N⁵To a mixture of bis (3, 3-difluorocyclobutyl) -biguanide (60mg, 0.22mmol) in MeOH (5mL) was added ethyl 4- (1, 1-difluoroethyl) thiazole-2-carboxylate (50mg, 0.26mmol) and NaOMe (23.7mg, 0.44 mmol). The reaction mixture was then stirred at room temperature for 48 hours and then partitioned between EtOAc and H₂And O is between. The organic layer was separated, washed with brine, and dried over anhydrous Na₂SO₄Dried, concentrated and purified by standard methods to obtain N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (4- (1, 1-difluoroethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine.

¹H NMR(400MHz,CDCl₃)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/z 495(M+H)⁺。

Using the procedure set forth in example 26, the following compounds were prepared using the appropriate starting materials.

N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (2- (1, 1-difluoroethyl) thiazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆)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/z 494(M+H)⁺。

N²,N⁴Bis (3, 3-difluorocyclopentyl) -6- (2- (1, 1-difluoroethyl) thiazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 467(M+H)⁺。

N²,N⁴Bis (3, 3-difluorocyclobutyl) -6- (2- (1, 1-difluoroethyl) thiazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)δ8.45-8.36(m,1H),5.71-5.36(m,2H),4.47-4.35(m,2H),3.05(s,4H),3.6 1(s,4H),2.24-2.03(m,3H)。LC-MS:m/z 439(M+H)⁺。

Example 27 the compounds of this example were prepared by general scheme 27, listed below.

Scheme 27

Step 1: preparing 2-bromothiazole-4-formaldehyde. DIBAL-H (7.35g, 0.052mol) was added slowly to a mixture of 2-bromo-N-methoxy-N-methylthiazole-4-carboxamide (10g, 0.04mol) in THF (80mL) at-78 ℃. The reaction mixture was stirred at-78 ℃ for 2 hours and then the pH was adjusted to 5-6. The mixture was partitioned between EtOAc (80mL) and H₂Between O (60 mL). The organic layer was separated, washed with brine (40mL), and dried over anhydrous Na₂SO₄Dried, concentrated and purified by standard methods to obtain the desired product. LC-MS M/z 192(M + H)⁺。

Step 2: preparation of 2-bromo-4- (difluoromethyl) thiazole. To a mixture of 2-bromothiazole-4-carbaldehyde (0.764g, 0.004mol) in DCM (7mL) was added DAST (3.22g, 0.02mol) dropwise at 0 ℃. The mixture was stirred at 25 ℃ for 48 hours and then saturated aqueous NaHCO₃Quench and adjust pH to 8-10. The resulting mixture was extracted with DCM (2 × 40 mL). The combined organic layers were washed with brine (30mL) and anhydrous Na₂SO₄Dried and concentrated and purified by standard methods to obtain the desired product. LC-MS M/z 214(M + H)⁺。

And step 3: preparation of methyl 4- (difluoromethyl) thiazole-2-carboxylate. 2-bromo-4- (difluoromethyl) thiazole (0.6g, 2.82mmol), dppf (0.14g, 0.28mmol), Et were stirred at 60 ℃ under a CO atmosphere₃N (0.43g, 4.23mmol) and Pd (OAc)₂A mixture of (0.13g, 0.56mmol) in MeOH (10mL) for 16 h. The resulting mixture was filtered, the filtrate was concentrated and the residue was partitioned between DCM (30mL) and H₂And O is between. The organic layer was separated, washed with brine (30mL), and dried over anhydrous Na₂SO₄Dried and concentrated and purified by standard methods to obtain the desired product. LC-MS M/z 194(M + H)⁺。

And 4, step 4: preparation of N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (4- (difluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine. To N¹,N⁵Bis (3, 3-difluorocyclobutyl) -biguanide (45mg, 13.3mmol) and methyl 4- (difluoromethyl) thiazole-2-carboxylate (40mg, 20.7mmol) in MeOH (10mL)To the suspension was added NaOMe (20mg, 37.0 mmol). The reaction mixture was stirred at room temperature overnight, then poured into water and extracted with EtOAc. With anhydrous Na₂SO₄The combined organic layers were dried, concentrated and purified by standard methods to obtain the desired product.

¹H NMR(400MHz,CDCl₃)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/z 481(M+H)⁺。

The following compounds were prepared using the procedure set forth in example 27, using the appropriate starting materials.

N²,N⁴Bis (3, 3-difluorocyclobutyl) -6- (4- (difluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400 MHz,CDCl₃)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/z 425(M+H)⁺。

N²,N⁴Bis (3, 3-difluorocyclopentyl) -6- (4- (difluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 453(M+H)⁺。

Example 28 the compounds of this example were prepared by general scheme 28, listed below.

Scheme 28

Step 1: preparation of 5-phenyl-1, 3, 4-oxathiazol-2-one. In N₂To a solution of benzamide (200mg, 1.65mmol) in toluene (2mL) was added carbonyl chloride hypohypochlorite (0.16mL, 1.98mmol) under an atmosphere. The mixture was stirred at 120 ℃ for 3 hours. The resulting mixture was cooled to room temperature and then treated with H₂Quench O and extract with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Dried, concentrated and purified by standard methods to obtain the desired product. LC-MS M/z 180(M + H)⁺。

Step 2: preparation of 3-phenyl-1, 2, 4-thiadiazole-5-carboxylate. A mixture of 5-phenyl-1, 3, 4-oxathiazol-2-one (270mg, 1.5mmol) and ethyl cyanoformate (790mg, 6.0mmol) in DCE (2mL) was stirred in a sealed vial under microwave irradiation at 160 ℃ for 0.5 h. The resulting mixture was concentrated and purified by standard methods to obtain the desired product. LC-MS M/z 235(M + H)⁺。

And step 3: preparation of N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (3-phenyl-1, 2, 4-thiadiazol-5-yl) -1,3, 5-triazine-2, 4-diamine. To N¹,N⁵To a mixture of (E) -bis (4, 4-difluorocyclohexyl) -biguanide (90mg, 0.27mmol) and ethyl 3-phenyl-1, 2, 4-thiadiazole-5-carboxylate (75mg, 0.32mmol) in MeOH (2mL) was added NaOMe (43mg, 0.8 mmol). The reaction mixture was then stirred at room temperature overnight. The resulting mixture was poured into water and extracted with EtOAc. With anhydrous Na₂SO₄The combined organic layers were dried and concentrated and purified by standard methods to obtain the desired product.

¹H NMR(400MHz,CDCl₃)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/z 508.2(M+H)⁺。

The following compounds were prepared using the procedure set forth in example 28, using the appropriate starting materials.

N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (3-methyl-1, 2, 4-thiadiazol-5-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 446(M+H)⁺。

Example 29 the compounds of this example were prepared by the general scheme 29 listed below.

Scheme 29

Step 1. preparation of 6-chloro-N²,N⁴Bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine. To a solution of 2,4, 6-trichloro-1, 3, 5-triazine (2g, 10.9mmol) in acetone (35mL) was added (S) -1-cyclopropylethylamine hydrochloride (2.7mg, 22.8mmol), DIPEA (3.5mg, 27mmol) and CsF (3.3mg, 21.8 mmol). The mixture was stirred at 50 ℃ overnight and then filtered. The filtrate was concentrated and purified by standard methods to give the desired product. LC-MS M/z282(M + H)⁺。

Step B. preparation of N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (4-methyl-1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine. To an ice-cooled solution of 4-methyl-1H-pyrazole (207mg, 1.07mmol) in dry THF (5mL) was slowly added NaH (34mg, 1.42mmol) over 30 minutes, followed by 6-chloro-N²,N⁴-a solution of bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine (200mg, 0.71mmol) in THF (3 mL). The reaction mixture was stirred at room temperature overnight, and then concentrated and purified by standard methods to obtain N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (4-methyl-1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine.

¹H NMR(400MHz,CDCl₃)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/z 328(M+H)⁺。

The following compounds were prepared using the procedure set forth in example 29, using the appropriate starting materials.

Compound N²,N⁴Bis ((R) -1-cyclopropylethyl) -6- (4-iodo-1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 440(M+H)⁺。

Compound 6- (4-chloro-1H-pyrazol-1-yl) -N²,N⁴Bis (4, 4-difluorocyclohexyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 448(M+H)⁺。

Compound N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 382(M+H)⁺。

Compound 6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N²,N⁴Bis (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 438.1(M+H)⁺。

Compound N²,N⁴-bis ((S) -1,1, 1-trifluorobutan-2-yl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 466(M+H)⁺。

Compound N²,N⁴-bis (3, 3-difluorocyclopentyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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 N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆)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/z 482(M+H)⁺。

Compound N²,N⁴-bis (3, 3-difluorocyclobutyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 426(M+H)⁺。

Example 30 the compounds of this example were prepared by general scheme 30, listed below.

Scheme 30

Step 1: preparation of 1-methyl-1H-pyrazole-3-carboxylic acid methyl ester. To a solution of 1-methyl-1H-pyrazole-3-carboxylic acid (504mg, 4mmol) in MeOH (5mL) at 0 deg.C was added SOCl₂(1.4mL, 20 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO₃Washed and concentrated to obtain 1-methyl-1H-pyrazole-3-carboxylic acid methyl ester. LC-MS M/z 141(M + H)⁺。

Step 2: preparation of N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (1-methyl-1H-pyrazol-3-yl) -1,3, 5-triazine-2, 4-diamine. To N¹,N⁵To a solution of-bis (4, 4-difluorocyclohexyl) -biguanide (120mg, 0.36mmol) and methyl 1-methyl-1H-pyrazole-3-carboxylate (60mg, 0.43mmol) in MeOH (2mL) was added NaOMe (28mg, 1.07 mmol). The reaction mixture was stirred at room temperature overnight, then poured into water and extracted with EtOAc. With anhydrous Na₂SO₄Drying and combiningAnd concentrated and purified by standard methods to obtain N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (1-methyl-1H-pyrazol-3-yl) -1,3, 5-triazine-2, 4-diamine.

¹H NMR(400MHz,CDCl₃)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/z 428(M+H)⁺。

Using the procedure set forth in example 30, the following compounds were prepared using the appropriate starting materials.

Compound N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (1H-pyrazol-3-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 414(M+H)⁺。

Compound N²,N⁴-bis (3, 3-difluorocyclopentyl) -6- (2-methyl-1H-imidazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 400.1(M+H)⁺。

Compound N²,N⁴Bis (3, 3-difluorocyclobutyl) -6- (2-methyl-1H-imidazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 372(M+H)⁺。

Compound N²,N⁴Bis (4, 4-difluorocyclohexyl) -6- (2-methyl-1H-imidazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 428.3(M+H)⁺。

Example 31 the compounds of this example were prepared by general scheme 31, listed below.

Scheme 31

Step 1: preparation of 4-iodo-3- (trifluoromethyl) -1H-pyrazole. To 3- (trifluoromethyl) -1H-pyrazole (500mg, 3.7mmol) in 50% H at 0 deg.C₂SO₄NIS (992mg, 4.4mmol) was added to the solution in (1). The suspension was stirred at 0 ℃ for 10 minutes and then at room temperature for 3 hours. The resulting mixture was quenched with water (50mL) and then stirred overnight. The precipitate was collected by filtration and dried to obtain 4-iodo-3- (trifluoromethyl) -1H-pyrazole. LC-MS M/z 263(M + H)⁺。

Step 2: preparation of 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3- (trifluoromethyl) -1H-pyrazole. To a mixture of 4-iodo-3- (trifluoromethyl) -1H-pyrazole (100mg, 0.38mmol) and (4,4,4',4',5,5,5',5' -octamethyl-2, 2 '-bis (1,3, 2-dioxaborolan) (397mg, 0.57mmol) in DMF (3mL) was added 1,1' -bis- (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (31mg, 0.04mmol) and potassium acetate (509mg, 0.76). the reaction mixture was stirred at 90 ℃ for 2 hours, then quenched with water and Et₂And (4) extracting. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Dried and concentrated to obtain 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3- (trifluoromethyl) -1H-pyrazole. LC-MS M/z 263(M + H)⁺。

And step 3: preparation of N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -1,3, 5-triazine-2, 4-diamine. In N₂Under the atmosphere, to 6-chloro-N²,N⁴Bis (4, 4-difluorocyclohexyl) -1,3, 5-triazine-2, 4-diamine (145mg, 0.38mmol) and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3- (trifluoromethyl) -1H-pyrazole (100mg, 0.38mmol) in DME (3mL) and H₂To a solution in O (1mL) was added K₂CO₃(158mg, 1.15mmol) and Pd (PPh)₃)₄(44mg, 0.04 mmol). The mixture was stirred at 90 ℃ for 16 hours, and then filtered. Partition the filtrate into EtOAc and H₂And O is between. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Dried, concentrated and purified by standard methods to obtain N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -1,3, 5-triazine-2, 4-diamine.

¹H NMR(400MHz,DMSO-d₆)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/z 482(M+H)⁺。

The following compounds were prepared using the procedure outlined in example 31, using the appropriate starting materials.

Compound N²,N⁴-bis (4, 4-difluorocyclohexyl) -N²-methyl-6- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 496(M+H)⁺。

Compound N²,N⁴-bis (4, 4-difluorocyclohexyl) -6- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 496(M+H)⁺。

Compound N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (5- (trifluoromethyl) pyridin-3-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆)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/z 393(M+H)⁺。

Compound N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 393(M+H)⁺。

Compound N²,N⁴Bis ((R) -1-cyclopropylethyl) -6- (2, 5-difluorophenyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 360(M+H)⁺。

Compound N²,N⁴-bis ((R) -1-cyclopropylethyl) -6- (3- (trifluoromethoxy) phenyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)：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/z 408(M+H)⁺。

The compound 3- (4, 6-bis (((R) -1-cyclopropylethyl) amino) -1,3, 5-triazin-2-yl) benzonitrile

¹H NMR(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/z 349(M+H)⁺。

Example 32 preparation of aromatic-aliphatic triazine compounds having formula Q. The compounds of this example were prepared by general scheme 32, listed below.

Scheme 32

Step 1: preparation of 4-chloro-N- (6- (1, 1-difluoroethyl) pyridin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-amine. To 2, 4-dichloro-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine (188mg, 0.64mmol) and 2- (1, 1-difluoroethyl) pir-zine were added under a nitrogen atmosphereTo a mixture of pyridin-4-amine (50mg, 0.32mmol) in 1, 4-dioxane (4mL) was added^tBuona (61mg, 0.64mmol) and Pd (dppf) Cl₂(22mg, 0.03 mmol). The reaction mixture was then stirred at 80 ℃ overnight and then filtered. The filtrate was concentrated and purified by standard methods to obtain the desired product.

LC-MS:m/z417.1(M+H)⁺。

Step 2: preparation of N²- (3, 3-difluorocyclopentyl) -N⁴- (2- (1, 1-difluoroethyl) pyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine to a mixture of 4-chloro-N- (6- (1, 1-difluoroethyl) pyridin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2-amine (35mg, 0.08mmol) and 3, 3-difluorocyclopentylamine (16mg, 0.13mmol) in THF (2mL) were added CsF (24mg, 0.16mmol) and DIPEA (0.03mL, 0.16 mmol). The reaction mixture was then stirred at 50 ℃ overnight. The mixture was filtered and the filtrate was concentrated and purified by standard methods to obtain the desired product.

¹H NMR(400MHz,CDCl₃)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/z 502(M+H)⁺。

Using the procedure set forth in example 32, the following compounds were prepared using the appropriate starting materials.

(S)-N²- (3, 3-difluorocyclopentyl) -N⁴- (2- (1, 1-difluoroethyl) pyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 502(M+H)⁺。

(R)-N²- (3, 3-difluorocyclopentyl) -N⁴- (2- (1, 1-difluoroethyl) pyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 502(M+H)⁺。

N²- (4, 4-difluorocyclohexyl) -N⁴- (2- (1, 1-difluoroethyl) pyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 516(M+H)⁺。

N²- (3, 3-difluorocyclobutyl) -N⁴- (2- (1, 1-difluoroethyl) pyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 488(M+H)⁺。

2- ((4- ((2- (1, 1-difluoroethyl) pyridin-4-yl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) propionitrile

¹H NMR(400MHz,DMSO-d₆)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/z 451(M+H)⁺。

2- ((4- ((2- (1, 1-difluoroethyl) pyridin-4-yl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -2-methylpropanenitrile

¹H NMR(400MHz,CDCl₃)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/z 465(M+H)⁺。

3- ((4- ((2- (1, 1-difluoroethyl) pyridin-4-yl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -2, 2-dimethylpropionitrile

¹H NMR(400MHz,DMSO-d₆)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-difluoroethyl) pyridin-4-yl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) butyronitrile

¹H NMR(400MHz,DMSO-d₆)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/z 465(M+H)⁺。

3- ((4- ((2- (1, 1-difluoroethyl) pyridin-4-yl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -3-methylbutanenitrile

¹H NMR(400MHz,DMSO-d₆)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)⁺。

N²- (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 506(M+H)⁺。

(R)-N²- (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 506(M+H)⁺。

(S)-N²- (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 506(M+H)⁺。

N²- (4, 4-Difluorocyclohexyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

1H NMR(400MHz,CDCl₃)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/z 520(M+H)⁺。

N²- (3, 3-Difluorocyclobutyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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)⁺。

N²- (6, 6-Difluorospiro [3.3]]Hept-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

1H NMR(400MHz,CDCl₃)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/z 532(M+H)⁺。

6- (6- (trifluoromethyl) pyridin-2-yl) -N²- (2- (trifluoromethyl) pyridin-4-yl) -N⁴- (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 498(M+H)⁺。

N²- (2,2, 2-trifluoroethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆)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/z 484(M+H)⁺。

N²- ((3, 3-Difluorocyclobutyl) methyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 506(M+H)⁺。

N²- ((2, 2-Difluorocyclopropyl) methyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆)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/z 492(M+H)⁺。

N²- (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (5- (trifluoromethyl) pyridin-3-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 506(M+H)⁺。

1- (4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(600MHz,CDCl₃)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/z 503(M+H)⁺

(R) -1- (4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,DMSO-d₆)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/z 503(M+H)⁺。

(S) -1- (4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,DMSO-d₆)δ10.47(s,1H),8.79-8.60(m,2H),8.49(s,1H),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/z 503(M+H)⁺。

1- (4- ((4- ((4, 4-difluorocyclohexyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 517(M+H)⁺。

1- (4- ((4- ((3, 3-difluorocyclobutyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,DMSO-d₆)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/z 489(M+H)⁺。

1- (4- ((4- ((6, 6-difluorospiro [3.3] hept-2-yl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 529(M+H)⁺。

1- (4- ((4- (((2, 2-difluorocyclopropyl) methyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 489(M+H)⁺。

1- (4- ((4- ((2,2, 2-trifluoroethyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 481.2(M+H)⁺。

1- (4- ((4- ((2-hydroxy-2-methylpropyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 471(M+H)⁺。

(R) -1- (4- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((1,1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 495(M+H)⁺。

(S) -1- (4- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((1,1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 495(M+H)⁺。

4- ((4- (tert-butylamino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridinecarbonitrile

1H NMR(400MHz,DMSO-d₆)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/z 415(M+H)⁺。

4- ((4- ((3, 3-Difluorocyclobutyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridinecarbonitrile

¹H NMR(400MHz,DMSO-d₆)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/z 449(M+H)⁺。

4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridinecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 463(M+H)⁺。

4- ((4- ((4, 4-Difluorocyclohexyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridinecarbonitrile

¹H NMR(400MHz,DMSO-d₆)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/z 477(M+H)⁺。

4- ((4- ((2-hydroxy-2-methylpropyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridinecarbonitrile

¹H NMR(400MHz,CDCl₃)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) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹H NMR(400MHz,CDCl₃)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/z 480(M+H)⁺。

3- ((4- ((4, 4-Difluorocyclohexyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹H NMR(400MHz,CDCl₃)：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/z 494(M+H)⁺。

3- ((4- ((3, 3-difluorocyclobutyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹H NMR(400MHz,DMSO-d₆)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/z 466(M+H)⁺。

3- ((4- ((cyclopropylmethyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹H NMR(400MHz,CDCl₃)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)⁺。

3-fluoro-5- ((4- ((2-hydroxy-2-methylpropyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) benzonitrile

¹H NMR(400MHz,DMSO-d₆)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/z 448(M+H)⁺。

1- ((4- ((3-chlorophenyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -2-methylpropan-2-ol

¹H NMR(400MHz,DMSO-d₆)δ10.11(m 1H),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(m 2H),1.17(d,J＝6.4Hz,6H)。LC-MS:m/z 439(M+H)⁺。

3- ((4- (tert-butylamino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) benzonitrile

¹H NMR(400MHz,DMSO-d₆)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/z 414(M+H)⁺。

N²- (3, 3-difluorocyclopentyl) -N⁴- (3, 5-difluorophenyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 473(M+H)⁺。

N²- (4, 4-difluorocyclohexyl) -N⁴- (3, 5-difluorophenyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 487.2(M+H)⁺。

N²- (4, 4-difluorocyclohexyl) -N⁴- (2-phenylpyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 528(M+H)⁺。

N²- (3, 3-difluorocyclopentyl) -N⁴- (2-phenylpyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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)⁺。

N²- (2-phenylpyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 506(M+H)⁺。

(R)-N²- (2-phenylpyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 506(M+H)⁺。

(R) -4- (4- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((1,1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) benzonitrile

¹HNMR(400MHz,CDCl₃)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/z 531(M+H)⁺。

(R)-N²- (2- (4-fluorophenyl) pyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 524.1(M+H)⁺。

(R)-N²- (2- (4-chlorophenyl) pyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N⁴- (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹HNMR(400MHz,CDCl₃)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/z 540(M+H)⁺。

N²- (3, 3-difluorocyclopentyl) -N⁴- (1H-indol-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆)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/z 476(M+H)⁺。

N²- (3, 3-difluorocyclopentyl) -N⁴- (1-methyl-1H-indol-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 490(M+H)⁺。

1- (4- ((4- ((4, 4-difluorocyclohexyl) amino) -6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 513(M+H)⁺。

1- (4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 499(M+H)⁺。

1- (4- ((4- ((3, 3-difluorocyclobutyl) amino) -6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 485(M+H)⁺。

(R) -1- (4- ((4- (6- (1, 1-difluoroethyl) pyridin-2-yl) -6- ((1,1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 491(M+H)⁺。

(S) -1- (4- ((4- (6- (1, 1-difluoroethyl) pyridin-2-yl) -6- ((1,1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 491(M+H)⁺。

1- ((4- ((3-chloro-5-fluorophenyl) amino) -6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -2-methylpropan-2-ol

¹H NMR(400MHz,DMSO-d₆)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/z 453(M+H)⁺。

3- ((4- (6- (1, 1-difluoroethyl) pyridin-2-yl) -6- ((2-hydroxy-2-methylpropyl) amino) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

1H NMR(400MHz,CDCl₃)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/z 444(M+H)⁺。

1- ((4- (6- (1, 1-difluoroethyl) pyridin-2-yl) -6- ((3-fluoro-5- (trifluoromethyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino) -2-methylpropan-2-ol

¹H NMR(400MHz,CDCl₃)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/z 487(M+H)⁺。

1- (4- ((4- (6-Chloropyridin-2-yl) -6- ((3, 3-Difluorocyclopentyl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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-Chloropyridin-2-yl) -6- ((1-Cyclopropylethyl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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-chloropyridin-2-yl) -6- ((2,2, 2-trifluoroethyl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 447(M+H)⁺。

1- (4- ((4- (6-chloropyridin-2-yl) -6- ((1,1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 461(M+H)⁺。

6- (6-Chloropyridin-2-yl) -N²- (3, 3-difluorocyclopentyl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 472(M+H)⁺。

6- (6-Chloropyridin-2-yl) -N2- (cyclopropylmethyl) -N4- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 422(M+H)⁺。

1- (4- ((4- ((3, 3-difluorocyclobutyl) amino) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHZz,CDCl₃)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/z 490(M+H)⁺。

1- (4- ((4- ((4, 4-difluorocyclohexyl) amino) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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-difluorospiro [3.3] hept-2-yl) amino) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,DMSO-d₆)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/z 530(M+H)⁺。

(R) -1- (4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,DMSO-d₆)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/z 504(M+H)⁺。

(S) -1- (4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 504(M+H)⁺。

(R) -1- (4- ((4- (6- (trifluoromethyl) pyrazin-2-yl) -6- ((1,1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 496(M+H)⁺。

(R)-N²- (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)δ9.81(m 1H),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/z 507(M+H)⁺。

(S)-N²- (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 507(M+H)⁺。

N²- (3, 3-Difluorocyclobutyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 493(M+H)⁺。

N²- (4, 4-difluorocyclohexyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

1H NMR(400MHz,CDCl₃)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/z 521(M+H)⁺。

N²- (cyclopropylmethyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -N4- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆)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(m 8H),0.39-0.30(m,8H)。LC-MS:m/z 457(M+H)⁺。

N²- (6, 6-Difluorospiro [3.3]]Hept-2-yl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

1H NMR(400MHz,CD₃OD)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/z 533(M+H)⁺。

(S)-N²- (3, 3-difluorocyclopentyl) -N⁴- (3, 5-difluorophenyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 474(M+H)⁺。

(R)-N²- (3, 3-difluorocyclopentyl) -N⁴- (3, 5-difluorophenyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

N²- (4, 4-difluorocyclohexyl) -N⁴- (3, 5-difluorophenyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 488(M+H)⁺。

1- (4- ((4- ((4, 4-difluorocyclohexyl) amino) -6- (6- (difluoromethyl) pyrazin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

1H NMR(400MHz,CDCl₃)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/z 500(M+H)⁺。

(S) -1- (4- ((4- (6- (difluoromethyl) pyrazin-2-yl) -6- ((1,1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 478(M+H)⁺。

(R) -1- (4- ((4- (6- (difluoromethyl) pyrazin-2-yl) -6- ((1,1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 478(M+H)⁺。

6- (6-chloropyrazin-2-yl) -N²- (3, 3-difluorocyclopentyl) -N⁴- (3, 5-difluorophenyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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-chloropyrazin-2-yl) -N²- (3, 3-difluorocyclobutyl) -N⁴- (3, 5-difluorophenyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 426(M+H)⁺。

(S)-N²- (3, 3-difluorocyclopentyl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 507(M+H)⁺。

(R)-N²- (3, 3-difluorocyclopentyl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 507(M+H)⁺。

(S) -1- (4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

1H NMR(400MHz,CDCl₃)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/z 504(M+H)⁺。

(R) -1- (4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 504(M+H)⁺。

1- (4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 504(M+H)⁺。

(S) -1- (4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 504(M+H)⁺。

(R) -1- (4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 504(M+H)⁺。

N²- (tert-butyl) -N⁴- (2- (1, 1-difluoroethyl) pyridin-4-yl) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 455(M+H)⁺。

N²- (2- (1, 1-difluoroethyl) pyridin-4-yl) -N⁴-isopropyl-6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 441(M+H)⁺。

3- ((4- (tert-butylamino) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹H NMR(400MHz,DMSO-d₆)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/z 433(M+1)⁺。

1- ((4- ((3, 5-difluorophenyl) amino) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazin-2-yl) amino) -2-methylpropan-2-ol

¹H NMR(400MHz,DMSO-d₆)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/z 442(M+H)⁺。

Example 33 preparation of aromatic-aliphatic triazine compounds. The compounds of this example were prepared by general scheme 33, listed below.

Scheme 33

Step 1: preparation of N¹- (3, 5-difluorophenyl) -N³-nitrile-guanidine. At 80 ℃ to NaN (CN)₂(4.1g, 46.5mmol) in water (34mL) was added a solution of 3, 5-difluoroaniline (3g, 23.2mmol) in a mixed solvent of water and concentrated HCl (2M, 2 mL). The reaction mixture was then stirred at 90 ℃ for 16 hours. The resulting mixture was cooled to room temperature and passed through saturated aqueous NaHCO₃Quenched and adjusted to pH 7-8. The mixture was filtered and the filter cake was collected and dried to obtain the desired product. LC-MS M/z 197(M + H)⁺。

Step 2: preparation of N¹- (3, 5-difluorophenyl) -N⁵- (4, 4-difluorocyclohexyl) -guanidine. Will N¹- (3, 5-difluorophenyl) -N³A mixture of nitrile-guanidine (300mg, 1.53mmol) and 4, 4-difluorocyclohexylamine hydrochloride (262mg, 1.53mmol) was mixed together thoroughly and then stirred at 160 ℃ for 1 hour. The resulting mixture was cooled to room temperature and then triturated with a mixed solvent of EtOAc and PE. The solid was collected by filtration and dried to obtain the desired product. LC-MS M/z 332(M + H)⁺。

And step 3: preparation of 3, 6-difluoro-2-hydrazinopyridine. To an ice-cooled mixture of 2,3, 6-trifluoropyridine (1.0g, 7.5mmol) in ethanol (10mL) was added hydrazine hydrate (0.75g, 15.0 mmol). The reaction mixture was warmed to room temperature and then heated to reflux for 2 hours. After cooling to room temperature, withThe reaction mixture was diluted with water (10mL) and extracted with DCM (2 × 20 mL). With anhydrous Na₂SO₄The combined organic layers were dried and concentrated under reduced pressure to obtain 3, 6-difluoro-2-hydrazinopyridine. LC-MS M/z 146(M + H)⁺。

And 4, step 4: preparation of 2-bromo-3, 6-difluoropyridine. To a stirred solution of 3, 6-difluoro-2-hydrazinopyridine (1.1g, 7.0mmol) in chloroform (20mL) was added dropwise bromine (1.8g, 11.2mmol) at room temperature. The reaction mixture was then stirred at 60 ℃ for 1.5 hours. The resulting mixture was cooled to room temperature and then diluted with saturated aqueous NaHCO₃Quenched and extracted with dichloromethane (2 × 20 mL). With anhydrous Na₂SO₄The combined organic layers were dried and concentrated, and purified by standard methods to obtain 2-bromo-3, 6-difluoropyridine. LC-MS M/z 194(M + H)⁺。

And 5: preparation of methyl 3, 6-difluoropicolinate. To a solution of 2-bromo-3, 6-difluoropyridine (0.8g, 4.1mmol) in MeOH (10mL) was added dppf (0.3g, 0.56mmol), Pd (OAc)₂(0.1g, 0.45mmol) and Et₃N (1.6mL, 8.2 mmol). The suspension was degassed and backfilled three times with a CO atmosphere. The mixture was then stirred under CO atmosphere (60psi) at 70 ℃ for 12 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with EtOAc (150 mL). The solid was filtered off and the filtrate was concentrated and purified by standard methods to obtain methyl 3, 6-difluoropicolinate. LC-MS M/z 174(M + H)⁺。

Step 6: preparation of N²- (4, 4-difluorocyclohexyl) -N⁴- (3, 5-difluorophenyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. To N¹- (3, 5-difluorophenyl) -N⁵To a suspension of (4, 4-difluorocyclohexyl) -guanidine (191mg, 0.58mmol) and methyl 3, 6-difluoropicolinate (100mg, 0.58mmol) in MeOH (3mL) was added NaOMe (94mg, 1.73 mmol). The reaction mixture was stirred at room temperature overnight, then poured into water and extracted with EtOAc. With anhydrous Na₂SO₄The combined organic layers were dried, concentrated and purified by standard methods to obtain N²- (4, 4-difluorocyclohexyl) -N⁴- (3, 5-difluorophenyl) -6- (3, 6-difluoropyridin-2-yl)1, 3, 5-triazine-2, 4-diamine.

¹H NMR(400MHz,CDCl₃)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)⁺。

The following compounds were prepared using the procedure set forth in example 33, using the appropriate starting materials.

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (3, 5-difluorophenyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 441(M+H)⁺。

Compound N²- (3, 3-difluorocyclobutyl) -N⁴- (3, 5-difluorophenyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 427(M+H)⁺。

Example 34 the compound of this example was prepared by general scheme 34, listed below.

Scheme 34

Step 1: preparation of N²- (4, 4-difluorocyclohexyl) -N⁴- (3, 5-difluorophenyl) -6- (3-fluoro-6-hydrazinopyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. To N²- (4, 4-difluorocyclohexyl) -N⁴To a solution of (3, 5-difluorophenyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (225mg, 0.49mmol) in THF (20mL) was added hydrazine hydrate (150mg, 3.0 mmol). The reaction mixture was then stirred at 60 ℃ for 2.5 hours. After cooling to room temperature, the reaction mixture was diluted with DCM (20mL) and washed with brine (2 × 10 mL). Separating the organic phase with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give the desired product.

LC-MS:m/z 467(M+H)⁺。

Step 2: preparation of 6- (6-amino-3-fluoropyridin-2-yl) -N²- (4, 4-difluorocyclohexyl) -N⁴- (3, 5-difluorophenyl) -1,3, 5-triazine-2, 4-diamine. To N²- (4, 4-difluorocyclohexyl) -N⁴To a solution of (3, 5-difluorophenyl) -6- (3-fluoro-6-hydrazinopyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (46mg, 0.1mmol) in methanol (5.0mL) was added raney nickel (100 mg). At room temperature in H₂The mixture was stirred under ambient overnight. The resulting mixture was filtered and the filtrate was concentrated and purified by standard methods to obtain 6- (6-amino-3-fluoropyridin-2-yl) -N²- (4, 4-difluorocyclohexyl) -N⁴- (3, 5-difluorophenyl) -1,3, 5-triazine-2, 4-diamine.

¹H NMR(400MHz,CDCl₃)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/z 452(M+H)⁺。

Using the procedure set forth in example 34, the following compounds were prepared using the appropriate starting materials.

Compound 6- (6-amino-3-fluoropyridin-2-yl) -N²- (3, 3-difluorocyclopentyl) -N⁴- (3, 5-difluorophenyl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 438(M+H)⁺。

Example 35: preparation of N⁴,N⁶-bis (4, 4-difluorocyclohexyl) -2- (6- (trifluoromethyl) pyrazin-2-yl) pyrimidine-4, 6-diamine

Scheme 35

Step A: 6- (trifluoromethyl) pyrazine-2-carboxamide. To a solution of methyl 6- (trifluoromethyl) pyrazine-2-carboxylate (15g, 72.8mmol) in EtOH (20mL) was added NH₄OH (6mL, 156 mmol). The reaction mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure. By H₂The residue was triturated with O (10mL) and then filtered to obtain 6- (trifluoromethyl) pyrazine-2-carboxamide. LC-MS M/z 192(M + H)⁺。

And B: 6- (trifluoromethyl) pyrazine-2-carbonitrile. 6- (trifluoromethyl) pyrazine-2-carboxamide (10g, 52mmol) was stirred in POCl at 100 deg.C₃(80mL) overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between DCM and ice water. The organic layer was separated, washed with brine, and dried over anhydrous Na₂SO₄Dried, concentrated, and purified by standard methods to obtain 6- (trifluoromethyl) pyrazine-2-carbonitrile. LC-MS M/z 174(M + H)⁺。

And C: 6- (trifluoromethyl) pyrazine-2-carboxamidine hydrochloride. To 6- (trifluoromethyl) pyrazineTo a solution of-2-carbonitrile (3.4g, 15mmol) in MeOH (5mL) was added a solution of sodium metal (35mg, 1.5mmol) in MeOH. The reaction mixture was stirred at room temperature for 12 hours, followed by addition of NH₄Cl (1.5g, 30 mmol). The mixture was stirred at 70 ℃ for 3 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOH (10mL) and stirred at reflux for 0.5 h. The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, thereby obtaining 6- (trifluoromethyl) pyrazine-2-carboxamidine hydrochloride. LC-MS M/z 191(M + H)⁺。

Step D: 2- (6- (trifluoromethyl) pyrazin-2-yl) pyrimidine-4, 6(1H,5H) -dione. To a mixture of 6- (trifluoromethyl) pyrazine-2-carboxamidine hydrochloride (1.6g, 7.0mmol) in diethyl malonate (3.2g, 21.2mmol) was added potassium carbonate (3.0g, 21.2 mmol). The reaction mixture was stirred at 120 ℃ for 8 hours. The resulting mixture was cooled to room temperature and triturated with petroleum ether. The solid was collected by filtration, washed with petroleum ether, and then treated with MeOH to form a suspension. The suspension was filtered and the filtrate was concentrated under reduced pressure, thereby obtaining 2- (6- (trifluoromethyl) pyrazin-2-yl) pyrimidine-4, 6- (1H,5H) -dione. LC-MS M/z 259(M + H)⁺。

Step E: 4, 6-dichloro-2- (6- (trifluoromethyl) pyrazin-2-yl) pyrimidine. 2- (6- (trifluoromethyl) pyrazin-2-yl) pyrimidine-4, 6(1H,5H) -dione (1.4g, 5.4mmol) was stirred in POCl at 100 deg.C₃(10mL) the mixture was allowed to stand overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA ═ 20/1 to 10/1) to obtain 4, 6-dichloro-2- (6- (trifluoromethyl) pyrazin-2-yl) pyrimidine. LC-MS M/z 295(M + H)⁺。

Step F: n is a radical of⁴,N⁶-bis (4, 4-difluorocyclohexyl) -2- (6- (trifluoromethyl) pyrazin-2-yl) pyrimidine-4, 6-diamine. To a mixture of 4, 6-dichloro-2- (6- (trifluoromethyl) pyrazin-2-yl) pyrimidine (100mg, 0.34mmol), CsF (103mg, 0.68mmol), and 4, 4-difluorocyclohexylamine hydrochloride (116mg, 0.68mmol) in DMSO (1mL) was added DIPEA (220mg, 0.17 mmol). The reaction mixture was stirred at 80 ℃ under nitrogen for 4 hours and then at 150 ℃ under microwave irradiation for 6 hours. The resulting mixture was cooled to room temperature and quenched with waterAnd extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by standard methods to obtain N⁴,N⁶-bis (4, 4-difluorocyclohexyl) -2- (6- (trifluoromethyl) pyrazin-2-yl) pyrimidine-4, 6-diamine.

¹H NMR(400MHz,CDCl₃)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/z 493(M+H)⁺。

Example 36 preparation of aromatic-aliphatic triazine compounds. The compounds of this example were prepared by general scheme 36, listed below.

Scheme 36

Step 1: preparation of 1- (4-bromopyridin-2-yl) cyclopropanecarbonitrile. Below-10 ℃ to a solution of 4-bromo-2-fluoropyridine (30g, 170.47mmol) and cyclopropanecarbonitrile (22.9g, 340.94mmol) in THF (400mL) was slowly added LiHMDS (1.2mmol/L, 284mL) dropwise. The reaction mixture was then stirred at room temperature for 12 hours. The resulting mixture was cooled to 0 ℃ and then quenched with brine (200 mL). The mixture was concentrated under reduced pressure. The residue was extracted with EtOAc (3 × 200 mL). With anhydrous Na₂SO₄The combined layers were dried and concentrated and purified by standard methods to obtain the desired product. LC-MS M/z223(M + H)⁺。

Step 2: preparation of 1- (4- (diphenylmethyleneamino) pyridin-2-yl) cyclopropanecarbonitrile. To a solution of 1- (4-bromopyridin-2-yl) cyclopropanecarbonitrile (30g, 134.48mmol) and diphenylmethanimine (29.3g, 161.38mmol) in dioxane (150mL) were added t-BuONa (19.4g, 201.73mmol), Binap (5.0g, 8.1mmol) and Pd₂(dba)₃(2.5g, 2.69 mmol). In N₂Heating the mixture to 100 deg.C under an atmosphereFor 1 hour, then cooled and filtered. The filtrate was concentrated to give the desired product. LC-MS M/z 324(M + H)⁺。

And step 3: preparation of 1- (4-aminopyridin-2-yl) cyclopropanecarbonitrile. 1- (4- (diphenylmethyleneamino) pyridin-2-yl) cyclopropanecarbonitrile (42.1g crude, 130mmol) and THF/aqueous HCl (2N) (200mL, V: V ═ 2:1) were stirred at room temperature for 1 hour and concentrated under reduced pressure. The aqueous layer was extracted with PE (3 × 100mL) and then saturated aqueous Na₂CO₃Adjusted to pH 8-9 and extracted with EtOAc (3X100 mL). With anhydrous Na₂SO₄The combined organic layers were dried and concentrated and purified by standard methods to obtain the desired product.¹HNMR(CDCl₃)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)⁺。

And 4, step 4: preparation of 1- (4- (4, 6-dichloro-1, 3, 5-triazin-2-ylamino) pyridin-2-yl) cyclopropanecarbonitrile. To a solution of 1- (4-aminopyridin-2-yl) cyclopropanecarbonitrile (2.5g, 15.7mmol), 2,4, 6-trichloro-1, 3, 5-triazine (3.5g, 18.8mmol) in THF (40mL) was added NaHCO₃(2.64g, 31.4 mmol). The reaction mixture was stirred at room temperature overnight and then filtered. The filtrate was concentrated and purified by standard methods to obtain the desired product. LC-MS M/z 307(M + H)⁺。

And 5: preparation of 1- (4- (4-chloro-6- (3, 3-difluorocyclopentylamino) -1,3, 5-triazin-2-ylamino) pyridin-2-yl) cyclopropanecarbonitrile. To a solution of 1- (4- (4, 6-dichloro-1, 3, 5-triazin-2-ylamino) pyridin-2-yl) cyclopropanecarbonitrile (0.75g, 2.44mmol) and 3, 3-difluorocyclopentylamine hydrochloride (0.39g, 2.44mmol) in THF (10mL) at 0 deg.C was slowly added DIPEA (0.63g, 4.88mmol) dropwise. The reaction mixture was stirred at room temperature for 8 hours, and then concentrated under reduced pressure. The residue was partitioned between EtOAc (20mL) and HCl solution (10% wt, 3 mL). The aqueous layer was separated and extracted with EtOAc (2 × 5 mL). With anhydrous Na₂SO₄The combined organic layers were dried and concentrated and purified by standard methods to obtain the desired product. LC-MS M/z 392(M + H)⁺。

Step 6: preparation of 1- (4- (4- (3, 3-difluorocyclopentylamino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-ylamino) pyridin-2-yl) cyclopropanecarbonitrile. To a solution of 1- (4- (4-chloro-6- (3, 3-difluorocyclopentylamino) -1,3, 5-triazin-2-ylamino) pyridin-2-yl) cyclopropanecarbonitrile (0.6g, 1.53mmol) in DMF (600mL) was added 3- (trifluoromethyl) -1H-pyrazole (0.2g, 1.53mmol) and K₂CO₃(0.42g, 3.06 mmol). The mixture was stirred at 35 ℃ overnight and then concentrated under reduced pressure. The residue was dissolved in EtOAc (20mL) and then successively treated with 10% aqueous LiCl (2X 5mL), 5% HCl (2X 5mL) and saturated aqueous NaHCO₃(2X 5mL) wash. Separating the organic layer with anhydrous Na₂SO₄Dried, concentrated and purified by standard methods to obtain the desired product.¹H NMR(400MHz,CDCl₃)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/z 492(M+H)⁺。

The following compounds were prepared using the procedure set forth in example 36, using the appropriate starting materials.

The compound (S) -1- (4- (4- (3, 3-difluorocyclopentylamino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-ylamino) pyridin-2-yl) cyclopropanecarbonitrile.

¹H NMR(400MHz,CDCl₃)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/z 492(M+H)⁺。

The compound (R) -1- (4- (4- (3, 3-difluorocyclopentylamino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-ylamino) pyridin-2-yl) cyclopropanecarbonitrile.

¹H NMR(400MHz,CDCl₃)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/z 492(M+H)⁺。

The compound 1- (4- ((4- ((4, 4-difluorocyclohexyl) amino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 506(M+H)⁺。

The compound 1- (4- ((4- ((3, 3-difluorocyclobutyl) amino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 478(M+H)⁺。

The compound 1- (4- ((4- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -6- ((1,1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 484(M+H)⁺。

The compound (R) -1- (4- ((4- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -6- ((1,1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 484(M+H)⁺。

The compound (S) -1- (4- ((4- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -6- ((1,1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 484(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 495(M+H)⁺。

Compound (S) -N²- (3, 3-difluorocyclopentyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 495(M+H)⁺。

Compound N²- (3, 3-difluorocyclobutyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CD₃OD)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/z 481(M+H)⁺。

Compound N²- (cyclopropylmethyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 445(M+H)⁺。

Compound 6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N²- (2- (trifluoromethyl) pyridin-4-yl) -N⁴- (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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) -N²- (2- (trifluoromethyl) pyridin-4-yl) -N⁴- (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 487(M+H)⁺。

The compound (S) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N²- (2- (trifluoromethyl) pyridin-4-yl) -N⁴- (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 487(M+H)⁺。

The compound 3- ((4- ((3, 3-difluorocyclobutyl) amino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹H NMR(400MHz,CDCl₃)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/z 455(M+H)⁺。

The compound 3-fluoro-5- ((4- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -6- ((1,1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) benzonitrile

¹H NMR(400MHz,CDCl₃)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)⁺。

The compound 3- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹H NMR(400MHz,CDCl₃)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/z 469(M+H)⁺。

The compound 4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-yl) amino) pyridinecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 452(M+H)⁺。

The compound (S) -4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-yl) amino) pyridinecarbonitrile

¹H NMR(400MHz,DMSO-d₆)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/z 452(M+H)⁺。

The compound 4- ((4- ((3, 3-difluorocyclobutyl) amino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-yl) amino) pyridinecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 438(M+H)⁺。

The compound (R) -4- ((4- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -6- ((1,1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridinecarbonitrile

¹H NMR(400MHz,CDCl₃)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/z 444(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (3, 5-difluorophenyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 462(M+H)⁺。

Compound N²- (3, 3-difluorocyclobutyl) -N⁴- (3, 5-difluorophenyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 448(M+H)⁺。

Compound N²- (3, 5-difluorophenyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N⁴- (1,1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 454(M+H)⁺。

The compound 1- ((4- ((3, 5-difluorophenyl) amino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-yl) amino) -2-methylpropan-2-ol

¹H NMR(400MHz,CDCl₃)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/z 430(M+H)⁺。

Example 37 preparation of aromatic-aliphatic triazine compounds of formula Ic. The compound of this example was prepared by the general scheme 37 listed below.

Scheme 37

Step 1: preparation of 4, 6-dichloro-N- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazin-2-amine. To a solution of 2- (trifluoromethyl) pyridin-4-amine (3g, 18.7mmol) and 2,4, 6-trichloro-1, 3, 5-triazine (3.6g, 19.5mmol) in THF (40mL) was added NaHCO₃(3.1g, 37.5 mmol). The reaction mixture was stirred at room temperature for 16 hours and filtered. The filtrate was concentrated and purified by standard methods to obtain the desired product. LC-MS M/z 310(M + H)⁺。

Step 2: preparation of 6-chloro-N²- (3, 3-difluorocyclobutyl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine. To a solution of 4, 6-dichloro-N- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazin-2-amine (4g, 12.9mmol) and 3, 3-difluorocyclobutylamine hydrochloride (1.9g, 13.5mmol) in THF (40mL) was added DIPEA (4.8g, 37.2 mmol). The reaction mixture was stirred at room temperature for 15 hours and then concentrated under reduced pressure. The residue was partitioned between EtOAc (200mL) and aqueous HCl (10% wt, 50 mL). The aqueous layer was separated and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated and purified by standard methods to obtain the desired product.

LC-MS:m/z 381(M+H)⁺。

And step 3: preparation of 4- (3, 3-difluorocyclobutylamino) -6- (2- (trifluoromethyl) pyridin-4-ylamino) -1,3, 5-triazine-2-carbonitrile. At room temperature to 6-chloro-N²- (3, 3-difluorocyclobutyl) -N⁴To a solution of (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine (2.2g, 5.77mmol) in MeCN (30mL) and DMSO (10mL) was added NaCN (2.9g, 60 mmol). The reaction mixture was stirred at 60 ℃ overnight and then partitioned between EtOAc (50mL) and H₂Between O (20 mL). The organic layer was separated, washed with brine, and dried over anhydrous Na₂SO₄Dried, concentrated and purified by standard methods to obtain the desired product. LC-MS M/z 372(M + H)⁺。

And 4, step 4: preparation of 4- (3, 3-difluorocyclobutylamino) -6- (2- (trifluoromethyl) pyridin-4-ylamino) -1,3, 5-triazine-2-carbothioamide. To 4- (3, 3-difluorocyclobutylamino) -6- (2- (trifluoromethyl) pyridin-4-ylamino) -1,3, 5-triazine-2-carbonitrile (0.7g, 1.88 g)mmol) in DMF (15mL) was added NaHS (0.5g, 9.0mmol) and MgCl₂(0.85g, 9.0 mmol). The reaction mixture was stirred at room temperature for 0.5H, then partitioned between EtOAc (30mL) and H₂O (10 mL). The organic layer was separated, washed with brine, and dried over anhydrous Na₂SO₄Dried, concentrated and purified by standard methods to obtain the desired product. LC-MS M/z 406(M + H)⁺。

And 5: preparation of 2- (4- (3, 3-difluorocyclobutylamino) -6- (2- (trifluoromethyl) pyridin-4-ylamino) -1,3, 5-triazin-2-yl) -4- (trifluoromethyl) -4, 5-dihydrothiazol-4-ol. A mixture of 4- (3, 3-difluorocyclobutylamino) -6- (2- (trifluoromethyl) pyridin-4-ylamino) -1,3, 5-triazine-2-carbothioamide (350mg, 0.86mmol) and 3-bromo-1, 1, 1-trifluoropropan-2-one (180mg, 0.95mmol) in MeCN (10mL) was stirred at 60 ℃ for 2H and then partitioned between EtOAc (20mL) and H₂O (10 mL). The organic layer was separated, washed with brine, and dried over anhydrous Na₂SO₄Dried, concentrated and purified by standard methods to obtain the desired product.

¹H NMR(400MHz,DMSO-d₆)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/z 516(M+H)⁺。

Step 6: preparation of N²- (3, 3-difluorocyclobutyl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine. To a solution of 2- (4- (3, 3-difluorocyclobutylamino) -6- (2- (trifluoromethyl) pyridin-4-ylamino) -1,3, 5-triazin-2-yl) -4- (trifluoromethyl) -4, 5-dihydrothiazol-4-ol (250mg, 0.48mmol) and TEA (0.4mL, 2.4mmol) in DCM (20mL) was added dropwise a solution of triphosgene (290mg, 0.96mmol) in DCM (5mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 0.5H and then partitioned between DCM (20mL) and H₂O (10 mL). The organic layer was separated, washed with brine, and dried over anhydrous Na₂SO₄Dried, concentrated and purified by standard methods to obtain the desired product.¹H NMR(400MHz,DMSO-d₆)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/z 498(M+H)⁺。

Using the procedure set forth in example 37 above, the following compounds were prepared using the appropriate starting materials.

Compound N²- (cyclopropylmethyl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 462(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (2- (trifluoromethyl) pyridin-4-yl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,DMSO-d₆)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/z 512(M+H)⁺。

Compound N²- (3, 3-difluorocyclopentyl) -N⁴- (3, 5-difluorophenyl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 479(M+H)⁺。

Compound N²- (3, 3-difluorocyclobutyl) -N⁴- (3, 5-difluorophenyl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹H NMR(400MHz,CDCl₃)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/z 465(M+H)⁺。

The compound 3- ((4- ((3, 3-difluorocyclobutyl) amino) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹H NMR(400MHz,CDCl₃)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/z 472(M+H)⁺。

The compound 3- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹H NMR(400MHz,CDCl₃)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/z 486(M+H)⁺。

Example 38 preparation of a dialiphatic pyrimidine compound of formula S. The compounds of this example were prepared by general scheme 32, listed below.

Scheme 32

Step 1: preparation of methyl 6-chloropyridylmethanimidate. To a solution of 6-chloropyridine carbonitrile (3g, 22mmol) in MeOH (25mL) was added a fresh preparation of sodium metal (55mg, 2.4mol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 16 hours, and then concentrated under reduced pressure, thereby obtaining the desired product. LC-MS M/z 171(M + H)⁺。

Step 2: preparation of 6-chloropyridine carboxamidine. A mixture of ammonium chloride (2.18g, 40mmol) and methyl 6-chloropyridylmethylimidate (3.5g, 20mmol) in MeOH (30mL) was stirred at 70 deg.C for 3h, then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOH (40mL) and stirred at reflux for 0.5 h. The resulting mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to give the desired product. LC-MS M/z 156(M + H)⁺。

And step 3: preparation of 2- (6-chloropyridin-2-yl) pyrimidine-4, 6-diol. To a solution of sodium metal (0.9g, 40mmol) in MeOH (10mL) was added 6-chloropyridine amidine (2g, 13mmol) and dimethyl malonate (1.7g, 13 mmol). The reaction mixture was stirred at 85 ℃ overnight and then concentrated under reduced pressure. The residue was triturated with EtOAc (30mL) and filtered. The solid was collected and dried under high vacuum to give the desired product. LC-MS M/z 224(M + H)⁺。

And 4, step 4: preparation of 4, 6-dichloro-2- (6-chloropyridin-2-yl) pyrimidine. 2- (6-Chloropyridin-2-yl) pyrimidine-4, 6-diol (2g, 9mmol) was stirred in POCl at 90 deg.C₃(20mL) the mixture was left overnight and then concentrated under reduced pressure. The residue was slowly poured into saturated aqueous NaHCO at 0 deg.C₃In (1). The resulting mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with water (30mL) and brine (30mL), and dried over anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by standard methods to give the desired product. LC-MS M/z 260(M + H)⁺。

And 5: preparation of (R) -6-chloro-2- (6-chloropyridin-2-yl)) -N- (1,1, 1-trifluoroprop-2-yl) pyrimidin-4-amine. A mixture of 4, 6-dichloro-2- (6-chloropyridin-2-yl) pyrimidine (200mg, 0.77mmol), 1,1, 1-trifluoropropan-2-amine hydrochloride (255mg, 1.7mmol), CsF (258mg, 1.7mmol) and DIPEA (497mg, 3.85mmol) in DMSO (3mL) was stirred at 100 ℃ overnight. By H₂The resulting mixture was quenched with O (30mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (30mL) and anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by standard methods to give the desired product.¹H NMR(400MHz,DMSO-d₆)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/z 337(M+H)⁺。

Step 6: preparation of (R) -2- (6-chloropyridin-2-yl) -N⁴- (4, 4-difluorocyclohexyl) -N⁶- (1,1, 1-trifluoropropan-2-yl) pyrimidine-4, 6-diamine. A mixture of (R) -6-chloro-2- (6-chloropyridin-2-yl) -N- (1,1, 1-trifluoropropan-2-yl) pyrimidin-4-amine (100mg, 0.3mmol), 4-difluorocyclohexylamine hydrochloride (114mg, 0.66mmol), CsF (100mg, 0.66mmol) and DIPEA (194mg, 1.5mmol) in DMSO (3mL) was stirred at 100 ℃ overnight. By H₂The resulting mixture was quenched with O (30mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (30mL) and anhydrous Na₂SO₄Dried, concentrated, and purified by standard methods to obtain the desired product.

¹H NMR(400MHz,DMSO-d₆)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/z 436(M+H)⁺

Example 8 enzyme and cellular assays

In vitro assay for IDH1m (R132H or R132C) inhibitors

Experimental procedures that can be used to obtain the data in columns 2 and 4 of table 7 and column 2 of table 8 are described below.

In the primary reaction, the reduction of α -KG acid to 2-HG is accompanied by concomitant oxidation of NADPH to NADP. The amount of NADPH remaining at the end of the reaction time was measured in a diaphorase/resazurin secondary reaction, where NADPH was consumed in a 1:1 molar ratio and resazurin was converted to highly fluorescent resorufin. Reactions that were not inhibited exhibited low fluorescence at the end of the assay, whereas reactions in which NADPH was consumed by R132H IDH1 that had been inhibited by small molecules showed high fluorescence.

Primary reactions in 50. mu.L volumes of 1 Xbuffer (150mM NaCl, 20mM Tris 7.5, 10mM MgCl)₂0.05% (w/v) bovine serum albumin), which buffer contains 0.25. mu.g/mL (2.7nM) of IDH1wt/IDH1R132H heterodimer, 0.3mM α -ketoglutarate, 4. mu.M NADPH and either 300. mu.M NADP (saturated) or 30. mu.M NADP (unsaturated) and 1. mu.L 50X compound in DMSO. The mixture of compound, enzyme and cofactor was preincubated for 1 hour at room temperature, and then α -ketoglutaric acid was added. To perform the secondary reaction, 10. mu.L of 1 Xbuffer containing 36. mu.g/ml diaphorase and 30mM Resazurin was added to the primary reaction and incubated at 25 ℃ for an additional 5 minutes. Fluorescence was read on a Spectramax plate reader under Ex544 Em 590. Dilutions of one or more compounds were prepared in 100% DMSO concentration and diluted 1:50 to the final reaction. IDH1wt/IDH1R132C were assayed under similar conditions except that the 1 Xbuffer was 50mM K₂HPO₄，pH 6.5；10mM MgCl₂(ii) a 10% glycerol; 0.03% (w/v) bovine serum albumin and final concentration of 0.4. mu.g/mL (4.3nM) IDH1wt/IDH1R132C heterodimer, 0.02mM α -ketoglutarate, 4. mu.M NADPH, and either 300. mu.M NADP (saturated) or 30. mu.M NADP (unsaturated). IC50 was determined.

IDH1 or IDH2 wild type (wt) and mutant heterodimers were expressed and purified by methods known in the art. For example, IDH1wt/R132m heterodimer was expressed and purified as follows. Co-expression of IDH1wt-his and IDH1R 132C-tag was carried out in sf9 insect cells. The cells (25g) were resuspended at 4 ℃ in 250ml of 50mM Tirs, 500mM NaCl, pH 7.4 with stirring. Cells were disrupted 4 times by passing through an M-Y110 microfluidizer (Microfluidics) set to 500psiAnd then centrifuged at 22,000rcf at 4 ℃ for 20 minutes. The supernatant was collected and loaded at 15cm/h onto a histap FF 5 x 1ml column (GE) equilibrated with 50mM Tirs, 500mM NaCl, pH 7.4. Host cell contaminants were removed by washing the column sequentially with equilibration buffer containing 20mM imidazole and equilibration buffer containing 60mM imidazole to reach baseline. IDH1wt-his homodimer and IDH1wt-his/IDH1R 132C-tag were eluted by equilibration buffer containing 250mM imidazole. Fractions eluted by 250mM imidazole were pooled together and loaded at 15cm/h into 10mlM2 affinity gel (Sigma) pre-filled column, the column with 50mM Tris, 500mM NaCl, pH 7.4 balance. After washing with equilibration buffer, IDH1wt-his/IDH1R 132C-tag heterodimer was eluted by equilibration buffer containing tag peptide (0.2 mg/ml). Flash freezing aliquots of IDH1wt-his/IDH1R 132C-tag in liquid N₂Neutralized and stored at-80 ℃. The same conditions were used to purify IDH1wt-his/IDH1R 132H-tag.

In vitro assay for IDH1m (R132H or R132C) inhibitors

The experimental procedures that can be used to obtain the data on columns 3 and 6 of table 7 are described below.

Test compounds were prepared in DMSO as 10mM stock and diluted to 50X final concentration in DMSO to give 50 μ l reaction mixture. An NADPH depletion assay was used to measure IDH enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. In this assay, at the end of the reaction, the remaining cofactors are measured by adding a catalytic excess of diaphorase and resazurin to produce a fluorescent signal proportional to the amount of NADPH remaining. In 40. mu.l assay buffer (150mM NaCl, 20mM Tris-Cl pH7.5, 10mM MgCl)₂0.05% BSA, 2mM β -mercaptoethanol) IDH1-R132 homodimer enzyme was diluted to 0.125 μ g/ml; add 1 μ l of test compound dilution in DMSO and incubate the mixture at room temperature for 60 minutes. The reaction was started with the addition of 10. mu.l of substrate mix (20. mu.l NADPH, 5 mM. alpha. -ketoglutarate in assay buffer)And the mixture was incubated at room temperature for 90 minutes. The reaction was stopped by adding 25 μ l of detection buffer (36 μ g/ml diaphorase, 30mM resazurin, in 1X assay buffer) and incubated for 1 min before reading at Ex544/Em590 on a SpectraMax plate reader.

The activity of these compounds against IDH1R132C was determined following the same assay as above but with the following modifications: the assay buffer was (50mM potassium phosphate, pH 6.5; 40mM sodium carbonate, 5mM MgCl)₂10% glycerol, 2mM beta-mercaptoethanol, and 0.03% BSA). The concentration of NADPH and alpha-ketoglutarate in the substrate buffer was 20. mu.M and 1mM, respectively.

In vitro assay for IDH1m (R132H or R132C) inhibitors

The experimental procedures that can be used to obtain the data on columns 3 and 5 of table 8 are described below.

Test compounds were prepared in DMSO as 10mM stock and diluted to 50X final concentration in DMSO to give 50 μ l reaction mixture. An NADPH depletion assay was used to measure IDH enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. In this assay, at the end of the reaction, the remaining cofactors are measured by adding a catalytic excess of diaphorase and resazurin to produce a fluorescent signal proportional to the amount of NADPH remaining. In 40. mu.l assay buffer (150mM NaCl, 20mM Tris-Cl pH7.5, 10mM MgCl) containing 5. mu.M NADPH and 37.5. mu.M NADP₂0.05% BSA, 2mM β -mercaptoethanol) IDH1-R132H homodimer enzyme was diluted to 0.125 μ g/ml; add 1 μ l of test compound dilution in DMSO and incubate the mixture at room temperature for 60 minutes. The reaction was started with the addition of 10 μ Ι substrate mix (20 μ Ι NADPH, 5mM α -ketoglutarate in assay buffer) and the mixture was incubated for 60 min at room temperature. The reaction was stopped by adding 25 μ l of detection buffer (36 μ g/ml diaphorase, 30mM resazurin, in 1X assay buffer) and incubated for 1 min before reading at Ex544/Em590 on a SpectraMax plate reader.

The activity of these compounds against IDH1R132C was determined following the same assay as above but with the following modifications: in 40. mu.l of assay buffer (50mM potassium phosphate, pH) containing 5. mu.M NADPH and 28.75. mu.M NADP6.5; 40mM sodium carbonate, 5mM MgCl₂10% glycerol, 2mM β -mercaptoethanol and 0.03% BSA) IDH1-R132C homodimer enzyme was diluted to 0.1875 μ g/ml. The concentration of alpha-ketoglutarate in the substrate buffer was 1 mM.

In vitro assay for IDH2m R140Q inhibitors

The experimental procedures that can be used to obtain the data on column 7 of table 7 are described below.

IDH2R140Q inhibitory activity of these compounds was determined by a cofactor depletion assay. The compound was preincubated with the enzyme, then the reaction was started by adding NADPH and a-KG and allowed to proceed for 60 minutes under conditions previously demonstrated to be linear with respect to the consumption time of both cofactor and substrate. The reaction was stopped by the addition of the second enzyme diaphorase and the corresponding substrate resazurin. Diaphorase reduces resazurin to highly fluorescent resorufin and NADPH is concomitantly oxidized to NADP, both interrupting the IDH2 reaction by depleting the pool of available cofactors and facilitating the quantitative production by readily detectable fluorophores, quantifying the amount of cofactor remaining after a specific period of time.

Specifically, to each of 12 wells of the 384-well plate, 1. mu.l of a 100 Xdilution series of the compound was placed, followed by addition of 40. mu.l of a buffer (50mM potassium phosphate (K) containing 0.25. mu.g/ml IDH2R140Q protein₂HPO₄)，pH 7.5；150mM NaCl；10mM MgCl₂10% glycerol, 0.05% bovine serum albumin, 2mM β -mercaptoethanol). The test compounds were then incubated with the enzyme for one hour at room temperature; the IDH2 reaction was then started by adding 10. mu.l of a substrate mixture containing 4. mu.M NADPH and 1.6mM α -KG in the buffer described above. After an additional 16 hours incubation at room temperature, the reaction was interrupted and the remaining NADPH was measured by converting Resazurin to resorufin by adding 25. mu.l of the stop mix (36. mu.g/ml diaphorase and 60. mu.M Resazurin; in buffer). After one minute of incubation, the plates were read on a plate reader under Ex544/Em 590.

To determine the inhibitory potency of these compounds against IDH2R140Q in a similar assay format as above, an analogous procedure was performed except that the final test concentrate was 0.25 μ g/ml IDH2R140Q protein, 4 μ M NADPH and 1.6mM α -KG.

To determine the inhibitory potency of these compounds against IDH2R140Q in a high throughput screening format, an analogous procedure was performed except that 0.25 μ g/ml IDH2R140Q protein was used in the pre-incubation step and the reaction was started with the addition of 4 μ M nadph and 8 μ M α -KG.

In vitro assay for IDH2m R140Q inhibitors

The experimental procedures that can be used to obtain the data on column 6 of table 8 are described below.

IDH2R140Q inhibitory activity of these compounds was determined by a cofactor depletion assay. These compounds were preincubated with enzyme and cofactor, then the reaction was started by addition of α -KG and allowed to proceed for 60 minutes under conditions previously demonstrated to be linear. The reaction was stopped by the addition of the second enzyme diaphorase and the corresponding substrate resazurin. Diaphorase reduces resazurin to highly fluorescent resorufin and NADPH is concomitantly oxidized to NADP, both interrupting the IDH2 reaction by depleting the pool of available cofactors and facilitating the quantitative production by readily detectable fluorophores, quantifying the amount of cofactor remaining after a specific period of time.

Specifically, to each of 12 wells of the 384-well plate, 1. mu.l of a 50 Xcompound dilution series was placed, followed by addition of 40. mu.l of a buffer (50mM potassium phosphate (K.K.) containing 0.39. mu.g/ml of IDH2R140Q protein, 5. mu.M NADPH, and 750. mu.M NADP₂HPO₄)，pH 7.5；150mM NaCl；10mM MgCl₂10% glycerol, 0.05% bovine serum albumin, 2mM β -mercaptoethanol). The test compound was then incubated with the enzyme and cofactor at room temperature for 16 hours, after which the IDH2 reaction was started by adding 10 μ l of substrate mixture containing 8mM α -KG (final concentration 1.6mM) in the buffer described above. After an additional 1 hour incubation at room temperature, the reaction was interrupted and the remaining NADPH was measured by converting Resazurin to resorufin by adding 25. mu.l of stop mix (36. mu.g/ml diaphorase and 60. mu.M Resazurin; in buffer). After one minute of incubation, the plates were read on a plate reader under Ex544/Em 590.

Cellular assays for IDH1m (R132H or R132C) inhibitors

The experimental procedures that can be used to obtain the data on column 5 of table 7 are described below.

Cells (HT1080 or U87MG) were grown in T125 flasks in DMEM containing 10% FBS, 1x penicillin/streptomycin, and 500 μ G/mL G418 (present only in U87MG cells). They were collected by trypsin and seeded at a density of 5000 cells/well in 100 μ L/well DMEM containing 10% FBS in a 96-well white bottom plate. No cells were placed in columns 1 and 12. At 37 ℃ in 5% CO₂The cells were incubated overnight. The next day, 2x final concentration of test compound was made and 100 μ l was added to each cell well. The final concentration of DMSO was 0.2% and DMSO control wells were coated in row G. The plates were then placed in an incubator for 48 hours. At 48 hours, 100. mu.l of medium was removed from each well and analyzed for 2-HG concentration by LC-MS. The cell plate was returned to the incubator for an additional 24 hours. 72 hours after compound addition, 10 mL/plate of Promega Cell Titer Glo reagent was thawed and mixed. The cell plates were removed from the incubator and allowed to equilibrate to room temperature. Then 100. mu.l of Promega Cell Titer Glo reagent was added to the medium in each well. The cell plate was then placed on an orbital shaker for 10 minutes and then allowed to stand at room temperature for 20 minutes. The plate is then read for luminescence over a 500ms integration time.

Assays based on U87MG pLVX-IDH2R140Q-neo and HT1080 cells

The experimental procedure used to obtain the data on column 8 of table 7 is described below.

U87MG pLVX-IDH2R140Q-neo cells were maintained in DMEM containing 10% FBS, 1 Xpenicillin/streptomycin, and 500. mu.g/. mu. L G418. HT1080 cells were maintained in RPMI with 10% FBS, 1x penicillin/streptomycin. Cells were seeded in 96-well microtiter plates at a density of 5,000(U87MG R140Q) or 2,500(HT1080) cells/well and incubated at 37 ℃ and 5% CO₂Incubate overnight. The next day, compounds were prepared in 100% DMSO and then diluted in culture medium to obtain a final concentration of 0.2% DMSO. Media was removed from the cell plate and 200 μ L of compound dilution was added to each well. After incubating the compounds at 37 ℃ for 48 hours, from each well100 μ L of medium was removed and the 2-HG concentration was analyzed by LC-MS as described in Dange, L. (Dang, L.) et al, Nature, 2009,462, 739-. The cell plates were then allowed to incubate for an additional 24 hours. 72 hours after compound addition, Promega Cell Titer Glo reagent was added to each well and the luminescence of these plates was read to determine the effect of any compound on Growth Inhibition (GI)₅₀)。

Cellular assays for IDH1m R132H inhibitors.

The experimental procedure that can be used to obtain the data on column 4 of table 8 is described below.

Neurosphere cells (TS603) were incubated at 37 ℃ in 5% CO₂In a stem cell technology neuroCult supplemented with 1% Primocin, 1% Normocin, 0.0002% heparin, 20ng/mL EGF and 10ng/mL bFGF^TMNS-A medium. Cells were collected, pelleted and resuspended in Ames (Accumax) for cell dissociation and counting. Cells were counted and then resuspended in NeuroCult media containing 2x heparin, EGF and bFGF at 4 million cells per 10mL of media. 100. mu.l of the cell solution was plated in each well except for column 1 and column 12 among 96 wells. Columns 1 and 12 contained 200 μ L PBS. Compound dose responses were established at 2x concentration in Neurocult medium without heparin, EGF and bFGF. The final concentration of DMSO was 0.25%. Control wells of DMSO only were coated in row H. The plates were then placed in an incubator for 48 hours. At 48 hours, 100. mu.l of medium was removed from each well and analyzed for 2-HG concentration by LC-MS. The cell plate was returned to the incubator for an additional 24 hours. 72 hours after compound addition, thaw and mix with 10 mL/plate of Promega Cell Titer Glo reagent. The cell plates were removed from the incubator and allowed to equilibrate to room temperature. Then 100. mu.l of Promega Cell Titer Glo reagent was added to the medium in each well. The cell plate was then placed on an orbital shaker for 10 minutes and then allowed to stand at room temperature for 20 minutes. The plate is then read for luminescence over a 500ms integration time.

Data for different compounds of one aspect of the invention in the R132H, R132C, R140Q, R132C and R140Q cell based or similar assays as described above are presented in tables 7 and 8 below. For each assay, values indicated as "a" represent an IC50 of less than 50 nM; values indicated as "B" represent IC50 between 50nM and 100 nM; values indicated as "C" represent IC50 greater than 100nM and less than 1 μ Μ; the value indicated as "D" represents an IC50 of greater than or equal to 1 μ Μ; the value indicated as "not suitable" is inactive and the blank value indicates that the compound is either inactive or not tested in the particular assay.

TABLE 7 inhibitory Activity of representative Compounds of formula I

TABLE 8 inhibitory Activity of representative Compounds of formula I

Having thus described several aspects of several embodiments of the present invention, it is to be appreciated various alterations, modifications, and improvements will readily occur to those skilled in the art. Such alterations, modifications, and improvements are intended to be part of this disclosure, and are intended to be within the spirit and scope of the invention. Accordingly, the foregoing description is by way of example only.

Claims

1. A compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein:

ring A is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, and thiazolyl, wherein ring A is optionally substituted with up to two substituents independently selected from halo, -C₁-C₄Alkyl, -C₁-C₄Haloalkyl, -C₁-C₄Hydroxyalkyl, -NH-S (O)₂-(C₁-C₄Alkyl), -S (O)₂NH(C₁-C₄Alkyl), -CN, -S (O)₂-(C₁-C₄Alkyl group), C₁-C₄Alkoxy, -NH (C)₁-C₄Alkyl), -OH, -OCF₃、-CN、-NH₂、-C(O)NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) -N (C)₁-C₄Alkyl radical)₂And cyclopropyl optionally substituted with OH;

R¹、R³、R⁴and R⁶Each independently selected from hydrogen and C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -O-C₁-C₄Alkyl and CN, wherein R¹、R³、R⁴And R⁶Each of said alkyl moieties of (a) is independently optionally substituted by-O-C₁-C₄Alkyl substitution;

R²and R⁵Each independently selected from: - (C)₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₂-C₆Alkenyl or C₂-C₆Alkynyl), - (C)₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₁-C₆Alkyl) and- (C)₀-C₆Alkylene) -C (O) - (C)₁-C₆Alkyl), wherein:

R⁷and R⁸Each independently is hydrogen;

R¹and R²Optionally together form C₃-C₁₂Cycloalkyl optionally substituted with up to 3 substituents independently selected from halo, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN, ═ O, -OH, phenyl, heteroaryl, -SO₂C₁-C₄Alkyl, -CO₂C₁-C₄Alkyl, -C (O) phenyl and-C (O) C₁-C₄An alkyl group; or

R⁴And R⁵Optionally together form C₃-C₁₂Cycloalkyl optionally substituted with up to 3 substituents independently selected from halo, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN, ═ O, -OH, phenyl, heteroaryl, -SO₂C₁-C₄Alkyl, -CO₂C₁-C₄Alkyl, -C (O) phenyl and-C (O) C₁-C₄An alkyl group;

wherein

"alkyl" refers to a fully saturated hydrocarbon chain, which may be straight or branched;

"haloalkyl" refers to an alkyl group wherein one or more hydrogen atoms are replaced with halo;

"alkylene" refers to a divalent alkyl group;

"alkenyl" refers to a straight or branched hydrocarbon chain having one or more double bonds, wherein one of the double bond carbons may optionally be the point of attachment of an alkenyl substituent;

"alkynyl" refers to a straight or branched hydrocarbon chain characterized by one or more triple bonds, wherein one of the triple bond carbons may optionally be the point of attachment of an alkynyl substituent;

"cycloalkyl" refers to a saturated cyclic, bicyclic, or tricyclic hydrocarbon group having 3 to 12 carbons;

"heteroaryl" refers to a fully aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N or S or oxidized forms thereof, and said oxidized forms selected from N⁺-O-, S (O) and S (O)₂；

"Heterocyclyl" refers to a non-aromatic 3-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N or S or oxidized forms thereof, and said oxidized forms selected from N, N or oxidized forms thereof⁺-O-, S (O) and S (O)₂Wherein the heteroatom may optionally be the point of attachment of a heterocyclyl substituent;

wherein:

(i) when A is phenyl optionally substituted as described above, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Different;

(ii) when A is pyridyl optionally substituted as described above, then (A) N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not NHCH₂CH₂OH or NH-cyclohexyl; and (B) when N (R)⁷)C(R⁴)(R⁵)(R⁶) Is NHC (CH)₃)₃Then N (R)⁸)C(R¹)(R²)(R³) Is not NH-CH₂CH₃；

(iii) When A is an optionally substituted heteroaryl group as described above selected from pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl or thiazolyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both not NHCH₂CH₂-isopropyl, or NHCH₂CH(CH₃)₂；

(iv) When A is 1-pyrazolyl optionally substituted as described above, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Neither is NH isopropyl nor NHCH₂CH₃，

(v) When A is substituted 1-pyrazolyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Both are not NHC (CH)₃)₃(ii) a And

(vi) the compound is not

N²-isopropyl-6-phenyl-N4- (tetrahydro-2H-pyran-4-yl) -1,3, 5-triazine-2, 4-diamine.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a is optionally halogen or C₁-C₄Haloalkyl substituted pyridyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a is

Wherein R is⁹Selected from hydrogen, halo and-C₁-C₄A haloalkyl group.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹And R²Together, and R⁴And R⁵Together, each form:

wherein ring C is phenyl, pyridyl or pyrimidinyl, which phenyl, pyridyl or pyrimidinyl is unsubstituted or substituted by cyano or halo.

5. A compound of formula (B), or a pharmaceutically acceptable salt thereof, wherein:

x is N, CH or C-halo;

R⁹Is halo, -C₁-C₄Alkyl or-C₁-C₄A haloalkyl group;

each R^9aIndependently selected from hydrogen, halo, -C₁-C₄Alkyl and-C₁-C₄A haloalkyl group;

R²and R⁵Each independently selected from: - (C)₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₂-C₆Alkenyl or C₂-C₆Alkynyl), - (C)₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), - (C)₀-C₆Alkylene) -C (O) N (R)⁶)-(C₁-C₆Alkyl), - (C)₀-C₆Alkylene) -Q and- (C)₀-C₆Alkylene) -C (O) - (C)₁-C₆Alkyl), wherein:

R⁷and R⁸Each is hydrogen; and is

Q is selected from C₃-C₁₂Cycloalkyl and heterocyclyl, any of which is optionally substituted with up to 3 halo; wherein

R¹And R²Optionally together form C₃-C₁₂Cycloalkyl or heterocyclyl, wherein said cycloalkyl or heterocyclyl is optionally substituted with up to 3 substituents independently selected from the group consisting of: halogen radical, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN, ═ O, -OH, phenyl, heteroaryl, -SO₂C₁-C₄Alkyl, -CO₂C₁-C₄Alkyl, -C (O) phenyl and-C (O) C₁-C₄An alkyl group; or

R⁴And R⁵Optionally together form C₃-C₁₂Cycloalkyl or heterocyclyl, wherein said cycloalkyl or heterocyclyl is optionally substituted with up to 3 substituents independently selected from the group consisting of: halogen radical, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN, ═ O, -OH, phenyl, heteroaryl, -SO₂C₁-C₄Alkyl, -CO₂C₁-C₄Alkyl, -C (O) phenyl and-C (O))C₁-C₄An alkyl group;

wherein

"alkylene" refers to a divalent alkyl group;

"Heterocyclyl" refers to a non-aromatic 3-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N or S or oxidized forms thereof, and said oxidized forms selected from N, N or oxidized forms thereof⁺-O-, S (O) and S (O)₂Wherein the heteroatom may optionally be the point of attachment of a heterocyclyl substituent; and

wherein the compound is not a compound selected from the group consisting of:

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

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

6. As in claimA compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R⁴And R⁵Optionally together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuryl, tetrahydropyranyl, oxetanyl, bicyclo [2.2.1]Heptyl, oxo-bicyclo [3.1.0]Hexyl or azetidinyl, either of which is optionally substituted with up to 2 substituents independently selected from C₁-C₄Alkyl radical, C₁-C₄Alkoxy, -OH, -C (O) CH₃Fluorine and chlorine.

7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein X is N.

8. A compound of formula (C), or a pharmaceutically acceptable salt thereof, wherein:

x is N, CH or C-halo;

each X^bIndependently is N-R^9bO, S, C-H or C-R^9cWith the proviso that at least one X^bIs C-R^9cAnd when an X is present^bIs C-H or C-R^9cAnd the other is C-R^9cThen X^cIs N; and when an X^bIs N-R^9bO or S, then X^cIs C;

R^9bis hydrogen or-C₁-C₄An alkyl group;

R^9cis halo, -C₁-C₄Alkyl, -C₁-C₄Haloalkyl, -C₁-C₄Hydroxyalkyl, -NH-S (O)₂-(C₁-C₄Alkyl), -S (O)₂NH(C₁-C₄Alkyl), -CN, -S (O)₂-(C₁-C₄Alkyl group), C₁-C₄Alkoxy, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-OH、-OCF₃、-CN、-NH₂、-C(O)NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) -N (C)₁-C₄Alkyl radical)₂、-(C₁-C₆Alkylene) -O- (C)₁-C₆Alkyl), phenyl and cyclopropyl optionally substituted with OH;

R²and R⁵Each independently selected from: - (C)₁-C₆Alkyl), - (C)₁-C₆Alkyl) -C (O) -NH₂、-(C₀-C₆Alkylene) -Q and- (C)₀-C₆Alkylene) -C (O) - (C)₁-C₆Alkyl), wherein:

R⁷and R⁸Each is hydrogen; and is

R¹And R²Optionally together form C₃-C₁₂Cycloalkyl or heterocyclyl, wherein said cycloalkyl or heterocyclyl is optionally substituted up to3 substituents independently selected from: halogen radical, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN, ═ O, -OH, phenyl, heteroaryl, -SO₂C₁-C₄Alkyl, -CO₂C₁-C₄Alkyl, -C (O) phenyl and-C (O) C₁-C₄An alkyl group; or

R⁴And R⁵Optionally together form C₃-C₁₂Cycloalkyl or heterocyclyl, wherein said cycloalkyl or heterocyclyl is optionally substituted with up to 3 substituents independently selected from the group consisting of: halogen radical, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN, ═ O, -OH, phenyl, heteroaryl, -SO₂C₁-C₄Alkyl, -CO₂C₁-C₄Alkyl, -C (O) phenyl and-C (O) C₁-C₄An alkyl group;

wherein

"alkylene" refers to a divalent alkyl group;

"Heterocyclyl" means a non-aromatic 3-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N or S or oxidized forms thereof, and saidOxidized form is selected from N⁺-O-, S (O) and S (O)₂Wherein the heteroatom may optionally be the point of attachment of a heterocyclyl substituent; and

wherein:

(i) when X is CH and said

When the ring is optionally substituted 1-pyrazolyl, then N (R)⁷)C(R⁴)(R⁵)(R⁶) And N (R)⁸)C(R¹)(R²)(R³) Are not NHCH₂CH₂OH。

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein:

R^9cis halo, -OH, CN, -NH₂、-O-C₁-C₄Alkyl, -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl radical)₂、-C₁-C₄Alkyl, -C₁-C₄Haloalkyl and- (C)₁-C₆Alkylene) -O- (C)₁-C₆Alkyl groups);

R¹and R⁴Each is hydrogen;

R³and R⁶Each independently selected from C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, -O-C₁-C₄Alkyl and CN; and is

R²And R⁵Each is- (C)₁-C₆Alkyl), wherein:

present in R²And R⁵The alkyl moiety of (A) is optionally substituted with one or more-OH, -O (C)₁-C₄Alkyl), -CO₂H or halo; and is present in R²And R⁵Any terminal methyl moiety in (a) is optionally substituted with-CH₂OH、CF₃、-CH₂F、-CH₂Cl、C(O)CH₃、C(O)CF₃CN or CO₂And (4) replacing H.

10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R¹And R⁴Each independently selected from C₁-C₄Alkyl and C₁-C₄Haloalkyl, and R²And R⁵Each is- (C)₁-C₆Alkyl groups).

11. The compound of claim 1, 5 or 8, or a pharmaceutically acceptable salt thereof, wherein R³And R⁶Are both hydrogen, R¹And R⁴Each independently selected from C₁-C₄Alkyl and C₁-C₄Haloalkyl, and R²And R⁵Each is- (C)₁-C₆Alkyl groups).

12. A compound of formula (Ig) or a pharmaceutically acceptable salt thereof, wherein:

ring a is phenyl or 5-6 membered monocyclic heteroaryl, which phenyl or 5-6 membered monocyclic heteroaryl is substituted with 0-2 of the following substituents: halo, -C₁-C₄Alkyl, -C₁-C₄Haloalkyl, -C₁-C₄Hydroxyalkyl, -NH-S (O)₂-(C₁-C₄Alkyl), -S (O)₂NH(C₁-C₄Alkyl), -S (O)₂-(C₁-C₄Alkyl group), C₁-C₄Alkoxy, -NH (C)₁-C₄Alkyl), -OH, -OCF₃、-CN、-NH₂、-C(O)NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) -N (C)₁-C₄Alkyl radical)₂Azetidinyl, phenyl and cyclopropyl substituted with 0-1 OH;

R³and R⁶Are both hydrogen;

R²And R⁵Each is- (C)₁-C₆Alkyl groups); or

R¹And R²Optionally together forming a single ring C₃-C₁₂Cycloalkyl substituted with 0-3 substituents independently selected from the group consisting of: halogen radical, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN, ═ O, -OH and-C (O) C₁-C₄An alkyl group; or

R⁴And R⁵Optionally together forming a single ring C₃-C₁₂Cycloalkyl substituted with 0-3 substituents independently selected from the group consisting of: halogen radical, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Alkoxy, -CN, ═ O, -OH and-C (O) C₁-C₄An alkyl group;

wherein

"monocyclic cycloalkyl" refers to a monocyclic non-aromatic hydrocarbon ring system;

"monocyclic heteroaryl" means a monocyclic fully aromatic ring system having 1-3 heteroatoms, optionally substituted by one or more substituents which do not form a fused bicyclic or tricyclic ring, said heteroatoms being selected from O, N or S or oxidized forms thereof, and said oxidized forms being selected from N⁺-O-, S (O) and S (O)₂(ii) a And

wherein:

(i) ring A is not triazolyl, 3, 5-dimethyl-1H-pyrazol-1-yl, which is substituted as described above,

(iii) The compound is not a compound selected from the group consisting of:

(2) N2, N4-bis (1-methylpropyl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein ring a is pyridyl, which is substituted with 0-2 of the following substituents: halo, -C₁-C₄Alkyl, -C₁-C₄Haloalkyl, -C₁-C₄Hydroxyalkyl, -NH-S (O)₂-(C₁-C₄Alkyl), -S (O)₂NH(C₁-C₄Alkyl), -S (O)₂-(C₁-C₄Alkyl group), C₁-C₄Alkoxy, -NH (C)₁-C₄Alkyl), -OH, -OCF₃、-CN、-NH₂、-C(O)NH₂、-C(O)NH(C₁-C₄Alkyl), -C (O) -N (C)₁-C₄Alkyl radical)₂Azetidinyl, phenyl and cyclopropyl substituted with 0-1 OH.

14. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

15. the compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure:

16. the compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure:

17. the compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure:

18. the compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure:

19. the compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure:

20. the compound of claim 14, or a pharmaceutically acceptable salt thereof, having the structure:

21. the compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure:

22. the compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure:

23. the compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure:

24. the compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure:

25. a pharmaceutical composition comprising a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. The pharmaceutical composition of claim 25, further comprising a second therapeutic agent useful in the treatment of cancer.

27. Use of the compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 25 or 26, in the manufacture of a medicament for treating a cancer characterized by the presence of the IDH1 mutation, wherein the IDH1 mutation contributes to the enzyme's ability to catalyze NADPH-dependent reduction of α -ketoglutarate to R (-) -2-hydroxyglutarate.

28. The use of claim 27, wherein the IDH1 mutation is an IDH1R132H or R132C mutation.

29. The use of claim 27, wherein the cancer is selected from glioma, acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer, cholangiocarcinoma, myelodysplastic syndrome, myeloproliferative neoplasms, colon cancer, and angioimmunoblastic non-hodgkin's lymphoma.

30. The use of claim 29, wherein the cancer is glioma.

31. The use of claim 29, wherein the cancer is chondrosarcoma.