CN111087353B

CN111087353B - Therapeutically active compounds and methods of use thereof

Info

Publication number: CN111087353B
Application number: CN201911272201.6A
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: Laboratoires Servier SAS
Current assignee: Laboratoires Servier SAS
Priority date: 2013-07-11
Filing date: 2014-07-10
Publication date: 2023-10-24
Anticipated expiration: 2034-07-10
Also published as: CN105473560A; CN105473560B; CN111087353A

Abstract

Compounds for use in the treatment of cancer and methods of treating cancer are provided, which methods comprise administering to a subject in need thereof a compound described herein. Methods of preparing the compounds are also provided.

Description

Therapeutically active compounds and methods of use thereof

The application is a divisional application of Chinese patent application (application date is 2014, 7, 10, application number is 201480046845.2, PCT application number is PCT/CN 2014/081957) with the name of 'therapeutically active compound and using method'.

Priority claim

The present application claims priority from international application serial number PCT/CN2013/079200 filed on 7/11 in 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., α -ketoglutarate). These enzymes belong to two different subclasses, one of which utilizes NAD (+) as an electron acceptor and the other of which utilizes NADP (+) as an electron acceptor. Five isocitrate dehydrogenases have been reported: three NAD (+) dependent isocitrate dehydrogenases located in the mitochondrial matrix; and two NADP (+) dependent isocitrate dehydrogenases, one of which is mitochondrial and the other of which is predominantly cytoplasmic. Each NADP (+) dependent isozyme is a homodimer.

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

The human IDH1 gene encodes a protein having 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 sequences of IDH1 are also described in each of the following: for example, kluy Tan Ke (Nekrutenko et al, mol. Biol. Evol.) 15:1674-1684 (1998); ji Sibu Lei Xite (Geisbrecht et al, J.Biol.chem.) 274:305730533 (1999); wieman (Wiemann) et al, genome research (Genome Res.) 11:422-435 (2001); MGC project group, genome research 14:2121-2127 (2004); lu Beike (Lubec) et al, submitted (month 12 of 2008) to the UniProt knowledge base; kullmann et al, filed (6 th 1996) to the EMBL/GenBank/DDBJ database; and cord Qiao Bulong (Sjoeblm) et al, science 314:268-274 (2006).

Non-mutant (e.g., wild-type) IDH1 catalyzes oxidative decarboxylation of isocitrate to alpha-ketoglutarate, thereby rendering NAD ⁺ (NADP ⁺ ) Reduction to NADH (NADPH), for example in the following positive reactions: isocitrate+NAD ⁺ (NADP ⁺ )→α-KG+CO ₂ +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 formation and progression of cancer (Dang, L) et al, nature 2009, 462:739-44).

IDH2 (isocitrate dehydrogenase 2 (nadp+), mitochondrial) is also known as IDH; IDP; IDHM; IDPM; ICD-M; or mNAP-IDH. The protein encoded by this gene is an NADP (+) dependent isocitrate dehydrogenase found in mitochondria. It plays a role in intermediary metabolism and productivity. Such proteins may tightly bind or interact 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 sequences of human IDH2 are also described in each of the following: for example, ha (Huh) et al, filed (month 11 1992) to the EMBL/GenBank/DDBJ database; and MGC project group, genome research 14:2121-2127 (2004).

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

isocitrate+NAD ⁺ (NADP ⁺ )→α-KG+CO ₂ +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 is not formed by wild-type IDH 2. The production of 2HG is thought to promote the formation and progression of cancer (Dang, 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 with novel alpha hydroxy 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;

R ¹ 、R ³ 、R ⁴ and R is ⁶ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, -O-C ₁ -C ₄ Alkyl and CN, wherein R ¹ 、R ³ 、R ⁴ And R is ⁶ Each of said alkyl moieties independently being optionally substituted with-OH, -NH ₂ 、-CN、-O-C ₁ -C ₄ Alkyl, -NH (C) ₁ -C ₄ Alkyl) or-N (C) ₁ -C ₄ Alkyl group ₂ Substitution;

R ² and R is ⁵ Each independently selected from: - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₁ -C ₆ Alkyl) -CO ₂ H、-(C ₂ -C ₆ Alkenyl or alkynyl) - (C) ₁ -C ₆ Alkylene) -N (R) ⁶ )-(C ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -N (R) ⁶ )-(C ₀ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -N (R) ⁶ )(R ⁶ )、-(C ₁ -C ₆ Alkylene) -N (R) ⁶ )-S(O) _1-2 -(C ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -N (R) ⁶ )-S(O) _1-2 -(C ₀ -C ₆ Alkyl) -Q, - (C ₁ -C ₆ Alkylene) -S (O) _1-2 -N(R ⁶ )(R ⁶ )、-(C ₁ -C ₄ Alkylene) -S (O) _1-2 -N(R ⁶ )-(C ₁ -C ₆ Alkylene) -Q, -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl), -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -O- (C ₀ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -O-C (O) - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -O-C (O) - (C) ₀ -C ₆ Alkyl) -Q, - (C ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -O-C (O) - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -O-C (O) - (C) ₀ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₀ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -N (R) ⁶ )C(O)-(C ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -N (R) ⁶ )C(O)-(C ₀ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -S (O) _0-2 -(C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -S (O) _0-2 -(C ₀ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -N (R) ⁶ )-C(O)-N(R ⁶ )-(C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -C (O) - (C) ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -Q, wherein:

exists in R ² And R is ⁵ Any alkyl or alkylene moiety of (C) is optionally substituted with one or more-OH, -O (C) ₁ -C ₄ Alkyl) -CO ₂ H or halo;

exists in R ² And R is ⁵ Any terminal methyl moiety in (a) is optionally substituted with-CH ₂ OH、CF ₃ 、-CH ₂ F、-CH ₂ Cl、C(O)CH ₃ 、C(O)CF ₃ CN or CO ₂ H replacement;

R ⁷ and R is ⁸ Each independently selected from hydrogen and C ₁ -C ₆ An alkyl group; and is also provided with

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

R ¹ And R is ³ Optionally together with the carbon atom to which it is attached form C (=o); or (b)

R ⁴ And R is ⁶ Optionally together with the carbon atom to which it is attached form C (=o); or (b)

R ¹ And R is ² Optionally together form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl; or (b)

R ⁴ And R is ⁵ Optionally together form an optionally substituted carbocyclyl, 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(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ NH ₂ 4- [ [2- [2- (2-aminoethoxy) ethoxy ]]Ethyl group]Amino group]And (b) N (R) ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Not both NHEt, NH (n-propyl), NH (n-butyl), NH (n-dodecyl), NH- [ (4-methoxyphenyl) methyl]、NHCH ₂ CH ₂ CHO、NHCH ₂ CH ₂ OCH ₃ 、NHCH ₂ CH ₂ OH、NHCH ₂ CH(OH)CH ₃ 、NHCH ₂ CH ₂ OC (O) phenyl, NHCH ₂ CH ₂ CH ₂ OH、NHCH ₂ CH ₂ CH ₂ N(CH ₃ ) Phenyl, NHCH ₂ C(O)OCH ₃ 、NHCH ₂ C(O)OCH ₂ CH ₃ 、NHCH ₂ Phenyl, NHCH (CH) ₃ )CH ₂ CH ₃ Or NHCH ₂ CH ₂ OC(O)CH ₃ ；

(ii) When X is CH or C-Cl and A is optionally substituted with F, cl or SO ₂ CH ₃ When substituted phenyl, then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is N (CH) ₃ )CH ₂ C (O) NH-isopropyl, NHCH (CH) ₃ )(CH ₂ ) ₃ N(CH ₂ CH ₃ ) ₂ 、NHCH ₂ CH ₂ OH、NHCH ₂ CH ₂ OCH ₃ 、NHCH ₂ CH ₂ OSO ₃ H、NHCH ₂ CH ₂ CH ₂ OCH ₂ CH ₂ O-phenyl, NHCH ₂ CH ₂ CH ₂ OH、NHCH ₂ CH ₂ CH ₂ OCH ₃ 、NHCH ₂ CH(OH)CH ₃ 、N(CH ₂ CH ₃ ) ₂ NH-isopropyl, NHCH ₂ CH ₂ NHC(O)OCH ₃ 、NHCH ₂ CH ₂ NHC(O)CH ₃ 、NHCH ₂ CH ₂ NH ₂ Or NHCH ₂ -phenyl;

(iii) When X is CH and A is optionally substituted pyridinyl, then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHCH ₂ -phenyl, NHCH ₂ - (2, 4-difluorophenyl), N (CH) ₃ )CH ₂ CH ₂ C(O)OH、NHCH ₂ CH ₂ C(O)OH、NHCH ₂ CH ₂ C(O)OCH ₂ CH ₃ 、NHCH ₂ CH ₂ C (O) O-tert-butyl, NHCH ₂ CH ₂ C(O)NH ₂ 、NHCH ₂ CH ₂ -phenyl, NHCH ₂ CH ₂ OH、NHCH ₂ CH ₂ NH ₂ 、NHCH ₂ CH ₂ N(CH ₃ ) ₂ Or NHCH ₂ CH ₂ CH ₃ ；

(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(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NH (CH) ₂ ) ₇ CH ₃ 、NHCH ₂ - (o-chloro-phenyl) or NHCH ₂ CH ₂ OH；

(v) When X is N and A is an optionally substituted pyridinyl group then (A) N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither NHC (O) - [ 2-chloro-4- (methylsulfonyl)]、N(CH ₃ ) ₂ 、NHCH ₂ CH ₂ CH ₂ SO ₂ CH ₂ CH ₂ Cl、NHCH ₂ CH ₂ OCH ₂ CH ₂ SO ₂ CH ₂ CH ₂ Cl or NHCH ₂ CH ₂ SO ₂ CH ₂ CH ₂ Cl；(B)N(R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHC (O) C (CH ₃ ) ₃ 、NHC(O)CH＝CH ₂ 、NHC(O)C(CH ₃ )＝CH ₂ 、NHCH ₂ CH ₂ OH, NH-cyclohexyl, NHCH ₂ -phenyl, NHC (O) (CH ₂ ) ₅ NH ₂ 、NHC(O)OCH ₃ 、NHC(O)CH ₃ And NHC (O) NH-optionally substituted phenyl; and (C) when N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) Is NHC (CH) ₃ ) ₃ When then N (R ⁸ )C(R ¹ )(R ² )(R ³ ) Not NHCH ₂ -phenyl or NH-CH ₂ CH ₃ ；

(vi) When X is N and A is optionally substituted heteroaryl then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Both are not N (CH) ₂ CH ₃ ) ₂ 、NHCH ₂ CH ₂ Isopropyl, NHCH ₂ CH(CH ₃ ) ₂ NHC (O) CH ₃ ；

(vii) When X is CH and A is unsubstituted 2-pyridyl then by R ⁴ And R is ⁵ The ring formed is not 5-methyl-1H-pyrazol-3-yl;

(viii) When A is optionally substituted 1-pyrazolyl then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is N (CH) ₃ ) ₂ 、NHCH ₃ NHAc, NH isopropyl, NHCH ₂ CH ₃ 、NHCH ₂ CH ₂ SO ₃ H or N (CH) ₂ CH ₃ ) ₂ ；

(ix) When X is N and A is optionally substituted phenyl, thienyl or pyridyl, then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NH cyclohexyl C (O) NHCH ₂ R, wherein R is OCF ₃ 、OCH ₃ Chlorine or CF ₃ Phenyl or pyridyl substituted with one or more of (a) a group(s);

(x) When X is N, A is optionally substituted phenyl and R ⁴ And R is ⁵ When an optionally substituted phenyl group is formed then N (R ⁸ )C(R ¹ )(R ² )(R ³ ) Not NHCH ₂ (4-fluorophenyl) NHCH ₂ CO ₂ H、NHCH ₂ C(O)Cl、NHCH(CO ₂ H)(CH ₂ SCH ₂ Phenyl group, NHCH ₂ C (O) NHC (O) NHR or NHCH ₂ C (O) NHC (S) NHR, wherein R is optionally substituted phenyl or naphthyl;

(xi) When X is N, A is an oxadiazole substituted with an optionally substituted pyridinyl group, then R ⁴ And R is ⁵ Not forming an optionally substituted phenyl group;

(xii) When A is substituted 1-pyrazolyl, then (A) N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHC (CH ₃ ) ₃ The method comprises the steps of carrying out a first treatment on the surface of the 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 is ¹ And R is ² Optionally together form an unsubstituted cyclohexyl group, and R ⁴ And R is ⁵ Optionally together form an unsubstituted cyclohexyl group, then A is not a disubstituted 1-pyrazolyl or unsubstituted phenyl; and is also provided with

(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-pyridinyl) -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)N ² -cyclopropyl-N ⁴ -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-pyridinyl) -1,3, 5-triazin-2-yl ] amino ] methyl ] cyclohexyl ] methyl ] -4-fluoro-benzenesulfonamide;

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

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

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

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

(11)N ² ,N ⁴ -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) -N ² -benzyl-N ⁴ - (tert-butyl) -1,3, 5-triazine-2, 4-diamine;

(18)N ² ,N ⁴ -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-pyridinyl) -4-pyrimidinyl ] - βalanine;

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

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

(24)N ² -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-pyridinyl) -1,3, 5-triazin-2-yl ] -benzamide;

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

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

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

(29) 5- [4, 6-bis (diethylamino) -1,3, 5-triazin-2-yl ] -2H-tetrazol-2-acetic acid ethyl ester;

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

(31) N, N' - [6- [4- (acetamido) -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-pyridinyl) -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) 2- [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-pyridinyl) -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, 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 ] -, (αr) -cyclohexanecalamide;

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

(46)N ² ,N ⁴ -bis (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 or IIId or a compound as described in any one of the examples herein inhibits mutant IDH1 or mutant IDH2. Also described herein are pharmaceutical compositions comprising compounds of formulas 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 IDH2.

Detailed Description

The details of 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 expressly 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.

Definition:

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

The term "alkyl" is meant to encompass the indicated amountsA fully saturated or unsaturated hydrocarbon chain of carbon atoms, which may be straight or branched. For example, C ₁ -C ₁₂ Alkyl means that the group may have from 1 to 12 (inclusive) carbon atoms in it. The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced with a halo group, and includes alkyl moieties in which all of the hydrogen has been replaced with a halo group (e.g., perfluoroalkyl). The term "arylalkyl" or "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced with an aryl group. Aralkyl groups include groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of "arylalkyl" or "aralkyl" include benzyl, 2-phenethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl. The term "alkyl" includes "alkenyl" and "alkynyl".

The term "alkylene" refers to a divalent alkyl group, e.g., -CH ₂ -、-CH ₂ CH ₂ -、-CH ₂ CH ₂ CH ₂ -and-CH ₂ CH(CH ₃ )CH ₂ -。

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 of an alkenyl substituent.

The term "alkynyl" refers to a straight or branched hydrocarbon chain containing from 2 to 12 carbon atoms and characterized by 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 an-O-alkyl group. The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms have been replaced with a halo group, and includes alkoxy moieties in which all of the hydrogen has been replaced with a halo group (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 indicated, 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 includes 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 indicated, any ring atom in a carbocyclyl group may be substituted with one or more substituents.

Bicyclic or tricyclic systems in which the aryl group is fused to a carbocyclyl group and the point of attachment from the ring system to the remainder of the molecule passes through a non-aromatic ring are considered carbocyclyl groups (e.g., cycloalkyl groups). 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 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 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) 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 compound having 1 to 3 heteroatoms (if monocyclic), 1 to 6 heteroatoms (if bicyclic), or 1 to 9Non-aromatic 3-10 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system having heteroatoms (if tricyclic) selected from O, N or S (or oxidized forms, e.g. N) ⁺ -O-, S (O) and S (O) ₂ ). The heteroatom may optionally be the point of attachment of the heterocyclyl substituent. Examples of heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, pyrrolinyl, pyrimidinyl, and pyrrolidinyl. Heterocyclyl groups include 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. A bi-or tricyclic ring system in which an aryl or heteroaryl group is fused to a carbocyclyl or heterocyclyl group and the point of attachment from the ring system to the rest of the molecule through the aromatic ring is correspondingly considered an aryl or heteroaryl group. A bicyclic or tricyclic ring system in which an aryl or heteroaryl group is fused to a carbocyclyl or heterocyclyl group and the point of attachment from the ring system to the remainder of the molecule through a non-aromatic ring is correspondingly considered a carbocyclyl (e.g., cycloalkyl) or heterocyclyl group.

Aryl, heteroaryl, carbocyclyl (including cycloalkyl), and heterocyclyl are optionally substituted at one or more substitutable atoms with substituents either alone or as part of a group (e.g., the aryl portion of an aralkyl group), the substituents being independently selected from the group consisting of, unless otherwise specified: halo, -C.ident. N, C ₁ -C ₄ Alkyl, =o, -OR ^b 、-OR ^b’ 、-SR ^b 、-SR ^b’ 、-(C ₁ -C ₄ Alkyl) -N (R) ^b )(R ^b )、-(C ₁ -C ₄ Alkyl) -N (R) ^b )(R ^b’ )、-N(R ^b )(R ^b )、-N(R ^b )(R ^b’ )、-O-(C ₁ -C ₄ Alkyl) -N (R) ^b )(R ^b )、-O-(C ₁ -C ₄ Alkyl) -N (R) ^b )(R ^b’ )、-(C ₁ -C ₄ Alkyl) -O- (C ₁ -C ₄ Alkyl) -N (R) ^b )(R ^b )、-(C ₁ -C ₄ Alkyl) -O- (C ₁ -C ₄ Alkyl) -N (R) ^b )(R ^b’ )、-C(O)-N(R ^b )(R ^b )、-(C ₁ -C ₄ Alkyl) -C (O) -N (R) ^b )(R ^b )、-(C ₁ -C ₄ Alkyl) -C (O) -N (R) ^b )(R ^b’ )、-OR ^b’ 、R ^b’ 、-C(O)(C ₁ -C ₄ Alkyl), -C (O) R ^b’ 、-C(O)N(R ^b’ )(R ^b )、-N(R ^b )C(O)(R ^b )、-N(R ^b )C(O)(R ^b’ )、-N(R ^b )SO ₂ (R ^b )、-SO ₂ N(R ^b )(R ^b )、-N(R ^b )SO ₂ (R ^b’ ) -SO ₂ N(R ^b )(R ^b’ ) Wherein any alkyl substituents are optionally further substituted by-OH, -O- (C) ₁ -C ₄ Alkyl), halo, -NH ₂ 、-NH(C ₁ -C ₄ Alkyl) or-N (C) ₁ -C ₄ Alkyl group ₂ One or more substitutions in (a);

each R ^b Are all independently selected from hydrogen and-C ₁ -C ₄ An alkyl group; or (b)

Two R ^b Together with the nitrogen atom to which they are bonded form a 4-to 8-membered heterocyclic group optionally containing an additional heteroatom selected from N, S and O; and is also provided with

Each R ^b’ Are all independently selected from C ₃ -C ₇ Carbocyclyl, phenyl, heteroaryl and heterocyclyl, wherein one or more substitutable positions on the phenyl, cycloalkyl, heteroaryl or heterocyclyl substituent are optionally further substituted by- (C) ₁ -C ₄ Alkyl) - (C) ₁ -C ₄ Fluoroalkyl), -OH, -O- (C) ₁ -C ₄ Alkyl), -O- (C) ₁ -C ₄ Fluoroalkyl), halo, -NH ₂ 、-NH(C ₁ -C ₄ Alkyl) or-N (C) ₁ -C ₄ Alkyl group ₂ One or more substitutions in (a).

Heterocyclyl is optionally oxo, -C, either alone or as part of a group, at one or more of any substitutable nitrogen atom ₁ -C ₄ Alkyl or fluoro-substituted C ₁ -C ₄ Alkyl groupAnd (3) substitution.

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

The term "body fluid" includes one or more of the following: amniotic fluid, aqueous fluid, blood (e.g., plasma), serum, cerebrospinal fluid, cerumen, chyme, cowper's fluid, female ejaculation, 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 surrounding the fetus.

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, either completely or partially.

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

As used herein, an amount of a compound or "therapeutically effective amount" effective to treat a disorder refers to an amount of the compound that is effective to treat cells or cure, alleviate or ameliorate a subject with a disorder beyond what would be expected in the absence of such treatment after administration of a single dose or multiple doses to the subject.

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, such as the disorders 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, domesticated and/or agriculturally useful animals, e.g., sheep, dogs, cats, cattle, pigs, etc.

Compounds of formula (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;

R ² and R is ⁵ Each independently selected from: - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₁ -C ₆ Alkyl) -CO ₂ H、-(C ₂ -C ₆ Alkenyl or alkynyl) - (C) ₁ -C ₆ Alkylene) -N (R) ⁶ )-(C ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -N (R) ⁶ )-(C ₀ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -N (R) ⁶ )(R ⁶ )、-(C ₁ -C ₆ Alkylene) -N (R) ⁶ )-S(O) _1-2 -(C ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -N (R) ⁶ )-S(O) _1-2 -(C ₀ -C ₆ Alkyl) -Q, - (C ₁ -C ₆ Alkylene) -S (O) _1-2 -N(R ⁶ )(R ⁶ )、-(C ₁ -C ₄ Alkylene) -S (O) _1-2 -N(R ⁶ )-(C ₁ -C ₆ Alkylene) -Q, -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene groupRadical) -O- (C ₁ -C ₆ Alkyl), -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -O- (C ₀ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -O-C (O) - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -O-C (O) - (C) ₀ -C ₆ Alkyl) -Q, - (C ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -O-C (O) - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -O-C (O) - (C) ₀ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₀ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -N (R) ⁶ )C(O)-(C ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -N (R) ⁶ )C(O)-(C ₀ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -S (O) _0-2 -(C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -S (O) _0-2 -(C ₀ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -N (R) ⁶ )-C(O)-N(R ⁶ )-(C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -C (O) - (C) ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -Q, wherein:

exists in R ² And R is ⁵ Optionally with one or more-OH,-O(C ₁ -C ₄ Alkyl) -CO ₂ H or halo;

wherein:

(vi) When X is N and A is optionally substituted heteroarylWhen then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Both are not N (CH) ₂ CH ₃ ) ₂ 、NHCH ₂ CH ₂ Isopropyl, NHCH ₂ CH(CH ₃ ) ₂ NHC (O) CH ₃ ；

(vii) When X is CH and A is unsubstituted 2-pyridyl then by R ⁴ And R is ⁵ The ring formed is not 5-methyl-1H-pyrazol-3-yl,

(viii) When A is optionally substituted 1-pyrazolyl then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is N (CH) ₃ ) ₂ 、NHCH ₃ NHAc, NH isopropyl, NHCH ₂ CH ₃ 、NHCH ₂ CH ₂ SO ₃ H or N (CH) ₂ CH ₃ ) ₂ ，

(ix) When X is N and A is optionally substituted phenyl, thienyl or pyridyl, then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NH cyclohexyl C (O) NHCH ₂ R, wherein R is OCF ₃ 、OCH ₃ Chlorine or CF ₃ Phenyl or pyridyl substituted with one or more substituents,

(x) When X is N, A is optionally substituted phenyl and R ⁴ And R is ⁵ When an optionally substituted phenyl group is formed then N (R ⁸ )C(R ¹ )(R ² )(R ³ ) Not NHCH ₂ (4-fluorophenyl) NHCH ₂ CO ₂ H、NHCH ₂ C(O)Cl、NHCH(CO ₂ H)(CH ₂ SCH ₂ Phenyl group, NHCH ₂ C (O) NHC (O) NHR or NHCH ₂ C (O) NHC (S) NHR where R is optionally substituted phenyl or naphthyl,

(xi) When X is N, A is an oxadiazole substituted with an optionally substituted pyridinyl group, then R ⁴ And R is ⁵ An optionally substituted phenyl group is not formed,

(xii) When A is substituted 1-pyrazolyl, then (A) N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHC (CH ₃ ) ₃ The method comprises the steps of carrying out a first treatment on the surface of the 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,

(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 ] thio ] -acetamide,

(4)N ² -cyclopropyl-N ⁴ -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 ] thio ] -acetic acid methyl ester,

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

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

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

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

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

(11)N ² ,N ⁴ 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) -N ² -benzyl-N ⁴ - (tert-butyl) -1,3, 5-triazine-2, 4-diamine,

(18)N ² ,N ⁴ -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-triazin-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-pyridinyl) -4-pyrimidinyl ] - βalanine,

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

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

(24)N ² -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-pyridinyl) -1,3, 5-triazin-2-yl ] -benzamide,

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

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

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

(29) 5- [4, 6-bis (diethylamino) -1,3, 5-triazin-2-yl ] -2H-tetrazol-2-acetic acid ethyl ester,

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

(31) N, N' - [6- [4- (acetamido) -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-pyridinyl) -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-pyridinyl) -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, 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) -cyclohexanecalamide,

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

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

wherein:

x is N, CH or C-halo;

R ¹ 、R ³ 、R ⁴ and R is ⁶ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, -O-C ₁ -C ₄ Alkyl and CN, wherein R ¹ 、R ³ 、R ⁴ And R is ⁶ Each independently optionally substituted with-OH, -NH ₂ 、-CN、-O-C ₁ -C ₄ Alkyl, -NH (C) ₁ -C ₄ Alkyl) or-N (C) ₁ -C ₄ Alkyl group ₂ Substitution;

R ⁴ And R is ⁵ Optionally together form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl;

wherein:

(i) When X is N and A is optionally substituted phenyl then (a) N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) None of them is 4- [ [2- [2- (2-aminoethoxy) ethoxy ]]Ethyl group]Amino group]And (b) N (R7) C (R4) (R5) (R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Not both NHEt, NH (n-propyl), NH (n-butyl), NH (n-dodecyl), NH- [ (4-methoxyphenyl) methyl]、NHCH ₂ CH ₂ CHO、NHCH ₂ CH ₂ OCH ₃ 、NHCH ₂ CH ₂ OH、NHCH ₂ CH(OH)CH ₃ 、NHCH ₂ CH ₂ OC (O) phenyl, NHCH ₂ CH ₂ CH ₂ OH、NHCH ₂ CH ₂ CH ₂ N(CH ₃ ) Phenyl, NHCH ₂ C(O)OCH ₃ 、NHCH ₂ C(O)OCH ₂ CH ₃ 、NHCH ₂ Phenyl, NHCH (CH) ₃ )CH ₂ CH ₃ Or NHCH ₂ CH ₂ OC(O)CH ₃ ；

(v) When X is N and A is an optionally substituted pyridinyl group then (A) N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither NHC (O) - [ 2-chloro-4- (methylsulfonyl)]；(B)N(R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHC (O) C (CH ₃ ) ₃ 、NHC(O)CH＝CH ₂ 、NHC(O)C(CH ₃ )＝CH ₂ 、NHCH ₂ CH ₂ OH, NH-cyclohexyl, NHCH ₂ -phenyl, NHC (O) (CH ₂ ) ₅ NH ₂ 、NHC(O)OCH ₃ 、NHC(O)CH ₃ Phenyl optionally substituted with NHC (O) NH; and (C) when N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) Is NHC (CH) ₃ ) ₃ When then N (R ⁸ )C(R ¹ )(R ² )(R ³ ) Not NHCH ₂ -phenyl or NH-CH ₂ CH ₃ ；

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

(1)N ² - [2- [2- (2-Aminoethoxy) ethoxy ]]Ethyl group]-N ⁴ Cyclopentyl-6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(2)N ² - [2- [2- (2-Aminoethoxy) ethoxy ]]Ethyl group]-N ⁴ Cyclopentyl-6- (4-methoxyphenyl) -1,3, 5-triazine-2, 4-diamine,

(3)N ² - [2- [2- (2-Aminoethoxy) ethoxy ]]Ethyl group]-N ⁴ Cyclopentyl-6- (3-nitrophenyl) -1,3, 5-triazine-2, 4-diamine,

(4)N ² - [2- [2- (2-Aminoethoxy) ethoxy ] ]Ethyl group]-N ⁴ Cyclopentyl-6- (4-fluorophenyl) -1,3, 5-triazine-2, 4-diamine,

(5)N ² - [2- [2- (2-Aminoethoxy) ethoxy ]]Ethyl group]-N ⁴ Cyclopentyl-6- (4-trifluoromethoxy-phenyl) -1,3, 5-triazine-2, 4-diamine,

(6)N ² - [2- [2- (2-Aminoethoxy) ethoxy ]]Ethyl group]-N ⁴ Cyclopentyl-6- (4-tert-butyl-phenyl) -1,3, 5-triazine-2, 4-diamine,

(7)N ² - [2- [2- (2-Aminoethoxy) ethoxy ]]Ethyl group]-N ⁴ 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)N ² - [2- [2- (2-Aminoethoxy) ethoxy ]]Ethyl group]-N ⁴ -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 ] thio ] -acetamide,

(12)N ² -cyclopropyl-N ⁴ -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 ] thio ] -acetic acid methyl ester,

(14)N ² - [2- [2- (2-Aminoethoxy) ethoxy ] ]Ethyl group]-N ⁴ -cyclopropyl-6- (2, 4, 6-trimethylphenyl) -1,3, 5-triazine-2, 4-diamine,

(15)N ² - [2- [2- (2-Aminoethoxy) ethoxy ]]Ethyl group]-N ⁴ Cyclopropyl-6-phenyl-1, 3, 5-triazine-2, 4-diamine,

(16)N ² - [2- [2- (2-Aminoethoxy) ethoxy ]]Ethyl group]-N ⁴ -cyclopropyl-6- (4-methylphenyl) -1,3, 5-triazine-2, 4-diamine,

(17)N ² - [2- [2- (2-Aminoethoxy) ethoxy ]]Ethyl group]-N ⁴ Cyclopropyl-6- (4-chlorophenyl) -1,3, 5-triazine-2, 4-diamine,

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

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

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

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

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

(23)N ² ,N ⁴ 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) -N ² -benzyl-N ⁴ - (tert-butyl) -1,3, 5-triazine-2, 4-diamine,

(30)N ² ,N ⁴ -bis (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-triazin-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-pyridinyl) -4-pyrimidinyl ] - βalanine,

(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)N ² -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-pyridinyl) -1,3, 5-triazin-2-yl ] -benzamide,

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

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

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

(41) 5- [4, 6-bis (diethylamino) -1,3, 5-triazin-2-yl ] -2H-tetrazol-2-acetic acid ethyl ester,

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

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

wherein:

x is N or CH;

wherein:

(i) When X is N and A is optionally substituted phenyl then (a) N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) None of them is 4- [ [2- [2- (2-aminoethoxy) ethoxy ]]Ethyl group]Amino group ]And (b) N (R7) C (R4) (R5) (R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Not both NHEt, NH (n-propyl), NH (n-butyl), NH (n-dodecyl), NH- [ (4-methoxyphenyl) methyl]、NHCH ₂ CH ₂ CHO、NHCH ₂ CH ₂ OCH ₃ 、NHCH ₂ CH ₂ OH、NHCH ₂ CH(OH)CH ₃ 、NHCH ₂ CH ₂ OC (O) phenyl, NHCH ₂ CH ₂ CH ₂ OH、NHCH ₂ CH ₂ CH ₂ N(CH ₃ ) Phenyl, NHCH ₂ C(O)OCH ₃ 、NHCH ₂ C(O)OCH ₂ CH ₃ 、NHCH ₂ Phenyl, NHCH (CH) ₃ )CH ₂ CH ₃ Or NHCH ₂ CH ₂ OC(O)CH ₃ ；

(iv) When X is CH andand A is optionally substituted 1-imidazolyl, optionally substituted 1-pyrrolyl or optionally substituted 1-pyrazolyl, then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NH (CH) ₂ ) ₇ CH ₃ 、NHCH ₂ - (o-chloro-phenyl) or NHCH ₂ CH ₂ OH；

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

(4)N ² - [2- [2- (2-Aminoethoxy) ethoxy ]]Ethyl group]-N ⁴ Cyclopentyl-6- (4-fluorophenyl) -1,3, 5-triazine-2, 4-diamine,

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

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

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

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

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

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

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

(42)N ² ,N ² ,N ⁴ ,N ⁴ -tetraethyl-6- (2H-tetrazol-5-yl) -1,3, 5-triazine-24-diamine, and

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

wherein:

x is N or CH;

wherein:

(v) When X is N and A is an optionally substituted pyridinyl group then (A) N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither NHC (O) - [ 2-chloro-4- (methylsulfonyl)]、N(CH ₃ ) ₂ 、NHCH ₂ CH ₂ CH ₂ SO ₂ CH ₂ CH ₂ Cl、NHCH ₂ CH ₂ OCH ₂ CH ₂ SO ₂ CH ₂ CH ₂ Cl or NHCH ₂ CH ₂ SO ₂ CH ₂ CH ₂ Cl；(B)N(R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHC (O) C (CH ₃ ) ₃ 、NHC(O)CH＝CH ₂ 、NHC(O)C(CH ₃ )＝CH ₂ 、NHCH ₂ CH ₂ OH, NH-cyclohexyl, NHCH ₂ -phenyl, NHC (O) (CH ₂ ) ₅ NH ₂ 、NHC(O)OCH ₃ 、NHC(O)CH ₃ And NHC (O) NH-optionally substituted phenyl; and (C) when N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) Is NHC(CH ₃ ) ₃ When then N (R ⁸ )C(R ¹ )(R ² )(R ³ ) Not NHCH ₂ -phenyl or NH-CH ₂ CH ₃ ；

(x) When X is N, A is optionally substituted phenyl and R ⁴ And R is ⁵ When an optionally substituted phenyl group is formed then N (R ⁸ )C(R ¹ )(R ² )(R ³ ) Not NHCH ₂ (4-fluorophenyl) NHCH ₂ CO ₂ H、NHCH ₂ C(O)Cl、NHCH(CO ₂ H)(CH ₂ SCH ₂ Phenyl group, NHCH ₂ C (O) NHC (O) NHR or NHCH ₂ C (O) NHC (S) NHR whereinR is optionally substituted phenyl or naphthyl,

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

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

(7)N ² -cyclopropyl-6- (3, 5-dimethyl-1H-pyrazol-1-yl) -N4-phenyl-1, 3, 5-triazine-2, 4-diylThe amine is used as a reactive component in the reaction of the amine,

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

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

(22)N ⁴ 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: />

R ² and R is ⁵ Each independently selected from: - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₁ -C ₆ Alkyl) -CO ₂ H、-(C ₂ -C ₆ Alkenyl or alkynyl) - (C) ₁ -C ₆ Alkylene) -N (R) ⁶ )-(C ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -N (R) ⁶ )-(C ₀ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -N (R) ⁶ )(R ⁶ )、-(C ₁ -C ₆ Alkylene) -N (R) ⁶ )-S(O) _1-2 -(C ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -N (R) ⁶ )-S(O) _1-2 -(C ₀ -C ₆ Alkyl) -Q, - (C ₁ -C ₆ Alkylene) -S (O) _1-2 -N(R ⁶ )(R ⁶ )、-(C ₁ -C ₄ Alkylene) -S (O) _1-2 -N(R ⁶ )-(C ₁ -C ₆ Alkylene) -Q, -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl), -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -O- (C ₀ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -O-C (O) - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -O-C (O) - (C) ₀ -C ₆ Alkyl) -Q _、 -(C ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -O-C (O) - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -O-C (O) - (C) ₀ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₀ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -N (R) ⁶ )C(O)-(C ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkylene) -N (R) ⁶ )C(O)-(C ₀ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -S (O) _0-2 -(C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -S (O) _0-2 -(C ₀ -C ₆ Alkylene) -Q, - (C ₁ -C ₆ Alkylene) -N (R) ⁶ )-C(O)-N(R ⁶ )-(C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -C (O) - (C) ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -Q, wherein:

wherein:

(i) When A is optionally substituted phenyl then (a) N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) None of them is 4- [ [2- [2- (2-aminoethoxy) ethoxy ]]Ethyl group]Amino group]And (b) N (R7) C (R4) (R5) (R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Not both NHEt, NH (n-propyl), NH (n-butyl), NH (n-dodecyl), NH- [ (4-methoxyphenyl) methyl]、NHCH ₂ CH ₂ CHO、NHCH ₂ CH ₂ OCH ₃ 、NHCH ₂ CH ₂ OH、NHCH ₂ CH(OH)CH ₃ 、NHCH ₂ CH ₂ OC (O) phenyl, NHCH ₂ CH ₂ CH ₂ OH、NHCH ₂ CH ₂ CH ₂ N(CH ₃ ) Phenyl, NHCH ₂ C(O)OCH ₃ 、NHCH ₂ C(O)OCH ₂ CH ₃ 、NHCH ₂ Phenyl, NHCH (CH) ₃ )CH ₂ CH ₃ Or NHCH ₂ CH ₂ OC(O)CH ₃ ；

(ii)When X is N and A is an optionally substituted pyridinyl group then (A) N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither NHC (O) - [ 2-chloro-4- (methylsulfonyl) ]；(B)N(R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHC (O) C (CH ₃ ) ₃ 、NHC(O)CH＝CH ₂ 、NHC(O)C(CH ₃ )＝CH ₂ 、NHCH ₂ CH ₂ OH, NH-cyclohexyl, NHCH ₂ -phenyl, NHC (O) (CH ₂ ) ₅ NH ₂ 、NHC(O)OCH ₃ 、NHC(O)CH ₃ Phenyl optionally substituted with NHC (O) NH; and (C) when N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) Is NHC (CH) ₃ ) ₃ When then N (R ⁸ )C(R ¹ )(R ² )(R ³ ) Not NHCH ₂ -phenyl or NH-CH ₂ CH ₃ ；

(iii) When X is N and A is optionally substituted heteroaryl then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Both are not N (CH) ₂ CH ₃ ) ₂ 、NHCH ₂ CH ₂ Isopropyl, NHCH ₂ CH(CH ₃ ) ₂ NHC (O) CH ₃ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

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

(7)N ² - [2- [2- (2-Aminoethoxy) ethoxy ] ]Ethyl group]-N ⁴ Cyclopentyl-6- (2-thienyl) -1,3, 5-triazine-2, 4-diamine,

(14)N ² - [2- [2- (2-Aminoethoxy) ethoxy ]]Ethyl group]-N ⁴ -cyclopropyl-6- (2, 4, 6-trimethylphenyl) -1,3, 5-triazine-2, 4-diamine,

(17)N ² - [2- [2- (2-Aminoethoxy) ethoxy ] ]Ethyl group]-N ⁴ Cyclopropyl-6- (4-chlorophenyl) -1,3, 5-triazine-2, 4-diamine,

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

(33)N ² -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-pyridinyl) -1,3, 5-triazin-2-yl ] -benzamide,

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

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

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

(38) 5- [4, 6-bis (diethylamino) -1,3, 5-triazin-2-yl ] -2H-tetrazol-2-acetic acid ethyl ester,

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

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

wherein:

(i) When A is optionally substituted phenyl then (a) N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ NH ₂ Or 4- [ [2- [2- (2-aminoethoxy) ethoxy ]]Ethyl group]Amino group]And (b) N (R) ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Not both NHEt, NH (n-propyl), NH (n-butyl), NH (n-dodecyl), NH- [ (4-methoxyphenyl) methyl]、NHCH ₂ CH ₂ CHO、NHCH ₂ CH ₂ OCH ₃ 、NHCH ₂ CH ₂ OH、NHCH ₂ CH(OH)CH ₃ 、NHCH ₂ CH ₂ OC (O) phenyl, NHCH ₂ CH ₂ CH ₂ OH、NHCH ₂ CH ₂ CH ₂ N(CH ₃ ) Phenyl, NHCH ₂ C(O)OCH ₃ 、NHCH ₂ C(O)OCH ₂ CH ₃ 、NHCH ₂ Phenyl, NHCH (CH) ₃ )CH ₂ CH ₃ Or NHCH ₂ CH ₂ OC(O)CH ₃ ；

(ii) When A is an optionally substitutedIn the case of pyridyl, then (A) N (R) ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither NHC (O) - [ 2-chloro-4- (methylsulfonyl)]、N(CH ₃ ) ₂ 、NHCH ₂ CH ₂ CH ₂ SO ₂ CH ₂ CH ₂ Cl、NHCH ₂ CH ₂ OCH ₂ CH ₂ SO ₂ CH ₂ CH ₂ Cl or NHCH ₂ CH ₂ SO ₂ CH ₂ CH ₂ Cl；(B)N(R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHC (O) C (CH ₃ ) ₃ 、NHC(O)CH＝CH ₂ 、NHC(O)C(CH ₃ )＝CH ₂ 、NHCH ₂ CH ₂ OH, NH-cyclohexyl, NHCH ₂ -phenyl, NHC (O) (CH ₂ ) ₅ NH ₂ 、NHC(O)OCH ₃ 、NHC(O)CH ₃ And NHC (O) NH-optionally substituted phenyl; and (C) when N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) Is NHC (CH) ₃ ) ₃ When then N (R ⁸ )C(R ¹ )(R ² )(R ³ ) Not NHCH ₂ -phenyl or NH-CH ₂ CH ₃ ；

(iii) When a is optionally substituted heteroaryl then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Both are not N (CH) ₂ CH ₃ ) ₂ 、NHCH ₂ CH ₂ Isopropyl, NHCH ₂ CH(CH ₃ ) ₂ NHC (O) CH ₃ ；

(iv) When A is optionally substituted 1-pyrazolyl then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is N (CH) ₃ ) ₂ 、NHCH ₃ NHAc, NH isopropyl, NHCH ₂ CH ₃ 、NHCH ₂ CH ₂ SO ₃ H or N (CH) ₂ CH ₃ ) ₂ ，

(v) When A is optionally substituted phenyl, thienyl or pyridyl, then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NH cyclohexyl C (O) NHCH ₂ R, wherein R is OCF ₃ 、OCH ₃ Chlorine or CF ₃ Phenyl or pyridyl substituted with one or more substituents,

(vi) When A is optionally substituted phenyl and R ⁴ And R is ⁵ When an optionally substituted phenyl group is formed then N (R ⁸ )C(R ¹ )(R ² )(R ³ ) Not NHCH ₂ (4-fluorophenyl) NHCH ₂ CO ₂ H、NHCH ₂ C(O)Cl、NHCH(CO ₂ H)(CH ₂ SCH ₂ Phenyl group, NHCH ₂ C (O) NHC (O) NHR or NHCH ₂ C (O) NHC (S) NHR where R is optionally substituted phenyl or naphthyl,

(vii) When a is an oxadiazole substituted with an optionally substituted pyridinyl group then R ⁴ And R is ⁵ An optionally substituted phenyl group is not formed,

(viii) When A is substituted 1-pyrazolyl, then (A) N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHC (CH ₃ ) ₃ The method comprises the steps of carrying out a first treatment on the surface of the And (B) a is not substituted with n=n—r, wherein R is a ring,

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

(x) When R is ¹ And R is ² Optionally together form an unsubstituted cyclohexyl group, and R ⁴ And R is ⁵ Optionally together form 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:

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

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

(21)N ² -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-pyridinyl) -1,3, 5-triazin-2-yl ] -benzamide,

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

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

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

(26) 5- [4, 6-bis (diethylamino) -1,3, 5-triazin-2-yl ] -2H-tetrazol-2-acetic acid ethyl ester,

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

(28) N, N' - [6- [4- (acetamido) -1,2, 5-oxadiazol-3-yl ] -1,3, 5-triazine-2, 4-diyl ] diacetamide,

(29) N- (2-chloro-6-methylphenyl) -5- [ [4- (dimethylamino) -6- (2-pyridinyl) -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-pyridinyl) -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, 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) -cyclohexanecalamide,

(41) N, N' - [6- [4- (acetamido) -1,2, 5-oxadiazol-3-yl ] -1,3, 5-triazine-2, 4-diyl ] diacetamide,

(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, R ¹ And R is ⁴ Each independently selected from hydrogen, -CH ₃ 、-CH ₂ CH ₃ ,-CH ₂ OH、-CH(CH ₃ )OH、-C(CH ₃ ) ₂ OH、CF ₃ CN; or R is ¹ And R is ³ Together form = O; or R is ⁴ And R is ⁶ Optionally together with the carbon atom to which it is attached form C (=o).

In some embodiments, R ¹ And R is ² Taken together, form a carbocyclyl or heterocyclyl, any of which is optionally substituted with up to 3 substituents independently selected from halo (e.g., fluoro), C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, -CN, =o, -OH, -C (O) C ₁ -C ₄ An alkyl group. In some embodiments, R ¹ And R is ² Together forming a carbocyclyl or heterocyclyl, any of which is optionally substituted with up to 3 substituents independently selected from halo (e.g., fluoro), C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, -CN, =o, -OH, aryl, heteroaryl-SO ₂ C ₁ -C ₄ Alkyl, -CO ₂ C ₁ -C ₄ Alkyl, -C (O) aryl and-C (O) C ₁ -C ₄ An alkyl group. In some embodiments, R ¹ And R is ² Together forming a carbocyclyl or heterocyclyl, either of which is optionally substituted with aryl or heteroaryl, which is optionally substituted with up to 2 substituents independently selected from halo, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, -CN, -OH. In some embodiments, R ¹ And R is ² Taken together form a carbocyclyl or heterocyclyl group, any of which is optionally substituted with phenyl, pyridinyl or pyrimidinylThe phenyl, pyridyl or pyrimidinyl group is optionally substituted with up to 2 substituents independently selected from halo, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, -CN, -OH.

In some embodiments, R ⁴ And R is ⁵ Taken together, form a carbocyclyl or heterocyclyl, any of which is optionally substituted with up to 3 substituents independently selected from halo (e.g., fluoro), C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, -CN, =o, -OH, -C (O) C ₁ -C ₄ An alkyl group. In some embodiments, R ⁴ And R is ⁵ Together forming a carbocyclyl or heterocyclyl, any of which is optionally substituted with up to 3 substituents independently selected from halo (e.g., fluoro), C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, -CN, =o, -OH, aryl, heteroaryl-SO ₂ C ₁ -C ₄ Alkyl, -CO ₂ C ₁ -C ₄ Alkyl, -C (O) aryl and-C (O) C ₁ -C ₄ An alkyl group. In some embodiments, R ¹ And R is ² Together forming a carbocyclyl or heterocyclyl, either of which is optionally substituted with aryl or heteroaryl, which is optionally substituted with up to 2 substituents independently selected from halo, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, -CN, -OH. In some embodiments, R ¹ And R is ² Together forming a carbocyclic or heterocyclic group, any of which is optionally substituted with phenyl, pyridyl or pyrimidinyl, which is optionally substituted with up to 2 substituents independently selected from halo, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, -CN, -OH.

In some embodiments, R ² And R is ⁵ Each independently selected from: - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₁ -C ₆ Alkyl) -CO ₂ H、-(C ₂ -C ₆ Alkenyl or alkynyl) - (C) ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -C (O) - (C) ₁ -C ₆ Alkyl) and- (C) ₀ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, =o, -C (O) -C ₁ -C ₄ Alkyl, -CN and halo.

In some embodiments, R ² And R is ⁵ Each independently selected from: - (C) optionally substituted by halo (e.g. fluoro) or-OH ₁ -C ₄ An alkyl group); - (C) ₀ -C ₄ Alkylene) -O- (C ₁ -C ₄ Alkyl) - (C) ₀ -C ₂ Alkylene) -N (R) ⁶ )-(C ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₀ -C ₂ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -C (O) - (C) ₁ -C ₆ Alkyl) and-O- (C) ₀ -C ₂ Alkylene) -Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, =o, -C (O) -C ₁ -C ₄ Alkyl, -CN and halo. In one aspect of these embodiments, Q is selected from the group consisting of pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl, and oxetanyl, wherein Q is optionally substituted with up to 2 substituents independently selected from the group consisting of C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, =o, fluorine, chlorine and bromine. In another aspect of these embodiments, Q is selected from the group consisting of pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl, and oxetanyl, where Q is optionally substituted with up to 2 substituents independently selected from the group consisting of-CH ₃ And = O.

In some embodiments, R ¹ And R is ² Together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, 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 C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OH, -C (O) CH ₃ Fluorine and chlorine.

In some embodiments, R ⁴ And R is ⁵ Together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo [2.2.1]Heptyl, oxo-bicyclo [3.1.0]Hexyl or azetidinyl, any of which is optionally substituted with up to 2 substituents independently selected from C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy, C ₃ -C ₆ Cycloalkyl, -OH, -C (O) CH ₃ Fluorine and chlorine. In some embodiments, R ⁴ And R is ⁵ Together forming phenyl, pyrazolyl, imidazolyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, thiadiazolyl, or isothiazolyl, any of which is optionally substituted with up to 2 substituents independently selected from halo, CN, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, C ₃ -C ₆ Cycloalkyl, phenyl, -OH, -C (O) CH ₃ Wherein any alkyl, cycloalkyl or phenyl moiety is optionally substituted with fluorine, chlorine, -OH, -NH ₂ or-CN substitution. In some embodiments, C ₃ -C ₆ Cycloalkyl radicals are

In some embodiments, R ¹ 、R ³ 、R ⁴ And R is ⁶ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, -O-C ₁ -C ₄ Alkyl and CN, wherein R ¹ 、R ³ 、R ⁴ And R is ⁶ Each of said alkyl moieties independently being optionally substituted with-OH, -NH ₂ 、-CN、-O-C ₁ -C ₄ Alkyl, -NH (C) ₁ -C ₄ Alkyl) or-N (C) ₁ -C ₄ Alkyl group ₂ Substitution; and R is ² And R is ⁵ Each independently selected from: - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₁ -C ₆ Alkyl) -CO ₂ H、-(C ₂ -C ₆ Alkenyl or alkynyl) - (C) ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkyl) and- (C) ₀ -C ₆ Alkylene) -C (O) - (C) ₁ -C ₆ Alkyl), wherein: exists in R ² And R is ⁵ Any alkyl or alkylene moiety of (C) is optionally substituted with one or more-OH, -O (C) ₁ -C ₄ Alkyl) -CO ₂ H or halo; and is also provided with

Exists in R ² And R is ⁵ Any terminal methyl moiety in (a) is optionally substituted with-CH ₂ OH、CF ₃ 、-CH ₂ F、-CH ₂ Cl、C(O)CH ₃ 、C(O)CF ₃ CN or CO ₂ H replacement; or R is ¹ And R is ³ Optionally together with the carbon atom to which it is attached form C (=o); or (b)

R ⁴ And R is ⁶ Optionally together with the carbon atom to which it is attached form C (=o); or R is ¹ And R is ² Optionally together form an optionally substituted carbocyclyl; or R is ⁴ And R is ⁵ Optionally together form an optionally substituted carbocyclyl group, wherein when A is an optionally substituted phenyl, 2-pyrrolyl or 1-imidazolyl group then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Is different 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, -C ₁ -C ₄ Alkyl, -C ₁ -C ₄ Haloalkyl, -C ₁ -C ₄ Hydroxyalkyl, -NH-S (O) ₂ -(C ₁ -C ₄ Alkyl), -S (O) ₂ NH(C ₁ -C ₄ Alkyl), -CN, -S (O) ₂ -(C ₁ -C ₄ Alkyl group, C ₁ -C ₄ Alkoxy, -NH (C) ₁ -C ₄ Alkyl), -OH, -OCF ₃ 、-CN、-NH ₂ 、-C(O)NH ₂ 、-C(O)NH(C ₁ -C ₄ Alkyl), -C (O) -N (C) ₁ -C ₄ Alkyl group ₂ 、-(C ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl), 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, CF ₃ 、CF ₂ 、-OH、-OCH ₃ 、-OCF ₃ 、-CN、-NH ₂ . In some embodiments, ring a is a substituted 6 membered monocyclic aryl. In some embodiments of the present invention, 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, -C ₁ -C ₄ Alkyl, -C ₁ -C ₄ Haloalkyl, -C ₁ -C ₄ Hydroxyalkyl, -NH-S (O) ₂ -(C ₁ -C ₄ Alkyl), -S (O) ₂ NH(C ₁ -C ₄ Alkyl), -CN, -S (O) ₂ -(C ₁ -C ₄ Alkyl group, C ₁ -C ₄ Alkoxy, -NH (C) ₁ -C ₄ Alkyl), -OH, -OCF ₃ 、-CN、-NH ₂ 、-C(O)NH ₂ 、-C(O)NH(C ₁ -C ₄ Alkyl), -C (O) -N (C) ₁ -C ₄ Alkyl group ₂ And cyclopropyl optionally substituted with OH.

In some embodiments, ring a is selected from phenyl, pyrazolyl, imidazolyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, thiadiazolyl, and isothiazolyl, wherein ring a is optionally substituted with up to two substituents independently selected from halo, -C ₁ -C ₄ Alkyl, -C ₁ -C ₄ Haloalkyl, -C ₁ -C ₄ Hydroxyalkyl, -NH-S (O) ₂ -(C ₁ -C ₄ Alkyl), -S (O) ₂ NH(C ₁ -C ₄ Alkyl), -CN, -S (O) ₂ -(C ₁ -C ₄ Alkyl group, C ₁ -C ₄ Alkoxy, -NH (C) ₁ -C ₄ Alkyl), -OH, -CN and-NH ₂ 。

In some embodiments, ring A is optionally halogenated, -C ₁ -C ₄ Alkyl, -C ₁ -C ₄ Haloalkyl, -O-C ₁ -C ₄ Haloalkyl, -OH, -CN and-NH ₂ Substituted monocyclic heteroaryl; r is R ¹ 、R ³ 、R ⁴ And R is ⁶ Each independently selected from hydrogen andC ₁ -C ₄ an alkyl group; and R is ² And R is ⁵ Each independently is- (C) ₀ -C ₆ Alkylene) -Q; or R is ¹ And R is ² Optionally together form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl; or R is ⁴ And R is ⁵ Optionally together form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

In some embodiments, ring A is optionally halogenated, -C ₁ -C ₄ Alkyl, -C ₁ -C ₄ Haloalkyl, -O-C ₁ -C ₄ Haloalkyl, -OH, -CN and-NH ₂ Substituted monocyclic heteroaryl; r is R ¹ 、R ³ 、R ⁴ And R is ⁶ Each independently selected from hydrogen and C ₁ -C ₄ An alkyl group; and R is ² And R is ⁵ Each independently is- (C) ₀ -C ₆ Alkylene) -Q; or R is ¹ And R is ² Optionally together form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl; or R is ⁴ And R is ⁵ Optionally together form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

In some embodiments, ring a is:wherein R is ⁹ Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group; each X is ^a Independently N or C-R ^9a Provided that when one X ^a When N is then two other X ^a Are all C-R ^9a The method comprises the steps of carrying out a first treatment on the surface of the And R is ^9a Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group.

In some embodiments, ring a is:wherein R is ⁹ Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group. In some embodiments, ring a is: />Wherein R is ⁹ Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group. In some embodiments, ring a is: />Wherein R is ⁹ Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group.

In some embodiments, ring A is optionally halogenated or-C ₁ -C ₄ Haloalkyl-substituted pyridinyl. In some embodiments, ring a is pyridinyl optionally substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is a quilt-C ₁ -C ₄ Haloalkyl (e.g. -CHF) ₂ And CF (compact F) ₃ ) Substituted pyridin-2-yl. In some embodiments, ring a is:wherein R is ⁹ Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group. In some embodiments, ring a is: />Wherein each R is ⁹ Independently selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group. In some embodiments, R ⁹ Is chlorine or fluorine. In some embodiments, R ⁹ is-CHF ₂ Or CF (CF) ₃ . In some embodiments, R ⁹ Is CF (CF) ₃ Or chlorine. In some embodiments, R ⁹ Is CF (CF) ₃ 。

In some embodiments, ring a is:wherein R is ^9b Selected from hydrogen and-C ₁ -C ₄ Alkyl, and wherein R ⁹ Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group.

In some embodiments, ring a is:wherein R is ^9b Selected from hydrogen and-C ₁ -C ₄ Alkyl, and wherein R ⁹ Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group. />

In some embodiments, ring a is:wherein R is ⁹ Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group. In some embodiments, ring A is optionally halogenated or-C ₁ -C ₄ Haloalkyl-substituted pyrazolyl. In some embodiments, ring a is pyrazolyl optionally substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is a quilt-C ₁ -C ₄ Haloalkyl (e.g. -CHF) ₂ And CF (compact F) ₃ ) Substituted 1H-pyrazol-1-yl. In some embodiments, ring a is: />Wherein R is ⁹ Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group. In some embodiments, R ⁹ Is chlorine or fluorine. In some embodiments, R ⁹ is-CHF ₂ Or CF (CF) ₃ . In some embodiments, R ⁹ Is CF (CF) ₃ Or chlorine. In some embodiments, R ⁹ Is CF (CF) ₃ 。

In some embodiments, ring a is: Wherein R is ⁹ Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group.

In some embodiments, ring a is:wherein R is ⁹ Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group.

In some embodiments, ring A is optionally halogenated or-C ₁ -C ₄ Haloalkyl-substituted pyridinyl. In some embodiments, ring A is halogenatedFor example chloro or fluoro). In some embodiments, ring A is a quilt-C ₁ -C ₄ Haloalkyl (e.g. -CHF) ₂ And CF (compact F) ₃ ) Substituted pyridyl. In some embodiments, ring A is optionally halogenated or-C ₁ -C ₄ Haloalkyl-substituted pyrazinyl. In some embodiments, ring a is pyrazinyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is a quilt-C ₁ -C ₄ Haloalkyl (e.g. -CHF) ₂ And CF (compact F) ₃ ) Substituted pyrazinyl. In some embodiments, ring A is optionally halogenated or-C ₁ -C ₄ Haloalkyl-substituted pyrimidinyl. In some embodiments, ring a is pyrimidinyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is a quilt-C ₁ -C ₄ Haloalkyl (e.g. -CHF) ₂ And CF (compact F) ₃ ) Substituted pyrimidinyl. In some embodiments, ring A is optionally halogenated or-C ₁ -C ₄ Haloalkyl-substituted pyrazolyl. In some embodiments, ring a is pyrazolyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is a quilt-C ₁ -C ₄ Haloalkyl (e.g. -CHF) ₂ And CF (compact F) ₃ ) Substituted pyrazolyl.

In some embodiments, R ¹ 、R ³ 、R ⁴ And R is ⁶ Each independently selected from hydrogen and C ₁ -C ₄ An alkyl group; a and R ² And R is ⁵ Each independently is- (C) ₀ -C ₆ Alkylene) -Q. In some embodiments, R ¹ And R is ⁴ Each hydrogen. In some embodiments, R ³ And R is ⁶ Each is C ₁ -C ₄ An alkyl group. In some embodiments, R ³ And R is ⁶ Each is C ₁ -C ₄ A 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, R ² And R is ⁵ Each independently is an unsubstituted cyclopropyl group. In some embodiments, R ¹ And R is ⁴ Each is hydrogen, R ³ And R is ⁶ Each is-CH ₃ And R is ² And R is ⁵ Each is unsubstituted cyclopropyl. In some embodiments, R ² Is- (C) ₀ -C ₆ Alkylene) -cyclopropyl and R ⁵ Is- (C) ₀ -C ₆ Alkylene) -aryl, such as optionally substituted phenyl. In some embodiments, R ² Is cyclopropyl and R ⁵ Is phenyl substituted with halo (e.g., fluoro).

In some embodiments, ring A is optionally halogenated or-C ₁ -C ₄ Haloalkyl-substituted pyridinyl. In some embodiments, ring a is pyridinyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is a quilt-C ₁ -C ₄ Haloalkyl (e.g. -CHF) ₂ And CF (compact F) ₃ ) Substituted pyridyl. In some embodiments, ring A is optionally halogenated or-C ₁ -C ₄ Haloalkyl-substituted pyrazinyl. In some embodiments, ring a is pyrazinyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is a quilt-C ₁ -C ₄ Haloalkyl (e.g. -CHF) ₂ And CF (compact F) ₃ ) Substituted pyrazinyl. In some embodiments, ring A is optionally halogenated or-C ₁ -C ₄ Haloalkyl-substituted pyrimidinyl. In some embodiments, ring a is pyrimidinyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is a quilt-C ₁ -C ₄ Haloalkyl (e.g. -CHF) ₂ And CF (compact F) ₃ ) Substituted pyrimidinyl. In some embodiments, ring A is optionally halogenated or-C ₁ -C ₄ Haloalkyl-substituted pyrazolyl. In some embodiments, ring a is pyrazolyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is a quilt-C ₁ -C ₄ Haloalkyl (e.g. -CHF) ₂ And CF (compact F) ₃ ) Substituted pyrazolyl.

In some embodiments, R ³ And R is ⁶ Each independently selected from hydrogen and C ₁ -C ₄ Alkyl group；R ¹ And R is ² Together form an optionally substituted carbocyclyl; and R is ⁴ And R is ⁵ Together form an optionally substituted carbocyclyl. In some embodiments, R ¹ And R is ² Together form a cyclobutyl, cyclopentyl or cyclohexyl group each of which is optionally substituted. In some embodiments, R ¹ And R is ² Together form a cyclopentyl or cyclohexyl group each optionally substituted. In some embodiments, R ⁴ And R is ⁵ Together form a cyclobutyl, cyclopentyl or cyclohexyl group each of which is optionally substituted. In some embodiments, R ⁴ And R is ⁵ Together form a cyclopentyl or cyclohexyl group each optionally substituted. In some embodiments, R ¹ And R is ² Together form a cyclopentyl or cyclohexyl group each substituted with one or more halo (e.g., fluoro); and R is ⁴ And R is ⁵ Together form a cyclobutyl, cyclopentyl or cyclohexyl group each substituted by one or more halo (e.g. fluoro). In some embodiments, R ¹ And R is ² Together form a bicyclo [3.1.0 ]]A hexyl group; and R is ⁴ And R is ⁵ Together form a bicyclo [3.1.0 ]]A hexyl group. In some embodiments, R ¹ And R is ² Together, and R ⁴ And R is ⁵ Together form: in some embodiments, R ¹ And R is ² Together, and R ⁴ And R is ⁵ Together form:in some embodiments, R ¹ And R is ² Together, and R ⁴ And R is ⁵ Together form:in some embodiments, R ¹ And R is ² Together, and R ⁴ And R is ⁵ Together form: />In some embodiments, R ¹ And R is ² Together; and R is ⁴ And R is ⁵ Together form: />The compounds are optionally substituted with cyano or halo (e.g., fluoro, chloro or bromo). In some embodiments, R ¹ And R is ² Together, and R ⁴ And R is ⁵ Together form:in some embodiments, R ¹ And R is ² Together 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 is ⁴ And R is ⁵ Together form a cyclobutyl, cyclopentyl or cyclohexyl group each substituted by one or more 6 membered monocyclic aryl groups (e.g. phenyl), which monocyclic aryl groups are optionally substituted by halo (e.g. fluoro, chloro or bromo). In some embodiments, R ¹ And R is ² Or R is ⁴ And R is ⁵ Together form: />Wherein ring C is phenyl, pyridinyl or pyrimidinyl, optionally substituted with cyano or halo (e.g., fluoro, chloro or bromo). In some embodiments, R ¹ And R is ² Or R is ⁴ And R is ⁵ Together form: />Wherein ring C is phenyl, pyridinyl or pyrimidinyl, optionally substituted with cyano or halo (e.g., fluoro, chloro or bromo). In some embodiments, R ¹ And R is ² Or R is ⁴ And R is ⁵ Together form:wherein ring C is phenyl, pyridinyl or pyrimidinyl, optionally substituted with cyano or halo (e.g., fluoro, chloro or bromo).

In some embodiments, R ¹ 、R ³ 、R ⁴ And R is ⁶ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl and-CN, wherein R ¹ 、R ³ 、R ⁴ And R is ⁶ Each of said alkyl moieties independently being optionally substituted with-OH, -NH ₂ 、-CN、-O-C ₁ -C ₄ Alkyl substitution; a and R ² And R is ⁵ Each independently selected from- (C) ₁ -C ₆ Alkyl) and- (C) ₀ -C ₆ Alkylene) -Q. In some embodiments, R ¹ 、R ³ 、R ⁴ And R is ⁶ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl and-CN; a and R ² And R is ⁵ Each independently is- (C) ₁ -C ₆ Alkyl) and- (C) ₀ -C ₆ Alkylene) -Q. In some embodiments, R ¹ 、R ³ 、R ⁴ And R is ⁶ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl and-CN; r is R ² Is- (C) ₁ -C ₆ An alkyl group); and R5 is- (C) ₀ -C ₆ Alkylene) -Q, wherein Q is optionally substituted carbocyclyl. In some embodiments, Q is unsubstituted carbocyclyl. In some embodiments, Q is cyclopropyl.

In some embodiments, ring A is optionally halogenated or-C ₁ -C ₄ Haloalkyl-substituted pyridinyl. In some embodiments, ring A is a quilt-C ₁ -C ₄ Haloalkyl (e.g. -CHF) ₂ And CF (compact F) ₃ ) Substituted pyridyl. In some embodiments, ring A is optionally halogenated or-C ₁ -C ₄ Haloalkyl-substituted pyrazinyl. In some embodiments, ring a is pyrazinyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is a quilt-C ₁ -C ₄ Haloalkyl (e.g. -CHF) ₂ And CF (compact F) ₃ ) Substituted pyrazinyl. In some embodiments, ring A is optionally halogenated or-C ₁ -C ₄ Haloalkyl-substituted pyrimidinyl. In some embodiments, ring a is pyrimidinyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is a quilt-C ₁ -C ₄ Haloalkyl (e.g. -CHF) ₂ And CF (compact F) ₃ ) Substituted pyrimidinyl. In some embodiments, ring A is optionally halogenated or-C ₁ -C ₄ Haloalkyl-substituted pyrazolyl. In some embodiments, ring a is pyrazolyl substituted with halo (e.g., chloro or fluoro). In some embodiments, ring A is a quilt-C ₁ -C ₄ Haloalkyl (e.g. -CHF) ₂ And CF (compact F) ₃ ) Substituted pyrazolyl.

In some embodiments, R ¹ 、R ³ And R is ⁶ Each independently selected from hydrogen and C ₁ -C ₄ Alkyl, wherein R is ¹ 、R ³ And R is ⁶ Each of said alkyl moieties independently being optionally substituted with-OH, -NH ₂ 、-CN、-O-C ₁ -C ₄ Alkyl, -NH (C) ₁ -C ₄ Alkyl) or-N (C) ₁ -C ₄ Alkyl group ₂ Substitution; r is R ² Is- (C) ₀ -C ₆ Alkylene) -Q; and R is ⁴ And R is ⁵ Together form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl. In some embodiments, R ⁴ And R is ⁵ Together form an optionally substituted carbocyclyl. In some embodiments, the carbocyclyl is selected from the group consisting of optionally substituted with-OH, -O (C ₁ -C ₄ Alkyl group, CO ₂ H or halo substituted cyclopentyl and cyclohexyl. In some embodiments, R ⁴ And R is ⁵ Together form an optionally substituted-OH, -O (C) ₁ -C ₄ Alkyl) -CO ₂ H or halo-substituted optionally substituted heterocyclyl. In some embodiments, R ⁴ And R is ⁵ Together forming an optionally substituted tetrahydrofuran. In some embodiments, R ¹ 、R ³ And R is ⁶ Each independently selected from hydrogen and C ₁ -C ₄ Alkyl, wherein R is ¹ 、R ³ And R is ⁶ Each of said alkyl moieties independently being optionally substituted with-OH, -NH ₂ 、-CN、-O-C ₁ -C ₄ Alkyl substitution; r is R ² Is- (C) ₀ -C ₆ Alkylene) -Q; and R is ⁵ Is C ₁ -C ₄ An alkyl group. In some embodiments, R ¹ 、R ³ And R is ⁶ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl or carbocyclyl, wherein R ¹ 、R ³ And R is ⁶ Each independently optionally substituted with-OH, -NH ₂ 、-CN、-O-C ₁ -C ₄ Alkyl, -SO ₂ -C ₁ -C ₄ Alkyl, -C (O) NH ₂ 、-O-R ¹² 、-CO ₂ R ¹² or-C (O) R ¹² Substitution, wherein R ¹² Is morpholinyl, piperidinyl, phenyl, pyridinyl or pyrimidinyl. In some embodiments, R ¹ 、R ³ And R is ⁶ Each independently selected from hydrogen and C ₁ -C ₄ Alkyl, wherein R is ¹ 、R ³ And R is ⁶ Each of said alkyl moieties independently being optionally substituted with-OH, -NH ₂ 、-CN、-O-C ₁ -C ₄ Alkyl, -O-R ¹² Substitution, wherein R ¹² Is phenyl, pyridinyl or pyrimidinyl; r is R ² Is- (C) ₀ -C ₆ Alkylene) -Q; and R is ⁵ Is C ₁ -C ₄ An alkyl group.

In some embodiments, R ⁷ Is H. In some embodiments, R ⁸ Is H. In some embodiments, R ⁷ And R is ⁸ Both are H.

In some embodiments, ring A, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ Selected from any of the foregoing 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 ^a is N or C-R ^9a Provided that when one X ^a When N is then two other X ^a Are all C-R ^9a ；

R ⁹ Is halo, -C ₁ -C ₄ Alkyl, -C ₁ -C ₄ Haloalkyl, -C ₁ -C ₄ Hydroxyalkyl, -NH-S (O) ₂ -(C ₁ -C ₄ Alkyl), -S (O) ₂ NH(C ₁ -C ₄ Alkyl), -CN, -S (O) ₂ -(C ₁ -C ₄ Alkyl group, C ₁ -C ₄ Alkoxy, -NH (C) ₁ -C ₄ Alkyl), -N (C) ₁ -C ₄ Alkyl group ₂ 、-OH、-OCF ₃ 、-CN、-NH ₂ 、-C(O)NH ₂ 、-C(O)NH(C ₁ -C ₄ Alkyl), -C (O) -N (C) ₁ -C ₄ Alkyl group ₂ 、-(C ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl), aryl, and cyclopropyl optionally substituted with OH;

each R ^9a Independently selected from hydrogen, halo, -C ₁ -C ₄ Alkyl, -C ₁ -C ₄ Haloalkyl, -C ₁ -C ₄ Hydroxyalkyl, -NH-S (O) ₂ -(C ₁ -C ₄ Alkyl), -S (O) ₂ NH(C ₁ -C ₄ Alkyl), -CN, -S (O) ₂ -(C ₁ -C ₄ Alkyl group, C ₁ -C ₄ Alkoxy, -NH (C) ₁ -C ₄ Alkyl), -N (C) ₁ -C ₄ Alkyl group ₂ 、-OH、-OCF ₃ 、-CN、-NH ₂ 、-C(O)NH ₂ 、-C(O)NH(C ₁ -C ₄ Alkyl), -C (O) -N (C) ₁ -C ₄ Alkyl group ₂ 、-(C ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl), aryl, and cyclopropyl optionally substituted with OH;

R ² and R is ⁵ Each independently selected from: - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₁ -C ₆ Alkyl) -CO ₂ H、-(C ₂ -C ₆ Alkenyl or alkynyl) - (C) ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkyl group),

-(C ₀ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -C (O) - (C) ₁ -C ₆ Alkyl) and- (C) ₀ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -Q, wherein:

R ⁴ And R is ⁵ Optionally together 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-pyridinyl) -N4, N6-dipropyl-4, 6-pyrimidinediamine;

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

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

(4) N6- [2- (dimethylamino) ethyl ] -N2', N4-tetramethyl- [2,4' -bipyrimidine ] -2',4, 6-triamine; or (b)

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

In some embodiments, R ⁴ And R is ⁵ Optionally together form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl.

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

wherein:

R ² and R is ⁵ Each independently selected from: - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₁ -C ₆ Alkyl) -CO ₂ H、-(C ₀ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -C (O) - (C) ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -Q, wherein:

exists in R ² And R is ⁵ Any alkyl or sub-group in (a)The alkyl moiety is optionally substituted with one or more-OH, -O (C ₁ -C ₄ Alkyl) -CO ₂ H or halo;

R ⁷ and R is ⁸ Each independently selected from hydrogen and C ₁ -C ₆ An alkyl group;

R ⁹ selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group; and is also provided with

R ¹ And R is ² Optionally together form an optionally substituted carbocyclyl, optionally substituted heterocyclyl; or (b)

R ⁴ And R is ⁵ Optionally together form an optionally substituted carbocyclyl, optionally substituted heterocyclyl;

wherein:

(i)N(R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither NHC (O) - [ 2-chloro-4- (methylsulfonyl)]Or N (CH) ₃ ) ₂ ，

(ii)N(R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHC (O) C (CH ₃ ) ₃ 、NHC(O)CH＝CH ₂ 、NHC(O)C(CH ₃ )＝CH ₂ 、NHCH ₂ CH ₂ OH, NH-cyclohexyl, NHCH ₂ -phenyl, NHC (O) (CH ₂ ) ₅ NH ₂ 、NHC(O)OCH ₃ 、NHC(O)CH ₃ And phenyl optionally substituted with NHC (O) NH, and

(iii) When N (R) ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) Is NHC (CH) ₃ ) ₃ When then N (R ⁸ )C(R ¹ )(R ² )(R ³ ) Not NHCH ₂ -phenyl or NH-CH ₂ CH ₃ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

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-pyridinyl) -1,3, 5-triazin-2-yl ] amino ] methyl ] cyclohexyl ] methyl ] -4-fluoro-benzenesulfonamide,

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

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

wherein:

R ³ and R is ⁶ Are all hydrogen;

R ¹ and R is ⁴ Each independently selected from C ₁ -C ₄ Alkyl and C ₁ -C ₄ A haloalkyl group; and is also provided with

R ² And R is ⁵ Each is- (C) ₁ -C ₆ An alkyl group); or (b)

R ¹ And R is ² Optionally together form an optionally substituted monocyclic carbocyclyl; or (b)

R ⁴ And R is ⁵ Optionally together form an optionally substituted monocyclic carbocyclyl;

wherein:

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

(ii) When R is ¹ And R is ² Optionally together form an unsubstituted cyclohexyl group, and R ⁴ And R is ⁵ Optionally together form an unsubstituted cyclohexyl group, then A is not a disubstituted 1-pyrazolyl or unsubstituted phenyl; and is also provided with

(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 is ^b Is independently N-R ^9b O, S, C-H or C-R ^9c Provided that at least one X ^b Is C-R ^9c And when an X ^b Is C-H or C-R ⁹ And the other is C-R ^9c Then X is ^c Is N; and when an X ^b Is N-R ^9b When O or S, then X ^c Is C;

R ^9b is hydrogen or-C ₁ -C ₄ An alkyl group;

R ^9c is halo, -C ₁ -C ₄ Alkyl, -C ₁ -C ₄ Haloalkyl, -C ₁ -C ₄ Hydroxyalkyl, -NH-S (O) ₂ -(C ₁ -C ₄ Alkyl), -S (O) ₂ NH(C ₁ -C ₄ Alkyl), -CN, -S (O) ₂ -(C ₁ -C ₄ Alkyl group, C ₁ -C ₄ Alkoxy group、-NH(C ₁ -C ₄ Alkyl), -N (C) ₁ -C ₄ Alkyl group ₂ 、-OH、-OCF ₃ 、-CN、-NH ₂ 、-C(O)NH ₂ 、-C(O)NH(C ₁ -C ₄ Alkyl), -C (O) -N (C) ₁ -C ₄ Alkyl group ₂ 、-(C ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl), aryl, and cyclopropyl optionally substituted with OH;

R ⁴ And R is ⁵ Optionally 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(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NH (CH) ₂ ) ₇ CH ₃ 、NHCH ₂ - (o-chloro-phenyl) or NHCH ₂ CH ₂ OH; and is also provided with

(ii) When X and X ^c All are N, then N (R) ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is N (CH) ₃ ) ₂ 、NHCH ₃ Or N (CH) ₂ CH ₃ ) ₂ 。

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

wherein:

R ⁹ is halo or-C ₁ -C ₄ A haloalkyl group; and is also provided with

R ⁴ And R is ⁶ Optionally together with the carbon atom to which it is attached form C (=o);

R ¹ and R is ² Optionally together form an optionalOptionally substituted carbocyclyl or optionally substituted heterocyclyl; or (b)

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 the method comprises the steps of

exists in R ² And R is ⁵ Optionally substituted with one or more of any alkyl or alkylene moietiesP-OH, -O (C) ₁ -C ₄ Alkyl) -CO ₂ H or halo;

R ⁴ And R is ⁵ Optionally together form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl.

A compound having the formula If:

wherein the method comprises the steps of

R ¹ 、R ³ 、R ⁴ And R is ⁶ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, -O-C ₁ -C ₄ Alkyl and CN, wherein R ¹ 、R ³ 、R ⁴ And R is ⁶ Each of said alkyl moieties independently being optionally substituted with-OH, -NH ₂ 、-CN、-O-C ₁ -C ₄ Alkyl group、-NH(C ₁ -C ₄ Alkyl) or-N (C) ₁ -C ₄ Alkyl group ₂ Substitution;

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

wherein:

exists in R ² And R is ⁵ Optionally any alkyl or alkylene moiety in (a)Is substituted with one or more groups of-OH, -O (C) ₁ -C ₄ Alkyl) -CO ₂ H or halo;

wherein:

(i) When A is optionally substituted with F, cl or SO ₂ CH ₃ When substituted phenyl, then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is N (CH) ₃ )CH ₂ C (O) NH-isopropyl, NHCH (CH) ₃ )(CH ₂ ) ₃ N(CH ₂ CH ₃ ) ₂ 、NHCH ₂ CH ₂ OH、NHCH ₂ CH ₂ OCH ₃ 、NHCH ₂ CH ₂ OSO ₃ H、NHCH ₂ CH ₂ CH ₂ OCH ₂ CH ₂ O-phenyl, NHCH ₂ CH ₂ CH ₂ OH、NHCH ₂ CH ₂ CH ₂ OCH ₃ 、NHCH ₂ CH(OH)CH ₃ 、N(CH ₂ CH ₃ ) ₂ NH-isopropyl, NHCH ₂ CH ₂ NHC(O)OCH ₃ 、NHCH ₂ CH ₂ NHC(O)CH ₃ 、NHCH ₂ CH ₂ NH ₂ Or NHCH ₂ -phenyl;

(ii) When A is optionally substituted pyridinyl, then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHCH ₂ -phenyl, NHCH ₂ - (2, 4-difluorophenyl), N (CH) ₃ )CH ₂ CH ₂ C(O)OH、NHCH ₂ CH ₂ C(O)OH、NHCH ₂ CH ₂ C(O)OCH ₂ CH ₃ 、NHCH ₂ CH ₂ C (O) O-tert-butyl, NHCH ₂ CH ₂ C(O)NH ₂ 、NHCH ₂ CH ₂ -phenyl, NHCH ₂ CH ₂ OH、NHCH ₂ CH ₂ NH ₂ 、NHCH ₂ CH ₂ N(CH ₃ ) ₂ Or NHCH ₂ CH ₂ CH ₃ ；

(iii) When A is optionally substituted 1-imidazolyl, optionally substituted 1-pyrrolyl or optionally substituted 1-pyrazolyl, then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NH (CH) ₂ ) ₇ CH ₃ 、NHCH ₂ - (o-chloro-phenyl) or NHCH ₂ CH ₂ OH；

(iv) When A is unsubstituted 2-pyridyl then by R ⁴ And R is ⁵ The ring formed is not 5-methyl-1H-pyrazol-3-yl; and is also provided with

(v) When A is optionally substituted 1-pyrazolyl then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is N (CH) ₃ ) ₂ 、NHCH ₃ NHAc, NH isopropyl, NHCH ₂ CH ₃ 、NHCH ₂ CH ₂ SO ₃ H or N (CH) ₂ CH ₃ ) ₂ ，

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

(vii) When R is ¹ And R is ² Optionally together form an unsubstituted cyclohexyl group, and R ⁴ And R is ⁵ Optionally together form an unsubstituted cyclohexyl group, then A is not a disubstituted 1-pyrazolyl or unsubstituted phenyl; and is also provided with

(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 R ⁹ Independently selected from halo, -C ₁ -C ₄ Alkyl, -C ₁ -C ₄ Haloalkyl, -C ₁ -C ₄ Hydroxyalkyl, -NH-S (O) ₂ -(C ₁ -C ₄ Alkyl), -S (O) ₂ NH(C ₁ -C ₄ Alkyl), -CN, -S (O) ₂ -(C ₁ -C ₄ Alkyl group, C ₁ -C ₄ Alkoxy, -NH (C) ₁ -C ₄ Alkyl group)、-N(C ₁ -C ₄ Alkyl group ₂ 、-OH、-OCF ₃ 、-CN、-NH ₂ 、-C(O)NH ₂ 、-C(O)NH(C ₁ -C ₄ Alkyl), -C (O) -N (C) ₁ -C ₄ Alkyl group ₂ 、-(C ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl), aryl, and cyclopropyl optionally substituted with OH;

n is 1 to 3;

Q is selected from carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein the method comprises the steps of

R ¹ And R is ² Optionally together form an optionally substituted carbocyclyl; or (b)

R ⁴ And R is ⁵ Optionally together form an optionally substituted carbocyclyl;

wherein:

(i)N(R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ NH ₂ Or 4- [ [2- [2- (2-aminoethoxy) ethoxy ]]Ethyl group]Amino group]，

(ii)N(R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Not both NHEt, NH (n-propyl), NH (n-butyl), NH (n-dodecyl), NH- [ (4-methoxyphenyl) methyl]、NHCH ₂ CH ₂ CHO、NHCH ₂ CH ₂ OCH ₃ 、NHCH ₂ CH ₂ OH、NHCH ₂ CH(OH)CH ₃ 、NHCH ₂ CH ₂ OC (O) phenyl, NHCH ₂ CH ₂ CH ₂ OH、NHCH ₂ CH ₂ CH ₂ N(CH ₃ ) Phenyl, NHCH ₂ C(O)OCH ₃ 、NHCH ₂ C(O)OCH ₂ CH ₃ 、NHCH ₂ Phenyl, NHCH (CH) ₃ )CH ₂ CH ₃ Or NHCH ₂ CH ₂ OC(O)CH ₃ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

(iii)N(R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NH cyclohexyl C (O) NHCH ₂ R, wherein R is OCF ₃ 、OCH ₃ Chlorine or CF ₃ Phenyl or pyridyl substituted with one or more substituents.

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;

R ¹ and R is ³ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, -O-C ₁ -C ₄ Alkyl and CN, wherein R ¹ 、R ³ 、R ⁴ And R is ⁶ Each of said alkyl moieties independently being optionally substituted with-OH, -NH ₂ 、-CN、-O-C ₁ -C ₄ Alkyl, -NH (C) ₁ -C ₄ Alkyl) or-N (C) ₁ -C ₄ Alkyl group ₂ Substitution;

R ² selected from: - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₁ -C ₆ Alkyl) -CO ₂ H、-(C ₂ -C ₆ Alkenyl or alkynyl) - (C) ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -Q, - (C ₀ -C ₆ Alkylene) -C (O) - (C) ₁ -C ₆ Alkyl) and- (C) ₀ -C ₆ Alkylene) -C (O) - (C) ₀ -C ₆ Alkylene) -Q, wherein:

exists in R ² Any alkyl or alkylene moiety of (C) is optionally substituted with one or more-OH, -O (C) ₁ -C ₄ Alkyl) -CO ₂ H or halo;

exists in R ² Any terminal methyl moiety in (a) is optionally substituted with-CH ₂ OH、CF ₃ 、-CH ₂ F、-CH ₂ Cl、C(O)CH ₃ 、C(O)CF ₃ CN or CO ₂ H replacement;

R ⁷ and R is ⁸ Each independently selected from hydrogenAnd C ₁ -C ₆ An alkyl group; and is also provided with

R ¹ And R is ² Optionally together form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl;

wherein when a is an oxadiazole substituted with an optionally substituted pyridinyl, 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, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, -CN, =o, -OH, aryl, heteroaryl-SO ₂ C ₁ -C ₄ Alkyl, -CO ₂ C ₁ -C ₄ Alkyl, -C (O) aryl and-C (O) C ₁ -C ₄ An 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 ^d is C or N;

each R ^b Independently selected from halo, CN, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, C ₃ -C ₆ Cycloalkyl, phenyl, -OH, -C (O) CH ₃ Wherein any alkyl, cycloalkyl or phenyl moiety is optionally substituted with fluorine, chlorine, -OH, -NH ₂ or-CN substitution;

p is 1 to 2;

R ² selected from: - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₁ -C ₆ Alkyl) -CO ₂ H、-(C ₂ -C ₆ Alkenyl or alkynyl) - (C) ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkyl group),

R ¹ And R is ² Optionally together form oneOptionally substituted carbocyclyl or optionally substituted heterocyclyl;

wherein when A is an oxadiazole substituted with an optionally substituted pyridinyl group then X ^d 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 also provided with

G is an optionally substituted carbocyclyl or heterocyclyl,

wherein a is not oxadiazole substituted with optionally substituted pyridinyl.

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;

Each R ^b Independently selected from halo, CN, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, C ₃ -C ₆ Cycloalkyl, phenyl, -OH, -C (O) CH ₃ Wherein any alkyl, cycloalkyl or phenyl moiety is optionally substituted with fluorine, chlorine, -OH, -NH ₂ or-CN substitution; and is also provided with

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 also provided with

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 of the compounds listed in table 1 below.

TABLE 1 representative Compounds

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Also included herein are methods for making a compound of formula I or a compound of any of the embodiments described herein, including reacting And->And (3) reacting. In some embodiments, the aforementioned method comprises the steps of (1) allowing +_>And->Reaction to give->And step (2) of->And->And (3) reacting. In other embodiments, the aforementioned method comprises the steps of (1) allowing +.>And->Reaction to give->Step (2) enable->And->Reaction to give->And step (3) of ∈ ->And->And (3) reacting.

Also included are methods for making a compound of formula I or a compound of any of the embodiments described herein, including reactingAnd->And (3) reacting.

Also included are methods for making a compound of formula I or a compound of any of the embodiments described herein, including reactingAnd->And (3) reacting. In some embodiments, the aforementioned method comprises the steps of (1) allowing +_>And->Reaction to give->And step (2) of->And->And (3) reacting.

Also included are methods for making a compound of formula I or a compound of any of the embodiments described herein, including reactingAnd->And (3) reacting. In other embodiments, the aforementioned method comprises the steps of (1) treating with +.>Transformation->To get +.>Step (2) of causingWith PCl ₅ 、POCl ₃ Reaction to give->Step (3) enable->And->Reaction to give->And step (4) of->And->And (3) reacting. In other embodiments, the aforementioned method comprises the steps of (1) treating with +. >Transformation->To get +.>Step (2) enable->With PCl ₅ 、POCl ₃ Reaction to give->Step (3) enable->And (3) withReaction to give->And step (4) of->And->And (3) reacting. At the position ofIn other embodiments, the aforementioned method comprises the steps of (1) treating with +.>Transformation->To get +.>Step (2) enable->With PCl ₅ 、POCl ₃ Reaction to give->Step (3) of causingAnd->Reaction to give->And step (4) of->And (3) withAnd (3) reacting. In other embodiments, the method comprises the steps of: make->And->Reacting 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->And->Reaction to give->And 2) let->And->Reaction to give->Wherein ring B is an aryl or heteroaryl ring. In other embodiments, the method comprises the steps of: make->And->Reacting 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->React with ring A to form->

The compounds of one aspect of the invention may contain one or more asymmetric centers and thus appear in the form: racemates, racemic mixtures, non-racemic mixtures and diastereomeric mixtures, as well as 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 the 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 for obtaining or synthesizing individual enantiomers or stereoisomers of a given compound are known in the art and, as applicable, may be adapted for use in 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 one or more structures having the 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, including ¹ H、 ² H (D or deuterium) and ³ h (T or tritium); c may be in any isotopic form, including ¹¹ C、 ¹² C、 ¹³ C and C ¹⁴ C, performing operation; the method comprises the steps of carrying out a first treatment on the surface of the N may be in any isotopic form, including ¹³ N、 ¹⁴ N and ¹⁵ n; o may be in any isotopic form, including ¹⁵ O、 ¹⁶ O and ¹⁸ o; f may be in any isotopic form, including ¹⁸ F；Etc. 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 that does not indicate stereochemistry and has one or more chiral centers, it is to be understood as meaning all possible stereoisomers of the compound.

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

The corresponding salts of the active compounds, for example pharmaceutically acceptable salts, can be conveniently or desirably prepared, purified and/or processed. Examples of pharmaceutically acceptable salts are discussed in Berry et al, 1977, "pharmaceutically acceptable salts (Pharmaceutically Acceptable salts)", journal of pharmaceutical science (J.Pharm.Sci.), volume 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-), then 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 Mg (magnesium) ²⁺ ) Other cations (e.g. Al ³⁺ ). Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH ₄ ⁺ ) And substituted ammonium ions (e.g., NH ₃ R ⁺ 、NH ₂ R ²⁺ 、NHR ³⁺ 、NR ⁴⁺ ). Examples of some suitable substituted ammonium ions are those derived from: ethylamineDiethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and bradykinin, along with amino acids such as lysine and arginine. One example of a common quaternary ammonium ion is N (CH ₃ ) ₄ ⁺ 。

If the compound is cationic, or has a functional group that may be cationic (e.g., -NH- ₂ Can be-NH ₃ ⁺ ) 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, hydroxymaleic acid, hydroxynaphthoic acid, hydroxyethanesulfonic acid, lactic acid, lactonic 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 expressly included herein. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid and 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, such as 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 for injection administration, alter metabolism, and alter excretion rates. 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 upon administration to a subject. If applicable, calcium phosphate and sodium phosphate of each of the compounds in Table 1 are expressly included herein. 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 the 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 that does not destroy its pharmacological activity and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that can 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) (such as d-alpha-tocopheryl polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (such as Tween (Tween) or other similar polymeric delivery matrices), serum proteins (such as human serum albumin), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate), polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin. Cyclodextrins (e.g., α -cyclodextrin, β -cyclodextrin, and γ -cyclodextrin) or chemically modified derivatives (e.g., hydroxyalkyl cyclodextrins, including 2-hydroxypropyl- β -cyclodextrin and 3-hydroxypropyl- β -cyclodextrin) or other solubilized derivatives may also be advantageously used to enhance delivery of compounds having the chemical 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 implantable reservoir, preferably by oral administration or injection. 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 a pharmaceutically acceptable acid, base, or buffer to enhance the stability of the formulated compound or delivery form thereof. The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

The pharmaceutical composition may be in the form of a sterile injectable preparation, for example, as 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 nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be employed are mannitol, water, ringer's solution (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 its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. 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 the formulation of 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 tween series or span series (Spans) and/or other similar emulsifying agents or bioavailability enhancers, may also be used for formulation purposes.

The pharmaceutical compositions of one aspect of the present 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, common carriers include lactose and corn starch. Typically, a lubricant such as magnesium stearate is also 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 can be suspended or dissolved in an oil phase combined with emulsifying and/or suspending agents. If desired, certain sweeteners and/or flavoring agents and/or coloring agents may be added.

The pharmaceutical compositions 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 therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

Topical administration of the pharmaceutical composition of one aspect of the invention is useful when the desired treatment involves areas or organs readily accessible by topical administration. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment comprising the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of compounds of one aspect of the 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 comprising the active compound suspended or dissolved in a carrier with a suitable emulsifying agent. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetostearyl 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 the form of a suitable enema formulation. Topical transdermal patches are also included in one aspect of the invention.

The pharmaceutical composition of one aspect of the present 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 physiological saline using 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 having the formula described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additive should be present at a dosage level of between about 1% to 100%, and more preferably between about 5% to 95%, of the dosage normally administered in a monotherapy regimen. As part of a multi-dose regimen, the additive may be administered separately from the compounds of one aspect of the invention. Alternatively, those agents may be part of a single dosage form, mixed in a single composition with the compounds of one aspect of the invention.

The compounds described herein may be administered, for example, by injection, intravenously, intra-arterially, 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 at a dose between 1mg and 1000mg per dose, every 4 to 120 hours, or as desired for a particular drug. These methods contemplate administration of an effective amount of a compound or combination of compounds to achieve the 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 a continuous infusion. Such administration may be used as chronic or acute therapy. The amount of active ingredient that can be combined with the carrier material 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 dosage and treatment regimen for any particular subject will depend upon a variety of factors including the activity of the particular 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 symptoms, the subject being susceptible to the disease, condition or symptoms, and the judgment of the treating physician.

After the condition of the subject is ameliorated, 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 dosage 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 the desired level. However, the subject may require intermittent treatment based on long-term consideration of any recurrence of disease symptoms.

The pharmaceutical composition comprising a compound of formula I, ia, ib, B, C, ic, id, ie, if, ig, II, III, IIIa, IIIb, IIIc or IIId described above or a compound described in any of this example may further comprise another therapeutic agent for treating cancer.

Application method

There is provided a method for inhibiting mutant IDH1 activity, 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 as described in any one of this example, 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 an R132X mutation. In one aspect of this embodiment, the R132X mutation is selected from R132H, R132C, R132L, R132V, R S 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 cancers characterized by the presence of a mutant allele of IDH1, comprising the steps of: administering to a subject in need thereof (a) a compound having formula I, ia, ib, B, C, ic, id, ie, if, ig, II, III, IIIa, IIIb, IIIc or IIId, or a compound described in any one of this examples, 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, R S and R132G. In another aspect, the R132X mutation is R132H or R132C. Cancers can be analyzed by sequencing cell samples to determine the presence and specific nature of mutations at amino acid 132 of IDH1 (e.g., altered amino acids present therein).

Without being bound by theory, applicants believe that the 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), and in particular the R132H mutation of IDH1 characterizes all types of cancer subgroups, irrespective 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 that confers such activity, and in particular the IDH 1R 132H or R132C mutation.

In one aspect of this embodiment, the efficacy of the cancer treatment is monitored by measuring the level of 2HG in the subject. Typically, 2HG levels are measured prior to treatment, with elevated levels indicating the use of 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 to treat cancer. Once elevated levels are established, 2HG levels are measured during and/or after the process of terminating the therapy to determine efficacy. In certain embodiments, 2HG levels are determined only during and/or after the course of terminating the therapy. A decrease in 2HG levels during the course of treatment and after treatment indicates therapeutic efficacy. Similarly, a determination that 2HG levels did not increase during or after the course of treatment also indicates therapeutic 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 the 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 may be collected and stored at-80 ℃ and then subjected to LC-MS/MS to assess 2-hydroxyglutarate levels. A variety of different Liquid Chromatography (LC) separation methods can be used. Each method may be coupled by negative electrospray ionization (ESI, -3.0 kV) to a triple quadrupole mass spectrometer operating in a Multiple Reaction Monitoring (MRM) mode, where the MS parameters are optimized with respect to the infused metabolite standard solution. The metabolite can be purified by reverse phase chromatographyThe isolation was performed according to a variant of the previously reported method (Luo et al J.chromatography A.J. (J chromatogrA) 1147,153-64,2007) using 10mM tributylamine as the ion-pairing agent in the aqueous mobile phase. One method allows resolution of TCA metabolites: t=0, 50% b; t=5, 95% b; t=7, 95% b; t=8, 0% B, where B refers to the organic mobile phase of 100% methanol. Another method is specific for 2-hydroxyglutarate and runs a rapid linear gradient from 50% to 95% b (buffer as defined above) over 5 minutes. As described above, a Synergi Hydro-RP,100mm 2mm,2.1 μm particle size (Phenomonex) can be used as column. Metabolites can be quantified by comparing peak areas to pure metabolite standards of known concentration. Can be obtained as described, for example, in Nature Biotechnology 26,1179-86,2008, nat Biotechnol, munger et al ¹³ C-glutamine was subjected to metabolic flux studies.

In one embodiment, 2HG is directly evaluated.

In another embodiment, the derivatives of 2HG formed during the performance of the assay method are evaluated. By way of example, such a derivative may be a derivative formed in 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), for example as formed in MS analysis.

In another embodiment, the metabolic derivative of 2HG is evaluated. Examples include substances that accumulate or rise 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 or salt adducts thereof provided below:

and +.>

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.

IDH1R 132X mutations are known to occur in certain types of cancers as indicated in table 2 below.

TABLE 2 IDH mutations associated with certain cancers

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The IDH 1R 132H 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 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 hematological malignancy to be treated is 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 of the cancer types listed in table 2, and the IDH R132X mutation is one or more of the IDH1R132X mutations listed in table 2 for a particular cancer type.

The methods of treatment described herein may additionally include different assessment 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 embodiments 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 having 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 one 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 one of the embodiments described herein. This can be achieved by: spectroscopic analysis, such as 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 surgical material, for example by mass spectrometry.

Also provided is a method for inhibiting mutant IDH2 activity, 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 one of this examples, 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 the subject. In one aspect of this embodiment, the mutant IDH2 has an 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 an R172X mutation. In another aspect of this embodiment, the R172X mutation is an R172K mutation. In another aspect of this embodiment, the R172X mutation is an R172G mutation.

Also provided are methods of treating cancers characterized by the presence of mutant alleles of IDH2, comprising the steps of: administering to a subject in need thereof (a) a compound having formula I, ia, ib, B, C, ic, id, ie, if, ig, II, III, IIIa, IIIb, IIIc or IIId, or a compound described in any one of this examples, 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 an 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 an R172X mutation. In another aspect of this embodiment, the R172X mutation is an R172K mutation. In another aspect of this embodiment, the R172X mutation is an R172G mutation. Cancers can be analyzed by sequencing cell samples to determine the presence and specific nature of mutations (e.g., altered amino acids present herein) at amino acids 140 and/or 172 of IDH 2.

Without being bound by theory, applicants believe that the 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), and in particular the R140Q and/or R172K mutation of IDH2 characterizes all types of cancer subgroups, irrespective 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 that confers such activity, and in particular the IDH2R140Q and/or R172K mutation.

In one aspect of this embodiment, the efficacy of the cancer treatment is monitored by measuring 2HG levels, as described herein.

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 IDH2R140Q, R W 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 cancer in a patient 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 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 in an amount 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 hereditary metabolic disorder 2-hydroxyglutarate. This disease is caused by the absence of the enzyme 2-hydroxyglutarate dehydrogenase, which converts 2HG to alpha-KG (Schtelus, E.A. (Struys, E.A.), et al, J Hum Genet) 76,358-60 (2005). Patients lacking 2-hydroxyglutarate dehydrogenase accumulate 2HG in the brain as assessed by MRI and CSF analysis, suffer from leukoencephalopathy, and have increased risk of suffering from brain tumors (aghuli, m.), zahel, f. (zahel, f.), (journal of neuro-tumors) (J neuroooncol) 91,233-6 (2009), colkel, s. (Kolker, s.), mayan, e. (mayan, e.), huffman, g.f. (Hoffmann, g.f.), (pediatric neurologic (neuropeditrics) 33,225-31 (2002)), watts, m. (wanner, m.)), latini (Latini, a), wisdom, wye (a.t.) (c. Du Tela, e.) (d.)) and f.) (d.34-35, c.37. 37. C. 35) are included. In addition, elevated brain levels of 2HG cause increased ROS levels (Kelcer, S. Et al, J. European neuroscience) 16,21-8 (2002); latinib, A. Et al, J. European neuroscience 17,2017-22 (2003)), potentially leading to increased risk of cancer. The ability of 2HG to act as an NMDA receptor agonist may facilitate this effect (Kelcer, S. et al J.European neuroscience 16,21-8 (2002)). 2HG may also be toxic to cells by competitively inhibiting enzymes that employ glutamate and/or αkg. These enzymes include transaminases that allow the use of glutamate nitrogen for amino and nucleic acid biosynthesis, and αkg-dependent prolyl hydroxylases, such as those that modulate HIF1- α levels.

Thus, according to another embodiment, one aspect of the invention provides a method of treating 2-hydroxyglutarate, especially D-2-hydroxyglutarate, 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 as described in any one of the embodiments described herein.

Also provided are methods of treating a disease selected from Ma Fuxi syndrome (Maffucci syndrome) and Oliler disease (Oliler disease) 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 one of this examples, 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 one 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 further step of co-administering to a subject in need thereof a second therapy, e.g., an additional cancer therapeutic agent or an additional cancer treatment. Exemplary additional cancer therapeutic agents include, for example, chemotherapy, targeted therapy, antibody therapy, immunotherapy, and hormonal therapy. Additional cancer treatments include, for example: surgery and radiation therapy. Examples of each of these treatments are provided below.

The term "co-administered" as used herein with respect to another cancer therapeutic agent means that the other cancer therapeutic agent may be administered with the compound of one aspect of the present invention in a single dosage form (e.g., a composition of one aspect of the present invention comprising the compound of one aspect of the present invention and a second therapeutic agent as described above) in a portion of a single dosage form or in separate multiple dosage forms. Alternatively, additional cancer therapeutic agents may be administered prior to, sequentially with, or after administration of the compounds 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 the separate administration of the same therapeutic agent, any other second therapeutic agent or any compound of one aspect of the invention to the subject at another time during the course of treatment. The term "co-administration" as used herein with respect to another cancer treatment means that the another cancer treatment may occur before, sequentially therewith, concurrently therewith, or thereafter with the administration of a compound of an 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 mustard, nitrosourea, platinum, alkyl sulfonates, hydrazine, triazenes, aziridines, spindle toxins, cytotoxic agents, topoisomerase inhibitors, etc.), and hypomethylating agents (e.g., decitabine (5-aza-deoxycytidine), zebulaine (zebulaine), isothiocyanates, azacytidine (5-azacytidine), 5-fluoro-2' -deoxycytidine, 5, 6-dihydro-5-azacytidine, etc.). Exemplary agents include doxorubicin, actinomycin, aliskiren, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotekang, bei Seluo statin, bendamustine, bleomycin, bortezomib, busulfan, camptothecine, capecitabine, carboplatin, carboquinone, carmofur, carmustine, celecoxib chlorambucil, cisplatin, cladribine, clofarabine, cleistase, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, decitabine, colchicine docetaxel, doxorubicin, etoricoxil, ai Limo moles, epothilone, enocitabine, epirubicin, estramustine, etodolac, etoposide, floxuridine, fludarabine fluorouracil (5 FU), fotemustine, gemcitabine, gliadel implant (Gliadel implant), hydroxyurea, idamycin, ifosfamide, irinotecan, ilofipronil, ixabepilone, leucovorin, liposomal doxorubicin, liposomal daunorubicin, lonidamine, lomustine, methione, mannsulfane, madolol, melphalan, mercaptopurine, sodium thioethane sulfonate, methotrexate, minolevulinate, dibromomannitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, orlistat, ol Ma Taxin, ostazol, oxaliplatin, pacific, paclitaxel, peginase, melphalan, praziquantel, pirarubicin, pramipexole, phenomycin, sodium phenobane, procarbazine, and pharmaceutical compositions containing the same, raltitrexed, ranimustine, lubitecan, sapatmostine, semustine, adenovirus vector localization code gene injection (Sitimagene ceradenovec), sarpatatin (straaplatin), streptozocin, talaporfin, pyranfludine-uracil, temoporfin, temozolomide, teniposide, temozolomide, testosterone, tetranitrate, thiotepa, thifurin, thioguanine, tepiroxicam, topotecan, trabectedin, triamine quinone, trolamine, terliplatin, retinoic acid, troostin, qu Luolin amine, uramustine, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, levorubicin, and other cytostatics or cytotoxic agents described herein.

Because some drugs work better together than alone, two or more drugs are typically 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), 4-hydroxy-phenyl-retinoic acid amide (4-HPR)); arsenic trioxide; histone deacetylase inhibitors HDAC (such as azacytidine (Vidaza) and butyrate (e.g., sodium phenylbutyrate)); mixing polar compounds (such as hexamethylenediacetamide ((HMBA)); vitamin D; and cytokines (such as 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 therapies constitute a therapeutic approach to cancer cellsThe use of agents specific for the deregulated protein of (2). Small molecule targeted therapy drugs are typically inhibitors of mutations, over-expression, or otherwise critical enzymatic domains of proteins within cancer cells. Prominent examples are tyrosine kinase inhibitors such as axitinib, bosutinib, ceritinib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, litatinib, nilotinib, simaflatinib, sorafenib, sunitinib and vandetanib; and cyclin-dependent kinase inhibitors such as acixidibu and plug Li Xibu. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody that specifically binds to a protein on the surface of cancer cells. Examples include trastuzumab, an anti-HER 2/neu antibody typically used in breast cancer And rituximab and tositumomab, anti-CD 20 antibodies typically used in a variety of B-cell malignancies. Other exemplary antibodies include cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, ibritumomab and gemtuzumab. Exemplary fusion proteins include albesii and dinium interleukins. In some embodiments, targeted therapies 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" that can bind to cell surface receptors or infected extracellular matrix surrounding tumors. If the nuclides decay in the vicinity of the cell, the radionuclides attached to these peptides (e.g., RGD) eventually kill the cancer cells. One example of such a therapy includes

In some embodiments, the additional cancer therapeutic agent is an immunotherapeutic 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 immune responses against tumors include intracapsular BCG immunotherapy for superficial bladder cancer and induction of immune responses in renal cell carcinoma and melanoma subjects using interferon and other cytokines.

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, the immunotherapeutic 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. Growth of some cancers may be inhibited by providing or blocking certain hormones. Common examples of hormone sensitive tumors include certain types of breast and prostate cancers. Removal or blocking 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, the hormone therapy agent may be used in combination with a compound or composition described herein.

Other possible additional modes of treatment include imatinib, gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxin, and radiolabeled drugs and antibodies.

Examples

General experimental notes:

in the following examples, reagents (chemicals) were purchased from commercial sources such as alpha (Alfa), an Kele s (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 Broker (Brucker) AMX-400NMR (Broker, switzerland). Chemical shifts are reported in parts per million (ppm, delta) low fields compared to tetramethylsilane. Mass spectra were given by electrospray ionization (ESI) from a Waters LCT TOF mass spectrometer (Waters, usa) or a Shimadzu LC-MS-2020 mass spectrometer (Shimadzu, japan). The microwave reaction was carried out on an Initiator 2.5 microwave synthesizer (Biotage, sweden).

The details regarding the exemplary compounds disclosed in this section, stereoisomers (e.g., (R) or (S) stereoisomers) demonstrate the preparation of the compounds such that the compounds are enriched at least about 90%, 95%, 96%, 97%, 98%, or 99% at the designated stereocenter. The chemical name of each of the exemplary compounds described below was generated by ChemDraw software.

List of abbreviations:

universal use

Anhy. Anhydrous

aq. aqueous solution

min

hrs hours

mL of

mmol millimoles

mol

MS mass spectrum

NMR nuclear magnetic resonance

TLC thin layer chromatography

HPLC high performance liquid chromatography

satd. Saturation

Spectrum of light

Hz hertz

Delta chemical shift

J coupling constant

s single peak

d double peak

t triplet

q quartet

m multiple peaks

br broad peak

qd quadruple double peak

dquin double five peaks

dd double doublet

dt double trimodal

Solvents and reagents

DAST diethylaminosulfur trifluoride

CHCl ₃ Chloroform (chloroform)

DCM dichloromethane

DMF dimethylformamide

Et ₂ O 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

H ₂ SO ₄ Sulfuric acid

NH ₄ Cl ammonium chloride

KOH potassium hydroxide

NaOH sodium hydroxide

K ₂ CO ₃ Potassium carbonate

Na ₂ CO ₃ Sodium carbonate

TFA trifluoroacetic acid

Na ₂ SO ₄ Sodium sulfate

NaBH ₄ Sodium borohydride

NaHCO ₃ Sodium bicarbonate

NaHMDS hexamethyldisilazane sodium amide

LiHMDS hexamethyldisilazane lithium amide

Lithium aluminum hydride LAH

NaBH ₄ Sodium borohydride

LDA lithium diisopropylamide

Et ₃ N-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 tetrafluoroboric acid 2- (1H-benzotriazol-1-yl) -1, 3-tetramethylurea

DPPA diphenyl azide phosphate

NH ₄ OH 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

Preparing the 1-phenylcyclopropylamine.

To a solution of benzonitrile (5 g,48mmol,3 eq.) and titanium tetraisopropoxide (21.5 mL,73mmol,1.5 eq.) in dry THF (140 mL) was added dropwise ethylmagnesium bromide (48.5 mL,146 mmol) over 30 minutes at-70 ℃. The solution was stirred at room temperature for 1.5 hours, followed by dropwise addition of boron trifluoride etherate (15 mL,121mmol,2.5 eq.) over 15 minutes. The mixture was stirred at room temperature for an additional 1.5 hours, followed by the addition of 1N aqueous HCl and Et ₂ O. The resulting mixture was poured into 10% aqueous NaOH and used with Et ₂ And O extraction. By anhydrous Na ₂ SO ₄ The combined organic layers were dried and concentrated. By column chromatography using PE/EtOAc/NH ₃ .H ₂ 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 NH ₄ KCN (5 g,76.9 mmol) was added to a mixture of Cl (4.9 g,92.3 mmol) and acetone (7 mL,92.3 mmol) in ammonium hydroxide (40 mL,230.7 mmol). The reaction mixture was stirred at room temperature for 3 days. The mixture was extracted with DCM (2X 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and concentration to obtain the desired product, which is used directly in the next step without any further purification.

Preparation of 2-aminopropionitrile

At room temperature, to NH ₄ KCN (1 g,15.4 mmol) was added to a mixture of Cl (981 mg,18.5 mmol), acetaldehyde (1 mL,18.5 mmol) in ammonium hydroxide (3 mL). The reaction mixture was stirred at room temperature for 2 days. The mixture was extracted with DCM (2X 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and concentration to obtain the desired product, which is used directly in the next step without any further purification.

Preparation of dicyclohexylmethylamine

Step 1, preparing the dicyclohexyl ketoxime. To a mixture of dicyclohexyl ketone (500 mg,4.5 mmol) in pyridine (5 mL) was added hydroxylamine hydrochloride (469 mg,6.75 mmol). The reaction mixture was stirred at 100deg.C for 4 hours and cooled to room temperature, followed by the addition of EtOAc. The resulting mixture was washed with 1N aqueous HCl and brine, and dried over anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure to give the desired product which is used directly in the next step without any further purification.

LC-MS:m/z 124.1(M-H) ^- 。

And 2, preparing the dicyclohexylmethylamine. To a cooled solution of dicyclohexylketoxime (550 mg,4.4 mmol) in THF (5 mL) was added LiAlH ₄ (200 mg,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. By anhydrous Na ₂ SO ₄ The 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: benzyl cyclopent-3-enyl carbamate was prepared. Et is added to a solution of cyclopent-3-enecarboxylic acid (5 g,44.6mmol,1 eq.) and DPPA (13.5 g,49mmol,1.1 eq.) in toluene (80 mL) at room temperature ₃ N (7.4 mL,53.5mmol,1.2 eq.). The mixture was then stirred at reflux for 2 hours during which time a greater amount of nitrogen was evolved. After addition of BnOH (7 mL,66.9mmol,1.5 eq.) the resulting mixture was stirred at 100deg.C overnight and cooled to room temperature. In the presence of saturated aqueous NaHCO ₃ After quenching, the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, 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]]Benzyl hex-3-ylcarbamate. To a solution of benzyl cyclopent-3-enyl carbamate (1 g,4.6mmol,1 eq.) in anhydrous DCM at 0deg.C under nitrogen atmosphere was added ZnEt ₂ (9.7 mL,9.7mmol,2.1 eq.) followed by dropwise addition of CH ₂ I ₂ (0.78 mL,9.7mmol,2.1 eq.). 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. By anhydrous Na ₂ SO ₄ The 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) ⁺ 。

Step 3: preparation of bicyclo [3.1.0] hex-3-amine. To a solution of benzyl bicyclo [3.1.0] hex-3-ylcarbamate (2 g) in MeOH (20 mL) at room temperature under nitrogen was added Pd/C (0.2 g) 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: preparing 4-chloro-N-methoxy-N-methylpyridine amide. To a solution of 4-chloropicolinic acid (10 g,63.5 mmol) in DMF (150 mL) was added TBTU (30.6 g,95.2 mmol), N, O-dimethylhydroxylamine (9.3 g,95.2 mmol) and DIPEA (24.6 g,190.4 mmol) at 0deg.C. The mixture was stirred at room temperature overnight. With saturated aqueous NH ₄ The reaction mixture was diluted with Cl and extracted with EtOAc. With Na ₂ SO ₄ The 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-methylpyridinamide (11.25 g,56.08 mmol) in THF (50 mL) was added MeMgBr (28.04 mL,84.12 mmol) at 0deg.C. The mixture was then stirred at room temperature overnight and saturated aqueous NH ₄ And (5) quenching Cl. The resulting mixture was extracted with EtOAc. By anhydrous Na ₂ SO ₄ The organic layer was dried and concentrated. The residue was purified by flash chromatography to give the desired product.

¹ H NMR(400MHz,CDCl ₃ ):δ8.52(d,J＝5.2Hz,1H),7.96(s,1H),7.40(d,J＝5.2Hz,1H),2.64(s,3H)。LC-MS:m/z 156.0(M+H) ⁺ 。

Step 3: 4-chloro-2- (1, 1-difluoroethyl) pyridine. DAST (65.2 g,405 mmol) was added to a solution of 1- (4-chloropyridin-2-yl) ethanone (6.3 g,40.5 mmol) in DCM (30 mL) at 0deg.C. The mixture was then stirred at room temperature overnight and saturated aqueous NaHCO ₃ Quenching. The resulting mixture was extracted with DCM. By anhydrous Na ₂ SO ₄ The organic layer was dried and concentrated. Purification of the residue by flash chromatographyThe desired product is obtained.

¹ H NMR(400MHz,CDCl ₃ ):δ8.48(d,J＝5.2Hz,1H),7.60(s,1H),7.31(d,J＝5.2Hz,1H),1.90-1.99(m,3H)。LC-MS:m/z 178.0(M+H) ⁺ 。

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 (6.0 g,33.8 mmol) in dioxane (20 mL) was added BocNH at room temperature ₂ (4.74g，40.5mmol)、X-phos(1.14g，1.7mmol)、CsCO ₃ (16.5 g,50.7 mmol) and Pd (OAc) ₂ (1.32 g,2.7 mmol). The mixture was then stirred at 80 ℃ overnight and then cooled to room temperature. With saturated aqueous NH ₄ The reaction mixture was diluted with Cl and extracted with EtOAc. By anhydrous Na ₂ SO ₄ The 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) ⁺ 。

Step 5: preparation of 2- (1, 1-difluoroethyl) pyridin-4-amine. A solution of tert-butyl (2- (1, 1-difluoroethyl) pyridin-4-yl) carbamate (7.97 g,30.86 mmol) in DCM (30 mL) was cooled under an ice-water bath. TFA (10 mL) 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 NaHCO ₃ Adjusting pH>7. The resulting mixture was extracted with DCM. By anhydrous Na ₂ SO ₄ The 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) cyclopropanecarbonitriles

Step 1: preparation of 1- (4-bromopyridin-2-yl) cyclopropanecarbonitrile. To a cold (-5 ℃) mixture of 4-bromo-2-fluoropyridine (1 g,5.7 mmol), cyclopropanecarbonitrile (1.25 mL,17mmol,3 eq.) and 4A MS in toluene (20 mL) was added LiHMDS (1M in toluene, 17.6mL,17.6mmol,3.1 eq.) 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 H ₂ The filtrate was diluted with O and extracted with EtOAc. The organic phase was washed with water and brine, with anhydrous Na ₂ SO ₄ Dried, 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 (0.45 g,2.1 mmol), BINAP (0.04 g,0.063 mmol), pd under a nitrogen atmosphere at room temperature ₂ (dba) ₃ (0.019 g,0.021 mmol) and NaO ^t To a mixture of Bu (0.282 g,2.94 mmol) in toluene (6 mL) was added diphenylazomethine (0.45 g,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) ⁺ 。

Step 3: preparation of 1- (4-aminopyridin-2-yl) cyclopropanecarbonitrile. A mixture of 1- (4- (diphenylmethyleneamino) pyridin-2-yl) cyclopropanecarbonitrile (0.48 g,1.49 mmol), THF (10 mL) and aqueous hydrochloric acid (2N, 2.0 mL) was stirred at room temperature for 1 hour. The mixture was then partitioned between EtOAc (15 mL) and water (15 mL). The aqueous phase was extracted with EtOAc (2X 25 mL). By anhydrous Na ₂ SO ₄ The 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 substituted pyridin-2-yl or phenyl. The compounds of this example were prepared by the general scheme 1 listed below.

Scheme 1

Step 1: preparation of 6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (2). Pd (OAc) was added to a solution of 2-chloro-6-trifluoromethyl-pyridine (2 g,11.1mmol,1.0 eq.) in MeOH (20 mL) under nitrogen atmosphere ₂ (124 mg,0.05 eq.) and dppf (600 mg,0.1 eq.). Et is then added to the resulting orange solution ₃ N (2.3 mL,1.5 eq). The reaction solution was then stirred at 60℃under an atmosphere of carbon monoxide (40 psi) for 22 hours. Once the reaction was complete, the mixture was filtered and the filtrate concentrated in high vacuum. The residue was purified by column chromatography to obtain the desired product.

¹ HNMR(400MHz,CDCl ₃ ):δ8.32(d,J＝8Hz,1H),8.06(t,J＝8Hz,1H),8.88(d,J＝8Hz,1H),4.04(s,3H)。LC-MS:m/z 206(M+H) ⁺ 。

Step 2: preparation of 6- (6-trifluoromethylpyridin-2-yl) -1,3, 5-triazine-2, 4-dione. To a solution of NaOEt (3.84 g,0.16mol,3 eq.) freshly prepared from Na in ethanol (500 mL) was added methyl 6-trifluoromethylpyridine formate (33 g,0.16mol,3 eq.) and biuret (5.3 g,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 ₃ Treatment to adjust pH to 7. The precipitated solid was collected by filtration and dried under air to give the desired compound.

¹ H NMR(400MHz,DMSO-d ₆ ):δ10.88(s,1H),8.46(d,J＝7.4Hz,1H),8.28(t,J＝7.3Hz,1H),8.11(d,J＝7.4Hz,1H)。LC-MS:m/z 259(M+H) ⁺ 。

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 (3.37 g,0.013 mol) in POCl ₃ PCl was added to the solution in (48 mL) ₅ (23 g,0.1 mol). The mixture was stirred at 100 ℃ for 2 hours and then concentrated. The residue was dissolved in EtOAc and then taken up with saturated aqueous NaHCO ₃ And (5) washing. By anhydrous Na ₂ SO ₄ The organic layer was dried and then concentrated to give the desired product.

¹ H NMR(400MHz,CDCl ₃ ):δ8.76(d,J＝7.9Hz,1H),8.19(t,J＝7.9Hz,1H),7.97(d,J＝7.8Hz,1H)。LC-MS:m/z 294.9(M+H) ⁺ 。

Step 4: preparation of N ² ,N ⁴ -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 (600 mg,2.0mmol,1.0 eq.) and (R) -1-cyclopropylethylamine hydrochloride (534 mg,4.4mmol,2.2 eq.) in THF (12 mL) was added CsF (1.2 g,8.0mmol,2 eq.) and DIPEA (1.4 mL,8.0mmol,4 eq.) 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.

¹ H NMR(400MHz,CD ₃ OD):δ 8.70-8.68(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/z 393.2(M+H) ⁺ 。

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

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.50(s,1H),7.99(t,J＝7.9Hz,1H),7.77(d,J＝7.7Hz,1H),5.44-5.18(m,2H),3.66-3.57(m,2H),1.27(d,J＝5.4Hz,6H),0.93-0.88(m,2H),0.52-0.27(m,8H)。LC-MS:m/z 393.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.51(s,1H),7.99(t,J＝7.9Hz,1H),7.77(d,J＝7.3Hz,1H),5.46-5.19(m,2H),3.67-3.54(m,2H),1.32-1.22(m,6H),0.95-0.83(m,2H),0.59-0.23(m,8H)。LC-MS:m/z 393.2(M+H) ⁺ 。

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

¹ HNMR(400MHz,CD ₃ OD):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 N ² ,N ⁴ -bis (cyclobutylmethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ ):δ8.54(m,1H),8.00(m,1H),7.78(d,J＝5.9Hz,1H),5.27(m,2H),3.69-3.32(m,4H),2.59(m,2H),2.10(m,4H),1.92(m,4H),1.84-1.62(m,4H)。LC-MS:m/z 393.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.71-8.41(m,1H),7.99(d,J＝7.4Hz,1H),7.77(d,J＝7.7Hz,1H),5.34-4.84(m,2H),4.30-3.96(m,2H),2.44-2.28(m,2H),2.09-1.96(m,4H),1.93-1.78(m,8H),1.14(d,J＝5.9Hz,6H)。LC-MS:m/z 421.2(M+H) ⁺ 。

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

¹ HNMR(400MHz,CD ₃ OD):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 N ² ,N ⁴ -bis (cyclopropylmethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CD ₃ OD):δ 8.60-8.68(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/z 365.2(M+H) ⁺ 。

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

¹ HNMR(400MHz,CD ₃ OD):δ 8.61-8.59(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 N ² ,N ⁴ -dicyclohexyl-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ ):δ8.67-8.38(m,1H),7.99(d,J＝6.8Hz,1H),7.78(d,J＝7.5Hz,1H),5.52(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 N ² ,N ⁴ Bis (bicyclo [ 3.1.0)]Hex-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CD ₃ OD):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

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¹ HNMR(400MHz,CD ₃ OD):δ 8.60-8.68(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/z 393.5(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.53(m,1H),8.08-8.02(m,1H),7.85-7.80(m,1H),5.78-5.18(m,2H),4.82-4.38(m,2H),2.82-2.50(m,2H),2.31-2.05(m,8H),1.93-1.80(m,2H)。LC-MS:m/z 465.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.64-8.42(m,1H),8.05(t,J＝7.8Hz,1H),7.84(d,J＝6.6Hz,1H),6.24-5.25(m,2H),4.18-4.01(m,2H),2.43-1.48(m,16H)。LC-MS:m/z 493.2(M+H) ⁺ 。

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

¹ HNMR(400MHz,DMSO-d ₆ ):δ 7.43-8.55(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 N ² ,N ⁴ -diisopropyl-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ ):δ8.67-8.41(m,1H),7.99(s,1H),7.77(d,J＝7.7Hz,1H),5.18(m,2H),4.45-4.03(m,2H),2.15(m,1H),1.26(d,J＝4.5Hz,12H)。LC-MS:m/z 341.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.44-8.31(m,1H),8.19-8.12(m,1H),7.93(d,J＝7.3Hz,1H),7.16-6.77(m,2H),1.35(s,18H)。LC-MS:m/z 369.2(M+H) ⁺ 。

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

¹ HNMR(400MHz,CD ₃ OD):δ 8.42-8.68(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/z 369.5(M+H) ⁺ 。

¹ HNMR(400MHz,CD ₃ OD):δ 8.72-8.79(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/z 369.2(M+H) ⁺ 。

Compound N ² ,N ⁴ -di-sec-butyl-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

Compound N ² - ((R) -sec-butyl) -N ⁴ - ((S) -sec-butyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CD ₃ OD):δ 8.59-8.65(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/z 369.2(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis (3-methylbutan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ ):δ8.58-8.47(m,1H),7.99(t,J＝7.2Hz,1H),7.77(d,J＝7.7Hz,1H),5.30-5.03(m,2H),4.16-3.97(m,2H),1.93-1.75(m,2H),1.16(d,J＝6.6Hz,6H),0.97-0.93(m,12H)。LC-MS:m/z 397.2(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis ((R) -3-methylbutan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.46(m,1H),8.21(m,1H),8.00(d,J＝7.7Hz,1H),7.36(m,2H),3.90(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 N ² ,N ⁴ -bis ((S) -3-methylbutan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.46(d,J＝7.9Hz,1H),8.24(d,J＝6.9Hz,1H),8.03(d,J＝7.7Hz,1H),7.55(m,2H),4.25-3.78(m,1H),1.93-1.65(m,1H),1.15-1.00(m,6H),0.89(t,J＝7.8Hz,12H)。LC-MS:m/z 397.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ9.20(s,1H),7.74(s,1H),5.46(m,2H),3.59(m,2H),1.26(m,8H),0.91(s,2H),0.65--0.27(m,8H)。LC-MS:m/z 394.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.52-8.33(m,1H),8.05-7.86(m,1H),7.76(d,J＝7.7Hz,1H),7.52-7.18(m,10H),5.82-5.40(m,2H),5.37-4.92(m,2H),1.65-1.39(m,6H)。LC-MS:m/z 465.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CD ₃ OD):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) -N ² ,N ⁴ -twoIsopropyl-1, 3, 5-triazine-2, 4-diamine

¹ HNMR(400MHz,CD3OD):δ 8.5-8.38(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-chloropyridin-2-yl) -N ² ,N ⁴ -diisopropyl-1, 3, 5-triazine-2, 4-diamine

¹ HNMR(400MHz,CD ₃ OD):δ 8.25-8.19(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 N ² ,N ⁴ -di (but-3-en-1-yl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine

¹ HNMR(400MHz,CD ₃ OD):δ 8.19-8.13(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 N ² ,N ⁴ -bis (3-oxabicyclo [ 3.1.0)]Hexadec-6-yl) -6-phenyl-1, 3, 5-triazine-2, 4-diamine

¹ HNMR(400MHz,CD ₃ OD):δ 8.35-8.1(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 N ² ,N ⁴ To a mixture of bis ((1 s,3 s) -3- (4-fluorophenyl) cyclobutyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine at room temperature was added CsF (0.6 g,2.0mmol,1 eq.) and DIPEA (0.7 mL,4.0mmol,2 eq.) in THF (12 mL) to a mixture of 2, 4-dichloro-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine (600 mg,2.0mmol,1.0 eq.) and (1 s,3 s) -3- (4-fluorophenyl) cyclobutylamine (726 mg,4.4mmol,2.2 eq.). The resulting mixture was stirred at 60 ℃ overnight and then filtered. The filtrate is concentrated and purified via standard techniques to yield the desired product.

¹ H NMR(400MHz,CDCl ₃ )δ8.48(m,1H),7.95(m,1H),7.75(d,J＝7.6Hz,1H),7.16-7.04(m,4H),6.93(t,J＝8.5Hz,4H),6.46-5.32(m,2H),4.47(m,2H),3.28-3.02(m,2H),2.81(d,J＝7.6Hz,4H),2.01(m,4H)。LC-MS:m/z 553.2(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis ((1 r,3 r) -3- (4-fluorophenyl) cyclobutyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.56(m,1H),8.01(s,1H),7.80(s,1H),7.25-6.93(m,8H),5.64(m,2H),4.82-4.37(m,2H),3.68(s,1H),3.24(s,1H),2.89(m,2H),2.54(m,4H),2.09-1.98(m,2H)。LC-MS:m/z 553.2(M+H) ⁺ 。

Compound 6- (6- (trifluoromethyl) pyridin-2-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

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

Compound N ² ,N ⁴ -bis ((S) -1, 1-trifluorobutan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.55(d,J＝8Hz,1H),8.06-8.02(m,1H),7.83(d,J＝8Hz,1H),5.64-5.15(m,2H),4.93-4.71(m,2H),2.0-1.94(m,2H),1.69-1.57(m,2H),1.08-1.02(m,6H)。LC-MS:m/z 477(M+H) ⁺ 。

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

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¹ H NMR(400MHz,CDCl ₃ )δ8.59-8.51(m,1H),8.02(bs,1H),7.80(d,J＝7.6Hz,1H),5.70-5.38(m,2H),3.81-3.41(m,4H),2.04-1.92(m,2H),1.73-1.59(m,2H),1.28-1.23(m,2H)。LC-MS:m/z 437(M+H) ⁺ 。

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

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

Compound N ² ,N ⁴ Bis (3, 3-difluorocyclobutyl) -6- (6-)(trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.56-8.48(m,1H),8.04-8.02(m,1H),7.82-7.80(m,1H),5.76-5.41(m,2H),4.52-4.37(m,2H),3.06(bs,4H),2.63-2.61(m,4H)。LC-MS:m/z 437.1(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )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 N ² ,N ⁴ -bis ((R) -3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ57-8.48(m,1H),8.02-8.01(m,1H),7.80(s,1H),5.66-5.32(m,2H),4.71-4.49(m,2H),2.64-2.61(m,2H),2.31-2.05(m,8H),1.86-1.79(m,2H)。LC-MS:m/z 465(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.56-8.48(m,1H),8.02(d,J＝8Hz,1H),7.80-7.81(m,1H),5.66-5.32(m,2H),4.71-4.54(m,2H),2.65-2.60(m,2H),2.31-2.05(m,8H),1.86-1.81(m,2H)。LC-MS:m/z 465(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )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 N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -6- (6-methoxypyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.18-7.65(m,2H),7.15-6.98(m,1H),6.34-5.67(m,2H),4.15(s,3H),3.71-3.48(m,2H),1.33-1.25(m,6H),0.98-0.86(m,2H),0.62-0.26(m,8H)。LC-MS:m/z 355.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.34-8.27(m,1H),7.96-7.92(m,1H),7.22(d,J＝8Hz,1H),5.83-5.41(m,2H),4.49-4.35(m,2H),3.05(d,J＝4Hz,4H),2.63-2.54(m,4H)。LC-MS:m/z 453(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.33-8.26(m,1H),7.95-7.92(m,1H),7.22(d,J＝8Hz,1H),5.65-5.28(m,2H),4.67-4.52(m,2H),2.64-2.59(m,2H),2.30-1.79(m,10H)。LC-MS:m/z 481(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.31(d,J＝8Hz,1H),7.98-7.92(m,1H),7.24(d,J＝12Hz,1H),5.44-5.08(m,2H),4.16-3.98(m,2H),2.15-1.65(m,16H)。LC-MS:m/z 509(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ7.45-7.41(t,1H),6.84(d,1H),5.43-5.07(m,2H),4.08-3.98(m,5H),2.11-2.01(m,8H),1.96-1.89(m,4H),1.87-1.83(m,4H)。LC-MS:m/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 substituted pyridin-2-yl or phenyl. The compounds of this example were prepared by the 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 (600 mg,2.0mmol,1.0 eq.) and (R) -1-cyclopropylethylamine hydrochloride (268 mg,2.2mmol,1.1 eq.) in THF (6 mL) was added CsF (608 mg,4.0mmol,2 eq.) and DIPEA (0.7 mL,4.0mmol,2 eq.) 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 N ² - ((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 (80 mg,0.23mmol,1.0 eq.) and pentan-2-amine (25 mg,0.28mmol,1.2 eq.) in THF (2 mL) was added CsF (70 mg,0.46mmol,2 eq.) and DIPEA (0.08 mL,0.46mmol,2 eq.) 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.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.54-8.42(m,1H),8.23(t,J＝7.8Hz,1H),8.02(d,J＝7.7Hz,1H),7.65(d,J＝8.4Hz,1H),7.52(t,J＝9.5Hz,1H),4.27-3.96(m,1H),3.65-3.47(m,1H),1.60-1.46(m,1H),1.41-1.29(m,3H),1.22(d,6.5Hz,3H),1.12(d,J＝6.1Hz,3H),1.01-0.96(m,1H),0.88(t,J＝7.1Hz,3H),0.50-0.29(m,3H),0.26-0.07(m,1H)。LC-MS:m/z 395.2(M+H) ⁺ 。

Using the procedure outlined in example 2, the following compounds were prepared using the appropriate starting materials.

¹ H NMR(400MHz,CDCl ₃ ):δ8.52(m,1H),8.00(t,J＝7.6Hz,1H),7.78(d,J＝7.7Hz,1H),5.63(m,2H),3.73(m,9H),2.66(d,J＝5.9Hz,2H),1.29(m,3H),1.01-0.79(m,1H),0.60-0.17(m,4H)。LC-MS:m/z 411.2(M+H) ⁺ 。

Compounds (R) -N ² - (1-cyclopropylethyl) -N ⁴ - (4, 4-difluorocyclohexyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ ):δ8.66-8.39(m,1H),8.02(t,J＝7.7Hz,1H),7.80(d,J＝7.7Hz,1H),5.34(m,2H),4.11(m,1H),3.63(m,1H),2.32-1.54(m,9H),1.29(m,3H),0.95(s,1H),0.70-0.16(m,4H)。LC-MS:m/z 443.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.54-8.49(m,1H),8.01(t,J＝7.3Hz,1H),7.78(d,J＝7.7Hz,1H),5.60-5.27(m,2H),4.57-4.37(m,1H),3.67-3.57(m,1H),2.70-2.65(m,2H),2.57(m,3H),2.22-1.92(m,4H),1.30(d,J＝5.8Hz,2H),0.93(s,1H),0.54-0.29(m,4H)。LC-MS:m/z 455.2(M+H) ⁺ 。

Compound N ² - ((1R, 3R,5R, 7R) -adamantan-2-yl) -N ⁴ - ((R) -1-cyclopropylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ ):δ8.63-8.34(m,1H),8.00(t,J＝7.8Hz,1H),7.78(d,J＝7.7Hz,1H),5.57(m,2H),4.21(m,1H),3.85-3.32(m,1H),2.22-1.57(m,15H),1.25(m,4H),0.90(m,1H),0.66-0.24(m,4H)。LC-MS:m/z 459.2(M+H) ⁺ 。

Compounds (R) -N ² - (1-cyclopropylethyl) -N ⁴ - (dicyclohexylmethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ ):δ8.49(d,J＝7.5Hz,1H),7.99(t,J＝7.9Hz,1H),7.77(d,J＝7.7Hz,1H),5.71-5.05(m,2H),3.59(m,2H),1.25(m,3H),1.07-0.80(m,3H),0.64-0.19(m,12H)。LC-MS:m/z 419.2(M+H) ⁺ 。

Compound N ² - ((R) -1-cyclopropylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ ):δ8.53(s,1H),8.01(s,1H),7.80(d,J＝7.6Hz,1H),5.91-4.65(m,3H),3.67(m,1H),1.51-1.15(m,6H),0.93(s,1H),0.74-0.10(m,4H)。LC-MS:m/z 421.1(M+H) ⁺ 。

Compounds (R) -N ² - (1-cyclopropylethyl) -N ⁴ - (2, 3-dihydro-1H-inden-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ ):δ8.61-8.46(m,1H),7.99(t,J＝8.1Hz,1H),7.77(d,J＝7.7Hz,1H),7.26-7.17(m,4H),5.75-5.30(m,2H),5.11-4.75(m,1H),3.78-3.54(m,1H),3.46-3.31(m,2H),2.94-2.88(m,2H),1.32(d,J＝6.4Hz,3H),1.24-1.19(m,1H),0.98-0.86(m,1H),0.52-043(m,3H),0.29(s,1H)。LC-MS:m/z 441.2(M+H) ⁺ 。

Compounds (R) -N ² - (1-cyclopropylethyl) -N ⁴ - (prop-2-yn-1-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ ):δ8.55(m,1H),8.01(t,J＝7.8Hz,1H),7.79(d,J＝7.7Hz,1H),5.94-5.12(m,2H),4.30(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) ⁺ 。

Compounds (R) -N ² - (1-cyclopropylethyl) -N ⁴ - (2-phenoxyethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ ):δ8.43(d,J＝8.0Hz,1H),7.93(t,J＝7.6Hz,1H),7.71(d,J＝7.7Hz,1H),7.34-7.18(m,2H),7.00-6.69(m,3H),6.03-5.08(m,2H),4.07(s,2H),3.94-3.71(m,2H),3.53(d,J＝6.8Hz,1H),1.34-1.04(m,4H),0.35(m,4H)。LC-MS:m/z 445.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.51(m,1H),7.99(t,J＝7.9Hz,1H),7.77(d,J＝7.7Hz,1H),5.55-5.33(m,2H),4.45-4.29(m,2H),3.68-3.39(m,4H),1.85(s,3H),1.28-0.93(m,6H),0.60-0.27(m,3H)。LC-MS:m/z 397.2(M+H) ⁺ 。

Compounds (R) -N ² - (1-cyclopropylethyl) -N ⁴ - (1, 3-dimethoxyprop-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ ):8.47(m,1H),8.05-7.80(m,1H),7.71(d,J＝7.7Hz,1H),5.90-5.06(m,2H),4.57-4.05(m,1H),3.65-3.38(m,4H),3.33(m,6H),1.23(m,4H),0.84(m,1H),0.61-0.05(m,4H)。LC-MS:m/z 427.2(M+H) ⁺ 。

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

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.56(d,J＝8.2Hz,1H),8.03(t,J＝7.7Hz,1H),7.80(d,J＝7.7Hz,1H),5.71-5.54(m,2H),3.70(m,1H),1.82(s,6H),1.36-1.25(m,4H),0.97(d,J＝7.7Hz,1H),0.62-0.26(m,4H)。LC-MS:m/z 392(M+H) ⁺ 。

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

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

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.48(d,J＝7.4Hz,1H),8.01(t,J＝7.8Hz,1H),7.79(d,J＝7.7Hz,1H),5.67-5.28(m,2H),3.65(m,4H),2.09(s,3H),1.47-1.23(m,8H),0.92(s,1H),0.62-0.40(m,3H),0.30(s,1H)。LC-MS:m/z 423.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.51(m,1H),8.01(t,J＝7.6Hz,1H),7.80(t,J＝6.4Hz,1H),5.40-5.31(m,1H),4.10-3.97(m,2H),3.69-3.52(m,1H),2.25-2.09(m,2H),1.95-1.55(m,7H),1.29(d,J＝6.0Hz,2H),0.93(d,J＝7.5Hz,1H),0.66-0.16(m,4H)。LC-MS:m/z 409.2(M+H) ⁺ 。

Compounds (R) -N ² -benzyl-N ⁴ - (1-cyclopropylethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ ):δ8.49(d,J＝7.2Hz,1H),7.98(t,J＝7.7Hz,1H),7.77(d,J＝7.7Hz,1H),7.31(m,5H),5.51(m,2H),4.67(m,2H),3.63(m,1H),1.27(m,3H),0.91(s,1H),0.38(m,4H)。LC-MS:m/z 415.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.45(t,J＝10.4Hz,1H),7.98(t,J＝7.7Hz,1H),7.77(d,J＝7.7Hz,1H),7.54-7.03(m,5H),5.70(d,J＝6.9Hz,1H),5.45(m,1H),5.15(m,1H),3.50(m,1H),1.55(m,3H),1.28(m,1H),0.96(m,3H),0.64-0.18(m,4H)。LC-MS:m/z 429.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.47(d,J＝8.3Hz,1H),7.98(t,J＝7.7Hz,1H),7.76(d,J＝7.7Hz,1H),7.50-7.02(m,5H),5.78-5.07(m,3H),3.55(m,1H),1.72(m,1H),1.56(d,J＝6.7Hz,3H),0.97(m,3H),0.58-0.15(m,4H)。LC-MS:m/z 429.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.55-8.36(m,1H),8.00(t,J＝7.7Hz,1H),7.78(d,J＝7.7Hz,1H),7.27(d,J＝7.8Hz,2H),7.18-6.90(m,3H),5.71-5.06(m,3H),3.78-3.32(m,1H),1.54(d,J＝6.8Hz,3H),1.34-1.22(m,3H),1.00(d,J＝6.3Hz,1H),0.94-0.72(m,1H),0.54-0.37(m,2H),0.31-0.20(m,1H)。LC-MS:m/z 447.2(M+H) ⁺ 。

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

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

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.47(d,J＝8.3Hz,1H),7.98(t,J＝7.7Hz,1H),7.76(d,J＝7.7Hz,1H),7.37(m,4H),7.23(m,1H),5.81-5.05(m,3H),3.55(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) ⁺ 。

Compounds (R) -N ² - (1-cyclopropylethyl) -N ⁴ - (1-phenylcyclopropyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.53-8.13(m,3H),7.99(m,1H),7.70(m,1H),7.45-7.04(m,5H),3.30-3.19(m,1H),1.38-1.09(m,5H),1.07-0.75(m,3H),0.43--0.09(m,4H)。LC-MS:m/z 441.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.32(d,J＝6.6Hz,1H),7.75(s,1H),7.42(s,1H),5.51(s,1H),3.62(m,5H),1.42-1.03(m,9H),0.92(d,J＝7.7Hz,1H),0.63-0.17(m,4H)。LC-MS:m/z 347.2(M+H) ⁺ 。

Compound (R) -3- ((4- ((1-cyclopropylethyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) propanoic acid methyl ester

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

¹ HNMR(400MHz,CD ₃ OD):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 N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (tetrahydrofuran-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CD ₃ OD):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) ⁺ 。

Compound 3- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyrrolidine-1-carboxylic acid tert-butyl ester

¹ H NMR(400MHz,CDCl ₃ ):δ8.62-8.46(m,1H),8.03(d,J＝6.9Hz,1H),7.81(d,J＝7.7Hz,1H),5.91-5.19(m,2H),4.61(m,2H),3.82-3.59(m,1H),3.50(s,1H),3.29(m,1H),2.65(m,1H),2.43-2.06(m,5H),1.97(s,1H),1.47(s,9H)。LC-MS:m/z 530.2(M+H) ⁺ 。

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

¹ HNMR(400MHz,CD ₃ OD):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 N ² - ((R) -1-cyclopropylethyl) -N ⁴ - (1- (2-methoxyethoxy) prop-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.61-8.42(m,1H),7.99(t,J＝7.9Hz,1H),7.77(d,J＝7.7Hz,1H),5.78-5.37(m,2H),4.52-4.22(m,1H),3.79-3.47(m,7H),3.40(s,3H),1.29(d,J＝5.7Hz,6H),0.99-0.80(m,1H),0.61-0.21(m,4H)。LC-MS:m/z 441(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.57-8.47(m,1H),8.01(t,J＝7.6Hz,1H),7.79(d,J＝7.6Hz,1H),5.62-5.20(m,2H),4.23(m,1H),3.82-3.49(m,3H),1.35-1.22(m,6H),0.93(m,1H),0.58-0.29(m,4H)。LC-MS:m/z 383.2(M+H) ⁺ 。

Compound N ² - ((R) -1-cyclopropylethyl) -N ⁴ - (1-isopropoxyprop-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.65-8.42(m,1H),7.99(t,J＝7.9Hz,1H),7.78(d,J＝7.3Hz,1H),5.92-5.08(m,2H),4.44-4.13(m,1H),3.73-3.27(m,4H),1.27(m,6H),1.17(d,J＝6.1Hz,6H),1.04-0.84(m,1H),0.63-0.16(m,4H)。LC-MS:m/z 425(M+H) ⁺ 。

Compound N ² - ((R) -1-cyclopropylethyl) -N ⁴ - (4-methoxybutan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.63-8.48(m,1H),8.01-7.97(m,1H),7.77(d,J＝7.6Hz,1H),5.54-5.25(m,2H),4.44-4.22(m,1H),3.64-3.49(m,3H),3.33(d,J＝2.4Hz,3H),1.89-1.78(m,2H),1.30-1.25(m,5H),0.93-0.83(m,2H),0.53-0.28(m,4H)。LC-MS:m/z 411(M+H) ⁺ 。

Compound N ² - ((R) -1-cyclopropylethyl) -N ⁴ - (1-phenylpropan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-dioAmines

¹ H NMR(400MHz,CDCl ₃ )δ8.41(d,J＝7.6Hz,1H),7.92(t,J＝7.8Hz,1H),7.70(d,J＝7.6Hz,1H),7.25-7.14(m,5H),5.50-4.92(m,2H),4.25(m,1H),3.68-3.39(m,1H),2.99(m,1H),2.61(m,1H),1.26-1.06(m,8H),0.52-0.28(m,3H)。LC-MS:m/z 443(M+H) ⁺ 。

Compound N ² - ((R) -1-cyclopropylethyl) -N ⁴ - (1-morpholinopropan-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.51-8.50(m,1H),8.22(s,1H),8.03-7.99(m,1H),7.83-7.79(m,1H),6.39-5.86(m,2H),4.44(m,7H),3.79-3.52(m,5H),3.25-2.53(m,5H),0.95(s,1H),0.54-0.26(m,4H)。LC-MS:m/z 452(M+H) ⁺ 。

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

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

¹ H NMR(400MHz,CDCl ₃ )δ8.52-8.37(m,1H),8.00-7.96(m,1H),7.87-7.75(m,1H),6.01-5.22(m,2H),4.26-3.53(m,3H),2.32-1.45(m,2H),1.41-1.29(m,8H),1.23-1.21(m,1H),0.97-0.28(m,5H)。LC-MS:m/z 424(M+H) ⁺ 。

Compound 3- ((4- (((R) -1-cyclopropylethyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) butyronitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.50(d,J＝7.6Hz,1H),8.03-7.99(m,1H),7.80(d,J＝7.6Hz,1H),5.64-5.17(m,2H),4.55-4.32(m,1H),3.70-3.51(m,1H),2.87-2.69(m,2H),1.46(d,J＝6.8Hz,3H),1.33-1.25(m,3H),0.96-0.89(m,1H),0.55-0.30(m,4H)。LC-MS:m/z 392(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

¹ H NMR(400MHz,CDCl ₃ )δ8.55(s,1H),8.11(s,1H),7.91(d,J＝8Hz,1H),3.73-3.62(m,4H),1.47-1.42(m,7H),1.37-1.35(m,3H),0.75-0.69(m,1H),0.58(m,2H),0.40-0.34(m,2H)。LC-MS:m/z 406(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.50(s,1H),8.03(d,J＝7.3Hz,1H),7.80(d,J＝7.4Hz,1H),5.68(m,2H),4.60(m,1H),3.83-3.03(m,3H),2.74-2.56(m,1H),2.31(s,2H),2.19-1.97(m,2H),1.83(m,1H),1.30(s,6H)。LC-MS:m/z 433(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ10.05-8.37(m,1H),8.31-7.54(m,2H),7.60-6.68(m,4H),5.49-4.41(m,4H),3.80-3.35(m,2H),2.55-2.12(m,6H)。LC-MS:m/z 510(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.50(s,1H),8.09(m,2H),7.80(s,1H),7.49(s,1H),6.66(s,1H),6.26(m,2H),5.77(m,1H),4.99-4.34(m,4H),3.96(m,2H),2.42-1.71(m,6H)。LC-MS:m/z 493(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.50(d,J＝8Hz,1H),8.07-8.01(m,2H),7.92(s,1H),7.80(d,J＝8Hz,1H),7.17-7.14(m,1H),6.80-6.79(m,1H),6.15-5.34(m,2H),5.14-4.51(m,2H),4.39-4.35(m,2H),3.89-3.78(m,2H),2.62-2.57(m,1H),2.30-2.11(m,5H)。LC-MS:m/z 493(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.55(d,J＝7.6Hz,1H),8.21-8.01(m,1H),7.88(m,1H),7.26-7.15(m,2H),7.04(t,J＝8.4Hz,2H),4.89-4.35(m,2H),3.88-3.40(m,1H),3.00-1.75(m,11H)。LC-MS:m/z 509(M+H) ⁺ 。

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

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

¹ H NMR(400MHz,CDCl ₃ )δ8.65-8.42(m,1H),8.01(t,J＝7.8Hz,1H),7.80(d,J＝7.4Hz,1H),7.42-7.29(m,3H),7.23(t,J＝6.4Hz,1H),6.07-5.20(m,2H),4.90-4.40(m,2H),4.13-3.56(m,1H),2.75-1.75(m,10H)。LC-MS:m/z 491(M+H) ⁺ 。

Chemical combinationObject N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (1-methylpyrrolidin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.62-8.48(m,1H),8.09-7.94(m,1H),7.80(t,J＝7.4Hz,1H),4.91-4.27(m,2H),3.42-2.56(m,9H),2.44-2.22(m,4H),2.00-1.57(m,4H)。LC-MS:m/z 444(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.76-8.35(m,1H),8.10-7.91(m,1H),7.84(s,1H),7.53(d,J＝7.4Hz,2H),7.43(d,J＝6.5Hz,3H),5.75-5.29(m,2H),4.86-3.77(m,4H),3.70-3.23(m,2H),2.79-1.74(m,8H)。LC-MS:m/z 534(M+H) ⁺ 。

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

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

¹ H NMR(400MHz,CDCl ₃ )δ8.66-8.29(m,3H),8.00(s,1H),7.73(m,2H),7.12-7.01(m,1H),5.73(m,2H),5.00-4.40(m,3H),4.24-4.05(m,1H),3.15(m,6.3Hz,1H),2.85-2.51(m,2H),2.21(m,5H)。LC-MS:m/z 521(M+H) ⁺ 。

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

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

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

1H NMR(400MHz,CDCl ₃ )：δ8.64-8.46(m,1H),8.01(d,J＝12.8Hz,1H),7.78(d,J＝7.6Hz,1H),7.21(m,3H),5.76-5.31(m,2H),5.02-4.44(m,2H),3.45-3.36(m,2H),2.97-2.91(m,2H),2.68-2.58(m,1H),2.31-2.09(m,4H),1.85-1.84(m,1H),1.25(m,1H)。LC-MS:m/z 477(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.57-8.48(m,1H),8.01(d,J＝8Hz,1H),7.81(d,J＝8Hz,1H),7.26-7.18(m,3H),6.02-5.36(m,2H),5.05-4.43(m,2H),3.48-3.32(m,2H),3.04-2.87(m,2H),2.70-2.58(m,1H),2.36-2.10(m,4H),1.99-1.82(m,1H)。LC-MS:m/z 511(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.59-8.47(m,1H),8.04-7.97(m,1H),7.79(d,J＝7.2Hz,1H),7.26-7.17(m,1H),6.96-6.87(m,2H),5.75-5.30(m,2H),5.06-4.44(m,2H),3.39-3.32(m,2H),2.95-2.62(m,3H),2.33-2.05(m,4H),1.87-1.82(m,1H)。LC-MS:m/z 495(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.57-8.47(m,1H),8.04-7.99(m,1H),7.82-7.78(m,1H),7.52-7.29(m,2H),7.18-7.00(m,1H),5.70-5.30(m,2H),5.03-4.48(m,2H),3.40-3.30(m,2H),2.96-2.63(m,3H),2.35-2.07(m,4H),1.87-1.25(m,1H)。LC-MS:m/z 556(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.57-8.47(m,1H),8.01(d,J＝8Hz,1H),7.80(d,J＝4Hz,1H),7.54-7.50(m,2H),7.37-7.33(m,1H),5.77-5.34(m,2H),5.07-4.56(m,2H),3.43(m,2H),3.03-2.99(m,2H),2.70-2.58(m,1H),2.32-2.04(m,5H)。LC-MS:m/z 502(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.69-8.46(m,1H),8.00(d,J＝8Hz,1H),7.79-7.74(m,1H),7.14(s,1H),6.81-6.75(m,2H),5.76-5.33(m,2H),5.02-4.78(m,1H),4.58-4.47(m,1H),3.80(s,3H),3.39-3.33(m,2H),2.93-2.62(m,4H),2.31-2.10(m,4H)。LC-MS:m/z 507(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ:8.64-8.35(m,2H),8.07-7.76(m,2H),7.53(m,1H),7.11(m,1H),5.86-5.30(m,2H),5.01-4.54(m,2H),3.62-2.60(m,5H),2.40-1.86(m,5H)。LC-MS:m/z 478.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.55-8.46(m,1H),8.07-7.99(m,1H),7.80(d,J＝8Hz,1H),7.51-7.44(m,2H),7.09-7.04(m,2H),6.03-5.38(m,2H),5.03-4.43(m,2H),3.48-3.25(m,2H),3.06-2.88(m,2H),2.69-2.58(m,1H),2.31-2.29(d,J＝8Hz,2H),2.17-2.01(m,2H),1.90-1.77(m,1H)。LC-MS:m/z 635(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.61-8.49(m,1H),8.04-7.98(m,1H),7.80-7.78(m,1H),7.27-7.23(m,2H),6.74-6.70(t,1H),6.59(d,2H),5.73-5.33(m,2H),4.91-4.48(m,2H),3.75-3.28(m,4H),2.62-1.87(m,8H)。LC-MS:m/z 506(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.67-8.44(m,1H),8.17(s,1H),8.01(d,J＝8.8Hz,1H),7.79(d,J＝6.4Hz,1H),7.48(t,J＝7.7Hz,1H),6.59(t,J＝5.9Hz,1H),6.39(d,J＝8.1Hz,1H),5.84-4.30(m,4H),4.07-3.51(m,4H),2.83-1.97(m,8H)。LC-MS:m/z 507(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.64-8.48(m,1H),8.34-8.33(m,2H),8.04-7.38(m,1H),7.80-7.79(m,1H),6.54-6.52(m,1H),5.73-5.35(m,2H),4.61-4.58(m,2H),4.00-3.93(m,1H),3.79-3.58(m,3H),2.90-2.61(m,1H),2.38-2.12(m,6H),1.88-1.82(m,1H)。LC-MS:m/z 508(M+H) ⁺ 。

Compound N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (6, 6-difluorospiro [3.3 ]]Hept-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.66-8.39(m,1H),8.02(d,J＝7.2Hz,1H),7.80(d,J＝6.6Hz,1H),5.73-5.20(m,2H),4.80-4.30(m,2H),2.83-1.78(m,14H)。LC-MS:m/z 491(M+H) ⁺ 。

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

¹ H NMR(400MHz,DMSO-d ₆ )δ8.63-8.45(m,1H),8.24(t,J＝7.7Hz,1H),8.03(d,J＝7.5Hz,1H),7.83(d,J＝7.2Hz,1H),7.57-7.10(m,1H),4.62(m,1H),4.03-4.04(m,1H),3.37(s,2H),2.08(s,2H),1.93-1.85(m,4H),1.62(d,J＝12.2Hz,2H),1.12(s,6H)。LC-MS:m/z 447(M+H) ⁺ 。

Compound N ² - (4, 4-difluorocyclohexyl) -N ⁴ - (tetrahydro-2H-pyran-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )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) ⁺ 。

Compound 4- ((4, 4-difluorocyclohexyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) piperidine-1-carboxylic acid tert-butyl ester

¹ H NMR(400MHz,CDCl ₃ )δ8.48-8.40(m,1H),7.97-7.91(m,1H),7.74-7.69(m,1H),5.56-5.15(m,2H),4.18-3.85(m,4H),2.95-2.82(m,2H),2.10-1.54(m,9H),1.40(m,12H)。LC-MS:m/z 558.3(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.54-8.48(m,1H),8.06-7.97(m,1H),7.81(d,J＝7.2Hz,1H),5.57-5.14(m,2H),4.54-3.83(m,4H),3.25-2.83(m,4H),2.24-2.05(m,7H),1.77-1.44(m,6H)。LC-MS:m/z 500.2(M+H) ⁺ 。

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

1H NMR(400MHz,CDCl ₃ )δ8.58-8.48(m,1H),8.05-7.96(m,1H),7.80(d,J＝6.8Hz,1H),5.56-5.18(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 N ² - (4, 4-difluorocyclohexyl) -N ⁴ - (6, 6-difluorospiro [3.3 ]]Hept-2-yl) -6- (6- (tris)Fluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.66-8.39(m,1H),8.14-7.94(m,1H),7.81(d,J＝7.7Hz,1H),6.04-5.01(m,2H),4.74-3.74(m,2H),2.79-2.42(m,6H),2.31-1.96(m,6H),1.85-1.50(m,4H)。LC-MS:m/z 505(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.54-8.48(m,1H),8.02(d,J＝8Hz,1H),7.81(d,J＝4Hz,1H),5.77-5.14(m,2H),4.53-3.96(m,2H),3.11-3.03(m,2H),2.70-2.54(m,2H),2.15-2.09(m,4H),1.93(m,2H),1.69(m,2H)。LC-MS:m/z 465(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.48-8.56(m,1H),8.01(d,J＝4Hz,1H),7.80(d,J＝4Hz,1H),5.63-5.13(m,2H),4.72-3.97(m,2H),2.62(m,1H),2.31(m,2H),2.14-1.86(m,9H),1.74(m,2H)。LC-MS:m/z 479(M+H) ⁺ 。

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

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¹ H NMR(400MHz,CDCl ₃ )δ8.40-8.34(m,1H),7.87-7.84(m,1H),7.53(d,J＝8Hz,1H),-6.15-5.83(m,1H),5.77-5.31(m,2H),5.17-4.76(m,1H),1.51-1.43(m,3H)；LC-MS:m/z 469(M+H) ⁺ 。

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

¹ H NMR(400MHz,DMSO-d ₆ )δ8.33(m,2H),8.13-7.92(m,2H),7.78-7.59(m,1H),5.21-4.76(m,1H),4.06(m,1H),2.23-1.45(m,8H),1.42-1.25(m,3H)。LC-MS:m/z 437(M+H) ⁺ 。

Table 4: the following objective was prepared by the procedure described in scheme 2 above.

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

Step 1: preparation of 6-chloro-N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine. To a mixture of 2,4, 6-trichloro-1, 3, 5-triazine (2 g,10.9mmol,1 eq.) and (R) -1-cyclopropylethylamine hydrochloride (2.7 g,22.8mmol,2.1 eq.) in acetone (50 mL) was added DIPEA (4.5 mL, 27).3mmol,2.5 equivalents) and CsF (3.3 g,21.8mmol,2.0 equivalents). The mixture was stirred at 40 ℃ for 3 hours and then continued for another 3 hours at 50 ℃. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by standard methods to give the desired product.

LC-MS:m/z 282.1(M+H) ⁺ 。

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

¹ H NMR(400MHz,DMSO-d ₆ ):δ7.61-7.28(m,6H),3.58-3.39(m,2H),1.23-1.10(m,3H),1.02-0.89(m,2H),0.48-0.26(m,6H),0.20-0.10(m,2H)。LC-MS:m/z 325.2(M+H) ⁺ 。

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

Compound 6- (3-chlorophenyl) -N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.30-8.14(m,2H),7.58(d,J＝7.7Hz,1H),7.52(t,J＝7.8Hz,1H),7.41(d,J＝8.2Hz,1H),7.35-7.26(m,1H),3.70-3.43(m,2H),1.26-1.15(m,6H),1.02-0.92(m,2H),0.49-0.30(m,6H),0.26-0.11(m,2H).LC-MS:m/z 358.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ7.99-7.64(m,2H),7.29(d,J＝7.9Hz,1H),6.96(d,J＝7.8Hz,1H),5.78-5.04(m,2H),4.07(s,1H),3.60(m,2H),1.27(d,J＝4.3Hz,6H),0.89(d,J＝3.6Hz,2H),0.43(m,8H)。LC-MS:m/z 340.2(M+H) ⁺ 。

Table 5: the following objective was prepared by the procedure described in scheme 3 above.

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

Scheme 4

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

LC-MS:m/z 430.2(M+H) ⁺ 。

Step 2, preparing N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (1- (methylsulfonyl) pyrrolidin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. Stirring N at room temperature ² - (3, 3-difluorocyclopentyl) -N ⁴ - (pyrrolidin-3-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (20 mg,0.05 mmol), et ₃ A mixture of N (9.4 mg,0.09 mmol), msCl (6 mg,0.06 mmol) in DCM (2 mL) was overnight. The mixture was concentrated and the residue purified by standard methods to give the desired product.

¹ H NMR(400MHz,CDCl ₃ ):δ8.62-8.46(m,1H),8.04(d,J＝7.5Hz,1H),7.81(d,J＝7.6Hz,1H),5.79-5.38(m,2H),4.80-4.53(m,2H),3.76-3.52(m,2H),3.39-3.23(m,1H),2.91(s,3H),2.69-2.57(m,1H),2.45-2.25(m,3H),2.20-1.98(m,3H),1.95-1.81(m,1H),1.22-1.18(m,1H)。LC-MS:m/z 508.1(M+H) ⁺ 。

Compound 3- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyrrolidine-1-carboxylic acid methyl ester.

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.55(m,1H),8.07(d,J＝6.8Hz,1H),7.85(t,J＝6.7Hz,1H),4.84-4.30(m,2H),3.97-3.52(m,4H),2.62(m,1H),2.50-2.22(m,3H),2.22-1.98(m,3H),1.25(s,3H)。LC-MS:m/z 472.2(M+H) ⁺ 。

Compound N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (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 (25 mg,0.05 mmol) in THF (3 mL) at 0deg.C was added LiAlH ₄ (5 mg,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. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, and concentrated. The residue was purified by standard methods to give the desired product.

¹ H NMR(400MHz,CDCl ₃ ):δ8.55(m,1H),8.08-7.93(m,1H),7.80(t,J＝7.4Hz,1H),4.63(m,2H),3.47-2.87(m,3H),2.69(m,6H),2.28(m,4H),1.84(m,4H)。LC-MS:m/z 444.2(M+H) ⁺ 。

Example 5 preparation of dialiphatic triazine Compounds. The compounds of this example were prepared by the general scheme 5 listed below.

Scheme 5

Step 1: preparation of 6- (6- (azetidin-1-yl) pyridin-2-yl) -N ² ,N ⁴ -bis ((R) -1-cyclopropyl-ethyl) -1,3, 5-triazine-2, 4-diamine. Stirring the 6- (6-chloropyridin-2-yl) -N at 100deg.C under nitrogen atmosphere ² ,N ⁴ A mixture of bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine (40 mg,0.11 mmol), azetidine (7.6 mg,0.13 mmol), 2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (6.9 mg,0.01 mmol), sodium t-butoxide (15 mg,0.16 mmol) and tris (dibenzylideneacetone) -dipalladium (10.2 mg,0.01 mmol) in toluene (3 mL) was 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 give the desired product.

¹ H NMR(400MHz,CD ₃ OD):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 N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -6- (pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. To 6- (6-chloropyridin-2-yl) -N under nitrogen atmosphere ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine (20 mg,0.05 mmol) in methanol (2 mL)Pd/C (2 mg) was added to the solution. 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 give the desired product.

¹ H NMR(400MHz,DMSO-d ₆ ):δ8.82-8.03(m,4H),7.75(m,2H),3.79-3.45(m,2H),1.21(d,J＝6.3Hz,6H),1.07-0.84(m,2H),0.55-0.05(m,8H)。LC-MS:m/z 325.2(M+H) ⁺ 。

Example 6 a dialiphatic triazine compound of formula H was prepared. The compounds of this example were prepared by the 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 (200 mg,0.6 mmol) in anhydrous DCM (3 mL) at-65℃was added dropwise BBr ₃ (0.6 mL) 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 ice ₃ The 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 Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue was purified by standard methods to give the desired product.

¹ H NMR(400MHz,CDCl ₃ ):δ7.20(s,1H),6.96(t,J＝9.6Hz,1H),6.83(d,J＝8.6Hz,1H),5.72(m,2H),4.26(s,1H),1.79(s,6H),1.26(d,J＝6.1Hz,6H)。LC-MS:m/z 331.2(M+H) ⁺ 。

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

Scheme 7

Step 1: preparation of 6- (trifluoromethyl) pyridine formamidine. To a solution of 6- (trifluoromethyl) pyridine carbonitrile (50 mg,0.3mmol,1 eq.) in EtOH (3 mL) was added NaOMe (1.6 mg,0.03mmol,0.1 eq.) at 0deg.C. The mixture was stirred at room temperature for 1 hour, followed by addition of NH ₄ Cl (21 mg,0.39mmol,13 eq.). The resulting mixture was stirred at 90 ℃ for 1 hour and cooled to room temperature. With saturated aqueous NaHCO ₃ The mixture was adjusted to pH 9 and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, and concentrated. The residue was purified by standard methods to give 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 (366 mg,15.9mmol,5.0 eq.) in absolute EtOH (6 mL) was added dropwise a solution of 6- (trifluoromethyl) pyridine formamidine (600 mg,3.2 mmol) in EtOH. The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of diethyl malonate (1 ml,6.4mmol,2.0 eq). The mixture was stirred at 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) ^- 。

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

LC-MS:m/z 294.0(M+H) ⁺ 。

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 (80 mg,0.27mmol,1 eq.) in THF (3 mL) was added (R) -1-cyclopropylethylamine (0.06 mL,0.6mmol,2.2 eq.) and Et ₃ N (0.07 mL,0.54mmol,2 eq.). 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) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.40(d,J＝7.9Hz,1H),7.87(t,J＝7.9Hz,1H),7.62(d,J＝7.8Hz,1H),5.19(m,3H),3.13(d,J＝6.3Hz,2H),1.19(d,J＝6.4Hz,6H),0.96-0.72(m,2H),0.52-0.33(m,4H),0.33-0.10(m,4H)。LC-MS:m/z 392.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.49(d,J＝7.8Hz,1H),7.95(t,J＝7.9Hz,1H),7.71(d,J＝7.8Hz,1H),5.22(m,3H),3.22(d,J＝6.5Hz,2H),1.40-1.15(m,6H),0.95(m,2H),0.61-0.44(m,4H),0.31(m,4H)。LC-MS:m/z 392.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ ):δ8.49(d,J＝7.8Hz,1H),7.97(t,J＝7.9Hz,1H),7.72(d,J＝7.8Hz,1H),5.22(m,3H),3.22(d,J＝6.5Hz,2H),1.68-1.25(m,6H),0.97(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 symmetrical dialiphatic triazine Compounds of formula K. The compounds of this example were prepared by the general scheme 9 listed below.

Scheme 9

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

DAST (84 mL,650 mmol) was added dropwise to a solution of 1- (6-bromopyridin-2-yl) ethanone (26 g,130 mmol) in dry DCM (150 mL) at 0deg.C over 30 min. The reaction mixture was then allowed to slowly warm to room temperature and stirred until the reaction was complete. The resulting mixture was slowly poured into ice (300 g) and extracted with DCM (2×50 ml). The combined organic layers were washed with water, dried over anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by standard methods to give 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 (30.2 g,136 mmol) in MeOH (300 mL) was added 1,1' -bis (diphenylphosphino) -ferrocene (7.5 g,13.6 mmol), triethylamine (28.4 mL,204 mmol), and Pd (OAc) ₂ (1.52 g,6.7 mmol). The mixture was stirred at 60℃under CO atmosphere (60 psi) for 16 hours. The resulting mixture was filtered and concentrated under reduced pressure. The residue is purified by standard methods to give 6- (1, 1-di)Fluoroethyl) picolinic acid methyl ester. LC-MS: M/z 202.2 (M+H) ⁺ 。

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 (1.9 g,82.6 mmol) and EtOH (150 mL) was added methyl 6- (1, 1-difluoroethyl) picolinate (2.8 g,28 mmol) and biuret (14.0 g,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 pH 7 with 1N HCl and then filtered. The filter cake was washed with water and dried under high vacuum to obtain 6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4 (1 h,3 h) -dione. LC-MS M/z 255.1 (M+H) ⁺ 。

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

Step 5: preparation of N ² ,N ⁴ Bis (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 (552 mg,2.0mmol,1.0 eq.) and 4, 4-difluorocyclohexylamine hydrochloride (552 mg,4.4mmol,2.2 eq.) in THF (12 mL) was added CsF (1.2 g,8.0mmol,2 eq.) and DIPEA (1.4 mL,8.0mmol,4 eq.) 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.

¹ H NMR(400MHz,CDCl ₃ )δ8.32-8.40(m,1H),7.94(bs,1H),7.78(bs,1H),5.07-5.46(m,2H),3.99-4.18(m,2H),1.71-2.17(m,19H)。LC-MS:m/z 489.2(M+H) ⁺ 。

Using the procedure outlined in example 9, the following compounds were prepared using the appropriate starting materials.

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

¹ H NMR(400MHz,CDCl ₃ )δ8.32-8.43(m,1H),7.93-7.95(m,1H),7.78(bs,1H),5.28-5.70(m,2H),4.54-4.71(m,2H),1.72-2.65(m,15H)。LC-MS:m/z 461.2(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.35-8.42(m,1H),7.95(bs,1H),7.80(bs,1H),5.42-5.85(m,2H),4.35-4.52(m,2H),3.04(bs,4H),2.62(bs,4H),2.04-2.16(m,3H)。LC-MS:m/z 433.2(M+H) ⁺ 。

Example 10. Preparation of symmetrical dialiphatic triazine Compounds of formula L. The compounds of this example were prepared by the 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 dry three-neck round bottomBiuret (14.8 g,0.14 mol), methyl 6-chloropicolinate (21 g,0.12 mol) and EtOH (250 mL) were added to the flask. By N ₂ The mixture was degassed three times and then stirred at 25 ℃ for 20 minutes. Then the temperature was raised to 50℃and HC (OMe) was added ₃ (17 mL,0.14 mol) and TFA (1.37 g,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 (200 mL) and concentrated under reduced pressure to remove residual ethanol. Water (300 mL) 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) ⁺ 。

Step 3: preparation of 6- (6-chloropyridin-2-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine. At N ₂ A mixture of 2, 4-dichloro-6- (6-chloro-pyridin-2-yl) -1,3, 5-triazine (0.27 g,1.04 mol), (R) -1, 1-trifluoropropan-2-amine hydrochloride (0.39 g,2.6 mol) and potassium carbonate (0.43 g,3.1 mol) in dry 1, 4-dioxane (2.5 mL) was stirred at 50℃for 36 hours under an atmosphere and then stirred at 100℃for another 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 purified by standard methods to give the desired product.

¹ H NMR(400MHz,CDCl ₃ )δ8.32(m,1H),7.80(m,1H),7.48(d,J＝7.9Hz,1H),5.61(m,1.5H),5.25(m,0.5H),5.09(m,0.5H),4.88(m,1.5H),1.54-1.26(m,6H)。LC-MS:m/z 415(M+H) ⁺ 。

Using the procedure outlined in example 10, the following compounds were prepared using the appropriate starting materials.

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

¹ H NMR(400MHz,CDCl ₃ )δ8.29-8.16(m,1H),7.72(d,J＝7.6Hz,1H),7.41(d,J＝7.9Hz,1H),5.70-5.13(m,2H),5.09-4.71(m,2H),1.34(m,6H)。LC-MS:m/z 415(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.41-8.23(m,1H),7.83(s,1H),7.51(d,J＝6.2Hz,1H),5.68-5.20(m,2H),5.18-4.81(m,2H),1.48-1.39(m,6H)。LC-MS:m/z 415(M+H) ⁺ 。

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

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

¹ H NMR(400MHz,CDCl ₃ )δ8.39-8.31(m,1H),7.86-7.79(m,1H),7.50(d,J＝7.8Hz,1H),5.67-5.12(m,2H),4.98-4.65(m,2H),2.07-1.91(m,2H),1.70-1.55(m,2H),1.06(dd,J＝8.6,6.0Hz,6H)。LC-MS:m/z 443(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.30-8.35(t,1H),7.78-7.82(t,1H),7.47-7.52(m,1H),5.49-5.63(m,2H),4.72-4.89(m,2H),1.95-1.99(m,2H),1.59(m,2H),1.02-1.08(t,6H)。LC-MS:m/z 443(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.31-8.35(t,1H),7.78-7.82(t,1H),7.47-7.49(m,1H),5.16-5.71(m,2H),4.72-4.74(m,2H),1.94-2.01(m,2H),1.62-1.64(m,2H),1.02-1.08(t,6H)。LC-MS:m/z 443(M+H) ⁺ 。

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

¹ HNMR(400MHz,CDCl ₃ )δ8.30-8.35(m,1H),7.81(s,1H),7.47-7.49(d,1H),5.35-5.66(m,2H),4.91-5.13(d,1H),4.72(s,1H),2.00-2.23(d,3H),1.31-1.42(d,1H),1.03-1.07(m,6H)。LC-MS:m/z 443(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.21(s,1H),7.73(t,J＝7.6Hz,1H),7.41(d,J＝7.8Hz,1H),5.61-5.18(m,2H),4.59-4.20(m,2H),2.85-2.60(m,4H),1.44-1.36(m,6H)。LC-MS:m/z 357(M+H) ⁺ 。

Compound 6- (6-chloropyridin-2-yl) -N ² ,N ⁴ -bis (1-cyclopropyl-propyl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.26(d,J＝7.3Hz,1H),7.76(t,J＝7.8Hz,1H),7.43(d,J＝7.8Hz,1H),5.37-5.08(m,2H),3.48-3.37(m,2H),1.73-1.56(m,4H),0.98(t,J＝7.3Hz,6H),0.92-0.80(m,2H),0.66-0.20(m,8H)。LC-MS(m/z):387.2(M+H) ⁺ 。

Compound 6- (6-chloropyridin-2-yl) -N ² ,N ⁴ -bis (dicyclohexylmethyl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.18(d,J＝7.6Hz,1H),7.69(t,J＝7.8Hz,1H),7.36(d,J＝7.8Hz,1H),5.50-5.01(m,2H),3.30(s,2H),0.89(m,4H),0.50-0.21(m,16H)。LC-MS:m/z 411.2(M+H) ⁺ 。

Compound 6- (6-chloropyridin-2-yl) -N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.28(d,J＝8.2Hz,1H),7.80(t,J＝7.5Hz,1H),7.44(d,J＝8.0Hz,1H),6.64-6.12(m,2H),4.17-3.98(m,2H),2.17-1.70(m,16H)。LC-MS:m/z 459(M+H) ⁺ 。

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

1H NMR(400MHz,CDCl ₃ )δ8.41-8.25(m,1H),7.85(t,J＝7.6Hz,1H),7.53(d,J＝7.6Hz,1H),5.78-5.37(m,2H),4.69-4.53(m,2H),2.65-2.55(m,2H),2.51-1.98(m,8H),1.85-1.76(m,2H)。LC-MS:m/z 431.1(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.48-8.26(m,1H),7.82(s,1H),7.49(s,1H),5.63(m,2H),4.70(m,2H),2.41-2.08(m,6H),1.83(m,4H),1.66(s,2H)。LC-MS:m/z 431(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.27-8.17(m,1H),7.77(t,J＝7.8Hz,1H),7.45(d,J＝7.9Hz,1H),6.30-5.83(m,1H),5.52(m,2H),5.00(m,1H),4.05-3.88(m,2H),2.32-2.17(m,2H),2.10(m,1H),2.01(s,1H),1.88-1.65(m,6H),1.51(m,2H)。LC-MS:m/z 391(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.25-7.78(m,4H),7.64(m,1H),4.45-4.24(m,2H),2.72-2.66(m,4H),2.61-2.50(m,4H),2.46-2.41(m,4H),2.22-2.19(m,4H)。LC-MS:m/z 483(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.68(d,J＝8.0Hz,1H),8.48(s,1H),7.62(d,J＝8.0Hz,1H),5.28(d,J＝8.0Hz,2H),4.20-4.02(m,2H),1.98-1.61(m,16H)。LC-MS:m/z 459.1(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ9.36(m,1H),8.65(d,J＝2.1Hz,1H),8.54(t,J＝1.9Hz,1H),5.46-5.06(m,2H),3.78-3.40(m,2H),1.29(s,6H),0.95-0.87(m,2H),0.56-0.38(m,6H),0.29(s,2H)。LC-MS:m/z 359(M+H) ⁺ 。

Example 11 the compound of this example was prepared by the general scheme 11 listed below.

Scheme 11

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

LC-MS:m/z 460(M+H) ⁺ 。

Step 2 preparation of 6- (6-aminopyridin-2-yl) -N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine. At N ₂ Under atmosphere, N is ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -6- (6- (4-methoxybenzylamino) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (80 mg,0.17 mmol) 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 give the desired product.

1H NMR(400MHz,CDCl ₃ )δ7.71-7.54(m,2H),6.74-6.69(m,1H),6.24-5.30(m,2H),3.70-3.54(m,2H),1.29-1.25(m,6H),0.95-0.90(m,2H),0.58-0.26(m,8H)。LC-MS:m/z 340.2(M+H) ⁺ 。

Example 12 the compound of this example was prepared by the 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 N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -6- (6-methoxypyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (50 mg,0.14 mmol) and NaI (63 mg,0.42 mmol) in dry CH ₃ TMSCl (46 mg,0.42 mmol) was added in one portion to a mixture in CN (1 mL). The reaction mixture was stirred at 80 ℃ for 6 hours and then concentrated under reduced pressure. The residue was purified by standard methods to give the desired product. ¹ H NMR(400MHz,CDCl ₃ )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 compound of this example was prepared by the general scheme 13 listed below.

Scheme 13

Step 1, preparing N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -6- (6-vinylpyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. At N ₂ To 6- (6-chloropyridin-2-yl) -N2, N4-bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine (200 mg,0.56 mmol), 2,4, 6-trivinyl-1,3,5,2,4,6-trioxatriborocyclohexane (135 mg,0.84 mmol) and K under an atmosphere ₂ CO ₃ (154 mg,1.11 mmol) in dioxane (2 mL) and H ₂ Pd (dppf) Cl was added in one portion to a suspension in O (0.8 mL) ₂ (41 mg,0.06 mmol). At 100 The reaction mixture was stirred overnight at c, then cooled to room temperature and quenched with water. The resulting mixture was extracted with EtOAc (20 ml x 2). The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue was purified by standard methods to give the desired product. ¹ H NMR(400MHz,CDCl ₃ )δ8.28-8.15(m,1H),7.77(t,J＝7.6Hz,1H),7.58(d,J＝7.6Hz,1H),7.05-6.99(m,1H),6.15(d,J＝17.6Hz,1H),5.42(d,J＝17.6Hz,1H),5.44-5.16(m,2H),3.72-3.52(m,2H),1.35-1.22(m,6H),0.98-0.86(m,2H),0.58-0.21(m,8H)。LC-MS:m/z 351.1(M+H) ⁺ 。

Example 14 the compound of this example was prepared by the general scheme 14 listed below.

Scheme 14

Step 1. 6- (4, 6-bis (((R) -1-cyclopropylethyl) amino) -1,3, 5-triazin-2-yl) pyridinecarboxaldehyde is prepared. Bubbling ozone into N at-78deg.C ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -6- (6-vinylpyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (120 mg,0.34 mmol) in DCM (2 mL) for 1 hour. In the process of passing through N ₂ After purifying the excess ozone, me is added at 0 DEG C ₂ S (0.2 mL) was added to the reaction mixture. The resulting mixture is concentrated and the residue is purified by standard methods to give the desired product. LC-MS: M/z 353 (M+H) ⁺ 。

Step 2, preparing N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -6- (6- (difluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. DAST (68 mg,0.43 mmol) was added dropwise to a solution of 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) pyridinecarbaldehyde (50 mg,0.14 mmol) in anhydrous DCM (2 mL) at 0deg.C. The reaction mixture was stirred at room temperature overnight. At 0℃with saturated aqueous NaHCO ₃ (5 mL) the resulting mixture was quenched slowly and then extracted with DCM (40 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ Dried, concentrated, and purified by standard methods to give the desired product. ¹ H NMR(400MHz,CDCl ₃ )δ8.46(s,1H),7.97(t,J＝7.6Hz,1H),7.77(d,J＝7.6Hz,1H),6.98-6.70(m,1H),5.47-5.21(m,2H),3.67-3.50(m,2H),1.32-1.25(m,6H),0.92-0.86(m,2H),0.58-0.21(m,8H)。LC-MS:m/z 375(M+H) ⁺ 。

Using the procedure outlined in example 14, the following compounds were prepared using the appropriate starting materials.

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

¹ H NMR(400MHz,CDCl ₃ )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 N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (6- (difluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.64-8.35(m,1H),8.10-7.92(m,1H),7.81(d,J＝7.7Hz,1H),6.82(m,1H),5.98-5.29(m,2H),4.70-4.16(m,2H),3.24-2.92(m,4H),2.79-2.44(m,4H)。LC-MS:m/z 419(M+H) ⁺ 。

Example 15 the compound of this example was prepared by the general scheme 15 listed below.

Scheme 15

Step 1: preparation 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) picolinic acid methyl ester. To 6- (6-chloropyridin-2-yl) -N ² ,N ⁴ To a mixture of bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine (0.25 g,0.7 mmol) in MeOH (10 mL) was added dppf (80 mg,0.15 mmol), pd (OAc) ₂ (60 mg,27 mmol) and Et ₃ N (150 mg,1.5 mmol). The reaction mixture was degassed and backfilled three times with CO and then stirred at 70 ℃ for 12 hours under CO (60 psi) atmosphere. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with EtOAc (100 mL) and filtered. The filtrate is concentrated and purified by standard methods to give methyl 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) picolinate. ¹ H NMR(400MHz,CDCl ₃ )δ8.50(m,1H),8.24-8.22(dd,1H),7.99-7.95(t,1H),5.49(m,2H),4.02(s,3H),3.57(m,2H),1.92(s,6H),0.96-0.87(m,2H),0.52-0.26(m,8H)。LC-MS:m/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 (150 mg,0.40 mmol) in water (2.0 mL) and THF (3.0 mL) was added lithium hydroxide (47 mg,2.0 mmol). The reaction mixture was stirred at room temperature overnight, then acidified with aqueous HCl (1N) to pH 5-6 and extracted with EtOAc. By anhydrous Na ₂ SO ₄ The combined organic layers were dried and concentrated under reduced pressure to give the desired product. LC-MS: M/z 367 (M-H) -.

Step 3: preparation of 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) pyridine amide. To an ice-cold mixture of 6- (4, 6-bis (((R) -1-cyclopropylethyl) amino) -1,3, 5-triazin-2-yl) picolinic acid (120 mg,0.32 mmol) in dry DCM (5.0 mL) and DMF (0.1 mL) was added oxalyl chloride (65 mg,0.5 mmol) 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. ¹ H NMR(400MHz,CDCl ₃ )δ13.59(s,1H),9.30-9.14(m,3H),8.58-8.30(m,3H),7.95(s,1H),3.77-3.54(m,2H),1.29(d,6H),1.02(m,2H),0.50-0.30(m,8H)。LC-MS:m/z 368(M+H) ⁺ 。

Step 4: preparation of 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) pyridine carbonitrile. To a mixture of 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) pyridine amide (36 mg,0.1 mmol) in dry pyridine (3.0 mL) was added phosphorus trichloride (0.1 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The residue is purified by standard methods to give 6- (4, 6-bis ((R) -1-cyclopropylethylamino) -1,3, 5-triazin-2-yl) pyridine carbonitrile. ¹ H NMR(400MHz,CDCl ₃ )δ8.50-8.48(m,1H),8.24-8.22(t,1H),7.73-7.71(dd,1H),5.46-5.14(m,2H),3.62-3.50(m,2H),1.22-1.18(m,6H),0.89-0.84(m,2H),0.46-0.20(m,8H)。LC-MS:m/z 350(M+H) ⁺ 。

Example 16 the compound of this example was prepared by the general scheme 16 listed below.

Scheme 16

Step 1: preparing 3, 6-difluoro-2-hydrazinopyridine. To an ice-cold solution of 2,3, 6-trifluoropyridine (1.0 g,7.5 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.75 g,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 (10 mL) and extracted with DCM (2×20 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried and concentrated under reduced pressure to give 3, 6-difluoro-2-hydrazinopyridine. LC-MS (M/z): 146 (M+H) ⁺ 。

Step 2: preparing 2-bromo-3, 6-difluoropyridine. To a stirred solution of 3, 6-difluoro-2-hydrazinopyridine (1.1 g,7.0 mmol) in chloroform (20 mL) was added dropwise bromine (1.8 g,11.2 mmol) at room temperature. The reaction mixture was heated to 60 ℃ for 1.5 hours. The resulting mixture was cooled to room temperature and saturated aqueous NaHCO ₃ Quench and extract with dichloromethane (2×20 ml). By anhydrous Na ₂ SO ₄ The combined organic layers were dried and concentrated and purified by standard methods to give 2-bromo-3, 6-difluoropyridine. LC-MS M/z 194 (M+H) ⁺ 。

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

Step 4: preparation of N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. To N ¹ ,N ⁵ To a suspension of bis (4, 4-difluorocyclohexyl) -biguanide (167 mg,0.50 mmol) and methyl 3, 6-difluoropicolinate (130 mg,0.75 mmol) in MeOH (5 mL) was added NaOMe (81 mg,1.5 mmol). The reaction mixture was stirred at room temperature overnight, then poured into water and extracted with EtOAc. By anhydrous Na ₂ SO ₄ The combined organic extracts were dried and concentrated under reduced pressure. Purification of the residue by standard methods gives N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. ¹ H NMR(400MHz,CDCl ₃ )δ7.67-7.61(m,1H),7.07-7.03(m,1H),5.46-5.10(m,2H),4.08-3.97(m,2H),2.17-2.09(m,8H),1.96-1.83(m,4H),1.73-1.63(m,4H)。LC-MS:m/z 461(M+H) ⁺ 。

Example 17 the compound of this example was prepared by the general scheme 17 listed below.

Scheme 17

Step 1: preparation of N ² ,N ⁴ Bis (4, 4)Difluorocyclohexyl) -6- (3-fluoro-6-hydrazinopyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. To N ² ,N ⁴ To a solution of bis (4, 4-difluoro-cyclohexyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (230 mg,0.50 mmol) in THF (20 mL) was added hydrazine hydrate (150 mg,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. The organic phase was separated with anhydrous Na ₂ SO ₄ Dried 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) -N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -1,3, 5-triazine-2, 4-diamine. To N ² ,N ⁴ To a solution of bis (4, 4-difluoro-cyclohexyl) -6- (3-fluoro-6-hydrazinopyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (47 mg,0.1 mmol) in methanol (5.0 mL) was added raney nickel (100 mg). At H ₂ The reaction mixture was stirred overnight at room temperature under an atmosphere, and then filtered. The filtrate is concentrated and purified by standard methods to give the desired product. ¹ H NMR(400MHz,CDCl ₃ )δ7.43-7.39(m,1H),7.03-7.01(m,1H),4.59(s,2H),4.10-4.05(m,2H),2.09-1.93(m,12H),1.76-1.68(m,4H)。LC-MS:m/z 458.2(M+H) ⁺ 。

Example 18 the compound of this example was prepared by the 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 100deg.C ² ,N ⁴ A mixture of bis (4, 4-difluorocyclohexyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (100 mg,0.22 mmol) in concentrated HCl (5.0 mL) was used overnight. The resulting mixture is concentrated and purified by standard methods to give the desired product. ¹ H NMR(400MHz,CDCl ₃ )δ9.96(m,1H),7.40-7.27(m,2H),6.73-6.67(m,1H),5.47-5.17(m,2H),4.02-3.92(m,2H),2.11-1.66(m,16H)。LC-MS:m/z 459(M+H) ⁺ 。

Example 19 the compound of this example was prepared by the general scheme 19 listed below.

Scheme 19

Step 1: preparation of N ¹ ,N ⁵ -bis (3, 3-difluorocyclopentyl) -biguanide. A mixture of 3, 3-difluorocyclopentylamine hydrochloride (3 g,19.1 mmol) and dicyandiamide sodium (1.7 g,19.1 mmol) was heated at 160deg.C 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: preparing the 6-cyclopropyl pyridine carboxylic acid ethyl ester. To a mixture of ethyl 6-bromopyridine carboxylate (200 mg,0.87 mmol) and cyclopropylboronic acid (149 mg,1.74 mmol) in toluene (15 mL) was added K ₃ PO ₄ (369 mg,1.74 mmol) and dichloro (diphenylphosphino ferrocene) palladium (11 mg,0.017 mmol). At N ₂ The resulting mixture was stirred at 100 ℃ overnight under an atmosphere, then cooled to room temperature and filtered. The filtrate is concentrated and purified by standard methods to give the desired product. LC-MS: M/z 192.1 (M+H) ⁺ 。

Step 3:6- (6-Cyclopropylpyridin-2-yl) -N ² ,N ⁴ -bis (3, 3-difluorocyclopentyl) -1,3, 5-triazine-2, 4-diamine. To N ¹ ,N ⁵ To a mixture of bis (3, 3-difluorocyclopentyl) -biguanide (50 mg,0.16 mmol) and ethyl 6-cyclopropylpyridinium carboxylate (62 mg,0.33 mmol) in methanol (5 mL) was added NaOMe (44 mg,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 Na ₂ SO ₄ Dried, concentrated, and purified by standard methods to give the desired product. ¹ H NMR(400MHz,CDCl ₃ )δ8.43-8.33(m,1H),8.06-7.99(m,1H),7.25-7.23(d,J＝8Hz,1H),6.66-6.52(m,1H),5.90-5.79(m,1H),4.74-4.45(m,2H),2.66-2.54(m,2H),2.38-2.16(m,8H),1.90-1.88(m,2H),1.42-1.40(m,2H),1.29-1.25(m,1H),1.25-1.01(m,2H)。LC-MS:m/z 437.2(M+H) ⁺ 。

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

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

¹ H NMR(400MHz,CDCl ₃ )δ8.21(s,1H),7.87(s,1H),7.14(s,1H),5.16(s,1H),4.17-4.01(m,2H),2.43(s,1H),2.16-1.74(m,16H),1.25(s,2H),1.02(s,2H),0.87(m,1H)。LC-MS:m/z 465(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (6-methylpyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.181-8.11(m,1H),7.71(s,1H),7.29(s,1H),5.46-5.07(m,2H),4.19-3.99(m,2H),2.69(s,3H),2.17-2.12(m,9H),1.97-1.84(m,4H),1.63-1.55(m,3H)。LC-MS:m/z 439(M+H) ⁺ 。

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

Step 1: preparation of methyl 6- (trifluoromethyl) pyrazine-2-carboxylate. To a mixture of 2-chloro-6- (trifluoromethyl) pyrazine (1 g,5.5 mol) in MeOH (5.5 mL) was added dppf (0.16 g,0.29 mmol), pd (OAc) ₂ (0.1 g,0.44 mmol) Et ₃ N (0.12 mL,8.2 mmol). The suspension was degassed in vacuo and then backfilled three times with CO. The resulting mixture was stirred at 70℃for 2 days under CO atmosphere (80 psi) until the reaction was complete. The mixture was cooled to room temperature and concentrated at 30 ℃ under reduced pressure. EtOAc (150 mL) was added to the residue. The suspension was filtered and the filtrate concentrated and purified by standard methods to give 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) ⁺ 。

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 (2.8 g, 0.0111 mol) in POCl ₃ Et was added to the solution in (30 mL) ₃ N (0.3 mL). The mixture was stirred at 100 ℃ for 16 hours until the reaction was complete. The resulting mixture is concentrated and purified by standard methods to give the desired product. LC-MS: M/z 296 (M+H) ⁺ 。

Step 4: preparation of N ² ,N ⁴ -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.

¹ H NMR(400MHz,CDCl ₃ )δ9.73(m,1H),9.07(s,1H),5.49-5.15(m,2H),4.17-3.99(m,2H),2.17-1.58(m,16H)。LC-MS:m/z 494(M+H) ⁺ 。

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

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

¹ H NMR(400MHz,CDCl ₃ )δ9.74(m,1H),9.07(d,J＝3.2Hz,1H),5.68-5.37(m,2H),4.71-4.53(m,2H),2.66-2.61(m,2H),2.32-1.85(m,10H)。LC-MS:m/z 466(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ9.77-9.71(m,1H),9.06(s,1H),5.68-5.37(m,2H),5.54-4.72(m,2H),3.12(m,1H),2.64(m,1H),2.32(m,3H),2.17-2.13(m,6H)。LC-MS:m/z 466(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ9.74(m,1H),9.07(d,J＝3.6Hz,1H),5.70-5.38(m,2H),4.83-4.38(m,2H),2.80-1.76(m,12H)。LC-MS:m/z 466(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ9.74(m,1H),9.07(d,J＝3.3Hz,1H),5.68-5.37(m,2H),4.81-4.40(m,2H),2.79-1.73(m,12H)。LC-MS:m/z 466(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ9.74(m,1H),9.08(s,1H),5.84-5.49(m,2H),4.53-4.37(m,2H),3.12-3.02(m,4H),2.70-2.57(m,4H)。LC-MS:m/z 438(M+H) ⁺ 。

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

1H NMR(400MHz,CD ₃ OD)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) ⁺ 。

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

¹ H NMR(400MHz,DMSO-d ₆ )δ9.86-9.69(m,1H),9.37(d,1H),8.68-8.28(m,2H),5.04-4.71(m,2H),1.81-1.68(m,4H),0.97-0.90,6H)。LC-MS:m/z 478.1(M+H) ⁺ 。

Example 21 a symmetrical dialiphatic triazine compound of formula N was prepared. The compounds of this example were prepared by the general scheme 21 listed below.

Scheme 21

Step 1: 1- (6-chloropyrazin-2-yl) ethanol is prepared. At-5 DEG CNext, CH was added dropwise to a solution of methyl 6-formylpyrazine-2-carboxylate (560 mg,4.15 mmol) in anhydrous THF (5 mL) ₃ MgB (2.1 mL,6.2 mmol). The reaction mixture was stirred at room temperature for 1 hour, then at 0℃with saturated aqueous NH ₄ Cl was quenched and extracted with DCM (3X 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Drying and concentrating to obtain the desired product. LC-MS M/z 159.0 (M+H) ⁺ 。

Step 2: preparation of 1- (6-chloropyrazin-2-yl) ethanone. To a solution of 1- (6-chloropyrazin-2-yl) ethanol (370 mg,2.3 mmol) in DCM (5 mL) was added DMP (1.5 g,3.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, and then filtered. The filtrate is concentrated and purified by standard methods to give the desired product. ¹ H NMR(400MHz,CDCl ₃ )δ9.12(s,1H),8.78(s,1H),2.72(s,3H)。LC-MS:m/z 157.1(M+H) ⁺ 。

Step 3: preparing 6-acetylpyrazine-2-methyl formate. To a solution of 1- (6-chloropyrazin-2-yl) ethanone (260.0 mg,1.7 mmol) in MeOH (3 mL) was added dppf (94.0 mg,0.17 mmol), pd (OAc) ₂ (20 mg,0.1 mmol) and Et ₃ N (0.4 mL,2.6 mmol). The mixture was stirred overnight at 60℃under CO (60 psi) atmosphere. The resulting mixture was cooled to room temperature and filtered. The filtrate is concentrated and purified by standard methods to give the desired product. LC-MS M/z 181.0 (M+H) ⁺ 。

Step 4: preparation of methyl 6- (1, 1-difluoroethyl) pyrazine-2-carboxylate. DAST (0.86 mL,6.5 mmol) was slowly added to a solution of methyl 6-acetylpyrazine-2-carboxylate (240 mg,1.3 mmol) in anhydrous DCM (3 mL) at 0deg.C. The reaction mixture was stirred at room temperature for 3 hours, then cooled to 0deg.C with cold saturated aqueous NaHCO ₃ Quench and extract with DCM (3×10 ml). By anhydrous Na ₂ SO ₄ The combined organic layers were dried and concentrated to give the desired product. LC-MS: M/z 203.1 (M+H) ⁺ 。

Step 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) ⁺ 。

Step 7: preparation of N ² ,N ⁴ -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.

¹ H NMR(400MHz,CDCl ₃ )δ9.59(m,1H),9.05(s,1H),5.46(s,1H),5.06(m,1H),4.07(m,2H),2.17(s,3H),2.09(s,4H),1.93(m,4H),1.79-1.55(m,8H)。LC-MS:m/z 490.2(M+H) ⁺ 。

Using the procedure outlined in example 21, the following compounds were prepared using the appropriate starting materials.

N ² ,N ⁴ -bis (3, 3-difluorocyclopentyl) -6- (6- (1, 1-difluoroethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.60(m,1H),9.04(d,J＝6.0Hz,1H),5.66-5.34(m,2H),4.70-4.52(m,2H),2.65-2.60(m,2H),2.32-2.08(m,10H),1.90-1.74(m,3H)。LC-MS:m/z 462.2(M+H) ⁺ 。

N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (6- (1, 1-difluoroethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.62-9.57(m,1H),9.05(s,1H),5.75-5.44(m,2H),4.51-4.37(m,2H),3.07(s,4H),2.65-2.61(m,4H),2.17-2.08(m,3H)。LC-MS:m/z 434.2(M+H) ⁺ 。

Example 22 symmetrical dialiphatic triazine Compounds of formula O were prepared. The compounds of this example were prepared by the general scheme 22 listed below.

Scheme 22

Step 1: 2- (methoxycarbonyl) pyrazine 1-oxide was prepared. To a solution of pyrazine-2-carboxylic acid methyl ester (10.0 g,70 mmol) in 1, 2-dichloroethane (120 mL) was added 3-chloroperoxybenzoic acid (25.0 g,140 mmol). The reaction mixture was stirred at 60 ℃ overnight. The resulting mixture was cooled to room temperature and filtered. By anhydrous K ₂ CO ₃ The filtrate was dried and concentrated under reduced pressure. The residue was triturated with hexane and filtered and dried to give 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 (4.8 g,30 mmol) was stirred at 85deg.C in SOCl ₂ (50 mL) was allowed to stand overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. By saturated aqueous NaHCO ₃ The residue was neutralized and extracted with DCM (3X 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried and concentrated, and purified by standard methods to give methyl 6-chloropyrazine-2-carboxylate. ¹ H NMR(600MHz,CDCl ₃ )δ8.59(s,1H),8.53(s,1H),4.84(s,2H),3.01(s,1H)。LC-MS:m/z 173.0(M+H) ⁺ 。

Step 3: (6-chloropyrazin-2-yl) methanol is prepared. To a solution of methyl 6-chloropyrazine-2-carboxylate (2.0 g,11.6 mmol) in water (20 mL) at 0deg.C was added NaBH in portions ₄ (2.3 g,58.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes, followed by the addition of saturated aqueous K ₂ CO ₃ (40 mL) and EtOH (20 mL). The resulting mixture was stirred for an additional 1 hour and extracted with EA (2X 20 mL). By anhydrous Na ₂ SO ₄ Dry and combineThe organic layer was concentrated and purified by standard methods to give (6-chloropyrazin-2-yl) methanol. LC-MS: M/z 145.0 (M+H) ⁺ 。

Step 4: preparing 6-chloropyrazine-2-formaldehyde. To a solution of (6-chloropyrazin-2-yl) methanol (600 mg,4.2 mmol) in DCM (10 mL) was added dess-martin reagent (2.6 g,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 give 6-chloropyrazine-2-carbaldehyde. LC-MS: M/z 143.0 (M+H) ⁺ 。

Step 5: preparation of methyl 6-formylpyrazine-2-carboxylate. To a mixture of 6-chloropyrazine-2-carbaldehyde (1.0 g,7.0 mmol) in MeOH (10 mL) was added dppf (3838 mg,0.7 mmol), pd (OAc) ₂ (90 mg,0.4 mmol) Et ₃ N (1.5 mL,10.5 mmol). The suspension was stirred at 60℃overnight 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 give methyl 6-formylpyrazine-2-carboxylate. LC-MS M/z 167.0 (M+H) ⁺ 。

Step 6: preparation of methyl 6- (difluoromethyl) pyrazine-2-carboxylate. DAST (16.3 mL,123.5 mmol) was slowly added to a mixture of methyl 6-formylpyrazine-2-carboxylate (4.1 g,24.7 mmol) in anhydrous DCM (40 mL) at 0deg.C. The reaction mixture was stirred at room temperature for 3 hours, then cooled to 0deg.C with cold saturated aqueous NaHCO ₃ Quench and extract with DCM (2×20 ml). By anhydrous Na ₂ SO ₄ The combined organic layers were dried and concentrated to give the desired product. LC-MS: M/z189.0 (M+H) ⁺ 。

Step 7: preparation of 6- (6- (difluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4 (1 h,3 h) -dione. To a flame-dried three-neck round bottom flask was added biuret (659 mg,6.4 mmol) and methyl 6- (difluoromethyl) pyrazine-2-carboxylate (1.0 g,5.3 mmol), followed by EtOH (12 mL). The mixture was degassed and used with N ₂ Backfilling for three times. The mixture was stirred at 25 ℃ for 20 minutes and then heated to 50 ℃. HC (OMe) was then added to the above mixture ₃ (0.7 mL,6.4 mmol) and TFA (0.04 mL,0.53 mmol). The mixture (pale yellow slurry) was stirred at this temperature for 30 minutes, followed by dropwise additionA solution of NaOEt in EtOH (20% wt,7.2g,21.2 mmol). The resulting mixture was heated under reflux for 2 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was treated with water (10 mL) and concentrated again to remove residual ethanol. The final residue was suspended in water (30 mL), cooled to 10 ℃ when acidity was adjusted to ph=1 by slow addition of 6N HCl (solid precipitated), 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) ⁺ 。

Step 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) ⁺ 。

Step 8: preparation of N ² ,N ⁴ -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.

¹ H NMR(400MHz,CDCl ₃ )δ9.69(m,1H),9.07(s,1H),6.89(m,1H),5.53-5.12(m,2H),4.08(m,2H),2.23-1.67(m,16H)。LC-MS:m/z 476.2(M+H) ⁺ 。

Using the procedure outlined in example 22, the following compounds were prepared using the appropriate starting materials.

N ² ,N ⁴ -bis (3, 3-difluorocyclopentyl) -6- (6- (difluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.73-9.67(m,1H),9.07(s,1H),7.03-6.76(m,1H),5.63-5.35(m,2H),4.73-4.55(m,2H),2.66-2.61(m,2H),2.32(s,4H),2.13-1.57(m,6H)。LC-MS:m/z 448.2(M+H) ⁺ 。

N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (6- (difluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.72-9.67(m,1H),9.07(s,1H),6.85(d,1H),5.76-5.48(m,2H),4.54-4.38(m,2H),3.08(s,4H),2.66-2.61(m,4H)。LC-MS:m/z 420.1(M+H) ⁺ 。

N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (4- (difluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.17(d,J＝4.9Hz,1H),7.77(d,J＝4.9Hz,1H),6.77(m,1H),5.76(m,2H),4.55(m,2H),3.07m,4H),2.61(m,4H)。LC-MS:m/z 420(M+H) ⁺ 。

N ² ,N ⁴ -bis (3, 3-difluorocyclopentyl) -6- (4- (difluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,DMSO-d ₆ )δ9.19(m,1H),8.16(m,1H),7.88(m,1H),7.04(m,1H),4.47(m,2H),2.63(m,1H),2.25(m,9H),1.83(m,2H)。LC-MS:m/z 448(M+H) ⁺ 。

N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (4- (difluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ(m,1H),7.79-7.78(m,1H),6.91-6.64(m,1H),5.72-5.20(m,2H),4.26-4.02(m,2H),2.13-2.10(m,8H),1.98-1.87(m,4H),1.76-1.73(m,4H)。LC-MS:m/z 476(M+H) ⁺ 。

Example 23 the compound of this example was prepared by the general scheme 23 listed below.

Scheme 23

Step 1: preparation of 6- (6-chloropyrazin-2-yl) -N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -1,3, 5-triazine-2, 4-diamine. To 6-chloropyrazine-2-carboxylic acid methyl ester (300 mg,1.74 mmol) and N ¹ ,N ⁵ To a mixture of bis- (4, 4-difluorocyclohexylamine) -biguanide (700 mg,2.10 mmol) in MeOH (8 mL) was added MeONa (340 mg,6.28 mmol). The reaction mixture was stirred at room temperature overnight and then partitioned between EtOAc (30 mL) and H ₂ O (30 mL). The organic layer was separated, washed with brine (30 mL), and dried over anhydrous Na ₂ SO ₄ Dried and concentrated, and purified by standard methods to give the desired product. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.48-9.32(m,1H),8.93(d,J＝8Hz,1H),7.92-7.59(m,2H),4.15-3.95(m,2H),2.08-1.60(m,16H)。LC-MS:m/z 460(M+H) ⁺ 。

Using the procedure outlined in example 23, the following compounds were prepared using the appropriate starting materials.

6- (6-Chloropyrazin-2-yl) -N ² ,N ⁴ -bis (3, 3-difluorocyclopentyl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.45(d,1H),8.72(s,1H),5.65(d,2H),4.53-4.37(m,2H),3.07-2.60(m,8H)。LC-MS:m/z 432(M+H) ⁺ 。

6- (6-Chloropyrazin-2-yl) -N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.45(d,1H),8.71(s,1H),5.69-5.36(m,2H),4.70-4.52(m,2H),2.65-2.05(m,12H)。LC-MS:m/z 404(M+H) ⁺ 。

6- (6-Chloropyrazin-2-yl) -N2, N4-bis (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

/>

¹ H NMR(400MHz,CDCl ₃ )δ9.42(d,1H),8.66(s,1H),5.61-5.24(m,2H),5.01-4.78(m,2H),1.41-1.34(m,6H)。LC-MS:m/z 416(M+H) ⁺ 。

Example 24 a symmetrical dialiphatic triazine compound of formula P was prepared. The compounds of this example were prepared by the 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 (10 g,54.9 mmol) in MeOH (60 mL) was added dppf (3.0 g,5.5 mmol), pd (OAc) ₂ (630 mg,2.8 mmol) and Et ₃ N (11.4 mL,41.2 mmol). The mixture was stirred at 60℃overnight under CO atmosphere (60 psi). The resulting mixture was cooled to room temperature and filtered. The filtrate is concentrated and purified by standard methods to give the desired product. LC-MS M/z 207.0 (M+H) ⁺ 。

Step 2: preparation of 6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione. This procedure is as described above for example 1Step 2 is the same. LC-MS M/z 260.0 (M+H) ⁺ 。

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) ⁺ 。

Step 4: preparation of N ² ,N ⁴ -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.

¹ H NMR(400MHz,CDCl ₃ )δ9.08(m,1H),8.42(m,1H),5.54-5.19(m,2H),4.16-3.99(m,2H),2.29-1.73(m,16H)。LC-MS:m/z 494.2(M+H) ⁺ 。

Using the procedure outlined in example 24, the following compounds were prepared using the appropriate starting materials.

N ² ,N ⁴ -bis (3, 3-difluorocyclopentyl) -6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.06-9.10(m,1H),8.39-8.45(m,1H),5.66-5.68(d,J＝8.0Hz,2H),4.52-4.70(m,2H),2.60-2.65(m,2H),2.13-2.32(m,8H),1.67-1.87(m,2H)。LC-MS:m/z 466.2(M+H) ⁺ 。

N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.10(m,1H),8.51-8.37(m,1H),5.93-5.48(m,2H),4.44(m,2H),3.07(m,4H),2.75-2.49(m,4H)。LC-MS:m/z 438.1(M+H) ⁺ 。

6- (2- (trifluoromethyl) pyrimidin-4-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.11(m,1H),8.45(t,J＝5.6Hz,1H),5.74-5.32(m,2H),5.16-4.79(m,2H),1.43(m,6H)。LC-MS:m/z 450.1(M+H) ⁺ 。

N ² ,N ⁴ -bis ((S) -1, 1-trifluorobutan-2-yl) -6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.11(m,1H),8.46(d,J＝5.0Hz,1H),5.78-5.22(m,2H),4.97-4.63(m,2H),2.12-1.90(m,2H),1.61-1.69(m,2H),1.05(t,J＝7.5Hz,6H)。LC-MS:m/z 478.1(M+H) ⁺ 。

N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine.

¹ H NMR(400MHz,CDCl ₃ )δ9.22(d,J＝4.9Hz,1H),7.77(d,J＝4.9Hz,1H),5.64-5.16(m,2H),4.21-4.01(m,2H),2.28-1.52(m,16H)。LC-MS:m/z 494.2(M+H) ⁺ 。

N ² ,N ⁴ -bis (3, 3-difluorocyclopentyl) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.22(d,1H),7.77(d,1H),5.87(d,2H),4.58-4.53(m,2H),2.69-2.56(m,2H),2.31-2.29(m,4H),2.17-2.08(m,4H),1.87-1.68(m,2H)。LC-MS:m/z 466.2(M+H) ⁺ 。

N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,DMSO-d ₆ )δ9.34(m,1H),8.64-8.00(m,3H),4.46-4.10(m,2H),3.07-2.83(m,4H),2.74-2.62(m,4H)。LC-MS:m/z 438.1(M+H) ⁺ 。

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

/>

¹ H NMR(400MHz,CDCl ₃ )δ9.19(s,0.6H),7.74-7.73(m,0.6H),5.63-5.43(m,2H),3.61-3.58(m,2H),1.27-1.26(m,8H),0.90(m,2H),0.50-0.26(m,8H)。LC-MS:m/z 394(M+H) ⁺ 。

N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (4- (2-methoxyethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.83-8.82(m,1H),7.40-7.39(m,1H),5.60-5.58(m,2H),4.26-4.01(m,2H),3.81-3.77(t,J＝8Hz,2H),3.35(s,3H),3.21-3.18(m,J＝8Hz,2H),2.11-2.05(m,8H),1.94-1.86(m,4H),1.74-1.69(m,4H)。LC-MS:m/z 484(M+H) ⁺ 。

Example 25 the compound of this example was prepared by the general scheme 25 listed below.

Scheme 25

Step 1: preparation of ethyl 2- (trifluoromethyl) thiazole-4-carboxylate. To a solution of 2, 2-trifluoroacetamide (1.42 g,12.6 mmol) in dry THF (60 mL) was added the Lawster reagent (3.06 g,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-oxopropionate (1.6 ml,12.6 mmol). The mixture was refluxed for an additional 18 hours and then cooled to room temperature. The resulting mixture was partitioned between EtOAc and water. The organic layer was separated with anhydrous Na ₂ SO ₄ Dried and concentrated, and purified by standard methods to give ethyl 2- (trifluoromethyl) thiazole-4-carboxylate. ¹ H NMR(400MHZ,CDCl ₃ )δ8.42(s,1H)4.47(q,J＝7.1Hz,2H),1.45(t,J＝7.2Hz,3H)。LC-MS:m/z 226(M+H) ⁺ 。

Step 2: preparation of N ¹ ,N ⁵ -bis (3, 3-difluorocyclobutyl) -biguanide. 3, 3-Difluorocyclobutylamine hydrochloride (3.024 g,0.021 mol) and NaN (CN) were stirred vigorously at 160 ℃ ₂ (890 mg,0.01 mol) 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/z 282 (M+H) ⁺ 。

Step 3: preparation of N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine. To N ¹ ,N ⁵ To a mixture of bis (3, 3-difluorocyclobutyl) -biguanide (60 mg,0.22 mmol) in MeOH (5 mL) was added ethyl 2- (trifluoromethyl) thiazole-4-carboxylate (58.5 mg,0.26 mmol) and NaOMe (23.7 mg,0.44 mmol). The reaction mixture was then stirred at room temperature for 48 hours, then partitioned between EtOAc and H ₂ And O. The organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, concentrated and purified by standard methods to give N ² ,N ⁴ -bis (3, 3-difluoro-ring)Butyl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine.

¹ H NMR(400MHz,CDCl ₃ )δ7.83(d,J＝5.2Hz,1H),7.01-6.74(m,1H),5.74-5.43(m,2H),4.45-4.32(m,2H),3.11-3.04(m,4H),2.63-2.48(m,4H)。LC-MS:m/z 443(M+H) ⁺ 。

Using the procedure outlined in example 25, the following compounds were prepared using the appropriate starting materials.

N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.84(s,1H),5.42-5.07(m,2H),3.89-3.79(m,2H),2.06-1.79(m,13H),1.67-1.57(m,3H)。LC-MS:m/z 499(M+H) ⁺ 。

N ² ,N ⁴ -bis (3, 3-difluorocyclopentyl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.91(d,J＝4Hz,1H),5.66-5.34(m,2H),4.64-4.51(m,2H),2.69-2.59(m,2H),2.31-2.04(m,8H),1.86-1.80(m,2H)。LC-MS:m/z 471(M+H) ⁺ 。

6- (4- (trifluoromethyl) thiazol-2-yl) -N ² ,N ⁴ -bis (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.94(s,1H),5.81-5.31(m,2H),5.01-4.83(m,2H),1.47-1.39(m,6H)。LC-MS:m/z 455(M+H) ⁺ 。

N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (2- (trifluoromethyl) thiazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.48(m,1H),5.41-5.09(m,2H),4.16-3.99(m,2H),2.28-1.66(m,16H)。LC-MS:m/z 499(M+H) ⁺ 。

N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (2- (trifluoromethyl) thiazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.50(m,1H),6.73-6.38(m,2H),4.46-4.36(m,2H),3.06(s,4H),2.61(s,4H)。LC-MS:m/z 443(M+H) ⁺ 。

6- (2- (trifluoromethyl) thiazol-4-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.49(d,1H),5.57-5.12(m,2H),4.97-4.49(m,2H),1.36-1.25(m,6H)。LC-MS:m/z 455(M+H) ⁺ 。

N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (2-methyloxazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.11(s,1H),5.27-4.92(m,2H),4.02-3.81(m,2H),2.47(s,3H),2.03-1.79(m,12H),1.63-1.54(m,4H)。LC-MS:m/z 429(M+H) ⁺ 。

N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (2-methyloxazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.24(m,1H),5.66(m,2H),4.31(s,2H),3.13-2.95(m,4H),2.60(m,7H)。LC-MS:m/z 373(M+H) ⁺ 。

N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (5-methylisoxazol-3-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ6.52-6.48(m,1H),5.44-5.09(m,2H),4.15-3.96(m,2H),2.49(s,3H),2.11-1.89(m,13H),1.70-1.63(m,3H)。LC-MS:m/z429(M+H) ⁺ 。

N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (5-methylisoxazol-3-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,DMSO-d ₆ )δ6.51(m,1H),5.86-5.33(m,2H),4.65-4.13(m,2H),3.04(dd,J＝6.2,5.4Hz,4H),2.70-2.55(m,4H),2.50(s,3H)。LC-MS:m/z 373(M+H) ⁺ 。

Example 26 the compound of this example was prepared by the general scheme 26 listed below.

Scheme 26

Step 1: preparing the ethyl 2-bromothiazole-4-carboxylate. To a solution of ethyl 2-aminothiazole-4-carboxylate (15.0 g,87.1 mmol) in MeCN (100 mL) was added isoamyl nitrite (24.5 g,209 mmol) and CuBr ₂ (27.5 g,122 mmol). The mixture was stirred at 70 ℃ overnight, then cooled to room temperature, diluted with water (200 mL), and extracted with EtOAc (2 x 200 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried and concentrated and purified by standard methods to give ethyl 2-bromothiazole-4-carboxylate. LC-MS M/z 236 (M+H) ⁺ 。

Step 2: 2-bromothiazole-4-carboxylic acid was prepared. To ethyl 2-bromothiazole-4-carboxylate (18.0 g,76.0 mmol) in THF (90 mL) and H ₂ To a solution of O (90 mL) was added LiOH (4.8 g,114 mmol). The mixture was stirred at room temperature for 3 hours and extracted with EtOAc (2X 150 mL). Separating the aqueous layer with saturated aqueous NH ₄ Cl was adjusted to pH 2-3 and filtered. The solid was collected and dried under high vacuum to give 2-bromothiazole-4-carboxylic acid. LC-MS: M/z 206 (M-H) -.

Step 3: preparation of 2-bromo-N-methoxy-N-methylthiazole-4-carboxamide. To a solution of 2-bromothiazole-4-carboxylic acid (11.4 g,55.0 mmol) in DCM (100 mL) was added N, O-dimethylhydroxylamine (6.9 g,71.0 mmol), HATU (27.0 g,71.0 mmol) and DIPEA (21.2 g,164.0 mmol). The mixture was stirred at room temperature overnight, then quenched with water (200 mL) and extracted with DCM (2×200 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried, concentrated and purified by standard methods to give 2-bromo-N-methoxy-N-methylthiazole-4-carboxamide. LC-MS M/z 251 (M+H) ⁺ 。

Step 4: preparation of 1- (2-bromothiazol-4-yl) ethanone. At N ₂ To a solution of 2-bromo-N-methoxy-N-methylthiazole-4-carboxamide (6.8 g,27.0 mmol) in THF (60 mL) was slowly added dropwise MeMgBr (9.9 mL,29.7mmol,3m in THF) under an atmosphere at 0 ℃. The mixture was allowed to warm slowly to room temperature and stirred at this temperature for 30 minutes. With saturated aqueous NH ₄ Cl (100 mL) quenchThe reaction mixture was extracted with EtOAc (2×100 ml). By anhydrous Na ₂ SO ₄ The combined organic layers were dried and concentrated and purified by standard methods to give 1- (2-bromothiazol-4-yl) ethanone. LC-MS M/z 206 (M+H) ⁺ 。

Step 5: preparing 4-acetyl thiazole-2-methyl formate. To a solution of 1- (2-bromothiazol-4-yl) ethanone (340 mg,1.65 mmol) in MeOH (10 mL) was added Pd (OAc) ₂ (20.0 mg,0.08 mmol), dppf (95.0 mg,0.16 mmol) and Et ₃ N (250 mg,2.5 mmol). The mixture was heated at 60℃under a CO atmosphere (0.4 mPa) overnight. The resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue purified by standard methods to give methyl 4-acetylthiazole-2-carboxylate. LC-MS M/z 186 (M+H) ⁺ 。

Step 6: preparation of methyl 4- (1, 1-difluoroethyl) thiazole-2-carboxylate. DAST (1.64 g,10.2 mmol) was slowly added dropwise to a solution of 4-acetylthiazole-2-carboxylic acid ester (200 mg,1.07 mmol) in DCM (10 mL) at 0deg.C. The mixture was then warmed to room temperature and stirred at room temperature overnight. With saturated aqueous NaHCO ₃ The mixture was quenched slowly (20 mL) and extracted with DCM (2X 20 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried, concentrated and purified by standard methods to give methyl 4- (1, 1-difluoroethyl) thiazole-2-carboxylate. LC-MS M/z 208 (M+H) ⁺ 。

Step 7: preparation of N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (4- (1, 1-difluoroethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine. To N ¹ ,N ⁵ To a mixture of bis (3, 3-difluorocyclobutyl) -biguanide (60 mg,0.22 mmol) in MeOH (5 mL) was added ethyl 4- (1, 1-difluoroethyl) thiazole-2-carboxylate (50 mg,0.26 mmol) and NaOMe (23.7 mg,0.44 mmol). The reaction mixture was then stirred at room temperature for 48 hours, and then partitioned between EtOAc and H ₂ And O. The organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO ₄ Drying, concentrating and purifying by standard methods to obtain N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (4- (1, 1-difluoroethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine.

¹ H NMR(400MHz,CDCl ₃ )δ7.75(d,J＝3.7Hz,1H),5.30(m,2H),4.05(d,J＝49.4Hz,2H),2.30-2.01(m,11H),1.94(d,J＝9.2Hz,4H),1.81-1.68(m,3H)。LC-MS:m/z 495(M+H) ⁺ 。

Using the procedure outlined in example 26, the following compounds were prepared using the appropriate starting materials.

N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (2- (1, 1-difluoroethyl) thiazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,DMSO-d ₆ )δ8.59(d,1H),7.52(m,2H),4.09(m,2H),3.25(m,3H),2.34(m,1H),1.58(m,16H)。LC-MS:m/z 494(M+H) ⁺ 。

N ² ,N ⁴ -bis (3, 3-difluorocyclopentyl) -6- (2- (1, 1-difluoroethyl) thiazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.44-8.36(m,1H),5.54-5.24(m,2H),4.67-4.53(m,2H),2.63-2.60(m,2H),2.31-2.02(m,11H),1.82-1.75(m,2H)。LC-MS:m/z 467(M+H) ⁺ 。

N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (2- (1, 1-difluoroethyl) thiazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.45-8.36(m,1H),5.71-5.36(m,2H),4.47-4.35(m,2H),3.05(s,4H),3.6 1(s,4H),2.24-2.03(m,3H)。LC-MS:m/z 439(M+H) ⁺ 。

Example 27 the compound of this example was prepared by the general scheme 27 listed below.

Scheme 27

Step 1: 2-bromothiazole-4-carbaldehyde was prepared. DIBAL-H (7.35 g,0.052 mol) was slowly added to a mixture of 2-bromo-N-methoxy-N-methylthiazole-4-carboxamide (10 g,0.04 mol) in THF (80 mL) at-78deg.C. 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 (80 mL) and H ₂ O (60 mL). The organic layer was separated, washed with brine (40 mL), and dried over anhydrous Na ₂ SO ₄ Dried, concentrated and purified by standard methods to give the desired product. LC-MS: M/z 192 (M+H) ⁺ 。

Step 2: preparing 2-bromo-4- (difluoromethyl) thiazole. DAST (3.22 g,0.02 mol) was added dropwise to a mixture of 2-bromothiazole-4-carbaldehyde (0.764 g, 0.04 mol) in DCM (7 mL) at 0deg.C. The mixture was stirred at 25℃for 48 hours, then saturated aqueous NaHCO ₃ Quenching and adjusting the pH to 8-10. The resulting mixture was extracted with DCM (2X 40 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Dried and concentrated, and purified by standard methods to give the desired product. LC-MS: M/z 214 (M+H) ⁺ 。

Step 3: preparation of methyl 4- (difluoromethyl) thiazole-2-carboxylate. Stirring 2-bromo-4- (difluoromethyl) thiazole (0.6 g,2.82 mmol), dppf (0.14 g,0.28 mmol), et at 60deg.C under CO atmosphere ₃ N (0.43 g,4.23 mmol) and Pd (OAc) ₂ (0.13 g,0.56 mmol) in MeOH (10 mL) for 16 h. The resulting mixture was filtered, the filtrate was concentrated and the residue partitioned between DCM (30 mL) and H ₂ And O. The organic layer was separated, washed with brine (30 mL), and dried over anhydrous Na ₂ SO ₄ Dried and concentrated, and purified by standard methods to give the desired product. LC-MS M/z 194 (M+H) ⁺ 。

Step 4: preparation of N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (4- (difluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine. To N ¹ ,N ⁵ To a suspension of bis (3, 3-difluorocyclobutyl) -biguanide (45 mg,13.3 mmol) and methyl 4- (difluoromethyl) thiazole-2-carboxylate (40 mg,20.7 mmol) in MeOH (10 mL) was added NaOMe (20 mg,37.0 mmol). The reaction mixture was stirred at room temperature overnight, then poured into water and extracted with EtOAc. By anhydrous Na ₂ SO ₄ The combined organic layers were dried, concentrated and purified by standard methods to give the desired product.

¹ H NMR(400MHz,CDCl ₃ )δ7.75(s,1H),6.94-6.67(t,1H),5.40-5.08(m,2H),4.04-3.90(m,2H),2.05-1.84(m,8H),1.79-1.64(m,4H),1.62-1.54(m,4H)。LC-MS:m/z 481(M+H) ⁺ 。

Using the procedure outlined in example 27, the following compounds were prepared using the appropriate starting materials.

N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (4- (difluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.84(d,J＝8Hz,1H),7.02-6.74(m,1H),5.74-5.44(m,2H),4.46-4.36(m,2H),3.06(d,J＝8Hz,4H),2.63-2.59(m,4H)。LC-MS:m/z 425(M+H) ⁺ 。

N ² ,N ⁴ -bis (3, 3-difluorocyclopentyl) -6- (4- (difluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.84(s,1H),7.04-6.76(m,1H),5.65-5.36(m,2H),4.66-4.55(m,2H),2.66-1.85(m,12H)。LC-MS:m/z 453(M+H) ⁺ 。

Example 28 the compound of this example was prepared by the general scheme 28 listed below.

Scheme 28

Step 1: preparation of 5-phenyl-1, 3, 4-oxathiazol-2-one. At N ₂ To a solution of benzamide (200 mg,1.65 mmol) in toluene (2 mL) was added carbonyl chloride thiophypochlorite (0.16 mL,1.98 mmol) under an atmosphere. The mixture was stirred at 120℃for 3 hours. The resulting mixture was cooled to room temperature and then treated with H ₂ O was quenched and extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, concentrated and purified by standard methods to give the desired product. LC-MS M/z 180 (M+H) ⁺ 。

Step 2: preparation of 3-phenyl-1, 2, 4-thiadiazole-5-carboxylic acid ester. A mixture of 5-phenyl-1, 3, 4-oxathiazol-2-one (270 mg,1.5 mmol) and ethyl cyanobenzoate (79mg, 6.0 mmol) in DCE (2 mL) was stirred in a sealed vial at 160℃for 0.5 h under microwave irradiation. The resulting mixture is concentrated and purified by standard methods to give the desired product. LC-MS M/z 235 (M+H) ⁺ 。

Step 3: preparation of N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (3-phenyl-1, 2, 4-thiadiazol-5-yl) -1,3, 5-triazine-2, 4-diamine. To N ¹ ,N ⁵ To a mixture of bis (4, 4-difluorocyclohexyl) -biguanide (90 mg,0.27 mmol) and 3-phenyl-1, 2, 4-thiadiazole-5-carboxylic acid ethyl ester (75 mg,0.32 mmol) in MeOH (2 mL) was added NaOMe (43 mg,0.8 mmol). The reaction mixture was then stirred at room temperature overnight. The resulting mixture was poured into water and treated with EtOAc extraction. By anhydrous Na ₂ SO ₄ The combined organic layers were dried and concentrated and purified by standard methods to give the desired product.

¹ H NMR(400MHz,CDCl ₃ )δ8.40(d,J＝3.3Hz,2H),7.48(s,3H),5.68-5.01(m,2H),4.27-3.87(m,2H),2.26-1.63(m,8H)。LC-MS:m/z 508.2(M+H) ⁺ 。

Using the procedure outlined in example 28, the following compounds were prepared using the appropriate starting materials.

N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (3-methyl-1, 2, 4-thiadiazol-5-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ5.58-5.10(m,2H),4.20-3.84(m,2H),2.77(s,3H),2.23-1.63(m,16H)。LC-MS:m/z 446(M+H) ⁺ 。

Example 29 the compound of this example was prepared by the general scheme 29 listed below.

Scheme 29

Step 1. Preparation of 6-chloro-N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine. To a solution of 2,4, 6-trichloro-1, 3, 5-triazine (2 g,10.9 mmol) in acetone (35 mL) was added (S) -1-cyclopropylethylamine hydrochloride (2.7 mg,22.8 mmol), DIPEA (3.5 mg,27 mmol) and CsF (3.3 mg,21.8 mmol). The mixture was stirred at 50 ℃ overnight and then filtered. The filtrate is concentrated and purified by standard methods to give the desired product. LC-MS M/z 282 (M+H) ⁺ 。

Step B, preparing N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -6- (4-methyl-1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine. To an ice-cold solution of 4-methyl-1H-pyrazole (207 mg,1.07 mmol) in dry THF (5 mL) was slowly added NaH (34 mg,1.42 mmol) over 30 min followed by 6-chloro-N ² ,N ⁴ A solution of bis ((R) -1-cyclopropylethyl) -1,3, 5-triazine-2, 4-diamine (200 mg,0.71 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature overnight and then concentrated and purified by standard methods to give N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -6- (4-methyl-1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine.

¹ H NMR(400MHz,CDCl ₃ )δ8.17(s,1H),7.56(s,1H),5.50-5.12(m,2H),3.56(d,J＝6.0Hz,2H),2.12(s,3H),1.25(s,6H),0.94-0.84(m,2H),0.54-0.32(m,6H),0.26(d,J＝4.1Hz,2H)。LC-MS:m/z 328(M+H) ⁺ 。

Using the procedure outlined in example 29, the following compounds were prepared using the appropriate starting materials.

Compound N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -6- (4-iodo-1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.51(s,1H),7.73(s,1H),5.49-5.20(m,2H),3.56(d,J＝6.8Hz,2H),1.26(d,J＝6.5Hz,6H),0.90(s,2H),0.55-0.24(m,8H)。LC-MS:m/z 440(M+H) ⁺ 。

Compound 6- (4-chloro-1H-pyrazol-1-yl) -N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.43-8.38(m,1H),7.68(d,J＝9.2Hz,1H),5.41-5.18(m,2H),4.10-3.98(m,2H),2.14-1.91(m,13H),1.86-1.73(m,1.2H),1.68-1.61(m,1.8H)。LC-MS:m/z 448(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.53(d,J＝10.0Hz,1H),6.66(d,J＝2.5Hz,1H),5.63-5.23(m,2H),3.63-3.45(m,2H),1.27(d,J＝6.5Hz,6H),0.91(d,J＝7.6Hz,2H),0.58-0.26(m,8H)。LC-MS:m/z 382(M+H) ⁺ 。

Compound 6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N ² ,N ⁴ -bis (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

/>

¹ H NMR(400MHz,CDCl ₃ )δ8.55(m,1H),6.70(d,J＝2.7Hz,1H),5.77-5.30(m,2H),5.05-4.78(m,2H),1.49-1.37(m,6H)。LC-MS:m/z438.1(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis ((S) -1, 1-trifluorobutan-2-yl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.60-8.57(m,1H),7.80-5.29(m,3H),4.76-4.69(m,2H),2.03-1.95(m,2H),1.72-1.63(m,2H),1.09-1.02(m,6H)。LC-MS:m/z 466(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis (3, 3-difluorocyclopentyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.57-8.50(m,1H),6.68(d,J＝4Hz,1H),5.74-5.44(m,2H),4.76-4.47(m,2H),2.66-2.57(m,2H),2.08-2.31(m,8H),1.81-1.86(m,2H)。LC-MS:m/z 454(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,DMSO-d ₆ )δ8.86-8.50(m,1H),8.13-7.76(m,2H),7.00(d,J＝9.7Hz,1H),4.18-3.92(m,2H),2.14-1.82(m,12H),1.62(s,4H)。LC-MS:m/z 482(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.56-8.50(m,1H),6.69(d,J＝6Hz,1H),5.85-5.52(m,2H),4.37(m,2H),3.05-3.12(m,4H),2.50-2.67(m,4H)。LC-MS:m/z 426(M+H) ⁺ 。

Example 30 the compound of this example was prepared by the general scheme 30 listed below.

Scheme 30

Step 1: 1-methyl-1H-pyrazole-3-carboxylic acid methyl ester is prepared. To a solution of 1-methyl-1H-pyrazole-3-carboxylic acid (504 mg,4 mmol) in MeOH (5 mL) at 0deg.C was added SOCl ₂ (1.4 mL,20 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in EtOAc with saturated aqueous NaHCO ₃ Washed and concentrated to obtain methyl 1-methyl-1H-pyrazole-3-carboxylate. LC-MS: M/z 141 (M+H) ⁺ 。

Step 2: preparation of N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (1-methyl-1H-pyrazol-3-yl) -1,3, 5-triazine-2, 4-diamine. To N ¹ ,N ⁵ To a solution of bis (4, 4-difluorocyclohexyl) -biguanide (120 mg,0.36 mmol) and methyl 1-methyl-1H-pyrazole-3-carboxylate (60 mg,0.43 mmol) in MeOH (2 mL) was added NaOMe (28 mg,1.07 mmol). The reaction mixture was stirred at room temperature overnight, then poured into water and extracted with EtOAc. By anhydrous Na ₂ SO ₄ The combined organic layers were dried, concentrated and purified by standard methods to give N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (1-methyl-1H-pyrazol-3-yl) -1,3, 5-triazine-2, 4-diamine.

¹ H NMR(400MHz,CDCl ₃ )δ7.40(d,J＝2.1Hz,1H),6.92(s,1H),5.75-4.94(m,2H),4.28-3.85(m,5H),2.26-1.54(m,16H)。LC-MS:m/z 428(M+H) ⁺ 。

Using the procedure outlined in example 30, the following compounds were prepared using the appropriate starting materials.

Compound N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (1H-pyrazol-3-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.57(s,1H),6.89(s,1H),5.55-4.84(m,2H),4.15-3.80(m,2H),2.05-1.56(m,16H)。LC-MS:m/z 414(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis (3, 3-difluorocyclopentyl) -6- (2-methyl-1H-imidazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.71(s,1H),5.65-5.07(m,2H),4.63-4.61(m,2H),2.61-2.49(m,3H),2.29(s,3H),2.09-1.92(m,9H)。LC-MS:m/z 400.1(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (2-methyl-1H-imidazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.62(s,1H),6.49-6.34(m,2H),4.36-4.33(m,2H),3.04(s,3H),2.69-2.49(m,8H)。LC-MS:m/z 372(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (2-methyl-1H-imidazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.67-7.66(m,1H),6.26-5.84(m,1H),5.11-4.81(m,1H),3.49-3.11(m,7H),2.48(s,2H),2.10-1.66(m,12H)。LC-MS:m/z428.3(M+H) ⁺ 。

Example 31 the compound of this example was prepared by the general scheme 31 listed below.

Scheme 31

Step 1: preparation of 4-iodo-3- (trifluoromethyl) -1H-pyrazole. To 3- (trifluoromethyl) -1H-pyrazole (500 mg,3.7 mmol) at 0deg.C in 50% H ₂ SO ₄ NIS (992 mg,4.4 mmol) was added to the solution in the above. The suspension was stirred at 0 ℃ for 10 minutes and then at room temperature for 3 hours. The resulting mixture was quenched with water (50 mL) 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, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -3- (trifluoromethyl) -1H-pyrazole. To a mixture of 4-iodo-3- (trifluoromethyl) -1H-pyrazole (100 mg,0.38 mmol) and (4, 4', 5' -octamethyl-2, 2 '-bis (1, 3, 2-dioxaborolan) (397 mg,0.57 mmol) in DMF (3 mL) was added 1,1' -bis- (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (mg, 0.04 mmol) and potassium acetate (509 mg, 0.76). The reaction mixture was stirred at 90℃for 2 hours, then quenched with water and quenched with Et ₂ And O extraction. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, and concentrated to give 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3- (trifluoromethyl) -1H-pyrazole. LC-MS: M/z 263 (M+H) ⁺ 。

Step 3: preparation of N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -1,3, 5-triazine-2, 4-diamine. At N ₂ In the atmosphere, 6-chloro-N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -1,3, 5-triazine-2, 4-diamine (145 mg,0.38 mmol) and 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3- (trifluoromethyl) -1H-pyrazole (100 mg,0.38 mmol) in DME (3 mL) and H ₂ K was added to the solution in O (1 mL) ₂ CO ₃ (158 mg,1.15 mmol) and Pd (PPh) ₃ ) ₄ (44 mg,0.04 mmol). The mixture was stirred at 90 ℃ for 16 hours and then filtered. The filtrate was partitioned between EtOAc and H ₂ And O. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ The drying is carried out,and concentrated and purified by standard methods to give N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -1,3, 5-triazine-2, 4-diamine.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.09-7.47(m,3H),7.29-7.00(m,1H),4.11-3.76(m,2H),2.19-1.46(m,16H)。LC-MS:m/z 482(M+H) ⁺ 。

Using the procedure outlined in example 31, the following compounds were prepared using the appropriate starting materials.

Compound N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -N ² -methyl-6- (3- (trifluoromethyl) -1H-pyrazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.75(s,1H),6.90(s,1H),5.45(d,J＝7.1Hz,1H),4.94-4.44(m,1H),4.09-3.84(m,1H),3.07(d,J＝11.0Hz,3H),2.35-2.02(m,6H),2.03-1.66(m,10H)。LC-MS:m/z 496(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis (4, 4-difluorocyclohexyl) -6- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.57-7.37(m,1H),5.18-4.88(m,2H),4.01-3.79(m,5H),2.21-1.46(m,16H)。LC-MS:m/z 496(M+H) ⁺ 。

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

¹ H NMR(400MHz,DMSO-d ₆ )δ9.60(s,1H),9.13(s,1H),8.75(s,1H),7.60(s,1H),7.46(s,1H),3.64-3.50(m,2H),1.21(d,J＝4Hz,6H),0.96(s,2H),0.43-0.33(m,6H),0.14(s,2H)。LC-MS:m/z 393(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ9.04-8.82(m,1H),8.68-8.28(m,2H),3.83-3.64(m,1H),3.60-3.51(m,1H),1.36(m,6H),0.91-0.85(m,2H),0.67-0.48(m,4H),0.34(m,4H)。LC-MS:m/z 393(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -6- (2, 5-difluorophenyl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.76-7.55(m,1H),7.08(dd,J＝7.6,5.8Hz,2H),5.43-5.02(m,2H),3.55(s,2H),1.27(d,J＝5.8Hz,6H),0.90(d,J＝7.4Hz,2H),0.55-0.37(m,6H),0.30-0.23(m,2H)。LC-MS:m/z 360(M+H) ⁺ 。

Compound N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -6- (3- (trifluoromethoxy) phenyl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )：δ8.25-8.18(m,2H),7.46-7.42(m,1H),7.32-7.26(m,1H),5.28-5.13(m,2H),3.68-3.55(m,2H),1.29-1.25(m,6H),0.95-0.88(m,2H),0.56-0.41(m,6H),0.28(s,2H)。LC-MS:m/z 408(M+H) ⁺ 。

The compound 3- (4, 6-bis (((R) -1-cyclopropylethyl) amino) -1,3, 5-triazin-2-yl) benzonitrile

¹ H 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 an aromatic-aliphatic triazine compound having the formula Q. The compounds of this example were prepared by the 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 a mixture of 2, 4-dichloro-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine (188 mg,0.64 mmol) and 2- (1, 1-difluoroethyl) pyridin-4-amine (50 mg,0.32 mmol) in 1, 4-dioxane (4 mL) under nitrogen was added ^t BuONa (61 mg,0.64 mmol) and Pd (dppf) Cl ₂ (22 mg,0.03 mmol). The reaction mixture was then stirred at 80 ℃ overnight and then filtered. The filtrate is concentrated and purified by standard methods to give the desired product.

LC-MS:m/z 417.1(M+H) ⁺ 。

Step 2: preparation of N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (2- (1, 1-difluoroethyl) pyridine)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-triazin-2-amine (35 mg,0.08 mmol) and 3, 3-difluorocyclopentylamine (16 mg,0.13 mmol) in THF (2 mL) was added CsF (24 mg,0.16 mmol) and DIPEA (0.03 mL,0.16 mmol). The reaction mixture was then stirred at 50 ℃ overnight. The mixture was filtered and the filtrate concentrated and purified by standard methods to give the desired product.

¹ H NMR(400MHz,CDCl ₃ )δ8.61(m,1H),8.52(d,J＝5.4Hz,1H),8.43(s,1H),8.08(d,J＝7.7Hz,1H),8.03-7.73(m,2H),7.73-7.34(m,1H),6.08-5.52(m,1H),4.88-4.55(m,1H),2.82-2.64(m,1H),2.46-2.12(m,4H),2.11-1.98(m,3H),1.94-1.81(m,1H)。LC-MS:m/z 502(M+H) ⁺ 。

Using the procedure listed in example 32, the following compounds were prepared using the appropriate starting materials.

(S)-N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (2- (1, 1-difluoroethyl) pyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.61(m,1H),8.53(d,J＝5.4Hz,1H),8.46-7.94(m,2H),7.91-7.32(m,3H),5.77(m,1H),4.70(m,1H),2.79-2.60(m,1H),2.50-2.11(m,4H),2.04(m,3H),1.87(m,1H)。LC-MS:m/z 502(M+H) ⁺ 。

(R)-N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (2- (1, 1-difluoroethyl) pyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.62(m,1H),8.53(d,J＝5.4Hz,1H),8.47-7.94(m,2H),7.93-7.33(m,3H),5.90-5.60(m,1H),4.96-4.46(m,1H),2.80-2.61(m,1H),2.50-2.10(m,4H),2.04(m,3H),1.87(m,1H)。LC-MS:m/z 502(M+H) ⁺ 。

N ² - (4, 4-difluorocyclohexyl) -N ⁴ - (2- (1, 1-difluoroethyl) pyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.69-8.43(m,3H),8.07(t,J＝7.8Hz,1H),8.01-7.73(m,2H),7.49(m,1H),5.61(m,1H),4.19(m,1H),2.24-2.13(m,4H),2.12-1.93(m,5H),1.76-1.65(m,2H)。LC-MS:m/z 516(M+H) ⁺ 。

N ² - (3, 3-difluorocyclobutyl) -N ⁴ - (2- (1, 1-difluoroethyl) pyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.72-8.26(m,3H),8.18-7.75(m,3H),7.72-7.33(m,1H),6.03(m,1H),4.53(m,1H),3.16(d,J＝8.2Hz,2H),2.59(m,2H),2.05(m,3H)。LC-MS:m/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

¹ H NMR(400MHz,DMSO-d ₆ )δ11.25-10.25(m,1H),9.16-8.47(m,3H),8.41-8.19(m,2H),8.15-7.80(m,2H),5.40-4.80(m,1H),2.00(t,J＝19.0Hz,3H),1.63(d,J＝7.2Hz,3H)。LC-MS:m/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

¹ H NMR(400MHz,CDCl ₃ )δ8.88-8.43(m,2H),8.03(m,4H),7.67(s,1H),5.97(m,1H),2.02(m,3H),1.86(s,6H)。LC-MS:m/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

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¹ H NMR(400MHz,DMSO-d ₆ )δ10.65(s,1H),8.91-8.38(m,4H),8.33(t,J＝7.9Hz,1H),8.21-7.51(m,2H),3.80-3.60(m,2H),2.00(m,3H),1.40(d,J＝3.9Hz,6H)。LC-MS:m/z 479(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) butanenitrile

¹ H NMR(400MHz,DMSO-d ₆ )δ:10.90-10.25(m,1H),8.75-8.52(m,2H),8.52-8.20(m,3H),8.18-7.75(m,2H),4.67-4.26(m,1H),3.09-2.72(m,2H),2.00(m,3H),1.35(t,J＝5.5Hz,3H)。LC-MS:m/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

¹ H NMR(400MHz,DMSO-d ₆ )δ8.65-8.44(m,2H),8.42-7.96(m,3H),7.92-7.35(m,2H),6.00-5.60(m,1H),3.40-3.10(m,2H),2.10-1.90(m,3H),1.75-1.50(m,6H)。LC-MS:m/z 479(M+H) ⁺ 。

N ² - (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.67-8.57(m,2H),8.53(d,J＝1.7Hz,1H),8.19-7.38(m,4H),6.03-5.53(m,1H),4.85-4.55(m,1H),2.81-2.58(m,1H),2.51-2.07(m,4H),1.98-1.81(m,1H),1.32-1.16(m,1H)。LC-MS:m/z 506(M+H) ⁺ 。

(R)-N ² - (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.65-8.52(m,3H),8.10-8.06(m,2H),7.86-7.85(m,1H),7.48-7.42(m,1H),6.00-5.86(m,1H),4.81-4.60(m,1H),2.77-2.62(m,1H),2.41-2.32(m,2H),2.12-2.19(m,2H),1.93-1.86(m,1H)。LC-MS:m/z 506(M+H) ⁺ 。

(S)-N ² - (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.67-8.56(m,2H),8.53(d,J＝1.8Hz,1H),8.20-7.82(m,3H),7.77-7.40(m,1H),6.09-5.51(m,1H),4.92-4.46(m,1H),2.80-2.59(m,1H),2.46-2.29(m,2H),2.29-2.08(m,2H),1.97-1.85(m,1H)。LC-MS:m/z 506(M+H) ⁺ 。

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

1H NMR(400MHz,CDCl ₃ )δ8.57-8.62(m,3H),7.85-8.17(m,3H),7.37-7.72(m,1H),5.45-5.82(m,1H),4.10-4.26(m,1H),2.17-2.19(d,J＝9.2Hz,4H),1.88-2.04(m,2H),1.66-1.81(m,2H)；LC-MS:m/z 520(M+H) ⁺ 。

N ² - (3, 3-difluorocyclobutyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.65-8.55(m,2H),8.51-8.32(m,1H)8.11-8.04(m,1H),7.86-7.83(m,1H),7.68-7.47(m,1H),6.33-6.06(m,1H),4.58-4.42(m,1H),3.17-3.10(m,2H),2.75-2.53(m,2H),2.29(s,1H)。LC-MS:m/z492(M+H) ⁺ 。

N ² - (6, 6-difluorospiro [3.3 ]]Hept-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

1H NMR(400MHz,CDCl ₃ )δ8.55-8.70(m,3H),7.84-8.20(m,3H),7.31-7.66(m,1H),5.68-6.00(m,1H),4.49-4.55(m,1H),2.57-2.76(m,6H),1.83-2.27(m,2H)。LC-MS:m/z 532(M+H) ⁺ 。

6- (6- (trifluoromethyl) pyridin-2-yl) -N ² - (2- (trifluoromethyl) pyridin-4-yl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.62-8.59(m,1H),8.44(s,1H),8.16-8.07(m,1H),7.87(d,J＝8Hz,1H),7.75-7.50(m,1H),1.53-1.49(m,3H)。LC-MS:m/z498(M+H) ⁺ 。

N ² - (2, 2-trifluoroethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

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¹ H NMR(400MHz,DMSO-d ₆ )δ10.91(s,1H),8.75-8.71(m,2H),8.61-8.57(m,2H),8.36-8.33(m,1H),8.21-7.83(m,2H),4.41-4.24(m,2H)。LC-MS:m/z 484(M+H) ⁺ 。

N ² - ((3, 3-difluorocyclobutyl) methyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.70-8.41(m,3H),7.96(m,4H),7.52(m,1H),5.95-5.58(m,1H),3.67(m,2H),2.77-2.13(m,5H)。LC-MS:m/z 506(M+H) ⁺ 。

N ² - ((2, 2-difluorocyclopropyl) methyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,DMSO-d ₆ )δ10.76-10.69(m,1H),8.74-8.66(m,2H),8.58-8.55(m,2H),8.34-8.30(m,1H),8.11(d,J＝8Hz,1H),7.96-7.86(m,1H),3.61-3.43(m,2H),2.17-2.09(m,1H),1.67-1.32(m,2H)。LC-MS:m/z 492(M+H) ⁺ 。

N ² - (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N ⁴ - (5- (trifluoromethyl) pyridin-3-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.86(t,J＝6.0Hz,1H),8.83-8.73(m,1H),8.64-8.55(m,2H),8.09-8.03(m,1H),7.89-7.83(m,1H),6.00-5.88(m,1H),4.80-4.55(m,1H),2.74-2.57(m,1H),2.47-2.05(m,4H),1.94-1.82(m,1H)。LC-MS:m/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

¹ H NMR(600MHz,CDCl ₃ )δ8.67(s,2H),8.29(t,J＝5.9Hz,1H),8.07(t,J＝7.6Hz,1H),7.91-7.79(m,2H),7.05(s,1H),5.97(d,J＝7.9Hz,1H),5.06-4.61(m,1H),2.81-2.66(m,1H),2.43-1.36(m,1H),2.34-2.18(m,2H),2.14-2.04(m,1H),1.87-1.77(m,3H),1.72(m,2H)。LC-MS:m/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

¹ H NMR(400MHz,DMSO-d ₆ )δ10.47(s,1H),8.77-8.59(m,2H),8.49(s,1H),8.36-8.20(m,2H),8.11(d,J＝7.8Hz,1H),7.55(d,J＝4.6Hz,1H),4.86-4.47(m,1H),2.75-2.57(m,1H),2.29-2.06(m,4H),1.97-1.82(m,1H),1.80-1.74(m,2H),1.71-1.63(m,2H)。LC-MS:m/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

¹ H NMR(400MHz,DMSO-d ₆ )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-difluorocyclohexyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.83-8.65(m,1H),8.58(m,1H),8.32(d,J＝5.4Hz,1H),8.10(t,J＝7.8Hz,1H),7.86(d,J＝7.7Hz,1H),7.62(m,1H),7.09(s,1H),5.65(m,1H),4.29(s,1H),2.12(m,6H),1.89-1.91(m,2H),1.82-1.63(m,4H)。LC-MS:m/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

¹ H NMR(400MHz,DMSO-d ₆ )δ10.48(brs,1H),8.89(d,J＝6.5Hz,1H),8.78-8.56(m,1H),8.42(s,1H),8.37-8.24(m,2H),8.10(d,J＝7.8Hz,1H),7.58(d,J＝4.1Hz,1H),4.45(s,1H),3.13-2.97(m,2H),2.71-2.56(m,2H),1.83-1.59(m,4H)。LC-MS:m/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

¹ H NMR(400MHz,CDCl ₃ )δ8.70-8.53(m,2H),8.31-8.28(m,1H),8.10-8.06(m,1H),7.85-7.83(d,J＝8Hz,1H),7.66-7.52(m,1H),7.20-7.07(m,1H),5.94-5.66(m,1H),4.67-4.63(m,1H),2.75-2.55(m,6H),2.25-2.10(m,2H),1.89-1.83(m,2H),1.74-1.71(m,2H)。LC-MS:m/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

¹ H NMR(400MHz,CDCl ₃ )δ8.72(m,2H),8.31(d,J＝5.5Hz,1H),8.09(d,J＝7.8Hz,1H),7.85(d,J＝7.8Hz,1H),7.58(m,1H),7.05(m,1H),5.92(m,1H),4.00(s,1H),3.61(m,1H),2.08(m,1H),1.83(m,2H),1.72(m,2H),1.52(m,2H)。LC-MS:m/z 489(M+H) ⁺ 。

1- (4- ((4- ((2, 2-trifluoroethyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.93-8.42(m,2H),8.34-8.29(m,1H),8.10(t,J＝7.8Hz,1H),8.03-7.58(m,2H),7.13(d,J＝4.2Hz,1H),6.34-6.03(m,1H),4.36-4.29(m,2H),1.74(s,4H)。LC-MS:m/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

¹ H NMR(400MHz,CDCl ₃ )δ8.77-8.44(m,2H),8.29(d,J＝5.5Hz,1H),8.07(t,J＝7.7Hz,1H),7.77(m,2H),6.96(s,1H),6.14(m,1H),3.79-3.55(m,2H),1.91-1.84(m,2H),1.73-1.69(m,2H),1.35(s,6H)。LC-MS:m/z 471(M+H) ⁺ 。

(R) -1- (4- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.73(m,2H),8.36(m,1H),8.11(d,J＝7.3Hz,1H),7.87(d,J＝7.8Hz,1H),7.52(s,1H),7.07(m,1H),5.82(m,1H),5.09(s,1H),4.81(m,4H),1.50(m,J＝8.5Hz,3H)。LC-MS:m/z 495(M+H) ⁺ 。

(S) -1- (4- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((1, 1-trifluoroprop-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.77(d,J＝9.2Hz,2H),8.66(m,J＝8Hz,1H),8.57(s,1H),8.10(m,1H),7.52(m,1H),7..10(d,J＝4Hz,1H),5.86(m,1H),5.05(m,1H),1.8(m,4H),1.62(m,3H)。LC-MS:m/z 495(M+H) ⁺ 。

4- ((4- (tert-butylamino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridinecarbonitrile

¹ H NMR(400MHz,DMSO-d ₆ )δ8.66-8.41(m,3H),8.12-8.00(m,1H),7.91-7.80(m,1H),7.65-7.55(m,1H),5.80-5.20(m,1H),1.58(m,9H)。LC-MS:m/z 415(M+H) ⁺ 。

4- ((4- ((3, 3-difluorocyclobutyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridinecarbonitrile

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¹ H NMR(400MHz,DMSO-d ₆ )δ10.78(s,1H),8.97-8.52(m,4H),8.38-8.25(m,1H),8.13(d,J＝7.8Hz,1H),8.01-7.80(m,1H),4.56-4.24(m,1H),3.17-2.95(m,2H),2.80-2.60(m,2H)。LC-MS:m/z 449(M+H) ⁺ 。

4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridine carbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.07-8.66(m,4H),7.86(d,J＝8.0Hz,2H),7.53-7.68(m,1H),5.85-6.03(m,1H),4.58-4.79(m,1H),2.66-2.75(m,1H),1.95-2.47(m,1H),1.88-1.93(m,1H)。LC-MS:m/z 463(M+H) ⁺ 。

4- ((4, 4-difluorocyclohexyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridine carbonitrile

¹ H NMR(400MHz,DMSO-d ₆ )δ10.72-10.76(m,1H),7.93-8.72(m,5H),4.03-4.23(m,1H),1.94-2.16(m,6H),1.64-1.73(m,2H)。LC-MS:m/z 477(M+H) ⁺ 。

4- ((4- ((2-hydroxy-2-methylpropyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridine carbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.57-8.50(m,2H),8.43-8.36(m,1H),8.22-8.02(m,2H),7.85(m,1H),7.60(s,1H),6.32-6.23(m,1H),3.74-3.58(m,2H),1.37(s,6H)。LC-MS:m/z 431(M+H) ⁺ 。

3- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.64-8.55(m,1H),8.16-7.74(m,5H),7.08-7.02(m,1H),5.97-5.71(m,1H),4.79-4.55(m,1H),2.69-2.64(m,1H),2.41-2.14(m,4H),2.01(s,1H)。LC-MS:m/z 480(M+H) ⁺ 。

3- ((4, 4-difluorocyclohexyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹ H NMR(400MHz,CDCl ₃ )：δ8.60-8.54(m,1H),8.08-8.07(m,1H),7.85-7.81(m,4H),7.08-7.03(m,1H),5.76-5.48(m,1H),4.22-4.04(m,1H),2.21-2.18(m,4H),2.02-1.92(m,2H),1.78-1.71(m,2H)。LC-MS:m/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

¹ H NMR(400MHz,DMSO-d ₆ )δ10.50(s,1H),8.81-8.67(m,1H),8.55(d,J＝8Hz,1H),8.24-8.09(m,3H),7.46-7.42(m,1H),4.45-4.28(m,2H),3.05-3.01(m,2H),2.77(d,J＝8Hz,2H)。LC-MS:m/z 466(M+H) ⁺ 。

3- ((4- ((cyclopropylmethyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.59-8.49(m,1H),8.01-7.97(m,1H),7.83-7.74(m,3H),7.56(s,1H),6.99-6.96(m,1H),5.83-5.62(m,1H),3.43-3.30(m,2H),1.07(d,J＝4Hz,1H),0.57-0.52(m,2H),0.29-0.24(m,2H)。LC-MS:m/z430(M+H) ⁺ 。

3-fluoro-5- ((4- ((2-hydroxy-2-methylpropyl) amino) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) benzonitrile

¹ H NMR(400MHz,DMSO-d ₆ )δ10.44(s,1H),8.61(m,1H),8.24(m,5H),7.43(t,J＝8.8Hz,1H),4.61(m,1H),3.45(m,2H),1.18(d,J＝4.4Hz,6H)。LC-MS:m/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

¹ H NMR(400MHz,DMSO-d ₆ )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

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¹ H NMR(400MHz,DMSO-d ₆ )δ10.80-10.20(m,1H),9.50-9.25(m,1H),8.36-7.96(m,4H),7.50-7.40(m,1H),1.47(s,9H)。LC-MS:m/z 414(M+H) ⁺ 。

N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (3, 5-difluorophenyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.59(m,1H),8.06(t,J＝7.8Hz,1H),7.84(d,J＝7.7Hz,1H),7.41(m,3H),6.56(t,J＝8.8Hz,1H),5.74(m,1H),4.83-4.53(m,1H),2.79-2.60(m,1H),2.46-2.06(m,4H),1.95-1.81(m,1H)。LC-MS:m/z473(M+H) ⁺ 。

N ² - (4, 4-difluorocyclohexyl) -N ⁴ - (3, 5-difluorophenyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.50(d,J＝10.5Hz,1H),7.98(t,J＝7.7Hz,1H),7.76(d,J＝7.7Hz,1H),7.25(d,J＝7.6Hz,2H),6.48(t,J＝8.9Hz,1H),5.67-5.34(m,1H),4.14-3.96(m,1H),2.13-2.11(m,4H),2.00-1.74(m,5H)。LC-MS:m/z 487.2(M+H) ⁺ 。

N ² - (4, 4-difluorocyclohexyl) -N ⁴ - (2-phenylpyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.59-8.58(m,2H),8.30(s,1H),8.08-7.81(m,5H),7.50-7.42(m,4H),5.87-5.85(m,1H),4.22-4.10(m,1H),2.15-1.68(m,8H)。LC-MS:m/z 528(M+H) ⁺ 。

N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (2-phenylpyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.61(m,2H),8.31-7.69(m,6H),7.69-7.40(m,4H),5.87(m,1H),4.72(m,1H),2.69(m,1H),2.34(m,2H),2.14(m,2H),1.86-1.80(m,1H)。LC-MS:m/z 514(M+H) ⁺ 。

N ² - (2-phenylpyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.63(m,2H),8.04(m,6H),7.62-7.30(m,5H),5.81(d,J＝9.1Hz,1H),5.39(m,1H),5.00(m,1H),1.50(d,J＝7.0Hz,3H)。LC-MS:m/z 506(M+H) ⁺ 。

(R)-N ² - (2-phenylpyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.67-8.58(m,2H),8.14(m,2H),8.01(d,J＝7.0Hz,2H),7.88(d,J＝7.6Hz,1H),7.71-7.34(m,5H),5.69(m,1H),5.22-4.92(m,1H),1.49(d,J＝7.1Hz,3H)。LC-MS:m/z 506(M+H) ⁺ 。

(R) -4- (4- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((1, 1-trifluoroprop-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) benzonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.87-8.53(m,2H),8.42(s,1H),8.11(d,J＝8.0Hz,3H),7.96-7.76(m,4H),7.40(s,1H),5.86-5.67(m,1H),5.18-4.91(m,1H),1.62-1.47(m,3H)。LC-MS:m/z 531(M+H) ⁺ 。

(R)-N ² - (2- (4-fluorophenyl) pyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.61(d,J＝8.0Hz,2H),8.27(s,1H),8.13-7.64(m,5H),7.36(s,1H),7.17(t,J＝8.6Hz,2H),6.83-6.64(m,1H),6.16-4.96(m,1H),1.50(d,J＝7.5Hz,3H)。LC-MS:m/z 524.1(M+H) ⁺ 。

(R)-N ² - (2- (4-chlorophenyl) pyridin-4-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.61(t,J＝6.4Hz,2H),8.31-8.05(m,2H),7.95(d,J＝8.5Hz,2H),7.89(d,J＝7.8Hz,1H),7.46(d,J＝8.4Hz,2H),6.10-5.91(m,1H),5.22-4.91(m,1H),1.51(t,J＝7.7Hz,3H)。LC-MS:m/z 540(M+H) ⁺ 。

N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (1H-indol-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,DMSO-d ₆ )δ10.76(s,1H),8.82-8.55(m,1H),8.16(m,4H),7.68(m,2H),7.02(m,3H),4.98(m,1H),2.68(s,1H),2.23(m,4H),1.97(m,1H)。LC-MS:m/z 476(M+H) ⁺ 。

N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (1-methyl-1H-indol-2-yl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.54(s,1H),8.35(d,J＝6.8Hz,1H),8.10(s,1H),7.81(d,J＝7.5Hz,1H),7.17(m,4H),5.57(m,1H),4.83(m,1H),3.59(s,3H),2.94-2.06(m,7H)。LC-MS:m/z 490(M+H) ⁺ 。

1- (4- ((4, 4-difluorocyclohexyl) amino) -6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.54(m,2H),8.32(d,J＝5.5Hz,1H),8.02(d,J＝7.8Hz,1H),7.84(d,J＝8.0Hz,1H),7.59(m,1H),7.20(s,1H),5.71(d,J＝7.9Hz,1H),4.34(m,1H),2.15(m,9H),1.85(m,2H),1.23(m,1H)。LC-MS:m/z513(M+H) ⁺ 。

1- (4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (6- (1, 1-difluoroethyl) pyridin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

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¹ H NMR(400MHz,CDCl ₃ )δ8.61(s,1H),8.53(s,1H),8.30(d,J＝4Hz,1H),8.02-7.98(m,1H),7.82(d,J＝8Hz,1H),7.52-7.10(m,2H),5.93-5.60(m,1H),4.87-4.75(m,1H),2.74-2.71(m,1H),2.44(m,1H),2.18-2.04(m,5H),1.89-1.85(m,3H),1.72(m,3H)。LC-MS:m/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

¹ H NMR(400MHz,CDCl ₃ )δ10.43(m,1H),8.78(d,J＝4.1Hz,1H),8.61(d,J＝7.8Hz,1H),8.32(d,J＝5.6Hz,2H),8.12(m,1H),7.9(m,1H),7.88(m,1H),4.45(s,1H),3.03(m,2H),2.78(m,2H),2.13(m,3H),1.43(m,4H)。LC-MS:m/z485(M+H) ⁺ 。

(R) -1- (4- ((4- (6- (1, 1-difluoroethyl) pyridin-2-yl) -6- ((1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.59-8.52(m,1H),8.46-8.45(d,J＝4Hz,1H),8.32-8.25(m,1H),8.02-7.98(m,1H),7.82(d,J＝8Hz,1H),7.69-7.50(m,1H),7.21-7.00(m,1H),5.83-5.56(m,1H),5.18-5.07(m,1H),2.18-2.07(m,3H),1.87-1.85(m,2H),1.73-1.71(m,2H),1.50-1.46(m,3H)。LC-MS:m/z491(M+H) ⁺ 。

(S) -1- (4- ((4- (6- (1, 1-difluoroethyl) pyridin-2-yl) -6- ((1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.59-8.52(m,1H),8.46(s,1H),8.33-8.32(d,J＝4Hz,1H)8.03-7.99(m,1H),7.92-7.84(m,1H),7.52(s,1H),7.26-7.22(d,J＝16Hz,1H),5.85-5.59(m,1H),5.18-5.09(m,1H),2.18-2.09(m,3H),1.88-1.85(m,4H),1.51-1.48(m,3H)。LC-MS:m/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

¹ H NMR(400MHz,DMSO-d ₆ )δ10.19(s,1H),8.43(m,1H),8.17(m,1H),7.88(m,3H),7.00(d,J＝7.9Hz,1H),4.54(s,1H),3.45(m,2H),2.10(m,3H),1.17(m,J＝7.0Hz,6H)。LC-MS:m/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,CDCl ₃ )δ8.40-8.42(d,J＝8Hz,1H),7.74-7.99(m,5H),7.03(m,1H),6.16-6.25(m,1H),3.49-3.64(m,2H),2.05-2.21(m,3H),1.33(s,6H)；LC-MS:m/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

¹ H NMR(400MHz,CDCl ₃ )δ8.42(bs,1H),7.57-7.96(m,5H),6.99-7.03(m,1H),6.16-6.28(m,1H),3.54-3.62(m,2H),2.00-2.21(m,3H),2.07-2.22(m,3H),1.28(s,6H)。LC-MS:m/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

¹ H NMR(400MHz,CDCl ₃ )δ8.68(s,1H),8.53-8.43(m,1H),8.30(d,J＝4Hz,1H),7.86-7.72(m,1H),7.59-7.49(m,2H),7.27-6.99(m,1H),5.96-5.71(m,1H),4.96-4.88(m,1H),2.76-2.70(m,1H),2.43-2.07(m,4H),1.89-1.79(m,3H),1.75-1.72(m,2H)。LC-MS:m/z 469(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

¹ H NMR(400MHz,CDCl ₃ )δ8.43(s,2H),8.23(d,J＝8Hz,1H),7.80-7.76(m,1H),7.43(d,J＝8Hz,2H),7.05-7.03(m,1H),5.79-5.50(m,1H),3.70-3.67(m,1H),1.80-1.77(m,2H),1.66-1.59(m,2H),1.29-1.18(m,4H),0.93-0.78(m,1H),0.48-0.33(m,4H)。LC-MS:m/z 433(M+H) ⁺ 。

1- (4- ((4- (6-chloropyridin-2-yl) -6- ((2, 2-trifluoroethyl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.54-8.42(m,2H),8.33-8.29(m,1H),7.88-7.50(m,3H),7.14-7.08(m,1H),6.19-5.99(m,1H),4.31(s,2H),1.88-1.71(m,4H)。LC-MS:m/z 447(M+H) ⁺ 。

1- (4- ((4- (6-chloropyridin-2-yl) -6- ((1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.56-8.43(m,2H),8.32(d,J＝4Hz,1H),7.88-7.84(m,1H),7.73-7.50(m,2H),7.07-7.00(m,1H),5.85-5.57(m,1H),5.30-5.07(m,1H),1.90-1.73(m,4H),1.50-1.46(m,3H)。LC-MS:m/z 461(M+H) ⁺ 。

6- (6-chloropyridin-2-yl) -N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.61-8.53(m,2H),8.41-8.33(m,1H),8.13-7.78(m,2H),7.68-7.27(m,2H),5.95-5.61(m,1H),4.79-4.60(m,1H),2.74-2.65(m,1H),2.44-2.29(m,2H),2.25-2.09(m,2H),1.92-1.83(m,1H)。LC-MS:m/z 472(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.60-8.57(m,1H),8.52-8.42(m,1H),8.36-8.19(m,1H),7.86-7.68(m,2H),7.51(d,J＝8Hz,2H),5.96-5.65(m,1H),3.51-3.39(m,2H),1.16(d,J＝8Hz,1H),0.63-0.60(m,2H),0.35-0.30(m,2H)。LC-MS:m/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

¹ H NMR(400MHZz,CDCl ₃ )δ9.84(s,1H),9.12(s,1H),8.49-8.31(m,2H),7.78-7.68(m,1H),7.15(s,1H),6.16-5.98(m,1H),4.73-4.58(m,1H),3.22(d,J＝8Hz,2H),2.62-2.54(m,2H),1.89-1.79(m,4H)。LC-MS:m/z 490(M+H) ⁺ 。

1- (4- ((4, 4-difluorocyclohexyl) amino) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ9.84(d,J＝4Hz,1H),9.12(s,1H),8.49(s,1H),8.34-8.31(m,1H),7.72-7.63(m,1H),7.27-7.13(m,1H),5.79-5.58(m,1H),4.36-4.26(m,1H),2.20-2.13(m,4H),1.90-1.72(m,8H)。LC-MS:m/z 518(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

¹ H NMR(400MHz,DMSO-d ₆ )δ10.53(s,1H),9.84-9.75(m,1H),9.39(d,J＝8Hz,1H),8.80(d,J＝8Hz,1H),8.41-8.21(m,2H),7.83-7.56(m,1H),4.57(d,J＝8Hz,1H),2.71-2.57(m,6H),2.27-2.22(m,2H),1.81-1.67(m,4H)。LC-MS:m/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

¹ H NMR(400MHz,DMSO-d ₆ )δ10.58(s,1H),9.87-9.77(m,1H),9.39(d,J＝4Hz,1H),8.77(d,J＝4Hz,1H),8.42-8.32(m,2H),7.82-7.57(m,1H),4.67(m,1H),2.67-1.69(m,10H)。LC-MS:m/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

¹ H NMR(400MHz,CDCl ₃ )δ9.85(s,1H),9.12(s,1H),8.61-8.44(m,1H),8.33(d,J＝8Hz,1H),7.52(s,1H),7.00(s,1H),5.97-5.75(m,1H),4.94-4.75(m,1H),2.75-1.73(m,10H)。LC-MS:m/z 504(M+H) ⁺ 。

(R) -1- (4- ((4- (6- (trifluoromethyl) pyrazin-2-yl) -6- ((1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ9.90-9.84(m,1H),9.14(s,1H),8.43-8.35(m,2H),7.52-7.15(m,2H),5.86-5.60(m,1H),5.14-4.80(m,1H),1.87(d,J＝8Hz,2H),1.74(m,2H),1.50-1.57(m,3H)。LC-MS:m/z 496(M+H) ⁺ 。

(R)-N ² - (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )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)-N ² - (3, 3-difluorocyclopentyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.81(m,1H),9.14(d,J＝3.1Hz,1H),8.74-8.08(m,2H),8.06-7.29(m,2H),6.22-5.58(m,1H),4.85-4.50(m,1H),2.70(m,1H),2.52-2.09(m,4H),2.01-1.82(m,1H)。LC-MS:m/z 507(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ9.81(d,J＝13.8Hz,1H),9.14(d,J＝3.5Hz,1H),8.80-8.19(m,2H),7.99-7.41(m,2H),6.31-5.71(m,1H),4.70-4.39(m,1H),3.29-3.06(m,2H),2.88-2.47(m,2H)。LC-MS:m/z 493(M+H) ⁺ 。

N ² - (4, 4-difluorocyclohexyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.80(d,J＝8.8Hz,1H),9.14(d,J＝3.4Hz,1H),8.62(d,J＝5.5Hz,1H),8.59-8.20(m,1H),5.83-5.49(m,1H),4.25-4.11(m,1H),2.33-1.71(m,6H)。LC-MS:m/z 521(M+H) ⁺ 。

N ² - (cyclopropylmethyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -N4- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,DMSO-d ₆ )82(s,4H),9.20(s,4H),8.73(s,3H),8.49(t,J＝6.2Hz,4H),8.37(s,1H),8.13(s,1H),7.79(d,J＝4.4Hz,3H),3.45-3.30(m,8H),1.29-1.16(m,5H),0.57(m 8H),0.39-0.30(m,8H)。LC-MS:m/z 457(M+H) ⁺ 。

N ² - (6, 6-difluorospiro [3.3 ]]Hept-2-yl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CD ₃ OD)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)-N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (3, 5-difluorophenyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.80(m,1H),9.12(d,J＝3.1Hz,1H),7.71-7.27(m,3H),6.73-6.44(m,1H),5.98-5.48(m,1H),4.68(m,1H),2.81-2.59(m,1H),2.50-2.02(m,4H),1.97-1.78(m,1H)。LC-MS:m/z 474(M+H) ⁺ 。

(R)-N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (3, 5-difluorophenyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

N ² - (4, 4-difluorocyclohexyl) -N ⁴ - (3, 5-difluorophenyl) -6- (6- (trifluoromethyl) pyrazin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.78(d,J＝7.6Hz,1H),9.11(s,1H),7.39(m,3H),6.58(t,J＝8.8Hz,1H),5.76-5.39(m,1H),4.22-4.06(m,1H),2.21(m,4H),1.95(m,2H),1.80-1.68(m,2H)。LC-MS:m/z 488(M+H) ⁺ 。

1- (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,CDCl ₃ )δ9.79(d,J＝7.0Hz,1H),9.12(s,1H),8.54(m,1H),8.32(d,J＝6.0Hz,1H),7.52(d,J＝6.1Hz,1H),7.14(m,1H),6.85(m,1H),5.68(m,1H),4.30(m,1H),2.18(m,6H),1.85(m,2H),1.73(m,4H)。LC-MS:m/z 500(M+H) ⁺ 。

(S) -1- (4- ((4- (6- (difluoromethyl) pyrazin-2-yl) -6- ((1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ9.83(m,1H),9.16(s,1H),8.42(m,2H),7.60(s,1H),7.13(m,1H),6.88(m,1H),5.88(m,J＝9.5Hz,1H),5.16(s,1H),1.89(m,J＝4.5Hz,2H),1.76(s,2H),1.52(d,J＝7.0Hz,3H)。LC-MS:m/z 478(M+H) ⁺ 。

(R) -1- (4- ((4- (6- (difluoromethyl) pyrazin-2-yl) -6- ((1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ9.81(m,1H),9.12(d,J＝10.5Hz,1H),8.34(m,2H),7.54(d,J＝13.1Hz,1H),7.08(m,1H),6.86(m,1H),5.85(d,J＝9.8Hz,1H),5.14(s,1H),1.92(m,2H),1.71(m,2H),1.51(m,J＝7.7Hz,3H)。LC-MS:m/z 478(M+H) ⁺ 。

6- (6-Chloropyrazin-2-yl) -N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (3, 5-difluorophenyl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.51(d,J＝17.3Hz,1H),8.76(s,1H),7.64-7.11(m,3H),6.57(t,J＝8.8Hz,1H),5.95-5.50(m,1H),4.86-4.50(m,1H),2.85-1.80(m,6H)。LC-MS:m/z 440(M+H) ⁺ 。

6- (6-Chloropyrazin-2-yl) -N ² - (3, 3-difluorocyclobutyl) -N ⁴ - (3, 5-difluorophenyl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.53-9.49(m,1H),8.76(s,1H),7.60-7.50(m,1H),7.29(s,1H),7.26(s,1H),6.61-6.56(m,1H),6.01-5.74(m,1H),4.59-4.42(m,1H),3.16(s,2H),3.16-2.55(m,2H)。LC-MS:m/z 426(M+H) ⁺ 。

(S)-N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.16(t,J＝6.1Hz,1H),8.68-7.76(m,4H),7.72-7.45(m,1H),5.86(m,1H),4.70(m,1H),2.86-1.84(m,6H)。LC-MS:m/z 507(M+H) ⁺ 。

(R)-N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -6- (2- (trifluoromethyl) pyrimidin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.18-9.15(m,1H),8.64-8.61(m,1H),8.53-8.51(m,1H),8.48(d,J＝4Hz,1H),8.17-7.80(m,1H)7.72-7.48(m,1H),6.02-5.71(m,1H),4.80-4.61(m,1H),2.76-2.63(m,4H),1.95-1.88(m,1H)。LC-MS:m/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,CDCl ₃ )δ9.15(d,J＝5.4Hz,1H),7.62(m,2H),8.33(d,J＝5.5Hz,1H),7.57(s,1H),7.00(s,1H),6.00(d,J＝8.0Hz,1H),4.76(d,J＝8.6Hz,1H),2.71(s,1H),2.32(m,4H),1.83(m,5H)。LC-MS:m/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

¹ H NMR(400MHz,CDCl ₃ )δ9.14(d,J＝5.1Hz,1H),8.35(m,2H),8.33(d,J＝5.5Hz,1H),7.56(s,1H),7.00(s,1H),5.99(d,J＝8.0Hz,1H),4.76(d,J＝7.1Hz,1H),2.73(m,1H),2.23(m,4H),1.78(m,5H)。LC-MS:m/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

¹ H NMR(400MHz,CDCl ₃ )δ9.27(d,J＝4.8Hz,1H),8.67(s,1H),8.29(d,J＝5.2Hz,1H),8.06(s,1H),7.81(d,J＝5.2Hz,1H),6.97(s,1H),6.19(d,J＝7.6Hz,1H),2.85-2.69(m,1H),2.53-2.05(m,5H),1.92-1.68(m,5H)。LC-MS:m/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

¹ H NMR(400MHz,CDCl ₃ )δ9.29(d,J＝4.9Hz,1H),8.58(m,1H),8.33(d,J＝5.5Hz,1H),7.82(t,J＝14.2Hz,2H),7.00(d,J＝13.0Hz,1H),6.14(d,J＝8.0Hz,1H),4.94(m,1H),2.89-2.69(m,1H),2.51(m,1H),2.34-2.07(m,3H),1.94-1.72(m,5H)。LC-MS:m/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

¹ H NMR(400MHz,CDCl ₃ )δ9.27(d,J＝4.9Hz,1H),8.68(s,1H),8.31(d,J＝5.5Hz,1H),7.80(dd,J＝20.2,12.7Hz,2H),6.95(s,1H),6.12(d,J＝8.1Hz,1H),5.02(s,1H),2.77(m,1H),2.56-2.41(m,1H),2.32-2.05(m,3H),1.95-1.69(m,5H)。LC-MS:m/z 504(M+H) ⁺ 。

N ² - (tert-butyl) -N ⁴ - (2- (1, 1-difluoroethyl) pyridin-4-yl) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.24(d,J＝5.0Hz,1H),8.50(d,J＝5.5Hz,1H),8.38(d,J＝1.4Hz,1H),7.97(s,1H),7.80(d,J＝5.0Hz,1H),7.37(s,1H),6.05(s,1H),2.04(d,J＝18.6Hz,3H),1.55(s,9H)。LC-MS:m/z 455(M+H) ⁺ 。

N ² - (2- (1, 1-difluoroethyl) pyridin-4-yl) -N ⁴ -isopropyl-6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ9.26(d,J＝5.0Hz,1H),8.52(d,J＝5.5Hz,1H),8.41(d,J＝1.5Hz,1H),7.84(m,2H),7.41(s,1H),5.86(d,J＝7.5Hz,1H),4.32(m,1H),2.04(m,3H),1.36(d,J＝6.5Hz,6H)。LC-MS:m/z 441(M+H) ⁺ 。

3- ((4- (tert-butylamino) -6- (4- (trifluoromethyl) pyrimidin-2-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹ H NMR(400MHz,DMSO-d ₆ )δ10.80-10.20(m,1H),9.50-9.25(m,1H),8.36-7.96(m,4H),7.50-7.40(m,1H),1.47(s,9H)。LC-MS:m/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

¹ H NMR(400MHz,DMSO-d ₆ )δ10.70-10.20(m,1H),9.50-9.27(m,1H),8.37-7.94(m,2H),7.80-7.50(m,2H),6.98-6.71(m,1H),4.75-4.48(m,1H),3.47-3.38(m,2H),1.14(s,6H)。LC-MS:m/z 442(M+H) ⁺ 。

Example 33. Preparation of aromatic-aliphatic triazine Compounds. The compound of this example was prepared by the general scheme 33 listed below.

Scheme 33

Step 1: preparation of N ¹ - (3, 5-difluorophenyl) -N ³ -nitrile-guanidine. At 80℃to NaN (CN) ₂ To a solution of (4.1 g,46.5 mmol) in water (34 mL) was added a solution of 3, 5-difluoroaniline (3 g,23.2 mmol) 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 purified by saturated aqueous NaHCO ₃ Quenched and adjusted to pH 7-8. The mixture is filtered and the filter cake is collected and dried to obtain the desired product. LC-MS: M/z 197 (M+H) ⁺ 。

Step 2: preparation of N ¹ - (3, 5-difluorophenyl) -N ⁵ - (4, 4-difluorocyclohexyl) -guanidine. Will N ¹ - (3, 5-difluorophenyl) -N ³ A mixture of nitrile-guanidine (300 mg,1.53 mmol) and 4, 4-difluorocyclohexylamine hydrochloride (262 mg,1.53 mmol) was thoroughly mixed together 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) ⁺ 。

Step 3: preparing 3, 6-difluoro-2-hydrazinopyridine. To an ice-cold mixture of 2,3, 6-trifluoropyridine (1.0 g,7.5 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.75 g,15.0 mmol). The reaction mixture was warmed to room temperature and then heated to reflux for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×20 mL). By anhydrous Na ₂ SO ₄ The combined organic layers were dried and concentrated under reduced pressure to give 3, 6-difluoro-2-hydrazinopyridine. LC-MS M/z 146 (M+H) ⁺ 。

Step 4: preparing 2-bromo-3, 6-difluoropyridine. To a stirred solution of 3, 6-difluoro-2-hydrazinopyridine (1.1 g,7.0 mmol) in chloroform (20 mL) was added dropwise bromine (1.8 g,11.2 mmol) 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 quenched with saturated aqueous NaHCO ₃ Quench and extract with dichloromethane (2×20 ml). By anhydrous Na ₂ SO ₄ The combined organic layers were dried and concentrated and purified by standard methods to give 2-bromo-3, 6-difluoropyridine. LC-MS M/z 194 (M+H) ⁺ 。

Step 5: preparing 3, 6-difluoro pyridine methyl formate. To a solution of 2-bromo-3, 6-difluoropyridine (0.8 g,4.1 mmol) in MeOH (10 mL) was added dppf (0.3 g,0.56 mmol), pd (OAc) ₂ (0.1 g,0.45 mmol) and Et ₃ N (1.6 mL,8.2 mmol). The suspension was degassed and backfilled three times with CO atmosphere. The mixture was then stirred under CO atmosphere (60 psi) 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 solids were filtered off and the filtrate was concentrated and purified by standard methods to give methyl 3, 6-difluoropicolinate. LC-MS M/z 174 (M+H) ⁺ 。

Step 6: preparation of N ² - (4, 4-difluorocyclohexyl) -N ⁴ - (3, 5-difluorophenyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. To N ¹ - (3, 5-difluorophenyl) -N ⁵ Suspension of- (4, 4-difluorocyclohexyl) -guanidine (191 mg,0.58 mmol) and methyl 3, 6-difluoropicolinate (100 mg,0.58 mmol) in MeOH (3 mL)NaOMe (94 mg,1.73 mmol) was added to the solution. The reaction mixture was stirred at room temperature overnight, then poured into water and extracted with EtOAc. By anhydrous Na ₂ SO ₄ The combined organic layers were dried, concentrated and purified by standard methods to give N ² - (4, 4-difluorocyclohexyl) -N ⁴ - (3, 5-difluorophenyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine.

¹ H NMR(400MHz,CDCl ₃ )δ7.70(td,J＝8.8,5.8Hz,1H),7.49-7.38(m,1H),7.37-7.17(m,2H),7.17-7.05(m,1H),6.55(t,J＝8.9Hz,1H),5.67-5.37(m,1H),4.13-4.02(m,1H),2.18(d,J＝8.3Hz,4H),2.03-1.87(m,2H),1.73-1.70(d,J＝11.2Hz,2H)。LC-MS:m/z 455(M+H) ⁺ 。

Using the procedure outlined in example 33, the following compounds were prepared using the appropriate starting materials.

Compound N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (3, 5-difluorophenyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.77-7.62(m,1H),7.47-7.27(m,2H),7.24(d,J＝7.7Hz,1H),7.11(ddd,J＝8.8,3.9,2.7Hz,1H),6.55(t,J＝8.7Hz,1H),5.94-5.29(m,1H),4.76-4.48(m,1H),2.90-1.72(m,6H)。LC-MS:m/z 441(M+H) ⁺ 。

Compound N ² - (3, 3-difluorocyclobutyl) -N ⁴ - (3, 5-difluorophenyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.70(m,1H),7.58-7.28(m,2H),7.25-7.19(m,1H),7.16-7.06(m,1H),6.73-6.30(m,1H),6.18-5.37(m,1H),4.63-4.31(m,1H),3.40-2.93(m,2H),2.88-2.19(m,2H)。LC-MS:m/z 427(M+H) ⁺ 。

Example 34 the compound of this example was prepared by the general scheme 34 listed below.

Scheme 34

Step 1: preparation of N ² - (4, 4-difluorocyclohexyl) -N ⁴ - (3, 5-difluorophenyl) -6- (3-fluoro-6-hydrazinopyridin-2-yl) -1,3, 5-triazine-2, 4-diamine. To N ² - (4, 4-difluorocyclohexyl) -N ⁴ To a solution of- (3, 5-difluorophenyl) -6- (3, 6-difluoropyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (225 mg,0.49 mmol) in THF (20 mL) was added hydrazine hydrate (150 mg,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 (20 mL) and washed with brine (2×10 mL). The organic phase was separated with anhydrous Na ₂ SO ₄ Dried 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) -N ² - (4, 4-difluorocyclohexyl) -N ⁴ - (3, 5-difluorophenyl) -1,3, 5-triazine-2, 4-diamine. To N ² - (4, 4-difluorocyclohexyl) -N ⁴ To a solution of- (3, 5-difluorophenyl) -6- (3-fluoro-6-hydrazinopyridin-2-yl) -1,3, 5-triazine-2, 4-diamine (46 mg,0.1 mmol) in methanol (5.0 mL) was added Raney nickel (100 mg). At room temperature under H ₂ The mixture was stirred overnight under an atmosphere. The resulting mixture is filtered and the filtrate is concentrated and purified by standard methods to give 6- (6-amino-3-fluoropyridin-2-yl) -N ² - (4, 4-difluorocyclohexyl) -N ⁴ - (3, 5-di)Fluorophenyl) -1,3, 5-triazine-2, 4-diamine.

¹ H NMR(400MHz,CDCl ₃ )δ7.52-7.50(m,2H),7.45-7.39(m,1H),7.02-6.97(m,1H),6.63-6.54(m,1H),4.60(s,1H),4.26-4.05(m,1H),1.73-2.21(m,8H)。LC-MS:m/z 452(M+H) ⁺ 。

Using the procedure outlined in example 34, the following compounds were prepared using the appropriate starting materials.

Compound 6- (6-amino-3-fluoropyridin-2-yl) -N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (3, 5-difluorophenyl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.50-7.36(m,3H),6.96-6.95(m,1H),6.59-6.53(m,1H),4.89-4.51(m,2H),2.66-2.60(m,1H),2.35-2.11(m,4H),1.92-1.58(m,2H)。LC-MS:m/z 438(M+H) ⁺ 。

Example 35: preparation of N ⁴ ,N ⁶ -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 (15 g,72.8 mmol) in EtOH (20 mL) was added NH ₄ OH (6 mL,156 mmol). The reaction mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure. By H ₂ O (10 mL) was triturated and then filtered to give 6- (trifluoromethyl) pyrazine-2-carboxamide. LC-MS: M/z 192 (M+H) ⁺ 。

And (B) step (B): 6- (trifluoromethyl)) Pyrazine-2-carbonitrile. Stirring 6- (trifluoromethyl) pyrazine-2-carboxamide (10 g,52 mmol) at 100deg.C in POCl ₃ (80 mL) was allowed to stand 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, dried over anhydrous Na ₂ SO ₄ Dried, concentrated, and purified by standard methods to give 6- (trifluoromethyl) pyrazine-2-carbonitrile. LC-MS M/z 174 (M+H) ⁺ 。

Step C:6- (trifluoromethyl) pyrazine-2-carboxamidine hydrochloride. To a solution of 6- (trifluoromethyl) pyrazine-2-carbonitrile (3.4 g,15 mmol) in MeOH (5 mL) was added a solution of sodium metal (35 mg,1.5 mmol) in MeOH. The reaction mixture was stirred at room temperature for 12 hours, followed by addition of NH ₄ Cl (1.5 g,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 (10 mL) 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 to obtain 6- (trifluoromethyl) pyrazine-2-carboxamidine hydrochloride. LC-MS: M/z 191 (M+H) ⁺ 。

Step D:2- (6- (trifluoromethyl) pyrazin-2-yl) pyrimidine-4, 6 (1 h,5 h) -dione. To a mixture of 6- (trifluoromethyl) pyrazine-2-carboxamidine hydrochloride (1.6 g,7.0 mmol) in diethyl malonate (3.2 g,21.2 mmol) was added potassium carbonate (3.0 g,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, then treated with MeOH to form a suspension. The suspension was filtered and the filtrate was concentrated under reduced pressure to obtain 2- (6- (trifluoromethyl) pyrazin-2-yl) pyrimidine-4, 6- (1 h,5 h) -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 (1.4 g,5.4 mmol) was stirred at 100deg.C in POCl ₃ The mixture in (10 mL) was allowed to cool to room temperature overnight 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 (N) ⁴ ,N ⁶ -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 (100 mg,0.34 mmol), csF (103 mg,0.68 mmol) and 4, 4-difluorocyclohexylamine hydrochloride (116 mg,0.68 mmol) in DMSO (1 mL) was added DIPEA (220 mg,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, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure. Purification of the residue by standard methods gives N ⁴ ,N ⁶ -bis (4, 4-difluorocyclohexyl) -2- (6- (trifluoromethyl) pyrazin-2-yl) pyrimidine-4, 6-diamine.

¹ H NMR(400MHz,CDCl ₃ )δ9.73(s,1H),9.00(s,1H),5.31(s,1H),4.95(m,2H),3.76(m,2H),2.20-2.09(m,8H),1.98-1.85(m,4H),1.72-1.63(m,4H)。LC-MS:m/z 493(M+H) ⁺ 。

Example 36. Preparation of aromatic-aliphatic triazine Compounds. The compounds of this example were prepared by the general scheme 36 listed below.

Scheme 36

Step 1: preparation of 1- (4-bromopyridin-2-yl) cyclopropanecarbonitrile. To a solution of 4-bromo-2-fluoropyridine (30 g,170.47 mmol) and cyclopropanecarbonitrile (22.9 g,340.94 mmol) in THF (400 mL) was slowly added LiHMDS (1.2 mmol/L,284 mL) dropwise below-10deg.C. 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. With EtOAc (3X 200 mL) extraction residue. By anhydrous Na ₂ SO ₄ The combined layers were dried and concentrated and purified by standard methods to give the desired product. LC-MS M/z 223 (M+H) ⁺ 。

Step 2: preparation of 1- (4- (diphenylmethyleneamino) pyridin-2-yl) cyclopropanecarbonitrile. To a solution of 1- (4-bromopyridin-2-yl) cyclopropanecarbonitrile (30 g,134.48 mmol) and diphenylazomethine (29.3 g,161.38 mmol) in dioxane (150 mL) was added t-Buona (19.4 g,201.73 mmol), binap (5.0 g,8.1 mmol) and Pd ₂ (dba) ₃ (2.5 g,2.69 mmol). At N ₂ The mixture was heated to 100 ℃ for 1 hour under atmosphere, then cooled and filtered. The filtrate was concentrated to give the desired product. LC-MS M/z 324 (M+H) ⁺ 。

Step 3: preparation of 1- (4-aminopyridin-2-yl) cyclopropanecarbonitrile. 1- (4- (diphenylmethyleneamino) pyridin-2-yl) cyclopropanecarbonitrile (42.1 g crude, 130 mmol) and THF/aqueous HCl (2N) (200 ml, v: v=2:1) were stirred at room temperature for 1 hour and concentrated under reduced pressure. The aqueous layer was extracted with PE (3X 100 mL) and then with saturated aqueous Na ₂ CO ₃ Adjust to pH 8-9 and extract with EtOAc (3 x 100 ml). By anhydrous Na ₂ SO ₄ The combined organic layers were dried and concentrated and purified by standard methods to give the desired product. ¹ HNMR(CDCl ₃ )δ8.04-8.05(d,J＝4Hz,1H),6.95-6.96(d,J＝4Hz),6.37-6.39(m,1H),4.23(br,2H),1.17-1.80(m,2H),1.61-1.63(m,2H)。LC-MS:m/z 160(M+H) ⁺ 。

Step 4: preparation of 1- (4, 6-dichloro-1, 3, 5-triazin-2-ylamino) pyridin-2-yl) cyclopropanecarbonitrile. To a solution of 1- (4-aminopyridin-2-yl) cyclopropanecarbonitrile (2.5 g,15.7 mmol), 2,4, 6-trichloro-1, 3, 5-triazine (3.5 g,18.8 mmol) in THF (40 mL) was added NaHCO ₃ (2.64 g,31.4 mmol). The reaction mixture was stirred at room temperature overnight and then filtered. The filtrate is concentrated and purified by standard methods to give the desired product. LC-MS: M/z 307 (M+H) ⁺ 。

Step 5: preparation of 1- (4- (4-chloro-6- (3, 3-difluorocyclopentylamino) -1,3, 5-triazin-2-ylamino) pyridin-2-yl) cyclopropanemethylA nitrile. To a solution of 1- (4, 6-dichloro-1, 3, 5-triazin-2-ylamino) pyridin-2-yl) cyclopropanecarbonitrile (0.75 g,2.44 mmol) and 3, 3-difluorocyclopentylamine hydrochloride (0.39 g,2.44 mmol) in THF (10 mL) was slowly added drop wise DIPEA (0.63 g,4.88 mmol) at 0deg.C. The reaction mixture was stirred at room temperature for 8 hours, and then concentrated under reduced pressure. The residue was partitioned between EtOAc (20 mL) and HCl solution (10% wt,3 mL). The aqueous layer was separated and extracted with EtOAc (2×5 ml). By anhydrous Na ₂ SO ₄ The combined organic layers were dried and concentrated and purified by standard methods to give 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 (0.6 g,1.53 mmol) in DMF (600 mL) was added 3- (trifluoromethyl) -1H-pyrazole (0.2 g,1.53 mmol) and K ₂ CO ₃ (0.42 g,3.06 mmol). The mixture was stirred at 35 ℃ overnight and then concentrated under reduced pressure. The residue was dissolved in EtOAc (20 mL) and then sequentially washed with 10% aqueous LiCl (2X 5 mL), 5% HCl (2X 5 mL) and saturated aqueous NaHCO ₃ (2X 5 mL) washing. The organic layer was separated with anhydrous Na ₂ SO ₄ Dried, and concentrated and purified by standard methods to give the desired product. ¹ H NMR(400MHz,CDCl ₃ )δ8.81-8.21(m,3H),7.75-7.43(m,1H),7.17-6.88(m,1H),6.74(d,J＝2.7Hz,1H),6.05-5.76(m,1H),5.12-4.41(m,1H),2.86-2.61(m,1H),2.57-2.00(m,4H),1.97-1.78(m,3H),1.76-1.68(m,2H)。LC-MS:m/z 492(M+H) ⁺ 。

Using the procedure outlined in example 36, the following compounds were prepared 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.

¹ H NMR(400MHz,CDCl ₃ )δ8.51-8.64(m,2H),8.30-8.32(m,1H),7.70-7.87(m,1H),7.96-7.14(m,1H),6.66-6.75(m,1H),5.86-6.07(m,1H),4.64-4.93(m,1H),2.44-2.76(m,1H),2.04-2.30(m,4H),1.72-1.94(m,5H)。LC-MS:m/z492(M+H) ⁺ 。

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.

¹ H NMR(400MHz,CDCl ₃ )δ8.59(m,2H),8.32(d,J＝5.5Hz,1H),7.52(s,1H),6.95(m,1H),6.74(d,J＝2.7Hz,1H),5.91(m,1H),4.83(m,1H),2.69(m,1H),2.31(m,4H),1.76(m,5H)。LC-MS:m/z 492(M+H) ⁺ 。

The compound 1- (4- ((4, 4-difluorocyclohexyl) amino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.80-8.11(m,3H),7.63(m,1H),7.17-6.97(m,1H),6.76(t,J＝3.4Hz,1H),5.75(m,1H),4.21(m,1H),2.14(m,6H),1.93-1.83(m,2H),1.77-1.61(m,4H)。LC-MS:m/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

¹ H NMR(400MHz,CDCl ₃ )δ:8.78-8.50(M,2H),8.32(m,1H),7.86-7.56(m,1H),7.13-6.98(M,1H),6.74(t,J＝3.9Hz,1H),6.18(d,J＝6.9Hz,1H),4.85-4.42(M,1H),3.28-3.05(m,2H),2.83-2.47(m,2H),1.91-1.85(m,2H),1.76-1.69(m,2H)。LC-MS:m/z 478(M+H) ⁺ 。

The compound 1- (4- ((4- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -6- ((1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.84-8.27(m,3H),7.71(m,1H),7.11(m,1H),6.76(d,J＝2.6Hz,1H),5.91(d,J＝9.6Hz,1H),5.03(s,1H),1.87(m,2H),1.76-1.72(m,2H),1.49(t,J＝8.4Hz,3H)。LC-MS:m/z 484(M+H) ⁺ 。

The compound (R) -1- (4- ((4- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -6- ((1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.65(s,1H),8.48(d,J＝1.7Hz,1H),8.35(d,J＝5.5Hz,1H),7.59(m,1H),7.14(m,1H),6.76(d,J＝2.7Hz,1H),5.75(m,1H),5.02(s,1H),1.93-1.76(m,2H),1.69(m,2H),1.49(t,J＝8.7Hz,3H)。LC-MS:m/z 484(M+H) ⁺ 。

The compound (S) -1- (4- ((4- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -6- ((1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridin-2-yl) cyclopropanecarbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.67(s,1H),8.50(d,J＝1.4Hz,1H),8.38(m,1H),7.64(m,1H),7.07(s,1H),6.77(d,J＝2.6Hz,1H),5.82(m,1H),5.34-4.85(m,1H),1.97-1.85(m,2H),1.77(m,2H),1.57-1.44(m,3H)。LC-MS:m/z 484(M+H) ⁺ 。

Compound N ² - (3, 3-difluorocyclopentyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.52(m,3H),8.01-7.37(m,2H),6.76(t,J＝3.7Hz,1H),5.92(m,1H),4.79-4.53(m,1H),2.67(m,1H),2.47-2.09(m,4H),1.93-1.86(m,1H)。LC-MS:m/z 495(M+H) ⁺ 。

Compounds (S) -N ² - (3, 3-difluorocyclopentyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.64-8.55(m,2H),8.48-8.11(m,1H),7.75-7.41(m,2H),6.77-6.75(m,1H),5.97-5.73(m,1H),4.71-4.61(m,1H),2.74-2.61(m,1H),2.42-2.36(m,2H),2.30-2.16(m,2H),1.93-1.86(m,1H)。LC-MS:m/z 495(M+H) ⁺ 。

Compound N ² - (3, 3-difluorocyclobutyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CD ₃ OD)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 N ² - (cyclopropyl methyl)Phenyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine

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¹ H NMR(400MHz,CDCl ₃ )δ8.87-8.36(m,3H),8.27-7.44(m,2H),7.01-6.54(m,1H),6.17-5.80(m,1H),3.43(m,2H),1.35-1.01(m,1H),0.75-0.56(m,2H),0.43-0.24(m,2H)。LC-MS:m/z 445(M+H) ⁺ 。

Compound 6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N ² - (2- (trifluoromethyl) pyridin-4-yl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.69-8.08(m,3H),7.68(m,2H),6.77(d,J＝2.7Hz,1H),5.86(m,1H),4.93(m,1H),1.52(dd,J＝7.1Hz,3H)。LC-MS:m/z 487(M+H) ⁺ 。

Compound (R) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N ² - (2- (trifluoromethyl) pyridin-4-yl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.74-8.48(m,2H),8.46-7.74(m,2H),7.72-7.34(m,1H),6.77(d,J＝2.7Hz,1H),6.08-5.53(m,1H),5.11-4.77(m,1H),1.52(m,3H)。LC-MS:m/z 487(M+H) ⁺ 。

Compound (S) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N ² - (2- (trifluoromethyl) pyridin-4-yl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.65-8.61(m,1H),8.56(d,J＝4Hz,1H)，8.37(m,1H),8.08-7.81(m,1H),7.70-7.44(m,1H),6.76-6.68(m,1H),5.97-5.78(m,1H),5.05-4.82(m,1H),1.53-1.49(m,3H)。LC-MS:m/z 487(M+H) ⁺ 。

Compound 3- ((4- ((3, 3-difluorocyclobutyl) amino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.61-8.54(m,1H),7.86-7.78(m,1H),7.69(s,1H)7.60(d,J＝8Hz,1H),7.13-7.08(m,1H),6.76-6.74(m,1H),6.01-5.94(m,1H),4.58-4.42(m,1H),3.20-3.10(m,2H),2.80-2.54(m,2H)。LC-MS:m/z 455(M+H) ⁺ 。

The compound 3-fluoro-5- ((4- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -6- ((1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) benzonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.60-8.53(m,1H),7.99-7.62(m,3H),7.14-7.09(m,1H),6.76(d,J＝4Hz,1H),5.90-5.82(m,1H),5.04-4.98(m,1H),4.87-4.81(m,3H)。LC-MS:m/z 461(M+H) ⁺ 。

Compound 3- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.63-8.55(m,1H),7.83-7.66(m,3H),7.12-7.08(m,1H),6.77-6.75(m,1H),6.68(d,J＝4Hz,1H),6.21-5.79(m,1H),5.56-4.69(m,1H),2.74-2.50(m,1H),2.40-2.15(m,4H),1.94-1.89(m,1H)。LC-MS:m/z 469(M+H) ⁺ 。

Compound 4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-yl) amino) pyridine carbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.74-8.31(m,4H),7.83-7.51(m,1H),6.76-6.67(m,1H),6.24-6.19(m,1H),4.70-4.55(m,1H),2.78-2.62(m,1H),2.45-2.13(m,4H),1.98-1.91(m,1H)。LC-MS:m/z 452(M+H) ⁺ 。

Compound (S) -4- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-yl) amino) pyridine carbonitrile

¹ H NMR(400MHz,DMSO-d ₆ )δ10.89(s,1H),8.90(d,J＝8Hz,1H),8.70-8.66(m,1H),8.58-8.42(m,2H),8.00-7.95(m,1H),7.09(s,1H),4.65-4.43(m,1H),2.69-2.57(m,1H),2.36-2.08(m,4H),1.91-1.80(m,1H)。LC-MS:m/z 452(M+H) ⁺ 。

Compound 4- ((4- ((3, 3-difluorocyclobutyl) amino) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazin-2-yl) amino) pyridine carbonitrile

¹ H NMR(400MHz,CDCl ₃ )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) ⁺ 。

Compound (R) -4- ((4- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -6- ((1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) amino) pyridine carbonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.64(d,J＝8Hz,1H),8.61-8.57(m,1H),8.45-8.32(m,1H),8.14-7.84(m,1H),7.78-7.48(m,1H),6.78-6.68(m,1H),6.05-5.96(m,1H),5.26-4.70(m,1H),1.57-1.51(m,3H)。LC-MS:m/z 444(M+H) ⁺ 。

Compound N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (3, 5-difluorophenyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.65-8.51(m,1H),7.65-7.40(m,1H),7.23(m,2H),6.78-6.69(m,1H),6.64-6.50(m,1H),5.95-5.70(m,1H),4.74-4.51(m,1H),2.78-2.58(m,1H),2.44-2.06(m,4H),1.87(d,J＝3.8Hz,1H)。LC-MS:m/z 462(M+H) ⁺ 。

Compound N ² - (3, 3-difluorocyclobutyl) -N ⁴ - (3, 5-difluorophenyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.73-8.40(m,1H),7.61(m,1H),7.22(m,2H),6.73(dd,J＝6.7,2.7Hz,1H),6.61-6.43(m,1H),6.00(m,1H),4.44(m,1H),3.29-3.02(m,2H),2.85-2.38(m,2H)。LC-MS:m/z 448(M+H) ⁺ 。

Compound N ² - (3, 5-difluorophenyl) -6- (3- (trifluoromethyl) -1H-pyrazol-1-yl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ8.62-8.51(m,1H),7.78-7.35(m,1H),7.25-7.12(m,2H),6.74(d,J＝2.0Hz,1H),6.65-6.52(m,1H),5.85-5.62(m,1H),5.06-4.80(m,1H),1.48(m,3H)。LC-MS:m/z 454(M+H) ⁺ 。

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

¹ H NMR(400MHz,CDCl ₃ )δ8.53(d,J＝4Hz,1H),7.70-7.53(m,1H),7.23-7.19(m,2H),6.71-6.67(m,1H),6.57-6.51(m,1H),6.28-6.08(m,1H),3.73-3.56(m,2H),2.46-1.49(m,6H),1.24(m,1H)。LC-MS:m/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

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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 (3 g,18.7 mmol) and 2,4, 6-trichloro-1, 3, 5-triazine (3.6 g,19.5 mmol) in THF (40 mL) was added NaHCO ₃ (3.1 g,37.5 mmol). The reaction mixture was stirred at room temperature for 16 hours and filtered. The filtrate is concentrated and purified by standard methods to give the desired product. LC-MS: M/z 310 (M+H) ⁺ 。

Step 2: preparation of 6-chloro-N ² - (3, 3-difluorocyclobutyl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine. To 4, 6-dichloro-N- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazin-2-amine (4 g, 12.9)To a solution of mmol) and 3, 3-difluorocyclobutane hydrochloride (1.9 g,13.5 mmol) in THF (40 mL) was added DIPEA (4.8 g,37.2 mmol). The reaction mixture was stirred at room temperature for 15 hours, then concentrated under reduced pressure. The residue was partitioned between EtOAc (200 mL) 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 give the desired product.

LC-MS:m/z 381(M+H) ⁺ 。

Step 3: preparation of 4- (3, 3-difluorocyclobutylamino) -6- (2- (trifluoromethyl) pyridin-4-ylamino) -1,3, 5-triazine-2-carbonitrile. To 6-chloro-N at room temperature ² - (3, 3-difluorocyclobutyl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazine-2, 4-diamine (2.2 g,5.77 mmol) to a solution of MeCN (30 mL) and DMSO (10 mL) was added NaCN (2.9 g,60 mmol). The reaction mixture was stirred at 60℃overnight and then partitioned between EtOAc (50 mL) and H ₂ O (20 mL). The organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, concentrated and purified by standard methods to give the desired product. LC-MS M/z 372 (M+H) ⁺ 。

Step 4: preparation of 4- (3, 3-difluorocyclobutylamino) -6- (2- (trifluoromethyl) pyridin-4-ylamino) -1,3, 5-triazine-2-carbothioamide. To a solution of 4- (3, 3-difluorocyclobutylamino) -6- (2- (trifluoromethyl) pyridin-4-ylamino) -1,3, 5-triazine-2-carbonitrile (0.7 g,1.88 mmol) in DMF (15 mL) was added NaHS (0.5 g,9.0 mmol) and MgCl ₂ (0.85 g,9.0 mmol). The reaction mixture was stirred at room temperature for 0.5H, then partitioned between EtOAc (30 mL) and H ₂ O (10 mL). The organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, and concentrated and purified by standard methods to give the desired product. LC-MS: M/z 406 (M+H) ⁺ 。

Step 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. Stirring 4- (3, 3-difluorocyclobutylamino) -6- (2- (trifluoromethyl) pyridin-4-ylamino) -1,3,5 at 60 ℃A mixture of triazine-2-thiocarboxamide (350 mg,0.86 mmol) and 3-bromo-1, 1-trifluoropropan-2-one (180 mg,0.95 mmol) in MeCN (10 mL) was allowed to stand for 2 hours, then partitioned between EtOAc (20 mL) and H ₂ O (10 mL). The organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, and concentrated and purified by standard methods to give the desired product.

¹ H NMR(400MHz,DMSO-d ₆ )δ10.94-10.86(m,1H),9.08(d,J＝6.0Hz,1H),8.69-8.48(m,2H),7.86-7.78(m,2H),4.30-4.21(m,1H),3.76-3.71(m,1H),3.53-3.41(m,1H),3.11-2.93(m,2H),2.87-2.66(m,2H)。LC-MS:m/z516(M+H) ⁺ 。

Step 6: preparation of N ² - (3, 3-difluorocyclobutyl) -N ⁴ - (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 (250 mg,0.48 mmol) and TEA (0.4 mL,2.4 mmol) in DCM (20 mL) was added dropwise a solution of triphosgene (290 mg,0.96 mmol) in DCM (5 mL) at 0 ℃. The reaction mixture was stirred at 0deg.C for 0.5H and then partitioned between DCM (20 mL) and H ₂ O (10 mL). The organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO ₄ Dried, and concentrated and purified by standard methods to give the desired product. ¹ H NMR(400MHz,DMSO-d ₆ )δ11..05-10.94(m,1H),9.10(d,J＝6.1Hz,1H),8.82(s,1H),8.70(s,1H),8.64(t,J＝5.4Hz,1H),7.83(d,J＝5.4Hz,1H),4.52-4.22(m,1H),3.18-2.99(m,2H),2.82(dt,J＝32.2,14.2Hz,2H)。LC-MS:m/z 498(M+H) ⁺ 。

Using the procedure outlined in example 37 above, the following compounds were prepared using the appropriate starting materials.

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

¹ H NMR(400MHz,CDCl ₃ )δ8.61(t,J＝5.7Hz,1H),8.52-8.15(m,1H),7.99(s,1H),7.77-7.41(m,2H),6.09-5.70(m,1H),3.50-3.34(m,2H),1.20-1.11(m,1H),0.67-0.57(m,2H),0.40-0.28(m,2H)。LC-MS:m/z 462(M+H) ⁺ 。

Compound N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (2- (trifluoromethyl) pyridin-4-yl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,DMSO-d ₆ )δ10.88(s,1H),8.83(d,J＝6.9Hz,1H),8.75(s,1H),8.62(s,1H),8.57(d,J＝5.5Hz,1H),7.79(d,J＝5.5Hz,1H),4.61-4.32(m,1H),2.59-2.51(m,1H),2.41-1.99(m,4H),1.95-1.74(m,1H)。LC-MS:m/z 512(M+H) ⁺ 。

Compound N ² - (3, 3-difluorocyclopentyl) -N ⁴ - (3, 5-difluorophenyl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.97(s,1H),7.45-7.26(m,4H),7.25-7.23(m,1H),6.60-6.56(m,1H),5.92-5.34(m,1H),4.68-4.57(m,1H),2.70-2.64(m,1H),2.37-2.16(m,4H),1.87(s,1H)。LC-MS:m/z 479(M+H) ⁺ 。

Compound N ² - (3, 3-difluorocyclobutyl) -N ⁴ - (3, 5-difluorophenyl) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazine-2, 4-diamine

¹ H NMR(400MHz,CDCl ₃ )δ7.97(d,J＝4Hz,1H),7.60-7.47(m,1H),7.26(m,1H),7.26-7.22(m,1H),6.61-6.53(m,1H),6.00-5.74(m,1H),4.52-4.41(m,1H),3.15(s,2H),2.70-2.57(m,2H)。LC-MS:m/z 465(M+H) ⁺ 。

Compound 3- ((4- ((3, 3-difluorocyclobutyl) amino) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.01(s,1H),7.87-7.797(m,2H),7.66(d,J＝8Hz,1H),7.14-7.10(m,1H),5.99-5.75(m,1H),4.72-4.58(m,1H),2.79-2.65(m,1H),2.40-2.18(m,3H)。LC-MS:m/z 472(M+H) ⁺ 。

Compound 3- ((4- ((3, 3-difluorocyclopentyl) amino) -6- (4- (trifluoromethyl) thiazol-2-yl) -1,3, 5-triazin-2-yl) amino) -5-fluorobenzonitrile

¹ H NMR(400MHz,CDCl ₃ )δ8.00(s,1H),7.28-7.02(m,3H),6.61(s,1H),6.01-5.76(m,1H),4.51-4.44(m,1H),3.18(s,1H),2.63(m,2H),1.60-1.50(m,1H),1.27-1.10(m,2H)。LC-MS:m/z 486(M+H) ⁺ 。

EXAMPLE 38 preparation of dialiphatic pyrimidine Compounds of formula S. The compounds of this example were prepared by the general scheme 32 listed below.

Scheme 32

Step 1: preparing the 6-chloropyridine methyl iminoate. To a solution of 6-chloropyridine carbonitrile (3 g,22 mmol) in MeOH (25 mL) was added a freshly prepared solution of sodium metal (55 mg,2.4 mol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 16 hours, and then concentrated under reduced pressure, therebyThe desired product is obtained. LC-MS M/z 171 (M+H) ⁺ 。

Step 2: preparing 6-chloropyridine formamidine. A mixture of ammonium chloride (2.18 g,40 mmol) and methyl 6-chloropyridine imidoester (3.5 g,20 mmol) in MeOH (30 mL) was stirred at 70℃for 3 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOH (40 mL) 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) ⁺ 。

Step 3: preparation of 2- (6-chloropyridin-2-yl) pyrimidine-4, 6-diol. To a solution of sodium metal (0.9 g,40 mmol) in MeOH (10 mL) was added 6-chloropyridine amidine (2 g,13 mmol) and dimethyl malonate (1.7 g,13 mmol). The reaction mixture was stirred at 85 ℃ overnight and then concentrated under reduced pressure. The residue was triturated with EtOAc (30 mL) and filtered. The solid was collected and dried under high vacuum to give the desired product. LC-MS: M/z 224 (M+H) ⁺ 。

Step 4: preparation of 4, 6-dichloro-2- (6-chloropyridin-2-yl) pyrimidine. 2- (6-Chloropyridin-2-yl) pyrimidine-4, 6-diol (2 g,9 mmol) was stirred at 90℃in POCl ₃ The mixture in (20 mL) was allowed to stand overnight and then concentrated under reduced pressure. The residue was slowly poured into saturated aqueous NaHCO at 0 °c ₃ Is a kind of medium. The resulting mixture was extracted with EtOAc (2 x 30 ml). The combined organic layers were washed with water (30 mL) and brine (30 mL), and dried over anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by standard methods to give the desired product. LC-MS M/z 260 (M+H) ⁺ 。

Step 5: preparation of (R) -6-chloro-2- (6-chloropyridin-2-yl) -N- (1, 1-trifluoropropan-2-yl) pyrimidin-4-amine. A mixture of 4, 6-dichloro-2- (6-chloropyridin-2-yl) pyrimidine (200 mg,0.77 mmol), 1-trifluoropropan-2-amine hydrochloride (255 mg,1.7 mmol), csF (258 mg,1.7 mmol) and DIPEA (497 mg,3.85 mmol) in DMSO (3 mL) was stirred overnight at 100deg.C. By H ₂ The resulting mixture was quenched with O (30 mL) and extracted with EtOAc (2X 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Dried and concentrated under reduced pressure. Purification by standard methodsResidue to give the desired product. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.37(m,2H),8.04(m,1H),7.68(d,J＝8Hz,1H),6.89(m,1H),5.02(m,1H),1.38(d,J＝8Hz,3H)。LC-MS:m/z 337(M+H) ⁺ 。

Step 6: preparation of (R) -2- (6-chloropyridin-2-yl) -N ⁴ - (4, 4-difluorocyclohexyl) -N ⁶ - (1, 1-trifluoropropan-2-yl) pyrimidine-4, 6-diamine. A mixture of (R) -6-chloro-2- (6-chloropyridin-2-yl) -N- (1, 1-trifluoropropan-2-yl) pyrimidin-4-amine (100 mg,0.3 mmol), 4-difluorocyclohexylamine hydrochloride (114 mg,0.66 mmol), csF (100 mg,0.66 mmol) and DIPEA (194 mg,1.5 mmol) in DMSO (3 mL) was stirred overnight at 100deg.C. By H ₂ The resulting mixture was quenched with O (30 mL) and extracted with EtOAc (2X 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ Dried, concentrated, and purified by standard methods to give the desired product.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.25(d,J＝8Hz,1H),8.15(s,1H),7.96(m,1H),7.56(d,J＝8Hz,1H),7.31(m,1H),7.06(d,J＝8Hz,1H),5.62(m,1H),5.30-4.84(m,1H),2.33(m,1H),2.14-1.90(m,5H),1.65(m,2H),1.32(d,J＝8Hz,3H)。LC-MS:m/z 436(M+H) ⁺

Example 8 enzyme and cell assays

In vitro assay of IDH1m (R132H or R132C) inhibitors

Experimental procedures that may be used to obtain the data on columns 2 and 4 of table 7 and column 2 of table 8 are described below.

In the primary reaction, the reduction of alpha-KG acid to 2-HG is accompanied by the 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 a highly fluorescent resorufin. The uninhibited reaction exhibited low fluorescence at the end of the assay, whereas the reaction in which NADPH was consumed by R132H IDH1 had been inhibited by small molecules exhibited high fluorescence.

The primary reaction was performed in a volume of 50. Mu.L of 1 Xbuffer (150 mM NaCl, 20mM Tris 7.5, 10mM MgCl) ₂ 0.05% (w/v) bovine serum albumin) in a buffer containing 0.25. Mu.g/mL (2.7 nM) IDH1 wt/IDH 1R 132H heterodimer, 0.3mM alpha-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 pre-incubated for 1 hour at room temperature, followed by the addition of alpha-ketoglutarate. 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 for an additional 5 minutes at 25 ℃. Fluorescence was read on a Spectramax reader at Ex 544em 590. Dilutions of one or more compounds were prepared in 100% dmso concentration and diluted 1:50 to final reactants. IDH1 wt/IDH 1R 132C was determined under similar conditions, except that the 1 Xbuffer was 50mM K ₂ HPO ₄ ，pH 6.5；10mM MgCl ₂ The method comprises the steps of carrying out a first treatment on the surface of the 10% glycerol; 0.03% (w/v) bovine serum albumin and final concentration was 0.4. Mu.g/mL (4.3 nM) IDH1 wt/IDH 1R 132C heterodimer, 0.02mM alpha-ketoglutarate, 4. Mu.M NADPH, and either 300. Mu.M NADP (saturated) or 30. Mu.M NADP (unsaturated). The IC50 was measured.

IDH1 or IDH2 wild-type (wt) and mutant heterodimers are 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 performed in sf9 insect cells. Cells (25 g) were resuspended in 250ml 50mM Tirs, 500mM NaCl,pH 7.4 with stirring at 4 ℃. Cells were disrupted by passing them through an M-Y110 microfluidizer (Microfluidics) set at 500psi 4 times and then centrifuged at 22,000rcf for 20 minutes at 4 ℃. The supernatant was collected and loaded at 15cm/h onto a Hiscap FF 5 x 1ml column (GE) equilibrated with 50mM Tirs, 500mM NaCl,pH 7.4. Host cell contaminants were removed to baseline by washing the column with equilibration buffer containing 20mM imidazole followed by equilibration buffer containing 60mM imidazole. IDH1wt-his homodimers and IDH1wt-h were eluted by equilibration buffer containing 250mM imidazoleis/IDH1R 132C-tag. Fractions eluted by 250mM imidazole were pooled together and loaded at 15cm/h to 10mlM2 affinity gel (Sigma) on a pre-filled column equilibrated with 50mM Tris, 500mM NaCl,pH 7.4. After washing with equilibration buffer, the IDH1wt-his/IDH1R 132C-tag heterodimer was eluted through equilibration buffer containing tag peptide (0.2 mg/ml). An aliquot of IDH1wt-his/IDH1R 132C-tag was flash frozen in liquid N ₂ And stored at-80 ℃. The same conditions were used to purify the IDH1wt-his/IDH1R 132H-tag.

In vitro assay of IDH1m (R132H or R132C) inhibitors

Experimental procedures that may 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 in DMSO to a final concentration of 50X to give 50 μl of reaction mixture. The IDH enzyme activity to convert alpha-ketoglutarate to 2-hydroxyglutarate was measured using an NADPH depletion assay. In this assay, at the end of the reaction, the remaining cofactor is measured by adding a catalytic excess of diaphorase and resazurin to generate a fluorescent signal proportional to the residual amount of NADPH. In 40. Mu.l assay buffer (150 mM NaCl, 20mM Tris-Cl pH 7.5, 10mM MgCl) ₂ IDH1-R132 homodimerase was diluted to 0.125 μg/ml in 0.05% bsa, 2mM β -mercaptoethanol; mu.l of test compound dilution in DMSO was added and the mixture incubated at room temperature for 60 minutes. The reaction was started with the addition of 10 μl of substrate mixture (20 μl NADPH, 5mM α -ketoglutarate in assay buffer) and the mixture was incubated for 90 min at room temperature. The reaction was stopped with the addition of 25 μl detection buffer (36 μg/ml diaphorase, 30mM resazurin in 1 Xassay buffer) and incubated for 1 min before reading on a SpectraMax reader at Ex544/Em 590.

The activity of these compounds against IDH 1R 132C was determined following the same assay as above, but with the following modifications: the assay buffer was (50 mM potassium phosphate, pH 6.5;40mM carbonSodium acid, 5mM MgCl ₂ 10% glycerol, 2mM beta-mercaptoethanol, and 0.03% BSA). The concentrations of NADPH and alpha-ketoglutarate in the substrate buffer were 20. Mu.M and 1mM, respectively.

In vitro assay of IDH1m (R132H or R132C) inhibitors

Experimental procedures that may 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 in DMSO to a final concentration of 50X to give 50 μl of reaction mixture. The IDH enzyme activity to convert alpha-ketoglutarate to 2-hydroxyglutarate was measured using an NADPH depletion assay. In this assay, at the end of the reaction, the remaining cofactor is measured by adding a catalytic excess of diaphorase and resazurin to generate a fluorescent signal proportional to the residual amount of NADPH. In 40. Mu.l assay buffer (150 mM NaCl, 20mM Tris-Cl pH 7.5, 10mM MgCl) containing 5. Mu.M NADPH and 37.5. Mu.M NADP ₂ The IDH1-R132H homodimeric enzyme was diluted to 0.125. Mu.g/ml in 0.05% BSA, 2mM beta-mercaptoethanol); mu.l of test compound dilution in DMSO was added and the mixture incubated at room temperature for 60 minutes. The reaction was started with the addition of 10 μl of substrate mixture (20 μl NADPH, 5mM α -ketoglutarate in assay buffer) and the mixture was incubated for 60 min at room temperature. The reaction was stopped with the addition of 25 μl detection buffer (36 μg/ml diaphorase, 30mM resazurin in 1 Xassay buffer) and incubated for 1 min before reading on a SpectraMax reader at Ex544/Em 590.

The activity of these compounds against IDH 1R 132C was determined following the same assay as above, but with the following modifications: in 40. Mu.l assay buffer (50 mM potassium phosphate, pH 6.5;40mM sodium carbonate, 5mM MgCl) containing 5. Mu.M NADPH and 28.75. Mu.M NADP ₂ IDH1-R132C homodimerase was diluted to 0.1875. Mu.g/ml in 10% glycerol, 2mM beta-mercaptoethanol, and 0.03% BSA). The concentration of alpha-ketoglutarate in the substrate buffer was 1mM.

In vitro assay for IDH2m R140Q inhibitors

Experimental procedures that may be used to obtain the data on column 7 of table 7 are described below.

The IDH 2R 140Q inhibitory activity of these compounds was determined by a cofactor depletion assay. The compounds were pre-incubated with enzyme, then the reaction was started by adding NADPH and a-KG, and allowed to proceed for 60 minutes under conditions that previously confirmed linearity with respect to the time spent on both cofactor and substrate. The reaction was stopped by adding a second enzyme diaphorase and the corresponding substrate resazurin. Diaphorase reduces resazurin to highly fluorescent resorufin and NADPH concomitantly oxidizes to NADP, both of which interrupt IDH2 reaction by depleting the pool of available cofactors and promote quantitative production by readily detectable fluorophores, quantifying the amount of cofactor remaining after a specific period of time.

Specifically, 1. Mu.l of 100 XCompound dilution series was placed into each of 12 wells of 384-well plates, followed by addition of 40. Mu.l of buffer containing 0.25. Mu.g/ml IDH 2R 140Q protein (50 mM potassium phosphate (K) ₂ HPO ₄ )，pH 7.5；150mM NaCl；10mM MgCl ₂ 10% glycerol, 0.05% bovine serum albumin, 2mM beta-mercaptoethanol). The test compound is then incubated with the enzyme for one hour at room temperature; the IDH2 reaction was then started by adding 10. Mu.l of substrate mixture containing 4. Mu.M NADPH and 1.6mM alpha-KG in the buffer described above. After an additional 16 hours incubation at room temperature, the reaction was discontinued and the residual NADPH was measured by adding 25. Mu.l of a stop mixture (36. Mu.g/ml diaphorase and 60. Mu.M resazurin; in buffer) to convert resazurin into resorufin. After one minute incubation, the plate was read on a plate reader at Ex544/Em 590.

To determine the inhibitory potency of these compounds against IDH 2R 140Q in a format similar to the assay above, a similar procedure was performed except that the final test concentrate was 0.25. Mu.g/ml IDH 2R 140Q protein, 4. Mu.M NADPH, and 1.6mM alpha-KG.

To determine the inhibitory potency of these compounds against IDH 2R 140Q in a high throughput screening format, a similar procedure was performed except that 0.25. Mu.g/ml IDH 2R 140Q protein was used in the pre-incubation step and the reaction was started with the addition of 4. Mu.M NADPH and 8. Mu.M. Alpha. -KG.

In vitro assay for IDH2m R140Q inhibitors

Experimental procedures that may be used to obtain the data on column 6 of table 8 are described below.

The IDH 2R 140Q inhibitory activity of these compounds was determined by a cofactor depletion assay. These compounds were pre-incubated with enzyme and cofactor, then the reaction was started by adding α -KG and allowed to proceed for 60 minutes under conditions that were previously confirmed to be linear. The reaction was stopped by adding a second enzyme diaphorase and the corresponding substrate resazurin. Diaphorase reduces resazurin to highly fluorescent resorufin and NADPH concomitantly oxidizes to NADP, both of which interrupt IDH2 reaction by depleting the pool of available cofactors and promote quantitative production by readily detectable fluorophores, quantifying the amount of cofactor remaining after a specific period of time.

Specifically, 1. Mu.l of a 50 Xdilution series of the compound was placed into each of 12 wells of 384-well plates, followed by the addition of 40. Mu.l of buffer (50 mM potassium phosphate (K) ₂ HPO ₄ )，pH 7.5；150mM NaCl；10mM MgCl ₂ 10% glycerol, 0.05% bovine serum albumin, 2mM beta-mercaptoethanol). The test compound was then incubated with enzyme and cofactor for 16 hours at room temperature, and then IDH2 reaction was started by adding 10 μl of substrate mixture containing 8mM α -KG (final concentration 1.6 mM) in the buffer described above. After an additional 1 hour incubation at room temperature, the reaction was discontinued and the residual NADPH was measured by adding 25. Mu.l of a stop mixture (36. Mu.g/ml diaphorase and 60. Mu.M resazurin; in buffer) to convert resazurin to resorufin. After one minute incubation, the plate was read on a plate reader at Ex544/Em 590.

Cell assay of IDH1m (R132H or R132C) inhibitors

Experimental procedures that may be used to obtain the data on column 5 of table 7 are described below.

Cells (HT 1080 or U87 MG) were grown in T125 flasks in DMEM containing 10% FBS, 1 Xpenicillin/streptomycin and 500. Mu.g/mL G418 (present only in U87MG cells). They were collected by trypsin and inoculated at a density of 5000 cells/well into DMEM containing 10% fbs in 96-well white bottom plate at 100 μl/well.Cells were not discharged in columns 1 and 12. At 37℃at 5% CO ₂ Cells were incubated overnight. The next day, 2x final concentration of test compound was made and 100 μl 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 μl of medium was removed from each well and analyzed for 2-HG concentration by LC-MS. The cell plates were 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 of each well. The cell plates were then placed on an orbital shaker for 10 minutes and then allowed to stand at room temperature for 20 minutes. The luminescence of the plate over the 500ms integration time is then read.

Assay based on U87MG pLVX-IDH 2R 140Q-neo and HT1080 cells

The experimental procedure used to obtain the data on column 8 of table 7 is described below.

U87MG pLVX-IDH 2R 140Q-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, 1 Xpenicillin/streptomycin. Cells were seeded at a density of 5,000 (U87 MG R140Q) or 2,500 (HT 1080) cells/well in 96 well microtiter plates and incubated at 37℃and 5% CO ₂ Incubate overnight. The following day, compounds were prepared in 100% dmso and then diluted in culture medium to obtain a final concentration of 0.2% dmso. The medium was removed from the cell plate and 200 μl of compound dilution was added to each well. After 48 hours incubation of the compounds at 37 ℃, 100 μl of medium was removed from each well and 2-HG concentration was analyzed by LC-MS as described in Dang, l. (Dang, l.), et al Nature (Nature), 2009,462,739-744. The cell plates were then allowed to incubate for an additional 24 hours. 72 hours after compound addition, a prasugrel 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 )。

Cell assay of IDH1m R132H inhibitors.

Experimental procedures that may be used to obtain the data on column 4 of table 8 are described below.

Neurosphere cells (TS 603) were incubated at 37℃with 5% CO ₂ In stem cell technology NeuroCurt supplemented with 1% Primocin, 1% Normocin, 0.0002% heparin, 20ng/mL EGF and 10ng/mL bFGF ^TM Grown in NS-A medium. Cells were collected, pelleted and resuspended in almus (Accumax) for cell dissociation and enumeration. Cells were counted and then resuspended in NeuroCult medium containing 2x heparin, EGF and bFGF at 4 million cells per 10mL medium. Mu.l of the cell solution was plated in each of the 96 wells except for columns 1 and 12. Columns 1 and 12 contain 200 μl 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 alone were coated in row H. The plates were then placed in an incubator for 48 hours. At 48 hours, 100 μl of medium was removed from each well and analyzed for 2-HG concentration by LC-MS. The cell plates were returned to the incubator for an additional 24 hours. 72 hours after compound addition, the 10 mL/plate of the pluripotency 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 of each well. The cell plates were then placed on an orbital shaker for 10 minutes and then allowed to stand at room temperature for 20 minutes. The luminescence of the plate over the 500ms integration time is then read.

The data for the different compounds of one aspect of the application in the R132H enzyme assay, R132C enzyme assay, R140Q enzyme assay, R132C cell-based assay, and R140Q cell-based assay or the like as described above are presented in tables 7 and 8 below. For each assay, a value indicated as "a" represents an IC50 of less than 50 nM; the value indicated as "B" represents an IC50 between 50nM and 100 nM; the value indicated as "C" represents an IC50 of greater than 100nM and less than 1 μM; the value indicated as "D" represents an IC50 of 1. Mu.M or more; the value indicated as "unsuitable" 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

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TABLE 8 inhibitory Activity of representative Compounds of formula I

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In summary, the present application relates to the following aspects:

1. a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

x is N, CH or C-halo;

wherein:

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

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

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

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

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

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

2. A compound of formula Ia or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

(i) When A is optionally substituted phenyl then (a) N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ NH ₂ Or 4- [ [2- [2- (2-aminoethoxy) ethoxy ]]Ethyl group]Amino group]And (b) N (R) ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Not both NHEt, NH (n-propyl), NH (n-butyl), NH (n-dodecyl), NH- [ (4-methoxyphenyl) methyl ]、NHCH ₂ CH ₂ CHO、NHCH ₂ CH ₂ OCH ₃ 、NHCH ₂ CH ₂ OH、NHCH ₂ CH(OH)CH ₃ 、NHCH ₂ CH ₂ OC (O) phenyl, NHCH ₂ CH ₂ CH ₂ OH、NHCH ₂ CH ₂ CH ₂ N(CH ₃ ) Phenyl, NHCH ₂ C(O)OCH ₃ 、NHCH ₂ C(O)OCH ₂ CH ₃ 、NHCH ₂ Phenyl, NHCH (CH) ₃ )CH ₂ CH ₃ Or NHCH ₂ CH ₂ OC(O)CH ₃ ；

(ii) When A is an optionally substituted pyridinyl group then (A) N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither NHC (O) - [ 2-chloro-4- (methylsulfonyl)]、N(CH ₃ ) ₂ 、NHCH ₂ CH ₂ CH ₂ SO ₂ CH ₂ CH ₂ Cl、NHCH ₂ CH ₂ OCH ₂ CH ₂ SO ₂ CH ₂ CH ₂ Cl or NHCH ₂ CH ₂ SO ₂ CH ₂ CH ₂ Cl；(B)N(R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHC (O) C (CH ₃ ) ₃ 、NHC(O)CH＝CH ₂ 、NHC(O)C(CH ₃ )＝CH ₂ 、NHCH ₂ CH ₂ OH, NH-cyclohexyl, NHCH ₂ -phenyl group,NHC (O) phenyl, NHC (O) (CH ₂ ) ₅ NH ₂ 、NHC(O)OCH ₃ 、NHC(O)CH ₃ And NHC (O) NH-optionally substituted phenyl; and (C) when N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) Is NHC (CH) ₃ ) ₃ When then N (R ⁸ )C(R ¹ )(R ² )(R ³ ) Not NHCH ₂ -phenyl or NH-CH ₂ CH ₃ ；

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

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

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

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

(40) α - [ [4- [ [ (3-chlorophenyl) methyl ] amino ] -6- (1H-imidazol-1-yl) -1,3, 5-triazin-2-yl ] amino ] -N- [ [4- (trifluoromethyl) phenyl ] methyl ] -, (αr) -cyclohexanecalamide.

3. The compound of item 2, wherein

R ¹ 、R ³ 、R ⁴ And R is ⁶ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, -O-C ₁ -C ₄ Alkyl and CN, wherein R ¹ 、R ³ 、R ⁴ And R is ⁶ Each of said alkyl moieties independently being optionally substituted with-OH, -NH ₂ 、-CN、-O-C ₁ -C ₄ Alkyl, -NH (C) ₁ -C ₄ Alkyl) or-N (C) ₁ -C ₄ Alkyl group ₂ Substitution; and is also provided with

R ² And R is ⁵ Each independently selected from: -C ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₁ -C ₆ Alkyl) -CO ₂ H、-(C ₂ -C ₆ Alkenyl or alkynyl) - (C) ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkyl) and- (C) ₀ -C ₆ Alkylene) -C (O) - (C) ₁ -C ₆ Alkyl), wherein:

exists in R ² And R is ⁵ Any alkyl or alkylene moiety of (C) is optionally substituted with one or more-OH, -O (C) ₁ -C ₄ Alkyl) -CO ₂ H or halo; and is also provided with

R ⁴ And R is ⁵ Optionally together form an optionally substituted carbocyclyl,

wherein when A is an optionally substituted phenyl, 2-pyrrolyl or 1-imidazolyl group then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Is different 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.

4. The compound of item 2, wherein a is a substituted 5-6 membered monocyclic aryl or monocyclic heteroaryl, which is substituted with up to two substituents independently selected from halo, -C ₁ -C ₄ Alkyl, -C ₁ -C ₄ Haloalkyl, -C ₁ -C ₄ Hydroxyalkyl, -NH-S (O) ₂ -(C ₁ -C ₄ Alkyl), -S (O) ₂ NH(C ₁ -C ₄ Alkyl), -CN, -S (O) ₂ -(C ₁ -C ₄ Alkyl group, C ₁ -C ₄ Alkoxy, -NH (C) ₁ -C ₄ Alkyl), -OH, -OCF ₃ 、-CN、-NH ₂ 、-C(O)NH ₂ 、-C(O)NH(C ₁ -C ₄ Alkyl), -C (O) -N (C) ₁ -C ₄ Alkyl group ₂ 、-(C ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl), azetidinyl, phenyl andcyclopropyl optionally substituted with OH.

5. A compound of formula B, or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

x is N, CH or C-halo;

R ² and R is ⁵ Each independently selected from: - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₁ -C ₆ Alkyl) -CO ₂ H _、 -(C ₂ -C ₆ Alkenyl or alkynyl) - (C) ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkyl group),

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

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

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

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

6. The compound of item 5, wherein R ⁴ And R is ⁵ Optionally together form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl.

7. A compound of formula C, or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

x is N, CH or C-halo;

each X is ^b Is independently N-R ^9b O, S, C-H or C-R ^9c Provided that at least one X ^b Is C-R ^9c And when an X ^b Is C-H or C-R ^9c And the other is C-R ^9c Then X is ^c Is N; and when an X ^b Is N-R ^9b When O or S, then X ^c Is C;

R ^9b is hydrogen or-C ₁ -C ₄ An alkyl group;

R ^9c is halo, -C ₁ -C ₄ Alkyl, -C ₁ -C ₄ Haloalkyl, -C ₁ -C ₄ Hydroxyalkyl, -NH-S (O) ₂ -(C ₁ -C ₄ Alkyl), -S (O) ₂ NH(C ₁ -C ₄ Alkyl), -CN, -S (O) ₂ -(C ₁ -C ₄ Alkyl group, C ₁ -C ₄ Alkoxy, -NH (C) ₁ -C ₄ Alkyl), -N (C) ₁ -C ₄ Alkyl group ₂ 、-OH、-OCF ₃ 、-CN、-NH ₂ 、-C(O)NH ₂ 、-C(O)NH(C ₁ -C ₄ Alkyl), -C (O) -N (C) ₁ -C ₄ Alkyl group ₂ 、-(C ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl), aryl, and cyclopropyl optionally substituted with OH;

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(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NH (CH) ₂ ) ₇ CH ₃ 、NHCH ₂ - (o-chloro-phenyl)) Or NHCH ₂ CH ₂ OH; and is also provided with

(ii) When X and X ^c All are N, then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is N (CH) ₃ ) ₂ 、NHCH ₃ Or N (CH) ₂ CH ₃ ) ₂ 。

8. The compound of item 7, wherein:

R ^9c is halo, -OH, CN, -NH ₂ 、-O-C ₁ -C ₄ Alkyl, -NH (C) ₁ -C ₄ Alkyl), -N (C) ₁ -C ₄ Alkyl group ₂ 、-C ₁ -C ₄ Alkyl, -C ₁ -C ₄ Haloalkyl and- (C) ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ An alkyl group);

R ¹ and R is ⁴ Each is hydrogen;

R ³ and R is ⁶ Each independently selected from C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, -O-C ₁ -C ₄ Alkyl and CN; and is also provided with

R ² And R is ⁵ Each is- (C) ₁ -C ₆ Alkyl), wherein:

exists in R ² And R is ⁵ Optionally substituted with one or more-OH, -O (C) ₁ -C ₄ Alkyl) -CO ₂ H or halo; and is present in R ² And R is ⁵ Any terminal methyl moiety in (a) is optionally substituted with-CH ₂ OH、CF ₃ 、-CH ₂ F、-CH ₂ Cl、C(O)CH ₃ 、C(O)CF ₃ CN or CO ₂ H replacement.

9. The compound of item 7, wherein R ¹ And R is ⁴ Each independently selected from C ₁ -C ₄ Alkyl and C ₁ -C ₄ Haloalkyl, and R ² And R is ⁵ Each is- (C) ₁ -C ₆ Alkyl).

10. The compound of item 1 or 2, wherein R ³ And R is ⁶ Are all hydrogen, R ¹ And R is ⁴ Each independently selected from C ₁ -C ₄ Alkyl and C ₁ -C ₄ Haloalkyl, and R ² And R is ⁵ Each is- (C) ₁ -C ₆ Alkyl).

11. A compound having the formula III, or a pharmaceutically acceptable salt or hydrate thereof:

wherein:

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

12. The compound of item 11 wherein G is substituted with 1 or 2 substituents selected from halo, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, -CN, =o, -OH, aryl, heteroaryl-SO ₂ C ₁ -C ₄ Alkyl, -CO ₂ C ₁ -C ₄ Alkyl, -C (O) aryl and-C (O) C ₁ -C ₄ An alkyl group.

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

14. The composition of claim 13, further comprising a second therapeutic agent useful in the treatment of cancer.

15. A method of treating cancer characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation contributes to a novel ability of the enzyme to catalyze the NAPH-dependent reduction of alpha-ketoglutarate to R (-) -2-hydroxyglutarate in a patient, comprising the step of administering to the patient in need thereof a composition of claim 13.

16. The method of claim 15, wherein the IDH1 mutation is an IDH 1R 132H or R132C mutation.

17. The method of claim 16, wherein in the patient the cancer is selected from 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).

18. The method of claim 16, further comprising administering to the patient in need thereof a second therapeutic agent useful for the treatment of cancer.

Having thus described several aspects of several embodiments of the 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 process for preparing a compound of formula (Ia), wherein:

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, -C ₁ -C ₄ Alkyl, -C ₁ -C ₄ Haloalkyl, -C ₁ -C ₄ Hydroxyalkyl, -NH-S (O) ₂ -(C ₁ -C ₄ Alkyl), -S (O) ₂ NH(C ₁ -C ₄ Alkyl), -CN, -S (O) ₂ -(C ₁ -C ₄ Alkyl group, C ₁ -C ₄ Alkoxy, -NH (C) ₁ -C ₄ Alkyl), -OH, -OCF ₃ 、-NH ₂ 、-C(O)NH ₂ 、-C(O)NH(C ₁ -C ₄ Alkyl), -C (O) -N (C) ₁ -C ₄ Alkyl group ₂ Cyclopropyl optionally substituted with OH;

R ¹ 、R ³ 、R ⁴ and R is ⁶ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, -O-C ₁ -C ₄ Alkyl and CN, wherein R ¹ 、R ³ 、R ⁴ And R is ⁶ Each of said alkyl moieties is independently optionally substituted with-OH, -CN, -O-C ₁ -C ₄ Alkyl, -NH (C) ₁ -C ₄ Alkyl) or-N (C) ₁ -C ₄ Alkyl group ₂ Substitution;

R ² and R is ⁵ Each independently selected from: - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₂ -C ₆ Alkenyl) or- (C) ₂ -C ₆ Alkynyl) - (C) ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -Q- (C ₀ -C ₆ Alkylene) -C (O) - (C) ₁ -C ₆ Alkyl), wherein:

q is selected from carbocyclyl and heterocyclyl, any of which is substituted with 0-3 of the following groups: halo, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, =o, -C (O) -C ₁ -C ₄ Alkyl and CN; wherein the method comprises the steps of

R ¹ And R is ² Optionally together form a carbocyclyl or heterocyclyl, any of which is optionally substituted with up to 3 substituents independently selected from halo, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, -CN, =o, -OH, aryl, heteroaryl, -SO ₂ C ₁ -C ₄ Alkyl, -CO ₂ C ₁ -C ₄ Alkyl, -C (O) aryl and-C (O) C ₁ -C ₄ An alkyl group; or (b)

R ⁴ And R is ⁵ Optionally together form a carbocyclyl or heterocyclyl, any of which is optionally substituted with up to 3 substituents independently selected from halo, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, -CN, =o, -OH, aryl, heteroaryl, -SO ₂ C ₁ -C ₄ Alkyl, -CO ₂ C ₁ -C ₄ Alkyl, -C (O) aryl and-C (O) C ₁ -C ₄ An alkyl group;

R ⁷ and R is ⁸ Is hydrogen;

wherein:

"alkyl" refers to a fully saturated hydrocarbon chain, which is straight or branched;

"haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with a halo group;

"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 is the point of attachment of an alkenyl substituent;

"alkynyl" refers to a straight or branched hydrocarbon chain having one or more triple bonds;

"aryl" refers to phenyl, naphthyl, or anthracenyl, wherein any carbon atom is optionally substituted;

"carbocyclyl" refers to a saturated monocyclic, bicyclic, or tricyclic hydrocarbon group having 3 to 12 carbons;

"heteroaryl" means 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;

"heterocyclyl" means a non-aromatic 3-to 10-membered monocyclic, 8-to 12-membered bicyclic or 11-to 14-membered tricyclic ring system if the monocyclic ring has 1-3 heteroatoms, if the bicyclic ring has 1-6 heteroatoms, or if the tricyclic ring has 1-9 heteroatoms, said heteroatoms selected from O, N or S, wherein the heteroatoms are points of attachment of the heterocyclyl substituents;

and wherein:

(i) When A is optionally substituted pyridinyl as described above, then (A) N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHCH ₂ CH ₂ OH or NH-cyclohexyl; and (B) when N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) Is NHC (CH) ₃ ) ₃ When then N (R ⁸ )C(R ¹ )(R ² )(R ³ ) Not NH-CH ₂ CH ₃ ；

(ii) When a is heteroaryl optionally substituted as described above selected from pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and thiazolyl, then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHCH ₂ CH ₂ Isopropyl or NHCH ₂ CH(CH ₃ ) ₂ ；

(iii) When A is optionally substituted 1-pyrazolyl as described above, then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither NH isopropyl or NHCH ₂ CH ₃ ，

(iv) When A is substituted 1-pyrazolyl, then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Neither is NHC (CH ₃ ) ₃ ；

(v) When A is optionally substituted phenyl then N (R ⁷ )C(R ⁴ )(R ⁵ )(R ⁶ ) And N (R) ⁸ )C(R ¹ )(R ² )(R ³ ) Different; and

(vi) The compound being other than N ² -isopropyl-6-phenyl-N4- (tetrahydro-2H-pyran-4-yl) -1,3, 5-triazine-2, 4-diamine;

The method includes causingThe reaction is carried out between the two components,

wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ And R is ⁶ As defined above in the present claims.

2. The method of claim 1, whereinPrepared by the following method: the method includes causingThe reaction is carried out between the two.

3. The method according to claim 2, wherein the method comprises,

wherein the method comprises the steps ofPrepared by a process comprising subjecting ++>With PCl ₅ Or POCl ₃ Reaction of->Is prepared by a process comprising reacting ++under alkaline conditions>The reaction is carried out between the two.

4. A process for preparing a compound of formula (Ia), wherein:

R ² and R is ⁵ Each independently selected from: - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₂ -C ₆ Alkenyl) or- (C) ₂ -C ₆ Alkynyl) - (C) ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C(O)N(R ⁶ )-(C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -Q- (C ₀ -C ₆ Alkylene) -C (O) - (C) ₁ -C ₆ Alkyl), wherein:

R ⁷ and R is ⁸ Is hydrogen;

wherein:

"alkylene" refers to a divalent alkyl group;

And wherein:

5. The method of claim 4, whereinPrepared by the following method: the method comprises the steps of>And->The reaction is carried out between the two.

6. The method of claim 1 or 4, wherein

R ¹ 、R ³ 、R ⁴ And R is ⁶ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, -O-C ₁ -C ₄ Alkyl and CN, wherein R ¹ 、R ³ 、R ⁴ And R is ⁶ Each of said alkyl moieties of (a) is independently substituted with: -OH, -CN, -O-C ₁ -C ₄ Alkyl, -NH (C) ₁ -C ₄ Alkyl) or-N (C) ₁ -C ₄ Alkyl group ₂ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

R ² And R is ⁵ Each independently selected from: - (C) ₁ -C ₆ Alkyl) - (C) ₁ -C ₆ Alkyl) -C (O) -NH ₂ 、-(C ₂ -C ₆ Alkenyl) or- (C) ₂ -C ₆ Alkynyl) - (C) ₁ -C ₆ Alkylene) -O- (C ₁ -C ₆ Alkyl) - (C) ₀ -C ₆ Alkylene) -C (O) N (R) ⁶ )-(C ₁ -C ₆ Alkyl) and- (C) ₀ -C ₆ Alkylene) -C (O) - (C) ₁ -C ₆ Alkyl), wherein:

exists in R ² And R is ⁵ Any alkyl or alkylene moiety in (C) is substituted with-OH, -O (C) ₁ -C ₄ Alkyl) -CO ₂ H or halo; and is also provided with

Exists in R ² And R is ⁵ Any terminal methyl moiety in (a) is substituted with-CH ₂ OH、CF ₃ 、-CH ₂ F、-CH ₂ Cl、C(O)CH ₃ 、C(O)CF ₃ CN or CO ₂ H replacement;

or R is ¹ And R is ² Taken together, form a carbocyclyl group substituted with 0 to 3 substituents independently selected from the group consisting of: halogen radical、C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, -CN, =o, -OH, and-C (O) -C ₁ -C ₄ An alkyl group; or (b)

Or R is ⁴ And R is ⁵ Taken together, form a carbocyclyl group substituted with 0 to 3 substituents independently selected from the group consisting of: halo, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, -CN, =o, -OH, and-C (O) -C ₁ -C ₄ An alkyl group.

7. The method of claim 1 or 4, wherein ring a is:wherein R is ⁹ Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group; each X is ^a Independently N or C-R ^9a Provided that when one X ^a When N is then two other X ^a Are all C-R ^9a The method comprises the steps of carrying out a first treatment on the surface of the And R is ^9a Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group.

8. The method of claim 1 or 4, wherein ring a is:wherein R is ⁹ Selected from hydrogen, halo and-C ₁ -C ₄ A haloalkyl group.

9. The method of claim 1 or 4, wherein R ¹ 、R ³ 、R ⁴ And R is ⁶ Each independently selected from hydrogen, C ₁ -C ₄ Alkyl and-CN, wherein R ¹ 、R ³ 、R ⁴ And R is ⁶ Each of said alkyl moieties of (E) is independently of the others-OH, -CN or-O-C ₁ -C ₄ Alkyl substitution; and R is ² And R is ⁵ Each independently selected from- (C) ₁ -C ₆ Alkyl) and- (C) ₀ -C ₆ Alkylene) -Q.

10. The method of claim 1 or 4 wherein Q is selected from the group consisting of tetrahydrofuranyl, cyclobutyl, cyclopropyl, morpholinyl, and oxetanyl, wherein Q is substituted with 0-2 substituents independently selected from the group consisting of C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, =o, fluorine, chlorine and bromine.

11. The method of claim 10 wherein Q is cyclopropyl.

12. The method of claim 1 or 4, wherein R ¹ And R is ² Together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo [2.2.1]Heptyl, oxo-bicyclo [3.1.0]Hexyl, azetidinyl, any of which is substituted with 0-2 substituents independently selected from C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy, -OH, -C (O) CH ₃ Fluorine and chlorine.

13. The method of claim 1 or 4, wherein R ⁴ And R is ⁵ Together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo [2.2.1]Heptyl, oxo-bicyclo [3.1.0]Hexyl or azetidinyl, any of which is substituted with 0-2 substituents independently selected from C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy, -OH, -C (O) CH ₃ Fluorine and chlorine.

14. The method of claim 1 or 4, wherein the compound is