Therapeutically active compounds and their methods of use

Abstract

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

Description

[0001] Attorney Docket Number: C2081 -

[0002] THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE

[0003] CLAIM OF PRIORITY

[0004] This application claims priority from International Application Serial No.

[0005] PCT / CN2013 / 079200 filed July 11, 2013, which is incorporated herein by reference in its entirety.

[0006] BACKGROUND OF INVENTION

[0007] Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate {i.e., a-ketoglutarate). These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer.

[0008] IDH1 (isocitrate dehydrogenase 1 (NADP+), cytosolic) is also known as IDH; IDP; IDCD; IDPC or PICD. The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-dienoyl- CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namelythe alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production.

[0009] The human IDHl gene encodes a protein of 414 amino acids. The nucleotide and amino acid sequences for human IDHl can be found as GenBank entries NM 005896.2 and

[0010] NP 005887.2 respectively. The nucleotide and amino acid sequences for IDHl are also described in, e.g., Nekrutenko etal, Mol. Biol. Evol. 15:1674-1684(1998); Geisbrecht et a / ., J. Biol. Chem. 274:30527-30533(1999); Wiemann et al, Genome Res. 11 :422-435(2001); The MGC Project Team, Genome Res. 14:2121-2127(2004); Lubec et al, Submitted (DEC-2008) toUniProtKB; Kullmann etal., Submitted (JUN-1996) to the EMBL / GenBank / DDBJ databases; and Sjoeblom eta / ., Science 314:268-274(2006).

[0011] Non-mutant, e.g., wild type, IDH1 catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate thereby reducing NAD+(NADP+) to NADH (NADPH), e.g., in the forward reaction:

[0012] Isocitrate + NAD+(NADP+)→ a-KG + C02+ NADH (NADPH) + H+.

[0013] It has been discovered that mutations of IDH1 present in certain cancer cells result in a new ability of the enzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate to R(-)- 2-hydroxyglutarate (2HG). The production of 2HG is believed to contribute to the formation and progression of cancer (Dang, L et al., Nature 2009, 462:739-44).

[0014] IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial) is also known as IDH; IDP; IDHM; IDPM; ICD-M; or mNADP-IDH. The protein encoded by this gene is the

[0015] NADP(+)-dependent isocitrate dehydrogenase found in the mitochondria. It plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with the pyruvate dehydrogenase complex. Human IDH2 gene encodes a protein of 452 amino acids. The nucleotide and amino acid sequences for IDH2 can be found as GenBank entries NM_002168.2 and NP_002159.2 respectively. The nucleotide and amino acid sequence for human IDH2 are also described in, e.g., Huh et al, Submitted (NOV-1992) to the

[0016] EMBL / GenBank / DDBJ databases; and The MGC Project Team, Genome Res.

[0017] 14:2121 -2127(2004).

[0018] Non-mutant, e.g., wild type, IDH2 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (a-KG) thereby reducing NAD+(NADP+) to NADH(NADPH), e.g., in the forward reaction:

[0019] Isocitrate + NAD+(NADP+)→ a-KG + C02+ NADH (NADPH) + H+. It has been discovered that mutations of IDH2 present in certain cancer cells result in a new ability of the enzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate to R{-) -2-hydroxyglutarate (2HG). 2HG is not formed by wild-type IDH2. The production of 2HG is believed to contribute to the formation and progression of cancer (Dang, L et al, Nature 2009, 462:739-44).The inhibition of mutant IDH1 and / or mutant IDH2 and their neoactivity is therefore a potential therapeutic treatment for cancer. Accordingly, there is an ongoing need for inhibitors of IDHland / orIDH2 mutants having alpha hydroxyl neoactivity.

[0020] SUMMARY OF INVENTION

[0021] Described herein are compounds of Formula I, or a pharmaceutically acceptable salt or hydrate thereof:

[0022] (I), wherein:

[0023] ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;

[0024] X is N, CH or C-halo;

[0025] R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, -O-C1-C4alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0026] R2and R5are each independently selected from: -(Ci-d alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(d-

[0027] C6alkyl)-C02H -(C2-C6alkenyl or alkynyl), -(Ci-C6alkylene)-N(R6)-(d-C6alkylene)-0-(d-C6alkyl), -(Ci-C6alkylene)-N(R6)-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)(R6), -(Ci-C6alkylene)-N(R6)-S(0)i-2-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)-S(O)i-2-(C0-C6alkyl)-Q, -(Ci-C6alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6

[0028] alkylene)-Q, -C(0)N(R6)-(Ci-C6alkylene)-C(O)- (C0-C6alkylene)-0-(Ci-C6

[0029] alkyl), -C(0)N(R6)-(Ci-C6alkylene)-C(O)-(C0-C6alkylene)-O-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-0-C(0)-(Ci-C6alkyl), -(Ci-C6alkylene)-O-C(O)-(C0-C6alkyl)-Q, -(Ci-C6

[0030] alkylene)-0-(Ci-C6alkyl), -(Ci-C6alkylene)-0-(d-C6alkylene)-Q, -(C0-C6

[0031] alkylene)-C(O)-(C0-C6alkylene)-0-(Ci-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-O-(Ci-C6alkylene)-Q, -(Ci-C6alkylene)-0-C(0)-(d-C6alkyl), -(Ci-C6alkylene)-O-C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)N(R6)-(Ci-C6alkyl), -(Co-C6alkylene)-C(O)N(R6)-(C0-C6alkylene)-Q, -(d-C6alkylene)-N(R6)C(0)-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-S(O)0-2-(Ci-C6alkyl), -(Co-C6alkylene)-S(0)o-2-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6alkyl), -(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)-(Ci-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0032] any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(d-C4alkyl), -C02H, or halo;

[0033] any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH,

[0034] CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0035] R7and R8are each independently selected from hydrogen and Ci-C6alkyl; and

[0036] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0037] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0038] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0039] R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

[0040] R4and R5are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; wherein:

[0041] (i) when X is N and A is optionally substituted phenyl, then (a) neither

[0042] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2CH2OCH2CH2OCH2CH2NH2,4-[[2-[2- (2-aminoethoxy)ethoxy]ethyl]amino]and (b) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH2CH2CHO, NHCH2CH2OCH3, NHCH2CH2OH, NHCH2CH(OH)CH3,

[0043] NHCH2CH2OC(0)phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2N(CH3)phenyl,

[0044] NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, orNHCH2CH2OC(0)CH3;

[0045] (ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, CI or S02CH3, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(0)NH-i-propyl, NHCH(CH3)(CH2)3N(CH2CH3)2, NHCH2CH2OH, NHCH2CH2OCH3, NHCH2CH2OS03H, NHCH2CH2CH2OCH2CH20-phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2OCH3,

[0046] NHCH2CH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCH2CH2NHC(0)OCH3,

[0047] NHCH2CH2NHC(0)CH3, NHCH2CH2NH2, or NHCH2-phenyl;

[0048] (iii) when X is CH and A is optionally substituted pyridyl, then neither

[0049] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2-phenyl, NHCH2-(2,4-difluorophenyl), N(CH3)CH2CH2C(0)OH, NHCH2CH2C(0)OH, NHCH2CH2C(0)OCH2CH3,

[0050] NHCH2CH2C(0)0-t-butyl, NHCH2CH2C(0)NH2, NHCH2CH2-phenyl, NHCH2CH2OH,

[0051] NHCH2CH2NH2, NHCH2CH2N(CH3)2, or NHCH2CH2CH3;

[0052] (iv) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1 - pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor

[0053] NtR8)^1)^2)^3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH;

[0054] (v) when X is N and A is an optionally substituted pyridyl, then (A) neither

[0055] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], N(CH3)2, NHCH2CH2CH2S02CH2CH2Cl,NHCH2CH2OCH2CH2S02CH2CH2Cl,or

[0056] NHCH2CH2S02CH2CH2C1, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not

[0057] bothNHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH- cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3;

[0058] (vi) when X is N and A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;

[0059] (vii) when X is CH and A is unsubstituted 2-pyridinyl, then the ring formed by R4and R5is not 5-methyl-lH-pyrazol-3-yl;

[0060] (viii) whenA is optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor NtR8)^1)^2)^3) is N(CH3)2, NHCH3,NHAc, NHisopropyl, NHCH2CH3, NHCH2CH2S03Hor N(CH2CH3)2;

[0061] (ix) when X is N and A is optionally substituted phenyl,thienyl, or pyridinyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexylC(0)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3;

[0062] (x) when X is N, A is an optionally substituted phenyl and R4and R5form an optionally substituted phenyl, then Ν^8)^1)^2)^3) is not NHCH2(4-fluorophenyl), NHCH2C02H, NHCH2C(0)C1, NHCH(C02H)(CH2SCH2phenyl), NHCH2C(0)NHC(0)NHR or

[0063] NHCH2C(0)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl;

[0064] (xi) when X is N, A is an oxadiazole substituted with an optionally substituted pyridinyl, then R4and R5do not form an optionally substituted phenyl;

[0065] (xii) when A is substituted 1-pyrazolyl, then (A) then N(R7)C(R4)(R5)(R6) and

[0066] NtR^CtR1)^2)^3) are not both NHC(CH3)3, and (B) A is not substituted with N=N-R, wherein R is a ring;

[0067] (xiii) ring A is not an optionally substituted triazolyl, 3, 5 -dimethyl- lH-pyrazol-l -yl;

[0068] (xix) when R1and R2are optionally taken together to form an unsubstituted cyclohexyl, and R4and R5are optionally taken together to form an unsubstituted cyclohexyl, then A is not a disubstituted 1-pyrazolyl or an unsubstituted phenyl; and

[0069] (xx) the compound is not selected from the group:

[0070] (1) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-lH-inden-2-yl)amino]-6-phenyl-l,3,5- triazin-2-yl]amino]methyl]-benzamide;

[0071] (2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4- (methylsulfonyl)-benzamide;

[0072] (3) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3- yl]thio]-acetamide;

[0073] (4) N2-cyclopropyl-N4-ethyl-6-[3-[(phenylmethyl)thio]-lH-l ,2,4-triazol-l-yl]-l,3,5- triazine-2,4-diamine;

[0074] (5) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3- yl]thio]- acetic acid methyl ester;

[0075] (6) N- [ [4- [ [ [4-(cyclopropylamino)-6-(2-pyridinyl)- 1 ,3 ,5 -triazin-2- yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide;(7) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-phenyl-l,3,5-triazine-2,4- diamine;

[0076] (8) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]-l,3,5- triazine-2,4-diamine;

[0077] (9) N2,N4-dicyclohexyl-6- [3 -(3 ,4-dimethoxyphenyl)-5 -(methylthio)- 1 H-pyrazol- 1 -yl] - 1 ,3,5-triazine-2,4-diamine;

[0078] ( 10) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 - yl] - 1 ,3 , 5 -triazine-2,4-diamine;

[0079] (11) N2,N4-dicyclohexyl-6-phenyl-l,3,5-triazine-2,4-diamine;

[0080] (12) 1 ,1 '-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone];

[0081] (13) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l,l- dimethylethyl)-phenol;

[0082] (14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3- (trifluoromethyl)phenyl] amino ]carbonyl] amino]-2-methylphenyl]-l ,3,5-triazin-2-yl]-glycine;

[0083] (15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3- fluorophenyl)-l ,3,5-triazin-2- yl]amino]ethyl]- phenol;

[0084] (16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4- fluorophenyl)-l ,3,5-triazin-2- yl]amino]ethyl]- phenol;

[0085] (17) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine;

[0086] (18) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l ,3,5-triazine-2,4-diamine;

[0087] (19) 4,4'-[[6-[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]-l,3,5-triazine-2,4- diyl]bis(imino- 3,l -propanediyl)]bis[2,6-bis(l,l-dimethylethyl)-phenol;

[0088] (20) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(imino-3,l-propanediyl)]bis[2,6-bis(l,l- dimethylethyl)-phenol;

[0089] (21) N-[6-[(2,3-dihydro-lH-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]- alanine;

[0090] (22) N4-cyclopentyl-2-phenyl-N6-(phenylmethyl)-4,6-pyrimidinediamine;

[0091] (23) 2-[[6-(bicyclo[2.2.1 ]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol;

[0092] (24) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l,3,5-triazine-2,4-diamine;(25) 2-chloro-4-(me lsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l ,3,5- triazin-2-yl]-benzamide;

[0093] (26) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide;

[0094] (27) [[4-[[[[[4-amino-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]amino]methoxy]methyl]amino]- 6-(4-pyridinyl)-l ,3,5-triazin-2-yl]imino]bis-methanol;

[0095] (28) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- yl]amino]methoxy]methyl](hydroxymethyl)am

[0096] methanol;

[0097] (29) 5-[4,6-bis(diethylamino)-l ,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester;

[0098] (30) N2,N2,N*,N*-tetrae ^

[0099] (31) N,A -[6-[4-(acetylamino)-l ,2,5-oxadiazol-3-yl]-l

[0100] (32) N-(2-chloro-6-methylphenyl)-5-[[4-(dimethylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]-l ,3,4-Oxadiazole-2-carboxamide;

[0101] (33) N4-(5-methyl-lH-pyrazol-3-yl)-2-(2-pyridinyl)-N6-(tetrahydro-2H-pyran-4-yl)-4,6- Pyrimidinediamine;

[0102] (34) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3- (diethylamino)propyl]- 1 ,3,5 -Triazine-2,4-diamine;

[0103] (35) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3- (dimethylamino)propyl]- 1 ,3,5-Triazine-2,4-diamine;

[0104] (36) N2-[3,5-bis(trifluoromethyl)phenyl]-6-(4-chlorophenyl)-N4-[3- (diethylamino)propyl]- 1 ,3,5 -Triazine-2,4-diamine;

[0105] (37) N2,N4-bis[(4-methoxyphenyl)methyl]-6-[4-(trifluoromethoxy)phenyl]-l ,3,5- Triazine-2,4-diamine;

[0106] (38) N,N"-(6-phenyl-l ,3,5-triazine-2,4-diyl)bis[N'-(2-chloroethyl)-Urea;

[0107] (39) N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-methyl-3-[[4-phenyl-6-(propylamino)- l ,3,5-triazin-2-yl]amino]phenyl]-urea;

[0108] (40) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]-glycine;

[0109] (41) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2-methylphenyl]amino]-6-(5-thiazolyl)-l, 3, 5-triazin-2-yl]-L- Valine;

[0110] (42) s-Triazine, 2-phenyl-4,6-bis[[6-[[4-phenyl-6-[[6-[[4-phenyl-6-(trichloromethyl)-s- triazin-2-yl]amino]hexyl]amino]-s-triazin-2-yl]amino]hexyl]amino]-;

[0111] (43 ) α,α'- [(6-phenyl- 1,3,5 -triazine-2,4-diyl)bis [imino( 1 , 1 ,2,2-tetrafluoro-3 -oxo-3 , 1 - propanediyl)]]bis[ro-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)- 1,2-ethanediyl]];

[0112] (44) a-[[4-[[(3-chlorophenyl)methyl]amino]-6-(lH-imidazol-l -yl)-l ,3,5-triazin-2- yl]amino]-N-[[4-(trifluoromethyl)phenyl]methyl]-, (aR)-Cyclohexanepropanamide;

[0113] (45) 6-(lH-imidazol-l-yl)-N2,N4-bis(l-methyle l)-l,3,5-Triazine-2,4-diamine;and

[0114] (46) N2,N4-bis(l -methylpropyl)-6-phenyl-l ,3,5-Triazine-2,4-diamine.

[0115] The compounds of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, Π, ΙΠ, Ilia, Illb, IIIc, and Illd, or as described in any one of the embodiments herein inhibits mutant IDHlor mutant IDH2. Also described herein are pharmaceutical compositions comprising a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, Π, III, Ilia, nib, Hie, and Hid, and methods of using such compositions to treat cancers characterized by the presence of a mutant IDHl or mutant IDH2.

[0116] DETAILED DESCRIPTION

[0117] The details of construction and the arrangement of components set forth in the following description or illustrated in the drawings are not meant to be limiting. Other embodiments and different ways to practice 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.

[0118] Definitions:

[0119] The term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine.The term "alkyl" refers to a fully saturated or unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C12 alkyl indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it. The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkyl).The terms "arylalkyl" or "aralkyl" refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of "arylalkyl" or "aralkyl" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups. The term "alkyl" includes "alkenyl" and "alkynyl".

[0120] The term "alkylene" refers to a divalent alkyl,

[0121] e.g., -CH2-, -CH2CH2-, -CH2CH2CH2- and -CH2CH(CH3)CH2-.

[0122] The term "alkenyl" refers to a straight or branched hydrocarbon chain containing 2-12 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 groups. One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent.

[0123] The term "alkynyl" refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and characterized in having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.

[0124] The term "alkoxy" refers to an -O-alkyl radical. The term "haloalkoxy" refers to an alkoxy in which one or more hydrogen atoms are replaced by halo, and includes alkoxy moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkoxy).

[0125] Unless otherwise specified, the term "aryl" refers to a fully aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system. Examples of aryl moieties are phenyl, naphthyl, and anthracenyl.Unless otherwise specified, any ring atom in an aryl can be substituted by one or more substituents. The term "monocyclic aryl" means a monocyclic fully romatic hydrocarbon ring system, optionally substituted by one or more substituents which can not form a fused bicyclic or tricyclic ring.The term "carbocyclyl" refers to a non-aromatic, monocyclic, bicyclic, or tricyclic hydrocarbon ring system. Carbocyclyl groups include fully saturated ring systems (e.g., cycloalkyls), and partially saturated ring systems. Carbocyclyl groups also include spirocyclic moieties. Examples of spirocyclic moieties include, but are not limited to, bicyclo[3.1.0]hexanyl, spiro[2.2]pentanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, and spiro[3.6]decanyl. Unless otherwise specified, any ring atom in a carbocyclyl can be substituted by one or more substituents.

[0126] Bicyclic or tricyclic ring systems where an aryl is fused to a carbocyclyl and the point of attachment from the ring system to the rest of the molecule is through the non-aromatic ring are considered to be carbocyclyl (e.g., cycloalkyl). Examples of such carbocyclyl moieties include, but are not limited to, 2,3-dihydro-lH-indene and 1 ,2,3,4-tetrahydronaphthalene.

[0127] The term "cycloalkyl" as employed herein includes saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12 carbons. Any ring atom can be substituted (e.g., by one or more substituents). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.

[0128] Unless otherwise specified, 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, said heteroatoms selected from O, N, or S (or the oxidized formssuch as IST-O", S(O) and S(0)2).The term "monocyclic heteroaryl" means a monocyclic fully romatic ring systemhaving 1 -3 heteroatoms, optionally substituted by one or more substituents which can not form a fused bicyclic or tricyclic ring.

[0129] The term "heterocyclyl" refers to a nonaromatic, 3-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1 -3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(or the oxidized formssuch as IST-O", S(O) and S(0)2). The heteroatom may optionally be the point of attachment of the heterocyclyl substituent. Examples of heterocyclyl include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino, pyrrolinyl, pyrimidinyl, and pyrrolidinyl. Heterocyclyl groups include fully saturated ring systems, and partially saturated ring systems.Bicyclic and tricyclic ring systems containing one or more heteroatoms and both aromatic and non-aromatic rings are considered to be heterocyclyl or heteroaryl groups. Bicyclic or tricyclic ring systems where an aryl or a heteroaryl is fused to a carbocyclyl or heterocyclyl and the point of attachment from the ring system to the rest of the molecule is through an aromatic ring are considered to be aryl or heteroaryl groups, respectively. Bicyclic or tricyclic ring systems where an aryl or a heteroaryl is fused to a carbocyclyl or heterocyclyl and the point of attachment from the ring system to the rest of the molecule is through the non-aromatic ring are considered to be carbocyclyl (e.g., cycloalkyl) or heterocyclyl groups, respectively.

[0130] Aryl, heteroaryl, carbocyclyl (including cycloalkyl), and heterocyclyl groups, either alone or a part of a group (e.g., the aryl portion of an aralkyl group), areoptionally substituted at one or more substitutable atoms with, unless specified otherwise, substituents independently selected from: halo, -C≡N, d-C4alkyl,

[0131] =0, -ORb, -ORb', -SRb, -SRb', -(Ci-C4alkyl)-N(Rb)(Rb), -(Ci-C4alkyl)-N(Rb)(Rb'),-N(Rb)(Rb), -N( Rb)(Rb'), -0-(Ci-C4alkyl)-N(Rb)(Rb), -0-(Ci-C4alkyl)-N(Rb)(Rb'), -(Ci-C4alkyl)-0-(Ci-C4alkyl)-N(Rb)(Rb), -(C1-C4 alkyl)-0-(Ci-C4alkyl)-N(Rb)(Rb'), -C(0)-N(Rb)(Rb), -(C1-C4 alkyl)-C(0)-N(Rb)(Rb), -(C1-C4 alkyl)-C(0)-N(Rb)(Rb), -ORb, Rb', -C(0)(Ci-C4

[0132] alkyl), -C(0)Rb', -C(0)N(Rb')(Rb), -N(Rb)C(0)(Rb), -N(Rb)C(0)(Rb), -N(Rb)S02(Rb), -S02N(Rb)(Rb), -N(Rb)S02(Rb'), and -S02N(Rb)(Rb'), wherein any alkyl substituent is optionally further substituted with one or more of -OH, -0-(d-C4alkyl), halo, -NH2, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0133] each Rbis independently selected from hydrogen, and -Ci-C alkyl; or two Rbs are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered heterocyclyl optionally comprising one additional heteroatom selected from N, S, and O; and

[0134] each Rbis independently selected from C3-C7carbocyclyl, phenyl, heteroaryl, and heterocyclyl, wherein one or more substitutablepositions on said phenyl, cycloalkyl, heteroaryl or heterocycle substituent is optionally further substituted with one or more of -(Ci-C4alkyl), -(C1-C4 fluoroalkyl), -OH, -0-(C C4alkyl), -0-(Ci-C4fluoroalkyl),

[0135] halo, -NH2, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2.Heterocyclyl groups, either alone or as part of a group,are optionally substituted on one or more any substitutable nitrogen atom with oxo,-Ci-C4alkyl, or fluoro-substituted C1-C4 alkyl.

[0136] The term "substituted" refers to the replacement of a hydrogen atom by another group. The term"bodily fluid" includes one or more of amniotic fluid surrounding a fetus, aqueous humour, blood (e.g., blood plasma), serum, Cerebrospinal fluid, cerumen, chyme, Cowper's fluid, female ejaculate, interstitial fluid, lymph, breast milk, mucus (e.g., nasal drainage or phlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal secretion, or vomit.

[0137] As used herein, the terms "inhibit" or "prevent" include both complete and partial inhibition and prevention. An inhibitor may completely or partially inhibit the intended target.

[0138] The term "treat" means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease / disorder (e.g., a cancer), lessen the severity of the disease / disorder (e.g., acancer) or improve the symptoms associated with the disease / disorder (e.g., a cancer).

[0139] As used herein, an amount of a compound effective to treat a disorder, or a "therapeutically effective amount" refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject, in treating a cell, or in curing, alleviating, relieving or improving a subject with a disorder beyond that expected in the absence of such treatment.

[0140] As used herein, the term "subject" is intended to include human and non-human animals.

[0141] Exemplary human subjects include a human patient (referred to as a patient) having a disorder, e.g., a disorder described herein or a normal subject. The term "non -human animals" of one aspect of the invention includes all vertebrates, e.g., non-mammals (such as chickens,

[0142] amphibians, reptiles) and mammals, such as non-human primates, domesticated and / or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.

[0143] Compounds

[0144] Provided is a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof:wherein:

[0145] ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;

[0146] X is N, CH or C-halo;

[0147] R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0148] R2and R5are each independently selected from: -(Ci-C6alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(Ci- C6alkyl)-C02H, -(C2-C6alkenyl or alkynyl), -(Ci-C6alkylene)-N(R6)-(d-C6alkylene)-0-(d-C6alkyl), -(C C6alkylene)-N(R6)-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)(R6), -(d-C6alkylene)-N(R6)-S(0)i-2-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)-S(O)i-2-(C0-C6alkyl)-Q, -(Ci-C6alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6

[0149] alkylene)-Q, -C(0)N(R6)-(Ci-C6alkylene)-C(O)- (C0-C6alkylene)-0-(Ci-C6

[0150] alkyl), -C(0)N(R6)-(Ci-C6alkylene)-C(O)-(C0-C6alkylene)-O-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-0-C(0)-(Ci-C6alkyl), -(Ci-C6alkylene)-O-C(O)-(C0-C6alkyl)-Q, -(Ci-C6

[0151] alkylene)-0-(Ci-C6alkyl), -(Ci-C6alkylene)-0-(d-C6alkylene)-Q, -(C0-C6

[0152] alkylene)-C(O)-(C0-C6alkylene)-0-(d-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6

[0153] alkylene)-0-(Ci-C6alkylene)-Q, -(Ci-C6alkylene)-0-C(0)-(Ci-C6alkyl), -(Ci-C6

[0154] alkylene)-O-C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)N(R6)-(Ci-C6alkyl), -(C0-C6alkylene)-C(O)N(R6)-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)C(0)-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-S(O)0-2-(Ci-C6alkyl), -(C0-C6alkylene)-S(0)o-2-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6alkyl), -(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)-(d-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(d-C4alkyl), -C02H, or halo;

[0155] any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH,

[0156] CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0157] R7and R8are each independently selected from hydrogen and Ci-C6alkyl; and

[0158] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0159] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0160] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0161] R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

[0162] R4and R5are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; wherein:

[0163] (i) when X is N and A is optionally substituted phenyl, then (a) neither

[0164] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2CH2OCH2CH2OCH2CH2NH2, 4-[[2-[2- (2-aminoethoxy)ethoxy]ethyl]amino] and (b) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH2CH2CHO, NHCH2CH2OCH3, NHCH2CH2OH, NHCH2CH(OH)CH3,

[0165] NHCH2CH2OC(0)phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2N(CH3)phenyl,

[0166] NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or

[0167] NHCH2CH2OC(0)CH3;

[0168] (ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, CI or S02CH3, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(0)NH-i-propyl, NHCH(CH3)(CH2)3N(CH2CH3)2, NHCH2CH2OH, NHCH2CH2OCH3, NHCH2CH2OS03H, NHCH2CH2CH2OCH2CH20-phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2OCH3,

[0169] NHCH2CH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCH2CH2NHC(0)OCH3,

[0170] NHCH2CH2NHC(0)CH3, NHCH2CH2NH2, or NHCH2-phenyl;(iii) when X is CH and A is optionally substituted pyridyl, then neither

[0171] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2-phenyl, NHCH2-(2,4-difluorophenyl), N(CH3)CH2CH2C(0)OH, NHCH2CH2C(0)OH, NHCH2CH2C(0)OCH2CH3,

[0172] NHCH2CH2C(0)0-t-butyl, NHCH2CH2C(0)NH2, NHCH2CH2-phenyl, NHCH2CH2OH,

[0173] NHCH2CH2NH2, NHCH2CH2N(CH3)2, or NHCH2CH2CH3;

[0174] (iv) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1 - pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor

[0175] NtR8)^1)^2)^3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH;

[0176] (v) when X is N and A is an optionally substituted pyridyl, then (A) neither

[0177] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], N(CH3)2, NHCH2CH2CH2S02CH2CH2C1, NHCH2CH2OCH2CH2S02CH2CH2Cl,or

[0178] NHCH2CH2S02CH2CH2C1, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and

[0179] NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3;

[0180] (vi) when X is N and A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;

[0181] (vii) when X is CH and A is unsubstituted 2-pyridinyl, then the ring formed by R4and R5is not 5 -methyl- lH-pyrazol-3-yl,

[0182] (viii) when A is optionally substituted 1 -pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor NtR8)^1)^2)^3) is N(CH3)2, NHCH3, NHAc, NHisopropyl, NHCH2CH3, NHCH2CH2S03H or N(CH2CH3)2,

[0183] (ix) when X is N and A is optionally substituted phenyl, thienyl, or pyridinyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexylC(0)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3,

[0184] (x) when X is N, A is an optionally substituted phenyl and R4and R5form an optionally substituted phenyl, then N(R8)C(R1)(R2)(R3) is not NHCH2(4-fluorophenyl), NHCH2C02H, NHCH2C(0)C1, NHCH(C02H)(CH2SCH2phenyl), or NHCH2C(0)NHC(0)NHR orNHCH2C(0)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl,

[0185] (xi) when X is N, A is an oxadiazole substituted with an optionally substituted pyridinyl, then R4and R5do not form an optionally substituted phenyl,

[0186] (xii) when A is substituted 1-pyrazolyl, then (A) then N(R7)C(R4)(R5)(R6) and

[0187] NtR^CtR1)^2)^3) are not both NHC(CH3)3, and (B) A is not substituted with N=N-R, wherein R is a ring,

[0188] (xiii) ring A is not an optionally substituted triazolyl, 3, 5 -dimethyl- lH-pyrazol-l -yl,

[0189] (xix) when R1and R2are optionally taken together to form an unsubstituted cyclohexyl, and R4and R5are optionally taken together to form an unsubstituted cyclohexyl, then A is not a disubstituted 1-pyrazolyl or an unsubstituted phenyl; and

[0190] (xx) the compound is not selected from the group:

[0191] (1) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-lH-inden-2-yl)amino]-6-phenyl-l ,3,5-triazin-2- yl ] amino] methyl] -b enzamide,

[0192] (2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4-(methylsulfonyl)- benzamide,

[0193] (3) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3-yl]thio]- acetamide,

[0194] (4) N2-cyclopropyl-N4-ethyl-6-[3-[(phenylmethyl)thio]-lH-l ,2,4-triazol-l-yl]-l,3,5-triazine-2,4- diamine,

[0195] (5) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3-yl]thio]- acetic acid methyl ester,

[0196] (6) N- [ [4- [ [ [4-(cyclopropylamino)-6-(2 -pyridinyl)- 1,3,5 -triazin-2-yl]amino]methyl] cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,

[0197] (7) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-phenyl-l,3,5-triazine-2,4-diamine,

[0198] (8) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]-l,3,5-triazine- 2,4-diamine,

[0199] (9) N2,N4-dicyclohexyl-6- [3 -(3 ,4-dimethoxyphenyl)-5 -(methylthio)- 1 H-pyrazol- 1 -yl] -1,3,5- triazine-2,4-diamine,

[0200] ( 10) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 -yl]- 1 ,3 , 5 -triazine-2,4-diamine,

[0201] (1 1) N2,N4-dicyclohexyl-6-phenyl-l,3,5-triazine-2,4-diamine,

[0202] (12) 1 ,1 '-[(6^henyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],

[0203] (13) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l,l- dimethylethyl)- phenol,

[0204] (14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-l,3,5-triazin-2-yl]-glycine,

[0205] (15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3- fluorophenyl)-l,3,5-triazin-2-yl]amino]ethyl]- phenol,

[0206] (16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4- fluorophenyl)-l,3,5-triazin-2-yl]amino]ethyl]- phenol,

[0207] (17) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine,

[0208] (18) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l ,3,5-triazine-2,4-diamine,

[0209] (19) 4,4'-[[6-[3,5-bis(U-dime lefoy^

[0210] 3,1 -propanediyl)]bis[2,6-bis(l ,1 -dimethylethyl)-phenol,

[0211] (20) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(imino-3,l-propanediyl)]bis[2,6-bis(l,l- dimethylethyl)-phenol,

[0212] (21) N-[6-[(2,3-dihydro-lH-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]- alanine,

[0213] (22) N4-cyclopentyl-2-phenyl-N6-(phenylmethyl)-4,6-pyrimidinediamine,

[0214] (23) 2-[[6-(bicyclo[2.2.1 ]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol,

[0215] (24) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l,3,5-triazine-2,4-diamine,

[0216] (25) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l,3,5-triazin-2- yl]-benzamide,

[0217] (26) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,

[0218] (27) [[4-[[[[[4-amino-6-(4^yridinyl)-l,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4- pyridinyl)-l ,3,5-triazin-2-yl]imino]bis-methanol,

[0219] (28) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]imi^ methanol,(29) 5-[4,6-bis(diethylamino)-l,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,

[0220] (30) N2,N2,N*,N*-tetrae ^

[0221] (31) N,A -[6-[4-(acetylamino)-l,2,5-oxadiazol-3^

[0222] (32) N-(2-chloro-6-methylphenyl)-5-[[4-(dime lamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]-l ,3,4-Oxadiazole-2-carboxamide,

[0223] (33) N4-(5-methyl-lH-pyrazol-3-yl)-2-(2-pyridinyl)-N6-(tetrahydro-2H-pyran-4-yl)-4,6- Pyrimidinediamine,

[0224] (34) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(diethylamino)propyl]- 1,3,5 -Triazine-2,4-diamine,

[0225] (35) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3- (dimethylamino)propyl]- 1 ,3,5-Triazine-2,4-diamine,

[0226] (36) N2-[3,5-bis(trifluorome l)phenyl]-6-(4-chlorophenyl)-N4-[3-(diethylamino)propyl]-1 Triazine-2,4-diamine,

[0227] (37) N2,N4-bis[(4-methoxyphenyl)me l]-6-[4-(trifluoromethoxy)phenyl]-l ,3,5-Triazine-2,4- diamine,

[0228] (38) N,N"-(6-phenyl-l,3,5-triazine-2,4-diyl)bis[N'-(2-chloroethyl)-Urea,

[0229] (39) N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-methyl-3-[[4-phenyl-6-(propylamino)-l ,3,5- triazin-2-yl]amino]phenyl]-urea,

[0230] (40) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]-glycine,

[0231] (41) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(5-thiazolyl)-l, 3, 5-triazin-2-yl]-L- Valine,

[0232] (42) s-Triazine, 2-phenyl-4,6-bis[[6-[[4-phenyl-6-[[6-[[4-phenyl-6-(trichloromethyl)-s-triazin-2- yl]amino]hexyl]amino]-s-triazin-2-yl]amino]hexyl]amino]-,

[0233] (43) a,a'-[(6-phenyl-l ,3,5-triazine-2,4-diyl)bis[imino(l,l,2,2-tetrafluoro-3-oxo-3,l- propanediyl)]]bis[ro-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)- 1,2-ethanediyl]],

[0234] (44) a-[[4-[[(3-chlorophenyl)methyl]amino]-6-(lH-imidazol-l-yl)-l,3,5-triazin-2-yl]amino]-N- [[4-(trifluoromethyl)phenyl]methyl]-, (aR)-Cyclohexanepropanamide,(45) 6-(lH-imidazol-l -yl)-N2,N4-bis(l -methyle l)-l,3,5-Triazine-2,4-diamine, and

[0235] (46) N2,N4-bis(l -methylpropyl)-6-phenyl-l ,3,5-Triazine-2,4-diamine.

[0236] Provided is a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof:

[0237] erein:

[0238] ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;

[0239] X is N, CH or C-halo;

[0240] R1, R3, R4, and R6are each independently selected from hydrogen, Ci-C4alkyl, Ci-C4haloalkyl, -O-C1-C4alkyl, and CN, wherein any alkyl portion of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0241] R2and R5are each independently selected from: -(Ci-C6alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(Ci-Cg alkyl)-C02H -(C2-C6alkenyl or alkynyl), -(Ci-C6alkylene)-N(R6)-(Ci-C6

[0242] alkylene)-0-(Ci-C6alkyl), -(Ci-Cg alkylene)-N(R6)-(C0-C6alkylene)-Q, -(Ci-Cg

[0243] alkylene)-N(R6)(R6X -(Ci-C6alkylene)-N(R6)-S(0)i-2-(Ci-C6alkyl), -(d-C6

[0244] alkylene)-N(R6)-S(O)i-2-(C0-C6alkyl)-Q, -(Ci-C6alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6alkylene)-Q, -C(0)N(R6)-(Ci-C6alkylene)-C(O)- (C0-C6alkylene)-0-(Ci-C6alkyl),-C(0)N(R6)-(Ci-C6alkylene)-C(O)-(C0-C6alkylene)-O-(C0-C6alkylene)-Q, -(Ci-Cg alkylene)-0-C(0)-(d-C6alkyl), -(Ci-Cg alkylene)-O-C(O)-(C0-C6alkyl)-Q, -(Ci-C6alkylene)-0-(Ci-C6alkyl), -(Ci-C6alkylene)-0-(Ci-C6alkylene)-Q, -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-0-(d-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6

[0245] alkylene)-0-(Ci-C6alkylene)-Q, -(Ci-Cg alkylene)-0-C(0)-(d-C6alkyl), -(d-C6

[0246] alkylene)-O-C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)N(R6)-(Ci-C6alkyl), -(C0-C6alkylene)-C(0)N(R6)-(Co-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)C(0)-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-S(O)0-2-(Ci-C6alkyl), -(Co-C6alkylene)-S(0)o-2-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6alkyl), -(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)-(Ci-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0247] any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(Ci-C4alkyl), -C02H, or halo;

[0248] any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH,

[0249] CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0250] R7and R8are each independently selected from hydrogen and Ci-C6alkyl; and

[0251] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0252] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0253] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0254] R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

[0255] R4and R5are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;

[0256] wherein:

[0257] (i) when X is N and A is optionally substituted phenyl, then (a) neither

[0258] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is 4-[[2-[2-(2-aminoethoxy)ethoxy]ethyl]amino] and (b) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n- butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH2CH2CHO, NHCH2CH2OCH3, NHCH2CH2OH, NHCH2CH(OH)CH3, NHCH2CH2OC(0)phenyl, NHCH2CH2CH2OH,

[0259] NHCH2CH2CH2N(CH3)phenyl, NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or NHCH2CH2OC(0)CH3;

[0260] (ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, CI or S02CH3, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(0)NH-i-propyl,NHCH(CH3)(CH2)3N(CH2CH3)2, NHCH2CH2OH, NHCH2CH2OCH3, NHCH2CH2OS03H, NHCH2CH2CH2OCH2CH20-phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2OCH3,

[0261] NHCH2CH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCH2CH2NHC(0)OCH3,

[0262] NHCH2CH2NHC(0)CH3, NHCH2CH2NH2, or NHCH2-phenyl;

[0263] (iii) when X is CH and A is optionally substituted pyridyl, then neither

[0264] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2-phenyl, NHCH2-(2,4-difluorophenyl), N(CH3)CH2CH2C(0)OH, NHCH2CH2C(0)OH, NHCH2CH2C(0)OCH2CH3,

[0265] NHCH2CH2C(0)0-t-butyl, NHCH2CH2C(0)NH2, NHCH2CH2-phenyl, NHCH2CH2OH, NHCH2CH2NH2, NHCH2CH2N(CH3)2, or NHCH2CH2CH3;

[0266] (iv) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1-pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor NCR^CCR'XR'XR3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH;

[0267] (v) when X is N and A is an optionally substituted pyridyl, then (A) neither

[0268] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3;

[0269] (vi) when X is N and A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;

[0270] (vii) the compound is not selected from the group:

[0271] (1 ) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-phenyl-l ,3,5-triazine-2,4- diamine,

[0272] (2) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-methoxyphenyl)-l,3,5- triazine-2,4-diamine,

[0273] (3) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(3-nitrophenyl)-l,3,5- triazine-2,4-diamine,

[0274] (4) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-fluorophenyl)-l ,3,5-triazine-2,4-diamine,

[0275] (5) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-trifluoromethoxy- phenyl)-l,3,5-triazine-2,4-diamine,

[0276] (6) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-t-butyl-phenyl)-l ,3,5- triazine-2,4-diamine,

[0277] (7) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(2-thienyl)-l ,3,5-triazine- 2,4-diamine,

[0278] (8) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-lH-inden-2-yl)amino]-6-phenyl-l,3,5- triazin-2-yl]amino]methyl]-benzamide,

[0279] (9) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4- (methylsulfonyl)-benzamide,

[0280] (10) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-methoxyphenyl)- 1 ,3,5-triazine-2,4-diamine,

[0281] (11) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3- yl]thio]-acetamide,

[0282] (12) N2-cyclopropyl-N4-ethyl-6-[3-[(phenylme l)thio]-lH ,2,4-triazol-l-yl]-l,3,5- triazine-2,4-diamine,

[0283] (13) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3- yl]thio]- acetic acid methyl ester,

[0284] (14) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(2,4,6-trimethylphenyl)- l,3,5-triazine-2,4-diamine,

[0285] (15) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-phenyl-l ,3,5-triazine- 2,4-diamine,

[0286] (16) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-methylphenyl)-l ,3,5- triazine-2,4-diamine,

[0287] (17) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-chlorophenyl)-l ,3,5- triazine-2,4-diamine,

[0288] (18) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,(19) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l -yl)-N4-phenyl-l,3,5-triazine-2,4- diamine,

[0289] (20) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]- 1 ,3,5-triazine-2,4-diamine,

[0290] (21) N2,N4-dicyclohexyl-6-[3-(3,4-dimethoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]- 1 ,3,5-triazine-2,4-diamine,

[0291] (22) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 - yl] - 1 ,3 , 5 -triazine-2,4-diamine,

[0292] (23) N2,N4-dicyclohexyl-6-phenyl-l,3,5-triazine-2,4-diamine,

[0293] (24) 1 ,1 '-[(6^henyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],

[0294] (25) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l,l- dimethylethyl)-phenol,

[0295] (26) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3- (trifluoromethyl)phenyl] amino ]carbonyl] amino]-2-methylphenyl]-l ,3,5-triazin-2-yl]-glycine,

[0296] (27) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3- fluorophenyl)- 1 ,3,5-triazin-2- yl]amino]ethyl]- phenol,

[0297] (28) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4- fluorophenyl)- 1 ,3,5-triazin-2- yl]amino]ethyl]- phenol,

[0298] (29) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine,

[0299] (30) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l,3,5-triazine-2,4-diamine,

[0300] (31) 4,4'-[[6-[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]-l,3,5-triazine-2,4- diyl]bis(imino- 3,l-propanediyl)]bis[2,6-bis(l,l-dimethylethyl)-phenol,

[0301] (32) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(imino-3,l-propanediyl)]bis[2,6-bis(l,l- dimethylethyl)-phenol,

[0302] (33) N-[6-[(2,3-dihydro-lH-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]- alanine,

[0303] (34) N4-cyclopentyl-2-phenyl-N6-(phenylmethyl)-4,6-pyrimidinediamine,

[0304] (35) 2-[[6-(bicyclo[2.2.1]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol,

[0305] (36) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l,3,5-triazine-2,4-diamine,(37) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l ,3,5- triazin-2-yl]-benzamide,

[0306] (38) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,

[0307] (39) [[4-[ [ [[ [4-amino-6-(4-pyridinyl)- 1 ,3 ,5-triazin-2-yl]amino]methoxy]methyl]amino]- 6-(4-pyridinyl)-l ,3,5-triazin-2-yl]imino]bis-methanol,

[0308] (40) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]i methanol,

[0309] (41) 5-[4,6-bis(diethylamino)-l ,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,

[0310] (42) N2,N2,N4,N4-tetraethyl-6-(2H-tetrazol-5-yl)-l ,3,5-triazine-2,4-diamine, and

[0311] (43) N V-[6-[4-(acetylamino)-l ,2,5-oxadiazol-3-yl]-l ,3,5-triazine-2,4-diyl]bis-acetamide.

[0312] Provided is a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof:

[0313] (I), wherein:

[0314] ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl; X is N or CH;

[0315] R1, R3, R4, and R6are each independently selected from hydrogen, Ci-C4alkyl, Ci-C4haloalkyl, -O-C1-C4 alkyl, and CN, wherein any alkyl portion of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0316] R2and R5are each independently selected from: -(d-C6alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(Ci-C6alkyl)-C02H -(C2-C6alkenyl or alkynyl), -(C C6alkylene)-N(R6)-(Ci-C6

[0317] alkylene)-0-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)(R6), -(Ci-C6alkylene)-N(R6)-S(0)i-2-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)-S(O)i-2-(C0-C6alkyl)-Q, -(Ci-C6alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6alkylene)-Q, -C(0)N(R6)-(Ci-C6alkylene)-C(O)- (C0-C6alkylene)-0-(Ci-C6alkyl), -C(0)N(R6)-(Ci-C6alkylene)-C(O)-(C0-C6alkylene)-O-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-0-C(0)-(d-C6alkyl), -(Ci-C6alkylene)-O-C(O)-(C0-C6alkyl)-Q, -(Ci-C6alkylene)-0-(Ci-C6alkyl), -(Ci-C6alkylene)-0-(Ci-C6alkylene)-Q, -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-0-(Ci-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6

[0318] alkylene)-0-(Ci-C6alkylene)-Q, -(Ci-C6alkylene)-0-C(0)-(d-C6alkyl), -(C C6

[0319] alkylene)-O-C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)N(R6)-(Ci-C6alkyl), -(C0-C6alkylene)-C(O)N(R6)-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)C(0)-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-S(O)0-2-(Ci-C6alkyl), -(C0-C6alkylene)-S(0)o-2-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6alkyl), -(C0-G alkylene)-Q, -(C0-C6alkylene)-C(0)-(d-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0320] any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(d-C4alkyl), -C02H, or halo;

[0321] any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH,

[0322] CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0323] R7and R8are each independently selected from hydrogen and d-C6alkyl; and

[0324] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0325] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0326] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0327] R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

[0328] R4and R5are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;

[0329] wherein:(i) when X is N and A is optionally substituted phenyl, then (a) neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is 4-[[2-[2-(2-aminoethoxy)ethoxy]ethyl]amino] and (b) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n- butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH2CH2CHO, NHCH2CH2OCH3, NHCH2CH2OH, NHCH2CH(OH)CH3, NHCH2CH2OC(0)phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2N(CH3)phenyl, NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or NHCH2CH2OC(0)CH3;

[0330] (ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, CI or S02CH3, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(0)NH-i-propyl, NHCH(CH3)(CH2)3N(CH2CH3)2, NHCH2CH2OH, NHCH2CH2OCH3, NHCH2CH2OS03H, NHCH2CH2CH2OCH2CH20-phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2OCH3,

[0331] NHCH2CH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCH2CH2NHC(0)OCH3,

[0332] NHCH2CH2NHC(0)CH3, NHCH2CH2NH2, or NHCH2-phenyl;

[0333] (iii) when X is CH and A is optionally substituted pyridyl, then neither

[0334] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2-phenyl, NHCH2-(2,4-difluorophenyl), N(CH3)CH2CH2C(0)OH, NHCH2CH2C(0)OH, NHCH2CH2C(0)OCH2CH3,

[0335] NHCH2CH2C(0)0-t-butyl, NHCH2CH2C(0)NH2, NHCH2CH2-phenyl, NHCH2CH2OH, NHCH2CH2NH2, NHCH2CH2N(CH3)2, or NHCH2CH2CH3;

[0336] (iv) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1 - pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor

[0337] NtR8)^1)^2)^3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH;

[0338] (v) when X is N and A is an optionally substituted pyridyl, then (A) neither

[0339] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3;(vi) when X is N and A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;

[0340] (vii) the compound is not selected from the group:

[0341] (1 ) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-phenyl-l ,3,5-triazine-2,4- diamine,

[0342] (2) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-methoxyphenyl)-l,3,5- triazine-2,4-diamine,

[0343] (3) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(3-nitrophenyl)-l,3,5- triazine-2,4-diamine,

[0344] (4) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-fluorophenyl)-l ,3,5- triazine-2,4-diamine,

[0345] (5) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-trifluoromethoxy- phenyl)-l,3,5-triazine-2,4-diamine,

[0346] (6) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-t-butyl-phenyl)-l ,3,5- triazine-2,4-diamine,

[0347] (7) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(2-thienyl)-l ,3,5-triazine- 2,4-diamine,

[0348] (8) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-lH-inden-2-yl)amino]-6-phenyl-l,3,5- triazin-2-yl]amino]methyl]-benzamide,

[0349] (9) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4- (methylsulfonyl)-benzamide,

[0350] (10) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-methoxyphenyl)- l,3,5-triazine-2,4-diamine,

[0351] (11) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3- yl]thio]-acetamide,

[0352] (12) N2-cyclopropyl-N4-ethyl-6-[3-[(phenylmethyl)thio]-lH-l,2,4-triazol-l-yl]-l,3,5- triazine-2,4-diamine,

[0353] (13) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3-yl]thio]- acetic acid methyl ester,

[0354] (14) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(2,4,6-trimethylphenyl)- l,3,5-triazine-2,4-diamine,

[0355] (15) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-phenyl-l ,3,5-triazine- 2,4-diamine,

[0356] (16) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-methylphenyl)-l ,3,5- triazine-2,4-diamine,

[0357] (17) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-chlorophenyl)-l ,3,5- triazine-2,4-diamine,

[0358] (18) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,

[0359] (19) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l -yl)-N4-phenyl-l,3,5-triazine-2,4- diamine,

[0360] (20) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]- l,3,5-triazine-2,4-diamine,

[0361] (21) N2,N4-dicyclohexyl-6-[3-(3,4-dimethoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]- l,3,5-triazine-2,4-diamine,

[0362] (22) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 - yl]-l,3,5-triazine-2,4-diamine,

[0363] (23) N2,N4-dicyclohexyl-6-phenyl-l,3,5-triazine-2,4-diamine,

[0364] (24) 1 ,1 '-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],

[0365] (25) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l,l- dimethylethyl)-phenol,

[0366] (26) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3- (trifluoromethyl)phenyl] amino ]carbonyl] amino]-2-methylphenyl]-l ,3,5-triazin-2-yl]-glycine,

[0367] (27) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3- fluorophenyl)- 1 ,3,5-triazin-2- yl]amino]ethyl]- phenol,

[0368] (28) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4- fluorophenyl)- 1 ,3,5-triazin-2- yl]amino]ethyl]- phenol,(29) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine,

[0369] (30) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l,3,5-triazine-2,4-diamine,

[0370] (31) 4,4'-[[6-[3,5-bis(l,l-dime lethyl)-4- hydroxyphenyl]-l,3,5-triazine-2,4- diyl]bis(imino- 3,l-propanediyl)]bis[2,6-bis(l,l-dimethylethyl)-phenol,

[0371] (32) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(imino-3,l-propanediyl)]bis[2,6-bis(l,l- dimethylethyl)-phenol,

[0372] (33) N-[6-[(2,3-dihydro-lH-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]- alanine,

[0373] (34) N4-cyclopentyl-2-phenyl-N6-(phenylmethyl)-4,6-pyrimidinediamine,

[0374] (35) 2-[[6-(bicyclo[2.2.1]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol,

[0375] (36) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l,3,5-triazine-2,4-diamine,

[0376] (37) 2-chloro-4-(methylsulfonyl)-N-[4 (phenylmethyl)amino]-6-(2-pyridinyl)-l,3,5- triazin-2-yl]-benzamide,

[0377] (38) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,

[0378] (39) [[4-[ [ [[ [4-amino-6-(4-pyridinyl)- 1 ,3 ,5-triazin-2-yl]amino]methoxy]methyl]amino]- 6-(4-pyridinyl)-l,3,5-triazin-2-yl]imino]bis-methanol,

[0379] (40) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]im methanol,

[0380] (41) 5-[4,6-bis(diethylamino)-l,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,

[0381] (42) N2,N2,N4,N4-tetraethyl-6-(2H-tetrazol-5-yl)-l ,3,5-triazine-2,4-diamine, and

[0382] (43) N V'-[6-[4-(acetylamino)-l,2,5-oxadiazol-3-yl]-l,3,5-triazine-2,4-diyl]bis-acetamide.

[0383] Also provided is a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof:

[0384] (I), wherein:

[0385] ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;

[0386] X is N or CH;

[0387] R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0388] R2and R5are each independently selected from: -(Ci-d alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(d- C6alkyl)-C02H, -(C2-C6alkenyl or alkynyl), -(Ci-C6alkylene)-N(R6)-(d-C6alkylene)-0-(d-C6alkyl), -(d-C6alkylene)-N(R6)-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)(R6), -(d-C6alkylene)-N(R6)-S(0)i-2-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)-S(O)i-2-(C0-C6alkyl)-Q, -(Ci-C6alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6

[0389] alkylene)-Q, -C(0)N(R6)-(Ci-C6alkylene)-C(O)- (C0-C6alkylene)-0-(Ci-C6

[0390] alkyl), -C(0)N(R6)-(Ci-C6alkylene)-C(O)-(C0-C6alkylene)-O-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-0-C(0)-(Ci-C6alkyl), -(Ci-C6alkylene)-O-C(O)-(C0-C6alkyl)-Q, -(Ci-C6

[0391] alkylene)-0-(Ci-C6alkyl), -(Ci-C6alkylene)-0-(Ci-C6alkylene)-Q, -(C0-C6

[0392] alkylene)-C(O)-(C0-C6alkylene)-0-(d-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6

[0393] alkylene)-0-(Ci-C6alkylene)-Q, -(Ci-Ce alkylene)-0-C(0)-(d-C6alkyl), -(d-C6

[0394] alkylene)-O-C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)N(R6)-(Ci-C6alkyl), -(C0-C6alkylene)-C(O)N(R6)-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)C(0)-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-S(O)0-2-(Ci-C6alkyl), -(C0-C6alkylene)-S(0)o-2-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6alkyl), -(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)-(d-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0395] any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(Ci-C4alkyl), -C02H, or halo;

[0396] any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH,

[0397] CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0398] R7and R8are each independently selected from hydrogen and C1-C6 alkyl; and

[0399] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0400] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0401] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0402] R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

[0403] R4and R5are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; wherein:

[0404] (i) when X is N and A is optionally substituted phenyl, then (a) neither

[0405] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2CH2OCH2CH2OCH2CH2NH2, 4-[[2-[2- (2-aminoethoxy)ethoxy]ethyl]amino] and (b) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH2CH2CHO, NHCH2CH2OCH3, NHCH2CH2OH, NHCH2CH(OH)CH3,

[0406] NHCH2CH2OC(0)phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2N(CH3)phenyl,

[0407] NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or

[0408] NHCH2CH2OC(0)CH3;

[0409] (ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, CI or S02CH3, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(0)NH-i-propyl, NHCH(CH3)(CH2)3N(CH2CH3)2, NHCH2CH2OH, NHCH2CH2OCH3, NHCH2CH2OS03H, NHCH2CH2CH2OCH2CH20-phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2OCH3,NHCH2CH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCH2CH2NHC(0)OCH3,

[0410] NHCH2CH2NHC(0)CH3, NHCH2CH2NH2, or NHCH2-phenyl;

[0411] (iii) when X is CH and A is optionally substituted pyridyl, then neither

[0412] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2-phenyl, NHCH2-(2,4-difluorophenyl), N(CH3)CH2CH2C(0)OH, NHCH2CH2C(0)OH, NHCH2CH2C(0)OCH2CH3,

[0413] NHCH2CH2C(0)0-t-butyl, NHCH2CH2C(0)NH2, NHCH2CH2-phenyl, NHCH2CH2OH, NHCH2CH2NH2, NHCH2CH2N(CH3)2, or NHCH2CH2CH3;

[0414] (iv) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1 - pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor

[0415] NtR8)^1)^2)^3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH;

[0416] (v) when X is N and A is an optionally substituted pyridyl, then (A) neither

[0417] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(0)-[2-chloro-4-(methylsulfonyl)],

[0418] N(CH3)2,NHCH2CH2CH2S02CH2CH2C1, NHCH2CH2OCH2CH2S02CH2CH2Cl,or

[0419] NHCH2CH2S02CH2CH2C1, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3;

[0420] (vi) when X is N and A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;

[0421] (vii) when X is CH and A is unsubstituted 2-pyridinyl, then the ring formed by R4and R5is not 5 -methyl- lH-pyrazol-3-yl,

[0422] (viii) when A is optionally substituted 1 -pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor NtR8)^1)^2)^3) is N(CH3)2, NHCH3, NHAc, NHisopropyl, NHCH2CH3, NHCH2CH2S03H or N(CH2CH3)2,

[0423] (ix) when X is N and A is optionally substituted phenyl,thienyl, or pyridinyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexylC(0)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3,

[0424] (x) when X is N, A is an optionally substituted phenyl and R4and R5form an optionallysubstituted phenyl, then NCR^CCR1)^2)^3) is not NHCH2(4-fluorophenyl), NHCH2C02H, NHCH2C(0)C1, NHCH(C02H)(CH2SCH2phenyl), or NHCH2C(0)NHC(0)NHR or

[0425] NHCH2C(0)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl,

[0426] (xi) when X is N, A is an oxadiazole substituted with an optionally substituted pyridinyl, then R4and R5do not form an optionally substituted phenyl,

[0427] (xii) when A is substituted 1-pyrazolyl, then (A) then N(R7)C(R4)(R5)(R6) and

[0428] NtR^CtR1)^2)^3) are not both NHC(CH3)3, and (B) A is not substituted with N=N-R, wherein R is a ring,

[0429] (xiii) ring A is not an optionally substituted triazolyl, 3,5-dimethyl-lH-pyrazol-l-yl,

[0430] (xix) when R1and R2are optionally taken together to form an unsubstituted cyclohexyl, and R4and R5are optionally taken together to form an unsubstituted cyclohexyl, then A is not a disubstituted 1-pyrazolyl or an unsubstituted phenyl; and

[0431] (xx) the compound is not selected from the group:

[0432] (1) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-lH-inden-2-yl)amino]-6-phenyl-l,3,5-triazin-2- yl ] amino] methyl] -b enzamide,

[0433] (2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4-(methylsulfonyl)- benzamide,

[0434] (3) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3-yl]thio]- acetamide,

[0435] (4) N2-cyclopropyl-N4-ethyl-6-[3 -[(phenylmethyl)thio]-lH-l ,2,4-triazol-l-yl]-l,3,5-triazine-2,4- diamine,

[0436] (5) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3-yl]thio]- acetic acid methyl ester,

[0437] (6) N- [ [4- [ [ [4-(cyclopropylamino)-6-(2 -pyridinyl)- 1,3,5 -triazin-2-yl]amino]methyl] cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,

[0438] (7) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-phenyl-l,3,5-triazine-2,4-diamine,

[0439] (8) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]-l,3,5-triazine- 2,4-diamine,

[0440] (9) N2,N4-dicyclohexyl-6- [3 -(3 ,4-dimethoxyphenyl)-5 -(methylthio)- 1 H-pyrazol- 1 -yl] -1,3,5-triazine-2,4-diamine,

[0441] ( 10) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 -yl]- 1 ,3 , 5 - triazine-2,4-diamine,

[0442] (1 1) N2,N4-dicyclohexyl-6-phenyl-l,3,5-triazine-2,4-diamine,

[0443] (12) 1 ,1 '-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],

[0444] (13) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l,l- dimethylethyl)- phenol,

[0445] (14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-l,3,5-triazin-2-yl]-glycine,

[0446] (15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3- fluorophenyl)-l,3,5-triazin-2-yl]amino]ethyl]- phenol,

[0447] (16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4- fluorophenyl)-l,3,5-triazin-2-yl]amino]ethyl]- phenol,

[0448] (17) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine,

[0449] (18) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l ,3,5-triazine-2,4-diamine,

[0450] (19) 4,4'-[[6-[3,5-bis(l,l-dime lethyl)-4- hydroxyphenyl]-l,3,5-triazine-2,4-diyl]bis(im^ 3,l-propanediyl)]bis[2,6-bis(l,l -dimethylethyl)-phenol,

[0451] (20) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(imino-3,l-propanediyl)]bis[2,6-bis(l,l- dimethylethyl)-phenol,

[0452] (21) N-[6-[(2,3-dihydro-lH-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]- alanine,

[0453] (22) N4-cyclopentyl-2-phenyl-N6-(phenylmethyl)-4,6-pyrimidinediamine,

[0454] (23) 2-[[6-(bicyclo[2.2.1 ]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol,

[0455] (24) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l,3,5-triazine-2,4-diamine,

[0456] (25) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l,3,5-triazin-2- yl]-benzamide,

[0457] (26) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,

[0458] (27) [[4-[[[[[4-amino-6-(4-pyridinyl)-l,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4- pyridinyl)-l ,3,5-triazin-2-yl]imino]bis-methanol,(28) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- y 1 ] amino ] methoxy] methyl ] (hydroxy meft^

[0459] methanol,

[0460] (29) 5-[4,6-bis(diethylamino)-l,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,

[0461] (30) N2,N2,N*,N*-tetrae ^

[0462] (S ^ N V-^-^^acetylamino^l^^-oxadiazol-S-ylj-l ^^-triazine^^-diyllbis-acetamide,

[0463] (32) N-(2-chloro-6-methylphenyl)-5-[[4-(dimethylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]-l ,3,4-Oxadiazole-2-carboxamide,

[0464] (33) N4-(5-methyl-lH-pyrazol-3-yl)-2-(2-pyridinyl)-N6-(tetrahydro-2H-pyran-4-yl)-4,6- Pyrimidinediamine,

[0465] (34) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(diethylamino)propyl]- 1,3,5 -Triazine-2,4-diamine,

[0466] (35) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3- (dimethylamino)propyl]- 1 ,3,5-Triazine-2,4-diamine,

[0467] (36) N2-[3,5-bis(trifluoromethyl)phenyl]-6-(4-chlorophenyl)-N4-[3-(diethylamino)propyl]-l ,3,5- Triazine-2,4-diamine,

[0468] (37) N2,N4-bis[(4-methoxyphenyl)methyl]-6-[4-(trifluoromethoxy)phenyl]-l ,3,5-Triazine-2,4- diamine,

[0469] (38) N,N"-(6-phenyl-l,3,5-triazine-2,4-diyl)bis[N'-(2-chloroethyl)-Urea,

[0470] (39) N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-methyl-3-[[4-phenyl-6-(propylamino)-l ,3,5- triazin-2-yl]amino]phenyl]-urea,

[0471] (40) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]-glycine,

[0472] (41) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(5-thiazolyl)-l, 3, 5-triazin-2-yl]-L- Valine,

[0473] (42) s-Triazine, 2-phenyl-4,6-bis[[6-[[4-phenyl-6-[[6-[[4-phenyl-6-(trichloromethyl)-s-triazin-2- yl]amino]hexyl]amino]-s-triazin-2-yl]amino]hexyl]amino]-,

[0474] (43 ) α,α'- [(6-phenyl- 1,3,5 -triazine-2,4-diyl)bis [imino( 1 , 1 ,2,2-tetrafluoro-3 -oxo-3 , 1 - propanediyl)]]bis[ro-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)-1,2-ethanediyl]],

[0475] (44) a-[[4-[[(3-chlorophenyl)methyl]amino]-6-(lH-imidazol-l -yl)-l,3,5-triazin-2-yl]amino]-N- [[4-(trifluoromethyl)phenyl]methyl]-, (aR)-Cyclohexanepropanamide,

[0476] (45) 6-(lH-imidazol-l -yl)-N2,N4-bis(l -methyle l)-l,3,5-Triazine-2,4-diamine, and

[0477] (46) N2,N4-bis(l -methylpropyl)-6-phenyl-l ,3,5-Triazine-2,4-diamine.

[0478] Also provided is a compound of Formula la, or a pharmaceutically acceptable salt or hydrate thereof:

[0479] (la), wherein:

[0480] ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;

[0481] R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4alkyl, and CN, wherein any alkyl portion of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0482] R2and R5are each independently selected from: -(Ci-d alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(d-

[0483] C6alkyl)-C02H, -(C2-C6alkenyl or alkynyl), -(Ci-C6alkylene)-N(R6)-(d-C6alkylene)-0-(d-C6alkyl),-(d-C6alkylene)-N(R6)-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)(R6),-(d-C6alkylene)-N(R6)-S(0)i-2-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)-S(O)i-2-(C0-C6alkyl)-Q, -(Ci-C6alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6

[0484] alkylene)-Q, -C(0)N(R6)-(Ci-C6alkylene)-C(O)- (C0-C6alkylene)-0-(Ci-C6

[0485] alkyl), -C(0)N(R6)-(Ci-C6alkylene)-C(O)-(C0-C6alkylene)-O-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-0-C(0)-(Ci-C6alkyl), -(Ci-C6alkylene)-O-C(O)-(C0-C6alkyl)-Q, -(Ci-C6

[0486] alkylene)-0-(Ci-C6alkyl), -(Ci-C6alkylene)-0-(d-C6alkylene)-Q, -(C0-C6

[0487] alkylene)-C(O)-(C0-C6alkylene)-0-(Ci-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6

[0488] alkylene)-0-(Ci-C6alkylene)-Q, -(Ci-Ce alkylene)-0-C(0)-(d-C6alkyl), -(Ci-C6alkylene)-O-C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)N(R6)-(Ci-C6alkyl), -(C0-C6alkylene)-C(O)N(R6)-(C0-C6alkylene)-Q, -(d-C6alkylene)-N(R6)C(0)-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-S(O)0-2-(Ci-C6alkyl), -(Co-Cs alkylene)-S(0)o-2-(Co-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6alkyl), -(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)-(Ci-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0489] any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(d-C4alkyl), -C02H, or halo;

[0490] any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH,

[0491] CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0492] R7and R8are each independently selected from hydrogen and Ci-C6alkyl; and

[0493] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0494] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0495] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0496] R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

[0497] R4and R5are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;

[0498] wherein:

[0499] (i) when A is optionally substituted phenyl, then (a) neither N(R7)C(R4)(R5)(R6) nor NCR8)^1)^2)^3) is 4-[[2-[2-(2-aminoethoxy)ethoxy]ethyl]amino] and (b)

[0500] N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH2CH2CHO, NHCH2CH2OCH3, NHCH2CH2OH, NHCH2CH(OH)CH3, NHCH2CH2OC(0)phenyl, NHCH2CH2CH2OH,

[0501] NHCH2CH2CH2N(CH3)phenyl, NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or NHCH2CH2OC(0)CH3;(ii) when X is N and A is an optionally substituted pyridyl, then (A) neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then Ν^8)^1)^2)^3) is not NHCH2-phenyl or NH-CH2CH3;

[0502] (iii) when X is N and A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3; and

[0503] (iv) the compound is not selected from the group:

[0504] (1) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-phenyl-l ,3,5-triazine-2,4- diamine,

[0505] (2) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-methoxyphenyl)-l,3,5- triazine-2,4-diamine,

[0506] (3) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(3-nitrophenyl)-l,3,5- triazine-2,4-diamine,

[0507] (4) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-fluorophenyl)-l ,3,5- triazine-2,4-diamine,

[0508] (5) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-trifluoromethoxy- phenyl)-l,3,5-triazine-2,4-diamine,

[0509] (6) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-t-butyl-phenyl)-l ,3,5- triazine-2,4-diamine,

[0510] (7) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(2-thienyl)-l ,3,5-triazine- 2,4-diamine,

[0511] (8) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-lH-inden-2-yl)amino]-6-phenyl-l,3,5- triazin-2-yl]amino]methyl]-benzamide,

[0512] (9) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4- (methylsulfonyl)-benzamide,(10) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-methoxyphenyl)- 1 ,3,5-triazine-2,4-diamine,

[0513] (11) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3- yl]thio]-acetamide,

[0514] (12) N2-cyclopropyl-N4-ethyl-6-[3-[(phenylme l)thio]-lH ,2,4-triazol-l-yl]-l,3,5- triazine-2,4-diamine,

[0515] (13) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3- yl]thio]- acetic acid methyl ester,

[0516] (14) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(2,4,6-trimethylphenyl)- l,3,5-triazine-2,4-diamine,

[0517] (15) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-phenyl-l ,3,5-triazine- 2,4-diamine,

[0518] (16) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-methylphenyl)-l ,3,5- triazine-2,4-diamine,

[0519] (17) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-chlorophenyl)-l ,3,5- triazine-2,4-diamine,

[0520] (18) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,

[0521] (19) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l -yl)-N4-phenyl-l,3,5-triazine-2,4- diamine,

[0522] (20) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]- l,3,5-triazine-2,4-diamine,

[0523] (21) N2,N4-dicyclohexyl-6-[3-(3,4-dimethoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]- l,3,5-triazine-2,4-diamine,

[0524] (22) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 - yl] - 1 ,3 , 5 -triazine-2,4-diamine,

[0525] (23) N2,N4-dicyclohexyl-6-phenyl-l,3,5-triazine-2,4-diamine,

[0526] (24) 1 ,1 '-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],

[0527] (25) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l,l-dimethylethyl)-phenol,

[0528] (26) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3- (trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-l ,3,5-triazin-2-yl]-glycine,

[0529] (27) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3-fluorophenyl)-l ,3,5-triazin-2-yl]amino]ethyl]- phenol,

[0530] (28) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4-fluorophenyl)-l ,3,5-triazin-2-yl]amino]ethyl]- phenol,

[0531] (29) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine,

[0532] (30) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l ,3,5-triazine-2,4-diamine,

[0533] (31) 4,4'-[[6-[3,5-bis(l ,l -dime lethyl)-4-hydroxyphenyl] ,3,5-triazine-2,4- diyl]bis(imino-3,l -propanediyl)]bis[2,6-bis(l ,1 -dimethylethyl)-phenol,

[0534] (32) 4,4 (6-phenyl-l ,3,5-triazine-2,4-diyl)bis^

[0535] dimethylethyl)-phenol,

[0536] (33) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l ,3,5-triazine-2,4-diamine,

[0537] (34) 2-chloro-4-(methylsulfonyl)-N- [4 -[(phenylmethyl)amino] -6-(2-pyridinyl)- 1 ,3,5- triazin-2-yl]-benzamide,

[0538] (35) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,

[0539] (36) [[4-[ [ [[ [4-amino-6-(4-pyridinyl)- 1 ,3 ,5-triazin-2-yl]amino]methoxy]methyl]amino]- 6-(4-pyridinyl)-l ,3,5-triazin-2-yl]imino]bis-methanol,

[0540] (37) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]i methanol,

[0541] (38) 5-[4,6-bis(diethylamino)-l ,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,

[0542] (39) N2,N2,N4,N4-tetraethyl-6-(2H-tetrazol-5-yl)-l ,3,5-triazine-2,4-diamine, and

[0543] (40) N V-[6-[4-(acetylamino)-l ,2,5-oxadiazol-3-yl]-l ,3,5-triazine-2,4-diyl]bis-acetamide.

[0544] Also provided is a compound of Formula la, or a pharmaceutically acceptable salt or hydrate thereof:

[0545] (la), wherein:

[0546] ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;

[0547] R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0548] R2and R5are each independently selected from: -(Ci-C6alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(Ci-Cg alkyl)-C02H -(C2-C6alkenyl or alkynyl), -(Ci-C6alkylene)-N(R6)-(Ci-C6

[0549] alkylene)-0-(Ci-C6alkyl), -(Ci-Cg alkylene)-N(R6)-(C0-C6alkylene)-Q, -(Ci-Cg

[0550] alkylene)-N(R6)(R6), -(Ci-C6alkylene)-N(R6)-S(0)i-2-(Ci-C6alkyl), -(d-C6

[0551] alkylene)-N(R6)-S(O)i-2-(C0-C6alkyl)-Q, -(Ci-C6alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4

[0552] alkylene)-S(0)i-2-N(R6)-(Ci-C6alkylene)-Q, -C(0)N(R6)-(Ci-C6alkylene)-C(O)- (C0-C6alkylene)-0-(Ci-C6alkyl), -C(0)N(R6)-(Ci-C6alkylene)-C(O)-(C0-C6alkylene)-O-(C0-C6alkylene)-Q, -(Ci-Cg alkylene)-0-C(0)-(d-C6alkyl), -(Ci-Cg alkylene)-O-C(O)-(C0-C6alkyl)-Q, -(Ci-C6alkylene)-0-(Ci-C6alkyl), -(Ci-C6alkylene)-0-(Ci-C6alkylene)-Q, -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-0-(d-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6

[0553] alkylene)-0-(Ci-C6alkylene)-Q, -(Ci-Cg alkylene)-0-C(0)-(d-C6alkyl), -(d-C6

[0554] alkylene)-O-C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)N(R6)-(Ci-C6alkyl), -(C0-C6alkylene)-C(O)N(R6)-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)C(0)-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-S(O)0-2-(Ci-C6alkyl), -(C0-C6alkylene)-S(0)o-2-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6alkyl), -(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)-(d-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0555] any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(Ci-C4alkyl), -C02H, or halo;any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH,

[0556] CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0557] R7and R8are each independently selected from hydrogen and Ci-C6alkyl; and

[0558] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0559] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0560] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0561] R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

[0562] R4and R5are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; wherein:

[0563] (i) when A is optionally substituted phenyl, then (a) neither N(R7)C(R4)(R5)(R6) nor NtR8)^1)^2)^3) is NHCH2CH2OCH2CH2OCH2CH2NH2or 4-[[2-[2-(2- aminoethoxy)ethoxy]ethyl]amino] and (b) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH2CH2CHO, NHCH2CH2OCH3, NHCH2CH2OH, NHCH2CH(OH)CH3,

[0564] NHCH2CH2OC(0)phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2N(CH3)phenyl,

[0565] NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or

[0566] NHCH2CH2OC(0)CH3;

[0567] (ii) when A is an optionally substituted pyridyl, then (A) neither N(R7)C(R4)(R5)(R6) nor NtR8)^1)^2)^3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], N(CH3)2,

[0568] NHCH2CH2CH2S02CH2CH2C1, NHCH2CH2OCH2CH2S02CH2CH2Cl,or

[0569] NHCH2CH2S02CH2CH2C1, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3;(iii) when A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and

[0570] NtR8)^1)^2)^3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;

[0571] (iv) when A is optionally substituted 1 -pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor NiR^CiR1)^2)^3) is N(CH3)2, NHCH3, NHAc, NHisopropyl, NHCH2CH3, NHCH2CH2S03H or N(CH2CH3)2,

[0572] (v) when A is optionally substituted phenyl,thienyl, or pyridinyl, then neither

[0573] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexylC(0)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3,

[0574] (vi) when A is an optionally substituted phenyl and R4and R5form an optionally substituted phenyl, then Ν^8)^1)^2)^3) is not NHCH2(4-fluorophenyl), NHCH2C02H, NHCH2C(0)C1, NHCH(C02H)(CH2SCH2phenyl), or NHCH2C(0)NHC(0)NHR or

[0575] NHCH2C(0)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl,

[0576] (vii) when A is an oxadiazole substituted with an optionally substituted pyridinyl, then R4and R5do not form an optionally substituted phenyl,

[0577] (viii) when A is substituted 1 -pyrazolyl, then (A) then N(R7)C(R4)(R5)(R6) and

[0578] N(R8)C(R1)(R2)(R3) are not both NHC(CH3)3, and (B) A is not substituted with N=N-R, wherein R is a ring,

[0579] (ix) ring A is not an optionally substituted triazolyl, 3,5-dimethyl-lH-pyrazol-l -yl,

[0580] (x) when R1and R2are optionally taken together to form an unsubstituted cyclohexyl, and R4and R5are optionally taken together to form an unsubstituted cyclohexyl, then A is not a disubstituted 1 -pyrazolyl or an unsubstituted phenyl;

[0581] (xi) the compound is not selected from the group:

[0582] (1) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-lH-inden-2-yl)amino]-6-phenyl-l,3,5-triazin-2- yl ] amino] methyl] -b enzamide,

[0583] (2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4-(methylsulfonyl)- benzamide,

[0584] (3) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3-yl]thio]- acetamide,

[0585] (4) N2-cyclopropyl-N4-ethyl-6-[3 -[(phenylmethyl)thio]-lH-l ,2,4-triazol-l-yl]-l,3,5-triazine-2,4-diamine,

[0586] (5) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3-yl]thio]- acetic acid methyl ester,

[0587] (6) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2-yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,

[0588] (7) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l -yl)-N4-phenyl-l ,3,5-triazine-2,4-diamine,

[0589] (8) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l -yl]-l ,3,5-triazine- 2,4-diamine,

[0590] (9) N2,N4-dicyclohexyl-6- [3 -(3 ,4-dimethoxyphenyl)-5 -(methylthio)- 1 H-pyrazol- 1 -yl] -1 ,3,5- triazine-2,4-diamine,

[0591] ( 10) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 -yl]- 1 ,3 , 5 - triazine-2,4-diamine,

[0592] (1 1) N2,N4-dicyclohexyl-6-phenyl-l ,3,5-triazine-2,4-diamine,

[0593] (12) 1 ,1 '-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],

[0594] (13) 4,4'-[(6-phenyl-l ,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l ,l - dimethylethyl)- phenol,

[0595] (14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-l ,3,5-triazin-2-yl]-glycine,

[0596] (15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3-fluorophenyl)-l ,3,5-triazin-2-yl]amino]ethyl]- phenol,

[0597] (16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4-fluorophenyl)-l ,3,5-triazin-2-yl]amino]ethyl]- phenol,

[0598] (17) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine,

[0599] (18) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l ,3,5-triazine-2,4-diamine,

[0600] (19) 4,4'-[[6-[3,5-bis(l ,l -dime lethyl)-4-hydroxyphenyl]-l ,3,5-triazine-2,4-diyl]bis(imm^ propanediyl)]bis[2,6-bis(l ,l -dimethylethyl)-phenol,

[0601] (20) 4,4'-[(6-phenyl-l ,3,5-triazine-2,4-diyl)bis(imino-3,l -propanediyl)]bis[2,6-bis(l J

[0602] dimethylethyl)-phenol,

[0603] (21) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l ,3,5-triazine-2,4-diamine,

[0604] (22) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]-benzamide,(23) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,

[0605] (24) [[4-[[[[[4-amino-6-(4^yridinyl)-l,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4- pyridinyl)-l ,3,5-triazin-2-yl]imino]bis-methanol,

[0606] (25) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- y 1 ] amino ] methoxy] methyl ] (hydroxy meft^

[0607] methanol,

[0608] (26) 5-[4,6-bis(diethylamino)-l,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,

[0609] (27) N2,N2-tetraethyl-6-(2H-tetrazol-5-yl)-l,3,5-triazine-2,4-diami^

[0610] (28) N V'-[6-[4-(acetylamino)-l,2,5-oxadiazol-3-yl]-l ,3,5-triazine-2,4-diyl]bis-acetamide,

[0611] (29) N-(2-chloro-6-methylphenyl)-5-[[4-(dimethylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]-l ,3,4-Oxadiazole-2-carboxamide,

[0612] (30) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(diethylamino)propyl]- 1,3,5 -Triazine-2,4-diamine,

[0613] (31) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3- (dimethylamino)propyl]- 1 ,3,5-Triazine-2,4-diamine,

[0614] (32) N2-[3,5-bis(trifluoromethyl)phenyl]-6-(4-chlorophenyl)-N4-[3-(diethylamino)propyl]-l ,3,5- Triazine-2,4-diamine,

[0615] (33) N2,N4-bis[(4-methoxyphenyl)methyl]-6-[4-(trifluoromethoxy)phenyl]-l ,3,5-Triazine-2,4- diamine,

[0616] (34) N,N"-(6-phenyl-l,3,5-triazine-2,4-diyl)bis[N'-(2-chloroethyl)-Urea,

[0617] (35) N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-methyl-3-[[4-phenyl-6-(propylamino)-l ,3,5- triazin-2-yl]amino]phenyl]-urea,

[0618] (36) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]-glycine,

[0619] (37) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(5-thiazolyl)-l, 3, 5-triazin-2-yl]-L- Valine,

[0620] (38) s-Triazine, 2-phenyl-4,6-bis[[6-[[4-phenyl-6-[[6-[[4-phenyl-6-(trichloromethyl)-s-triazin-2- yl]amino]hexyl]amino]-s-triazin-2-yl]amino]hexyl]amino]-,

[0621] (39) α,α'- [(6-phenyl- 1,3,5 -triazine-2,4-diyl)bis [imino( 1 , 1 ,2,2-tetrafluoro-3 -oxo-3 , 1 -propanediyl)]]bis[ro-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)- 1,2-ethanediyl]],

[0622] (40) a-[[4-[[(3-chlorophenyl)methyl]amino]-6-(lH-imidazol-l-yl)-l,3,5-triazin-2-yl]amino]-N^ [[4-(trifluoromethyl)phenyl]methyl]-, (aR)-Cyclohexanepropanamide,

[0623] (41) N,A -[6-[4-(acetylamino)-l,2,5-oxadiazol-3-yl]^

[0624] (42) 6-(l H-imidazol- 1 -yl)-N2,N4-bis( 1 -methylethyl)- 1,3,5 -Triazine-2,4-diamine, and

[0625] (43) N2,N4-bis(l -methylpropyl)-6-phenyl-l ,3,5-Triazine-2,4-diamine.

[0626] In some embodiments, R and R4are eachindependently selected from

[0627] hydrogen, -CH3, -CH2CH3,-CH2OH, -CH(CH3)OH,-C(CH3)2OH, CF3, CN, or R1and R3are taken together to form =0; orR4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0).

[0628] In some embodiments, R1and R2are taken together to form carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, -CN, =0, -OH, and -C(0)Ci-C4alkyl.In some embodiments, R1and R2are taken together to form a carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, Ci-C alkyl, Ci-C haloalkyl, Ci-C alkoxy, -CN, =0, -OH, aryl, heteroaryl- S02Ci-C4alkyl, -C02Ci-C4alkyl, -C(0)aryl,and -C(0)d-C4alkyl. In some embodiments R1and R2are taken together to form 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, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, -CN, and -OH. In some embodiments R1and R2are taken together to form a carbocyclyl or heterocyclyl, either of which is optionally substituted with phenyl, pyridinyl or pyrimidinyl, which is optionally substituted with up to 2 substituents independently selected from halo, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, -CN, and -OH.

[0629] In some embodiments, R4and R5are taken together to form carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, C C4alkyl, C C4haloalkyl, C C4alkoxy, -CN, =0, -OH, and -C(0)Ci-C4alkyl.In some embodiments, R4and R5are taken together to form a carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, -CN, =0, -OH, aryl, heteroaryl - SO2C1-C4 alkyl, -CO2C1-C4 alkyl, -C(0)aryl, and -C(0)Ci-C4alkyl. In some embodiments R1and R2are taken together to form 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, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, and -OH. In some embodiments R1and R2are taken together to form a carbocyclyl or heterocyclyl, either of which is optionally substituted with phenyl, pyridinyl or pyrimidinyl, which is optionally substituted with up to 2 substituents independently selected from halo, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, -CN, and -OH.

[0630] In some embodiments,R2and R5are each independently selected from: -(Ci-C6alkyl), - (Ci-C6alkyl)-C(0)-NH2, -(Ci-C6alkyl)-C02H -(C2-C6alkenyl or alkynyl), -(Ci-C6

[0631] alkylene)-0-(Ci-C6alkyl), -(C0-C6alkylene)-C(0)N(R6)-(Ci-C6alkyl),

[0632] -(Co-Cg alkylene)-Q, -(C0-C6alkylene)-C(0)-(d-C6alkyl), and -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, =0, -C(0)-Ci-C4alkyl, -CN, and halo.

[0633] In some embodiments, R2and R5are each independently selected from: -(C1-C4alkyl) optionally substituted with halo, e.g., fluoro or -OH;-(C0-C4alkylene)-0-(Ci-C4alkyl), -(C0-C2alkylene)-N(R6)-(Ci-C6alkyl), -(Ci-C6alkyl)-C(O)-NH2,-(C0-C2alkylene)-Q, -(C0-C6

[0634] alkylene)-C(0)-(Ci-C6alkyl), and -O-(C0-C2alkylene)-Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, =0, -C(0)-Ci-C4 alkyl, -CN, and halo. In one aspect of these embodiments, Q is selected from pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl and oxetanyl, wherein Q is optionally substituted with up to 2 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, =0, fluoro, chloro, and bromo. In another aspect of these embodiments, Q is selected from pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl and oxetanyl, wherein Q is optionally substituted with up to 2

[0635] substituents independently selected from -CH3and =0.In some embodiments, R1and R2are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl, oxobicyclo[3.1.0]hexanyl, azetidinyl, any of which is optionally substituted with up to 2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy,C3-C6

[0636] cycloalkyl, -OH, -C(0)CH3, fluoro, and chloro.

[0637] In some embodiments, R4and R5are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl, oxobicyclo[3.1.0]hexanyl, or azetidinyl, any of which is optionally substituted with up to 2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy,C3-C6

[0638] cycloalkyl, -OH, -C(0)CH3, fluoro, and chloro. In some embodiments, R4and R5are taken together to form 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, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C3-C6 cycloalkyl, phenyl,-OH, -C(0)CH3, wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH2, or-CN. In some

[0639] embodiments the C3-C6cycloalkyl is

[0640] In some embodiments, R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, - NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2; and R2and R5are each independently selected

[0641] from: -(Ci-C6alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(d-C6alkyl)-C02H -(C2-C6alkenyl or alkynyl), -(Ci-C6alkylene)-0-(Ci-C6alkyl), -(C0-C6alkylene)-C(0)N(R6)-(Ci-C6alkyl), and -(C0-C6alkylene)-C(0)-(Ci-C6alkyl), wherein:any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(Ci-C4alkyl), -C02H, or halo; and any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH,

[0642] CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H; or R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0643] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0);or R1and R2are optionally taken together to form an optionally substituted carbocyclyl; or R4and R5are optionally taken together to form an optionally substituted carbocyclyl, wherein, when A is an optionally substituted phenyl, 2-pyrrolyl, or 1-imidazolyl, then N(R7)C(R4)(R5)(R6) is not the same as

[0644] NCR^CCR'XR'XR3), and the compound is not 2-(l,2-dibromoethyl)-4-phenyl-6-(l, 1,2,2,3,3 ,4,4,5,5,6,6,6- tridecafluorohexyl- 1 ,3 ,5 -Triazine.

[0645] 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.

[0646] In some embodiments, ring A is a substituted 5-6 member monocyclic aryl or monocyclic heteroaryl, which is substituted with up to two substituents independently selected from halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(0)2-(Ci-C4

[0647] alkyl), -S(0)2NH(Ci-C4alkyl), -CN, -S(0)2-(d-C4alkyl), C1-C4 alkoxy, -NH(Ci-C4

[0648] alkyl), -OH, -OCF3, -CN, -NH2, -C(0)NH2, -C(0)NH(Ci-C4alkyl), -C(0)-N(Ci-C4

[0649] alkyl)2, -(Ci-C6alkylene)-0-(Ci-C6alkyl), azetidinyl, phenyl, and cyclopropyl optionally substituted with OH. In some embodiments, ring A is a substituted 5-6 member monocyclic aryl or monocyclic heteroaryl, which is substituted with up to two substituents independently selected from fluoro, chloro, CF3, CF2, -OH, -OCH3, -OCF3, -CN, -NH2.In some embodiments, ring A is a substituted 6-membered monocyclic aryl. In some embodiments, ring A is a substituted 5-6 membered heteroaryl. In some embodiments, ring A is a substituted 5-membered heteroaryl.

[0650] 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, -Ci-C alkyl, -Ci-C haloalkyl, -Ci-C hydroxyalkyl, -NH-S(0)2-(Ci-C4alkyl), -S(0)2NH(Ci-C4alkyl), -CN, -S(0)2-(Ci-C4alkyl), Ci-C4alkoxy, -NH(Ci-C4alkyl), -OH, -OCF3, -CN, -NH2, -C(0)NH2, -C(0)NH(Ci-C4alkyl), - C(0)-N(Ci-C alkyl)2, and cyclopropyl optionally substituted with OH.

[0651] In some embodiments, ring A is selected from phenyl, pyrazolyl, imidazolyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl,thiazolyl, thiadiazolyland isothiazolyl, wherein ring A is optionally substituted with up to two substituents independently selected from halo, -Ci-C4alkyl, -Ci-C4haloalkyl, -Ci-C4hydroxyalkyl, -NH-S(0)2-(Ci-C4alkyl), -S(0)2NH(Ci-C4alkyl), -CN, -S(0)2-(Ci-C4alkyl), Ci-C4alkoxy, -NH(Ci-C4

[0652] alkyl), -OH, -CN, and -NH2.In some embodiments, ring A is monocyclic heteroaryl optionally substituted with halo, -C1-C4alkyl, -C1-C4haloalkyl, -O-C1-C4haloalkyl, -OH, -CN, and -NH2; R1, R3, R4, and R6are each independently selected from hydrogen and C1-C4alkyl; and R2and R5are each independently -(C0-C6 alkylene)-Q; or R1and R2are optionally taken together to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl; orR4and R5are optionally taken together to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

[0653] In some embodiments, ring A is monocyclic heteroaryl optionally substituted with halo, -C1-C4alkyl, -C1-C4haloalkyl, -O-C1-C4haloalkyl, -OH, -CN, and -NH2; R1, R3, R4, and R6are each independently selected from hydrogen and C1-C4alkyl; and R2and R5are each independently -(C0-C6alkylene)-Q; or R1and R2are optionally taken together to form an optionally substituted carbocyclyl oran optionally substituted heterocyclyl; orR4and R5are optionally taken together to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroar l.

[0654] In some embodiments, ring A is:, wherein R is selected from hydrogen, halo, and -C1-C4haloalkyl; each Xais independently N or C-R9a, provided that when one Xais N, then the other two Xaare both C-R9a; and R9ais selected from hydrogen, halo, and -C1-C4haloalkyl.

[0655] In some embodiments, ring A is:, wherein R9is selected from hydrogen, halo,

[0656] and -C1-C4haloalkyl. In some embodiments, ring A is:, wherein R9is selected from h drogen, halo, and -C1-C4haloalkyl. In some embodiments, ring A is:

[0657] is selected from hydrogen, halo, and -C1-C4haloalkyl.

[0658] In some embodiments, ring A is pyridinyl optionally substituted with halo or -C1-C4haloalkyl. In some embodiments, ring A is pyridinyl optionally substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyridi -2-yl substituted with -C1-C4haloalkyl, e.g., -CHF2and

[0659] CF3. In some embodiments, ring A is:wherein R is selected from hydnhalo, and -C1-C4 haloalkyl. In some embodiments, ring A is:, wherein each R9is independently selected from hydrogen, halo, and -C1-C4 haloalkyl. In some embodiments, R9is chloro or fluoro. In some embodiments, R9is -CHF2or CF3. In some embodiments, R9is CF3or chloro. In some embodiments, R9is CF3.

[0660] In some embodiments, ring A is:is selected from hydrogen and -C1-C4 alkyl, and wherein R9is selected from hydrogen, halo, and -C1-C4 haloalkyl.

[0661] In some embodiments, ring A is:, wherein R is selected from hydrogen and -C1-C4 alkyl, and wherein R is selected from h drogen, halo, and -C1-C4 haloalkyl.

[0662] In some embodiments, ring A is:, wherein R is selected from hydrogen and -C1-C4 alkyl, and wherein R is selected from hydrogen, halo, and -C1-C4 haloalkyl.

[0663] In some embodiments, ring A is:, wherein R is selected from hydrogen, halo, and -C1-C4 haloalkyl. In some embodiments, ring A is pyrazolyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrazolyl optionally substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is IH-pyrazol-l- l substituted with -C1-C4

[0664] haloalkyl, e.g., -CHF2and CF3. In some embodiments, ring A is:, wherein R is selected from hydrogen, halo, and -C1-C4 haloalkyl. In some embodiments, R9is chloro or fluoro. In some embodiments, R9is -CHF2or CF3. In some embodiments, R9is CF3or chloro. In some embodiments, R9is CF3.

[0665] g

[0666] In some embodiments, ring A is:, wherein R is selected from hydrogen, halo, and -C1-C4 haloalkyl.

[0667] In some embodiments, ring A is:wherein R9is selected from hydi halo, and -C1-C4 haloalkyl.

[0668] In some embodiments, ring A is:, wherein R is selected from hydrogen, halo, and -C1-C4 haloalkyl.

[0669] In some embodiments, ring A is:is selected from hydrogen, halo, and -C1-C4 haloalkyl.

[0670] In some embodiments, ring A is:, wherein R is selected from hydrogen, halo, and -C1-C4 haloalkyl.

[0671] In some embodiments, ring A is:, wherein R9is selected from hyd:

[0672] halo, and -C1-C4haloalkyl.

[0673] In some embodiments, ring A is:, wherein R9is selected from hydrogen, halo, and -C1-C4haloalkyl.

[0674] In some embodiments, ring A is pyridinyl optionally substituted with halo or -C1-C4haloalkyl. In some embodiments, ring A is pyridinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyridinyl substituted with -C1-C4haloalkyl, e.g., -CHF2and CF3. In some embodiments, ring A is pyrazinyl optionally substituted with halo or -C1-C4haloalkyl. In some embodiments, ring A is pyrazinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazinyl substituted with -C1-C4haloalkyl, e.g., -CF£F2and CF3. In some embodiments, ring A is pyrimidinyl optionally substituted with halo or -C1-C4haloalkyl. In some embodiments, ring A is pyrimidinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrimidinyl substituted with -C1-C4haloalkyl, e.g., -CF£F2and CF3. In some embodiments, ring A is pyrazolyl optionally substituted with halo or -C1-C4haloalkyl. In some embodiments, ring A is pyrazolyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazolyl substituted with -C1-C4haloalkyl, e.g., -CF£F2and CF3.

[0675] In some embodiments, R1, R3, R4, and R6are each independently selected from hydrogen and C1-C4alkyl; and R2and R5are each independently -(C0-C6alkylene)-Q. In some embodiments, R1and R4are each hydrogen. In some embodiments, R3and R6are each C1-C4alkyl. In someembodiments, R3and R6are each C1-C4haloalkyl. In some embodiments, Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted. In some embodiments, Q is optionally substituted carbocyclyl. In some embodiments, Q is optionally substituted cyclopropyl.In some embodiments, Q is unsubstituted cyclopropyl. In some embodiments, R2and R5are each independently unsubstituted cyclopropyl. In some

[0676] embodiments, R1and R4are each hydrogen, R3and R6are each -CH3, and R2and R5are each unsubstituted cyclopropyl. In some embodiments, R2is -(C0-C6 alkylene)-cyclopropyl and R5is -(C0-C6alkyl en e)-aryl, e.g., optionally substituted phenyl. In some embodiments, R2is cyclopropyl and R5is phenyl substituted with halo, e.g., fluoro.

[0677] In some embodiments, ring A is pyridinyl optionally substituted with halo or -C1-C4haloalkyl. In some embodiments, ring A is pyridinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyridinyl substituted with -C1-C4haloalkyl, e.g., -CHF2and CF3. In some embodiments, ring A is pyrazinyl optionally substituted with halo or -C1-C4haloalkyl. In some embodiments, ring A is pyrazinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazinyl substituted with -C1-C4haloalkyl, e.g., -CHF2and CF3. In some embodiments, ring A is pyrimidinyl optionally substituted with halo or -C1-C4haloalkyl. In some embodiments, ring A is pyrimidinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrimidinyl substituted with -C1-C4haloalkyl, e.g., -CHF2and CF3. In some embodiments, ring A is pyrazolyl optionally substituted with halo or -C1-C4haloalkyl. In some embodiments, ring A is pyrazolyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazolyl substituted with -C1-C4haloalkyl, e.g., -CF£F2and CF3.

[0678] In some embodiments, R3and R6are each independently selected from hydrogen and C1-C4alkyl; R1and R2are taken together to form an optionally substituted carbocyclyl; and R4and R5are taken together to form an optionally substituted carbocyclyl.In some embodiments, R1and R2are taken together to form a cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted. In some embodiments, R1and R2are taken together to form a cyclopentyl or cyclohexyl, each optionally substituted. In some embodiments, R4and R5are taken together to form a cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted. In some embodiments, R4and R5are taken together to form a cyclopentyl or cyclohexyl, each optionally substituted. In some embodiments, R1and R2are taken together to form a cyclopentyl or cyclohexyl, each substitutedby one or more halo, e.g., fluoro; and R4and R5are taken together to form a cyclobutyl, cyclopentyl or cyclohexyl, each substituted by one or more halo, e.g., fluoro. In some embodiments, R1and R2are taken together to form a bicyclo[3.1.OJhexanyl; and R4and R5are taken together to form a bic clo[3.1.O hexanyl.In some embodiments, R1and R2taken together,

[0679] or

[0680] 1and R taken together, and R4and R5taken

[0682] halo, e.g. fluoro, chloro, or bromo. In some embodiments, R1and R2taken together, and R4andR5taken together form:.In some embodiments, R1and R2are taken together to form a cyclobutyl, cyclopentyl or cyclohexyl, each substituted by one or more 6-member monocyclic aryl, e.g., phenyl, which is optionally substituted with halo, e.g. fluoro, chloro, or bromo; and R4and R5are taken together to form a cyclobutyl, cyclopentyl or cyclohexyl, each substituted by one or more 6-member monocyclic aryl, e.g., phenyl, which is optionally substituted with halo, e.g. fluoro, chloro, or bromo. In some embodiments, R1and R2or R4and

[0683] R3are taken together form:, wherein Ring C is phenyl, pyridyl, or pyrimidinyl, which is optionally substituted with cyano or halo, e.g. fluoro, chloro, or bromo.In

[0684] some embodiments, R1and R2or R4and R5are taken together form:

[0685] wherein Ring C is phenyl, pyridyl, or pyrimidinyl, which is optionally substituted with cyano or halo, e.g. fluoro, chloro, or bromo.In some embodiments, R1and R2or R4and R5are taken

[0686] togetherphenyl, pyridyl, or pyrimidinyl, which is optionally substituted with cyano or halo, e.g. fluoro, chloro, or bromo.

[0687] In som embodiments, ring A is pyridinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyridinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyridinyl substituted with -C1-C4 haloalkyl, e.g., -CHF2and CF3. Insome embodiments, ring A is pyrazinyl optionally substituted with halo or -C1-C4haloalkyl. In some embodiments, ring A is pyrazinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazinyl substituted with -C1-C4haloalkyl, e.g., -CHF2and CF3. In some embodiments, ring A is pyrimidinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrimidinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrimidinyl substituted with -C1-C4haloalkyl, e.g., -CF£F2and CF3. In some embodiments, ring A is pyrazolyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrazolyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazolyl substituted with -C1-C4haloalkyl, e.g., -CF£F2and CF3.

[0688] In some embodiments, R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4alkyl, and -CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4alkyl; and R2and R5are each

[0689] independently selected from -(Ci-C6alkyl) and -(C0-C6alkylene)-Q. In some embodiments, R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4 alkyl, and -CN; and R2and R5are each independently -(Ci-C6alkyl) and -(C0-C6alkylene)-Q. In some embodiments, R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4alkyl, and -CN; R2is -(Ci-C6alkyl); and R5is -(C0-C6 alkylene)-Q, wherein Q is optionally substituted carbocyclyl. In some embodiments, Q is unsubstituted carbocyclyl. In some embodiments, Q is cyclopropyl.

[0690] In some embodiments, ring A is pyridinyl optionally substituted with halo or -C1-C4haloalkyl. In some embodiments, ring A is pyridinyl substituted with -C1-C4haloalkyl, e.g., -CF£F2and CF3. In some embodiments, ring A is pyrazinyl optionally substituted with halo or -C1-C4haloalkyl. In some embodiments, ring A is pyrazinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazinyl substituted with -C1-C4haloalkyl, e.g., -CF£F2and CF3. In some embodiments, ring A is pyrimidinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrimidinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrimidinyl substituted with -C1-C4haloalkyl, e.g., -CF£F2and CF3. In some embodiments, ring A is pyrazolyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrazolyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazolyl substituted with -C1-C4haloalkyl, e.g., -CF£F2and CF3.In some embodiments, R1, R3, and R6are each independently selected from hydrogen and C1-C4alkyl, wherein each said alkyl moiety of R1, R3, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4alkyl), or -N(d-C4alkyl)2; R2is -(C0-C6 alkylene)-Q; and R4and R5taken together form an optionally substituted carbocyclyl, optionally substituted heterocyclyl or optionally substituted heteroaryl. In some embodiments, R4and R5taken together form an optionally substituted carbocyclyl. In some embodiments, the carbocyclyl is selected from cyclopentyl and cyclohexyl optionally substituted

[0691] with -OH, -0(Ci-C4alkyl), -C02H, or halo. In some embodiments, R4and R5taken together form an optionally substituted heterocyclyl optionally substituted with -OH, -0(Ci-C4alkyl), - C02H, or halo. In some embodiments, R4and R5taken together form an optionally substituted tetrahydrofuran. In some embodiments, R1, R3, and R6are each independently selected from hydrogen and C1-C4alkyl, wherein each said alkyl moiety of R1, R3, and R6are each

[0692] independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4alkyl; R2is -(C0-C6alkylene)-Q; and R5is C1-C4 alkyl. In some embodiments, R1, R3, and R6are each independently selected from hydrogen, C1-C4alkyl, or carbocyclyl, wherein any alkyl or carbocyclyl portion of R1, R3, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4alkyl, -S02-Ci-C4alkyl, -C(0)NH2, -0-R12,-C02R12or -C(0)R12, wherein R12is morpholino, piperidinyl, phenyl, pyridyl, or pyrimidinyl. In some embodiments, R1, R3, and R6are each independently selected from hydrogen and C1-C4alkyl, wherein each said alkyl moiety of R1, R3, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4alkyl, -O- R12, wherein R12is phenyl, pyridyl, or pyrimidinyl; R2is -(C0-C6alkylene)-Q; and R5is C1-C4alkyl.

[0693] In some embodiments, R7is H. In some embodiments, R8is H. In some embodiments, both R7and R8are H.

[0694] In some embodiments, ring A, R1, R2, R3, R4, R5, R6, R7, R8are selected from any one of the preceding embodiments.

[0695] Also provided is a compound of Formula B, or pharmaceutically acceptable salt or hydrate thereof:(B), wherein:

[0696] X isN, CH or C-halo;

[0697] Xais N or C-R9a, provided that when one Xais N, then the other two Xaare both C-R9a;

[0698] R9is halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(0)2-(Ci-C4

[0699] alkyl), -S(0)2NH(Ci-C4alkyl), -CN, -S(0)2-(d-C4alkyl), C1-C4 alkoxy, -NH(Ci-C4alkyl), - N(Ci-C4alkyl)2, -OH, -OCF3, -CN, -NH2, -C(0)NH2, -C(0)NH(Ci-C4alkyl), -C(0)-N(d-C4alkyl)2, -(Ci-C6alkylene)-0-(Ci-C6alkyl), aryl, and cyclopropyl optionally substituted with OH; each R9ais independently selected from hydrogen, halo, -C1-C4alkyl, -C1-C4haloalkyl, -C1-C4hydroxyalkyl, -NH-S(0)2-(Ci-C4alkyl), -S(0)2NH(Ci-C4alkyl), -CN, -S(0)2-(Ci-C4alkyl), C1-C4alkoxy, -NH(Ci-C4alkyl), -N(d-C4alkyl)2, -OH, -OCF3, -CN, -NH2, -C(0)NH2, - C(0)NH(Ci-C4alkyl), -C(0)-N(d-C4alkyl)2, -(Ci-C6alkylene)-0-(Ci-C6alkyl), aryl, and cyclopropyl optionally substituted with OH;

[0700] R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, -O-C1-C4alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4alkyl, -NH(d-C4alkyl), or -N(Ci-C4alkyl)2;

[0701] R2and R5are each independently selected from: -(Ci-d alkyl), -(Ci-d alkyl)-C(0)-NH2, -(d- C6alkyl)-C02H -(C2-C6alkenyl or alkynyl), -(Ci-C6alkylene)-0-(d-C6alkyl), -(C0-C6alkylene)-C(0)N(R6)-(Ci-C6alkyl),

[0702] -(Co-Cg alkylene)-Q,-(C0-C6alkylene)-C(0)-(d-C6alkyl), and-(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0703] any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(d-C4alkyl), -C02H, or halo;any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH,

[0704] CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0705] R7and R8are each independently selected from hydrogen and Ci-C6alkyl; and

[0706] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0707] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0708] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0709] R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

[0710] R4and R5are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, an optionally substituted 5-6 member monocyclic aryl, or an optionally substituted 5-6 member monocyclic heteroaryl;

[0711] whereinthe compound is not selected from the group:

[0712] (1) 4,6-Pyrimidinediamine, 2-(6-methyl-2-pyridinyl)-N4,N6-dipropyl-;

[0713] (2) 4,6-Pyrimidinediamine, N4-ethyl-2-(6-methyl-2-pyridinyl)-N6-propyl-;

[0714] (3) 4,6-Pyrimidinediamine, N4,N4-diethyl-2-(6-methyl-2-pyridinyl)-N6-propyl-;

[0715] (4) [2,4'-Bipyrimidine]-2',4,6-triamine, N6-[2-(dimethylamino)ethyl]-N2',N2',N4,N4- tetramethyl-; or

[0716] (5) [2,4'-Bipyrimidine]-2',4,6-triamine, N6-[2-(dimethylamino)ethyl]-N2',N2',N4,N4- tetramethyl-, phosphate.

[0717] In some embodiments, X is N and R4and R5are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.

[0718] Also provided is a compound of Formula lb, or pharmaceutically acceptable salt or hydrate thereof:

[0719] (lb), wherein:

[0720] R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, -O-C1-C4alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0721] R2and R5are each independently selected from: -(Ci-C6alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(Ci-Cg alkyl)-C02H -(Co-Cg alkylene)-Q, -(C0-C6alkylene)-C(0)-(d-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0722] any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(d-C4alkyl), -C02H, or halo;

[0723] any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH, CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0724] R7and R8are each independently selected from hydrogen and Ci-C6alkyl;

[0725] R9is selected from hydrogen, halo, and -C1-C4 haloalkyl; and

[0726] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0727] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0728] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0729] R1and R2are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl; or

[0730] R4and R5are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl;

[0731] wherein:(i) neither N(R7)C(R4)(R5)(R6) nor NCR^CCR1)^2)^3) is NHC(0)-[2-chloro-4-(methylsulfonyl)] or N(CH3)2,

[0732] (ii) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3,

[0733] NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and

[0734] (iii) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3; and

[0735] wherein the compound is not:

[0736] (1) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2-yl]-4-(methylsulfonyl)- benzamide,

[0737] (2) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2-yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,

[0738] (3) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l ,3,5-triazin-2-yl]- benzamide, or

[0739] (4) N- [ [4- [ [ [4-(cyclopropylamino)-6-(2-pyridinyl)- 1 ,3,5 -triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide.

[0740] Also provided is a compound of Formula la, or a pharmaceutically acceptable salt or hydrate thereof:

[0741] (Ig), wherein: ring A is is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;

[0742] R3and R6are both hyd:R1and R4are each independently selected from C1-C4alkyl and C1-C4haloalkyl;and R2and R5are each -(Ci-C6alkyl); or

[0743] R1and R2are optionally taken together to form an optionally substituted monocyclic carbocyclyl; or

[0744] R4and R5are optionally taken together to form an optionally substituted monocyclic carbocyclyl ;

[0745] wherein:

[0746] (i) ring A is not an optionally substituted triazolyl, 3,5-dimethyl-lH-pyrazol-l-yl,

[0747] (ii) when R1and R2are optionally taken together to form an unsubstituted cyclohexyl, and R4and R5are optionally taken together to form an unsubstituted cyclohexyl, then A is not a disubstituted 1-pyrazolyl or an unsubstituted phenyl; and

[0748] (iii) the compound is not selected from the group:

[0749] (1) 6-(lH-imidazol-l-yl)-N2,N4-bis(l -methylethyl)-l ,3,5-Triazine-2,4-diamine, or

[0750] (2) N2,N4-bis(l -methylpropyl)-6-phenyl-l ,3,5-Triazine-2,4-diamine.

[0751] Also provided is a compound of Formula C, or pharmaceutically acceptable salt or hydrate thereof:

[0752] (C), wherein:

[0753] X is N, CH or C-halo;

[0754] each Xbis independently N-R9b, O, S, C-H, or C-R9c, provided that at least one Xbis C-R9c, and when one Xbis C-H or C-R9and the other is C-R9cthen Xcis N, and when one Xbis N-R9b, O, or S,then Xcis C;

[0755] R9bis hydrogen or -C1-C4alkyl;

[0756] R9cis halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(0)2-(Ci-C4alkyl), -S(0)2NH(Ci-C4alkyl), -CN, -S(0)2-(Ci-C4alkyl), C1-C4 alkoxy, -NH(Ci-C4alkyl), -N(Ci-C4alkyl)2, -OH, -OCF3, -CN, -NH2, -C(0)NH2, -C(0)NH(d-C4alkyl), -C(0)-N(d-C4alkyl)2, -(Ci-C6alkylene)-0-(Ci-C6alkyl), aryl, and cyclopropyl optionally substituted with OH; R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4 alkyl, C1-C4

[0757] haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0758] R2and R5are each independently selected from: -(Ci-C6alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(Ci- C6alkyl)-C02H -(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)-(d-C6alkyl), -(C0-C6

[0759] alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0760] any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(d-C4alkyl), -C02H, or halo;

[0761] any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH,

[0762] CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0763] R7and R8are each independently selected from hydrogen and Ci-d alkyl; and

[0764] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0765] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0766] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0767] R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

[0768] R4and R5are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, an optionally substituted 5-6 member monocyclic aryl, or an optionally substituted heteroaryl;

[0769] wherein:

[0770] (i) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1-pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH; and

[0771] (ii) when X and Xcare both N, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) isN(CH3)2, NHCH3, or N(CH2CH3)2.

[0772] Also provided is a compound having Formula Id, or pharmaceutically acceptable salt or hydrate thereof:

[0773] (Id), wherein:

[0774] R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0775] R2and R5are each independently selected from: -(Ci-C6alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(Ci-Cg alkyl)-C02H -(Co-Cg alkylene)-Q, -(C0-C6alkylene)-C(0)-(Ci-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0776] any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(d-C4alkyl), -C02H, or halo;

[0777] any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH, CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0778] R7and R8are each independently selected from hydrogen and Ci-C6alkyl;

[0779] R9is halo or-Ci-C4haloalkyl; and

[0780] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0781] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0782] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0);R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

[0783] R4and R5are optionally taken together to form an optionally substituted

[0784] carbocyclyl,optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;

[0785] whereinthe compound is not:

[0786] (1) N2,N2,N4-trimethyl-6-[3-(trifluoromethyl)-lH-pyrazol-l -yl]- l,3,5-Triazine-2,4-diamine, or

[0787] (2) N4-ethyl-N2,N2-dimethyl-6-[3-(trifluoromethyl H-pyrazol-l -yl]-l ,3,5-Triazine-2,4-diamine.

[0788] A com ound having Formula Ie, or pharmaceutically acceptable salt or hydrate thereof:

[0789] (Ie), wherein

[0790] R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4alkyl, C1-C4

[0791] haloalkyl, -O-C1-C4alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0792] R2and R5are each independently selected from: -(Ci-C6alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(Ci-Cg alkyl)-C02H -(Co-Cg alkylene)-Q, -(C0-C6alkylene)-C(0)-(d-C6alkyl), -(C0-C6alkylene)-C(0)-(Co-C6 alkylene)-Q, wherein:

[0793] any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(d-C4alkyl), -C02H, or halo;

[0794] any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH, CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0795] R7and R8are each independently selected from hydrogen and Ci-C6alkyl;

[0796] R9is selected from hydrogen, halo, and -C1-C4haloalkyl; andQ is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0797] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0798] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0);

[0799] R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

[0800] R4and R5are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.

[0801] A com ound having Formula If, or pharmaceutically acceptable salt or hydrate thereof:

[0802] (If), wherein

[0803] R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, -O-C1-C4alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0804] R2and R5are each independently selected from: -(Ci-C6alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(Ci-Cg alkyl)-C02H -(Co-Cg alkylene)-Q, -(C0-C6alkylene)-C(0)-(Ci-C6alkyl), -(C0-C6alkylene)-C(0)-(Co-C6 alkylene)-Q, wherein:

[0805] any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(d-C4alkyl), -C02H, or halo;

[0806] any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH, CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;R7and R8are each independently selected from hydrogen and Ci-C6alkyl;

[0807] R9is selected from hydrogen, halo, and -C1-C4haloalkyl; and

[0808] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0809] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0810] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0);

[0811] R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

[0812] R4and R5are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.

[0813] Also provided is a compound of Formula Π, or pharmaceutically acceptable salt or hydrate thereof:

[0814] (Π), wherein:

[0815] ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;

[0816] R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, -O-C1-C4alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0817] R2and R5are each independently selected from: -(Ci-C6alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(Ci-Cg alkyl)-C02H -(C2-C6alkenyl or alkynyl), -(C C6

[0818] alkylene)-N(R6)-(Ci-C6alkylene)-0-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)-(C0-C6

[0819] alkylene)-Q, -(Ci-C6alkylene)-N(R6)(R6), -(Ci-C6alkylene)-N(R6)-S(0)i-2-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)-S(O)i-2-(C0-C6alkyl)-Q, -(Ci-C6alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6alkylene)-Q, -C(0)N(R6)-(Ci-C6alkylene)-C(O)- (C0-C6alkylene)-0-(Ci-C6alkyl),-C(0)N(R6)-(Ci-C6alkylene)-C(O)-(C0-C6alkylene)-O-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-0-C(0)-(Ci-C6alkyl), -(Ci-C6alkylene)-O-C(O)-(C0-C6alkyl)-Q, -(Ci-C6alkylene)-0-(Ci-C6alkyl), -(Ci-C6alkylene)-0-(Ci-C6alkylene)-Q, -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-0-(d-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6

[0820] alkylene)-0-(Ci-C6alkylene)-Q, -(Ci-C6alkylene)-0-C(0)-(Ci-C6alkyl), -(Ci-C6

[0821] alkylene)-O-C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)N(R6)-(Ci-C6alkyl),-(C0-C6alkylene)-C(O)N(R6)-(C0-C6alkylene)-Q, -(Ci-C6alkylene)-N(R6)C(0)-(Ci-C6alkyl), -(Ci-C6alkylene)-N(R6)C(O)-(C0-C6alkylene)-Q, -(C0-C6alkylene)-S(O)0-2-(Ci-C6alkyl),-(C0-C6alkylene)-S(0)o-2-(C0-C6alkylene)-Q,-(Ci-C6alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6alkyl),-(C0-C6alkylene)-Q, -(C0-C6alkylene)-C(0)-(d-C6alkyl), -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0822] any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(d-C4alkyl), -C02H, or halo;

[0823] any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH, CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0824] R7and R8are each independently selected from hydrogen and Ci-C6alkyl; and

[0825] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0826] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0827] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0828] R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

[0829] R4and R5are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;

[0830] wherein:(i) when A is phenyl optionally substituted with F, CI or S02CH3, then neither

[0831] N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(0)NH-i-propyl,

[0832] NHCH(CH3)(CH2)3N(CH2CH3)2, NHCH2CH2OH, NHCH2CH2OCH3, NHCH2CH2OS03H, NHCH2CH2CH2OCH2CH20-phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2OCH3,

[0833] NHCH2CH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCH2CH2NHC(0)OCH3,

[0834] NHCH2CH2NHC(0)CH3, NHCH2CH2NH2, or NHCH2-phenyl;

[0835] (ii) when A is optionally substituted pyridyl, then neither N(R7)C(R4)(R5)(R6) nor

[0836] NtR8)^1)^2)^3) is NHCH2-phenyl, NHCH2-(2,4-difluorophenyl), N(CH3)CH2CH2C(0)OH, NHCH2CH2C(0)OH, NHCH2CH2C(0)OCH2CH3, NHCH2CH2C(0)0-t-butyl,

[0837] NHCH2CH2C(0)NH2, NHCH2CH2-phenyl, NHCH2CH2OH, NHCH2CH2NH2,

[0838] NHCH2CH2N(CH3)2, or NHCH2CH2CH3;

[0839] (iii) when A is optionally substituted 1-imidazolyl, optionally substituted 1 -pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is

[0840] NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH;

[0841] (iv) when A is unsubstituted 2-pyridinyl, then the ring formed by R4and R5is not 5 -methyl- 1H- pyrazol-3-yl; and

[0842] (v) when A is optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor

[0843] NtR8)^1)^2)^3) is N(CH3)2, NHCH3, NHAc, NHisopropyl, NHCH2CH3, NHCH2CH2S03H or N(CH2CH3)2,

[0844] (vi) ring A is not an optionally substituted triazolyl, 3, 5 -dimethyl- lH-pyrazol-l-yl,

[0845] (vii) when R1and R2are optionally taken together to form an unsubstituted cyclohexyl, and R4and R5are optionally taken together to form an unsubstituted cyclohexyl, then A is not a disubstituted 1-pyrazolyl or an unsubstituted phenyl; and

[0846] (viii) the compound is not selected from the group:

[0847] (1) 6-(lH-imidazol-l-yl)-N2,N4-bis(l -methylethyl)-l ,3,5-Triazine-2,4-diamine, or

[0848] (2) N2,N4-bis(l -methylpropyl)-6-phenyl-l ,3,5-Triazine-2,4-diamine.Also provided is a compound of Formula Ic, or pharmaceutically acceptable salt or hydrate thereof:

[0849] (Ic), wherein:

[0850] R1, R3, R4, and R6are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0851] each R9is independently selected fromhalo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4

[0852] hydroxyalkyl, -NH-S(0)2-(Ci-C4alkyl), -S(0)2NH(Ci-C4alkyl), -CN, -S(0)2-(d-C4alkyl), C1-C4 alkoxy, -NH(Ci-C4alkyl), -N(d-C4alkyl)2, -OH, -OCF3, -CN, -NH2, -C(0)NH2, - C(0)NH(Ci-C4alkyl), -C(0)-N(d-C4alkyl)2, -(Ci-C6alkylene)-0-(Ci-C6alkyl), aryl, and cyclopropyl optionally substituted with OH;

[0853] n is 1 to 3 ;

[0854] R2and R5are each independently selected from: -(Ci-d alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(d- C6alkyl)-C02H -(C2-C6alkenyl or alkynyl), -(Ci-C6alkylene)-0-(Ci-C6alkyl), -(C0-C6alkylene)-C(0)N(R6)-(Ci-C6alkyl),

[0855] -(Co-Cg alkylene)-Q, -(C0-C6alkylene)-C(0)-(d-C6alkyl), and -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0856] any alkyl or alkylene moiety present in R2and R5is optionally substituted with one or more -OH, -0(d-C4alkyl), -C02H, or halo;

[0857] any terminal methyl moiety present in R2and R5is optionally replaced with -CH2OH,

[0858] CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0859] R7and R8are each independently selected from hydrogen and Ci-C6alkyl; and

[0860] Q is selected from carbocyclyl and heterocyclyl, any of which is optionally substituted; whereinR1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0861] R4and R6are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0862] R1and R2are optionally taken together to form an optionally substituted carbocyclyl; or

[0863] R4and R5are optionally taken together to form an optionally substituted carbocyclyl;

[0864] wherein:

[0865] (i) neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2CH2OCH2CH2OCH2CH2NH2, or 4-[[2-[2-(2-aminoethoxy)ethoxy]ethyl]amino],

[0866] (ii) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH2CH2CHO, NHCH2CH2OCH3, NHCH2CH2OH, NHCH2CH(OH)CH3, NHCH2CH2OC(0)phenyl, NHCH2CH2CH2OH,

[0867] NHCH2CH2CH2N(CH3)phenyl, NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or NHCH2CH2OC(0)CH3; and

[0868] (iii) neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexylC(0)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3.

[0869] Also provided is a compound of Formula ΠΙ, or pharmaceutically acceptable salt or hydrate thereof:

[0871] (ΙΠ), wherein:

[0872] ring A is an optionally substituted 5-6 member monocyclic heteroaryl;

[0873] ring B is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;

[0874] R1and R3are each independently selected from hydrogen, Ci-C4alkyl, Ci-C4haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independentlyoptionally substituted with -OH, -NH2, -CN, -O-C1-C4alkyl, -NH(d-C4alkyl), or -N(d-C4alkyl)2;

[0875] R2is selected from: -(Ci-C6alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(d-C6alkyl)-C02H -(C2-C6alkenyl or alkynyl), -(Ci-C6alkylene)-0-(Ci-C6alkyl), -(C0-C6alkylene)-C(0)N(R6)-(Ci-C6alkyl),-(Co-C6alkylene)-Q, -(C0-C6alkylene)-C(0)-(d-C6alkyl), and -(C0-C6

[0876] alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0877] any alkyl or alkylene moiety present in R2is optionally substituted with one or

[0878] more -OH, -0(d-C4alkyl), -C02H, or halo;

[0879] any terminal methyl moiety present in R2is optionally replaced with -CH2OH,

[0880] CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0881] R7and R8are each independently selected from hydrogen and Ci-C6alkyl; and

[0882] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0883] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0884] R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;

[0885] wherein when A is an oxadiazole substituted with an optionally substituted pyridinyl, then G is not an optionally substituted phenyl.

[0886] In some embodiments, G is substituted with 1 or 2 substituents selected from halo, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, -CN, =0, -OH, aryl, heteroaryl -S02Ci-C4alkyl, -C02Ci-C4alkyl, -C(0)aryl, and -C(0)d-C4alkyl.

[0887] Also provided is a compound of Formula nia, or pharmaceutically acceptable salt or hydrate thereof:(Ilia), wherein:

[0888] ring A is a substituted 5-6 member monocyclic heteroaryl;

[0889] Xdis C or N;

[0890] each Rbis independently selected from halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -OH, -C(0)CH3, wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH2, or -CN;

[0891] p is 1 to 2;

[0892] R1and R3are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(d-C4alkyl), or -N(d-C4alkyl)2;

[0893] R2is selected from: -(Ci-C6alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(Ci-C6alkyl)-C02H -(C2-C6alkenyl or alkynyl), -(Ci-C6alkylene)-0-(d-C6alkyl), -(C0-C6alkylene)-C(0)N(R6)-(d-C6alkyl),

[0894] -(Co-C6alkylene)-Q, -(C0-C6alkylene)-C(0)-(Ci-C6alkyl), and -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0895] any alkyl or alkylene moiety present in R2is optionally substituted with one or

[0896] more -OH, -0(d-C4alkyl), -C02H, or halo;

[0897] any terminal methyl moiety present in R2is optionally replaced with -CH2OH,

[0898] CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0899] R7and R8are each independently selected from hydrogen and Ci-C6alkyl; and

[0900] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0901] R1and R3are optionally taken together with the carbon atom to which they are attached to form

[0902] C(=0); orR1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;

[0903] wherein when A is an oxadiazole substituted with an optionally substituted pyridinyl, then Xdis not C.

[0904] Also provided is a compound of Formula nib, or pharmaceutically acceptable salt or hydrate thereof:

[0905] (nib), wherein:

[0906] ring A is a substituted 5-6 member monocyclic heteroaryl;

[0907] R7and R8are each independently selected from hydrogen and Ci-C6alkyl;

[0908] each Rbis independently selected from halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -OH, -C(0)CH3, wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH2, or -CN;

[0909] p is 1 to 2;and

[0910] G is an optionally substituted carbocyclyl or heterocyclyl,

[0911] wherein A is not an oxadiazole substituted with an optionally substituted pyridinyl.

[0912] Also provided is a compound of Formula Hie, or pharmaceutically acceptable salt or hydrate thereof:

[0914] (IIIc), wherein:ring A is a substituted 5-6 member monocyclic heteroaryl;

[0915] R1and R3are each independently selected from hydrogen, C1-C4alkyl, C1-C4haloalkyl, -O-C1-C4alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4alkyl), or -N(Ci-C4alkyl)2;

[0916] R2is selected from: -(Ci-C6alkyl), -(Ci-C6alkyl)-C(0)-NH2, -(d-C6alkyl)-C02H -(C2-C6alkenyl or alkynyl), -(Ci-C6alkylene)-0-(Ci-C6alkyl), -(C0-C6alkylene)-C(0)N(R6)-(Ci-C6alkyl),

[0917] -(Co-Cg alkylene)-Q, -(C0-C6alkylene)-C(0)-(d-C6alkyl), and -(C0-C6alkylene)-C(O)-(C0-C6alkylene)-Q, wherein:

[0918] any alkyl or alkylene moiety present in R2is optionally substituted with one or

[0919] more -OH, -0(d-C4alkyl), -C02H, or halo;

[0920] any terminal methyl moiety present in R2is optionally replaced with -CH2OH,

[0921] CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;

[0922] R7and R8are each independently selected from hydrogen and Ci-C6alkyl; and

[0923] Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein

[0924] R1and R3are optionally taken together with the carbon atom to which they are attached to form C(=0); or

[0925] R1and R2are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;

[0926] each Rbis independently selected from halo, CN, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C3-C6cycloalkyl, phenyl, -OH, -C(0)CH3, wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH2, or -CN; and

[0927] p is 1 to 2.

[0928] Also provided is a compound of Formula Hid, or pharmaceutically acceptable salt or hydrate thereof:

[0929] ring A is a substituted 5-6 member monocyclic heteroaryl;

[0930] R7and R8are each independently selected from hydrogen and Ci-C6alkyl;

[0931] each Rbis independently selected from halo, CN, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C3-C6 cycloalkyl, phenyl, -OH, -C(0)CH3, wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH2, or -CN;

[0932] p is 1 to 2;and

[0933] G is an optionally substituted carbocyclyl or heterocyclyl.

[0934] Further embodiments provided herein include combinations of one or more of the particular embodiments set forth above.

[0935] In another embodiment, the compound is selected from any one of the compounds set forth in Table 1 , below.

[0936] Table 1. Representative Compounds

[0943] 87

[0945] 88

[0947] 

[0949] 90

[0951] 92

[0953] 93

[0955] 95

[0957] 96

[0959] 97

[0961] 98

[0963] 99

[0965] 100

[0967] 104

[0969] 105

[0971] 106

[0973] 107

[0975] 108

[0977] 109

[0979] 110

[0981] 111

[0983] 112

[0985] 113

[0987] 114

[0989] 115

[0991] 116

[0993] 117

[0995] 118

[0998] Included herein are also methods for making compounds of Formula I or a com ound of any one

[0999] of the embodiments described herein comprising reacting

[1001] embodiments, the preceding methods comprise step (1) reacting.. I inn o otthheerr e emmbbooddimments, the recedin methods comprise step

[1002] (1) reacting (2) reacting

[1003] ; and step (3) reacting

[1004] Also included are methods for making compounds of Formula or a compound of any one of the embodiments described herein comprising reacting.Also included are methods for making compounds of Formula I or a compound of any

[1005] In some embodiments, the preceding methods comprise step (1) reacting

[1006] ; and step (2) reacting

[1008] Also included are methods for making compounds of Formula I or a compound of any one of the embodiments described herein comprising reacting

[1009] Hwith . In other embodiments, the preceding methods comprise step

[1010] (1) converting0Etunder basic conditions to give HO H ;

[1011] step (2) reacting;step (3) reactingstep (4) reacting the preceding methods comprise step (1) converting asic conditions to give 3 to give;step (3) nd step (4) reacting. In other embodiments, the preceding methods comprisestep (1) converti step (2) reactingI ; step (3) reacting

[1012] CIto give

[1013] with R6.In other embodiments, the methodunder basic conditions t

[1014] ring Gis a carbocycl l or heteroc cl l rin .In other embodiments, the method comprises the steps of l)reactingand 2) reactingto give5wherein ring B is an aryl

[1015] under basic conditions to give5wherein ring B is an aryl or heteroaryl ring, and ring G is a carbocyclyl or heterocyclyl ring. In other

[1016] embodiments, the method comprises the step ofreacting ©AH H® with ring A to

[1018] The compounds of one aspect of this invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, scalemic mixtures,anddiastereomeric mixtures, as well as single enantiomers or individual stereoisomersthat are substantially free from another possible enantiomer or stereoisomer. The term "substantially free of other stereoisomers" as used herein means a preparation enriched in a compound having a selected stereochemistry at one or more selected stereocentersby at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. The term "enriched" means that at least the designated percentage of a preparation is the compound having a selected stereochemistry at one or more selectedstereocenters. Methods of obtaining or synthesizing an individual enantiomer or stereoisomer for a given compound are known in the art and may be applied as practicable to final compounds or to starting material or intermediates.

[1019] In certain embodiments, the compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig,n, ΙΠ, Ilia, Illb, Hie, or IIId,is enriched for a structure or structures having a selected stereochemistry at one or more carbon atoms. For example, the compound is enriched in the specific stereoisomer by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.

[1020] The compounds of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, Π, ΙΠ, Ilia, Illb, IIIc, or Mdmay also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including ¾2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, includingnC,12C,13C, and14C; N may be in any isotopic form, including13N,14N and15N; O may be in any isotopic form, including150,160 and180; F may be in any isotopic form, including18F; and the like. For example, the compound is enriched in a specific isotopic formof H, C, N, O and / or Fby at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.

[1021] Unless otherwise indicated when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

[1022] The compounds of one aspect of this invention may also be represented in multiple tautomeric forms, in such instances, one aspect of the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented (e.g., alkylation of a ring system may result in alkylation at multiple sites, one aspect of the invention expressly includes all such reaction products; and keto-enol tautomers). All such isomeric forms of such compounds are expressly included herein.

[1023] It may be convenient or desirable to prepare, purify, and / or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of

[1024] pharmaceutically acceptable salts are discussed in Berge etal, 1977, "Pharmaceutically

[1025] Acceptable Salts." J. Pharm. Sci. Vol. 66, pp. 1-19.

[1026] For example, if the compound is anionic, or has a functional group which 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 such as Na+and K+,alkaline earth cations such as Ca2+and Mg2+, and other cations such as Al3+. Examples of suitable organic cations include, but are not limited to, ammonium ion {i.e., NH4+) and substituted ammonium ions {e.g., NH3R+, NH2R2+, NHR3+, NR4+). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine,

[1027] dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+.

[1028] If the compound is cationic, or has a functional group that may be cationic {e.g.,-NH2may be -NH3+), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids:

[1029] hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.

[1030] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Mesylates of each compound in Table 1 are explicitly included herein. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

[1031] The compounds provided herein therefore include the compounds themselves, as well as their salts, hydrates and their prodrugs, if applicable. The compounds provided herein may be modified and converted to prodrugs by appending appropriate functionalities to enhance selected biological properties, e.g., targeting to a particular tissue. Such modifications (i.e., prodrugs) are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion. Examples of prodrugs include esters (e.g., phosphates, amino acid (e.g., valine) esters),carbamates and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active compounds. Calcium and sodium phosphates of each compound in Table 1 , if applicable, are explicitly included herein. Amino acid (e.g., valine) esters of each compound in Table 1, if applicable, are explicitly included herein.

[1032] Compositions and routes of administration

[1033] The compounds utilized in the methods described herein may be formulated together with a pharmaceutically acceptable carrier or adjuvant into pharmaceutically acceptable compositions prior to be administered to a subject. In another embodiment, such pharmaceutically acceptable compositions further comprise additional therapeutic agents in amounts effective for achieving a modulation of disease or disease symptoms, including those described herein.

[1034] The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a subject, together with a compound of one aspect of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

[1035] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the

[1036] pharmaceutical compositions of one aspect of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems

[1037] (SEDDS) such as d-a-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, 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, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium

[1038] carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and

[1039] 3-hydroxypropyl- -cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.The pharmaceutical compositions of one aspect of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of one aspect of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[1040] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and 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 which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[1041] The pharmaceutical compositions of one aspect of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions andaqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and / or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

[1042] The pharmaceutical compositions of one aspect of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of one aspect of this 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.

[1043] Topical administration of the pharmaceutical compositions of one aspect of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of one aspect of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of one aspect of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation.

[1044] Topically-transdermal patches are also included in one aspect of this invention.

[1045] The pharmaceutical compositions of one aspect of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employingbenzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[1046] When the compositions of one aspect of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of one aspect of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of one aspect of this invention in a single composition.

[1047] The compounds described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg / kg of body weight, alternatively dosages between 1 mg and 1000 mg / dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of one aspect of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound.

[1048] Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the subject's disposition to the disease, condition or symptoms, and the judgment of the treating physician.Upon improvement of a subject's condition, a maintenance dose of a compound, composition or combination of one aspect of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Subjects may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

[1049] The pharmaceutical compositions described above comprising a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ilia, nib, IIIc, or Illdor a compound described in any one of the embodiments herein, may further comprise another therapeutic agent useful for treating cancer.

[1050] Methods of Use

[1051] Provided is a method for inhibiting mutant IDHl activity comprising contacting a subject in need thereof with a compound (including its tautomers and / or isotopologues) of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, ΙΠ, Ilia, Illb, Hie, or Hid, or a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer to be treated is characterized by a mutant allele of IDHl wherein the IDHl mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of a- ketoglutarate to i?(-)-2-hydroxyglutarate in a subject. In one aspect of this embodiment, the mutant IDHl has an R132X mutation. In one aspect of this embodiment, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G. In another aspect, the R132X mutation is R132H or R132C. In yet another aspect, the R132X mutation is R132H. Also provided are methods of treating a cancer characterized by the presence of a mutant allele of IDHl comprising the step of administering to subject in need thereof (a) a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ilia, nib, IIIc, or ind, or a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof, or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.

[1052] In one embodiment, the cancer to be treated is characterized by a mutant allele of IDHl wherein the IDHl mutation results in a new ability of the enzyme to catalyze the NAPH- dependent reduction of a-ketoglutarate to i?(-)-2-hydroxyglutarate in a patient. In one aspect of this embodiment, the IDHl mutation is an R132X mutation. In another aspect of thisembodiment, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G. In another aspect, the R132X mutation is R132 H or R132C. A cancer can be analyzed by sequencing cell samples to determine the presence and specific nature of (e.g., the changed amino acid present at) a mutation at amino acid 132 of IDH1.

[1053] Without being bound by theory, applicants believe that mutant alleles of IDHl wherein the IDHl mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of a-ketoglutarate to i?(-)-2-hydroxyglutarate, and in particular R132H mutations of IDHl, characterize a subset of all types of cancers, without regard to their cellular nature or location in the body. Thus, the compounds and methods of this invention are useful to treat any type of cancer that is characterized by the presence of a mutant allele of IDHl imparting such acitivity and in particular an IDHl R132H or R132C mutation.

[1054] In one aspect of this embodiment, the efficacy of cancer treatment is monitored by measuring the levels of 2HG in the subject. Typically levels of 2HG are measured prior to treatment, wherein an elevated level is indicated for the use of the compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ma, mb, IIIc, or Hid, or a compound described in any one of the embodiments described herein to treat the cancer. Once the elevated levels are established, the level of 2HG is determined during the course of and / or following termination of treatment to establish efficacy. In certain embodiments, the level of 2HG is only determined during the course of and / or following termination of treatment. A reduction of 2HG levels during the course of treatment and following treatment is indicative of efficacy. Similarly, a determination that 2HG levels are not elevated during the course of or following treatment is also indicative of efficacy. Typically, the these 2HG measurements will be utilized together with other well- known determinations of efficacy of cancer treatment, such as reduction in number and size of tumors and / or other cancer-associated lesions, improvement in the general health of the subject, and alterations in other biomarkers that are associated with cancer treatment efficacy.

[1055] 2HG can be detected in a sample by LC MS. The sample is mixed 80:20 with methanol, and centrifuged at 3,000 rpm for 20 minutes at 4 degrees Celsius. The resulting supernatant can be collected and stored at -80 degrees Celsius prior to LC-MS MS to assess 2-hydroxyglutarate levels. A variety of different liquid chromatography (LC) separation methods can be used. Each method can be coupled by negative electrospray ionization (ESI, -3.0 kV) to triple-quadrupolemass spectrometers operating in multiple reaction monitoring (MRM) mode, with MS parameters optimized on infused metabolite standard solutions. Metabolites can be separated by reversed phase chromatography using 10 mM tributyl-amine as an ion pairing agent in the aqueous mobile phase, according to a variant of a previously reported method (Luo etal.J Chromatogr A 1147, 153-64, 2007). 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 an organic mobile phase of 100% methanol. Another method is specific for 2-hydroxyglutarate, running a fast linear gradient from 50% -95% B (buffers as defined above) over 5 minutes. A Synergi Hydro-RP, 100mm x 2 mm, 2.1 μιτι particle size (Phenomonex) can be used as the column, as described above. Metabolites can be quantified by comparison of peak areas with pure metabolite standards at known concentration. Metabolite flux studies from13C-glutamine can be performed as described, e.g., in Munger et al. Nat Biotechnol 26, 1179-86, 2008.

[1056] In one embodiment 2HG is directly evaluated.

[1057] In anotherembodiment a derivative of 2HGformed in process of performing the analytic method is evaluated. By way of example such a derivative can be a derivative formed in MS analysis. Derivatives can include a salt adduct, e.g., a Na adduct, a hydration variant, or a hydration variant which is also a salt adduct, e.g., a Na adduct, e.g., as formed in MS analysis.

[1058] In anotherembodiment a metabolic derivative of 2HG is evaluated. Examples include species that build up or are elevated, or reduced, as a result of the presence of 2HG, such as glutarate or glutamate that will be correlated to 2HG, e.g., R-2HG.

[1059] Exemplary 2HG derivatives include dehydrated derivatives such as the compounds rovided below or a s lt adduct thereof:

[1060] In one embodiment the cancer is a tumor wherein at least 30, 40, 50, 60, 70, 80 or 90% of the tumor cells cany an IDHl mutation, and in particular an IDHl R132H or R132C mutation, at the time of diagnosis or treatment.

[1061] IDHl R132X mutations are known to occur in certain types of cancers as indicated in Table 2, below.Table 2. IDH mutations associated with certain cancers

[1063] IDH1 R132H mutations have been identified in glioblastoma, acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer, cholangiocarcinomas,

[1064] chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer, and angio-immunoblastic non-Hodgkin's lymphoma (NHL). Accordingly, in one embodiment, the methods described herein are used to treat glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferativeneoplasm (MPN), colon cancer, or angio-immunoblastic non-Hodgkin's lymphoma (NHL) in a patient.

[1065] In another embodiment, the methods described herein are used to treat glioma

[1066] (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas (e.g., intrahepatic cholangiocarcinoma (IHCC)),

[1067] chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), prostate cancer, chronic myelomonocytic leukemia (CMML), B-acute lymphoblastic leukemias (B-ALL), B-acute lymphoblastic leukemias (B-ALL), myeloid sarcoma, multiple myeloma, lymphoma colon cancer, or angio-immunoblastic non-Hodgkin's lymphoma (NHL) in a patient.

[1068] In another embodiment, the advanced hematologic malignancy to be treated is lymphoma (e.g., Non-Hodgkin lymphoma (NHL) such B-cell lymphoma (e.g., Burkitt 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).

[1069] Accordingly in one embodiment, the cancer is a cancer selected from any one of the cancer types listed in Table 2, and the IDH R132X mutation is one or more of the IDHl R132X mutations listed in Table 2 for that particular cancer type.

[1070] Treatment methods described herein can additionally comprise various evaluation steps prior to and / or following treatment with a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, Π, III, Ilia, nib, Hie, or Illdor a compound described in any one of the embodiments described herein.

[1071] In one embodiment, prior to and / or after treatment with a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ma, inb, IIIc, or Illdor a compound described in any one of the embodiments described herein, the method further comprisesthe step of evaluating the growth, size, weight, invasiveness, stage and / or other phenotype of the cancer.

[1072] In one embodiment, prior to and / or after treatmentwith a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ma, Mb, IIIc, or Hid or a compound described in any one of the embodiments described herein, the method further comprisesthe step of evaluating the IDHlgenotype of the cancer. This may be achieved by ordinary methods in the art, such as DNA sequencing, immuno analysis, and / or evaluation of the presence, distribution or level of 2HG.

[1073] In one embodiment, prior to and / or after treatmentwith a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ma, Illb, IIIc, or Illdor a compound described in any one of the embodiments described herein, the method further comprises the step of determining the 2HG level in the subject. This may be achieved by spectroscopic analysis, e.g., magnetic resonance- based analysis, e.g., MRI and / or MRS measurement, sample analysis of bodily fluid, such as serum or spinal cord fluid analysis, or by analysis of surgical material, e.g., by mass- spectroscopy.

[1074] Also provided is a method for inhibiting a mutant IDH2 activity comprising contacting a subject in need thereof with a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, Π, III, Ilia, Illb, Hie, or Hid, a compound described in any one of the embodiments herein, 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 results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of a-ketoglutarate to i?(-)-2-hydroxyglutarate in a subject. In one aspect of this embodiment, the mutant IDH2 has an R140X mutation. In another aspect of this embodiment, the R140X mutation is a R140Q mutation. In another aspect of this embodiment, the R140X mutation is a R140W mutation. In another aspect of this embodiment, the R140X mutation is a 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 a R172K mutation. In another aspect of this embodiment, the R172X mutation is a R172G mutation. Also provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH2 comprising the step of administering to subject in need thereof (a) a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ilia, nib, IIIc, or ind or a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof, or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.

[1075] In one embodiment, the cancer to be treated is characterized by a mutant allele of IDH2 wherein the IDH2 mutation results in a new ability of the enzyme to catalyze the

[1076] NAPH-dependent reduction of a-ketoglutarate to i?(-)-2-hydroxyglutarate in a patient. In one aspect of this embodiment, the mutant IDH2 has an R140X mutation. In another aspect of thisembodiment, the R140X mutation is a R140Q mutation. In another aspect of this embodiment, the R140X mutation is a R140W mutation. In another aspect of this embodiment, the R140X mutation is a 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 a R172K mutation. In another aspect of this embodiment, the R172X mutation is a R172G mutation. A cancer can be analyzed by sequencing cell samples to determine the presence and specific nature of (e.g., the changed amino acid present at) a mutation at amino acid 140 and / or 172 of IDH2.

[1077] Without being bound by theory, applicants believe that mutant alleles of IDH2wherein the IDH2 mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of a-ketoglutarate to i?(-)-2-hydroxyglutarate, and in particular R140Q and / or R172K mutations of IDH2, characterize a subset of all types of cancers, without regard to their cellular nature or location in the body. Thus, the compounds and methods of one aspect of this invention are useful to treat any type of cancer that is characterized by the presence of a mutant allele of IDH2 imparting such acitivity and in particular an IDH2 R140Q and / or R172K mutation.

[1078] In one aspect of this embodiment, the efficacy of cancer treatment is monitored by measuring the levels of 2HG as described herein.

[1079] In one embodiment the cancer is a tumor wherein at least 30, 40, 50, 60, 70, 80 or 90% of the tumor cells cany an IDH2 mutation, and in particular an IDH2R140Q, R140W, or R140L and / or R172K or R172G mutation, at the time of diagnosis or treatment.

[1080] In another embodiment, one aspect of the invention provides a method of treating a cancer selected fromglioblastoma (glioma), myelodysplastic syndrome (MDS),

[1081] myeloproliferative neoplasm (MPN), acute myelogenous leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinomas or angioimmunoblastic lymphoma in a patient by administering to the patient a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, ΠΙ, Ma, Illb, IIIc, or Illdin 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).

[1082] 2HG is known to accumulate in the inherited metabolic disorder 2-hydroxyglutaric aciduria. This disease is caused by deficiency in the enzyme 2-hydroxyglutarate dehydrogenase,which converts 2HGto a-KG (Struys, E. A. et al. Am J Hum Genet 76, 358-60 (2005)). Patients with 2-hydroxyglutarate dehydrogenase deficiencies accumulate 2HG in the brain as assessed by MRI and CSF analysis, develop leukoencephalopathy, and have an increased risk of developing brain tumors (Aghili, M., Zahedi, F. & Rafiee, J Neurooncol 91, 233-6 (2009); Kolker, S., Mayatepek, E. & Hoffmann, G. F. Neuropediatrics 33, 225-31 (2002); Wajner, M., Latini, A, Wyse, A. T. & Dutra-Filho, C. S. J Inherit Metab Dis 27, 427-48 (2004)). Furthermore, elevated brain levels of 2HG result in increased ROS levels (Kolker, S. et al. Eur J Neurosci 16, 21 -8 (2002); Latini, A. et al. Eur J Neurosci 17, 2017-22 (2003)), potentially contributing to an increased risk of cancer. The ability of 2HG to act as an NMDA receptor agonist may contribute to this effect (Kolker, S. et al. Eur J Neurosci 16, 21-8 (2002)). 2HG may also be toxic to cells by competitively inhibiting glutamate and / or aKG utilizing enzymes. These include

[1083] transaminases which allow utilization of glutamate nitrogen for amino and nucleic acid biosynthesis, and aKG-dependent prolyl hydroxylases such as those which regulate FflFl -alpha levels.

[1084] Thus, according to another embodiment, one aspect of the invention provides a method of treating 2-hydroxyglutaric aciduria, particularly D-2-hydroxyglutaric aciduria, in a patient by administering to the patient a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, Π, III, Ilia, Illb, IIIc, or indor a compound described in any one of the embodiments described herein.

[1085] Also provided are methods of treating a disease selected from Maffucci syndrome and Oilier disease, characterized by the presence of a mutant allele of IDH1 comprising the step of administering to subject in need thereof (a) a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, ΠΙ, Ma, Illb, IIIc, or Hid, or a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof, or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.

[1086] Treatment methods described herein can additionally comprise various evaluation steps prior to and / or following treatment with a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, Π, III, Ilia, nib, Hie, or Illdor a compound described in any one of the embodiments described herein.

[1087] In one embodiment, prior to and / or after treatment with a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ma, Mb, IIIc, or Mdor a compound described in any one of theembodiments described herein, the method further comprisesthe step of evaluating the growth, size, weight, invasiveness, stage and / or other phenotype of the cancer.

[1088] In one embodiment, prior to and / or after treatmentwith a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ma, Illb, IIIc, or Illdor a compound described in any one of the embodiments described herein, the method further comprisesthe step of evaluating the IDH2 genotype of the cancer. This may be achieved by ordinary methods in the art, such as DNA sequencing, immuno analysis, and / or evaluation of the presence, distribution or level of 2HG. In one embodiment, prior to and / or after treatmentwith a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, ΠΙ, Ma, b, IIIc, or Illdor a compound described in any one of the embodiments described herein, the method further comprises the step of determining the 2HG level in the subject. This may be achieved by spectroscopic analysis, e.g., magnetic resonance-based analysis, e.g., MRI and / or MRSmeasurement, sample analysis of bodily fluid, such as serum or spinal cord fluid analysis, or by analysis of surgical material, e.g., by mass-spectroscopy.

[1089] Combination therapies

[1090] In some embodiments, the methods described herein comprise the additional step of co -administering to a subject in need thereof a second therapy e.g., an additional cancer therapeutic agent or an additional cancer treatment. Exemplary additional cancer therapeutic agents include for example, chemotherapy, targeted therapy, antibody therapies,

[1091] immunotherapy,and hormonal therapy. Additional cancer treatments include, for example: surgery, and radiation therapy. Examples of each of these treatments are provided below.

[1092] The term "co-administering" as used herein with respect to an additional cancer therapeutic agents means that the additional cancer therapeutic agent may be administered together with a compound of one aspect of this invention as part of a single dosage form (such as a composition of one aspect of this invention comprising a compound of one aspect of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional cancer therapeutic agent may be administered prior to, consecutively with, or following the administration of a compound of one aspect of this invention. In such combination therapy treatment, both the compounds of one aspect of this invention and the second therapeutic agent(s) are administered by conventional methods. Theadministration of a composition of one aspect of this 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 that same therapeutic agent, any other second therapeutic agent or any compound of one aspect of this invention to said subject at another time during a course of treatment. The term "co -administering" as used herein with respect to an additional cancer treatment means that the additional cancer treatment may occurprior to, consecutively with, concurrently with or following the administration of a compound of one aspect of this invention. In some embodiments, the additional cancer therapeutic agent is a chemotherapy agent.

[1093] Examples of chemotherapeutic agents used in cancer therapy include, for example,

[1094] antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives), alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others), and hypomethylating agents(e.g., decitabine (5-aza-deoxycytidine), zebularine, isothiocyanates, azacitidine (5- azacytidine), 5-flouro-2'-deoxycytidine, 5,6-dihydro-5-azacytidine and others). Exemplary agents include Aclarubicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin,

[1095] Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, bendamustine, Bleomycin, Bortezomib, Busulfan,

[1096] Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Crisantaspase,

[1097] Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin, Estramustine, Etoglucid, Etoposide, Floxuridine, Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine, Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin, Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine, Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine, Semustine, Sitimagene ceradenovec, Strataplatin,Streptozocin, Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine, Tioguanine, Tipifarnib, Topotecan,

[1098] Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine,

[1099] Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein. Because some drugs work better together than alone, two or more drugs are often given at the same time. Often, two or more chemotherapy agents are used as combination chemotherapy. In some embodiments, the additional cancer therapeutic agent is a differentiation agent. Such differentiation agent includes retinoids (such as all-trans-retinoic acid (ATRA), 9-cis retinoic acid, 13 -cz's -retinoic acid (13-cRA) and 4-hydroxy-phenretinamide (4-HPR)); arsenic trioxide; histone deacetylase inhibitors HDACs (such as azacytidine (Vidaza) and butyrates (e.g., sodium phenylbutyrate)); hybrid polar compounds (such as hexamethylene bisacetamide ((HMBA)); vitamin D; and cytokines (such as colony-stimulating factors including G-CSF and GM-CSF, and interferons).

[1100] In some embodiments the additional cancer therapeutic agent is a targeted therapy agent.

[1101] Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and also cyclin-dependent kinase inhibitors such as Alvocidib and Seliciclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the

[1102] anti-HER2 / neu antibody trastuzumab (HERCEPTIN®) typically used in breast cancer, and the anti-CD20 antibody rituximab and Tositumomab typically used in a variety of B-cell

[1103] malignancies. Other exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab. Exemplary fusion proteins include Aflibercept and Denileukin diftitox. In some embodiments, the targeted therapy can be used in combination with a compound described herein, e.g., a biguanide such as metformin or phenformin, preferably phenformin.Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. An example of such therapy includes BEXXAR®.

[1104] In some embodiments, the additional cancer therapeutic agent is an immunotherapy agent.

[1105] Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the subject's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma subjects.

[1106] Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a graft-versus-tumor effect. In some embodiments, the immunotherapy agents can be used in combination with a compound or composition described herein.

[1107] In some embodiments, the additional cancer therapeutic agent is a hormonal therapy agent. The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial. In some embodiments, the hormonal therapy agents can be used in combination with a compound or a composition described herein.

[1108] Other possible additional therapeutic modalities include imatinib, gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies.

[1109] EXAMPLES

[1110] General experimental notes:

[1111] In the following examples, the reagents (chemicals) were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company), and used without further purification. Nuclear magnetic resonance (NMR) spectra were obtained on aBrucker AMX-400 NMR (Brucker, Switzerland). Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were given with electrospray ionization (ESI) from a Waters LCT TOF Mass Spectrometer (Waters, USA) or Shimadzu LCMS-2020 Mass Spectrometer (Shimadzu, Japan). Microwave reactions were run on an Initiator 2.5 Microwave Synthesizer (Biotage, Sweden).

[1112] For exemplary compounds disclosed in this section, the specification of a stereoisomer (e.g., an (R) or (S) stereoisomer) indicates a preparation of that compound such that the compound is enriched at the specified stereocenter by at least about 90%, 95%, 96%, 97%, 98%, or 99%. The chemical name of each of the exemplary compound described below is generated by ChemDraw software.

[1113] Abbreviations list:

[1114] General

[1115] anhy. anhydrous

[1116] aq. aqueous

[1117] min minute(s)

[1118] hrs hours

[1119] mL milliliter

[1120] mmol millimole(s)

[1121] mol mole(s)

[1122] MS mass spectrometry

[1123] NMR nuclear magnetic resonance

[1124] TLC thin layer chromatography

[1125] HPLC high-performance liquid chromatography

[1126] satd. saturated

[1127] Spectrum

[1128] Hz hertz

[1129] δ chemical shiftJ coupling constant s singlet

[1130] d doublet

[1131] t triplet

[1132] q quartet

[1133] m multiplet

[1134] br broad

[1135] qd quartet of doublets dquin doublet of quintets dd doubletof doublets dt doublet of triplets

[1136] Solvents and Reagents

[1137] DAST diethylaminosulfurtri fluoride

[1138] CHCls chloroform

[1139] DCM dichloromethane

[1140] DMF dimethylformamide

[1141] Et20 diethyl ether

[1142] EtOH ethyl alcohol

[1143] EtOAc ethyl acetate

[1144] MeOH methyl alcohol

[1145] MeCN acetonitrile

[1146] PE petroleum ether

[1147] THF tetrahydrofuran

[1148] DMSO dimethyl sulfoxide

[1149] AcOH acetic acid

[1150] HC1 hydrochloric acid

[1151] H2S04sulfuric acid

[1152] NH4CI ammonium chloride

[1153] KOH potassium hydroxideNaOH sodium hydroxide

[1154] K2C03potassium carbonate

[1155] Na2C03sodium carbonate

[1156] TFA trifluoroacetic acid

[1157] Na2S04sodium sulfate

[1158] NaBH4sodium borohydride

[1159] NaHC03sodium bicarbonate

[1160] NaHMDS sodium hexamethyldisilylamide

[1161] LiHMDS lithium hexamethyldisilylamide

[1162] LAH lithium aluminum hydride

[1163] NaBH4sodium borohydride

[1164] LDA lithium diisopropylamide

[1165] Et3N triethylamine

[1166] Py pyridine

[1167] DMAP 4-(dimethylamino)pyridine

[1168] DIPEA NN-diisopropylethylamine

[1169] Xphos 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

[1170] BINAP 2,2'-bis(diphenylphosphanyl)-l ,1 '-binaphthyl dppf 1 ,1 '-bis(diphenylphosphino)ferrocene

[1171] TBTU 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate

[1172] DPPA diphenylphosphoryl azide

[1173] NH4OH ammonium hydroxide

[1174] EDCI 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide

[1175] HOBt 1 -hydroxybenzotriazole

[1176] Py Pyridine

[1177] Dppf 1 , 1 '-bis(diphenylphosphino)ferrocene

[1178] HATU 0-(7-azabenzotriazol- 1 -yl)-NNN',N'-tetra-methyluronium

[1179] BINAP 2,2'-bis(diphenylphosphanyl)-l ,1 '-binaphthylPreparation of Intermediates

[1180] Preparation of 1-phenylcyclopropanamine.

[1181] Ethylmagnesium bromide (48.5 mL, 146 mmol) was added dropwise over 30 min to a solution of benzonitrile (5 g, 48 mmol, 3 eq) and titanium tetraisopropanolate (21.5 mL, 73 mmol, 1.5 eq) in dry THF (140 mL) at -70°C. The solution was stirred at r.t. for 1.5 hr, followed by dropwise addition of boron trifluorideetherate (15 mL, 121 mmol, 2.5 eq) over 15 min. The mixture was stirred at r.t. for another 1.5 hr followed by addition of IN aq. HC1 and Et20. The resulting mixture was poured into 10% aq. NaOH, and extracted with Et20. Combined organic layers were dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography using PE / EtOAc / NH3.H20 (4:1 :0.1%) to afford the desired product. LC-MS: m / z 134.1 (M+H)+.

[1182] Preparation of 2-amino-2-methylpropanenitrile

[1183] To a mixture of NH4CI (4.9 g, 92.3 mmol) and acetone (7 mL, 92.3 mmol) in ammonium hydroxide (40 mL, 230.7 mmol) was added KCN (5 g, 76.9 mmol) at r.t. The reaction mixture was stirred at r.t for 3 days. The mixture was extracted with DCM (2 x 30 mL). Combined organic layers were washed with brine, dried over anhydrous Na2S04and concentrated to afford the desired product which was used directly in the next step without any further purification.

[1184] Preparation of 2-aminopropanenitrile

[1185] To a mixture of NH4CI (981 mg, 18.5mmol), acetaldehyde (1 mL, 18.5mmol) in ammonium hydroxide (3 mL) was added KCN (1 g, 15.4mmol) at room temperature. The reaction mixturewas stirred at r.t for 2 days. The mixture was extracted with DCM (2 x 30 mL). Combined organic layers were washed with brine, dried over anhydrous Na2S04and concentrated to afford the desired product which was used directly in the next step without any further purification.

[1186] Preparation ofdicyclopropylmethanamine

[1187] Stepl. Preparation of dicyclopropylmethanoneoxime. To a mixture of dicyclopropylmethanone (500 mg, 4.5 mmol) in pyridine (5 mL) was added hydroxylamine hydrochloride (469 mg, 6.75 mmol). The reaction mixture was stirred at 100°C for 4 hr and cooled to r.t followed by addition of EtOAc. The resulting mixture was washed with 1 N aq. HCl and brine, dried over anhydrous Na2S04, andconcentrated under reduced pressure to give the desired product which was used directly in the next step without any further purification.

[1188] LC-MS : m / z 124.1 (M-H)".

[1189] Step 2.Preparation of dicyclopropylmethanamine. To a cooled solution of dicyclopropylmethanoneoxime (550 mg, 4.4 mmol) in THF (5 mL) was added LiAlH4(200 mg, 5.3 mmol). The mixture was then stirred at 80°C for 6 hr and cooled to room temperature. The mixture was quenched by IN aq.NaOH until gas evolution ceased and then filtered. The filtrate was extracted with EtOAc. Combined organic layers were dried over anhydrous Na2S04, and concentrated under reduced pressure to give the desired product which was used directly in the next step without any further purification.

[1190] LC-MS : m / z 112.1 (M+Hf.

[1191] Preparation of bicyclo[3.1.0]hexan-3-amine

[1192] Step 1: Preparation of benzyl cycIopent-3-en / carbamate. To a solution of cyclopent-3- enecarboxylic acid (5 g, 44.6 mmol, l eq) and DPPA (13.5 g, 49 mmol, 1.1 eq) in toluene (80 mL) was added Et3N (7.4 mL, 53.5 mmol, 1.2 eq) at r.t. The mixture was then stirred at reflux for 2hr during which period a larger amount of nitrogen evolved. After BnOH (7 mL, 66.9 mmol, 1.5 eq) was added, the resulting mixture was stirred at 100°C overnight and cooled to room temperature. After quenched with saturated aqueous NaHC03. The resulting mixture was extracted with EtOAc. Combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by flash chromatography using

[1193] 1) as eluent to give the desired product.

[1194] LC-MS: m / z 218.0 (M+H)+.

[1195] Step 2: Preparation ofbemyl bicyclo[3.1.0]hexan-3-ylcarbamate. To a solution of benzyl cyclopent-3-enyl carbamate (1 g, 4.6 mmol, 1 eq) in anhydrous DCM at 0°C under an atmosphere of nitrogen was added ZnEt2(9.7 mL, 9.7 mmol, 2.1 eq), followed by dropwise addition of CH2I2(0.78 mL, 9.7 mmol, 2.1 eq). The reaction mixture was warmed to room temperature and stirred for 4 hr. The resulting reaction mixture was quenched with brine and extracted with DCM. The organic layer was dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography using PE / EtOAc (5:1) as eluent to give the desired product.

[1196] LC-MS: m / z 232.1 (M+H)+.

[1197] Step 3: Preparation ofl>icyclo[3.1.0]hexan-3-amine. To a solution of benzyl bicyclo [3.1.0]hexan-3-yl carbamate (2 g) in MeOH (20 mL) at r.t. under an atmosphere of 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.

[1198] LC-MS: m / z 98.1 (M+H)+.

[1199] Preparation of 2-(l,l-difluoroethyl)pyridin

[1201] Step 1: Preparation of 4-chloro-N-methox -N-methylpicolinamide. 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,0-dimethylhydroxylamine(9.3 g, 95.2 mmol) and DIPEA (24.6 g, 190.4 mmol) at 0°C.The mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous NH4C1 and extracted with EtOAc. The organic layer was dried over Na2S04and concentrated. The residue was purified by flash chromatography to give the desired product.

[1202] LC-MS: lz 201.0 (M+H) .

[1203] Step 2: Preparation of l-(4-chloropyridin-2-yl)ethanone. To a solution of 4-chloro-N-methoxy- N-methylpicolinamide (11.25 g, 56.08 mmol) in THF (50 mL) at 0°Cwas added MeMgBr (28.04mL, 84.12 mmol). The mixture was then stirred at r.t. overnight and quenched with saturated aqueous NH4C1. The resulting mixture was extracted with EtOAc. The organic layerwas dried over anhydrous Na2S04and concentrated. The residue was purified by flash chromatography to give the desired product,

[1204] 1H NMR (400 MHz, CDC13): 58.52(d, J = 5.2 Hz, 1H), 7.96 (s, 1H), 7.40 (d, J = 5.2 Hz, 1H), 2.64 (s, 3H).LC-MS: m / z 156.0 (M+H)+.

[1205] Step 3: 4-chloro-2-(l,l-difluoroethyl)pyridine. To a solution of 1 -(4-chloropyridin-2- yl)ethanone (6.3 g, 40.5 mmol) in DCM (30 mL)was added DAST (65.2 g, 405 mmol) at 0°C. The mixture was then stirred at r.t. overnight and quenched with saturated aqueous NaHC03. The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous Na2S04and concentrated. The residue was purified by flash chromatography to give the desired product.

[1206] Ή NMR (400 MHz, CDC13):58.48 (d, J = 5.2 Hz, lH), 7.60 (s, 1H), 7.31 (d, J = 5.2 Hz, 1H) , 1.90-1.99 (m, 3H).LC-MS: m / z 178.0 (M+H)+.

[1207] Step 4:Preparation of tert-butyl (2-(l,l-difluoroethyl)pyridin-4-yl)carbamate. To a solution of 4-chloro-2-(l,l-difluoroethyl)pyridine (6.0 g, 33.8 mmol) in dioxane(20 mL)was added BocNH2(4.74 g, 40.5 mmol), X-phos (1.14 g, 1.7 mmol), CsC03(16.5 g, 50.7 mmol) and Pd(OAc)2(1.32 g, 2.7 mmol) at room temperature. The mixture was then stirred at 80 °C overnight and then cooled to room temperature. The reaction mixture was diluted with Sat. aq. NH4CI and extracted with EtOAc. The organic layer was dried over anhydrous Na2S04andconcentrated. The residuewas purified by flash chromatography to give the desired product.

[1208] LC-MS: m / z 259.1 (M+H) .

[1209] Step 5:Preparation of 2-(l,l-difluoroethyl)pyridin-4-amine. A solution of tert-butyl (2-(l,l- difluoroethyl)pyridin-4-yl)carbamate (7.97 g, 30.86 mmol) in DCM (30 mL) was cooled under ice-water bath. TFA (10 mL) was then added dropwise. The reaction mixture was stirred at room temperature for 4 hrs and monitored by TLC. Once the reaction completed, the mixture was diluted with water and adjusted pH>7by saturated aqueous NaHC03. The resulting mixture was extracted with DCM. Combined organic layers were dried over anhydrous Na2S04 and concentrated to give the desired product which was used in the next step without further purification.

[1210] LC-MS: m / z 159.1 (M+H) .

[1211] Preparation of -(4-aminopyridin-2-yl)cyclopropanecarbonitrile

[1213] Step 1: Preparation ofl- (4-broinopyridin -2-yl)cycloprop n ec rbon itrile. L iHMD S (1M in toluene, 17.6 mL, 17.6 mmol, 3.1 eq) was added dropwise to a cold (-5°C) mixture of 4-bromo- 2-fluoropyridine (1 g, 5.7 mmol), cyclopanecarbonitrile (1.25 mL, 17 mmol, 3 eq) and4A MS in toluene (20 mL). The reaction mixture was allowed to warm to room temperature and stirred for 16 hr. After it was poured into water, the mixture was filtered. The filtrate was diluted with EtOAc and H20, and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography using PE / EtOAc (9:1) as eluent to give the desired product.

[1214] LC-MS: m / z 223.0 (M+H)+.

[1215] Step 2: Preparation ofl-(4-(diphenylmethyleneamino)pyridin-2- yl)cyclopropanecarbonitrile.To a mixture of l -(4-bromopyridin-2-yl)cyclopropanecarbonitrile (0.45g, 2.1 mmol), BINAP (0.04 g, 0.063 mmol), Pd2(dba)3(0.019g, 0.021 mmol) and NaO'Bu (0.282 g, 2.94 mmol) in toluene (6 mL) at r.t. under an atmosphere of nitrogen was added diphenylmethanimine (0.45 g, 2.51 mmol). The reaction mixture was stirred at reflux for 2 hr 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.

[1216] LC-MS: m / z 324.1 (M+H) .

[1217] Step 3: Preparation ofl-(4-aminopyridin-2-yl)cyclopropanecarbonitrile.A mixture of l-(4- (diphenylmethyleneamino)pyridin-2-yl)cyclopropanecarbonitrile (0.48 g, 1.49 mmol), THF (10 mL) and aq. HCl (2N, 2.0 mL)was stirred at room temperature for lhour. The mixture was then partitioned between EtOAc (15 mL) and water (15 mL). The aqueous phase was extracted with EtOAc (2 x 25 mL). Combined organic layers were dried over anhydrous Na2S04 and concentrated. The residue was purified by column chromatography to give the desired product.

[1218] LC-MS: m / z 160.1 (M+H) .

[1219] Example 1 Preparation of Di-aliphatic Triazine Compounds of Formula DWherein Ring A is substituted Pyridin-2-yl or Phenyl. The compounds of this Example are prepared by general Scheme 1, set forth below.Scheme 1

[1220] Formula D

[1221] Step 1: Preparation of 6-trifluomethyl-pyridine-2-carboxylic acid methyl ester (2). To a solution of 2-chloro-6-trifluoromethyl-pyridine (2 g, 1 1.1 mmol, 1.0 eq) in MeOH (20 mL) was add Pd(OAc)2(124 mg, 0.05eq) and dppf (600 mg, 0.1 eq) under an atmosphere of nitrogen. Et3N

[1222] (2.3 mL, 1.5eq) was then added to the resulting orange solution. The reaction solution was then stirred under an atmosphere of carbon monoxide (40 psi) at 60°C for 22 hr. Once the reaction completed, the mixture was filtered and the filtrate was concentrated in high vacuum. The residue was purified by column chromatography to afford the desired product.

[1224] 1HNMR (400 MHz, CDC13): δ 8.32 (d, J = 8 Hz, 1H), 8.06 (t, J = 8 Hz, 1H), 8.88 (d, J = 8 Hz, 1H), 4.04 (s, 3H).LC-MS: m / z 206 (M+H)+.

[1225] Step 2:Preparation of 6-(6- trifluomethylpyridin-2-yl)-l,3,5-triazine-2,4-dione. To a solution of freshly prepared NaOEt from Na (3.84 g, 0.16 mol, 3 eq) in ethanol (500 mL) was added methyl

[1226] 6-trifluoromethylpicolinate (33 g, 0.16 mol, 3eq) and biuret (5.3 g, 0.052 mol). Theresulting mixture was heated to reflux for 1 hr and then concentrated. The residue was poured into waterand treated with Sat. aq. NaHC03to adjust pH to 7. The precipitated solid was collected by filtration and dried under air to give the desired compound.

[1228] 1H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 8.46 (d, J= 7.4 Hz, 1H), 8.28 (t, J= 7.3 Hz, 1H), 8.11 (d, J= 7.4 Hz, 1H).LC-MS: m / z 259 (M+H)+.

[1229] Step 3: Preparation of 2,4-dichloro-6-(6-trifluomethyl-pyridin-2-yl)-l,3,5-triazine. To a solution of 6-(6-trifluomethyl-pyridin-2-yl)-l,3,5-triazine-2,4(lH,3H)-dione (3.37 g, 0.013mol) in POCl3(48 mL) was added PC15(23 g, 0.1 mol). The mixture was stirred at 100°C for 2 hr and then concentrated. The residue was dissolved inEtOAc and then washed with Sat. aq. NaHC03. The organic layer was dried over anhydrous Na2S04and thenconcentrated to give the desired roduct.

[1231] Ή NMR (400 MHz, CDC13): δ 8.76 (d, J= 7.9 Hz, 1H), 8.19 (t, J = 7.9 Hz, 1H), 7.97 (d, J= 7.8 Hz, 1H).LC-MS: m / z 294.9 (M+H)+.

[1232] Step 4: Preparation of N2,N* -bis((R)-l -cyclopropylethyl)-6-(6-(trifluoroinethyl) -pyridin-2-yl)- l,3,5-triazine-2,4-diamine. To a mixture of 2,4-dichloro-6-(6-(trifluoromethyl)pyridine-2-yl)- 1,3,5-triazine (600 mg, 2.0mmol, 1.0 eq) and (R)-l-cyclopropylethanamine hydrochloride salt (536 mg, 4.4mmol, 2.2eq) in THF (12 mL) were added CsF (1.2 g, 8.0mmol, 2eq) and DIPEA (1.4 mL, 8.0mmol, 4eq) at room temperature. The mixture was stirred at 60°C overnight and thenfiltered. The filtrate was concentrated under reduced pressure and the residue was purified by a standard method to give the desired product.

[1234] Ή NMR (400 MHz, CD3OD): δ 8.70-8.68 (m, 1 H), 8.34-8.32 (m, 1 H), 8.16-8.14 (m, 1 H), 3.61 -3.57 (m, 2 H), 1.36-1.32 (m, 6 H), 1.06-1.01 (m, 2 H), 0.61 -0.39 (m, 8 H).LC-MS: m / z 393.2 (M+H)+.

[1235] The procedure set forth in Example lwas used to produce the following compounds using the appropriate starting materials.

[1236] CompoundN'!,7V(-bis((S)-l-cychpropylethyl)-6-(6-(trifluoromethyl)pyridin-2-yl)- 1,3,5-tr zine- 2,4-diamine

[1238] Ή NMR (400 MHz, CDC13): δ 8.50 (s, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 5.44 - 5.18 (m, 2H), 3.66 - 3.57 (m, 2H), 1.27 (d, J = 5.4 Hz, 6H), 0.93 - 0.88 (m, 2H), 0.52 - 0.27 (m, 8H).LC-MS: m / z 393.2 (M+H)+.

[1239] Compound N2-((R)-l-cyclopropylethyl)-N*-((S)-l-cycfapropytethyl)-6-(6-(trifluoro methyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1240] 1H NMR (400 MHz, CDC13): δ 8.51 (s, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.77 (d, J = 7.3 Hz, 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)+.

[1241] CornpoundN1',Ν(-bis(l-cyclopropylethyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5 -triazine- 2,4-diamine

[1243] 1HNMR (400 MHz, CD3OD): 58.6 (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)+.

[1244] CornpoundN,N '-bisfcyclobuiylmethyty-d-fd-ftrifluoromethytypyridin^-yl)-!^^ -triazine-2,4- diamine

[1245] Ή NMR (400 MHz, CDC13): δ 8.54 (m, 1H), 8.00 (m, 1H), 7.78 (d, J = 5.9 Hz, 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)+.

[1246] CompoundN' ',Ν(-bis((R)-l-cyclobutytethyl)-6-(6-(trifluoromethyl)pyridin-2-yl)- 1,3, 5-tr zine- 2,4-diamine

[1248] 'H NMR (400 MHz, CDC13): δ 8.71 - 8.41 (m, 1H), 7.99 (d, J = 1.4 Hz, 1H), 7.77 (d, J= 7.7 Hz, 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 = 5.9 Hz, 6H).LC-MS: m / z 421.2

[1249] (M+H)+.

[1250] CompoundN2, rf-bis(2-methylcyclopropyl)-6-(6-(trifluoromethyl)pyrM -triazine- 24-diamine

[1252] 1HNMR (400 MHz, CD3OD): 68.65-8.4 (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)+.

[1253] CompoundN ',Ν '-bis(cyclopropylmethyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5 -triazine-2,4- diamine

[1254] 1H NMR (400 MHz, CD3OD): δ 8.60-8.68 (m, 1H), 8.21 (t, J = 8.0 Hz, 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)+.

[1255] CompoundN!,7V(-bis((l-methyl(yclopropyl)methyl)-6-(6-(trifluoromethyl)pyridin-2 -yl)-l,3, 5- tria ine-2 ,4-diamine

[1257] 1HNMR (400 MHz, CD3OD): δ 8.61-8.59 (m, 1 H), 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)+.

[1258] Compound N2,rf-dicyclobutyl-6-(6-(trifluoromethyl)pyridin-2-yl)-l,^ 2,4-diamine

[1260] Ή NMR (400 MHz, CDC13): δ 8.67 - 8.38 (m, 1H), 7.99 (d, J= 6.8 Hz, 1H), 7.78 (d, J= 7.5 Hz, 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)+.CompoundN2,Ν4-di(bicyclo[3.1.0Jhexan-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl) -1,3, 5- triazine-2 ,4-diamine

[1262] H NMR (400 MHz, CD3OD): δ 8.66 - 8.57 (m, 1H), 8.14 (t, J= 8.0 Hz, 1H), 7.92 (d, J= 7.5 Hz, 1H), 4.60 -4.44 (m, 2H), 2.44 - 2.21 (m, 4H), 1.80 - 1.69 (m, 4H), 1.35 (d, J= 3.4 Hz, 4H), 0.69 - 0.53 (m, 2H), 0.32 (d, J= 4.3 Hz, 2H).LC-MS: m / z 417.2 (M+H)+.

[1263] Com ound N,N'-dicyclopentyl-6-(6-trifluoromethyl-pyridin-2-yl)-[l, 3, 5]triazine- 2,4-diamine

[1265] 1HNMR (400 MHz, CD3OD): δ 8.60-8.68 (m, lH), 8.20 (t, J = 7.6 Hz, 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)+.

[1266] CompoundN2, N4-bis (3, 3-difluorocyclopentyl)-6-(6-(trifluoromethyl)pyridin-2-yl)- triazine-2 ,4-diamine

[1268] Ή NMR (400 MHz, CDC13): δ 8.53 (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)+.

[1269] CompoundN2,l^-bh(4,4-dijluorocyclohexyl)-6-(6-(trty 1,3,5- triazine-2 ,4-diamine

[1271] 1H NMR (400 MHz, CDC13): δ 8.64 - 8.42 (m, 1H), 8.05 (t, J = 7.8 Hz, 1H), 7.84 (d, J = 6.6 Hz, 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)+.

[1272] Co^oundN,N'-bis-(tetrahydro-pyran-4-yl)-6-(6-trifluoromethyl-pyridin- 2-yl)-fl ,3,5Jtr zine- -diamine

[1274] 1HNMR (400 MHz, DMSO-d6): 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)+.CompoundN ',Ν(-diisopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-tr zine -2,4-diamine

[1276] ¾ NMR (400 MHz, CDC13): δ 8.67 - 8.41 (m, 1H), 7.99 (s, 1H), 7.77 (d, J = 7.7 Hz, 1H), 5.18 (m, 2H), 4.45 - 4.03 (m, 2H), 2.15 (m, 1H), 1.26 (d, J = 4.5 Hz, 12H).LC-MS: m / z 341.2 (M+H)+.

[1277] Compound N2,N*-di-tert-butyl-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-trmzine -2,4-diamine

[1279] 'H NMR (400 MHz, DMSO-d6): δ 8.44 - 8.31 (m, 1H), 8.19 - 8.12 (m, 1H), 7.93 (d, .7 = 7.3 Hz, 1H), 7.16 - 6.77 (m, 2H), 1.35 (s, 18H).LC-MS: m / z 369.2 (M+H)+.

[1280] CompoundN,N'-di-sec-bufyl-6-(6-trifluoromethyl-pyrMin-2-yl)-fl,3,5Jtr zine- 2,4-diamine

[1281] 1HNMR (400 MHz, CD3OD): δ 8.42-8.68 (m, 1H), 8.15-8.21 (m, 1H), 7.94 (d, J = 8.0 Hz, 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)+.

[1282] CompoundN,N'-Di-sec-butyl-6-(6 rifluoromethyl^yridin-2-yl)-[l,3,5]triaz

[1284] 1HNMR (400 MHz, CD3OD): δ 8.72-8.79 (m, 1H), 8.38-8.43 (m, 1 H), 8.20-8.23 (m, 1H), 4.13- 4.45 (m, 2H), 1.67-1.74 (m, 4H), 1.29-1.33 (m, 6H), 1.01-1.05 (m, 6H).LC-MS: m / z 369.2 (M+H)+.

[1285] CompoundN'!,7V(-di-sec-buiyl-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4- diamine

[1287] 1HNMR (400 MHz, CD3OD): δ 8.72-8.79 (m, 1H), 8.38-8.43 (m, 1 H), 8.20-8.23 (m, 1H), 4.13- 4.45 (m, 2H), 1.67-1.74 (m, 4H), 1.29-1.33 (m, 6H), 1.01-1.05 (m, 6H).LC-MS: m / z 369.2 (M+H)+.

[1288] CompoundN2-((R)-sec-butyl)-rf-((S)-sec-butyl)-6-(6-(trifluorome 2-yl)-l,3,5- triazine-2 ,4-diamine

[1290] ¾ NMR (400 MHz, CD3OD): δ 8.59-8.65 (m, lH), 8.15-8.19 (m, 1 H), 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)+.

[1291] CompoundN2,Ν4-bis (3-methylbutan-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)- 1,3, 5-triazine- -diamine

[1293] 1H NMR (400 MHz, CDC13): δ 8.58 - 8.47 (m, 1H), 7.99 (t, J = 7.2 Hz, 1H), 7.77 (d, J= 7.7 Hz, 1H), 5.30 - 5.03 (m, 2H), 4.16 - 3.97 (m, 2H), 1.93 - 1.75 (m, 2H), 1.16 (d, J = 6.6 Hz, 6H), 0.97 - 0.93 (m, 12H).LC-MS: m / z 397.2 (M+H)+.

[1294] CompoundN' ',Ν(-bis((R)-3-methylbutan-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)- 1,3,5- triazine-2 ,4-diamine

[1295] Ή NMR (400 MHz, DMSO-d6): δ 8.46 (m, 1H), 8.21 (m, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.36 (m, 2H), 3.90 (m 2H), 1.79 (m, 2H), 1.05 (t, J = 7.6 Hz, 6H), 0.87 (t, J = 7.6 Hz, 12H).LC-MS: m / z 397.2 (M+H)+.

[1296] CompoundN1',Ν(-bis((S)-3-methylbutan-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)- 1,3, 5- triazine-2 ,4-diamine

[1298] 1H NMR (400 MHz, DMSO-d6): δ 8.46 (d, J = 7.9 Hz, 1H), 8.24 (d, J = 6.9 Hz, 1H), 8.03 (d, J = 7.7 Hz, 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 = 7.8 Hz, 12H).LC-MS: m / z 397.2 (M+H)+.

[1299] CompoundN2, TV '-bis ((R)-l-cyclopropylethyl)-6-(4-(trifluoromethyl)pyrimidin -2-yl)-l,3,5- triazine-2 ,4-diamine

[1301] 1H NMR (400 MHz, CDC13): δ 9.20 (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)+.

[1302] Compound ^-((RJ-l-phenylethyfy-rf-ffSJ-l-phenytethyfy-e-fe-ftrifluoromethyl) pyridin-2-yl)- 1,3, 5-triazine-2 ,4-diamine

[1303] 1H NMR (400 MHz, CDC13): δ 8.52 - 8.33 (m, 1H), 8.05 - 7.86 (m, 1H), 7.76 (d, J = 7.7 Hz, 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)+.

[1304] Cotnpound6-(6-chloropyridin-2-yl)-N'!,7V '-bisffRj-l-cyclopropylethyfy-l^^-tria -zine-2,4- diamine

[1306] 1H NMR (400 MHz, CD3OD): δ 8.37 (t, J = 7.8 Hz, 1H), 8.02 (t, J = 7.8 Hz, 1H), 7.71 - 7.65 (m, 1H), 3.74 - 3.54 (m, 2H), 1.32 (d, J = 6.6 Hz, 6H), 1.08 - 0.94 (m, 2H), 0.63 - 0.21 (m, 8H).LC-MS: m / z 359.2 (M+H)+.

[1308] 'HNMR (400 MHz, CD30D): 58.5-8.38 (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)+.Compound6-(6-chloropyridin-2-yl)-j2,N*-diisopropyl-l,3,5-triazine-2,4-diamine

[1310] 1HNMR (400 MHz, CD3OD): δ 8.25-8.19 (m, 1H), 7.81 (brs, 1 H), 7.46 (d, J

[1311] 4.26-4.11 (m, 2H), 1.15 (d, J = 6.0 Hz, 12H).LC-MS: m / z 307.1 (M+H)+.

[1312] Compound N2,N*-di(but-3-en-l-yl)-6^henyl-l,3,5Jriazine-2,4-dwmine

[1314] 'HNMR (400 MHz, CD3OD): 58.19-8.13 (m, 2H), 7.77-7.61 (m, 3H), 5.95-5.85 (m, 2H), 5. 5.11 (m, 4H), 3.72-3.59 (m, 4H), 2.49-2.44 (m, 4H).LC-MS: m / z 296.3 (M+H)+.

[1315] Compound N2,N* -di(3-oxabicyclo[3.1.0Jhexan-6-yl)-6-phenyl-l,3,5-triazine-2,4- diamine

[1317] 1HNMR (400 MHz, CD3OD): 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)+.

[1318] Compound N2,N* -bis((lS,3S)-3-(4-fluorophenyl)cyclobutyl)-6-(6- (triflu oromethyl )pyridin -2- yl)-l,3,5-triazine-2,4-diamine To a mixture of 2,4-dichloro-6-(6-(trifluoromethyl)pyridine-2-yl)- 1,3,5-triazine (600 mg, 2.0 mmol, 1.0 eq) and (ls,3s)-3-(4-fluorophenyl)cyclobutanamine (726mg, 4.4 mmol, 2.2 eq) in THF (12 mL) at r.t.were added CsF (0.6 g, 2.0 mmol, 1 eq.) and DIPEA (0.7 mL, 4.0 mmol, 2 eq). The resulting mixture was stirred at 60°C overnight and then filtered. The filtrate was concentrated and purified via standard techniques to afford the desired product.

[1320] ¾ NMR (400 MHz, CDC13) δ 8.48 (m, 1H), 7.95 (m, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.16 - 7.04 (m, 4H), 6.93 (t, J = 8.5 Hz, 4H), 6.46 - 5.32 (m, 2H), 4.47 (m, 2H), 3.28 - 3.02 (m, 2H), 2.81 (d, J= 7.6 Hz, 4H), 2.01 (m, 4H).LC-MS: m / z 553.2 (M+H)+.

[1321] Compound N2,N* -bis((l R,3R)-3-(4-fluorophenyl)cyclobutyl)-6-(6-(trifluor

[1322] -l,3,5-triazine-2,4-diamine

[1324] Ή NMR (400 MHz, CDC13) δ 8.56 (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)+.

[1325] Compound 6-(6-(Trifluoromethyl)pyridin-2-yl)-N N '-bisffRj-lfl -trifluoropropan^-yl)- 1,3, 5-triazine-2,4-diamine

[1327] IH NMR (400 MHz, CDC13) δ 8.62 (m, IH), 8.03 (d, J = 7.8 Hz, IH), 7.83 (d, J

[1328] 5.59 (d, J= 9.4 Hz, IH), 5.34 (m, 3H), 1.42 (m, 6H); LC-MS: m / z449 (M+H)+.

[1329] Compound N' ' ,l^-bh((S)A,l,l-tvijluorobutan-2-yl)-6-(6-(trijfa

[1331] ¾ NMR( 400MHz, CDC13)58.55 (d, J=8 Hz, IH), 8.06 - 8.02(m, IH), 7.83 (d, J=8Hz, IH), 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). LCMS: m / z 477(M+H)+.

[1332] Compound N l^-bis((2,2-difluorocyclopropyl)methyl)-6-(6-(tri

[1333] -triazine-2,4-diamine

[1334] Ή NMR (400 MHz, CDC13) 58.59-8.51 (m, 1H), 8.02 (bs, 1H), 7.80 (d, J=7.6 Hz, 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)+.

[1335] Compound N2,rf-bis((3,3-difluorocyclobutyl)methyl)-6-(6-(triflu^

[1336] triazine-2 ,4-diamine

[1338] Ή NMR (400 MHz, CDC13) δ 8.54 (m, 1H), 8.02 (m, 1H), 7.80 (d, J = 7.2 Hz, 1H), 5.84 - 5.11 (m, 2H), 3.95 - 3.27 (m, 4H), 2.94 - 1.99 (m, lOH). LC-MS: m / z 465 (M+H)+.

[1339] Compound N2,rf-bis(3,3-difluorocyclobutyl)-6-(6-(trifluoromethyl)pyrM^

[1340] -diamine

[1342] 1H NMR (400 MHz, CDC13) 58.56 - 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)+.

[1343] Compound N2,]^-bis((S)-3,3-difluorocyclopentyl)-6-(6-(trifluoromethyl)pyridm^ triazine-2 ,4-diamine

[1345] Ή NMR (400 MHz, CDC13) 58.54 - 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). LCMS: m / z 465.1 (M+H)+.

[1346] Compound N l^-bis((R)-3,3-difluorocyclopentyl)-6-(6-(trijluorom^

[1347] triazine-2 ,4-diamine

[1349] 1H NMR (400 MHz, CDCl3)557-8.48 (m, 1H), 8.02-8.01 (m, 1H),7.80 (s,lH), 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)+.

[1350] Compound N2-((R)-3,3-difluorocyclopentyl)-N4-((S)-3,3-difluorocyclopentyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1351] H NMR (400 MHz, CDC13) 58.56-8.48 (m, 1H), 8.02(d, J=8 Hz, 1H),7.80-7.81 (m,lH), 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).

[1352] LC-MS: m / z 465 (M+H)+.

[1353] Compound N2,]S4-bis(4,4-difluorocyclohexyl)-6-(4-(trifluoromethyl)pyridin^

[1355] Ή NMR (400 MHz, CDC13) δ 8.70-8.62 (m, 2H), 7.62 (d, 1H), 6.70-6.43 (m, 1H), 5.22-3.95 (m, 3H), 2.11-1.69 (m, 16H). LCMS: m / z 493(M+H)+.

[1356] N N '-bisffRJ-l-cycfapropylethyfy-e-fe-methoxypyridin^-yfy-l^ -Mazine^^-

[1358] 1H NMR (400 MHz, CDC13) δ 8.18 - 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). LCMS: m / z 355.2 (M+H)+.

[1359] Compound N2,N4-bis(3,3-difluorocyclobutyl)-6-(6-(trifluoromethoxy)pyrMin^ triazine-2 ,4-diamine

[1360] 1H NMR (400 MHz, CDC13) δ 8.34 - 8.27 (m, 1H), 7.96 - 7.92 (m, 1H), 7.22 (d,J = 8 Ηζ,ΙΗ), 5.83 - 5.41 (m, 2H), 4.49 - 4.35 (m, 2H), 3.05 (d, J = 4 Hz, 4H), 2.63 - 2.54 (m, 4H).LCMS: m / z 453 (M+H)+.

[1361] N2,]S4-bis(3,3-difluorocyclopentyl)-6-(6-(trifluoromethoxy)pyridin^

[1363] Ή NMR (400 MHz, CDC13) δ 8.33 - 8.26 (m, 1H), 7.95 - 7.92 (m, 1H), 7.22(d, J = 8 Hz, 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) .LCMS: m / z 481 (M+H)+.

[1364] Compound N2,Nt-bis(4,4-difluorocyclohexyl)-6-(6-(trifluoroinethoxy)py M

[1365] tria ine-2 ,4-diamine

[1367] 1H NMR (400 MHz, CDC13) δ 8.31 (d, J = 8 Hz, 1H), 7.98 - 7.92 (m, 1H), 7.24 (d, J = 12 Hz, 1H), 5.44 - 5.08 (m, 2H), 4.16 - 3.98 (m, 2H), 2.15 - 1.65 (m, 16H).LCMS: m / z 509(M+H).+Compound N2,rf-bis(4,4-difluorocyclohexyl)-6-(3-fluoro-6-methoxypyridin^ triazine-2 ,4-diamine

[1369] Ή NMR (400 MHz, CDC13) δ 7.45-7.41 (t, IH), 6.84 (d, IH), 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). LCMS : m / z 473(M+H)+.

[1370] Table 1: The followingcompounds were prepared by following theprocedure described in Scheme 1 above.

[1372] diamine

[1373] Example 2 Preparation of Di-aliphatic Triazine Compounds of Formula EWherein Ring A is substituted Pyridin-2-yl or Phenyl. The compounds of this Example are prepared by general Scheme 2, set forth below.

[1375] Formula E

[1376] Step l:Preparationof(R)-4-chloro-N-(l-cyclopropylethyl)-6-(6-(trifluorom^

[1377] l,3,5-triazin-2-amine.To a mixture of 2,4-dichloro-6-(6-(trifluoromethyl)pyridine -2-yl)-l,3,5- triazine (600 mg, 2.0mmol, 1.0 eq) and (R)-l-cyclopropylethanamine hydrochloride salt (268 mg, 2.2mmol, 1.1 eq) in THF (6 mL) were added CsF (608 mg, 4.0mmol, 2eq) and DIPEA (0.7 mL, 4.0mmol, 2 eq) at room temperature. The mixture was stirred at 40°C overnight and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a standard method to give the desired product.

[1378] LC-MS: m / z 344.1 (M+Hf .

[1379] Step2: Preparation N2-((R)-l-cyclopropylethyl)-N4-(pentan-2-yl)-6- (6-

[1380] (trifluoromethyl)pyridin-2-yl) -l,3,5-triazine-2,4-diamine. To a mixture of (R)-4-chloro-N-(l- cyclopropylethyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazin-2-amine (80 mg, 0.23 mmol, 1.0 eq) and pentan-2 -amine (25 mg,0.28mmol, 1.2eq) in THF (2 mL) were added CsF (70 mg, 0.46mmol, 2eq) and DIPEA (0.08 mL, 0.46 mmol, 2 eq) at room temperature. The mixture was stirred at 60°C ovemight and filtered. The filtrate was concentrated under reduced pressure and then purified by a standard method to give the desired product.

[1382] ¾ NMR (400 MHz, DMSO-d6): δ 8.54 - 8.42 (m, 1H), 8.23 (t, J = 7.8 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 9.5 Hz, 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, 6.5 Hz, 3H), 1.12 (d, J = 6.1 Hz, 3H), 1.01 - 0.96 (m, 1H), 0.88 (t, J = 7.1 Hz, 3H), 0.50 - 0.29 (m, 3H), 0.26 - 0.07 (m, 1H).LC-MS: m / z 395.2 (M+H)+.

[1383] The procedure set forth in Example 2was used to produce the following compounds using the appropriate starting materials.

[1385] Ή NMR (400 MHz, CDC13): δ 8.52 (m, 1H), 8.00 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 5.63 (m, 2H), 3.73 (m, 9H), 2.66 (d, J = 5.9 Hz, 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)+.

[1386] Compound (R)-N2-(l-cyclopropylethyl)-N*-(4,4-difluorocyclohexyl)-6-(6-(trifluoro methyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1388] 1H NMR (400 MHz, CDC13): δ 8.66 - 8.39 (m, 1H), 8.02 (t, J = 7.7 Hz, 1H), 7.80 (d, J= 7.7 Hz, 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)+.

[1389] Compound N2-((R)-l-cyclopropylethyl)-N*-(6,6-difluorospiro[3.3]heptan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1391] 1H NMR (400 MHz, CDC13): δ 8.54 - 8.49 (m, IH), 8.01 (t, J = 7.3 Hz, 1H), 7.78 (d, J= 7.7 Hz, 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 = 5.8 Hz, 2H), 0.93 (s, 1H), 0.54 - 0.29 (m, 4H).LC-MS: m / z 455.2 (M+H)+.

[1392] Compound

[1393] (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1395] Ή NMR (400 MHz, CDC13): δ 8.63 - 8.34 (m, IH), 8.00 (t, J = 7.8 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 5.57 (m, 2H), 4.21 (m, IH), 3.85 - 3.32 (m, IH), 2.22 - 1.57 (m, 15H), 1.25 (m, 4H), 0.90 (m, IH), 0.66 -0.24 (m, 4H).LC-MS: m / z 459.2 (M+H)+.

[1396] Compound (R)-N2-(l-cyclopropylethyl)-N*-(di(yclopropylmethyl)-6-(6-(trifluoro methyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1398] Ή NMR (400 MHz, CDC13): δ 8.49 (d, J = 7.5 Hz, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.77 (d, J= 7.7 Hz, 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)+.

[1399] Compound rf-fffy-l-cyclopropylethyfy-d-fd-ftrifluoromethytypyridin^-yfy-N4- (1,1,1- trifluoropropan-2-yl)-l,3,5-triazine-2,4-d mine

[1401] 1H NMR (400 MHz, CDC13): δ 8.53 (s, 1H), 8.01 (s, 1H), 7.80 (d, J = 7.6 Hz, 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)+.

[1402] Compound (RJ-rf-fl-cyclopropylethyfy-N'-fi^-dihydro-lH-inden^-yfy-e-fe

[1403] (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1404] Ή NMR (400 MHz, CDC13): δ 8.61 - 8.46 (m, 1H), 7.99 (t, J = 8.1 Hz, 1H), 7.77 (d, J= 7.7 Hz, 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= 6.4 Hz, 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)+.

[1405] Compound (R)-N2-(l-cycfapropylethyl)-N*^rop-2-yn-l-yl)-6-(6-(trifluoromethyl) pyridin-2- yl)-l,3,5-triazine-2,4-diamine

[1407] Ή NMR (400 MHz, CDC13): δ 8.55 (m, 1H), 8.01 (t, J = 7.8 Hz, 1H), 7.79 (d, J = 7.7 Hz, 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)+.

[1408] Compound (R)-N '-(l-cyclopropylethyl)-N1-(2-phenoxyethyl)-6-(6-(trifluoromethyl)pyridin-2- yl)-l,3,5-triazine-2,4-diamine

[1409] ¾ NMR (400 MHz, CDC13): δ 8.43 (d, J = 8.0 Hz, 1H), 7.93 (t, J = 7.6 Hz, 1H), 7.71 (d, J= 7.7 Hz, 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= 6.8 Hz, 1H), 1.34 - 1.04 (m, 4H), 0.35 (m, 4H).LC-MS: m / z 445.2 (M+H)+.

[1410] Compound N2-((R)-l-cyclopropylethyl)-rf-(l-m thoxypropan-2-yl)-6-(6-(trifluoro methyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1412] Ή NMR (400 MHz, CDC13): δ 8.51 (m, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.77 (d, J = 7.7 Hz, 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)+.

[1413] Compound (RJ-rf-fl-cyclopropylethyfy-N'-fl^-dimethoxypropan^-yfy-e-fe- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1414] ¾ NMR (400 MHz, CDC13): 8.47 (m, 1H), 8.05 - 7.80 (m, 1H), 7.71 (d, J = 7.7 Hz, 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)+.

[1415] Compound 2-((4-(((R)-l-cyclopropykthyl)amino)-6-(6-(trifluoromethyl)pyridine -2-yl)-l,3,5- triazin-2-yl)amino)propanenitrile

[1417] Ή NMR (400 MHz, CDC13): δ 8.56 (m, 1H), 8.03 (t, J = 7.8 Hz, 1H), 7.81 (d, J = 7.7 Hz, 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)+.

[1418] Compound (R)-2-(4-(l-cycfapropytethylamino)-6-(6-(trifluoromethyl)pyrMin-2-yl)- 1,3,5- tria in-2-ylamino)-2-methylpropanenitrile

[1419] 13): δ 8.56 (d, J = 8.2 Hz, 1H), 8.03 (t, J = 7.7 Hz, 1H), 7.80 (d, J = 7.7 Hz, 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 = 7.7 Hz, 1H), 0.62 - 0.26 (m, 4H).LC-MS: m / z 392 (M+H)+.

[1420] CompoundN2-((R)-l-cyc^propylethyl)-l^-(tetrahydrofuran-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1421] 1HNMR(400 MHz, CDC13): δ 8.57-8.47 (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 / z 395.2 (M+H)+.

[1422] Compound(lS,2S)-2-(4-((R)A-cyclopropylethylandno)-6-(6-(t¥ifl^

[1423] l3,5-triazin-2-ylamino)cyclohexanol

[1425] 'H MR (400 MHz, CDCI3): δ 8.48 (d, J= 7.4 Hz, 1H), 8.01 (t, J= 7.8 Hz, 1H), 7.79 {A, J =1.1 Hz, 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)+.

[1426] Compound(lR,2S)-2-(4-((R)-l-cyclopropylethylamino)-6-(6-(trifluoromethyl) -pyridin-2-yl)- l,3,5-triazin-2-ylamino)cyclopentanol

[1428] Ή NMR (400 MHz, CDC13): δ 8.51 (m, 1H), 8.01 (t, J= 7.6 Hz, 1H), 7.80 (t, J= 6.4 Hz, 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 = 6.0 Hz, 2H), 0.93 (d, J = 7.5 Hz, 1H), 0.66 - 0.16 (m, 4H).LC-MS: m / z 409.2 (M+H)+.

[1429] Compound (R)-N2-benzyl-]^-(l-cyclopropylethyl)-6-(6-(trifluoromethyl)pyridin- 2-yl)-l,3,5- triazine-2 ,4-diamine

[1431] Ή NMR (400 MHz, CDC13): δ 8.49 (d, J = 7.2 Hz, lH), 7.98 (t, J= 7.7 Hz, 1H), 7.77 (d, J= 7.7 Hz, 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)+.

[1432] Compound N2-((R)-l-cyclopropylethyl)-rf-((S) ^henylethyl)-6-(6-(trifluoromethyl) pyridin- -yl)-l,3,5-triazine-2,4-diamine

[1434] Ή NMR (400 MHz, CDC13): δ 8.45 (t, J= 10.4 Hz, lH), 7.98 (t, J= 7.7 Hz, 1H), 7.77 (d, J= 7.7 Hz, 1H), 7.54 - 7.03 (m, 5H), 5.70 (d, J= 6.9 Hz, 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)+.

[1435] Compound N2-((R)-l-cyclopropylethyl)-rf-((R)-l^henylethyl)-6-(6-(trifluoro methyl) pyridin- 2-yl)-l,3,5-triazine-2,4-diamine

[1436] Ή NMR (400 MHz, CDC13): δ 8.47 (d, J = 8.3 Hz, 1H), 7.98 (t, J = 7.7 Hz, 1H), 7.76 (d, J= 7.7 Hz, 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 = 6.7 Hz, 3H), 0.97 (m, 3H), 0.58 - 0.15 (m, 4H).LC-MS: m / z 429.2 (M+H)+.

[1437] Compound N2-((ltyA-cyctopropylethyl)-l^-(l-(3-fluorophenyl)ethyl)-6-(6

[1438] (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1440] 1H NMR (400 MHz, CDC13): δ 8.55 - 8.36 (m, 1H), 8.00 (t, J = 7.7 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.27 (d, J = 7.8 Hz, 2H), 7.18 - 6.90 (m, 3H), 5.71 - 5.06 (m, 3H), 3.78 - 3.32 (m, 1H), 1.54 (d, J = 6.8 Hz, 3H), 1.34 - 1.22 (m, 3H), 1.00 (d, J = 6.3 Hz, 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)+.

[1441] Compound N2-((R)-l-cycfapropylethyl)-N*-(l-(3-(trifluoromethyl)phenyl)ethyl)

[1442] (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1444] ¾ NMR (400 MHz, CDC13): δ 8.42 (m, 1H), 8.08 - 7.93 (m, 1H), 7.79 (d, J = 7.6 Hz, 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 = 6.9 Hz, 3H), 1.26 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 6.4 Hz, 1H), 0.73 (m, 1H), 0.53 - 0.41 (m, 1H), 0.37 (m, 1H), 0.25 (m, 1H).LC-MS: m / z 497.2 (M+H)+.

[1445] Compound^-ffR^l-cyclopropylethy^-N^-fflR^S^-phenyliyclopropy^-e-fe

[1446] (Mfluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1448] 1H NMR (400 MHz, CDC13): δ 8.47 (d, J = 8.3 Hz, 1H), 7.98 (t, J = 7.7 Hz, 1H), 7.76 (d, J = 7.7 Hz, 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 = 6.7 Hz, 3H), 0.97 (m 3H), 0.63 - 0.18 (m, 4H).LC-MS: m / z 441.2 (M+H)+.

[1449] Compound (R)-N2-(l-cyclopropylethyl)-N*-(l^henyl(yclopropyl)-6-(6-(trifluoro methyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1450] 1H NMR (400 MHz, DMSO-d6): δ 8.53 - 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)+.

[1451] Compound (Rj-d-fd-chloropyridin^-ylj-^-fl-cyclopropylethylj-N^^-diethyl- 1,3,5-triazine- 24-diamine

[1453] Ή NMR (400 MHz, CDC13): δ 8.32 (d, J = 6.6 Hz, 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 = 7.7 Hz, 1H), 0.63 - 0.17 (m, 4H). LC-MS: m / z 347.2 (M+H)+.

[1454] Compound (R)-methyl 3-((4-((l-cyclopropylethyl)amino)-6-(6-(trifluoromethyl)pyri -din-2-yl)- -triazin-2-yl)amino)propanoate

[1455] Ή NMR (400 MHz, CDC13): δ 8.52 (m, 1H), 8.00 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 5.63 (m, 2H), 3.73 (m, 9H), 2.66 (d, J = 5.9 Hz, 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)+.

[1456] Compound (R)-N2-(l-cyclopropylethyl)-]^-(2^henoxyethyl)-6-(6-(trifluoromethyl) pyridin-2- yl)-l,3,5-triazine-2,4-diamine

[1458] Ή NMR (400 MHz, CDC13): δ 8.43 (d, J = 8.0 Hz, 1H), 7.93 (t, J = 7.6 Hz, 1H), 7.71 A, J = 1.1 Hz, 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 = 6.8 Hz, 1H), 1.34 - 1.04 (m, 4H), 0.35 (m, 4H).LC-MS: m / z 445.2 (M+H)+.

[1459] Compound (lR,2S)-2-((4-(cyclopentylamino)-6-(6-(trifluoromethyl)pyridin-2 -yl)-l,3,5-triazin- -yl)amino)cyclopentanol

[1461] 1HNMR (400 MHz, CD3OD): 68.63-8.57 (m, 1H), 8.17-8.14 (m, 1 H), 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).

[1462] Compound N2-(3,3-difluorocycfapentyl)-N*-(tetrahydrofuran-3-yl)-6-(6-(trifluoro methyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1463] Ή NMR (400 MHz, CD3OD): δ 8.68-8.56 (m, 1H), 8.15 (t, J = 8.3 Hz, 1H), 7.93 A, J = 1.5 Hz, 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)+.

[1464] Compound tert-butyl 3-((4-((3,3-difluorocyclopentyl)amino)-6-(6-(trifluoromethyl) pyridin-2- -l,3,5-triazin-2-yl)amino)pyrrolidine-l-carboxylate

[1466] 1H NMR (400 MHz, CDC13): δ 8.62 - 8.46 (m, 1H), 8.03 (d, J= 6.9 Hz, 1H), 7.81 (d, J= 7.7 Hz, 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)+.

[1467] Compound ^-isobufyl-N^-ftetrahydro^H^yran^-y^-e-fe-fMfluoromethyl^yrMin^-yl)- 1,3, 5-triazine-2,4-diamine

[1468] 1HNMR (400 MHz, CD3OD): 68.7-8.6 (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)+.

[1469] Compound N2-((R)-l-cyclopropylethyl)-N4-(l-(2-methoxyethoxy)propan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1471] Ή NMR (400 MHz, CDC13) δ 8.61 - 8.42 (m, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.77 (d, J = 7.7 Hz, 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 = 5.7 Hz, 6H), 0.99 - 0.80 (m, 1H), 0.61 - 0.21 (m, 4H). LC-MS: m / z 441 (M+H)+.

[1472] Compound 2-((4-(((R) -cyclopropylethyl)amino)-6-(6-(trifluoromethyl)pyridin-2

[1473] triazin-2-yl)amino)propan-l -ol

[1475] 1H NMR (400 MHz, CDC13) δ 8.57 - 8.47 (m, 1H), 8.01 (t, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 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). LCMS: m / z 383.2 (M+H)+.

[1476] Compound N2-((R)-l-cyclopropylethyl)-N4-(l-isopropoxypropan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1477] 1H NMR (400 MHz, CDC13) δ 8.65 - 8.42 (m, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 7.3 Hz, 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 = 6.1 Hz, 6H), 1.04 - 0.84 (m, 1H), 0.63 - 0.16 (m, 4H). LC-MS: m / z 425 (M+H)+.

[1478] Compound N2-((R)-l-cyclopropylethyl)- '-(4-methoxybutan-2-y i)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1480] 1H NMR (400MHz, CDC13)5 8.63 - 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). LCMS: m / z 411(M+H)+.

[1481] Compound N2-((R)-l-cyclopropylethyl)-N4-(l-phenylpropan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1482] Ή NMR (400 MHz, CDC13) δ 8.41 (d, J = 7.6 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 7.6 Hz, 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)+.

[1483] Compound N2-((R)-l-cyclopropylethyl)-N4-(l-morpholinopropan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1485] Ή NMR (400MHz, CDC13)5 8.51 - 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). LCMS: m / z 452(M+H)+.

[1486] Compound N2-((R)-l-cyclopropylethyl)-N4-(l-(piperidin-l-yl)propan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1488] 1H NMR (400MHz, CDC13): δ 8.54 - 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). LCMS: m / z 450(M+H)+.

[1489] Compound (R)-3-((4-((l-cyclopropylethyl)amino)-6-(6-(trifluoromethyl)pyridm^

[1490] triazin-2-yl)amino)-2,2-dimethylpropanamide

[1491] Ή NMR (400MHz, CDC13)5 8.52 - 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). LCMS: m / z 424(M+H)+.

[1492] Compound 3-((4-(((R)-l-cyclopropylethyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5- triazin-2-yl)amino)butanenitrile

[1494] 1H NMR (400MHz, CDC13)5 8.50 (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). LCMS: m / z 392(M+H)+.

[1495] Compound (R)-3-((4-((l-cyclopropylethyl)amino)-6-(6-(trifluoromethyl)pyrM

[1496] triazin-2-yl)amino)-2,2-dimethylpropanenitrile

[1497] Ή NMR (400MHz, CDC13) δ 8.55(s, 1H), 8.1 l(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). LCMS: m / z 406(M+H)+.

[1498] Compound l-((4-((3,3-Difluorocyclopentyl)amino)-6-(6-(trifluoromethyl)pyridm^

[1499] triazin-2-yl)amino)-2-methylpropan-2-ol

[1501] Ή NMR (400 MHz, CDC13) δ 8.50 (s, 1H), 8.03 (d, J = 7.3 Hz, 1H), 7.80 (d, J = 7.4 Hz, 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).LCMS: m / z 433 (M+H)+.

[1502] Compound N '-(3, 3-difluorocyclopentyl)-Nt-(l-(4-fluorophenyl)azetidin-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1504] 1H NMR (400 MHz, CDC13) δ 10.05 - 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)+.

[1505] Compound TV' '-(3 ,3-difluorocyclopeniyl)-N*-(l- yridin-2-yl)azetidin-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1507] ¾ NMR (400 MHz, CDC13) δ 8.50 (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).LCMS: m / z 493(M+H)+.

[1508] Compound'N '-(3 ,3-difluorocyclopeniyl)-N*-(l- yridin-3-yl)azetidin-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1510] 1H NMR (400MHz, CDC13): δ 8.50 (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).LCMS: m / z 493(M+H)+.

[1511] Compound rf-fi^-difluorocyclopentyfy-N'-fflr^rJ-S-ft-fluorophenyfycyclobutyfy-e-fe- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1512] Ή NMR (400 MHz, CDC13) δ 8.55 (d, J = 7.6 Hz, 1H), 8.21 - 8.01 (m, 1H), 7.88 (m, 1H), 7.26 - 7.15 (m, 2H), 7.04 (t, J= 8.4 Hz, 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)+.

[1513] Compound'Nl-(3 ,3-difluorocyclopentyl)-N '-((Is, 3s)-3-(4-fluorophenyl)cyclobutyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1515] Ή NMR (400 MHz, CDC13) δ 8.65 - 8.42 (m, 1H), 8.02 (t, J = 7.3 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.20 - 7.12 (m, 2H), 7.01 (t, J= 8.6 Hz, 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)+.

[1516] Compound N2-(3,3-difluorocyclopentyl)-N4-(3-phenylcyclobutyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1518] Ή NMR (400 MHz, CDC13) δ 8.65 - 8.42 (m, 1H), 8.01 (t, J = 7.8 Hz, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.42 - 7.29 (m, 3H), 7.23 (t, J= 6.4 Hz, 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)+.

[1519] Compound N2-(3,3-difluorocyclopeniyl)-N*-(l-methylpyrrolidin-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1520] Ή NMR (400 MHz, CDC13) δ 8.62 - 8.48 (m, 1H), 8.09 - 7.94 (m, 1H), 7.80 (t, J= 7.4 Hz, 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)+.

[1521] Compound (3-((4-((3,3-Difluorocycfapentyl)amino)-6-(6-(trifluoromethyl)pyrMin-2-y^ triazin-2-yl)amino)pyrrolidin-l-yl)(phenyl)methanone

[1523] Ή NMR (400 MHz, CDC13) δ 8.76 - 8.35 (m, lH), 8.10 - 7.91 (m, 1H), 7.84 (s, 1H), 7.53 (d, J = 7.4 Hz, 2H), 7.43 (d, J = 6.5 Hz, 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)+.

[1524] Compound N2-(l-benzylpyrrolidin-3-yl)-N*-(3,3-difluorocyclopentyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1525] Ή NMR (400 MHz, CDC13) δ: 8.62 - 8.40 (m, 1H), 8.12 - 7.93 (m, 1H), 7.79 (d, J = 7.3 Hz, 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)+.

[1526] Compound (4S)-4-((4-((3,3-difluorocyclopentyl)amino)-6-(6-(trifluoromethyl)pyrM

[1527] -triazin-2-yl)amino)A-(pyrulin-2-yl)pyrrolidin-2-one

[1529] Ή NMR (400 MHz, CDC13) δ 8.66 - 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, 6.3 Hz, 1H), 2.85 - 2.51 (m, 2H), 2.21 (m, 5H). LCMS: m / z 521 (M+H)+.

[1530] Compound N2-(3, 3-difluorocyclopentyl)-T^-(3-phenylcyclopentyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1532] Ή NMR (400MHz, CDC13)5 8.59 - 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). LCMS: m / z 505(M+H)+.

[1533] Compound N2-(3,3-difluorocyclopentyl)-Nt-(2,3-dihydro-lH-inden-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1535] IH NMR (400MHz, CDC13): δ 8.64 - 8.46 (m, IH), 8.01 (d,J=12.8Hz , IH), 7.78 (d, J=7.6Hz , IH), 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, IH), 2.31 - 2.09 (m, 4H), 1.85 - 1.84 (m, IH), 1.25(m, IH). LCMS: m / z 477(M+H)+.

[1536] Compound ^-(S-chloro^^-dihydro-lH^den^-y^-N^-fS^-difluoroiyclopeniy^-e-fe- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1538] Ή NMR (400 MHz,CDCl3) δ 8.57 - 8.48 (m, 1H),8.01 (d, J = 8 Hz, IH), 7.81 (d, J = 8 Ηζ,ΙΗ), 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, IH), 2.36 - 2.10 (m, 4H), 1.99 - 1.82 (m, 1H).LCMS: m / z 511 (M+H)+.

[1539] Compound N2-(3, 3-difluorocyclopentyl)-]^-(5-fluoro-2, 3-dihydro^H-inden-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1540] Ή NMR (400MHz, CDC13)5 8.59 - 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). LCMS: m / z 495(M+H)+.

[1541] Compound N2-(5-bromo-2,3-dihydro-lH-inden-2-yl)-N''-(3, 3-difluorocyclopentyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1543] Ή NMR (400 MHz, CDC13) δ 8.57 - 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).LCMS: m / z 556 (M+H)+.

[1544] Compound 2-((4-((3,3-Difluorocyclopentyl)amino)-6-(6-(trifluoromethyl)pyridm^

[1545] triazin-2-yl)amino)-2,3-dihydro-lH-indene-5-carbonitrile

[1547] Ή NMR (400 MHz, CDC13) δ 8.57 - 8.47 (m, 1H), 8.01 (d, J= 8 Hz, 1H), 7.80 (d, J= 4 Hz, 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).LCMS: m / z 502 (M+H)+.

[1548] Compound TV '-(3, 3-difluorocyclopentyl)-]^-(5-methoxy-2,3-dihydro-lH-inden-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1549] Ή NMR (400 MHz, CDC13) δ 8.69 - 8.46 (m, lH),8.00(d, J = 8 Hz, 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).LCMS: m / z 507 (M+H)+.

[1550] Compound N '-(3, 3-difluorocyclopentyl)-N '-(6, 7-dihydro-5H-cyclopenta[b]pyridin-6-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1552] 1H NMR (400 MHz, CDC13) 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). LCMS: m / z 478.2 (M+H)+.

[1553] Compound N2-(4,6-dibromo-2,3-dihydro-lH-inden-2-yl)-N' '-(3, 3-difluorocyclopentyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1554] Ή NMR (400 MHz, CDC13) δ 8.55 - 8.46 (m, 1H), 8.07 - 7.99 (m, 1H), 7.80(d, J = 8 Ηζ,ΙΗ), 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 = 8 Hz, 2H) ,2.17 - 2.01 (m, 2H), 1.90 - 1.77 (m, 1H).LCMS: m / z 635(M+H)+.

[1555] Compound rf-fi^-difluorocyclopentyfy-N'-fl-phenylpyrrolidin-S-yfy-e-fe- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1557] Ή NMR (400 MHz, CDC13) δ 8.61-8.49 (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). LCMS: m / z 506 (M+H)+.

[1558] Compound TV' '-(3 ,3-difluorocyclopeniyl)-N*-(l^yridin-2-yl)pyrrolidin-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1560] Ή NMR (400 MHz, CDC13) δ 8.67 - 8.44 (m, 1H), 8.17 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 6.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, IH), 6.59 (t, J = 5.9 Hz, 1H), 6.39 (d, J = 8.1 Hz, 1H), 5.84 - 4.30 (m, 4H), 4.07 - 3.51 (m, 4H), 2.83 - 1.97 (m, 8H). LC-MS: m / z 507 (M+H)+.Compound N2-(3,3-difluorocyclopentyl)-]^-(l^yrimidin-2-yl)pyrrolidin-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1562] 1H NMR (400 MHz, CDC13) δ 8.64 - 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). LCMS: m / z 508(M+H)+.

[1563] Compound N2-(3, 3-difluorocyclopentyl)-]^-(6,6-difluorospiro[3.3]heptan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1565] Ή NMR (400 MHz, CDC13) δ 8.66 - 8.39 (m, lH), 8.02 (d, J= 7.2 Hz, 1H), 7.80 (d, J = 6.6 Hz, 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)+.

[1566] Compound l-((4-((4,4-Difluorocyclohexyl)amino)-6-(6-(trifluoroinethyl)py M

[1567] triazin-2-yl)amino)-2-methylpropan-2-ol

[1568] Ή NMR (400 MHz, DMSO-d6) δ 8.63 - 8.45 (m, 1H), 8.24 (t, J = 7.7 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.83 (d, J = 7.2 Hz, 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 = 12.2 Hz, 2H), 1.12 (s, 6H). LC-MS: m / z 447 (M+H)+.

[1569] Compound'N '-(4, 4-difluorocyclohexyl)-Nt-(tetrahydro-2H-pyran-4-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1571] Ή NMR (400 MHz, CDC13) δ 8.55 - 8.48 (m, 1H), 8.05 - 7.99 (m, 1H), 7.80 (d, J= 7.6 Hz, 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); LCMS: m / z 459.2 (M+H)+.

[1572] Compound Tert-butyl 4-((4-((4,4-difluorocyclohexyl)amino)-6-(6-(ti,ifluoromethyl)pyridin -2- -l,3,5-triazin-2-yl)amino)piperidine-l-carboxylate

[1574] 1H NMR (400 MHz, CDC13) δ 8.48 - 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). LCMS: m / z 558.3 (M+H)+.

[1575] Compound l-(4-((4-((4,4-Difluorocyclohexyl)amino)-6-(6-(trifluoromethyl)pyrid

[1576] triazin-2-yl)amino)piperidin-l-yl)ethanone

[1577] Ή NMR (400 MHz, CDC13) δ 8.54 - 8.48 (m, 1H), 8.06 - 7.97 (m, 1H), 7.81 (d, J= 7.2 Hz, 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). LCMS: m / z 500.2 (M+H)+.

[1578] Compound N '-(4, 4-difluorocyclohexyl)-rf-(l-(methylsulfonyl)piperidin-4-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1580] 1H NMR (400 MHz, CDC13) δ 8.58 - 8.48 (m, 1H), 8.05 - 7.96 (m, 1H), 7.80 (d, J = 6.8 Hz, 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). LCMS: m / z 536.2 (M+H)+.

[1581] Compound N2- (4,4-diflu orocyclohexyfy-N*- ( 6, 6-difluorospiro[3.3]heptan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1582] Ή NMR (400 MHz, CDC13) δ 8.66 - 8.39 (m, 1H), 8.14 - 7.94 (m, 1H), 7.81 (d, J= 7.7 Hz, 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)+.

[1583] Compound N2-(3 ,3-difluorocyclobutyl)-N' '-(4,4-difluorocyclohexyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1585] Ή NMR (400MHz, CDC13)5 8.54 - 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).LCMS: m / z 465(M+H)+

[1586] Compound N2-(4, 4-difluorocyclohexyl)-Nt-(3, 3-difluorocyclopentyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine

[1588] Ή NMR (400MHz, CDC13)5 8.48 - 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). LCMS: m / z 479(M+H)+.

[1589] Compound (Rj-d-fd-chloropyridin^-ylj-^-fl ^^^-hex fluoropropan^-ylj-N^-fl,!,!- trifluoropropan-2-yl)-l,3,5-triazine-2,4-d mine

[1590] 1H NMR (400 MHz, CDC13) 58.40-8.34 (m, 1H), 7.87 - 7.84 (m, 1H), 7.53 (d, J = 8 Hz, 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)+.

[1591] Compound (R)-6-( 6-chloropyridin-2-yl)-N2- (4,4-difluorocyclohexyl)-Nt-(l, 1,1- trifluoropropan-2-yl)-l,3,5-triazine-2,4-d mine

[1593] 1H NMR (400 MHz, DMSO-d6) δ 8.33 (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). LCMS: m / z 437 (M+H)+.

[1594] Table 2: The following targets were prepared by the procedure described in Scheme 2 above.

[1597] triazine-2,4 -diamine H H

[1598] Example 3 Preparation of Di-aliphatic Triazine Compounds of Formula F. The compounds of this Example are prepared by general Scheme 3, set forth below.

[1599] 9

[1600] Step 1: Preparation ofe-chloro-^^-bisff^-l-cychpropylethy^-l^^^ zine^^-diamine.

[1601] To a mixture of 2,4,6-trichloro-l ,3,5-triazine (2g, 10.9 mmol, 1 eq) and (R)-l- cyclopropylethanamine hydrochloride (2.7 g, 22.8 mmol, 2.1 eq)in acetone (50 mL) was added DIPEA (4.5 mL, 27.3 mmol, 2.5 eq) and CsF (3.3 g, 21.8 mmol, 2.0 eq). The mixture was stirred at 40°C for 3 hr and then at 50°C for another 3 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by a standard method to afford the desired product.

[1602] LC-MS: m / z 282.1 (M+H)+Step 2: Preparation of N2,N* -bis((R)-l -cyclopropylethyl)-6-(pyridin-4-yl)- l,3,5-triazine-2,4- diamine.To a mixture of 6-chloro-N2,N4-bis((R)-l-cyclo -propylethyl)-l,3,5-triazine-2,4-diamine (100 mg, 0.36 mmol), pyridin-4-ylboronic acid (66 mg, 0.52 mmol), and K2C03(99 mg, 0.72 mmol) in 1,4-dioxane (3 mL) and water (1 mL) stirred at r.t. under the atmosphere of nitrogenwas added Pd(PPh3)4(42 mg, 0.036 mmol) in one portion. The reaction mixture was stirred at 80°C ovemight. The mixture was partitioned between water and EtOAc. The organic layer was dried over anhydrous Na2S04and concentrated. The residue was purified by a standard method to ive the desired product.

[1604] 1H NMR (400 MHz, DMSO-d6): δ 7.61 - 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)+.

[1605] The procedure set forth above was used to produce the following compounds using the appropriate starting materials.

[1606] Com ound6-(3-chlorophenyl)-N -bh((R)A-cyclopropylethyl)A,3,54riazine -2,4-diatnine

[1608] Ή NMR (400 MHz, DMSO-d6):5 8.30 - 8.14 (m, 2H), 7.58 (d, J = 7.7 Hz, 1H), 7.52 (t, J

[1609] Hz, 1H), 7.41 (d, J= 8.2 Hz, 1H), 7.35 - 7.26 (m, 1H), 3.70 - 3.43 (m, 2H), 1.26 - 1.15 (m 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)+.Compound3-(4,6-bis((R)-l-cyclopropylethylamino)-l,3,5-triazin-2-yl)phenol

[1611] 1H NMR (400 MHz, CDC13): δ 7.99 - 7.64 (m, 2H), 7.29 (d, J= 7.9 Hz, 1H), 6.96 (d, J= 7.8 Hz, 1H), 5.78 - 5.04 (m, 2H), 4.07 (s, 1H), 3.60 (m, 2H), 1.27 (d, J= 4.3 Hz, 6H), 0.89 (d, J= 3.6 Hz, 2H), 0.43 (m, 8H). LC-MS: m / z 340.2 (M+H)+.

[1612] Table 3: The following targets were prepared by the procedure described in Scheme 3 above.

[1614] Example 4 Preparation of Di-aliphatic Triazine Compounds of Formula G. The compounds of this Example are prepared by general Scheme 4, set forth below.

[1615] Scheme 4

[1617] 12 13

[1618] Formula G

[1619] Step 1. Preparation of N2-(3,3-difluorocyclopentyl)-Nt-(pyrroHdin-3-yl)-6-(6- (trifluoro methyl)pyridin-2-yl)-l,3,5-triazine-2,4-diarnine. To a solution of tert-butyl 3-(4-(3,3- difluorocyclopentylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l ,3,5-triazin-2- ylamino)pyrrolidine-l-carboxylate (160 mg, 0.3 mmol) in DCM (3 mL) at 0°C was added TFA (1 mL). The mixture was stirred at room temperature for 2hrs and then concentrated. The residue was extracted with EtOAc. Combined organic layerswere washed with saturated aqueous NaHC03and brine, dried over anhydrous Na2S04and then concentrated to afford the desired product which was used in the next step without any further purification.

[1621] LC-MS: m / z 430.2 (M+H)+.

[1622] Step 2. Preparation of N' ~-(3,3-difluorocyclopentyl)-N ' -(l-(methylsulfonyl)pyrroli -din-3-yl)-6- (6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine. A mixture of N2-(3,3- difluorocyclopentyl)-N4-(pyrrolidin-3-yl)-6-(6-(trifluoromethyl) pyridin-2-yl)-l,3,5-triazine-2,4- diamine (20 mg, 0.05 mmol), Et3N (9.4 mg, 0.09 mmol), MsCl (6 mg, 0.06 mmol) in DCM (2mL) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by a standard method to afford the desired product.

[1624] 1H NMR (400 MHz, CDC13): δ 8.62 - 8.46 (m, 1H), 8.04 (d, J= 7.5 Hz, 1H), 7.81 (d, J= 7.6 Hz, 1H), 5.79 - 5.38 (m, 2H), 4.80 - 4.53 (m, 2H), 3.76 - 3.52 (m, 2H), 3.39 - 3.23 (m,lH), 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)+.

[1625] The procedure set forth above was used to produce the following compoundsusing the appropriate starting material.

[1626] Coumpound methyl 3-((4-((3,3-difluorocyclopentyl)amino)-6-(6-(trifluoro methyl)pyridin-2- yl)-l,3,5-triazin-2-yl)amino)pyrrolidine-l-carboxylate.

[1628] 1H NMR (400 MHz, CDC13): δ 8.58-8.48 (m, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 7.5 Hz, 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)+.Compound! -(3-((4-((3,3-difluorocyc1openty1)amino)-6-(6-(trifl -2-yl)-l ,3,5- triazin-2-yl)amino)pyrrolidin-l-yl)ethanone

[1630] 1H NMR (400 MHz, CDC13): δ 8.55 (m, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.85 (t, J = 6.7 Hz, 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)+.

[1631] Compound N' '-(3,3-difluorocyclopeniyl)-N" ' -(l-methylpyrrolidin-3-yl) -6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine.To a solution of tert-butyl 3-(4-(3,3- difluorocyclopentylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l ,3,5-triazin-2- ylamino)pyrrolidine-l-carboxylate (25 mg, 0.05mmol) in THF (3 mL) at 0°C was added LiAlH4(5 mg, 0.14 mmol). The mixture was stirred at 0°Cfor 2hr, then at r.t for 30 min, and finally at 60 °C for 2hr. The reaction mixture was quenched with water and extracted by EtOAc. Combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by a standard method to give the desired product.

[1633] Ή NMR (400 MHz, CDC13): δ 8.55 (m, 1H), 8.08 - 7.93 (m, 1H), 7.80 (t, J = 7.4 Hz, 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 SPreparation of Di-aliphatic Triazine Compounds. The compounds of this Example are prepared by general Scheme 5, set forth below.

[1634] Scheme 5

[1636] 14

[1637] Step 1: Preparation of 6-(6-(azetidin-l-yl)pyridin-2-yl)-N2,N*-bis((R)-l-cyclopropyl -ethyl) - l,3,5-triazine-2,4-diatnine. A mixture of 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-l- cyclopropylethyl) -l ,3,5-triazine-2,4-diamine (40 mg, 0.11 mmol), azetidine (7.6 mg, 0.13 mmol), 2,2'-bis-(diphenylphosphino)-l,r-binaphthyl (6.9 mg, 0.01 mmol), sodium tert-butoxide (15 mg, 0.16 mmol) and tris(dibenzylideneacetone) -dipalladium (10.2 mg, 0.01 mmol) in toluene (3 mL) was stirred at 100°C under an atmosphere of nitrogen ovemight. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressureand the residue was purified by a standard method to afford the desired product.

[1638] Ή NMR (400 MHz, CD3OD): δ 8.49 (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)+.

[1639] Step 2: Preparation of ^^-bisffR^l-cychpropykthy^-e^yridin^-y^-l^^-tr zine^^- diamine. To a solution of 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-l-cyclopropylethyl)-l,3,5- triazine-2,4-diamine (20 mg, 0.05 mmol) in methanol (2 mL) was added Pd / C (2 mg) under an atmosphere of nitrogen. The mixture was then stirred at room temperature under ahydrogen balloon overnight. The mixture was filtered and the filtrate was concentrated. The residue was purified by a standard method to afford the desired product.

[1641] 1H NMR (400 MHz, DMSO-d6): δ 8.82 - 8.03 (m, 4H), 7.75 (m, 2H), 3.79 - 3.45 (m, 2H), 1.21 (d, J= 6.3 Hz, 6H), 1.07 - 0.84 (m, 2H), 0.55 - 0.05 (m, 8H). LC-MS: m / z 325.2 (M+H)+.

[1642] Example 6 Preparation of Di-aliphatic Triazine Compounds of Formula ELThe compounds of this Example are prepared by general Scheme 6, set forth below.

[1643] 6

[1645] 18 Formula H

[1646] Step 1: Preparationof 2-((4-(2-fluoro-5-hydroxyphenyl)-6-(isopropylamino)-l, 3,5-triazin-2- yl)amino)-2-methylpropanenitrile.To a solution of 2-((4-(2-fluoro-5-methoxyphenyl)-6- (isopropylamino)-l ,3,5-triazin-2-yl)amino)-2-methylpropanenitrile (200 mg, 0.6 mmol) in anhydrous DCM (3 mL) at -65°C was added dropwise BBr3(0.6 mL) and the reaction mixture was stirred at this temperature for 20 min. The mixture was slowly warmed up to 0°C and stirredfor 10 min. and then stirred at room temperature for 1 hr. The reaction was quenched with icy Sat. aq. NaHC03till pH = 8. The resulting mixture was extracted with EtOAc(2 x 10 mL). Combined organic layers were washed with brine, dried over anhydrous Na2S04and concentrated under reduced pressure. Theresidue was purified by a standard method to afford the desired product.

[1648] Ή NMR (400 MHz, CDC13): δ 7.20 (s, 1H), 6.96 (t, J = 9.6 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 5.72 (m, 2H), 4.26 (s, 1H), 1.79 (s, 6H), 1.26 (d, J= 6.1 Hz, 6H). LC-MS: m / z 331.2 (M+H)+.

[1649] Example 7Preparation of Di-aliphatic Pyrimidine Compounds of Formula J.The compounds of this Example are prepared by general Scheme 7, set forth below.

[1650] Scheme 7

[1653] Step 1: Preparation of6-(trifluoromethyl)picolinirnidarnide. To a solution of6- (trifluoromethyl)picolinonitrile (50 mg, 0.3 mmol, 1 eq) in EtOH (3 mL) was added NaOMe (1.6 mg, 0.03 mmol, 0.1 eq) at 0°C. The mixture was stirred at r.t. for 1 hr, followed by addition of NH4C1 (21 mg, 0.39 mmol, 13 eq). The resulting mixture was stirred at 90°C for 1 hr and cooled to room temperature. The mixture was adjusted pH to 9 with saturated aqueous NaHC03andthen extracted with EtOAc. Combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by a standard method to afford the desired product.

[1655] LC-MS: m / z 190.1 (M+H)+.

[1656] Step 2: Preparation of2-(6-(trifluoromethyl)pyridin-2-yl)pyrimidine-4,6-diol. To a solution of sodium (366 mg, 15.9 mmol, 5.0 eq) in anhydrous EtOH (6 mL) was added dropwise a solution of 6-(trifluoromethyl)picolinimidamide (600 mg, 3.2 mmol) in EtOH. The reaction mixture was stirred at r.t. for 1 hr, followed by addition of diethyl malonate (1 mL, 6.4 mmol, 2.0 eq). The mixture was stirred at reflux overnight and then cooled to room temperature. The resulting mixture was adjusted pH to 7 by 1 N aq. HClsolution. 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.

[1658] LC-MS: m / z 256.0 (M-H)".

[1659] Step 3: Preparation of4,6-dichloro-2-(6-(trifluoromethyl)pyridin-2-yl)pyrimidine. A solution of 2-(6-(trifluoromethyl)pyridin-2-yl)pyrimidine-4,6-diol (1 g, 3.9 mmol) in POCl3(6 mL) was stirred at 90°C overnight and then concentrated to remove the volatile. The residue was purified by a standard method to afford the desired product.

[1660] LC-MS: m / z 294.0 (M+H)+.

[1661] Step 4: Preparation of(R)-6-chloro-N-(l-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, 0.27 mmol, 1 eq) in THF (3 mL) was added (R)-l- - cyclopropylethanamine (0.06 mL, 0.6 mmol, 2.2 eq) and EtsN (0.07 mL, 0.54 mmol, 2 eq). The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified by a standard method to give the desired product.

[1663] LC-MS: m / z 343.1 (M+H) .

[1664] Step 5 : Preparation ofiV4,N6-bis((R)-l-cyclopropylethyl)-2-(6-(trifluoromethyl)pyri din-2- yl)pyrimidine-4,6-diamine.To a solution of (R)-6-chloro-N-(l-cyclopro pylethyl)-2-(6- (trifluoromethyl) -pyridin-2-yl)pyrimidin-4-amine (50 mg, 0.15 mmol, 1 eq) in DMSO (2 mL) was added (R)-l -cyclopropylethanamine hydrochloride (22 mg, 0.18 mmol, 1.2 eq) and DIPEA (0.08 mL, 0.45 mmol, 3 eq). The mixture was irradiated under microwave at 160 °C for 1.5 hr. After addition of (R)-l -cyclopropylethanamine (0.18 mmol, 1.2 eq),the resulting mixture was stirred and irradiated under microwave at 160 °C for another 2 hr. The mixture was cooled to r.t. and then partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by a standard method to give the desired product.

[1666] Ή NMR (400 MHz, CDC13): δ 8.40 (d, J = 7.9 Hz, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.62 (d, J= 7.8 Hz, 1H), 5.19 (m, 3H), 3.13 (d, J = 6.3 Hz, 2H), 1.19 (d, J = 6.4 Hz, 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)+.

[1667] The procedure set forth above was used to produce the following compounds using the appropriate starting materials.

[1668] CompoundN1',Ν* ^-bis((S) -cyclopropylethyl)-2-(6-(trifluoromethyl)pyridin-2-yl) pyrimidine-

[1670] Ή NMR (400 MHz, CDC13): δ 8.49 (d, J = 7.8 Hz, 1H), 7.95 (t, J = 7.9 Hz, 1H), 7.71 (d, J= 7.8 Hz, 1H), 5.22 (m, 3H), 3.22 (d, J = 6.5 Hz, 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)+.

[1671] Co^oundNi-((R)-l-cychpropylethyl)-N6-((S)-l-(yclopropylethyl)-2-(6-(t^^

[1672] methyl)pyridin-2-yl)pyrimidine-4,6-diamine

[1673] Ή NMR (400 MHz, CDC13): δ 8.49 (d, J = 7.8 Hz, 1H), 7.97 (t, J = 7.9 Hz, 1H), 7.72 (d, J= 7.8 Hz, 1H), 5.22 (m, 3H), 3.22 (d, J = 6.5 Hz, 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)+.

[1674] Table 7: The following compounds were prepared by the procedure described in Scheme 7 above.

[1676] Example 9. Preparation of Symmetric Di-aliphatic Triazine Compounds of Formula K.

[1677] The compounds of this Example are prepared by general Scheme 9, set forth below.

[1679] Formula KStep 1: Preparation of 2-bromo-6-(l,l-difluoroethyl)pyridine.

[1680] To a solution of l-(6-bromopyridin-2-yl)ethanone (26 g, 130 mmol) in dry DCM (150 mL) at 0 °C was added dropwise DAST (84 mL, 650 mmol) over 30 min. The reaction mixture was then slowly allowed to warm up to r.t, and stirred until the reaction was complete. The resulting mixture was slowly poured into ice (300 g) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water, dried over anhydrous Na2S04and concentrated under reduced pressure. The residue was purified by standard methods to afford 2-bromo-6-(l,l- difluoroethyl)pyridine.LC-MS: m / z 222.0 (M+H)+.

[1681] Step 2:Preparation of methyl 6-(l,l-difluoroethyl)picolinate.

[1682] To a solution of 2-bromo-6-(l ,l -difluoroethyl)pyridine (30.2 g, 136 mmol) in MeOH (300 mL) were added l ,l '-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°C under CO atmosphere (60 psi) for 16 hr. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified bystandard methods to afford methyl 6-(l,l-difluoroethyl) picolinate.LC-MS: m / z 202.2 (M+H)+.

[1683] Step 3: Preparation of6-(6-(l,l-difluoroethyl)pyridin-2-yl)-l,3,5-triazine-2,4(lH,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-(l,l-difluoroethyl)picolinate(2.8 g, 28 mmol) and biuret(14.0 g, 70 mmol). The mixture was stirred at 90°C for 16 hr and concentrated under reduced pressure. To the residue was added water (50 mL). The resulting mixture was adjusted the pH to 7 with IN HCl, and then filtered. The filter cake was washed with water, and dried under high vacuum to afford 6-(6-(l,l-difluoroethyl)pyridin-2-yl) ,3,5-triazine-2,4(lH,3H)-dione.LC-MS: m / z 255.1 (M+H)+.

[1684] Step 4: Preparation of2,4-dichloro-6-(6-(l,l-difluoroethyl)pyridin-2-yl)-l,3,5-triazine.

[1685] To a solution of6-(6-(l,l -difluoroethyl)pyridin-2-yl)-l,3,5-triazine-2,4(lH,3H)-dione (6 g, 25 mmol) in POCl3(60 mL) was added PC15(26 g, 125 mmol). The mixture was stirred at 100°C for 16 hr and concentrated under reduced pressure. The residue was purified by standard methods toafford 2,4-dichloro-6-(6-(l,l-difluoroethyl)pyridin-2-yl)-l,3,5-triazine. Ή NMR (400MHz, CDCI3) 58.62 (d, 1H), 8.07 (t, 1H), 7.94 (d, 1H), 2.16 (q, 3H). LC-MS: m / z 292.1 (M+H)+.

[1686] Step 5: Preparation of N2,Nt-bis(4,4-difluorocyclohexyl)-6-(6-(l,l-difluoroethyl) pyridin-2-yl)- l,3,5-triazine-2,4-diamine To a mixture of 2,4-dichloro-6-(6-(l,l-difluoroethyl)pyridin-2-yl)- 1,3,5-triazine (582 mg, 2.0 mmol, 1.0 eq) and 4,4-difluorocyclohexanamine hydrochloride (752 mg, 4.4 mmol, 2.2 eq) in THF (12 mL) at r.t.were added CsF (1.2 g, 8.0 mmol, 2eq) and DIPEA (1.4 mL, 8.0 mmol, 4 eq). The mixture was stirred at 60°C overnight and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by standard methods to give the desired product.

[1688] Ή NMR (400 MHz, CDC13) δ 8.32-8.40 (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)+.

[1689] The procedure set forth in Example 9 was used to produce the following compounds using the appropriate starting materials.

[1690] Compound N2,N4-bis(3,3-difluorocyclopentyl)-6-(6-(l,l-difluoroethyl)pyridin-2-yl)-l,3,5-

[1691] Ή NMR (400 MHz, CDC13) δ 8.32-8.43 (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)+.

[1692] Compound N2J\4-bis(3,3-difluorocyclobutyl)-6-(6-(l,l-difluoroethyl)pyridin-2-yl)-l,3,5-

[1694] 1H NMR (400 MHz, CDC13) δ 8.35-8.42 (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)+.

[1695] Example 10. Preparation of Symmetric Di-aliphatic Triazine Compounds of Formula L.

[1696] The compounds of this Example are prepared by general Scheme 10, set forth below.

[1697] Scheme 10

[1699] Formula L

[1700] Step 1: Preparation of 6-(6-chloropyridin-2-yl)-l,3,5-triazine-2,4(lH,3H)-dione.To a dried three-necked round bottom flask were added biuret (14.8 g, 0.14 mol), methyl 6-chloropicolinate (21 g, 0.12 mol) and EtOH (250 mL). The mixture was degassed with N2three times and then stirred at 25°C for 20 min. Then the temperature was allowed to rise to 50°C, followed byaddition of HC(OMe)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 min, followed by drop wise addition of a solution of NaOEt in EtOH (20%wt, 163 g, 0.48 mol). The resulting yellowish thick slurry was heated to reflux for 2hr until the reaction was complete. The mixture was cooled to r.t. and concentrated under reduced pressure. The residue was treated with water (200 mL) and concentrated under reduced pressure to remove the remaining ethanol. Then water (300 mL) was added to the residue (while stirring) to form a clear brown solution. The solution was cooled to 10°C and slowly adjusted to pH 1 by 6N HC1. The resulting mixture was stirred for another 2 hr and filtered. The filter cake was washed with aq. HC1 (pH=l), collected and suspended in DCM (300 mL). The suspension was stirred at r.t. for 2hr, filtered and dried to afford the desired product. LC-MS: m / z 225.0 (M+H)+.

[1701] Step 2: Preparation of 2,4-dichloro-6-(6-chloropyridin-2-yl)-l,3,5-triazine. The procedure is the same as Example 1 Step 3 described above.LC-MS: m / z 260.9 (M+H)+.

[1702] Step 3 : Preparation of 6-(6-chloropyridin-2-yl)-N2,N*-bis((R)-l -trifluoropropan-2-yl)- l,3,5-triazine-2,4-diamine. A mixture of 2,4-dichloro-6-(6-chloro -pyridin-2-yl)-l,3,5-triazine (0.27 g, 1.04 mol), (R)-l,l,l-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 under the atmosphere of N2at 50°C for 36 hr then at 100°C for another 36 hr until the reaction was complete. The resulting mixture was filtered through Celite and the cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by standard methods to give the desired roduct.

[1703] Ή NMR (400 MHz, CDC13) δ 8.32 (m, 1H), 7.80 (m, 1H), 7.48 (d, J = 7.9 Hz, 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)+.

[1704] The procedure set forth in Example 10 was used to produce the following compounds using the appropriate starting materials.

[1705] 6-(6-Chloropyridin-2-yl)-N2,N4-bis((S)-l,l,l-trifluoropropan-2-yl)-l,3,5-

[1707] 1H NMR (400 MHz, CDC13)5 8.29 - 8.16 (m, 1H), 7.72 (d, J= 7.6 Hz, 1H), 7.41 (d, J= 7.9 Hz, 1H), 5.70 - 5.13 (m, 2H), 5.09 - 4.71 (m, 2H), 1.34 (m, 6H).LC-MS: m / z 415 (M+H)+.

[1708] Compound6-(6-Chloropyridin-2-yl)-N2-((R)-l,l,l-trifluoropropan-2-yl)-N4-((S)-l,l,l- rifluoro ropan-2-yl)-l,3,5-triazine-2,4-diamine

[1710] XH NMR (400 MHz, CDC13) δ 8.41 - 8.23 (m, 1H), 7.83 (s, 1H), 7.51 (d, J= 6.2 Hz, 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)+.

[1711] Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(l,1 -trifluoropropan-2-yl)-l,3,5-triazine- 2,4-diamine

[1712] 1H NMR (400 MHz, CDC13) δ 8.29 - 8.16 (m, IH), 7.72 (d, J = 7.6 Hz, IH), 7.41 (d, J= 7.9 Hz, IH), 5.70 - 5.13 (m, 2H), 5.09 - 4.71 (m, 2H), 1.34 (m, 6H).LC-MS: m / z 415 (M+H)+.

[1713] Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(l,1 -trifluorobutan-2-yl)-l,3,5-triazine-2,4- diamine

[1715] 1H NMR (400 MHz, CDC13) δ 8.39 - 8.31 (m, IH), 7.86 - 7.79 (m, IH), 7.50 (d, J= 7.8 Hz, IH), 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, 6.0 Hz, 6H).LC-MS: m / z443 (M+H)+.

[1716] Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis((S)-l,1 -trifluorobutan-2-yl)-l,3,5-triazine- -diamine

[1718] H NMR (400 MHz, CDC13) δ 8.30-8.35 (t, IH), 7.78-7.82 (t, IH), 7.47-7.52 (m, IH), 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)+.Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis((R)-l,1 -trifluorobutan-2-yl)-l,3,5-triazine- 2,4-diamine

[1720] ¾ NMR (400 MHz, CDC13) δ 8.31-8.35 (t, IH), 7.78-7.82 (t, IH), 7.47-7.49 (m, IH), 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)+.

[1721] Compound6-(6-Chloropyridin-2-yl)-N2-((R)-l,l,l-trifluorobutan-2-yl)-N4-((S)-l,l,l- trifluorobutan-2-yl)-l,395-triazine-2,4-diamine

[1723] 1HNMR (400MHz, CDC13) 58.30-8.35 (m, IH), 7.81 (s, IH), 7.47-7.49 (d, IH), 5.35-5.66 (m, 2H), 4.91-5.13 (d, IH), 4.72 (s, IH), 2.00-2.23 (d, 3H), 1.31-1.42 (d, IH), 1.03-1.07 (m, 6H).LC- MS: m / z 443 (M+H)+.

[1724] Compound3,3'-((6-(6-Chloropyridin-2-yl)-l,395-triazine-2,4- diyl)bis(azanediyl))dibutanenitrile

[1725] Ή NMR (400 MHz, CDC13) δ 8.21 (s, lH), 7.73 (t, J= 7.6 Hz, 1H), 7.41 (d, J= 7.8 Hz, 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)+.

[1726] Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(l-cyclopropylpropyl)-l,395-triazine-2,4- diamine

[1728] 1H NMR (400 MHz, CDC13) δ 8.26 (d, J = 7.3 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 5.37 - 5.08 (m, 2H), 3.48 - 3.37 (m, 2H), 1.73 - 1.56 (m, 4H), 0.98 (t, J = 7.3 Hz, 6H), 0.92 - 0.80 (m, 2H), 0.66 - 0.20 (m, 8H). LC-MS (m / z): 387.2 (M+H)+.

[1729] Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(dicyclopropylmethyl)-l,3,5-triazine-2,4- diamine

[1731] Ή NMR (400 MHz, CDC13) δ 8.18 (d, J= 7.6 Hz, 1H), 7.69 (t, J= 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 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)+.

[1732] Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(4,4-difluorocyclohexyl)-l,3,5-triazine-2,4- diamine

[1733] 1H NMR (400 MHz, CDC13) δ 8.28 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 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)+.

[1734] Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(3,3-difluorocyclopentyl)-l,3,5-triazine-2,4- diamine

[1736] 1H NMR (400 MHz, CDC13) δ 8.41 - 8.25 (m, IH), 7.85 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 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). LCMS: m / z 431.1 (M+H)+.

[1737] Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(2,2-difluorocyclopentyl)-l,3,5-triazine-2,4- iamine

[1739] Ή NMR (400 MHz, CDC13) δ 8.48 - 8.26 (m, IH), 7.82 (s, IH), 7.49 (s, IH), 5.63 (m, 2H), 4.70 (m, 2H), 2.41-2.08 (m, 6H), 1.83 (m, 4H), 1.66 (s, 2H). LCMS: m / z 431(M+H)+..Compound2,2'-((6-(6-Chloropyridin-2-yl)-l,3,5-triazine-2,4- diyl)bis(azanediyl))dicyclopentanol

[1741] Ή NMR (400 MHz, CDC13) δ 8.27 - 8.17 (m, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.9 Hz, 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). LCMS: m / z 391(M+H)+.

[1742] Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(6,6-difluorospiro[3.3]heptan-2-yl)-l,3,5- triazine-2,4-diamine

[1744] 1H NMR (400MHz, CDC13) 58.25 - 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). LCMS: m / z 483(M+H)+.

[1745] Compound6-(4-Chloropyridin-2-yl)-N2J\4-bis(4,4-difluorocyclohexyl)-l,3,5-triazine-2,4- diamine

[1747] Ή NMR (400 MHz, CDC13) δ 8.68 (d, J = 8.0 Hz, 1H), 8.48 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 5.28 (d, J = 8.0 Hz, 2H), 4.20-4.02 (m, 2H), 1.98-1.61 (m, 16H). LC-MS: m / z 459.1 (M+H)+.Compound6-(5-Chloropyridin-3-yl)-N2,N4-bis((R)-l-cyclopropylethyl)-l,3,5-triazine-2,4- iamine

[1749] 1H NMR (400 MHz, CDC13) δ 9.36 (m, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.54 (t, J = 1.9 Hz, 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)+.

[1750] Example 11 The compounds of this Example are prepared by general Scheme 11, set forth below.

[1751] Scheme 11

[1753] Step 1. Preparation of N2,1^ -bh((ltyA-cyclopropylethyl)-6-(6-((4-methoxybenzyl) arnino)pyridin-2-yl)-l,3,5-triazine-2,4-diamine. To a solution of 6-(6-chloropyridin-2-yl)- N2,N4-bis((R)-l-cyclopropylethyl)-l,3,5-triazine-2,4-diamine (120 mg, 0.33 mmol), (4- methoxyphenyl)methanamine (69 mg, 0.51 mmol), ΒΓΝΑΡ (42 mg, 0.66 mmol) and t-BuONa (63 mg, 0.66 mmol) in anhydrous dioxane (2 mL) at r.t. under N2atmospherewas added Pd2(dba)3(30 mg, 0.033 mmol) in one portion. The reaction mixture was then stirred at 100 °C overnight then concentrated under reduced pressure to afford the desired product.

[1754] LCMS: m / z 460 (M+Hf.

[1755] Step 2. Preparation of 6-(6-aminopyridin-2-yl)-Nl,N '-bisfflty-l-cyclopropyl ethyl)-l,3,5- triazine-2,4-diamine. N2,N4-bis((R)-l-cyclopropylethyl)-6-(6-(4-methoxybenzylamino) pyridin- 2-yl)-l,3,5-triazine-2,4-diamine (80 mg, 0.17 mmol) was dissolved in TFA (0.5 mL) under N2atmosphere. The solution mixture was then stirred at r.t. overnight then concentrated under reduced pressure. The residue was purified by standard methods to afford the desired product.

[1757] 1H NMR (400 MHz, CDC13) δ 7.71 - 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). LCMS: m / z 340.2 (M+H)+.

[1758] Example 12 The compounds of this example are prepared by general Scheme 12, set forth below.

[1759] Scheme 12

[1761] Step 1. Preparation of 6-(4,6-bis((R)-l-cyclopropylethylamino)-l,3,5 riazin-2-yl)pyridin-2-oL

[1762] To a mixture of N2,N4-bis((R)-l-cyclopropylethyl)-6-(6-methoxypyridin-2-yl)- 1,3,5-triazine- 2,4-diamine (50 mg, 0.14 mmol) and Nal (63 mg, 0.42 mmol) in anhydrous CH3CN (1 mL) at r.t. was added TMSC1 (46 mg, 0.42 mmol) in one portion. The reaction mixture was stirred 80 °C for 6 hr then concentrated under reduced pressure. The residue was purified by standard methods to afford the desired product. ¾ NMR (400 MHz, CDC13) δ 10.24 (br s, 1H), 7.51 (t, J = 8.0 Hz,1H), 7.29 - 7.20 (m, 1H), 6.71 (d, J = 8.0 Hz, 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).LCMS: m / z 341.2 (M+H)+.

[1763] Example 13 The compounds of this Example are prepared by general Scheme 13, set forth below.

[1764] Scheme 13

[1766] Step 1. Preparation ofN2,N*-bis((R)-l-cycfapropytethyl)-6-(6-vinylpyridin-2-yl)- 1,3,5-triazine- 2,4-diamine. To a suspension of 6-(6-chloropyridin-2-yl)-N2,N4-bis ((R)-l-cyclopropylethyl)- l,3,5-triazine-2,4-diamine (200 mg, 0.56 mmol), 2,4,6-trivinyl-l ,3,5,2,4,6-trioxatriborinane (135 mg, 0.84 mmol) and K2CO3(154 mg, 1.11 mmol) in dioxane (2 mL) and H20 (0.8 mL) under an atmosphere of N2was added Pd(dppf)Cl2(41 mg, 0.06 mmol) in one portion. The reaction mixture was stirred at 100 °C overnight then cooled to r.t. 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 Na2S04, and concentrated under reduced pressure. The residue was purified by standard methods to afford the desired product. H NMR

[1767] (400 MHz, CDCI3) δ 8.28 - 8.15 (m, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.05 - 6.99 (m, 1H), 6.15 (d, J = 17.6 Hz, 1H), 5.42 (d, J = 17.6 Hz, 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). LCMS: m / z 351.1

[1768] (M+H)+.

[1769] Example 14 The compounds of this Example are prepared by general Scheme 14, set forth below.Scheme 14

[1771] Step 1. Preparation of 6-(4,6-bis(((R)-l-c clopropylethyl)amino)-l,3,5-triazin-2-yl) picolinaldehyde. Ozone was bubbled into a solution of N2, N4-bis((R)-l-cyclopropylethyl)-6-(6- vinylpyridin-2-yl)-l ,3,5-triazine-2,4-diamine (120 mg, 0.34 mmol) in DCM (2 mL) at -78 °C for lhr. After excess ozone was purged by N2, Me2S (0.2 mL) was added into the reaction mixture at 0 °C. The resulting mixture was concentrated and the residue was purified by standard methods to afford the desired product. LCMS: m / z 353 (M+H)+.

[1772] Step 2. Preparation of N2,Ν4-kis((R)-1 -cyclopropylethyl)-6-(6-(difluoroinethyl) pyridin-2-yl)- l,3,5-triazine-2,4-diamine. To a solution of 6-(4,6-bis((R)-l -cyclo propylethylamino)-l,3,5- triazin-2-yl)picolinaldehyde (50 mg, 0.14 mmol) in anhydrous DCM (2 mL) at 0 °C was added dropwise DAST (68 mg, 0. 43 mmol). The reaction mixture was stirred at r.t overnight. The resulting mixture was slowly quenched with satd. aq. NaHC03(5 mL) at 0°C, then extracted with DCM (40 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2S04, concentrated, and purified by standard methods to afford the desired product. 1H NMR (400 MHz, CDC13) δ 8.46 (s, 1H), 7.97 (t, J = 7.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 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). LCMS: m / z 375 (M+H)+.

[1773] The procedure set forth in Example 14 was used to produce the following compounds using the appropriate starting materials.

[1774] CompoundN2,N4-bis(4,4-difluorocyclohexyl)-6-(6-(difluoromethyl)pyridin-2-yl)-l,3,5- triazine-2,4-diamine

[1775] 1H NMR (400 MHz, CDC13) δ 8.48 (, 1H), 8.01 (br s., 1H), 7.81 (d, J = 8.0 Hz, 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)+.

[1776] CompoundN2J\4-bis(3,3-difluorocyclobutyl)-6-(6-(difluoromethyl)pyridin-2-yl)-l,395- triazine-2,4-diamine

[1778] 1H NMR (400 MHz, CDC13) δ 8.64 - 8.35 (m, 1H), 8.10 - 7.92 (m, 1H), 7.81 (d, J= 7.7 Hz, 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)+.

[1779] Example 15 The compounds of this Example are prepared by general Scheme 15, set forth below.

[1780] Scheme 15

[1782] Step 1: Preparation of methyl 6-(4,6-bis((R)-l-cyclopropylethylamino)-l,3,5-triazin-2- yl)picolinate. To a mixture of 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-l-cyclopropylethyl)-l,3,5- triazine-2,4-diamine (0.25g, 0.7mmol) in MeOH (l OmL) were added dppf (80mg, 0.15mmol), Pd(OAc)2(60mg, 0. 27 mmol) and EtsN (150mg, 1.5 mmol). The reaction mixture was degassed and back-filled with CO three times and then stirred under an atmosphere of CO (60 psi) at 70°C for 12hr. The resulting mixture was cooled to r.t. and concentrated under reduced pressure. The residue was triturated with EtOAc (lOOmL) and filtered. The filtrate was concentrated and purified by standard methods to afford methyl 6-(4,6-bis((R)-l-cyclopropylethylamino)-l,3,5- triazin-2-yl)picolinate. Ή NMR (400 MHz, CDC13) δ 8.50 (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). LCMS: m / z 383(M+H)+.

[1783] Step 2: Preparation of6-(4,6-bis(((R)-l-cyclopropylethyl)amino)-l,3,5-triazin-2-yl) picolinic acid. To a mixture of methyl 6-(4,6-bis((R)-l -cyclopropylethylamino)-l,3,5-triazin-2- yl)picolinate (150 mg, 0.40 mmol) in water(2.0mL) and THF(3.0mL) was added lithium hydroxide(47 mg, 2.0 mmol). The reaction mixture was stirred at r.t. overnight then acidified withaq.HCl (1 N) to pH5-6 and extracted with EtOAc. The combined organic layers weredried over anhydrous Na2S04, and concentrated under reduced pressure to give the desired product.LCMS: m / z 367 (M-H)".Step 3: Preparation of 6-(4,6-bis((R)-l-cyclopropylethylamino)-l,3,5-triazin-2-yl)picolinami

[1784] To an ice cold mixture of 6-(4,6-bis(((R)-l-cyclopropylethyl)amino)-l ,3,5-triazin-2-yl)picolinic acid (120mg, 0.32mmol) in dry DCM(5.0mL) and DMF(O.lmL) was added dropwise oxalyl chloride(65mg, 0.5mmol). The reaction mixture was stirred at r.t. for 2 hr then treated with ammonia. The resulting mixture wasstirred for lOmin at 0°C, and then concentrated and purified by standard methods to give 6-(4,6-bis((R)-l-cyclopropylethylamino)- l,3,5-triazin-2- yl)picolinamide. ¾ NMR (400 MHz, CDC13) δ 13.59 (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). LCMS: m / z 368(M+H)+.

[1785] Step 4: Preparation of 6-(4,6-bis((R)-l-cyclopropylethylamino)-l,3,5-triazin-2- yl)picolinonitrile. To a mixture of 6-(4,6-bis((R)-l -cyclopropylethylamino)-l,3,5-triazin-2- yl)picolinamide(36mg, O. lmmol) in dry pyridine(3.0mL) was added phosphorous trichloride (0.1 mL). The reaction mixture was stirred at r.t. for 2 hr then concentrated under reduced pressure. The residue was purified by standard methods to give 6-(4,6-bis((R)-l- cyclopropylethylamino)-l,3,5-triazin-2-yl)picolinonitrile. H NMR (400 MHz, CDC13) δ 8.50- 8.48 (m, 1H), 8.24-8.22 (t, 1H), 7.73-7.71 (dd, lH), 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). LCMS: m / z 350(M+H)+.

[1786] Example 16 The compounds of this Example are prepared by general Scheme 16, set forth below.

[1787] Scheme 16

[1788] Step 1: Preparation of 3,6-difluoro-2-hydrazinylpyridine. 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 up to r.t. and then heated at reflux for 2 hr. After it was cooled to r.t., the reaction mixture was diluted with water (10 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2S04and concentrated under reduced pressure to afford 3,6-difluoro-2-hydrazinylpyridine.LC-MS (m / z): 146 (M+H)+.

[1789] Step 2: Preparation of 2-bromo-3,6-difluoropyridine. To a stirred solution of 3,6-difluoro-2- hydrazinylpyridine(l .l g, 7.0 mmol) in chloroform (20 mL) at r.t. was added dropwise bromine (1.8 g, 11.2 mmol). The reaction mixture was heated to 60°C for 1.5 hr. The resulting mixture was cooled to r.t., quenched with satd. aq. NaHC03, and extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over anhydrous Na2S04and concentrated and purified by standard methods to afford 2-bromo-3,6-difluoropyridine. LC-MS: m / z 194 (M+H)+.

[1790] Step 3.'Preparation of methyl 3,6-difluoropicolinate. To a solution of 2-bromo-3,6- difluoropyridine (0.8 g, 4.1mmol) in MeOH (10 mL) were added dppf (0.3 g, 0.56 mmol), Pd(OAc)2(0.1 g, 0. 45 mmol) and EtsN (1.6 mL, 8.2 mmol). The suspension was degassed and back-filled with CO atmosphere three times. The resulting mixture was stirred under CO atmosphere (60 psi) at 70°C for 12 hr, then cooled to r.t. and concentrated under reduced pressure. The residue was triturated with EtOAc (150 mL) and filtered. The filtrate was concentrated and purified by standard methods to afford methyl 3,6-difluoropicolinate.LC-MS: m / z 174 (M+H)+.

[1791] Step 4:Preparation of N2,N4-bis(4,4-difluorocyclohexyl)-6-(3,6-difluoropyrMin-2-yl)-l,3,5- triazine-2,4-diamine. To a suspension of N1,N5-bis(4,4-difluorocyclo hexyl)-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 r.t. overnight, then poured into water, and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by standard methods to afford N2, N4-bis (4,4-difluorocyclohexyl)-6-(3,6-difluoropyridin-2-yl)-l,3,5-triazine-2,4-diamine. ¾ NMR (400 MHz, CDC13) δ 7.67-7.61 (m, 1H), 7.07-7.03 (m, lH), 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)+.

[1792] Example 17 The compounds of this Example are prepared by general Scheme 17, set forth below.

[1793] Scheme 17

[1795] Step 1: Preparation of N2,Ni-bis(4,4-difluorocyclohexyl)-6-(3-fluoro-6-hydrazinylpyridin-2- yl)-l,3,5-triazine-2,4-diamine. To a solution of N2,N4-bis(4,4-difluoro -cyclohexyl)-6-(3,6- difluoropyridin-2-yl)-l ,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°C for 2.5 hr. After cooling to r.t., the reaction mixture was diluted with DCM and washed with water. The organic phase was separated,dried over anhydrous Na2S04, and concentrated under reduced pressure to give the desired product. LC-MS (m / z): 473.2 (M+H)+.

[1796] Step 2: Preparation of 6-(6-amino-3-fluoropyridin-2-yl)-N2,N4-bis(4,4-difluorocyclohexyl)- l,3,5-triazine-2,4-diamine. To a solution of N2,N4-bis(4,4-difluoro -cyclohexyl)-6-(3-fluoro-6- hydrazinylpyridin-2-yl)-l,3,5-triazine-2,4-diamine (47 mg, 0.1 mmol) in methanol (5.0 mL) was added Raney Ni (100 mg).The reaction mixture was stirred under H2atmosphere overnight at r.t. then filtered. The filtrate was concentrated and purified by standard methodsto afford the desired product. ¾ NMR (400 MHz, CDC13) δ 7.43-7.39 (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)+.

[1797] Example 18 The compounds of this Example are prepared by general Scheme 18, set forth below.Scheme 18

[1799] Step 1: Preparation of 6-(4,6-bis((4,4-difluorocyclohexyl)amino)-l,3,5-triazin- 2-yl)-5- fluoropyridin-2-ol. A mixture of N2,N4-bis(4,4-difluorocyclohexyl)-6-(3,6-difluoropyridin-2- yl)-l,3,5-triazine-2,4-diamine (100 mg, 0.22 mmol) in cone. HC1 (5.0 mL) was stirred at 100°C overnight. The resulting mixture was concentrated and purified by standard methods to afford the desired product. ¾ NMR (400 MHz, CDC13) δ 9.96 (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). LCMS: m / z 459(M+H)+.

[1800] Example 19 The compounds of this Example are prepared by general Scheme 19, set forth below.

[1802] Step 1: Preparation of NJ l,N'-bis(3,3-difluorocyclopentyl)-biguanide. A mixture of 3,3- difluorocyclopentanamine hydrochloride (3 g, 19.1 mmol) and sodium dicyanamide (1.7 g, 19.1 mmol) was heated at 160°C for 1 hr. The resulting product was dissolved in MeOH then filtered. The filtrate was concentrated to afford the desired product. LC-MS: m / z 310.2 (M+H)+.

[1803] Step 2: Preparation of ethyl 6-cyclopropylpicolinate. To a mixture of ethyl 6-bromopicolinate (200 mg, 0.87 mmol) andcyclopropylboronic acid (149 mg, 1.74 mmol) in toluene (15 mL) were addedK3P04(369 mg, 1.74 mmol) anddichloro(diphenylphosphinoferrocene)palladium (11 mg,0.017 mmol). The resulting mixture was stirred under N2atmosphere at 100 C overnight, then cooled to r.t. and filtered. The filtrate was concentrated and purified by standard methodsto afford the desired product. LC-MS: m / z 192.1 (M+H)+.

[1804] Step 3: 6-(6-cyclopropylpyridin-2-yl)-N:' ,T^-bis(3^-difluorocyclopentyl)A,3,5-triazine-2,4- diamine. To a mixture of N\N5-bis(3,3-difluorocyclopentyl)-biguanide (50 mg,0.16 mmol) and ethyl 6-cyclopropylpicolinate (62 mg, 0.33 mmol) in methanol (5 mL) was added NaOMe (44 mg , 0.80 mmol). The reaction mixture was stirred at r.t. 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 Na2S04,concentrated, and purified by standard methods to afford the desired product.XH NMR (400 MHz, CDC13) 58.43-8.33 (m, 1H), 8.06-7.99 (m, 1H), 7.25-7.23 (d, J=8 Hz, 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)+.

[1805] The procedure set forth in Example 19 was used to produce the following compounds using the appropriate starting materials.

[1806] Compound 6-(6-Cyclopropylpyridin-2-yl)-N2,N4-bis(4,4-difluorocyclohexyl)-l,3,5-triazine- -diamine

[1808] 1H NMR (400 MHz, CDC13) δ 8.21 (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).LCMS: m / z 465(M+H)+.Compound N2,N4-bis(4,4-difluorocyclohexyl)-6-(6-methylpyridin-2-yl)-l,3,5-triazine-2,4- diamine

[1810] Ή NMR (400MHz, CDC13)5 8.181 - 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).LCMS: m / z 439(M+H)+.

[1811] Example 20 Preparation of Symmetric Di-aliphatic Triazine Compounds of Formula M.

[1812] The compounds of this Example are prepared by general Scheme 20, set forth below.

[1813] Scheme 20 iuret, EtONa, EtOH

[1814] HC(OMe)3, TFA

[1816] Formula M

[1817] 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) and Et3N (0.12 mL, 8.2 mmol). The suspension was degassed under vacuum and then backfilled with CO three times. The resulting mixture was stirred under CO atmosphere (80 psi) at 70°C for 2 days until the reaction was completed. The mixture was cooled to r.t. and concentrated under reduced pressure at 30°C. To the residue wasadded EtOAc (150 mL). The suspension was filtered and the filtrate was concentrated and purified by standard methods to afford the desired product.LC-MS: m / z 207 (M+H)+.

[1818] Step 2: Preparation of 6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazine-2,4(lH,3H) -dione.

[1819] The procedure is the same as Example 1 Step 2 described above. LC-MS: m / z 260 (M+H)+.

[1820] Step 3: Preparation of 2,4-dichloro-6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazine. To a solution of 6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazine-2,4(lH,3H)-dione (2.8 g, 0.011 mol) in POCl3(30 mL) was added Et3N (0.3 mL). The mixture was stirred at 100°C for 16 hr until the reaction was completed. The resulting mixture was concentrated and purified by standard methods to afford the desired product. LC-MS: m / z 296 (M+H)+.

[1821] Step 4: Preparation of N2,Ν4-kis(4,4-difluorocyclohexyl)-6-(6-(trifluoroinethyl) pyrazin-2 -yl)- l 3,5-triazine-2,4-diamine.T\\Q procedure is the same as Example 1 Step 4.

[1823] 1H NMR (400 MHz, CDC13) δ 9.73 (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)+.

[1824] The procedure set forth in Example 20 above was used to produce the following compounds using the appropriate starting materials.

[1825] N2^4-bis(3 -difluorocyclopentyl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazine-2,4- diamine

[1826] Ή NMR (400 MHz, CDC13) δ 9.74 (m, 1H), 9.07 (d, J = 3.2 Hz, 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)+.

[1827] N2J\4-bis((R)-3,3-difluorocyclopentyl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazine- -diamine

[1829] 1H NMR (400 MHz, CDC13) δ 9.77-9.71 (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)+.

[1830] N2^4-bis((S)-3,3-difluorocyclopentyl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazine- -diamine

[1832] 1H NMR (400 MHz, CDC13) δ 9.74 (m, 1H), 9.07 (d, J= 3.6 Hz, 1H), 5.70 -5.38 (m, 2H), 4.83 - 4.38 (m, 2H), 2.80 - 1.76 (m, 12H). LC-MS: m / z 466 (M+H)+.N2-((R)-3,3-difluorocyclopentyl)-N4-((S)-3,3-difluorocyclopentyl)-6-(6- (trifluoromethyl)pyrazin-2-yl)-l,395-triazine-2,4-diamine

[1833] NMR (400 MHz, CDC13) δ 9.74 (m, 1H), 9.07 (d, J= 3.3 Hz, 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)+.

[1834] N2J\4-bis(3,3-difluorocyclobutyl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazine-2,4- diamine

[1836] NMR MHz, CDC13) δ 9.74 (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)+.

[1837] 6-(6-(Trifluoromethyl)pyrazin-2-yl)-N2,N4-bis((R)-l,l,l-trifluoropropan-2-yl)-l,3,5- triazine-2 4-diamine

[1839] 1H NMR (400 MHz, CD3OD) δ 9.80 (s, 1H), 9.17 (s, 1H), 5.22-4.88 (m, 2H), 1.43-1.38 (m, 6H).LC-MS: m / z 450.1 (M+H)+.N2^4-bis((S)-1 -trifluorobutan-2-yl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-195-triazine- -diamine

[1841] 1HNMR(400MHz,DMSO-d6) 59.86-9.69 (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)+.

[1842] Example 21 Preparation of Symmetric Di-aliphatic Triazine Compounds of Formula N.

[1843] The compounds of this Example are prepared by general Scheme 21, set forth below.

[1844] Scheme 21

[1846] Formula N

[1847] Step 1: Preparation of l-(6-chloropyrazin-2-yl)ethanol. To a solution of methyl 6- formylpyrazine-2-carboxylate (590 mg, 4.15 mmol) in anhydrous THF (5 mL) at -5°C was added dropwise CH3MgBr (2.1 mL, 6.2 mmol). The reaction mixture was stirred at r.t. for 1 hr, thenquenched with satd. a.q. NH4C1 at 0°C and extracted with DCM (3 x 10 mL). The combined organic layers were was...

Claims

Claims1. A compound having Formula I or a pharmaceutically acceptable salt or hydrate thereof:###0001### :ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;X is N, CH or C-halo;R1, R3, R4, and R6 are each independently selected from hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;R2 and R5 are each independently selected from: -(Ci-d alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d- C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-N(R6)-(d-C6 alkylene)-0-(d-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)(R6), -(Ci-C6 alkylene)-N(R6)-S(0)i-2-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-S(O)i-2-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6alkylene)-Q, -C(0)N(R6)-(Ci-C6 alkylene)-C(O)- (C0-C6 alkylene)-0-(Ci-C6alkyl), -C(0)N(R6)-(Ci-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-O-C(O)-(C0-C6 alkyl)-Q, -(Ci-C6alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-0-(d-C6 alkylene)-Q, -(C0-C6alkylene)-C(O)-(C0-C6 alkylene)-0-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6alkylene)-0-(Ci-C6 alkylene)-Q, -(Ci-Ce alkylene)-0-C(0)-(d-C6 alkyl), -(d-C6alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)C(0)-(Ci-C6 alkyl), -(Ci-d alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-S(O)0-2-(Ci-C6 alkyl), -(C0-C6 alkylene)-S(0)o-2-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6 alkyl), -(C0-C6alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(Ci-C4 alkyl), -C02H, or halo;any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl; andQ is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; whereinR1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); orR4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); orR1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; orR4 and R5 are optionally taken together to 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) neitherN(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2CH2OCH2CH2OCH2CH2NH2, 4-[[2-[2- (2-aminoethoxy)ethoxy]ethyl]amino] and (b) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH2CH2CHO, NHCH2CH2OCH3, NHCH2CH2OH, NHCH2CH(OH)CH3,NHCH2CH2OC(0)phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2N(CH3)phenyl,NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, orNHCH2CH2OC(0)CH3;(ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, CI or S02CH3, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(0)NH-i-propyl,NHCH(CH3)(CH2)3N(CH2CH3)2, NHCH2CH2OH, NHCH2CH2OCH3, NHCH2CH2OS03H, NHCH2CH2CH2OCH2CH20-phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2OCH3, NHCH2CH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCH2CH2NHC(0)OCH3,NHCH2CH2NHC(0)CH3, NHCH2CH2NH2, or NHCH2-phenyl;(iii) when X is CH and A is optionally substituted pyridyl, then neither N(R7)C(R4)(R5)(R6) nor NtR8)^1)^2)^3) is NHCH2-phenyl, NHCH2-(2,4-difluorophenyl), N(CH3)CH2CH2C(0)OH, NHCH2CH2C(0)OH, NHCH2CH2C(0)OCH2CH3, NHCH2CH2C(0)0-t-butyl,NHCH2CH2C(0)NH2, NHCH2CH2-phenyl, NHCH2CH2OH, NHCH2CH2NH2,NHCH2CH2N(CH3)2, or NHCH2CH2CH3;(iv) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1 -pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH;(v) when X is N and A is an optionally substituted pyridyl, then (A) neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], N(CH3)2,NHCH2CH2CH2S02CH2CH2C1, NHCH2CH2OCH2CH2S02CH2CH2Cl,orNHCH2CH2S02CH2CH2C1, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3;(vi) when X is N and A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;(vii) when X is CH and A is unsubstituted 2-pyridinyl, then the ring formed by R4 and R5 is not 5 -methyl- 1 H-pyrazol-3 -yl,(viii) when A is optionally substituted 1 -pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N R8)^1)^2)^3) is N(CH3)2, NHCH3, NHAc, NHisopropyl, NHCH2CH3, NHCH2CH2S03H or N(CH2CH3)2,(ix) when X is N and A is optionally substituted phenyl, thienyl, or pyridinyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexylC(0)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3,(x) when X is N, A is an optionally substituted phenyl and R4 and R5 form an optionally substituted phenyl, then Ν^8)^1)^2)^3) is not NHCH2(4-fluorophenyl), NHCH2C02H, NHCH2C(0)C1, NHCH(C02H)(CH2SCH2phenyl), or NHCH2C(0)NHC(0)NHR orNHCH2C(0)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, then R4 and R5 do not form an optionally substituted phenyl,(xii) when A is substituted 1-pyrazolyl, then (A) then N(R7)C(R4)(R5)(R6) andNtR^CtR1)^2)^3) are not both NHC(CH3)3, and (B) A is not substituted with N=N-R, wherein R is a ring,(xiii) the compound is not selected from the group:(1) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-lH-inden-2-yl)amino]-6-phenyl-l,3,5-triazin-2- yl ] amino] methyl] -b enzamide,(2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4-(methylsulfonyl)- benzamide,(3) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3-yl]thio]- acetamide,(4) N2-cyclopropyl-N4-ethyl-6-[3 -[(phenylmethyl)thio]-lH-l ,2,4-triazol-l-yl]-l,3,5-triazine-2,4- diamine,(5) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,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) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-phenyl-l,3,5-triazine-2,4-diamine,(8) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]-l,3,5-triazine- 2,4-diamine,(9) N2,N4-dicyclohexyl-6- [3 -(3 ,4-dimethoxyphenyl)-5 -(methylthio)- 1 H-pyrazol- 1 -yl] -1,3,5- triazine-2,4-diamine,( 10) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 -yl]- 1 ,3 , 5 - triazine-2,4-diamine,(11) N2,N4-dicyclohexyl-6-phenyl-l,3,5-triazine-2,4-diamine, (12) 1 ,1 '-[(6^henyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],(13) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l,l- dimethylethyl)- phenol,(14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-l,3,5-triazin-2-yl]-glycine,(15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3- fluorophenyl)-l,3,5-triazin-2-yl]amino]ethyl]- phenol,(16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4- fluorophenyl)-l,3,5-triazin-2-yl]amino]ethyl]- phenol,(17) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine,(18) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l ,3,5-triazine-2,4-diamine,(19) 4,4 [6-[3,5-bis(l,l-dime lethyl)-4- hydro^^3,1 -propanediyl)]bis[2,6-bis(l ,1 -dimethylethyl)-phenol,(20) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(imino-3,l-propanediyl)]bis[2,6-bis(l,l- dimethylethyl)-phenol,(21) N-[6-[(2,3-dihydro-lH-inden-2-yl)amino]-2-(2^yridinyl)-4-pyrimidinyl]- alanine,(22) N4-cyclopentyl-2-phenyl-N6-(phenylmethyl)-4,6-pyrimidinediamine,(23) 2-[[6-(bicyclo[2.2.1 ]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol,(24) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l,3,5-triazine-2,4-diamine,(25) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l,3,5-triazin-2- yl]-benzamide,(26) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,(27) [[4-[[[[[4-amino-6-(4^yridinyl)-l,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4- pyridinyl)-l ,3,5-triazin-2-yl]imino]bis-methanol,(28) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- yl]amino]methoxy]methyl](hydroxymethyl)ammethanol,(29) 5-[4,6-bis(diethylamino)-l,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,(30) N2,N2,N*,N*-tetrae ^ (31) N,A -[6-[4-(acetylamino)-l,2,5-oxadiazo(32) N-(2-chloro-6-me lphenyl)-5-[[4-(dimethylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]-l ,3,4-Oxadiazole-2-carboxamide,(33) N4-(5-methyl-lH-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(trifluorome l)phenyl]-6-(4-chlorophenyl)-N4-[3-(diethylamino)propyl]-l ,3,5- Triazine-2,4-diamine,(37) N2,N4-bis[(4-methoxyphenyl)me l]-6-[4-(trifluoromethoxy)phenyl]-l ,3,5-Triazine-2,4- diamine,(38) N,N"-(6-phenyl-l,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)-l ,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)-l ,3,5-triazin-2-yl]-glycine,(41) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(5-thiazolyl)-l, 3, 5-triazin-2-yl]-L- Valine,(42) s-Triazine, 2^henyl-4,6-bis[[6-[[4-phenyl-6-[[6-[[4^henyl-6-(trichloromethyl)-s-triazin-2- yl]amino]hexyl]amino]-s-triazin-2-yl]amino]hexyl]amino]-,(43) a,a'-[(6^henyl ,3,5 riazine-2,4-diyl)bis[imino(l,l,2,2-tetrafluoro-3-oxo-3,l- propanediyl)]]bis[ro-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)- 1,2-ethanediyl]], and(44) a-[[4-[[(3-chlorophenyl)methyl]amino]-6-(lH-imidazol-l-yl)-l,3,5-triazin-2-yl]amino]-N- [[4-(trifluoromethyl)phenyl]methyl]-, (aR)-Cyclohexanepropanamide.

2. A compound having Formula la or a pharmaceutically acceptable salt or hydrate thereof: ###0002### (la), wherein:ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;R2 and R5 are each independently selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(Ci-C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(d-C6 alkylene)-N(R6)-(Ci-C6alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6alkylene)-N(R6)(R6), -(Ci-C6 alkylene)-N(R6)-S(0)i-2-(Ci-C6 alkyl), -(C C6alkylene)-N(R6)-S(O)i-2-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4alkylene)-S(0)i-2-N(R6)-(Ci-C6 alkylene)-Q, -C(0)N(R6)-(Ci-C6 alkylene)-C(O)- (C0-C6 alkylene)-0-(Ci-C6 alkyl), -C(0)N(R6)-(Ci-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-O-C(O)-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-0-(Ci-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6alkylene)-0-(Ci-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(Ci-C6 alkyl), -(Ci-C6alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-S(O)0-2-(Ci-C6 alkyl), -(C0-C6 alkylene)-S(0)o-2-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein: any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH, CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; andQ is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; whereinR1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); orR4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); orR1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; orR4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;wherein:(i) when A is optionally substituted phenyl, then (a) neither N(R7)C(R4)(R5)(R6) norNtR8)^1)^2)^3) is NHCH2CH2OCH2CH2OCH2CH2NH2 or 4-[[2-[2-(2- aminoethoxy)ethoxy]ethyl]amino] and (b) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH2CH2CHO, NHCH2CH2OCH3, NHCH2CH2OH, NHCH2CH(OH)CH3,NHCH2CH2OC(0)phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2N(CH3)phenyl,NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, orNHCH2CH2OC(0)CH3;(ii) when A is an optionally substituted pyridyl, then (A) neither N(R7)C(R4)(R5)(R6) nor NiR^CiR1)^2)^3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], N(CH3)2,NHCH2CH2CH2S02CH2CH2C1, NHCH2CH2OCH2CH2S02CH2CH2Cl,orNHCH2CH2S02CH2CH2C1, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3;(iii) when A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) andNtR8)^1)^2)^3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;(iv) when A is optionally substituted 1 -pyrazolyl, then neither N(R7)C(R4)(R5)(R6) norNtR8)^1)^2)^3) is N(CH3)2, NHCH3, NHAc, NHisopropyl, NHCH2CH3, NHCH2CH2S03H or N(CH2CH3)2,(v) when A is optionally substituted phenyl, thienyl, or pyridinyl, then neitherN(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexylC(0)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3,(vi) when A is an optionally substituted phenyl and R4 and R5 form an optionally substituted phenyl, then N(R8)C(R1)(R2)(R3) is not NHCH2(4-fluorophenyl), NHCH2C02H, NHCH2C(0)C1, NHCH(C02H)(CH2SCH2phenyl), or NHCH2C(0)NHC(0)NHR or NHCH2C(0)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl,(vii) when A is an oxadiazole substituted with an optionally substituted pyridinyl, then R4 and R5 do not form an optionally substituted phenyl,(viii) when A is substituted 1 -pyrazolyl, then (A) then N(R7)C(R4)(R5)(R6) andN(R8)C(R1)(R2)(R3) are not both NHC(CH3)3, and (B) A is not substituted with N=N-R, wherein R is a ring,(ix) the compound is not selected from the group:(1) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-lH-inden-2-yl)amino]-6-phenyl-l,3,5-triazin-2- yl ] amino] methyl] -b enzamide,(2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4-(methylsulfonyl)- benzamide,(3 ) 2- [[ 1 - [4-(cyclopropylamino)-6-(ethylamino)- 1,3,5 -triazin-2-yl] - 1 H- 1 ,2,4-triazol-3 -yl]thio] - acetamide,(4) N2-cyclopropyl-N4-ethyl-6-[3 -[(phenylmethyl)thio]-lH-l ,2,4-triazol-l-yl]-l,3,5-triazine-2,4- diamine, (5) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3-yl]thio]- acetic acid methyl ester,(6) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5 riazin-2-yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,(7) N2-cyclopropyl-6-(3,5-dimethyl-lH^yrazol-l -yl)-N4-phenyl-l ,3,5-triazine-2,4-diamine,(8) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l -yl]-l ,3,5-triazine- 2,4-diamine,(9) N2,N4-dicyclohexyl-6- [3 -(3 ,4-dimethoxyphenyl)-5 -(methylthio)- 1 H-pyrazol- 1 -yl] -1 ,3,5- triazine-2,4-diamine,( 10) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 -yl]- 1 ,3 , 5 - triazine-2,4-diamine,(1 1) N2,N4-dicyclohexyl-6-phenyl-l ,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-l ,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l ,l - dimethylethyl)- phenol,(14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-l ,3,5-triazin-2-yl]-glycine,(15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3-fluorophenyl)-l ,3,5-triazin-2-yl]amino]ethyl]- phenol,(16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4-fluorophenyl)-l ,3,5-triazin-2-yl]amino]ethyl]- phenol,(17) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine,(18) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l ,3,5-triazine-2,4-diamine,(19) 4,4'-[[6-[3,5-bis(l ,l -dime lethyl)-4-hydroxyphenyl]-l ,3,5-triazine-2,4-diyl]bis(imm^ propanediyl)]bis[2,6-bis(l ,l -dimethylethyl)-phenol,(20) 4,4'-[(6-phenyl-l ,3,5-triazine-2,4-diyl)bis(imino-3,l -propanediyl)]bis[2,6-bis(l ,l ^ dimethylethyl)-phenol,(21) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l ,3,5-triazine-2,4-diamine,(22) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]-benzamide,(23) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,(24) [[4-[[[[[4-amino-6-(4^yridinyl)-l,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4- pyridinyl)-l ,3,5-triazin-2-yl]imino]bis-methanol,(25) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- yl]amino]methoxy]methyl](hydroxymethyl)amm^methanol,(26) 5-[4,6-bis(diethylamino)-l,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,(27) N2,N2 -tetraethyl-6-(2H-tetrazol-5-yl)-l,3,5-triazine-2,4-diam^(28) N V'-[6-[4-(acetylamino)-l,2,5-oxadiazol-3-yl]-l ,3,5-triazine-2,4-diyl]bis-acetami^^(29) N-(2-chloro-6-methylphenyl)-5-[[4-(dime lamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]-l ,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(trifluorome l)phenyl]-6-(4-chlorophenyl)-N4-[3-(diethylamino)propyl]-l ,3,5- Triazine-2,4-diamine,(33) N2,N4-bis[(4-methoxyphenyl)methyl]-6-[4-(trifluoromethoxy)phenyl]-l ,3,5-Triazine-2,4- diamine,(34) N,N"-(6-phenyl-l,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)-l ,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)-l ,3,5-triazin-2-yl]-glycine,(37) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(5-thiazolyl)-l, 3, 5-triazin-2-yl]-L- Valine,(38) s-Triazine, 2-phenyl-4,6-bis[[6-[[4-phenyl-6-[[6-[[4-phenyl-6-(trichloromethyl)-s-triazin-2- yl]amino]hexyl]amino]-s-triazin-2-yl]amino]hexyl]amino]-,(39) α,α'- [(6-phenyl- 1,3,5 -triazine-2,4-diyl)bis [imino( 1 , 1 ,2,2-tetrafluoro-3 -oxo-3 , 1 - propanediyl)]]bis[ro-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)- 1,2-ethanediyl]], and(40) a-[[4-[[(3-chlorophenyl)methyl]amm^[[4-(trifluoromethyl)phenyl]methyl]-, (aR)-Cyclohexanepropanamide.

3. The compound of claim 2, whereinR1, R3, R4, and R6 are each independently selected from hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2; andR2 and R5 are each independently selected from: -(Ci-Ce alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d- C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), and -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), wherein:any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo; andany terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); orR4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); orR1 and R2 are optionally taken together to form an optionally substituted carbocyclyl; orR4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, wherein, when A is an optionally substituted phenyl, 2-pyrrolyl, or 1-imidazolyl, thenN(R7)C(R4)(R5)(R6) is not the same as N(R8)C(R1)(R2)(R3), and the compound is not 2-(l,2- dibromoethyl)-4-phenyl-6-(l, 1,2,2,3,3,4,4,5 ,5 ,6,6 ,6-tridecafluorohexyl-l,3,5-Triazine.

4. The compound of claim 2, wherein ring A is a substituted 5-6 member monocyclic aryl or monocyclic heteroaryl, which is substituted with up to two substituents independently selected from halo, -C C4 alkyl, -C1-C4 haloalkyl, -C1 -C4 hydroxyalkyl, -NH-S(0)2-(Ci-C4 alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(d-C4 alkyl), C1-C4 alkoxy, -NH(Ci-C4alkyl), -OH, -OCF3, -CN, -NH2, -C(0)NH2, -C(0)NH(Ci-C4 alkyl), -C(0)-N(Ci-C4alkyl)2, -(C1-C6 alkylene)-0-(Ci-C6 alkyl), azetidinyl, phenyl, and cyclopropyl optionally substituted with OH.

5. A com ound having Formula B, or pharmaceutically acceptable salt or hydrate thereof:###0003### wherein:X isN, CH or C-halo;Xa is N or C-R9a, provided that when one Xa is N, then the other two Xa are both C-R9a;R9 is halo, -Ci-C4 alkyl, -C C4 haloalkyl, -Ci-C4 hydroxyalkyl, -NH-S(0)2-(Ci-C4alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(Ci-C4 alkyl), Ci-C4 alkoxy, -NH(Ci-C4 alkyl), - N(Ci-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, -C(0)NH2, -C(0)NH(Ci-C4 alkyl), -C(0)-N(Ci-C4 alkyl)2, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), aryl, and cyclopropyl optionally substituted with OH; each R9a is independently selected from hydrogen, halo, -Ci-C alkyl, -Ci-C haloalkyl, -Ci-C hydroxyalkyl, -NH-S(0)2-(Ci-C4 alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(Ci-C4 alkyl), Ci-C4 alkoxy, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, -C(0)NH2, - C(0)NH(Ci-C4 alkyl), -C(0)-N(Ci-C4 alkyl)2, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), aryl, and cyclopropyl optionally substituted with OH;R1, R3, R4, and R6 are each independently selected from hydrogen, Ci-C alkyl, Ci-Chaloalkyl, -0-Ci-C alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -0-Ci-C alkyl, -NH(Ci-C alkyl), or -N(Ci-C4 alkyl)2; R2 and R5 are each independently selected from: -(Ci-Ce alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d- C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl),-(Co-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(Ci-C6 alkyl), and -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(Ci-C4 alkyl), -C02H, or halo;any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; andQ is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; whereinR1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); orR4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); orR1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; orR4 and R5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, an optionally substituted 5-6 member monocyclic aryl, or an optionally substituted 5-6 member monocyclic heteroaryl;whereinthe compound is not selected from the group:(1) 4,6-Pyrimidinediamine, 2-(6-methyl-2-pyridinyl)-N4,N6-dipropyl-;(2) 4,6-Pyrimidinediamine, N4-ethyl-2-(6-methyl-2-pyridinyl)-N6-propyl-;(3) 4,6-Pyrimidinediamine, N4,N4-diethyl-2-(6-methyl-2-pyridinyl)-N6-propyl-;(4) [2,4'-Bipyrimidine]-2',4,6-triamine, N6-[2-(dimethylamino)ethyl]-N2',N2',N4,N4- tetramethyl-; or(5) [2,4'-Bipyrimidine]-2',4,6-triamine, N6-[2-(dimethylamino)ethyl]-N2',N2',N4,N4- tetramethyl-, phosphate.

6. The compound of claim 5, wherein R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.

7. A compound having Formula C, or pharmaceutically acceptable salt or hydrate thereof:###0004### (C), wherein:X is N, CH or C-halo;each Xb is independently N-R9b, O, S, C-H, or C-R9c, provided that at least one Xb is C-R9c, and when one Xb is C-H or C-R9c and the other is C-R9c then X° is N, and when one Xb is N-R9b, O, or S,then Xc is C;R9bis hydrogen or -C1-C4 alkyl;R9c is halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(0)2-(Ci-C4 alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(d-C4 alkyl), C1-C4 alkoxy, -NH(Ci-C4 alkyl), - N(Ci-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, -C(0)NH2, -C(0)NH(Ci-C4 alkyl), -C(0)-N(d-C4 alkyl)2, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), aryl, and cyclopropyl optionally substituted with OH; R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;R2 and R5 are each independently selected from: -(Ci-Ce alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d- C6 alkyl)-C02H -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(Ci-C6 alkyl), -(C0-C6alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H; R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; andQ is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; whereinR1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); orR4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); orR1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; orR4 and R5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, an optionally substituted 5-6 member 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 neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH; and(ii) when X and Xc are both N, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)2, NHCH3, or N(CH2CH3)2.

8. The compound of claim 7 wherein:R9c is halo, -OH, CN, -NH2, -O-C1-C4 alkyl, -NH(d-C4 alkyl), -N(d-C4 alkyl)2, -C1-C4 alkyl, -C1-C4 haloalkyl, and -(Ci-C6 alkylene)-0-(d-C6 alkyl);R and R4are each hydrogen;R3 and R6 are each independently selected from C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN; andR2 and R5 are each -(Ci-C6 alkyl), wherein:the alkyl moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(Ci-C4 alkyl), -C02H, or halo; and any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH, CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H.

9. The compound of claim 7 wherein R1 and R4 are each independently selected from Ci-C4 alkyl and Ci-C4 haloalkyl,and R2 and R5 are each -(Ci-C6 alkyl).

10. The compound of claim 1 or 2 whereinR3 and R6 are both hydrogen, R1 and R4 are each independently selected from Ci-C4 alkyl and C1-C4 haloalkyl,andR2 and R5 are each -(Ci-C6 alkyl).

11. A compound having Formula ΠΙ, or pharmaceutically acceptable salt or hydrate thereof:###0005### (ΙΠ), wherein:ring A is an optionally substituted 5-6 member monocyclic heteroaryl;ring B is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;R1 and R3are each independently selected from hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, -0-Ci-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -0-Ci-C4 alkyl, -NH(C C4 alkyl), or -N(Ci-C4 alkyl)2;R2is selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d-C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(0)N(R6)-(d-C6 alkyl),-(Co-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), and -(C0-C6alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:any alkyl or alkylene moiety present in R2 is optionally substituted with one ormore -OH, -0(Ci-C4 alkyl), -C02H, or halo; any terminal methyl moiety present in R2 is optionally replaced with -CH2OH,CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; andQ is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; whereinR1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); orR1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;wherein when A is an oxadiazole substituted with an optionally substituted pyridinyl, then G is not an optionally substituted phenyl.

12. The compound of claim 11 , wherein G is substituted with 1 or 2 substituents selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, =0, -OH, aryl, heteroaryl - S02Ci-C4 alkyl, -C02Ci-C4 alkyl, -C(0)aryl, and -C(0)d-C4 alkyl.

13. A pharmaceutical composition comprising a compound of claim 1 , and apharmaceutically 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 a cancer characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in a new ability of the enzyme to catalyze theNAPH-dependent reduction of a-ketoglutarate to i?(-)-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 IDH1 R132H or R132C mutation.

17. The method of claim 16, wherein the cancer is selected from from glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer,or angio-immunoblastic non-Hodgkin's lymphoma (NHL) in a patient.

18. The method of claims 16, further comprising administering to the patient in need thereof a second therapeutic agent useful in the treatment of cancer.