CLAIM OF PRIORITY

This application is a divisional of U.S. Ser. No. 14/328,885, filed Jul. 11, 2014, which claims priority from International Application Serial No. PCT/CN2013/079200, filed Jul. 11, 2013, and International Application Serial No. PCT/CN2014/081957, filed Jul. 10, 2014, each of which is incorporated herein by reference in its entirety.

BACKGROUND OF INVENTION

Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., Î±-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.

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, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production.

The human IDH1 gene encodes a protein of 414 amino acids. The nucleotide and amino acid sequences for human IDH1 can be found as GenBank entries NM_005896.2 and NP_005887.2 respectively. The nucleotide and amino acid sequences for IDH1 are also described in, e.g., Nekrutenko et al., Mol. Biol. Evol. 15:1674-1684(1998); Geisbrecht et al., 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 (December-2008) to UniProtKB; Kullmann et al., Submitted (June-1996) to the EMBL/GenBank/DDBJ databases; and Sjoeblom et al., Science 314:268-274(2006).

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

Isocitrate+NAD⁺(NADP⁺)â†’Î±-KG+CO₂+NADH(NADPH)+H⁺.

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 Î±-ketoglutarate to R(âˆ’)-2-hydroxy glutarate (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).

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 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 (November-1992) to the EMBL/GenBank/DDBJ databases; and The MGC Project Team, Genome Res. 14:2121-2127(2004).

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

Isocitrate+NAD⁺(NADP⁺)â†’Î±-KG+CO₂+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 Î±-ketoglutarate to R(âˆ’)-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 IDH1 and/or IDH2 mutants having alpha hydroxyl neoactivity.

SUMMARY OF INVENTION

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

[Image Omitted]

wherein:

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

X is N, CH or C-halo;

R²and R⁵are each independently selected from: â€”(C₁-C₆alkyl), â€”(C₁-C₆alkyl)-C(O)â€”NH₂, â€”(C₁-C₆alkyl)-CO₂H, â€”(C₂-C₆alkenyl or alkynyl), â€”(C₁-C₆alkylene)-N(R⁶)â€”(C₁-C₆alkylene)-Oâ€”(C₁-C₆alkyl), â€”(C₁-C₆alkylene)-N(R⁶)â€”(C₀-C₆alkylene)-Q, â€”(C₁-C₆alkylene)-N(R⁶)(R⁶), â€”(C₁-C₆alkylene)-N(R⁶)â€”S(O)_1-2â€”(C₁-C₆alkyl), â€”(C₁-C₆alkylene)-N(R⁶)â€”S(O)_1-2â€”(C₀-C₆alkyl)-Q, â€”(C₁-C₆alkylene)-S(O)_1-2â€”N(R⁶)(R⁶), â€”(C₁-C₄alkylene)-S(O)_1-2â€”N(R⁶)â€”(C₁-C₆alkylene)-Q, â€”C(O)N(R⁶)â€”(C₁-C₆alkylene)-C(O)â€” (C₀-C₆alkylene)-Oâ€”(C₁-C₆alkyl), â€”C(O)N(R⁶)â€”(C₁-C₆alkylene)-C(O)â€”(C₀-C₆alkylene)-Oâ€”(C₀-C₆alkylene)-Q, â€”(C₁-C₆alkylene)-Oâ€”C(O)â€”(C₁-C₆alkyl), â€”(C₁-C₆alkylene)-Oâ€”C(O)â€”(C₀-C₆alkyl)-Q, â€”(C₁-C₆alkylene)-Oâ€”(C₁-C₆alkyl), â€”(C₁-C₆alkylene)-Oâ€”(C₁-C₆alkylene)-Q, â€”(C₀-C₆alkylene)-C(O)â€”(C₀-C₆alkylene)-Oâ€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-C(O)â€”(C₀-C₆alkylene)-Oâ€”(C₁-C₆alkylene)-Q, â€”(C₁-C₆alkylene)-Oâ€”C(O)â€”(C₁-C₆alkyl), â€”(C₁-C₆alkylene)-Oâ€”C(O)â€”(C₀-C₆alkylene)-Q, â€”(C₀-C₆alkylene)-C(O)N(R⁶)â€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-C(O)N(R⁶)â€”(C₀-C₆alkylene)-Q, â€”(C₁-C₆alkylene)-N(R⁶)C(O)â€”(C₁-C₆alkyl), â€”(C₁-C₆alkylene)-N(R⁶)C(O)â€”(C₀-C₆alkylene)-Q, â€”(C₀-C₆alkylene)-S(O)_0-2â€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-S(O)_0-2â€”(C₀-C₆alkylene)-Q, â€”(C₁-C₆alkylene)-N(R⁶)â€”C(O)â€”N(R⁶)â€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-Q, â€”(C₀-C₆alkylene)-C(O)â€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-C(O)â€”(C₀-C₆alkylene)-Q, wherein:

- any alkyl or alkylene moiety present in R²and R⁵is optionally substituted with one or more â€”OH, â€”O(C₁-C₄alkyl), â€”CO₂H, or halo;
- any terminal methyl moiety present in R²and R⁵is optionally replaced with â€”CH₂OH, CF₃, â€”CH₂F, â€”CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;

R⁷and R⁸are each independently selected from hydrogen and C₁-C₆alkyl; and

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

R¹and R³are optionally taken together with the carbon atom to which they are attached to form C(â• O); or

R⁴and R⁶are optionally taken together with the carbon atom to which they are attached to form C(â• O); or

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

R⁴and R⁵are 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) neither 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, NHCH₂CH₂OC(O)phenyl, NHCH₂CH₂CH₂OH, NHCH₂CH₂CH₂N(CH₃)phenyl, NHCH₂C(O)OCH₃, NHCH₂C(O)OCH₂CH₃, NHCH₂phenyl, NHCH(CH₃)CH₂CH₃, or NHCH₂CH₂OC(O)CH₃;
- (ii) when X is CH or Câ€”Cl and A is phenyl optionally substituted with F, Cl or SO₂CH₃, then neither N(R⁷)C(R⁴)(R⁵)(R⁶) nor N(R⁸)C(R¹)(R²)(R³) is N(CH₃)CH₂C(O)NH-i-propyl, NHCH(CH₃)(CH₂)₃N(CH₂CH₃)₂, NHCH₂CH₂OH, NHCH₂CH₂OCH₃, NHCH₂CH₂OSO₃H, NHCH₂CH₂CH₂OCH₂CH₂O-phenyl, NHCH₂CH₂CH₂OH, NHCH₂CH₂CH₂OCH₃, NHCH₂CH(OH)CH₃, N(CH₂CH₃)₂, NH-i-propyl, NHCH₂CH₂NHC(O)OCH₃, NHCH₂CH₂NHC(O)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 N(R⁸)C(R¹)(R²)(R³) is NHCH₂-phenyl, NHCH₂-(2,4-difluorophenyl), N(CH₃)CH₂CH₂C(O)OH, NHCH₂CH₂C(O)OH, NHCH₂CH₂C(O)OCH₂CH₃, NHCH₂CH₂C(O)O-t-butyl, NHCH₂CH₂C(O)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(O)-[2-chloro-4-(methylsulfonyl)], N(CH₃)₂, NHCH₂CH₂CH₂SO₂CH₂CH₂Cl, NHCH₂CH₂OCH₂CH₂SO₂CH₂CH₂Cl, or NHCH₂CH₂SO₂CH₂CH₂Cl, (B) N(R⁷)C(R⁴)(R⁵)(R⁶) and N(R⁸)C(R¹)(R²)(R³) are not both NHC(O)C(CH₃)₃, NHC(O)CHâ• CH₂, NHC(O)C(CH₃)â• CH₂, NHCH₂CH₂OH, NH-cyclohexyl, NHCH₂-phenyl, NHC(O)phenyl, NHC(O)(CH₂)₅NH₂, NHC(O)OCH₃, NHC(O)CH₃, and NHC(O)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 NHâ€”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(O)CH₃;
- (vii) when X is CH and A is unsubstituted 2-pyridinyl, then the ring formed by R⁴and R⁵is not 5-methyl-1H-pyrazol-3-yl;
- (viii) when A is optionally substituted 1-pyrazolyl, then neither N(R⁷)C(R⁴)(R⁵)(R⁶) nor N(R⁸)C(R¹)(R²)(R³) is N(CH₃)₂, NHCH₃, NHAc, NHisopropyl, NHCH₂CH₃, NHCH₂CH₂SO₃H 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(O)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 R⁴and R⁵form an optionally substituted phenyl, then N(R⁸)C(R¹)(R²)(R³) is not NHCH₂(4-fluorophenyl), NHCH₂CO₂H, NHCH₂C(O)Cl, NHCH(CO₂H)(CH₂SCH₂phenyl), NHCH₂C(O)NHC(O)NHR or NHCH₂C(O)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl;
- (xi) when X is N, A is an oxadiazole substituted with an optionally substituted pyridinyl, then R⁴and R⁵do not form an optionally substituted phenyl;
- (xii) when A is substituted 1-pyrazolyl, then (A) then N(R⁷)C(R⁴)(R⁵)(R⁶) and N(R⁸)C(R¹)(R²)(R³) are not both NHC(CH₃)₃, and (B) A is not substituted with Nâ• Nâ€”R, wherein R is a ring;
- (xiii) ring A is not an optionally substituted triazolyl, 3,5-dimethyl-1H-pyrazol-1-yl;
- (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
- (xx) the compound is not selected from the group:
(1) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-1H-inden-2-yl)amino]-6-phenyl-1,3,5-triazin-2-yl]amino]methyl]-benzamide;
(2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]-4-(methylsulfonyl)-benzamide;
(3) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-1H-1,2,4-triazol-3-yl]thio]-acetamide;
(4) N²-cyclopropyl-N⁴-ethyl-6-[3-[(phenylmethyl)thio]-1H-1,2,4-triazol-1-yl]-1,3,5-triazine-2,4-diamine;
(5) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-1H-1,2,4-triazol-3-yl]thio]-acetic acid methyl ester;
(6) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide;
(7) N²-cyclopropyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)-N⁴-phenyl-1,3,5-triazine-2,4-diamine;
(8) N²,N⁴-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine;
(9) N²,N⁴-dicyclohexyl-6-[3-(3,4-dimethoxyphenyl)-5-(methylthio)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine;
(10) N²,N⁴-dicyclohexyl-6-[5-(methylthio)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine;
(11) N²,N⁴-dicyclohexyl-6-phenyl-1,3,5-triazine-2,4-diamine;
(12) 1,1â€²-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone];
(13) 4,4â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis(iminomethylene)]bis[2,6-bis(1,1-dimethylethyl)-phenol;
(14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-1,3,5-triazin-2-yl]-glycine;
(15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3-fluorophenyl)-1,3,5-triazin-2-yl]amino]ethyl]-phenol;
(16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4-fluorophenyl)-1,3,5-triazin-2-yl]amino]ethyl]-phenol;
(17) 6-(4-aminopyridin-3-yl)-N²-benzyl-N⁴-(tert-butyl)-1,3,5-triazine-2,4-diamine;
(18) N²,N⁴-bis(cyclohexylmethyl)-6-phenyl-1,3,5-triazine-2,4-diamine;
(19) 4,4â€²-[[6-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,5-triazine-2,4-diyl]bis(imino-3,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol;
(20) 4,4â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis(imino-3,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol;
(21) N-[6-[(2,3-dihydro-1H-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]-Î² alanine;
(22) N⁴-cyclopentyl-2-phenyl-N⁶-(phenylmethyl)-4,6-pyrimidinediamine;
(23) 2-[[6-(bicyclo[2.2.1]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol;
(24) N²-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4-diamine;
(25) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-1,3,5-triazin-2-yl]-benzamide;
(26) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide;
(27) [[4-[[[[[4-amino-6-(4-pyridinyl)-1,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]imino]bis-methanol;
(28) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]imino]bis-methanol;
(29) 5-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]-2H-tetrazole-2-acetic acid ethyl ester;
(30) N²,N²,N⁴,N⁴-tetraethyl-6-(2H-tetrazol-5-yl)-1,3,5-triazine-2,4-diamine;
(31) N,Nâ€²-[6-[4-(acetylamino)-1,2,5-oxadiazol-3-yl]-1,3,5-triazine-2,4-diyl]bis-acetamide;
(32) N-(2-chloro-6-methylphenyl)-5-[[4-(dimethylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]-1,3,4-Oxadiazole-2-carboxamide;
(33) N4-(5-methyl-1H-pyrazol-3-yl)-2-(2-pyridinyl)-N6-(tetrahydro-2H-pyran-4-yl)-4,6-Pyrimidinediamine;
(34) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(diethylamino)propyl]-1,3,5-Triazine-2,4-diamine;
(35) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(dimethylamino)propyl]-1,3,5-Triazine-2,4-diamine;
(36) N2-[3,5-bis(trifluoromethyl)phenyl]-6-(4-chlorophenyl)-N4-[3-(diethylamino)propyl]-1,3,5-Triazine-2,4-diamine;
(37) N2,N4-bis[(4-methoxyphenyl)methyl]-6-[4-(trifluoromethoxy)phenyl]-1,3,5-Triazine-2,4-diamine;
(38) N,Nâ€³-(6-phenyl-1,3,5-triazine-2,4-diyl)bis[Nâ€²-(2-chloroethyl)-Urea;
(39) N-[4-chloro-3-(trifluoromethyl)phenyl]-Nâ€²-[4-methyl-3-[[4-phenyl-6-(propylamino)-1,3,5-triazin-2-yl]amino]phenyl]-urea;
(40) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2-methylphenyl]amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]-glycine;
(41) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2-methylphenyl]amino]-6-(5-thiazolyl)-1,3,5-triazin-2-yl]-L-Valine;
(42) 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]-;
(43) Î±,Î±â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis[imino(1,1,2,2-tetrafluoro-3-oxo-3,1-propanediyl)]]bis[Ï‰-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)-1,2-ethanediyl]];
(44) Î±-[[4-[[(3-chlorophenyl)methyl]amino]-6-(1H-imidazol-1-yl)-1,3,5-triazin-2-yl]amino]-N-[[4-(trifluoromethyl)phenyl]methyl]-, (Î±R)-Cyclohexanepropanamide;
(45) 6-(1H-imidazol-1-yl)-N2,N4-bis(1-methylethyl)-1,3,5-Triazine-2,4-diamine; and
(46) N2,N4-bis(1-methylpropyl)-6-phenyl-1,3,5-Triazine-2,4-diamine.

The compounds of Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, and IIId, or as described in any one of the embodiments herein inhibits mutant IDH1 or mutant IDH2. Also described herein are pharmaceutical compositions comprising a compound of Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, and IIId, and methods of using such compositions to treat cancers characterized by the presence of a mutant IDH1 or mutant IDH2.

DETAILED DESCRIPTION

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 â€œincluding,â€ â€œcomprising,â€ or â€œhaving,â€ â€œcontainingâ€ , â€œinvolvingâ€ , and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

DEFINITIONS

The term â€œhaloâ€ or â€œhalogenâ€ refers to any radical of fluorine, chlorine, bromine or iodine.

The term â€œalkylâ€ 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-C₁₂alkyl indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it. The term â€œhaloalkylâ€ 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 â€œarylalkylâ€ or â€œaralkylâ€ 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 â€œarylalkylâ€ or â€œaralkylâ€ include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups. The term â€œalkylâ€ includes â€œalkenylâ€ and â€œalkynylâ€ .

The term â€œalkyleneâ€ refers to a divalent alkyl, e.g., â€”CH₂â€”, â€”CH₂CH₂â€”, â€”CH₂CH₂CH₂â€” and â€”CH₂CH(CH₃)CH₂â€”.

The term â€œalkenylâ€ 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.

The term â€œalkynylâ€ 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.

The term â€œalkoxyâ€ refers to an â€”O-alkyl radical. The term â€œhaloalkoxyâ€ 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).

Unless otherwise specified, the term â€œarylâ€ 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 â€œmonocyclic arylâ€ 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 â€œcarbocyclylâ€ 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.

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-1H-indene and 1,2,3,4-tetrahydronaphthalene.

The term â€œcycloalkylâ€ 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.

Unless otherwise specified, the term â€œheteroarylâ€ 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 forms such as N⁺â€”O^âˆ’, S(O) and S(O)₂). The term â€œmonocyclic heteroarylâ€ means a monocyclic fully romatic ring system having 1-3 heteroatoms, optionally substituted by one or more substituents which can not form a fused bicyclic or tricyclic ring.

The term â€œheterocyclylâ€ 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 forms such as N⁺â€”O^âˆ’, S(O) and S(O)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.

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), are optionally substituted at one or more substitutable atoms with, unless specified otherwise, substituents independently selected from: halo, â€”Câ‰¡N, C₁-C₄alkyl, â• O, â€”OR^b, â€”OR^bâ€², â€”SR^b, â€”SR^bâ€², â€”(C₁-C₄alkyl)-N(R^b)(R^b), â€”(C₁-C₄alkyl)-N(R^b)(R^bâ€²), â€”N(R^b)(R^b), â€”N(R^b)(R^bâ€²), â€”Oâ€”(C₁-C₄alkyl)-N(R^b)(R^b), â€”Oâ€”(C₁-C₄alkyl)-N(R^b)(R^bâ€²), â€”(C₁-C₄alkyl)-Oâ€”(C₁-C₄alkyl)-N(R^b)(R^b), â€”(C₁-C₄alkyl)-Oâ€”(C₁-C₄alkyl)-N(R^b)(R^bâ€²), â€”C(O)â€”N(R^b)(R^b), â€”(C₁-C₄alkyl)-C(O)â€”N(R^b)(R^b), â€”(C₁-C₄alkyl)-C(O)â€”N(R^b)(R^bâ€²), â€”OR^bâ€², R^bâ€², â€”C(O)(C₁-C₄alkyl), â€”C(O)R^bâ€², â€”C(O)N(R^bâ€²)(R^b), â€”N(R^b)C(O)(R^b), â€”N(R^b)C(O)(R^bâ€²), â€”N(R^b)SO₂(R^b), â€”SO₂N(R^b)(R^b), â€”N(R^b)SO₂(R^bâ€²), and â€”SO₂N(R^b)(R^bâ€²), wherein any alkyl substituent is optionally further substituted with one or more of â€”OH, â€”Oâ€”(C₁-C₄alkyl), halo, â€”NH₂, â€”NH(C₁-C₄alkyl), or â€”N(C₁-C₄alkyl)₂;

- each R^bis independently selected from hydrogen, and â€”C₁-C₄alkyl; or
- two R^bs 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
- each R^bâ€² is independently selected from C₃-C₇carbocyclyl, phenyl, heteroaryl, and heterocyclyl, wherein one or more substitutable positions on said phenyl, cycloalkyl, heteroaryl or heterocycle substituent is optionally further substituted with one or more of â€”(C₁-C₄alkyl), â€”(C₁-C₄fluoroalkyl), â€”OH, â€”Oâ€”(C₁-C₄alkyl), â€”Oâ€”(C₁-C₄fluoroalkyl), halo, â€”NH₂, â€”NH(C₁-C₄alkyl), or â€”N(C₁-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, â€”C₁-C₄alkyl, or fluoro-substituted C₁-C₄alkyl.

The term â€œsubstitutedâ€ refers to the replacement of a hydrogen atom by another group. The term â€œbodily fluidâ€ 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.

As used herein, the terms â€œinhibitâ€ or â€œpreventâ€ include both complete and partial inhibition and prevention. An inhibitor may completely or partially inhibit the intended target.

The term â€œtreatâ€ 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., a cancer) or improve the symptoms associated with the disease/disorder (e.g., a cancer).

As used herein, an amount of a compound effective to treat a disorder, or a â€œtherapeutically effective amountâ€ 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. As used herein, the term â€œsubjectâ€ is intended to include human and non-human animals. 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 â€œnon-human animalsâ€ of one aspect of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.

Compounds

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

[Image Omitted]

wherein:

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

X is N, CH or C-halo;

- any alkyl or alkylene moiety present in R²and R⁵is optionally substituted with one or more â€”OH, â€”O(C₁-C₄alkyl), â€”CO₂H, or halo;
- any terminal methyl moiety present in R²and R⁵is optionally replaced with â€”CH₂OH, CF₃, â€”CH₂F, â€”CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;

R⁷and R⁸are each independently selected from hydrogen and C₁-C₆alkyl; and

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

R¹and R³are optionally taken together with the carbon atom to which they are attached to form C(â• O); or

R⁴and R⁶are optionally taken together with the carbon atom to which they are attached to form C(â• O); or

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

R⁴and R⁵are 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) neither 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, NHCH₂CH₂OC(O)phenyl, NHCH₂CH₂CH₂OH, NHCH₂CH₂CH₂N(CH₃)phenyl, NHCH₂C(O)OCH₃, NHCH₂C(O)OCH₂CH₃, NHCH₂phenyl, NHCH(CH₃)CH₂CH₃, or NHCH₂CH₂OC(O)CH₃;

(ii) when X is CH or Câ€”Cl and A is phenyl optionally substituted with F, Cl or SO₂CH₃, then neither N(R⁷)C(R⁴)(R⁵)(R⁶) nor N(R⁸)C(R¹)(R²)(R³) is N(CH₃)CH₂C(O)NH-i-propyl, NHCH(CH₃)(CH₂)₃N(CH₂CH₃)₂, NHCH₂CH₂OH, NHCH₂CH₂OCH₃, NHCH₂CH₂OSO₃H, NHCH₂CH₂CH₂OCH₂CH₂O-phenyl, NHCH₂CH₂CH₂OH, NHCH₂CH₂CH₂OCH₃, NHCH₂CH(OH)CH₃, N(CH₂CH₃)₂, NH-i-propyl, NHCH₂CH₂NHC(O)OCH₃, NHCH₂CH₂NHC(O)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 N(R⁸)C(R¹)(R²)(R³) is NHCH₂-phenyl, NHCH₂-(2,4-difluorophenyl), N(CH₃)CH₂CH₂C(O)OH, NHCH₂CH₂C(O)OH, NHCH₂CH₂C(O)OCH₂CH₃, NHCH₂CH₂C(O)O-t-butyl, NHCH₂CH₂C(O)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(O)-[2-chloro-4-(methylsulfonyl)], N(CH₃)₂, NHCH₂CH₂CH₂SO₂CH₂CH₂Cl, NHCH₂CH₂OCH₂CH₂SO₂CH₂CH₂Cl, or NHCH₂CH₂SO₂CH₂CH₂Cl, (B) N(R⁷)C(R⁴)(R⁵)(R⁶) and N(R⁸)C(R¹)(R²)(R³) are not both NHC(O)C(CH₃)₃, NHC(O)CHâ• CH₂, NHC(O)C(CH₃)â• CH₂, NHCH₂CH₂OH, NH-cyclohexyl, NHCH₂-phenyl, NHC(O)phenyl, NHC(O)(CH₂)₅NH₂, NHC(O)OCH₃, NHC(O)CH₃, and NHC(O)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 NHâ€”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(O)CH₃;

(vii) when X is CH and A is unsubstituted 2-pyridinyl, then the ring formed by R⁴and R⁵is not 5-methyl-1H-pyrazol-3-yl,

(viii) when A is optionally substituted 1-pyrazolyl, then neither N(R⁷)C(R⁴)(R⁵)(R⁶) nor N(R⁸)C(R¹)(R²)(R³) is N(CH₃)₂, NHCH₃, NHAc, NHisopropyl, NHCH₂CH₃, NHCH₂CH₂SO₃H 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(O)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 R⁴and R⁵form an optionally substituted phenyl, then N(R⁸)C(R¹)(R²)(R³) is not NHCH₂(4-fluorophenyl), NHCH₂CO₂H, NHCH₂C(O)Cl, NHCH(CO₂H)(CH₂SCH₂phenyl), or NHCH₂C(O)NHC(O)NHR or NHCH₂C(O)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl,

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

(xii) when A is substituted 1-pyrazolyl, then (A) then N(R⁷)C(R⁴)(R⁵)(R⁶) and N(R⁸)C(R¹)(R²)(R³) are not both NHC(CH₃)₃, and (B) A is not substituted with Nâ• Nâ€”R, wherein R is a ring,

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

(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

(xx) the compound is not selected from the group:

(1) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-1H-inden-2-yl)amino]-6-phenyl-1,3,5-triazin-2-yl]amino]methyl]-benzamide,
(2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]-4-(methylsulfonyl)-benzamide,
(3) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-1H-1,2,4-triazol-3-yl]thio]-acetamide,
(4) N²-cyclopropyl-N⁴-ethyl-6-[3-[(phenylmethyl)thio]-1H-1,2,4-triazol-1-yl]-1,3,5-triazine-2,4-diamine,
(5) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-1H-1,2,4-triazol-3-yl]thio]-acetic acid methyl ester,
(6) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,
(7) N²-cyclopropyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)-N⁴-phenyl-1,3,5-triazine-2,4-diamine,
(8) N²,N⁴-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(9) N²,N⁴-dicyclohexyl-6-[3-(3,4-dimethoxyphenyl)-5-(methylthio)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(10) N²,N⁴-dicyclohexyl-6-[5-(methylthio)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(11) N²,N⁴-dicyclohexyl-6-phenyl-1,3,5-triazine-2,4-diamine,
(12) 1,1â€²-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],
(13) 4,4â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis(iminomethylene)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-1,3,5-triazin-2-yl]-glycine,
(15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3-fluorophenyl)-1,3,5-triazin-2-yl]amino]ethyl]-phenol,
(16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4-fluorophenyl)-1,3,5-triazin-2-yl]amino]ethyl]-phenol,
(17) 6-(4-aminopyridin-3-yl)-N²-benzyl-N⁴-(tert-butyl)-1,3,5-triazine-2,4-diamine,
(18) N²,N⁴-bis(cyclohexylmethyl)-6-phenyl-1,3,5-triazine-2,4-diamine,
(19) 4,4â€²-[[6-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,5-triazine-2,4-diyl]bis(imino-3,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(20) 4,4â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis(imino-3,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(21) N-[6-[(2,3-dihydro-1H-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]-0 alanine,
(22) N⁴-cyclopentyl-2-phenyl-N⁶-(phenylmethyl)-4,6-pyrimidinediamine,
(23) 2-[[6-(bicyclo[2.2.1]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol,
(24) N²-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4-diamine,
(25) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-1,3,5-triazin-2-yl]-benzamide,
(26) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,
(27) [[4-[[[[[4-amino-6-(4-pyridinyl)-1,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]imino]bis-methanol,
(28) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]imino]bis-methanol,
(29) 5-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]-2H-tetrazole-2-acetic acid ethyl ester,
(30) N²,N²,N⁴,N⁴-tetraethyl-6-(2H-tetrazol-5-yl)-1,3,5-triazine-2,4-diamine,
(31) N,Nâ€²-[6-[4-(acetylamino)-1,2,5-oxadiazol-3-yl]-1,3,5-triazine-2,4-diyl]bis-acetamide,
(32) N-(2-chloro-6-methylphenyl)-5-[[4-(dimethylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]-1,3,4-Oxadiazole-2-carboxamide,
(33) N4-(5-methyl-1H-pyrazol-3-yl)-2-(2-pyridinyl)-N6-(tetrahydro-2H-pyran-4-yl)-4,6-Pyrimidinediamine,
(34) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(diethylamino)propyl]-1,3,5-Triazine-2,4-diamine,
(35) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(dimethylamino)propyl]-1,3,5-Triazine-2,4-diamine,
(36) N2-[3,5-bis(trifluoromethyl)phenyl]-6-(4-chlorophenyl)-N4-[3-(diethylamino)propyl]-1,3,5-Triazine-2,4-diamine,
(37) N2,N4-bis[(4-methoxyphenyl)methyl]-6-[4-(trifluoromethoxy)phenyl]-1,3,5-Triazine-2,4-diamine,
(38) N,Nâ€³-(6-phenyl-1,3,5-triazine-2,4-diyl)bis[Nâ€²-(2-chloroethyl)-Urea,
(39) N-[4-chloro-3-(trifluoromethyl)phenyl]-Nâ€²-[4-methyl-3-[[4-phenyl-6-(propylamino)-1,3,5-triazin-2-yl]amino]phenyl]-urea,
(40) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2-methylphenyl]amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]-glycine,
(41) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2-methylphenyl]amino]-6-(5-thiazolyl)-1,3,5-triazin-2-yl]-L-Valine,
(42) 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]-,
(43) Î±,Î±â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis[imino(1,1,2,2-tetrafluoro-3-oxo-3,1-propanediyl)]]bis[Ï‰-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)-1,2-ethanediyl]],
(44) Î±-[[4-[[(3-chlorophenyl)methyl] amino]-6-(1H-imidazol-1-yl)-1,3,5-triazin-2-yl]amino]-N-[[4-(trifluoromethyl)phenyl]methyl]-, (Î±R)-Cyclohexanepropanamide,
(45) 6-(1H-imidazol-1-yl)-N2,N4-bis(1-methylethyl)-1,3,5-Triazine-2,4-diamine, and
(46) N2,N4-bis(1-methylpropyl)-6-phenyl-1,3,5-Triazine-2,4-diamine.

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

[Image Omitted]

wherein:

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 R⁶are each independently selected from hydrogen, C₁-C₄alkyl, C₁-C₄haloalkyl, â€”Oâ€”C₁-C₄alkyl, and CN, wherein any alkyl portion of R¹, R³, R⁴, and R⁶are each independently optionally substituted with â€”OH, â€”NH₂, â€”CN, â€”Oâ€”C₁-C₄alkyl, â€”NH(C₁-C₄alkyl), or â€”N(C₁-C₄alkyl)₂;

R²and R⁵are each independently selected from: â€”(C₁-C₆alkyl), â€”(C₁-C₆alkyl)-C(O)â€”NH₂, â€”(C₁-C₆alkyl)-CO₂H, â€”(C₂-C₆alkenyl or alkynyl), â€”(C₁-C₆alkylene)-N(R⁶)â€”(C₁-C₆alkylene)-Oâ€”(C₁-C₆alkyl), â€”(C₁-C₆alkylene)-N(R⁶)â€”(C₀-C₆alkylene)-Q, â€”(C₁-C₆alkylene)-N(R⁶)(R⁶), â€”(C₁-C₆alkylene)-N(R⁶)â€”S(O)_1-2â€”(C₁-C₆alkyl), â€”(C₁-C₆alkylene)-N(R⁶)â€”S(O)_1-2â€”(C₀-C₆alkyl)-Q, â€”(C₁-C₆alkylene)-S(O)_1-2â€”N(R⁶)(R⁶), â€”(C₁-C₄alkylene)-S(O)_1-2â€”N(R⁶)â€”(C₁-C₆alkylene)-Q, â€”C(O)N(R⁶)â€”(C₁-C₆alkylene)-C(O)â€” (C₀-C₀alkylene)-Oâ€”(C₁-C₆alkyl), â€”C(O)N(R⁶)â€”(C)â€”C₆alkylene)-C(O)â€”(C₀-C₆alkylene)-Oâ€”(C₀-C₆alkylene)-Q, â€”(C₁-C₆alkylene)-Oâ€”C(O)â€”(C₁-C₆alkyl), â€”(C₁-C₆alkylene)-Oâ€”C(O)â€”(C₀-C₆alkyl)-Q, â€”(C₁-C₆alkylene)-Oâ€”(C₁-C₆alkyl), â€”(C₁-C₆alkylene)-Oâ€”(C₁-C₆alkylene)-Q, â€”(C₀-C₆alkylene)-C(O)â€”(C₀-C₆alkylene)-Oâ€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-C(O)â€”(C₀-C₆alkylene)-Oâ€”(C₁-C₆alkylene)-Q, â€”(C₁-C₆alkylene)-Oâ€”C(O)â€”(C₁-C₆alkyl), â€”(C₁-C₆alkylene)-Oâ€”C(O)â€”(C₀-C₆alkylene)-Q, â€”(C₀-C₆alkylene)-C(O)N(R⁶)â€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-C(O)N(R⁶)â€”(C₀-C₆alkylene)-Q, â€”(C₁-C₆alkylene)-N(R⁶)C(O)â€”(C₁-C₆alkyl), â€”(C₁-C₆alkylene)-N(R⁶)C(O)â€”(C₀-C₆alkylene)-Q, â€”(C₀-C₆alkylene)-S(O)_0-2â€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-S(O)_0-2â€”(C₀-C₆alkylene)-Q, â€”(C₁-C₆alkylene)-N(R⁶)â€”C(O)â€”N(R⁶)â€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-Q, â€”(C₀-C₆alkylene)-C(O)â€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-C(O)â€”(C₀-C₆alkylene)-Q, wherein:

- any alkyl or alkylene moiety present in R²and R⁵is optionally substituted with one or more â€”OH, â€”O(C₁-C₄alkyl), â€”CO₂H, or halo;
- any terminal methyl moiety present in R²and R⁵is optionally replaced with â€”CH₂OH,

CF₃, â€”CH₂F, â€”CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;

R⁷and R⁸are each independently selected from hydrogen and C₁-C₆alkyl; and

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

R¹and R³are optionally taken together with the carbon atom to which they are attached to form C(â• O); or

R⁴and R⁶are optionally taken together with the carbon atom to which they are attached to form C(â• O); or

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

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

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(O)phenyl, NHCH₂CH₂CH₂OH, NHCH₂CH₂CH₂N(CH₃)phenyl, NHCH₂C(O)OCH₃, NHCH₂C(O)OCH₂CH₃, NHCH₂phenyl, NHCH(CH₃)CH₂CH₃, or NHCH₂CH₂OC(O)CH₃;

(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(O)-[2-chloro-4-(methylsulfonyl)], (B) N(R⁷)C(R⁴)(R⁵)(R⁶) and N(R⁸)C(R¹)(R²)(R³) are not both NHC(O)C(CH₃)₃, NHC(O)CHâ• CH₂, NHC(O)C(CH₃)â• CH₂, NHCH₂CH₂OH, NH-cyclohexyl, NHCH₂-phenyl, NHC(O)phenyl, NHC(O)(CH₂)₅NH₂, NHC(O)OCH₃, NHC(O)CH₃, and NHC(O)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 NHâ€”CH₂CH₃;

(vii) the compound is not selected from the group:

(1) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-phenyl-1,3,5-triazine-2,4-diamine,
(2) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(4-methoxyphenyl)-1,3,5-triazine-2,4-diamine,
(3) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(3-nitrophenyl)-1,3,5-triazine-2,4-diamine,
(4) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(4-fluorophenyl)-1,3,5-triazine-2,4-diamine,
(5) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(4-trifluoromethoxy-phenyl)-1,3,5-triazine-2,4-diamine,
(6) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(4-t-butyl-phenyl)-1,3,5-triazine-2,4-diamine,
(7) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(2-thienyl)-1,3,5-triazine-2,4-diamine,
(8) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-1H-inden-2-yl)amino]-6-phenyl-1,3,5-triazin-2-yl]amino]methyl]-benzamide,
(9) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-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,
(11) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-1H-1,2,4-triazol-3-yl]thio]-acetamide,
(12) N²-cyclopropyl-N⁴-ethyl-6-[3-[(phenylmethyl)thio]-1H-1,2,4-triazol-1-yl]-1,3,5-triazine-2,4-diamine,
(13) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-1H-1,2,4-triazol-3-yl]thio]-acetic acid methyl ester,
(14) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopropyl-6-(2,4,6-trimethylphenyl)-1,3,5-triazine-2,4-diamine,
(15) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopropyl-6-phenyl-1,3,5-triazine-2,4-diamine,
(16) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopropyl-6-(4-methylphenyl)-1,3,5-triazine-2,4-diamine,
(17) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopropyl-6-(4-chlorophenyl)-1,3,5-triazine-2,4-diamine,
(18) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,
(19) N²-cyclopropyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)-N⁴-phenyl-1,3,5-triazine-2,4-diamine,
(20) N²,N⁴-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(21) N²,N⁴-dicyclohexyl-6-[3-(3,4-dimethoxyphenyl)-5-(methylthio)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(22) N²,N⁴-dicyclohexyl-6-[5-(methylthio)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(23) N²,N⁴-dicyclohexyl-6-phenyl-1,3,5-triazine-2,4-diamine,
(24) 1,1â€²-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],
(25) 4,4â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis(iminomethylene)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(26) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-1,3,5-triazin-2-yl]-glycine,
(27) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3-fluorophenyl)-1,3,5-triazin-2-yl]amino]ethyl]-phenol,
(28) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4-fluorophenyl)-1,3,5-triazin-2-yl]amino]ethyl]-phenol,
(29) 6-(4-aminopyridin-3-yl)-N²-benzyl-N⁴-(tert-butyl)-1,3,5-triazine-2,4-diamine,
(30) N²,N⁴-bis(cyclohexylmethyl)-6-phenyl-1,3,5-triazine-2,4-diamine,
(31) 4,4â€²-[[6-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,5-triazine-2,4-diyl]bis(imino-3,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(32) 4,4â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis(imino-3,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(33) N-[6-[(2,3-dihydro-1H-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]-Î² alanine,
(34) N⁴-cyclopentyl-2-phenyl-N⁶-(phenylmethyl)-4,6-pyrimidinediamine,
(35) 2-[[6-(bicyclo[2.2.1]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol,
(36) N²-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4-diamine,
(37) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-1,3,5-triazin-2-yl]-benzamide,
(38) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,
(39) [[4-[[[[[4-amino-6-(4-pyridinyl)-1,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]imino]bis-methanol,
(40) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl] imino]bis-methanol,
(41) 5-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]-2H-tetrazole-2-acetic acid ethyl ester,
(42) N²,N²,N⁴,N⁴-tetraethyl-6-(2H-tetrazol-5-yl)-1,3,5-triazine-2,4-diamine, and
(43) N,Nâ€²-[6-[4-(acetylamino)-1,2,5-oxadiazol-3-yl]-1,3,5-triazine-2,4-diyl]bis-acetamide.

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

[Image Omitted]

wherein:

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

X is N or CH;

- any alkyl or alkylene moiety present in R²and R⁵is optionally substituted with one or more â€”OH, â€”O(C₁-C₄alkyl), â€”CO₂H, or halo;
- any terminal methyl moiety present in R²and R⁵is optionally replaced with â€”CH₂OH, CF₃, â€”CH₂F, â€”CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;
  R⁷and R⁸are each independently selected from hydrogen and C₁-C₆alkyl; and
  Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
  R¹and R³are optionally taken together with the carbon atom to which they are attached to form C(â• O); or
  R⁴and R⁶are optionally taken together with the carbon atom to which they are attached to form C(â• O); or
  R¹and R²are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
  R⁴and R⁵are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;

wherein:

(vii) the compound is not selected from the group:

(1) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-phenyl-1,3,5-triazine-2,4-diamine,
(2) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(4-methoxyphenyl)-1,3,5-triazine-2,4-diamine,
(3) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(3-nitrophenyl)-1,3,5-triazine-2,4-diamine,
(4) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(4-fluorophenyl)-1,3,5-triazine-2,4-diamine,
(5) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(4-trifluoromethoxy-phenyl)-1,3,5-triazine-2,4-diamine,
(6) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(4-t-butyl-phenyl)-1,3,5-triazine-2,4-diamine,
(7) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(2-thienyl)-1,3,5-triazine-2,4-diamine,
(8) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-1H-inden-2-yl)amino]-6-phenyl-1,3,5-triazin-2-yl]amino]methyl]-benzamide,
(9) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-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,
(11) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-1H-1,2,4-triazol-3-yl]thio]-acetamide,
(12) N²-cyclopropyl-N⁴-ethyl-6-[3-[(phenylmethyl)thio]-1H-1,2,4-triazol-1-yl]-1,3,5-triazine-2,4-diamine,
(13) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-1H-1,2,4-triazol-3-yl]thio]-acetic acid methyl ester,
(14) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopropyl-6-(2,4,6-trimethylphenyl)-1,3,5-triazine-2,4-diamine,
(15) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopropyl-6-phenyl-1,3,5-triazine-2,4-diamine,
(16) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopropyl-6-(4-methylphenyl)-1,3,5-triazine-2,4-diamine,
(17) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopropyl-6-(4-chlorophenyl)-1,3,5-triazine-2,4-diamine,
(18) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,
(19) N²-cyclopropyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)-N⁴-phenyl-1,3,5-triazine-2,4-diamine,
(20) N²,N⁴-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(21) N²,N⁴-dicyclohexyl-6-[3-(3,4-dimethoxyphenyl)-5-(methylthio)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(22) N²,N⁴-dicyclohexyl-6-[5-(methylthio)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(23) N²,N⁴-dicyclohexyl-6-phenyl-1,3,5-triazine-2,4-diamine,
(24) 1,1â€²-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],
(25) 4,4â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis(iminomethylene)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(26) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-1,3,5-triazin-2-yl]-glycine,
(27) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3-fluorophenyl)-1,3,5-triazin-2-yl]amino]ethyl]-phenol,
(28) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4-fluorophenyl)-1,3,5-triazin-2-yl]amino]ethyl]-phenol,
(29) 6-(4-aminopyridin-3-yl)-N²-benzyl-N⁴-(tert-butyl)-1,3,5-triazine-2,4-diamine,
(30) N²,N⁴-bis(cyclohexylmethyl)-6-phenyl-1,3,5-triazine-2,4-diamine,
(31) 4,4â€²-[[6-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,5-triazine-2,4-diyl]bis(imino-3,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(32) 4,4â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis(imino-3,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(33) N-[6-[(2,3-dihydro-1H-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]-Î²alanine,
(34) N⁴-cyclopentyl-2-phenyl-N⁶-(phenylmethyl)-4,6-pyrimidinediamine,
(35) 2-[[6-(bicyclo[2.2.1]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol,
(36) N²-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4-diamine,
(37) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-1,3,5-triazin-2-yl]-benzamide,
(38) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,
(39) [[4-[[[[[4-amino-6-(4-pyridinyl)-1,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]imino]bis-methanol,
(40) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]imino]bis-methanol,
(41) 5-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]-2H-tetrazole-2-acetic acid ethyl ester,
(42) N²,N²,N⁴,N⁴-tetraethyl-6-(2H-tetrazol-5-yl)-1,3,5-triazine-2,4-diamine, and
(43) N,Nâ€²-[6-[4-(acetylamino)-1,2,5-oxadiazol-3-yl]-1,3,5-triazine-2,4-diyl]bis-acetamide.
Also provided is a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof:

[Image Omitted]

wherein:
ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;

X is N or CH;

- any alkyl or alkylene moiety present in R²and R⁵is optionally substituted with one or more â€”OH, â€”O(C₁-C₄alkyl), â€”CO₂H, or halo;
- any terminal methyl moiety present in R²and R⁵is optionally replaced with â€”CH₂OH,

CF₃, â€”CH₂F, â€”CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;

R⁷and R⁸are each independently selected from hydrogen and C₁-C₆alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R¹and R³are optionally taken together with the carbon atom to which they are attached to form

C(â• O); or

R⁴and R⁶are optionally taken together with the carbon atom to which they are attached to form C(â• O); or
R¹and R²are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R⁴and R⁵are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; wherein:

(vii) when X is CH and A is unsubstituted 2-pyridinyl, then the ring formed by R⁴and R⁵is not 5-methyl-1H-pyrazol-3-yl,

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

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

(xx) the compound is not selected from the group:

(1) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-1H-inden-2-yl)amino]-6-phenyl-1,3,5-triazin-2-yl]amino]methyl]-benzamide,
(2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]-4-(methylsulfonyl)-benzamide,
(3) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-1H-1,2,4-triazol-3-yl]thio]-acetamide,
(4) N²-cyclopropyl-N⁴-ethyl-6-[3-[(phenylmethyl)thio]-1H-1,2,4-triazol-1-yl]-1,3,5-triazine-2,4-diamine,
(5) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-1H-1,2,4-triazol-3-yl]thio]-acetic acid methyl ester,
(6) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,
(7) N²-cyclopropyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)-N⁴-phenyl-1,3,5-triazine-2,4-diamine,
(8) N²,N⁴-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(9) N²,N⁴-dicyclohexyl-6-[3-(3,4-dimethoxyphenyl)-5-(methylthio)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(10) N²,N⁴-dicyclohexyl-6-[5-(methylthio)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(11) N²,N⁴-dicyclohexyl-6-phenyl-1,3,5-triazine-2,4-diamine,
(12) 1,1â€²-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],
(13) 4,4â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis(iminomethylene)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-1,3,5-triazin-2-yl]-glycine,
(15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3-fluorophenyl)-1,3,5-triazin-2-yl]amino]ethyl]-phenol,
(16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4-fluorophenyl)-1,3,5-triazin-2-yl]amino]ethyl]-phenol,
(17) 6-(4-aminopyridin-3-yl)-N²-benzyl-N⁴-(tert-butyl)-1,3,5-triazine-2,4-diamine,
(18) N²,N⁴-bis(cyclohexylmethyl)-6-phenyl-1,3,5-triazine-2,4-diamine,
(19) 4,4â€²-[[6-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,5-triazine-2,4-diyl]bis(imino-3,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(20) 4,4â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis(imino-3,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(21) N-[6-[(2,3-dihydro-1H-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]-0 alanine,
(22) N⁴-cyclopentyl-2-phenyl-N6-(phenylmethyl)-4,6-pyrimidinediamine,
(23) 2-[[6-(bicyclo[2.2.1]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol,
(24) N²-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4-diamine,
(25) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-1,3,5-triazin-2-yl]-benzamide,
(26) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,
(27) [[4-[[[[[4-amino-6-(4-pyridinyl)-1,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]imino]bis-methanol,
(28) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]imino]bis-methanol,
(29) 5-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]-2H-tetrazole-2-acetic acid ethyl ester,
(30) N²,N²,N⁴,N⁴-tetraethyl-6-(2H-tetrazol-5-yl)-1,3,5-triazine-2,4-diamine,
(31) N,Nâ€²-[6-[4-(acetylamino)-1,2,5-oxadiazol-3-yl]-1,3,5-triazine-2,4-diyl]bis-acetamide,
(32) N-(2-chloro-6-methylphenyl)-5-[[4-(dimethylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]-1,3,4-Oxadiazole-2-carboxamide,
(33) N4-(5-methyl-1H-pyrazol-3-yl)-2-(2-pyridinyl)-N6-(tetrahydro-2H-pyran-4-yl)-4,6-Pyrimidinediamine,
(34) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(diethylamino)propyl]-1,3,5-Triazine-2,4-diamine,
(35) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(dimethylamino)propyl]-1,3,5-Triazine-2,4-diamine,
(36) N2-[3,5-bis(trifluoromethyl)phenyl]-6-(4-chlorophenyl)-N4-[3-(diethylamino)propyl]-1,3,5-Triazine-2,4-diamine,
(37) N2,N4-bis[(4-methoxyphenyl)methyl]-6-[4-(trifluoromethoxy)phenyl]-1,3,5-Triazine-2,4-diamine,
(38) N,Nâ€³-(6-phenyl-1,3,5-triazine-2,4-diyl)bis[Nâ€²-(2-chloroethyl)-Urea,
(39) N-[4-chloro-3-(trifluoromethyl)phenyl]-Nâ€²-[4-methyl-3-[[4-phenyl-6-(propylamino)-1,3,5-triazin-2-yl]amino]phenyl]-urea,
(40) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2-methylphenyl]amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]-glycine,
(41) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2-methylphenyl]amino]-6-(5-thiazolyl)-1,3,5-triazin-2-yl]-L-Valine,
(42) 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]-,
(43) Î±,Î±â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis[imino(1,1,2,2-tetrafluoro-3-oxo-3,1-propanediyl)]]bis[Ï‰-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)-1,2-ethanediyl]],
(44) Î±-[[4-[[(3-chlorophenyl)methyl]amino]-6-(1H-imidazol-1-yl)-1,3,5-triazin-2-yl]amino]-N-[[4-(trifluoromethyl)phenyl]methyl]-, (Î±R)-Cyclohexanepropanamide,
(45) 6-(1H-imidazol-1-yl)-N2,N4-bis(1-methylethyl)-1,3,5-Triazine-2,4-diamine, and
(46) N2,N4-bis(1-methylpropyl)-6-phenyl-1,3,5-Triazine-2,4-diamine.

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

[Image Omitted]

wherein:

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

- any alkyl or alkylene moiety present in R²and R⁵is optionally substituted with one or more â€”OH, â€”O(C₁-C₄alkyl), â€”CO₂H, or halo;
- any terminal methyl moiety present in R²and R⁵is optionally replaced with â€”CH₂OH, CF₃, â€”CH₂F, â€”CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;
  R⁷and R⁸are each independently selected from hydrogen and C₁-C₆alkyl; and
  Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
  R¹and R³are optionally taken together with the carbon atom to which they are attached to form C(â• O); or
  R⁴and R⁶are optionally taken together with the carbon atom to which they are attached to form C(â• O); or
  R¹and R²are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
  R⁴and R⁵are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;

wherein:

- (i) when 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(O)phenyl, NHCH₂CH₂CH₂OH, NHCH₂CH₂CH₂N(CH₃)phenyl, NHCH₂C(O)OCH₃, NHCH₂C(O)OCH₂CH₃, NHCH₂phenyl, NHCH(CH₃)CH₂CH₃, or NHCH₂CH₂OC(O)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(O)-[2-chloro-4-(methylsulfonyl)], (B) N(R⁷)C(R⁴)(R⁵)(R⁶) and N(R⁸)C(R¹)(R²)(R³) are not both NHC(O)C(CH₃)₃, NHC(O)CHâ• CH₂, NHC(O)C(CH₃)â• CH₂, NHCH₂CH₂OH, NH-cyclohexyl, NHCH₂-phenyl, NHC(O)phenyl, NHC(O)(CH₂)₅NH₂, NHC(O)OCH₃, NHC(O)CH₃, and NHC(O)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 NHâ€”CH₂CH₃;
- (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(O)CH₃; and
- (iv) the compound is not selected from the group:
(1) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-phenyl-1,3,5-triazine-2,4-diamine,
(2) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(4-methoxyphenyl)-1,3,5-triazine-2,4-diamine,
(3) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(3-nitrophenyl)-1,3,5-triazine-2,4-diamine,
(4) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(4-fluorophenyl)-1,3,5-triazine-2,4-diamine,
(5) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(4-trifluoromethoxy-phenyl)-1,3,5-triazine-2,4-diamine,
(6) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(4-t-butyl-phenyl)-1,3,5-triazine-2,4-diamine,
(7) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopentyl-6-(2-thienyl)-1,3,5-triazine-2,4-diamine,
(8) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-1H-inden-2-yl)amino]-6-phenyl-1,3,5-triazin-2-yl]amino]methyl]-benzamide,
(9) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-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,
(11) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-1H-1,2,4-triazol-3-yl]thio]-acetamide,
(12) N²-cyclopropyl-N⁴-ethyl-6-[3-[(phenylmethyl)thio]-1H-1,2,4-triazol-1-yl]-1,3,5-triazine-2,4-diamine,
(13) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-1H-1,2,4-triazol-3-yl]thio]-acetic acid methyl ester,
(14) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopropyl-6-(2,4,6-trimethylphenyl)-1,3,5-triazine-2,4-diamine,
(15) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopropyl-6-phenyl-1,3,5-triazine-2,4-diamine,
(16) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopropyl-6-(4-methylphenyl)-1,3,5-triazine-2,4-diamine,
(17) N²-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N⁴-cyclopropyl-6-(4-chlorophenyl)-1,3,5-triazine-2,4-diamine,
(18) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,
(19) N²-cyclopropyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)-N⁴-phenyl-1,3,5-triazine-2,4-diamine,
(20) N²,N⁴-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(21) N²,N⁴-dicyclohexyl-6-[3-(3,4-dimethoxyphenyl)-5-(methylthio)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(22) N²,N⁴-dicyclohexyl-6-[5-(methylthio)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(23) N²,N⁴-dicyclohexyl-6-phenyl-1,3,5-triazine-2,4-diamine,
(24) 1,1â€²-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],
(25) 4,4â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis(iminomethylene)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(26) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2-methylphenyl]-1,3,5-triazin-2-yl]-glycine,
(27) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3-fluorophenyl)-1,3,5-triazin-2-yl]amino]ethyl]-phenol,
(28) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4-fluorophenyl)-1,3,5-triazin-2-yl]amino]ethyl]-phenol,
(29) 6-(4-aminopyridin-3-yl)-N²-benzyl-N⁴-(tert-butyl)-1,3,5-triazine-2,4-diamine,
(30) N²,N⁴-bis(cyclohexylmethyl)-6-phenyl-1,3,5-triazine-2,4-diamine,
(31) 4,4â€²-[[6-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,5-triazine-2,4-diyl]bis(imino-3,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(32) 4,4â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis(imino-3,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(33) N²-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4-diamine,
(34) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-1,3,5-triazin-2-yl]-benzamide,
(35) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,
(36) [[4-[[[[[4-amino-6-(4-pyridinyl)-1,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]imino]bis-methanol,
(37) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]imino]bis-methanol,
(38) 5-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]-2H-tetrazole-2-acetic acid ethyl ester, (39) N²,N²,N⁴,N⁴-tetraethyl-6-(2H-tetrazol-5-yl)-1,3,5-triazine-2,4-diamine, and
(40) N,Nâ€²-[6-[4-(acetylamino)-1,2,5-oxadiazol-3-yl]-1,3,5-triazine-2,4-diyl]bis-acetamide.
Also provided is a compound of Formula Ia, or a pharmaceutically acceptable salt or hydrate thereof:

[Image Omitted]

wherein:

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

- any alkyl or alkylene moiety present in R²and R⁵is optionally substituted with one or more â€”OH, â€”O(C₁-C₄alkyl), â€”CO₂H, or halo;
- any terminal methyl moiety present in R²and R⁵is optionally replaced with â€”CH₂OH, CF₃, â€”CH₂F, â€”CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;
  R⁷and R⁸are each independently selected from hydrogen and C₁-C₆alkyl; and
  Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
  R¹and R³are optionally taken together with the carbon atom to which they are attached to form C(â• O); or
  R⁴and R⁶are optionally taken together with the carbon atom to which they are attached to form C(â• O); or
  R¹and R²are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
  R⁴and R⁵are 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) nor N(R⁸)C(R¹)(R²)(R³) 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, NHCH₂CH₂OC(O)phenyl, NHCH₂CH₂CH₂OH, NHCH₂CH₂CH₂N(CH₃)phenyl, NHCH₂C(O)OCH₃, NHCH₂C(O)OCH₂CH₃, NHCH₂phenyl, NHCH(CH₃)CH₂CH₃, or NHCH₂CH₂OC(O)CH₃;

(ii) when A is an optionally substituted pyridyl, then (A) neither N(R⁷)C(R⁴)(R⁵)(R⁶) nor N(R⁸)C(R¹)(R²)(R³) is NHC(O)-[2-chloro-4-(methylsulfonyl)], N(CH₃)₂, NHCH₂CH₂CH₂SO₂CH₂CH₂Cl, NHCH₂CH₂OCH₂CH₂SO₂CH₂CH₂Cl, or NHCH₂CH₂SO₂CH₂CH₂Cl, (B) N(R⁷)C(R⁴)(R⁵)(R⁶) and N(R⁸)C(R¹)(R²)(R³) are not both NHC(O)C(CH₃)₃, NHC(O)CHâ• CH₂, NHC(O)C(CH₃)â• CH₂, NHCH₂CH₂OH, NH-cyclohexyl, NHCH₂-phenyl, NHC(O)phenyl, NHC(O)(CH₂)₅NH₂, NHC(O)OCH₃, NHC(O)CH₃, and NHC(O)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 NHâ€”CH₂CH₃;

(iii) when 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(O)CH₃;

(iv) when A is optionally substituted 1-pyrazolyl, then neither N(R⁷)C(R⁴)(R⁵)(R⁶) nor N(R⁸)C(R¹)(R²)(R³) is N(CH₃)₂, NHCH₃, NHAc, NHisopropyl, NHCH₂CH₃, NHCH₂CH₂SO₃H or N(CH₂CH₃)₂,

(v) when 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(O)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 R⁴and R⁵form an optionally substituted phenyl, then N(R⁸)C(R¹)(R²)(R³) is not NHCH₂(4-fluorophenyl), NHCH₂CO₂H, NHCH₂C(O)Cl, NHCH(CO₂H)(CH₂SCH₂phenyl), or NHCH₂C(O)NHC(O)NHR or NHCH₂C(O)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl,

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

(viii) when A is substituted 1-pyrazolyl, then (A) then N(R⁷)C(R⁴)(R⁵)(R⁶) and N(R⁸)C(R¹)(R²)(R³) are not both NHC(CH₃)₃, and (B) A is not substituted with Nâ• Nâ€”R, wherein R is a ring,

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

(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;

(xi) the compound is not selected from the group:

(1) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-1H-inden-2-yl)amino]-6-phenyl-1,3,5-triazin-2-yl]amino]methyl]-benzamide,
(2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]-4-(methylsulfonyl)-benzamide,
(3) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-1H-1,2,4-triazol-3-yl]thio]-acetamide,
(4) N²-cyclopropyl-N⁴-ethyl-6-[3-[(phenylmethyl)thio]-1H-1,2,4-triazol-1-yl]-1,3,5-triazine-2,4-diamine,
(5) 2-[[1-[4-(cyclopropylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-1H-1,2,4-triazol-3-yl]thio]-acetic acid methyl ester,
(6) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,
(7) N²-cyclopropyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)-N⁴-phenyl-1,3,5-triazine-2,4-diamine,
(8) N²,N⁴-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(9) N²,N⁴-dicyclohexyl-6-[3-(3,4-dimethoxyphenyl)-5-(methylthio)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(10) N²,N⁴-dicyclohexyl-6-[5-(methylthio)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-1-yl]-1,3,5-triazine-2,4-diamine,
(11) N²,N⁴-dicyclohexyl-6-phenyl-1,3,5-triazine-2,4-diamine,
(12) 1,1â€²-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],
(13) 4,4â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis(iminomethylene)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2-methylphenyl]-1,3,5-triazin-2-yl]-glycine,
(15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3-fluorophenyl)-1,3,5-triazin-2-yl]amino]ethyl]-phenol,
(16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4-fluorophenyl)-1,3,5-triazin-2-yl]amino]ethyl]-phenol,
(17) 6-(4-aminopyridin-3-yl)-N²-benzyl-N⁴-(tert-butyl)-1,3,5-triazine-2,4-diamine,
(18) N²,N⁴-bis(cyclohexylmethyl)-6-phenyl-1,3,5-triazine-2,4-diamine,
(19) 4,4â€²-[[6-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,5-triazine-2,4-diyl]bis(imino-3,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(20) 4,4â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis(imino-3,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol,
(21) N²-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4-diamine,
(22) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-1,3,5-triazin-2-yl]-benzamide,
(23) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,
(24) [[4-[[[[[4-amino-6-(4-pyridinyl)-1,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]imino]bis-methanol,
(25) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]imino]bis-methanol,
(26) 5-[4,6-bis(diethylamino)-1,3,5-triazin-2-yl]-2H-tetrazole-2-acetic acid ethyl ester,
(27) N²,N²,N⁴,N⁴-tetraethyl-6-(2H-tetrazol-5-yl)-1,3,5-triazine-2,4-diamine,
(28) N,Nâ€²-[6-[4-(acetylamino)-1,2,5-oxadiazol-3-yl]-1,3,5-triazine-2,4-diyl]bis-acetamide,
(29) N-(2-chloro-6-methylphenyl)-5-[[4-(dimethylamino)-6-(2-pyridinyl)-1,3,5-triazin-2-yl]amino]-1,3,4-Oxadiazole-2-carboxamide,
(30) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(diethylamino)propyl]-1,3,5-Triazine-2,4-diamine,
(31) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(dimethylamino)propyl]-1,3,5-Triazine-2,4-diamine,
(32) N2-[3,5-bis(trifluoromethyl)phenyl]-6-(4-chlorophenyl)-N4-[3-(diethylamino)propyl]-1,3,5-Triazine-2,4-diamine,
(33) N2,N4-bis[(4-methoxyphenyl)methyl]-6-[4-(trifluoromethoxy)phenyl]-1,3,5-Triazine-2,4-diamine,
(34) N,Nâ€³-(6-phenyl-1,3,5-triazine-2,4-diyl)bis[Nâ€²-(2-chloroethyl)-Urea,
(35) N-[4-chloro-3-(trifluoromethyl)phenyl]-Nâ€²-[4-methyl-3-[[4-phenyl-6-(propylamino)-1,3,5-triazin-2-yl]amino]phenyl]-urea,
(36) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2-methylphenyl]amino]-6-(4-pyridinyl)-1,3,5-triazin-2-yl]-glycine,
(37) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2-methylphenyl]amino]-6-(5-thiazolyl)-1,3,5-triazin-2-yl]-L-Valine,
(38) 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) Î±,Î±â€²-[(6-phenyl-1,3,5-triazine-2,4-diyl)bis[imino(1,1,2,2-tetrafluoro-3-oxo-3,1-propanediyl)]]bis[Ï‰-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)-1,2-ethanediyl]],
(40) Î±-[[4-[[(3-chlorophenyl)methyl]amino]-6-(1H-imidazol-1-yl)-1,3,5-triazin-2-yl]amino]-N-[[4-(trifluoromethyl)phenyl]methyl]-, (Î±R)-Cyclohexanepropanamide,
(41) N,Nâ€²-[6-[4-(acetylamino)-1,2,5-oxadiazol-3-yl]-1,3,5-triazine-2,4-diyl]bis-acetamide,
(42) 6-(1H-imidazol-1-yl)-N2,N4-bis(1-methylethyl)-1,3,5-Triazine-2,4-diamine, and
(43) N2,N4-bis(1-methylpropyl)-6-phenyl-1,3,5-Triazine-2,4-diamine.

In some embodiments, R¹and R⁴are each independently selected from hydrogen, â€”CH₃, â€”CH₂CH₃, â€”CH₂OH, â€”CH(CH₃)OH, â€”C(CH₃)₂OH, CF₃, CN, or R¹and R³are taken together to form â• O; or R⁴and R⁶are optionally taken together with the carbon atom to which they are attached to form C(â• O).

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, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, â€”CN, â• O, â€”OH, and â€”C(O)C₁-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, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, â€”CN, â• O, â€”OH, aryl, heteroaryl â€”SO₂C₁-C₄alkyl, â€”CO₂C₁-C₄alkyl, â€”C(O)aryl, and â€”C(O)C₁-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-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, â€”CN, and â€”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, â€”CN, and â€”OH.

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, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, â€”CN, â• O, â€”OH, and â€”C(O)C₁-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, â€”CN, â• O, â€”OH, aryl, heteroaryl â€”SO₂C₁-C₄alkyl, â€”CO₂C₁-C₄alkyl, â€”C(O)aryl, and â€”C(O)C₁-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-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, â€”CN, and â€”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, â€”CN, and â€”OH.

In some embodiments, R²and R⁵are each independently selected from: â€”(C₁-C₆alkyl), â€”(C₁-C₆alkyl)-C(O)â€”NH₂, â€”(C₁-C₆alkyl)-CO₂H, â€”(C₂-C₆alkenyl or alkynyl), â€”(C₁-C₀alkylene)-Oâ€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-C(O)N(R⁶)â€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-Q, â€”(C₀-C₆alkylene)-C(O)â€”(C₁-C₆alkyl), and â€”(C₀-C₆alkylene)-C(O)â€”(C₀-C₆alkylene)-Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, â• O, â€”C(O)â€”C₁-C₄alkyl, â€”CN, and halo.

In some embodiments, R²and R⁵are each independently selected from: â€”(C₁-C₄alkyl) optionally substituted with halo, e.g., fluoro or â€”OH; â€”(C₀-C₄alkylene)-Oâ€”(C₁-C₄alkyl), â€”(C₀-C₂alkylene)-N(R⁶)â€”(C₁-C₆alkyl), â€”(C₁-C₆alkyl)-C(O)â€”NH₂, â€”(C₀-C₂alkylene)-Q, â€”(C₀-C₆alkylene)-C(O)â€”(C₁-C₆alkyl), and â€”Oâ€”(C₀-C₂alkylene)-Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, â• O, â€”C(O)â€”C₁-C₄alkyl, â€”CN, and halo. In one aspect of these embodiments, Q is selected from pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl and oxetanyl, wherein Q is optionally substituted with up to 2 substituents independently selected from C₁-C₄alkyl, C₁-C₄haloalkyl, â• O, 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 substituents independently selected from â€”CH₃and â• O.

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-C₄alkyl, C₁-C₄alkoxy, C₃-C₆cycloalkyl, â€”OH, â€”C(O)CH₃, fluoro, and chloro.

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-C₄alkyl, C₁-C₄alkoxy, C₃-C₆cycloalkyl, â€”OH, â€”C(O)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-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₃-C₆cycloalkyl, phenyl, â€”OH, â€”C(O)CH₃, wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, â€”OH, â€”NH₂, or â€”CN. In some embodiments the C₃-C₆cycloalkyl is

[Image Omitted]

In some embodiments, R¹, R³, R⁴, and R⁶are each independently selected from hydrogen, C₁-C₄alkyl, C₁-C₄haloalkyl, â€”Oâ€”C₁-C₄alkyl, and CN, wherein each said alkyl moiety of R¹, R³, R⁴, and R⁶are each independently optionally substituted with â€”OH, â€”NH₂, â€”CN, â€”Oâ€”C₁-C₄alkyl, â€”NH(C₁-C₄alkyl), or â€”N(C₁-C₄alkyl)₂; and R²and R⁵are each independently selected from: â€”(C₁-C₆alkyl), â€”(C₁-C₆alkyl)-C(O)â€”NH₂, â€”(C₁-C₆alkyl)-CO₂H, â€”(C₂-C₆alkenyl or alkynyl), â€”(C₁-C₆alkylene)-Oâ€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-C(O)N(R⁶)â€”(C₁-C₆alkyl), and â€”(C₀-C₆alkylene)-C(O)â€”(C₁-C₆alkyl), wherein: any alkyl or alkylene moiety present in R²and R⁵is optionally substituted with one or more â€”OH, â€”O(C₁-C₄alkyl), â€”CO₂H, or halo; and any terminal methyl moiety present in R²and R⁵is optionally replaced with â€”CH₂OH, CF₃, â€”CH₂F, â€”CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H; or R¹and R³are optionally taken together with the carbon atom to which they are attached to form C(â• O); or

R⁴and R⁶are optionally taken together with the carbon atom to which they are attached to form C(â• O); 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 N(R⁸)C(R¹)(R²)(R³), and the compound is not 2-(1,2-dibromoethyl)-4-phenyl-6-(1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluorohexyl-1,3,5-Triazine.

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

In some embodiments, ring A is a substituted 5-6 member monocyclic aryl or monocyclic heteroaryl, which is substituted with up to two substituents independently selected from halo, â€”C₁-C₄alkyl, â€”C₁-C₄haloalkyl, â€”C₁-C₄hydroxyalkyl, â€”NHâ€”S(O)₂â€”(C₁-C₄alkyl), â€”S(O)₂NH(C₁-C₄alkyl), â€”CN, â€”S(O)₂â€”(C₁-C₄alkyl), C₁-C₄alkoxy, â€”NH(C₁-C₄alkyl), â€”OH, â€”OCF₃, â€”CN, â€”NH₂, â€”C(O)NH₂, â€”C(O)NH(C₁-C₄alkyl), â€”C(O)â€”N(C₁-C₄alkyl)₂, â€”(C₁-C₆alkylene)-Oâ€”(C₁-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, â€”OH, â€”OCH₃, â€”OCF₃, â€”CN, â€”NH₂. In some embodiments, ring A is a substituted 6-membered monocyclic aryl. In some embodiments, ring A is a substituted 5-6 membered heteroaryl. In some embodiments, ring A is a substituted 5-membered heteroaryl.

In some embodiments, ring A is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, wherein ring A is optionally substituted with up to two substituents independently selected from halo, â€”C₁-C₄alkyl, â€”C₁-C₄haloalkyl, â€”C₁-C₄hydroxyalkyl, â€”NHâ€”S(O)₂â€”(C₁-C₄alkyl), â€”S(O)₂NH(C₁-C₄alkyl), â€”CN, â€”S(O)₂â€”(C₁-C₄alkyl), C₁-C₄alkoxy, â€”NH(C₁-C₄alkyl), â€”OH, â€”OCF₃, â€”CN, â€”NH₂, â€”C(O)NH₂, â€”C(O)NH(C₁-C₄alkyl), â€”C(O)â€”N(C₁-C₄alkyl)₂, and cyclopropyl optionally substituted with OH.

In some embodiments, ring A is selected from phenyl, pyrazolyl, imidazolyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, thiadiazolyl and isothiazolyl, wherein ring A is optionally substituted with up to two substituents independently selected from halo, â€”C₁-C₄alkyl, â€”C₁-C₄haloalkyl, â€”C₁-C₄hydroxyalkyl, â€”NHâ€”S(O)₂â€”(C₁-C₄alkyl), â€”S(O)₂NH(C₁-C₄alkyl), â€”CN, â€”S(O)₂â€”(C₁-C₄alkyl), C₁-C₄alkoxy, â€”NH(C₁-C₄alkyl), â€”OH, â€”CN, and â€”NH₂.

In some embodiments, ring A is monocyclic heteroaryl optionally substituted with halo, â€”C₁-C₄alkyl, â€”C₁-C₄haloalkyl, â€”Oâ€”C₁-C₄haloalkyl, â€”OH, â€”CN, and â€”NH₂; R¹, R³, R⁴, and R⁶are each independently selected from hydrogen and C₁-C₄alkyl; and R²and R⁵are each independently â€”(C₀-C₆alkylene)-Q; or R¹and R²are optionally taken together to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl; or R⁴and R⁵are optionally taken together to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

In some embodiments, ring A is monocyclic heteroaryl optionally substituted with halo, â€”C₁-C₄alkyl, â€”C₁-C₄haloalkyl, â€”Oâ€”C₁-C₄haloalkyl, â€”OH, â€”CN, and â€”NH₂; R¹, R³, R⁴, and R⁶are each independently selected from hydrogen and C₁-C₄alkyl; and R²and R⁵are each independently â€”(C₀-C₆alkylene)-Q; or R¹and R²are optionally taken together to form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl; or R⁴and R⁵are optionally taken together to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

In some embodiments, ring A is:

[Image Omitted]

wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl; each X^ais independently N or Câ€”R^9a, provided that when one X^ais N, then the other two X^aare both Câ€”R^9a; and R^9ais selected from hydrogen, halo, and â€”C₁-C₄haloalkyl.

In some embodiments, ring A is

[Image Omitted]

wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl. In some embodiments, ring A is:

[Image Omitted]

wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl. In some embodiments, ring A is:

[Image Omitted]

wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl.

In some embodiments, ring A is pyridinyl optionally substituted with halo or â€”C₁-C₄haloalkyl. In some embodiments, ring A is pyridinyl optionally substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyridin-2-yl substituted with â€”C₁-C₄haloalkyl, e.g., â€”CHF₂and CF₃. In some embodiments, ring A is:

[Image Omitted]

wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl. In some embodiments, ring A is:

[Image Omitted]

wherein each R⁹is independently selected from hydrogen, halo, and â€”C₁-C₄haloalkyl. In some embodiments, R⁹is chloro or fluoro. In some embodiments, R⁹is â€”CHF₂or CF₃. In some embodiments, R⁹is CF₃or chloro. In some embodiments, R⁹is CF₃.

In some embodiments, ring A is:

[Image Omitted]

wherein R^9bis selected from hydrogen and â€”C₁-C₄alkyl, and wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl.

In some embodiments, ring A is:

[Image Omitted]

wherein R^9bis selected from hydrogen and â€”C₁-C₄alkyl, and wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl.

In some embodiments, ring A is:

[Image Omitted]

wherein R^9bis selected from hydrogen and â€”C₁-C₄alkyl, and wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl.

In some embodiments, ring A is:

[Image Omitted]

wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl. In some embodiments, ring A is pyrazolyl optionally substituted with halo or â€”C₁-C₄haloalkyl. In some embodiments, ring A is pyrazolyl optionally substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is 1H-pyrazol-1-yl substituted with â€”C₁-C₄haloalkyl, e.g., â€”CHF₂and CF₃. In some embodiments, ring A is:

[Image Omitted]

wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl. In some embodiments, R⁹is chloro or fluoro. In some embodiments, R⁹is â€”CHF₂or CF₃. In some embodiments, R⁹is CF₃or chloro. In some embodiments, R⁹is CF₃.

In some embodiments, ring A is:

[Image Omitted]

wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl.

In some embodiments, ring A is

[Image Omitted]

wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl.

In some embodiments, ring A is:

[Image Omitted]

wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl.

In some embodiments, ring A is:

[Image Omitted]

wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl.

In some embodiments, ring A is:

[Image Omitted]

wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl.

In some embodiments, ring A is:

[Image Omitted]

wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl.

In some embodiments, ring A is:

[Image Omitted]

wherein R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl.

In some embodiments, ring A is pyridinyl optionally substituted with halo or â€”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 â€”C₁-C₄haloalkyl, e.g., â€”CHF₂and CF₃. In some embodiments, ring A is pyrazinyl optionally substituted with halo or â€”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 â€”C₁-C₄haloalkyl, e.g., â€”CHF₂and CF₃. In some embodiments, ring A is pyrimidinyl optionally substituted with halo or â€”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 â€”C₁-C₄haloalkyl, e.g., â€”CHF₂and CF₃. In some embodiments, ring A is pyrazolyl optionally substituted with halo or â€”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 â€”C₁-C₄haloalkyl, e.g., â€”CHF₂and CF₃.

In some embodiments, R¹, R³, R⁴, and R⁶are each independently selected from hydrogen and C₁-C₄alkyl; and R²and R⁵are each independently â€”(C₀-C₆alkylene)-Q. In some embodiments, R¹and R⁴are each hydrogen. In some embodiments, R³and R⁶are each C₁-C₄alkyl. In some embodiments, 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 embodiments, R¹and R⁴are each hydrogen, R³and R⁶are each â€”CH₃, and R²and R⁵are each unsubstituted cyclopropyl. In some embodiments, R²is â€”(C₀-C₆alkylene)-cyclopropyl and R⁵is â€”(C₀-C₆alkylene)-aryl, e.g., optionally substituted phenyl. In some embodiments, R²is cyclopropyl and R⁵is phenyl substituted with halo, e.g., fluoro.

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 substituted by 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[3.1.0]hexanyl; and R⁴and R⁵are taken together to form a bicyclo[3.1.0]hexanyl. In some embodiments, R¹and R²taken together, and R⁴and R⁵taken together form:

[Image Omitted]

In some embodiments, R¹and R²taken together, and R⁴and R⁵taken together form:

[Image Omitted]

In some embodiments, R¹and R²taken together, and R⁴and R⁵taken together form:

[Image Omitted]

In some embodiments, R¹and R²taken together, and R⁴and R⁵taken together form:

[Image Omitted]

In some embodiments, R¹and R²taken together, and R⁴and R⁵taken together form:

[Image Omitted]

which is optionally substituted with cyano or halo, e.g. fluoro, chloro, or bromo. In some embodiments, R¹and R²taken together, and R⁴and R⁵taken together form:

[Image Omitted]

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 R⁵are taken together form:

[Image Omitted]

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 together form:

[Image Omitted]

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, R¹, R³, R⁴, and R⁶are each independently selected from hydrogen, C₁-C₄alkyl, and â€”CN, wherein each said alkyl moiety of R¹, R³, R⁴, and R⁶are each independently optionally substituted with â€”OH, â€”NH₂, â€”CN, â€”Oâ€”C₁-C₄alkyl; and R²and R⁵are each independently selected from â€”(C₁-C₆alkyl) and â€”(C₀-C₆alkylene)-Q. In some embodiments, R¹, R³, R⁴, and R⁶are each independently selected from hydrogen, C₁-C₄alkyl, and â€”CN; and R²and R⁵are each independently â€”(C₁-C₆alkyl) and â€”(C₀-C₆alkylene)-Q. In some embodiments, R¹, R³, R⁴, and R⁶are each independently selected from hydrogen, C₁-C₄alkyl, and â€”CN; R²is â€”(C₁-C₆alkyl); and R⁵is â€”(C₀-C₆alkylene)-Q, wherein Q is optionally substituted carbocyclyl. In some embodiments, Q is unsubstituted carbocyclyl. In some embodiments, Q is cyclopropyl.

In some embodiments, ring A is pyridinyl optionally substituted with halo or â€”C₁-C₄haloalkyl. In some embodiments, ring A is pyridinyl substituted with â€”C₁-C₄haloalkyl, e.g., â€”CHF₂and CF₃. In some embodiments, ring A is pyrazinyl optionally substituted with halo or â€”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 â€”C₁-C₄haloalkyl, e.g., â€”CHF₂and CF₃. In some embodiments, ring A is pyrimidinyl optionally substituted with halo or â€”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 â€”C₁-C₄haloalkyl, e.g., â€”CHF₂and CF₃. In some embodiments, ring A is pyrazolyl optionally substituted with halo or â€”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 â€”C₁-C₄haloalkyl, e.g., â€”CHF₂and 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 â€”OH, â€”NH₂, â€”CN, â€”Oâ€”C₁-C₄alkyl, â€”NH(C₁-C₄alkyl), or â€”N(C₁-C₄alkyl)₂; R²is â€”(C₀-C₆alkylene)-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 with â€”OH, â€”O(C₁-C₄alkyl), â€”CO₂H, or halo. In some embodiments, R⁴and R⁵taken together form an optionally substituted heterocyclyl optionally substituted with â€”OH, â€”O(C₁-C₄alkyl), â€”CO₂H, 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 independently optionally substituted with â€”OH, â€”NH₂, â€”CN, â€”Oâ€”C₁-C₄alkyl; R²is â€”(C₀-C₆alkylene)-Q; and R⁵is C₁-C₄alkyl. 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 â€”OH, â€”NH₂, â€”CN, â€”Oâ€”C₁-C₄alkyl, â€”SO₂â€”C₁-C₄alkyl, â€”C(O)NH₂, â€”Oâ€”R¹², â€”CO₂R¹²or â€”C(O)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 â€”OH, â€”NH₂, â€”CN, â€”Oâ€”C₁-C₄alkyl, â€”Oâ€”R¹², wherein R¹²is phenyl, pyridyl, or pyrimidinyl; R²is â€”(C₀-C₆alkylene)-Q; and R⁵is C₁-C₄alkyl.

In some embodiments, R⁷is H. In some embodiments, R⁸is H. In some embodiments, both R⁷and R⁸are H.

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

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

[Image Omitted]

wherein:

X is N, CH or C-halo;

X^ais N or Câ€”R^9a, provided that when one X^ais N, then the other two X^aare both Câ€”R^9a;

R⁹is halo, â€”C₁-C₄alkyl, â€”C₁-C₄haloalkyl, â€”C₁-C₄hydroxyalkyl, â€”NHâ€”S(O)₂â€”(C₁-C₄alkyl), â€”S(O)₂NH(C₁-C₄alkyl), â€”CN, â€”S(O)₂â€”(C₁-C₄alkyl), C₁-C₄alkoxy, â€”NH(C₁-C₄alkyl), â€”N(C₁-C₄alkyl)₂, â€”OH, â€”OCF₃, â€”CN, â€”NH₂, â€”C(O)NH₂, â€”C(O)NH(C₁-C₄alkyl), â€”C(O)â€”N(C₁-C₄alkyl)₂, â€”(C₁-C₆alkylene)-Oâ€”(C₁-C₆alkyl), aryl, and cyclopropyl optionally substituted with OH;

each R^9ais independently selected from hydrogen, halo, â€”C₁-C₄alkyl, â€”C₁-C₄haloalkyl, â€”C₁-C₄hydroxyalkyl, â€”NHâ€”S(O)₂â€”(C₁-C₄alkyl), â€”S(O)₂NH(C₁-C₄alkyl), â€”CN, â€”S(O)₂â€”(C₁-C₄alkyl), C₁-C₄alkoxy, â€”NH(C₁-C₄alkyl), â€”N(C₁-C₄alkyl)₂, â€”OH, â€”OCF₃, â€”CN, â€”NH₂, â€”C(O)NH₂, â€”C(O)NH(C₁-C₄alkyl), â€”C(O)â€”N(C₁-C₄alkyl)₂, â€”(C₁-C₆alkylene)-Oâ€”(C₁-C₆alkyl), aryl, and cyclopropyl optionally substituted with OH;

any alkyl or alkylene moiety present in R²and R⁵is optionally substituted with one or more â€”OH, â€”O(C₁-C₄alkyl), â€”CO₂H, or halo;

any terminal methyl moiety present in R²and R⁵is optionally replaced with â€”CH₂OH, CF₃, â€”CH₂F, â€”CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;

R⁷and R⁸are each independently selected from hydrogen and C₁-C₆alkyl; and

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

R¹and R³are optionally taken together with the carbon atom to which they are attached to form C(â• O); or

R⁴and R⁶are optionally taken together with the carbon atom to which they are attached to form C(â• O); or

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

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;

wherein the 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) [2,4â€²-Bipyrimidine]-2â€²,4,6-triamine, N6-[2-(dimethylamino)ethyl]-N2â€²,N2â€²,N4,N4-tetramethyl-; or
(5) [2,4â€²-Bipyrimidine]-2â€²,4,6-triamine, N6-[2-(dimethylamino)ethyl]-N2â€²,N2â€²,N4,N4-tetramethyl-, phosphate.

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

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

[Image Omitted]

wherein:

- R¹, R³, R⁴, and R⁶are each independently selected from hydrogen, C₁-C₄alkyl, C₁-C₄haloalkyl, â€”Oâ€”C₁-C₄alkyl, and CN, wherein each said alkyl moiety of R¹, R³, R⁴, and R⁶are each independently optionally substituted with â€”OH, â€”NH₂, â€”CN, â€”Oâ€”C₁-C₄alkyl, â€”NH(C₁-C₄alkyl), or â€”N(C₁-C₄alkyl)₂;
- R²and R⁵are each independently selected from: â€”(C₁-C₆alkyl), â€”(C₁-C₆alkyl)-C(O)â€”NH₂, â€”(C₁-C₆alkyl)-CO₂H, â€”(C₀-C₆alkylene)-Q, â€”(C₀-C₆alkylene)-C(O)â€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-C(O)â€”(C₀-C₆alkylene)-Q, wherein:
- any alkyl or alkylene moiety present in R²and R⁵is optionally substituted with one or more â€”OH, â€”O(C₁-C₄alkyl), â€”CO₂H, or halo;
- any terminal methyl moiety present in R²and R⁵is optionally replaced with â€”CH₂OH, CF₃, â€”CH₂F, â€”CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;
- R⁷and R⁸are each independently selected from hydrogen and C₁-C₆alkyl;

R⁹is selected from hydrogen, halo, and â€”C₁-C₄haloalkyl; and

- Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
- R¹and R³are optionally taken together with the carbon atom to which they are attached to form C(â• O); or
- R⁴and R⁶are optionally taken together with the carbon atom to which they are attached to form C(â• O); or

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

- R⁴and R⁵are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl;

wherein:

(i) neither N(R⁷)C(R⁴)(R⁵)(R⁶) nor N(R⁸)C(R¹)(R²)(R³) is NHC(O)-[2-chloro-4-(methylsulfonyl)] or N(CH₃)₂,

(ii) N(R⁷)C(R⁴)(R⁵)(R⁶) and N(R⁸)C(R¹)(R²)(R³) are not both NHC(O)C(CH₃)₃, NHC(O)CHâ• CH₂, NHC(O)C(CH₃)â• CH₂, NHCH₂CH₂OH, NH-cyclohexyl, NHCH₂-phenyl, NHC(O)phenyl, NHC(O)(CH₂)₅NH₂, NHC(O)OCH₃, NHC(O)CH₃, and NHC(O)NH-optionally substituted phenyl, and

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

wherein the compound is not:

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

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

[Image Omitted]

wherein:

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

R³and R⁶are both hydrogen;

R¹and R⁴are each independently selected from C₁-C₄alkyl and C₁-C₄haloalkyl; and

R²and R⁵are each â€”(C₁-C₆alkyl); or

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

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

wherein:

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

(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

(iii) the compound is not selected from the group:

(1) 6-(1H-imidazol-1-yl)-N2,N4-bis(1-methylethyl)-1,3,5-Triazine-2,4-diamine, or
(2) N2,N4-bis(1-methylpropyl)-6-phenyl-1,3,5-Triazine-2,4-diamine.
Also provided is a compound of Formula C, or pharmaceutically acceptable salt or hydrate thereof:

[Image Omitted]

wherein:

X is N, CH or C-halo;

each X^bis independently Nâ€”R^9b, O, S, Câ€”H, or Câ€”R⁹, provided that at least one X^bis Câ€”R⁹, and when one X^bis Câ€”H or Câ€”R⁹and the other is Câ€”R^9cthen X^cis N, and when one X^bis Nâ€”R^9b, O, or S, then X^cis C;

R^9bis hydrogen or â€”C₁-C₄alkyl;

R¹, R³, R⁴, and R⁶are each independently selected from hydrogen, C₁-C₄alkyl, C₁-C₄haloalkyl, â€”Oâ€”C₁-C₄alkyl, and CN, wherein each said alkyl moiety of R¹, R³, R⁴, and R⁶are each independently optionally substituted with â€”OH, â€”NH₂, â€”CN, â€”Oâ€”C₁-C₄alkyl, â€”NH(C₁-C₄alkyl), or â€”N(C₁-C₄alkyl)₂;
R²and R⁵are each independently selected from: â€”(C₁-C₆alkyl), â€”(C₁-C₆alkyl)-C(O)â€”NH₂, â€”(C₁-C₆alkyl)-CO₂H, â€”(C₀-C₆alkylene)-Q, â€”(C₀-C₆alkylene)-C(O)â€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-C(O)â€”(C₀-C₆alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R²and R⁵is optionally substituted with one or more â€”OH, â€”O(C₁-C₄alkyl), â€”CO₂H, or halo;
any terminal methyl moiety present in R²and R⁵is optionally replaced with â€”CH₂OH, CF₃, â€”CH₂F, â€”CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;
R⁷and R⁸are each independently selected from hydrogen and C₁-C₆alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R¹and R³are optionally taken together with the carbon atom to which they are attached to form C(â• O); or
R⁴and R⁶are optionally taken together with the carbon atom to which they are attached to form C(â• O); or
R¹and R²are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
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;
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 X^care 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.

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

[Image Omitted]

wherein:

R²and R⁵are each independently selected from: â€”(C₁-C₆alkyl), â€”(C₁-C₆alkyl)-C(O)â€”NH₂, â€”(C₁-C₆alkyl)-CO₂H, â€”(C₀-C₆alkylene)-Q, â€”(C₀-C₆alkylene)-C(O)â€”(C₁-C₆alkyl), â€”(C₀-C₆alkylene)-C(O)â€”(C₀-C₆alkylene)-Q, wherein:

any alkyl or alkylene moiety present in R²and R⁵is optionally substituted with one or more â€”OH, â€”O(C₁-C₄alkyl), â€”CO₂H, or halo;

any terminal methyl moiety present in R²and R⁵is optionally replaced with â€”CH₂OH, CF₃, â€”CH₂F, â€”CH₂Cl, C(O)CH₃, C(O)CF₃, CN, or CO₂H;

R⁷and R⁸are each independently selected from hydrogen and C₁-C₆alkyl;

R⁹is halo or â€”C₁-C₄haloalkyl; and

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

R¹and R³are optionally taken together with the carbon atom to which they are attached to form C(â• O); or

R⁴and R⁶are optionally taken together with the carbon atom to which they are attached to form C(â• O);

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

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

wherein the compound is not:

(1) N2,N2,N4-trimethyl-6-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-1,3,5-Triazine-2,4-diamine, or
(2) N4-ethyl-N2,N2-dimethyl-6-[3-(trifluoromethyl-1H-pyrazol-1-yl]-1,3,5-Triazine-2,4-diamine.
A compound having Formula Ie, or pharmaceutically acceptable salt or hydrate thereof:

[Image Omitted]

wherein
R¹, R³, R⁴, and R⁶are each independently selected from hydrogen, C₁-C₄alkyl, C₁-C₄haloalkyl, â€”Oâ€”C₁-C₄alkyl, and CN, wherein each said alkyl moiety of R¹, R³, R⁴, and R⁶are each independently optionally substituted with â€”OH, â€”NH₂, â€”CN, â€”Oâ€”C₁-C₄alkyl, â€”NH(C₁-C₄alkyl), or â€”N(C₁-C₄alkyl)₂;