WO2015003640A1 - Therapeutically active compounds and their methods of use - Google Patents

Therapeutically active compounds and their methods of use Download PDF

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Publication number
WO2015003640A1
WO2015003640A1 PCT/CN2014/081957 CN2014081957W WO2015003640A1 WO 2015003640 A1 WO2015003640 A1 WO 2015003640A1 CN 2014081957 W CN2014081957 W CN 2014081957W WO 2015003640 A1 WO2015003640 A1 WO 2015003640A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
alkylene
nhch
optionally substituted
phenyl
Prior art date
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PCT/CN2014/081957
Other languages
French (fr)
Inventor
Zenon D. Konteatis
Janeta Popovici-Muller
Jeremy M. Travins
Robert Zahler
Zhenwei CAI
Ding Zhou
Original Assignee
Agios Pharmaceuticals, Inc.
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Family has litigation
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Priority to CN201480046845.2A priority Critical patent/CN105473560B/en
Priority to LTEP14822106.2T priority patent/LT3019483T/en
Priority to DK14822106.2T priority patent/DK3019483T3/en
Priority to CN201911272201.6A priority patent/CN111087353B/en
Priority to EP14822106.2A priority patent/EP3019483B1/en
Priority to EP19209249.2A priority patent/EP3686190A1/en
Priority to JP2016524672A priority patent/JP6538037B2/en
Priority to MYPI2016000020A priority patent/MY175824A/en
Priority to CA2917358A priority patent/CA2917358C/en
Priority to BR122017014843-5A priority patent/BR122017014843B1/en
Priority to NZ715717A priority patent/NZ715717B2/en
Priority to AU2014289744A priority patent/AU2014289744C1/en
Priority to EA201690206A priority patent/EA030199B9/en
Priority to BR112016000561A priority patent/BR112016000561B8/en
Priority to CR20200479A priority patent/CR20200479A/en
Priority to RS20200156A priority patent/RS59922B1/en
Priority to SG11201600185UA priority patent/SG11201600185UA/en
Priority to UAA201601119A priority patent/UA122387C2/en
Priority to KR1020227005567A priority patent/KR102519463B1/en
Priority to ES14822106T priority patent/ES2773321T3/en
Priority to MX2016000360A priority patent/MX369319B/en
Application filed by Agios Pharmaceuticals, Inc. filed Critical Agios Pharmaceuticals, Inc.
Priority to SI201431492T priority patent/SI3019483T1/en
Priority to KR1020167003499A priority patent/KR102366734B1/en
Priority to PL14822106T priority patent/PL3019483T3/en
Priority to TW110137062A priority patent/TWI759251B/en
Priority to TW103123881A priority patent/TWI692472B/en
Priority to TW107138083A priority patent/TWI756482B/en
Priority to US14/328,885 priority patent/US9579324B2/en
Publication of WO2015003640A1 publication Critical patent/WO2015003640A1/en
Priority to IL243494A priority patent/IL243494B/en
Priority to PH12016500077A priority patent/PH12016500077A1/en
Priority to SA516370384A priority patent/SA516370384B1/en
Priority to SA520411465A priority patent/SA520411465B1/en
Priority to ZA2016/00667A priority patent/ZA201600667B/en
Priority to CR20160069A priority patent/CR20160069A/en
Priority to US15/093,345 priority patent/US10028961B2/en
Priority to HK16105978.7A priority patent/HK1217948A1/en
Priority to US15/392,681 priority patent/US10172864B2/en
Priority to US16/167,725 priority patent/US10946023B2/en
Priority to AU2019201179A priority patent/AU2019201179B2/en
Priority to PH12019501197A priority patent/PH12019501197A1/en
Priority to IL267743A priority patent/IL267743B/en
Priority to CY20201100149T priority patent/CY1122671T1/en
Priority to HRP20200274TT priority patent/HRP20200274T1/en
Priority to US17/158,867 priority patent/US11844758B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/48—Two nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate ⁇ i.e., a-ketoglutarate). These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer.
  • IDH1 isocitrate dehydrogenase 1 (NADP+), cytosolic
  • IDP isocitrate dehydrogenase 1
  • IDCD isocitrate dehydrogenase 1
  • PICD protein encoded by this gene
  • the protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence.
  • the presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-dienoyl- CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namelythe alpha-hydroxylation of phytanic acid.
  • the cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production.
  • the human IDHl gene encodes a protein of 414 amino acids.
  • the nucleotide and amino acid sequences for human IDHl can be found as GenBank entries NM 005896.2 and
  • NP 005887.2 respectively.
  • the nucleotide and amino acid sequences for IDHl are also described in, e.g., Nekrutenko etal, Mol. Biol. Evol. 15:1674-1684(1998); Geisbrecht et a/., J. Biol. Chem. 274:30527-30533(1999); Wiemann et al, Genome Res. 11 :422-435(2001); The MGC Project Team, Genome Res.
  • Non-mutant e.g., wild type
  • IDH1 catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate thereby reducing NAD + (NADP + ) to NADH (NADPH), e.g., in the forward reaction:
  • IDH2 isocitrate dehydrogenase 2 (NADP+), mitochondrial
  • IDH isocitrate dehydrogenase 2 (NADP+), mitochondrial
  • IDP isocitrate dehydrogenase 2
  • IDHM isocitrate dehydrogenase 2
  • IDPM isocitrate dehydrogenase 2
  • ICD-M isocitrate dehydrogenase 2
  • mNADP-IDH mNADP-IDH.
  • NADP(+)-dependent isocitrate dehydrogenase found in the mitochondria. It plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with the pyruvate dehydrogenase complex.
  • Human IDH2 gene encodes a protein of 452 amino acids. The nucleotide and amino acid sequences for IDH2 can be found as GenBank entries NM_002168.2 and NP_002159.2 respectively. The nucleotide and amino acid sequence for human IDH2 are also described in, e.g., Huh et al, Submitted (NOV-1992) to the
  • Non-mutant e.g., wild type, IDH2 catalyzes the oxidative decarboxylation of isocitrate to ⁇ -ketoglutarate (a-KG) thereby reducing NAD + (NADP + ) to NADH(NADPH), e.g., in the forward reaction:
  • mutations of IDH2 present in certain cancer cells result in a new ability of the enzyme to catalyze the NAPH-dependent reduction of ⁇ -ketoglutarate to R ⁇ -) -2-hydroxyglutarate (2HG).
  • 2HG is not formed by wild-type IDH2.
  • the production of 2HG is believed to contribute to the formation and progression of cancer (Dang, L et al, Nature 2009, 462:739-44).
  • the inhibition of mutant IDH1 and/or mutant IDH2 and their neoactivity is therefore a potential therapeutic treatment for cancer. Accordingly, there is an ongoing need for inhibitors of IDHland/orIDH2 mutants having alpha hydroxyl neoactivity.
  • ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl
  • X is N, CH or C-halo
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C 1 -C 4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 and R 5 are each independently selected from: -(Ci-d alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(d-
  • alkylene 0-(Ci-C 6 alkyl), -(Ci-C 6 alkylene)-0-(d-C 6 alkylene)-Q, -(C 0 -C 6
  • any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more -OH, -0(d-C 4 alkyl), -C0 2 H, or halo;
  • any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH,
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; wherein:
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 NH 2 ,4-[[2-[2- (2-aminoethoxy)ethoxy]ethyl]amino]and (b) N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH 2 CH 2 CHO, NHCH 2 CH 2 OCH 3 , NHCH 2 CH 2 OH, NHCH 2 CH(OH)CH 3 ,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is N(CH 3 )CH 2 C(0)NH-i-propyl, NHCH(CH 3 )(CH 2 )3N(CH 2 CH 3 ) 2 , NHCH 2 CH 2 OH, NHCH 2 CH 2 OCH 3 , NHCH 2 CH 2 OS0 3 H, NHCH 2 CH 2 CH 2 OCH 2 CH 2 0-phenyl, NHCH 2 CH 2 CH 2 OH, NHCH 2 CH 2 CH 2 OCH 3 ,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHCH 2 -phenyl, NHCH 2 -(2,4-difluorophenyl), N(CH 3 )CH 2 CH 2 C(0)OH, NHCH 2 CH 2 C(0)OH, NHCH 2 CH 2 C(0)OCH 2 CH 3 ,
  • NtR 8 ) ⁇ 1 ) ⁇ 2 ) ⁇ 3 ) is NH(CH 2 ) 7 CH 3 , NHCH 2 -(o-chloro-phenyl), or NHCH 2 CH 2 OH;
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHC(0)-[2-chloro-4-(methylsulfonyl)], N(CH 3 ) 2 , NHCH 2 CH 2 CH 2 S0 2 CH 2 CH 2 Cl,NHCH 2 CH 2 OCH 2 CH 2 S0 2 CH 2 CH 2 Cl,or
  • NHC(0)CH CH 2
  • NHC(0)C(CH 3 ) CH 2
  • NHCH 2 CH 2 OH NH- cyclohexyl
  • NHCH 2 -phenyl NHC(0)phenyl
  • NHC(0)(CH 2 ) 5 NH 2
  • NHC(0)OCH 3 NHC(0)CH 3
  • NHC(0)NH-optionally substituted phenyl and (C) when N(R 7 )C(R 4 )(R 5 )(R 6 ) is NHC(CH 3 ) 3 , then N(R 8 )C(R 1 )(R 2 )(R 3 ) is not NHCH 2 -phenyl or NH-CH 2 CH 3 ;
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both N(CH 2 CH 3 ) 2 , NHCH 2 CH 2 -i-propyl, NHCH 2 CH(CH 3 ) 2 , and NHC(0)CH 3 ;
  • (xiii) ring A is not an optionally substituted triazolyl, 3, 5 -dimethyl- lH-pyrazol-l -yl;
  • compositions comprising a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, ⁇ , ⁇ , Ilia, Illb, IIIc, and Illd, or as described in any one of the embodiments herein inhibits mutant IDHlor mutant IDH2.
  • pharmaceutical compositions comprising a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, ⁇ , III, Ilia, nib, Hie, and Hid, and methods of using such compositions to treat cancers characterized by the presence of a mutant IDHl or mutant IDH2.
  • halo or halogen refers to any radical of fluorine, chlorine, bromine or iodine.
  • alkyl refers to a fully saturated or unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C12 alkyl indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it.
  • haloalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkyl).
  • arylalkyl or “aralkyl” refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group.
  • Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of “arylalkyl” or “aralkyl” include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.
  • alkyl includes “alkenyl” and "alkynyl”.
  • alkylene refers to a divalent alkyl
  • alkenyl refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and having one or more double bonds.
  • 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.
  • alkynyl refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and characterized in having one or more triple bonds.
  • 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.
  • alkoxy refers to an -O-alkyl radical.
  • haloalkoxy refers to an alkoxy in which one or more hydrogen atoms are replaced by halo, and includes alkoxy moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkoxy).
  • aryl refers to a fully aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system. Examples of aryl moieties are phenyl, naphthyl, and anthracenyl. Unless otherwise specified, any ring atom in an aryl can be substituted by one or more substituents.
  • monocyclic aryl means a monocyclic fully romatic hydrocarbon ring system, optionally substituted by one or more substituents which can not form a fused bicyclic or tricyclic ring.
  • carbocyclyl refers to a non-aromatic, monocyclic, bicyclic, or tricyclic hydrocarbon ring system.
  • Carbocyclyl groups include fully saturated ring systems (e.g., cycloalkyls), and partially saturated ring systems. Carbocyclyl groups also include spirocyclic moieties. Examples of spirocyclic moieties include, but are not limited to, bicyclo[3.1.0]hexanyl, spiro[2.2]pentanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, and spiro[3.6]decanyl. Unless otherwise specified, any ring atom in a carbocyclyl can be substituted by one or more substituents.
  • 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).
  • carbocyclyl moieties include, but are not limited to, 2,3-dihydro-lH-indene and 1 ,2,3,4-tetrahydronaphthalene.
  • cycloalkyl as employed herein includes saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12 carbons. Any ring atom can be substituted (e.g., by one or more substituents). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.
  • heteroaryl refers to a fully aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11 -14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (or the oxidized formssuch as IST-O " , S(O) and S(0) 2 ).
  • monocyclic heteroaryl means a monocyclic fully romatic ring systemhaving 1 -3 heteroatoms, optionally substituted by one or more substituents which can not form a fused bicyclic or tricyclic ring.
  • heterocyclyl refers to a nonaromatic, 3-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1 -3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(or the oxidized formssuch as IST-O " , S(O) and S(0) 2 ).
  • the heteroatom may optionally be the point of attachment of the heterocyclyl substituent.
  • heterocyclyl examples 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), areoptionally substituted at one or more substitutable atoms with, unless specified otherwise, substituents independently selected from: halo, -C ⁇ N, d-C 4 alkyl,
  • any alkyl substituent is optionally further substituted with one or more of -OH, -0-(d-C 4 alkyl), halo, -NH 2 , -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • each R b is independently selected from hydrogen, and -Ci-C alkyl; or two R b s 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 b is independently selected from C 3 -C 7 carbocyclyl, phenyl, heteroaryl, and heterocyclyl, wherein one or more substitutablepositions on said phenyl, cycloalkyl, heteroaryl or heterocycle substituent is optionally further substituted with one or more of -(Ci-C 4 alkyl), -(C 1 -C4 fluoroalkyl), -OH, -0-(C C 4 alkyl), -0-(Ci-C 4 fluoroalkyl),
  • Heterocyclyl groups either alone or as part of a group,are optionally substituted on one or more any substitutable nitrogen atom with oxo,-Ci-C 4 alkyl, or fluoro-substituted C 1 -C4 alkyl.
  • the term “substituted” refers to the replacement of a hydrogen atom by another group.
  • the term "bodily fluid” includes one or more of amniotic fluid surrounding a fetus, aqueous humour, blood (e.g., blood plasma), serum, Cerebrospinal fluid, cerumen, chyme, Cowper's fluid, female ejaculate, interstitial fluid, lymph, breast milk, mucus (e.g., nasal drainage or phlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal secretion, or vomit.
  • blood e.g., blood plasma
  • serum Cerebrospinal fluid
  • cerumen cerumen
  • chyme chyme
  • Cowper's fluid female ejaculate
  • interstitial fluid lymph, breast milk
  • mucus e.g., nasal drainage or phlegm
  • pleural fluid pus, saliva, se
  • inhibitor or “prevent” include both complete and partial inhibition and prevention.
  • An inhibitor may completely or partially inhibit the intended target.
  • treat means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease/disorder (e.g., a cancer), lessen the severity of the disease/disorder (e.g., acancer) or improve the symptoms associated with the disease/disorder (e.g., a cancer).
  • a disease/disorder e.g., a cancer
  • lessen the severity of the disease/disorder e.g., acancer
  • improve the symptoms associated with the disease/disorder e.g., a cancer
  • an amount of a compound effective to treat a disorder 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.
  • subject 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.
  • a disorder e.g., a disorder described herein or a normal subject.
  • non -human animals 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.
  • ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl
  • X is N, CH or C-halo
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C 1 -C 4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 and R 5 are each independently selected from: -(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(Ci- C 6 alkyl)-C0 2 H, -(C 2 -C 6 alkenyl or alkynyl), -(Ci-C 6 alkylene)-N(R 6 )-(d-C 6 alkylene)-0-(d-C 6 alkyl), -(C C 6 alkylene)-N(R 6 )-(C 0 -C 6 alkylene)-Q, -(Ci-C 6 alkylene)-N(R 6 )(R 6 ), -(d-C 6 alkylene)-N(R 6 )-S(0)i -2 -(Ci-C 6 alkyl), -(Ci-C 6 alkylene)-N(R 6 )-S(O)i -2 -(C 0 -C 6 alkyl
  • alkylene 0-(Ci-C 6 alkyl), -(Ci-C 6 alkylene)-0-(d-C 6 alkylene)-Q, -(C 0 -C 6
  • any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH,
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; wherein:
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 NH 2 , 4-[[2-[2- (2-aminoethoxy)ethoxy]ethyl]amino] and (b) N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH 2 CH 2 CHO, NHCH 2 CH 2 OCH 3 , NHCH 2 CH 2 OH, NHCH 2 CH(OH)CH 3 ,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is N(CH 3 )CH 2 C(0)NH-i-propyl, NHCH(CH 3 )(CH 2 ) 3 N(CH 2 CH 3 ) 2 , NHCH 2 CH 2 OH, NHCH 2 CH 2 OCH 3 , NHCH 2 CH 2 OS0 3 H, NHCH 2 CH 2 CH 2 OCH 2 CH 2 0-phenyl, NHCH 2 CH 2 CH 2 OH, NHCH 2 CH 2 CH 2 OCH 3 ,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHCH 2 -phenyl, NHCH 2 -(2,4-difluorophenyl), N(CH 3 )CH 2 CH 2 C(0)OH, NHCH 2 CH 2 C(0)OH, NHCH 2 CH 2 C(0)OCH 2 CH 3 ,
  • NtR 8 ) ⁇ 1 ) ⁇ 2 ) ⁇ 3 ) is NH(CH 2 ) 7 CH 3 , NHCH 2 -(o-chloro-phenyl), or NHCH 2 CH 2 OH;
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHC(0)-[2-chloro-4-(methylsulfonyl)], N(CH 3 ) 2 , NHCH 2 CH 2 CH 2 S0 2 CH 2 CH 2 C1, NHCH 2 CH 2 OCH 2 CH 2 S0 2 CH 2 CH 2 Cl,or
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both NHC(0)C(CH 3 ) 3
  • NHC(0)CH CH 2
  • NHC(0)C(CH 3 ) CH 2
  • NHC(0)CH 3 NHC(0)CH 2 CH 2 S0 2 CH 2 CH 2 C1
  • NHC(0)NH-optionally substituted phenyl and (C) when N(R 7 )C(R 4 )(R 5 )(R 6 ) is NHC(CH 3 ) 3 , then N(R 8 )C(R 1 )(R 2 )(R 3 ) is not NHCH 2 -phenyl or NH-CH 2 CH 3 ;
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both N(CH 2 CH 3 ) 2 , NHCH 2 CH 2 -i-propyl, NHCH 2 CH(CH 3 ) 2 , and NHC(0)CH 3 ;
  • N(R 8 )C(R 1 )(R 2 )(R 3 ) is not NHCH 2 (4-fluorophenyl), NHCH 2 C0 2 H, NHCH 2 C(0)C1, NHCH(C0 2 H)(CH 2 SCH 2 phenyl), or NHCH 2 C(0)NHC(0)NHR or NHCH 2 C(0)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl,
  • (xiii) ring A is not an optionally substituted triazolyl, 3, 5 -dimethyl- lH-pyrazol-l -yl,
  • ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl
  • X is N, CH or C-halo
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, -O-C 1 -C 4 alkyl, and CN, wherein any alkyl portion of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C1-C4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 and R 5 are each independently selected from: -(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(Ci-Cg alkyl)-C0 2 H -(C 2 -C 6 alkenyl or alkynyl), -(Ci-C 6 alkylene)-N(R 6 )-(Ci-C 6
  • alkylene 0-(Ci-C 6 alkyl), -(Ci-Cg alkylene)-N(R 6 )-(C 0 -C 6 alkylene)-Q, -(Ci-Cg
  • alkylene 0-(Ci-C 6 alkylene)-Q, -(Ci-Cg alkylene)-0-C(0)-(d-C 6 alkyl), -(d-C 6
  • any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more -OH, -0(Ci-C 4 alkyl), -C0 2 H, or halo;
  • any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH,
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is 4-[[2-[2-(2-aminoethoxy)ethoxy]ethyl]amino] and (b) N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both NHEt, NH(n-propyl), NH(n- butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH 2 CH 2 CHO, NHCH 2 CH 2 OCH 3 , NHCH 2 CH 2 OH, NHCH 2 CH(OH)CH 3 , NHCH 2 CH 2 OC(0)phenyl, NHCH 2 CH 2 CH 2 OH,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is N(CH 3 )CH 2 C(0)NH-i-propyl, NHCH(CH 3 )(CH 2 )3N(CH 2 CH 3 ) 2 , NHCH 2 CH 2 OH, NHCH 2 CH 2 OCH 3 , NHCH 2 CH 2 OS0 3 H, NHCH 2 CH 2 CH 2 OCH 2 CH 2 0-phenyl, NHCH 2 CH 2 CH 2 OH, NHCH 2 CH 2 CH 2 OCH 3 ,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHCH 2 -phenyl, NHCH 2 -(2,4-difluorophenyl), N(CH 3 )CH 2 CH 2 C(0)OH, NHCH 2 CH 2 C(0)OH, NHCH 2 CH 2 C(0)OCH 2 CH 3 ,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both N(CH 2 CH 3 ) 2 , NHCH 2 CH 2 -i-propyl, NHCH 2 CH(CH 3 ) 2 , and NHC(0)CH 3 ;
  • ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl; X is N or CH;
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein any alkyl portion of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C1-C4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 and R 5 are each independently selected from: -(d-C 6 alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(Ci-C 6 alkyl)-C0 2 H -(C 2 -C 6 alkenyl or alkynyl), -(C C 6 alkylene)-N(R 6 )-(Ci-C 6
  • any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more -OH, -0(d-C 4 alkyl), -C0 2 H, or halo;
  • any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH,
  • R 7 and R 8 are each independently selected from hydrogen and d-C 6 alkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is 4-[[2-[2-(2-aminoethoxy)ethoxy]ethyl]amino] and (b) N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both NHEt, NH(n-propyl), NH(n- butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH 2 CH 2 CHO, NHCH 2 CH 2 OCH 3 , NHCH 2 CH 2 OH, NHCH 2 CH(OH)CH 3 , NHCH 2 CH 2 OC(0)pheny
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is N(CH 3 )CH 2 C(0)NH-i-propyl, NHCH(CH 3 )(CH 2 ) 3 N(CH 2 CH 3 ) 2 , NHCH 2 CH 2 OH, NHCH 2 CH 2 OCH 3 , NHCH 2 CH 2 OS0 3 H, NHCH 2 CH 2 CH 2 OCH 2 CH 2 0-phenyl, NHCH 2 CH 2 CH 2 OH, NHCH 2 CH 2 CH 2 OCH 3 ,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHCH 2 -phenyl, NHCH 2 -(2,4-difluorophenyl), N(CH 3 )CH 2 CH 2 C(0)OH, NHCH 2 CH 2 C(0)OH, NHCH 2 CH 2 C(0)OCH 2 CH 3 ,
  • NtR 8 ) ⁇ 1 ) ⁇ 2 ) ⁇ 3 ) is NH(CH 2 ) 7 CH 3 , NHCH 2 -(o-chloro-phenyl), or NHCH 2 CH 2 OH;
  • ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl
  • X is N or CH
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C1-C4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 and R 5 are each independently selected from: -(Ci-d alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(d- C 6 alkyl)-C0 2 H, -(C 2 -C 6 alkenyl or alkynyl), -(Ci-C 6 alkylene)-N(R 6 )-(d-C 6 alkylene)-0-(d-C 6 alkyl), -(d-C 6 alkylene)-N(R 6 )-(C 0 -C 6 alkylene)-Q, -(Ci-C 6 alkylene)-N(R 6 )(R 6 ), -(d-C 6 alkylene)-N(R 6 )-S(0)i -2 -(Ci-C 6 alkyl), -(Ci-C 6 alkylene)-N(R 6 )-S(O)i -2 -(C 0 -C 6 alkyl)
  • alkylene 0-(Ci-C 6 alkylene)-Q, -(Ci-Ce alkylene)-0-C(0)-(d-C 6 alkyl), -(d-C 6
  • any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more -OH, -0(Ci-C 4 alkyl), -C0 2 H, or halo;
  • any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH,
  • R 7 and R 8 are each independently selected from hydrogen and C1-C6 alkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; wherein:
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 NH 2 , 4-[[2-[2- (2-aminoethoxy)ethoxy]ethyl]amino] and (b) N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH 2 CH 2 CHO, NHCH 2 CH 2 OCH 3 , NHCH 2 CH 2 OH, NHCH 2 CH(OH)CH 3 ,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is N(CH 3 )CH 2 C(0)NH-i-propyl, NHCH(CH 3 )(CH 2 ) 3 N(CH 2 CH 3 ) 2 , NHCH 2 CH 2 OH, NHCH 2 CH 2 OCH 3 , NHCH 2 CH 2 OS0 3 H, NHCH 2 CH 2 CH 2 OCH 2 CH 2 0-phenyl, NHCH 2 CH 2 CH 2 OH, NHCH 2 CH 2 CH 2 OCH 3 , NHCH 2 CH(OH)CH 3 , N(CH 2 CH 3 ) 2 , NH-i-propyl, NHCH 2 CH 2 NHC(0)OCH 3 ,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHCH 2 -phenyl, NHCH 2 -(2,4-difluorophenyl), N(CH 3 )CH 2 CH 2 C(0)OH, NHCH 2 CH 2 C(0)OH, NHCH 2 CH 2 C(0)OCH 2 CH 3 ,
  • NtR 8 ) ⁇ 1 ) ⁇ 2 ) ⁇ 3 ) is NH(CH 2 ) 7 CH 3 , NHCH 2 -(o-chloro-phenyl), or NHCH 2 CH 2 OH;
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHC(0)-[2-chloro-4-(methylsulfonyl)],
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both NHC(0)C(CH 3 ) 3
  • NHC(0)CH CH 2
  • NHC(0)C(CH 3 ) CH 2
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) is NHC(CH 3 ) 3
  • N(R 8 )C(R 1 )(R 2 )(R 3 ) is not NHCH 2 -phenyl or
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both N(CH 2 CH 3 ) 2 , NHCH 2 CH 2 -i-propyl, NHCH 2 CH(CH 3 ) 2 , and NHC(0)CH 3 ;
  • NCR ⁇ CCR 1 ) ⁇ 2 ) ⁇ 3 ) is not NHCH 2 (4-fluorophenyl), NHCH 2 C0 2 H, NHCH 2 C(0)C1, NHCH(C0 2 H)(CH 2 SCH 2 phenyl), or NHCH 2 C(0)NHC(0)NHR or
  • ring A is not an optionally substituted triazolyl, 3,5-dimethyl-lH-pyrazol-l-yl,
  • ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C 1 -C 4 alkyl, and CN, wherein any alkyl portion of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C 1 -C 4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 and R 5 are each independently selected from: -(Ci-d alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(d-
  • alkylene 0-(Ci-C 6 alkyl), -(Ci-C 6 alkylene)-0-(d-C 6 alkylene)-Q, -(C 0 -C 6
  • any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more -OH, -0(d-C 4 alkyl), -C0 2 H, or halo;
  • any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH,
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH 2 CH 2 CHO, NHCH 2 CH 2 OCH 3 , NHCH 2 CH 2 OH, NHCH 2 CH(OH)CH 3 , NHCH 2 CH 2 OC(0)phenyl, NHCH 2 CH 2 CH 2 OH,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both N(CH 2 CH 3 ) 2 , NHCH 2 CH 2 -i-propyl, NHCH 2 CH(CH 3 ) 2 , and NHC(0)CH 3 ;
  • ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C1-C4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 and R 5 are each independently selected from: -(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(Ci-Cg alkyl)-C0 2 H -(C 2 -C 6 alkenyl or alkynyl), -(Ci-C 6 alkylene)-N(R 6 )-(Ci-C 6
  • alkylene 0-(Ci-C 6 alkyl), -(Ci-Cg alkylene)-N(R 6 )-(C 0 -C 6 alkylene)-Q, -(Ci-Cg
  • alkylene 0-(Ci-C 6 alkylene)-Q, -(Ci-Cg alkylene)-0-C(0)-(d-C 6 alkyl), -(d-C 6
  • any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more -OH, -0(Ci-C 4 alkyl), -C0 2 H, or halo; any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH,
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; wherein:
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor NtR 8 ) ⁇ 1 ) ⁇ 2 ) ⁇ 3 ) is NHCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 NH 2 or 4-[[2-[2-(2- aminoethoxy)ethoxy]ethyl]amino] and (b) N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH 2 CH 2 CHO, NHCH 2 CH 2 OCH 3 , NHCH 2 CH 2 OH, NHCH 2 CH(OH)CH 3 ,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both NHC(0)C(CH 3 ) 3
  • NHC(0)CH CH 2
  • NHC(0)C(CH 3 ) CH 2
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) is NHC(CH 3 ) 3
  • N(R 8 )C(R 1 )(R 2 )(R 3 ) is not NHCH 2 -phenyl or
  • NtR 8 ) ⁇ 1 ) ⁇ 2 ) ⁇ 3 ) are not both N(CH 2 CH 3 ) 2 , NHCH 2 CH 2 -i-propyl, NHCH 2 CH(CH 3 ) 2 , and NHC(0)CH 3 ;
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHcyclohexylC(0)NHCH 2 R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF 3 , OCH 3 , chloro, or CF 3 ,
  • (ix) ring A is not an optionally substituted triazolyl, 3,5-dimethyl-lH-pyrazol-l -yl,
  • R and R 4 are eachindependently selected from
  • R 1 and R 2 are taken together to form a carbocyclyl or heterocyclyl, either of which is optionally substituted with aryl or heteroaryl, which is optionally substituted with up to 2 substituents independently selected from halo, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy, -CN, and -OH.
  • R 1 and R 2 are taken together to form a carbocyclyl or heterocyclyl, either of which is optionally substituted with phenyl, pyridinyl or pyrimidinyl, which is optionally substituted with up to 2 substituents independently selected from halo, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy, -CN, and -OH.
  • R 1 and R 2 are taken together to form a carbocyclyl or heterocyclyl, either of which is optionally substituted with aryl or heteroaryl, which is optionally substituted with up to 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, and -OH.
  • R 1 and R 2 are 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, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, -CN, and -OH.
  • R 2 and R 5 are each independently selected from: -(Ci-C 6 alkyl), - (Ci-C 6 alkyl)-C(0)-NH 2 , -(Ci-C 6 alkyl)-C0 2 H -(C 2 -C 6 alkenyl or alkynyl), -(Ci-C 6
  • R 2 and R 5 are each independently selected from: -(C 1 -C 4 alkyl) optionally substituted with halo, e.g., fluoro or -OH;-(C 0 -C 4 alkylene)-0-(Ci-C 4 alkyl), -(C 0 -C 2 alkylene)-N(R 6 )-(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-C(O)-NH 2 ,-(C 0 -C 2 alkylene)-Q, -(C 0 -C 6
  • Q is selected from pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl and oxetanyl, wherein Q is optionally substituted with up to 2
  • R 1 and R 2 are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl, oxobicyclo[3.1.0]hexanyl, azetidinyl, any of which is optionally substituted with up to 2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy,C3-C6
  • R 4 and R 5 are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl, oxobicyclo[3.1.0]hexanyl, or azetidinyl, any of which is optionally substituted with up to 2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy,C 3 -C 6
  • R 4 and R 5 are taken together to form phenyl, pyrazolyl, imidazolyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, thiadiazolyl or isothiazolyl,any of which is optionally substituted with up to 2 substituents independently selected from halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C3-C6 cycloalkyl, phenyl,-OH, -C(0)CH 3 , wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH 2 ,
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C1-C4 alkyl, - NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ; and R 2 and R 5 are each independently selected
  • 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.
  • ring A is a substituted 5-6 member monocyclic aryl or monocyclic heteroaryl, which is substituted with up to two substituents independently selected from halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(0) 2 -(Ci-C 4
  • 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, CF 3 , CF 2 , -OH, -OCH 3 , -OCF 3 , -CN, -NH 2 .
  • ring A is a substituted 6-membered monocyclic aryl.
  • ring A is a substituted 5-6 membered heteroaryl.
  • ring A is a substituted 5-membered heteroaryl.
  • ring A is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, wherein ring A is optionally substituted with up to two substituents independently selected from halo, -Ci-C alkyl, -Ci-C haloalkyl, -Ci-C hydroxyalkyl, -NH-S(0) 2 -(Ci-C 4 alkyl), -S(0) 2 NH(Ci-C 4 alkyl), -CN, -S(0) 2 -(Ci-C 4 alkyl), Ci-C 4 alkoxy, -NH(Ci-C 4 alkyl), -OH, -OCF 3 , -CN, -NH 2 , -C(0)NH 2 , -C(0)NH(Ci-C 4 alkyl), - C(0)-N(Ci-
  • ring A is selected from phenyl, pyrazolyl, imidazolyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl,thiazolyl, thiadiazolyland isothiazolyl, wherein ring A is optionally substituted with up to two substituents independently selected from halo, -Ci-C 4 alkyl, -Ci-C 4 haloalkyl, -Ci-C 4 hydroxyalkyl, -NH-S(0) 2 -(Ci-C 4 alkyl), -S(0) 2 NH(Ci-C 4 alkyl), -CN, -S(0) 2 -(Ci-C 4 alkyl), Ci-C 4 alkoxy, -NH(Ci-C 4
  • ring A is monocyclic heteroaryl optionally substituted with halo, -C 1 -C 4 alkyl, -C 1 -C 4 haloalkyl, -O-C 1 -C 4 haloalkyl, -OH, -CN, and -NH 2 ;
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen and C 1 -C 4 alkyl; and
  • R 2 and R 5 are each independently -(C0-C6 alkylene)-Q; or R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl; orR 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl.
  • ring A is monocyclic heteroaryl optionally substituted with halo, -C 1 -C 4 alkyl, -C 1 -C 4 haloalkyl, -O-C 1 -C 4 haloalkyl, -OH, -CN, and -NH 2 ;
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen and C 1 -C 4 alkyl; and
  • R 2 and R 5 are each independently -(C 0 -C 6 alkylene)-Q; or R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl oran optionally substituted heterocyclyl; orR 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroar l.
  • ring A is: , wherein R is selected from hydrogen, halo, and -C 1 -C 4 haloalkyl; each X a is independently N or C-R 9a , provided that when one X a is N, then the other two X a are both C-R 9a ; and R 9a is selected from hydrogen, halo, and -C 1 -C 4 haloalkyl.
  • ring A is: , wherein R 9 is selected from hydrogen, halo,
  • ring A is: , wherein R 9 is selected from h drogen, halo, and -C 1 -C 4 haloalkyl. In some embodiments, ring A is:
  • halo is selected from hydrogen, halo, and -C 1 -C 4 haloalkyl.
  • ring A is pyridinyl optionally substituted with halo or -C 1 -C 4 haloalkyl. In some embodiments, ring A is pyridinyl optionally substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyridi -2-yl substituted with -C 1 -C 4 haloalkyl, e.g., -CHF 2 and
  • ring A is: wherein R is selected from hydn halo, and -C 1 -C4 haloalkyl. In some embodiments, ring A is: , wherein each R 9 is independently selected from hydrogen, halo, and -C 1 -C4 haloalkyl. In some embodiments, R 9 is chloro or fluoro. In some embodiments, R 9 is -CHF 2 or CF 3 . In some embodiments, R 9 is CF 3 or chloro. In some embodiments, R 9 is CF 3 .
  • ring A is: is selected from hydrogen and -C 1 -C4 alkyl, and wherein R 9 is selected from hydrogen, halo, and -C 1 -C4 haloalkyl.
  • ring A is: , wherein R is selected from hydrogen and -C 1 -C4 alkyl, and wherein R is selected from h drogen, halo, and -C 1 -C4 haloalkyl.
  • ring A is: , wherein R is selected from hydrogen and -C 1 -C4 alkyl, and wherein R is selected from hydrogen, halo, and -C 1 -C4 haloalkyl.
  • ring A is: , wherein R is selected from hydrogen, halo, and -C 1 -C4 haloalkyl. In some embodiments, ring A is pyrazolyl optionally substituted with halo or -C 1 -C4 haloalkyl. In some embodiments, ring A is pyrazolyl optionally substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is IH-pyrazol-l- l substituted with -C 1 -C4
  • haloalkyl e.g., -CHF 2 and CF 3 .
  • ring A is: , wherein R is selected from hydrogen, halo, and -C 1 -C4 haloalkyl.
  • R 9 is chloro or fluoro.
  • R 9 is -CHF 2 or CF 3 .
  • R 9 is CF 3 or chloro.
  • R 9 is CF 3 .
  • ring A is: , wherein R is selected from hydrogen, halo, and -C 1 -C4 haloalkyl.
  • ring A is: wherein R 9 is selected from hydi halo, and -C 1 -C4 haloalkyl.
  • ring A is: , wherein R is selected from hydrogen, halo, and -C 1 -C4 haloalkyl.
  • ring A is: is selected from hydrogen, halo, and -C 1 -C4 haloalkyl.
  • ring A is: , wherein R is selected from hydrogen, halo, and -C1-C4 haloalkyl.
  • ring A is: , wherein R 9 is selected from hyd:
  • ring A is: , wherein R 9 is selected from hydrogen, halo, and -C 1 -C 4 haloalkyl.
  • ring A is pyridinyl optionally substituted with halo or -C 1 -C 4 haloalkyl. In some embodiments, ring A is pyridinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyridinyl substituted with -C 1 -C 4 haloalkyl, e.g., -CHF 2 and CF 3 . In some embodiments, ring A is pyrazinyl optionally substituted with halo or -C 1 -C 4 haloalkyl.
  • ring A is pyrazinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazinyl substituted with -C 1 -C 4 haloalkyl, e.g., -CF£F 2 and CF 3 . In some embodiments, ring A is pyrimidinyl optionally substituted with halo or -C 1 -C 4 haloalkyl. In some embodiments, ring A is pyrimidinyl substituted with halo, e.g., chloro or fluoro.
  • ring A is pyrimidinyl substituted with -C 1 -C 4 haloalkyl, e.g., -CF£F 2 and CF 3 .
  • ring A is pyrazolyl optionally substituted with halo or -C 1 -C 4 haloalkyl.
  • ring A is pyrazolyl substituted with halo, e.g., chloro or fluoro.
  • ring A is pyrazolyl substituted with -C 1 -C 4 haloalkyl, e.g., -CF£F 2 and CF 3 .
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen and C 1 -C 4 alkyl; and R 2 and R 5 are each independently -(C 0 -C 6 alkylene)-Q.
  • R 1 and R 4 are each hydrogen.
  • R 3 and R 6 are each C 1 -C 4 alkyl.
  • R 3 and R 6 are each C 1 -C 4 haloalkyl.
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted. In some embodiments, Q is optionally substituted carbocyclyl.
  • Q is optionally substituted cyclopropyl. In some embodiments, Q is unsubstituted cyclopropyl. In some embodiments, R 2 and R 5 are each independently unsubstituted cyclopropyl. In some
  • R 1 and R 4 are each hydrogen, R 3 and R 6 are each -CH 3 , and R 2 and R 5 are each unsubstituted cyclopropyl.
  • R 2 is -(C0-C6 alkylene)-cyclopropyl and R 5 is -(C 0 -C 6 alkyl en e)-aryl, e.g., optionally substituted phenyl.
  • R 2 is cyclopropyl and R 5 is phenyl substituted with halo, e.g., fluoro.
  • ring A is pyridinyl optionally substituted with halo or -C 1 -C 4 haloalkyl. In some embodiments, ring A is pyridinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyridinyl substituted with -C 1 -C 4 haloalkyl, e.g., -CHF 2 and CF 3 . In some embodiments, ring A is pyrazinyl optionally substituted with halo or -C 1 -C 4 haloalkyl.
  • ring A is pyrazinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazinyl substituted with -C 1 -C 4 haloalkyl, e.g., -CHF 2 and CF 3 . In some embodiments, ring A is pyrimidinyl optionally substituted with halo or -C 1 -C 4 haloalkyl. In some embodiments, ring A is pyrimidinyl substituted with halo, e.g., chloro or fluoro.
  • ring A is pyrimidinyl substituted with -C 1 -C 4 haloalkyl, e.g., -CHF 2 and CF 3 .
  • ring A is pyrazolyl optionally substituted with halo or -C 1 -C 4 haloalkyl.
  • ring A is pyrazolyl substituted with halo, e.g., chloro or fluoro.
  • ring A is pyrazolyl substituted with -C 1 -C 4 haloalkyl, e.g., -CF£F 2 and CF 3 .
  • R 3 and R 6 are each independently selected from hydrogen and C 1 -C 4 alkyl; R 1 and R 2 are taken together to form an optionally substituted carbocyclyl; and R 4 and R 5 are taken together to form an optionally substituted carbocyclyl.
  • R 1 and R 2 are taken together to form a cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted.
  • R 1 and R 2 are taken together to form a cyclopentyl or cyclohexyl, each optionally substituted.
  • R 4 and R 5 are taken together to form a cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted. In some embodiments, R 4 and R 5 are taken together to form a cyclopentyl or cyclohexyl, each optionally substituted. In some embodiments, R 1 and R 2 are taken together to form a cyclopentyl or cyclohexyl, each substituted by one or more halo, e.g., fluoro; and R 4 and R 5 are taken together to form a cyclobutyl, cyclopentyl or cyclohexyl, each substituted by one or more halo, e.g., fluoro.
  • R 1 and R 2 are taken together to form a bicyclo[3.1.OJhexanyl; and R 4 and R 5 are taken together to form a bic clo[3.1.O hexanyl.In some embodiments, R 1 and R 2 taken together,
  • R 1 and R 2 taken together, and R 4 and R 5 taken together form: .
  • R 1 and R 2 are 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.
  • R 4 and R 5 are 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.
  • R 3 are taken together form: , wherein Ring C is phenyl, pyridyl, or pyrimidinyl, which is optionally substituted with cyano or halo, e.g. fluoro, chloro, or bromo.
  • Ring C is phenyl, pyridyl, or pyrimidinyl, which is optionally substituted with cyano or halo, e.g. fluoro, chloro, or bromo.
  • R 1 and R 2 or R 4 and R 5 are taken together form:
  • Ring C is phenyl, pyridyl, or pyrimidinyl, which is optionally substituted with cyano or halo, e.g. fluoro, chloro, or bromo.
  • R 1 and R 2 or R 4 and R 5 are taken
  • phenyl, pyridyl, or pyrimidinyl which is optionally substituted with cyano or halo, e.g. fluoro, chloro, or bromo.
  • ring A is pyridinyl optionally substituted with halo or -C 1 -C4 haloalkyl. In some embodiments, ring A is pyridinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyridinyl substituted with -C 1 -C4 haloalkyl, e.g., -CHF 2 and CF 3 . In some embodiments, ring A is pyrazinyl optionally substituted with halo or -C 1 -C 4 haloalkyl.
  • ring A is pyrazinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazinyl substituted with -C 1 -C 4 haloalkyl, e.g., -CHF 2 and CF 3 . In some embodiments, ring A is pyrimidinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrimidinyl substituted with halo, e.g., chloro or fluoro.
  • ring A is pyrimidinyl substituted with -C 1 -C 4 haloalkyl, e.g., -CF£F 2 and CF 3 .
  • ring A is pyrazolyl optionally substituted with halo or -C1-C4 haloalkyl.
  • ring A is pyrazolyl substituted with halo, e.g., chloro or fluoro.
  • ring A is pyrazolyl substituted with -C 1 -C 4 haloalkyl, e.g., -CF£F 2 and CF 3 .
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, and -CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C 1 -C 4 alkyl; and R 2 and R 5 are each
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C1-C4 alkyl, and -CN; and R 2 and R 5 are each independently -(Ci-C 6 alkyl) and -(C 0 -C 6 alkylene)-Q.
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, and -CN; R 2 is -(Ci-C 6 alkyl); and R 5 is -(C0-C6 alkylene)-Q, wherein Q is optionally substituted carbocyclyl. In some embodiments, Q is unsubstituted carbocyclyl. In some embodiments, Q is cyclopropyl.
  • ring A is pyridinyl optionally substituted with halo or -C 1 -C 4 haloalkyl. In some embodiments, ring A is pyridinyl substituted with -C 1 -C 4 haloalkyl, e.g., -CF£F 2 and CF 3 . In some embodiments, ring A is pyrazinyl optionally substituted with halo or -C 1 -C 4 haloalkyl. In some embodiments, ring A is pyrazinyl substituted with halo, e.g., chloro or fluoro.
  • ring A is pyrazinyl substituted with -C 1 -C 4 haloalkyl, e.g., -CF£F 2 and CF 3 .
  • ring A is pyrimidinyl optionally substituted with halo or -C1-C4 haloalkyl.
  • ring A is pyrimidinyl substituted with halo, e.g., chloro or fluoro.
  • ring A is pyrimidinyl substituted with -C 1 -C 4 haloalkyl, e.g., -CF£F 2 and CF 3 .
  • ring A is pyrazolyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrazolyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazolyl substituted with -C 1 -C 4 haloalkyl, e.g., -CF£F 2 and CF 3 .
  • R 1 , R 3 , and R 6 are each independently selected from hydrogen and C 1 -C 4 alkyl, wherein each said alkyl moiety of R 1 , R 3 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C1-C4 alkyl, -NH(Ci-C 4 alkyl), or -N(d-C 4 alkyl) 2 ; R 2 is -(C0-C6 alkylene)-Q; and R 4 and R 5 taken together form an optionally substituted carbocyclyl, optionally substituted heterocyclyl or optionally substituted heteroaryl. In some embodiments, R 4 and R 5 taken together form an optionally substituted carbocyclyl. In some embodiments, the carbocyclyl is selected from cyclopentyl and cyclohexyl optionally substituted
  • R 1 , R 3 , and R 6 are each independently selected from hydrogen and C 1 -C 4 alkyl, wherein each said alkyl moiety of R 1 , R 3 , and R 6 are each
  • R 2 is -(C 0 -C 6 alkylene)-Q; and R 5 is C1-C4 alkyl.
  • R 1 , R 3 , and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, or carbocyclyl, wherein any alkyl or carbocyclyl portion of R 1 , R 3 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C 1 -C 4 alkyl, -S0 2 -Ci-C 4 alkyl, -C(0)NH 2 , -0-R 12 ,-C0 2 R 12 or -C(0)R 12 , wherein R 12 is morpholino, piperidinyl, phenyl, pyridyl, or pyrimidinyl.
  • R 1 , R 3 , and R 6 are each independently selected from hydrogen and C 1 -C 4 alkyl, wherein each said alkyl moiety of R 1 , R 3 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C 1 -C 4 alkyl, -O- R 12 , wherein R 12 is phenyl, pyridyl, or pyrimidinyl; R 2 is -(C 0 -C 6 alkylene)-Q; and R 5 is C 1 -C 4 alkyl.
  • R 7 is H. In some embodiments, R 8 is H. In some embodiments, both R 7 and R 8 are H.
  • ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are selected from any one of the preceding embodiments.
  • X isN, CH or C-halo
  • X a is N or C-R 9a , provided that when one X a is N, then the other two X a are both C-R 9a ;
  • R 9 is halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(0) 2 -(Ci-C 4
  • each R 9a is independently selected from hydrogen, halo, -C 1 -C 4 alkyl, -C 1 -C 4 haloalkyl, -C 1 -C 4 hydroxyalkyl, -NH-S(0) 2 -(Ci-C 4 alkyl), -CN, -S(0) 2 -(d-C 4 alkyl), C1-C4 alkoxy, -NH(Ci-C 4 alkyl), - N(Ci-C 4 alkyl) 2 , -OH, -OCF 3 , -CN, -NH 2 , -C(0)NH 2 , -C(0)NH(Ci-C 4 alkyl), -C(0)-N(d-C 4 alkyl) 2 , -(Ci-C 6 alkylene)-0-(Ci-C 6 alkyl), aryl, and cyclopropyl optionally substituted with OH; each R 9a is independently selected from hydrogen, halo, -C
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C 1 -C 4 alkyl, -NH(d-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 and R 5 are each independently selected from: -(Ci-d alkyl), -(Ci-d alkyl)-C(0)-NH 2 , -(d- C 6 alkyl)-C0 2 H -(C 2 -C 6 alkenyl or alkynyl), -(Ci-C 6 alkylene)-0-(d-C 6 alkyl), -(C 0 -C 6 alkylene)-C(0)N(R 6 )-(Ci-C 6 alkyl),
  • any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more -OH, -0(d-C 4 alkyl), -C0 2 H, or halo; any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH,
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, an optionally substituted 5-6 member monocyclic aryl, or an optionally substituted 5-6 member monocyclic heteroaryl;
  • X is N and R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C1-C4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 and R 5 are each independently selected from: -(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(Ci-Cg alkyl)-C0 2 H -(Co-Cg alkylene)-Q, -(C 0 -C 6 alkylene)-C(0)-(d-C 6 alkyl), -(C 0 -C 6 alkylene)-C(O)-(C 0 -C 6 alkylene)-Q, wherein:
  • any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more -OH, -0(d-C 4 alkyl), -C0 2 H, or halo;
  • any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH, CF 3 , -CH 2 F, -CH 2 C1, C(0)CH 3 , C(0)CF 3 , CN, or C0 2 H;
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • R 9 is selected from hydrogen, halo, and -C1-C4 haloalkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl; or
  • R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl;
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor NCR ⁇ CCR 1 ) ⁇ 2 ) ⁇ 3 ) is NHC(0)-[2-chloro-4-(methylsulfonyl)] or N(CH 3 ) 2 ,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both NHC(0)C(CH 3 ) 3 ,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) is NHC(CH 3 ) 3 , then N(R 8 )C(R 1 )(R 2 )(R 3 ) is not NHCH 2 -phenyl or NH-CH 2 CH 3 ;
  • ring A is is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl
  • R 3 and R 6 are both hyd: R 1 and R 4 are each independently selected from C 1 -C 4 alkyl and C 1 -C 4 haloalkyl;and R 2 and R 5 are each -(Ci-C 6 alkyl); or
  • R 1 and R 2 are optionally taken together to form an optionally substituted monocyclic carbocyclyl
  • R 4 and R 5 are optionally taken together to form an optionally substituted monocyclic carbocyclyl ;
  • ring A is not an optionally substituted triazolyl, 3,5-dimethyl-lH-pyrazol-l-yl,
  • X is N, CH or C-halo
  • each X b is independently N-R 9b , O, S, C-H, or C-R 9c , provided that at least one X b is C-R 9c , and when one X b is C-H or C-R 9 and the other is C-R 9c then X c is N, and when one X b is N-R 9b , O, or S,then X c is C;
  • R 9b is hydrogen or -C 1 -C 4 alkyl
  • R 9c is halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(0) 2 -(Ci-C 4 alkyl), -S(0) 2 NH(Ci-C 4 alkyl), -CN, -S(0) 2 -(Ci-C 4 alkyl), C1-C4 alkoxy, -NH(Ci-C 4 alkyl), - N(Ci-C 4 alkyl) 2 , -OH, -OCF 3 , -CN, -NH 2 , -C(0)NH 2 , -C(0)NH(d-C 4 alkyl), -C(0)-N(d-C 4 alkyl) 2 , -(Ci-C 6 alkylene)-0-(Ci-C 6 alkyl), aryl, and cyclopropyl optionally substituted with OH; R 1 , R 3 , R
  • haloalkyl, -O-C1-C4 alkyl, and CN wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C1-C4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 and R 5 are each independently selected from: -(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(Ci- C 6 alkyl)-C0 2 H -(C 0 -C 6 alkylene)-Q, -(C 0 -C 6 alkylene)-C(0)-(d-C 6 alkyl), -(C 0 -C 6
  • any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more -OH, -0(d-C 4 alkyl), -C0 2 H, or halo;
  • any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH,
  • R 7 and R 8 are each independently selected from hydrogen and Ci-d alkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, an optionally substituted 5-6 member monocyclic aryl, or an optionally substituted heteroaryl;
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C 1 -C4 alkyl, C 1 -C4 haloalkyl, -O-C 1 -C4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C 1 -C4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 and R 5 are each independently selected from: -(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(Ci-Cg alkyl)-C0 2 H -(Co-Cg alkylene)-Q, -(C 0 -C 6 alkylene)-C(0)-(Ci-C 6 alkyl), -(C 0 -C 6 alkylene)-C(O)-(C 0 -C 6 alkylene)-Q, wherein:
  • any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more -OH, -0(d-C 4 alkyl), -C0 2 H, or halo;
  • any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH, CF 3 , -CH 2 F, -CH 2 C1, C(0)CH 3 , C(0)CF 3 , CN, or C0 2 H;
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • R 9 is halo or-Ci-C 4 haloalkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 4 and R 5 are optionally taken together to form an optionally substituted
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4
  • haloalkyl -O-C 1 -C 4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C 1 -C 4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 and R 5 are each independently selected from: -(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(Ci-Cg alkyl)-C0 2 H -(Co-Cg alkylene)-Q, -(C 0 -C 6 alkylene)-C(0)-(d-C 6 alkyl), -(C 0 -C 6 alkylene)-C(0)-(Co-C6 alkylene)-Q, wherein:
  • any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more -OH, -0(d-C 4 alkyl), -C0 2 H, or halo;
  • any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH, CF 3 , -CH 2 F, -CH 2 C1, C(0)CH 3 , C(0)CF 3 , CN, or C0 2 H;
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • R 9 is selected from hydrogen, halo, and -C 1 -C 4 haloalkyl; and Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C 1 -C 4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 and R 5 are each independently selected from: -(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(Ci-Cg alkyl)-C0 2 H -(Co-Cg alkylene)-Q, -(C 0 -C 6 alkylene)-C(0)-(Ci-C 6 alkyl), -(C 0 -C 6 alkylene)-C(0)-(Co-C6 alkylene)-Q, wherein:
  • any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more -OH, -0(d-C 4 alkyl), -C0 2 H, or halo;
  • any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH, CF 3 , -CH 2 F, -CH 2 C1, C(0)CH 3 , C(0)CF 3 , CN, or C0 2 H;
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl;
  • R 9 is selected from hydrogen, halo, and -C 1 -C 4 haloalkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.
  • ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C 1 -C 4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 and R 5 are each independently selected from: -(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(Ci-Cg alkyl)-C0 2 H -(C 2 -C 6 alkenyl or alkynyl), -(C C 6
  • any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more -OH, -0(d-C 4 alkyl), -C0 2 H, or halo;
  • any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH, CF 3 , -CH 2 F, -CH 2 C1, C(0)CH 3 , C(0)CF 3 , CN, or C0 2 H;
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is N(CH 3 )CH 2 C(0)NH-i-propyl
  • NtR 8 ) ⁇ 1 ) ⁇ 2 ) ⁇ 3 ) is NHCH 2 -phenyl, NHCH 2 -(2,4-difluorophenyl), N(CH 3 )CH 2 CH 2 C(0)OH, NHCH 2 CH 2 C(0)OH, NHCH 2 CH 2 C(0)OCH 2 CH 3 , NHCH 2 CH 2 C(0)0-t-butyl,
  • NtR 8 ) ⁇ 1 ) ⁇ 2 ) ⁇ 3 ) is N(CH 3 ) 2 , NHCH 3 , NHAc, NHisopropyl, NHCH 2 CH 3 , NHCH 2 CH 2 S0 3 H or N(CH 2 CH 3 ) 2 ,
  • ring A is not an optionally substituted triazolyl, 3, 5 -dimethyl- lH-pyrazol-l-yl,
  • R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C 1 -C4 alkyl, C 1 -C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C 1 -C4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • each R 9 is independently selected fromhalo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4
  • n 1 to 3 ;
  • R 2 and R 5 are each independently selected from: -(Ci-d alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(d- C 6 alkyl)-C0 2 H -(C 2 -C 6 alkenyl or alkynyl), -(Ci-C 6 alkylene)-0-(Ci-C 6 alkyl), -(C 0 -C 6 alkylene)-C(0)N(R 6 )-(Ci-C 6 alkyl),
  • any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more -OH, -0(d-C 4 alkyl), -C0 2 H, or halo;
  • any terminal methyl moiety present in R 2 and R 5 is optionally replaced with -CH 2 OH,
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl
  • R 4 and R 5 are optionally taken together to form an optionally substituted carbocyclyl
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 NH 2 , or 4-[[2-[2-(2-aminoethoxy)ethoxy]ethyl]amino],
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH 2 CH 2 CHO, NHCH 2 CH 2 OCH 3 , NHCH 2 CH 2 OH, NHCH 2 CH(OH)CH 3 , NHCH 2 CH 2 OC(0)phenyl, NHCH 2 CH 2 CH 2 OH,
  • N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHcyclohexylC(0)NHCH 2 R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF 3 , OCH 3 , chloro, or CF 3 .
  • ring A is an optionally substituted 5-6 member monocyclic heteroaryl
  • ring B is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl
  • R 1 and R 3 are each independently selected from hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C 1 -C 4 alkyl, -NH(d-C 4 alkyl), or -N(d-C 4 alkyl) 2 ;
  • R 2 is selected from: -(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(d-C 6 alkyl)-C0 2 H -(C 2 -C 6 alkenyl or alkynyl), -(Ci-C 6 alkylene)-0-(Ci-C 6 alkyl), -(C 0 -C 6 alkylene)-C(0)N(R 6 )-(Ci-C 6 alkyl),-(Co-C 6 alkylene)-Q, -(C 0 -C 6 alkylene)-C(0)-(d-C 6 alkyl), and -(C 0 -C 6
  • any alkyl or alkylene moiety present in R 2 is optionally substituted with one or
  • any terminal methyl moiety present in R 2 is optionally replaced with -CH 2 OH,
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • ring A is a substituted 5-6 member monocyclic heteroaryl
  • X d is C or N
  • each R b is independently selected from halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -OH, -C(0)CH 3 , wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH 2 , or -CN;
  • p 1 to 2;
  • R 1 and R 3 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C1-C4 alkyl, -NH(d-C 4 alkyl), or -N(d-C 4 alkyl) 2 ;
  • R 2 is selected from: -(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(Ci-C 6 alkyl)-C0 2 H -(C 2 -C 6 alkenyl or alkynyl), -(Ci-C 6 alkylene)-0-(d-C 6 alkyl), -(C 0 -C 6 alkylene)-C(0)N(R 6 )-(d-C 6 alkyl) ,
  • any alkyl or alkylene moiety present in R 2 is optionally substituted with one or
  • any terminal methyl moiety present in R 2 is optionally replaced with -CH 2 OH,
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 3 are optionally taken together with the carbon atom to which they are attached to form
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • ring A is a substituted 5-6 member monocyclic heteroaryl
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • each R b is independently selected from halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -OH, -C(0)CH 3 , wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH 2 , or -CN;
  • p 1 to 2;
  • G is an optionally substituted carbocyclyl or heterocyclyl
  • A is not an oxadiazole substituted with an optionally substituted pyridinyl.
  • ring A is a substituted 5-6 member monocyclic heteroaryl
  • R 1 and R 3 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -O-C 1 -C 4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with -OH, -NH 2 , -CN, -O-C1-C4 alkyl, -NH(Ci-C 4 alkyl), or -N(Ci-C 4 alkyl) 2 ;
  • R 2 is selected from: -(Ci-C 6 alkyl), -(Ci-C 6 alkyl)-C(0)-NH 2 , -(d-C 6 alkyl)-C0 2 H -(C 2 -C 6 alkenyl or alkynyl), -(Ci-C 6 alkylene)-0-(Ci-C 6 alkyl), -(C 0 -C 6 alkylene)-C(0)N(R 6 )-(Ci-C 6 alkyl) ,
  • any alkyl or alkylene moiety present in R 2 is optionally substituted with one or
  • any terminal methyl moiety present in R 2 is optionally replaced with -CH 2 OH,
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted;
  • R 1 and R 2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
  • each R b is independently selected from halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, phenyl, -OH, -C(0)CH 3 , wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH 2 , or -CN; and
  • p 1 to 2.
  • ring A is a substituted 5-6 member monocyclic heteroaryl
  • R 7 and R 8 are each independently selected from hydrogen and Ci-C 6 alkyl
  • each R b is independently selected from halo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C3-C6 cycloalkyl, phenyl, -OH, -C(0)CH 3 , wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH 2 , or -CN;
  • p 1 to 2;
  • G is an optionally substituted carbocyclyl or heterocyclyl.
  • the compound is selected from any one of the compounds set forth in Table 1 , below.
  • the preceding methods comprise step (1) reacting .. I inn o otthheerr e emmbbooddimments
  • the recedin methods comprise step

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Abstract

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

Description

Attorney Docket Number: C2081 -
THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
CLAIM OF PRIORITY
This application claims priority from International Application Serial No.
PCT/CN2013/079200 filed July 11, 2013, 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., a-ketoglutarate). These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer.
IDH1 (isocitrate dehydrogenase 1 (NADP+), cytosolic) is also known as IDH; IDP; IDCD; IDPC or PICD. The protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-dienoyl- CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namelythe alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production.
The human IDHl gene encodes a protein of 414 amino acids. The nucleotide and amino acid sequences for human IDHl can be found as GenBank entries NM 005896.2 and
NP 005887.2 respectively. The nucleotide and amino acid sequences for IDHl are also described in, e.g., Nekrutenko etal, Mol. Biol. Evol. 15:1674-1684(1998); Geisbrecht et a/., J. Biol. Chem. 274:30527-30533(1999); Wiemann et al, Genome Res. 11 :422-435(2001); The MGC Project Team, Genome Res. 14:2121-2127(2004); Lubec et al, Submitted (DEC-2008) to UniProtKB; Kullmann etal., Submitted (JUN-1996) to the EMBL/GenBank/DDBJ databases; and Sjoeblom eta/., Science 314:268-274(2006).
Non-mutant, e.g., wild type, IDH1 catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate thereby reducing NAD+ (NADP+) to NADH (NADPH), e.g., in the forward reaction:
Isocitrate + NAD+ (NADP+)→ a-KG + C02 + 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 α-ketoglutarate to R(-)- 2-hydroxyglutarate (2HG). The production of 2HG is believed to contribute to the formation and progression of cancer (Dang, L et al., Nature 2009, 462:739-44).
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 (NOV-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 α-ketoglutarate (a-KG) thereby reducing NAD+ (NADP+) to NADH(NADPH), e.g., in the forward reaction:
Isocitrate + NAD+ (NADP+)→ a-KG + C02 + NADH (NADPH) + H+. It has been discovered that mutations of IDH2 present in certain cancer cells result in a new ability of the enzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate to R{-) -2-hydroxyglutarate (2HG). 2HG is not formed by wild-type IDH2. The production of 2HG is believed to contribute to the formation and progression of cancer (Dang, L et al, Nature 2009, 462:739-44). The inhibition of mutant IDH1 and/or mutant IDH2 and their neoactivity is therefore a potential therapeutic treatment for cancer. Accordingly, there is an ongoing need for inhibitors of IDHland/orIDH2 mutants having alpha hydroxyl neoactivity.
SUMMARY OF INVENTION
Described herein are compounds of Formula I, or a pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000004_0001
(I), 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 R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-d alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d-
C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-N(R6)-(d-C6 alkylene)-0-(d-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)(R6), -(Ci-C6 alkylene)-N(R6)-S(0)i-2-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-S(O)i-2-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6
alkylene)-Q, -C(0)N(R6)-(Ci-C6 alkylene)-C(O)- (C0-C6 alkylene)-0-(Ci-C6
alkyl), -C(0)N(R6)-(Ci-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-O-C(O)-(C0-C6 alkyl)-Q, -(Ci-C6
alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-0-(d-C6 alkylene)-Q, -(C0-C6
alkylene)-C(O)-(C0-C6 alkylene)-0-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6alkylene)-O-(Ci-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(d-C6 alkyl), -(Ci-C6 alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), -(Co-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(d-C6 alkylene)-N(R6)C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-S(O)0-2-(Ci-C6 alkyl), -(Co-C6 alkylene)-S(0)o-2-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; wherein:
(i) when X is N and A is optionally substituted phenyl, then (a) 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(0)phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2N(CH3)phenyl,
NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or NHCH2CH2OC(0)CH3;
(ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, CI or S02CH3, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(0)NH-i-propyl, NHCH(CH3)(CH2)3N(CH2CH3)2, NHCH2CH2OH, NHCH2CH2OCH3, NHCH2CH2OS03H, NHCH2CH2CH2OCH2CH20-phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2OCH3,
NHCH2CH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCH2CH2NHC(0)OCH3,
NHCH2CH2NHC(0)CH3, NHCH2CH2NH2, or NHCH2-phenyl;
(iii) when X is CH and A is optionally substituted pyridyl, then neither
N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2-phenyl, NHCH2-(2,4-difluorophenyl), N(CH3)CH2CH2C(0)OH, NHCH2CH2C(0)OH, NHCH2CH2C(0)OCH2CH3,
NHCH2CH2C(0)0-t-butyl, NHCH2CH2C(0)NH2, NHCH2CH2-phenyl, NHCH2CH2OH,
NHCH2CH2NH2, NHCH2CH2N(CH3)2, or NHCH2CH2CH3;
(iv) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1 - pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor
NtR8)^1)^2)^3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH;
(v) when X is N and A is an optionally substituted pyridyl, then (A) neither
N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], N(CH3)2, NHCH2CH2CH2S02CH2CH2Cl,NHCH2CH2OCH2CH2S02CH2CH2Cl,or
NHCH2CH2S02CH2CH2C1, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not
bothNHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH- cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3;
(vi) when X is N and A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;
(vii) when X is CH and A is unsubstituted 2-pyridinyl, then the ring formed by R4 and R5 is not 5-methyl-lH-pyrazol-3-yl;
(viii) whenA is optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor NtR8)^1)^2)^3) is N(CH3)2, NHCH3,NHAc, NHisopropyl, NHCH2CH3, NHCH2CH2S03H or N(CH2CH3)2;
(ix) when X is N and A is optionally substituted phenyl,thienyl, or pyridinyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexylC(0)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3;
(x) when X is N, A is an optionally substituted phenyl and R4 and R5 form an optionally substituted phenyl, then Ν^8)^1)^2)^3) is not NHCH2(4-fluorophenyl), NHCH2C02H, NHCH2C(0)C1, NHCH(C02H)(CH2SCH2phenyl), NHCH2C(0)NHC(0)NHR or
NHCH2C(0)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl;
(xi) when X is N, A is an oxadiazole substituted with an optionally substituted pyridinyl, then R4 and R5 do not form an optionally substituted phenyl;
(xii) when A is substituted 1-pyrazolyl, then (A) then N(R7)C(R4)(R5)(R6) and
NtR^CtR1)^2)^3) are not both NHC(CH3)3, and (B) A is not substituted with N=N-R, wherein R is a ring;
(xiii) ring A is not an optionally substituted triazolyl, 3, 5 -dimethyl- lH-pyrazol-l -yl;
(xix) when R1 and R2 are optionally taken together to form an unsubstituted cyclohexyl, and R4 and R5 are 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-lH-inden-2-yl)amino]-6-phenyl-l,3,5- triazin-2-yl]amino]methyl]-benzamide;
(2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4- (methylsulfonyl)-benzamide;
(3) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3- yl]thio]-acetamide;
(4) N2-cyclopropyl-N4-ethyl-6-[3-[(phenylmethyl)thio]-lH-l ,2,4-triazol-l-yl]-l,3,5- triazine-2,4-diamine;
(5) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3- yl]thio]- acetic acid methyl ester;
(6) N- [ [4- [ [ [4-(cyclopropylamino)-6-(2-pyridinyl)- 1 ,3 ,5 -triazin-2- yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide; (7) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-phenyl-l,3,5-triazine-2,4- diamine;
(8) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]-l,3,5- triazine-2,4-diamine;
(9) N2,N4-dicyclohexyl-6- [3 -(3 ,4-dimethoxyphenyl)-5 -(methylthio)- 1 H-pyrazol- 1 -yl] - 1 ,3,5-triazine-2,4-diamine;
( 10) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 - yl] - 1 ,3 , 5 -triazine-2,4-diamine;
(11) N2,N4-dicyclohexyl-6-phenyl-l,3,5-triazine-2,4-diamine;
(12) 1 ,1 '-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone];
(13) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l,l- dimethylethyl)-phenol;
(14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3- (trifluoromethyl)phenyl] amino ]carbonyl] amino]-2-methylphenyl]-l ,3,5-triazin-2-yl]-glycine;
(15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3- fluorophenyl)-l ,3,5-triazin-2- yl]amino]ethyl]- phenol;
(16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4- fluorophenyl)-l ,3,5-triazin-2- yl]amino]ethyl]- phenol;
(17) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine;
(18) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l ,3,5-triazine-2,4-diamine;
(19) 4,4'-[[6-[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]-l,3,5-triazine-2,4- diyl]bis(imino- 3,l -propanediyl)]bis[2,6-bis(l,l-dimethylethyl)-phenol;
(20) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(imino-3,l-propanediyl)]bis[2,6-bis(l,l- dimethylethyl)-phenol;
(21) N-[6-[(2,3-dihydro-lH-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]- alanine;
(22) N4-cyclopentyl-2-phenyl-N6-(phenylmethyl)-4,6-pyrimidinediamine;
(23) 2-[[6-(bicyclo[2.2.1 ]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol;
(24) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l,3,5-triazine-2,4-diamine; (25) 2-chloro-4-(me lsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l ,3,5- triazin-2-yl]-benzamide;
(26) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide;
(27) [[4-[[[[[4-amino-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]amino]methoxy]methyl]amino]- 6-(4-pyridinyl)-l ,3,5-triazin-2-yl]imino]bis-methanol;
(28) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- yl]amino]methoxy]methyl](hydroxymethyl)am
methanol;
(29) 5-[4,6-bis(diethylamino)-l ,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester;
(30) N2,N2,N*,N*-tetrae ^
(31) N,A -[6-[4-(acetylamino)-l ,2,5-oxadiazol-3-yl]-l
Figure imgf000009_0001
(32) N-(2-chloro-6-methylphenyl)-5-[[4-(dimethylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]-l ,3,4-Oxadiazole-2-carboxamide;
(33) N4-(5-methyl-lH-pyrazol-3-yl)-2-(2-pyridinyl)-N6-(tetrahydro-2H-pyran-4-yl)-4,6- Pyrimidinediamine;
(34) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3- (diethylamino)propyl]- 1 ,3,5 -Triazine-2,4-diamine;
(35) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3- (dimethylamino)propyl]- 1 ,3,5-Triazine-2,4-diamine;
(36) N2-[3,5-bis(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]-l ,3,5- Triazine-2,4-diamine;
(38) N,N"-(6-phenyl-l ,3,5-triazine-2,4-diyl)bis[N'-(2-chloroethyl)-Urea;
(39) N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-methyl-3-[[4-phenyl-6-(propylamino)- l ,3,5-triazin-2-yl]amino]phenyl]-urea;
(40) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]-glycine;
(41) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(5-thiazolyl)-l, 3, 5-triazin-2-yl]-L- Valine;
(42) s-Triazine, 2-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 ) α,α'- [(6-phenyl- 1,3,5 -triazine-2,4-diyl)bis [imino( 1 , 1 ,2,2-tetrafluoro-3 -oxo-3 , 1 - propanediyl)]]bis[ro-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)- 1,2-ethanediyl]];
(44) a-[[4-[[(3-chlorophenyl)methyl]amino]-6-(lH-imidazol-l -yl)-l ,3,5-triazin-2- yl]amino]-N-[[4-(trifluoromethyl)phenyl]methyl]-, (aR)-Cyclohexanepropanamide;
(45) 6-(lH-imidazol-l-yl)-N2,N4-bis(l-methyle l)-l,3,5-Triazine-2,4-diamine;and
(46) N2,N4-bis(l -methylpropyl)-6-phenyl-l ,3,5-Triazine-2,4-diamine.
The compounds of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, Π, ΙΠ, Ilia, Illb, IIIc, and Illd, or as described in any one of the embodiments herein inhibits mutant IDHlor mutant IDH2. Also described herein are pharmaceutical compositions comprising a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, Π, III, Ilia, nib, Hie, and Hid, and methods of using such compositions to treat cancers characterized by the presence of a mutant IDHl or mutant IDH2.
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 "including," "comprising," or "having," "containing", "involving", and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
Definitions:
The term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine. The term "alkyl" refers to a fully saturated or unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C12 alkyl indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it. The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkyl).The terms "arylalkyl" or "aralkyl" refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of "arylalkyl" or "aralkyl" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups. The term "alkyl" includes "alkenyl" and "alkynyl".
The term "alkylene" refers to a divalent alkyl,
e.g., -CH2-, -CH2CH2-, -CH2CH2CH2- and -CH2CH(CH3)CH2-.
The term "alkenyl" refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and having one or more double bonds. Examples of alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent.
The term "alkynyl" refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and characterized in having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
The term "alkoxy" refers to an -O-alkyl radical. The term "haloalkoxy" refers to an alkoxy in which one or more hydrogen atoms are replaced by halo, and includes alkoxy moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkoxy).
Unless otherwise specified, the term "aryl" refers to a fully aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system. Examples of aryl moieties are phenyl, naphthyl, and anthracenyl.Unless otherwise specified, any ring atom in an aryl can be substituted by one or more substituents. The term "monocyclic aryl" means a monocyclic fully romatic hydrocarbon ring system, optionally substituted by one or more substituents which can not form a fused bicyclic or tricyclic ring. The term "carbocyclyl" refers to a non-aromatic, monocyclic, bicyclic, or tricyclic hydrocarbon ring system. Carbocyclyl groups include fully saturated ring systems (e.g., cycloalkyls), and partially saturated ring systems. Carbocyclyl groups also include spirocyclic moieties. Examples of spirocyclic moieties include, but are not limited to, bicyclo[3.1.0]hexanyl, spiro[2.2]pentanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, and spiro[3.6]decanyl. Unless otherwise specified, any ring atom in a carbocyclyl can be substituted by one or more substituents.
Bicyclic or tricyclic ring systems where an aryl is fused to a carbocyclyl and the point of attachment from the ring system to the rest of the molecule is through the non-aromatic ring are considered to be carbocyclyl (e.g., cycloalkyl). Examples of such carbocyclyl moieties include, but are not limited to, 2,3-dihydro-lH-indene and 1 ,2,3,4-tetrahydronaphthalene.
The term "cycloalkyl" as employed herein includes saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12 carbons. Any ring atom can be substituted (e.g., by one or more substituents). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.
Unless otherwise specified, the term "heteroaryl" refers to a fully aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11 -14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (or the oxidized formssuch as IST-O", S(O) and S(0)2).The term "monocyclic heteroaryl" means a monocyclic fully romatic ring systemhaving 1 -3 heteroatoms, optionally substituted by one or more substituents which can not form a fused bicyclic or tricyclic ring.
The term "heterocyclyl" refers to a nonaromatic, 3-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1 -3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(or the oxidized formssuch as IST-O", S(O) and S(0)2). The heteroatom may optionally be the point of attachment of the heterocyclyl substituent. Examples of heterocyclyl include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino, pyrrolinyl, pyrimidinyl, and pyrrolidinyl. Heterocyclyl groups include fully saturated ring systems, and partially saturated ring systems. Bicyclic and tricyclic ring systems containing one or more heteroatoms and both aromatic and non-aromatic rings are considered to be heterocyclyl or heteroaryl groups. Bicyclic or tricyclic ring systems where an aryl or a heteroaryl is fused to a carbocyclyl or heterocyclyl and the point of attachment from the ring system to the rest of the molecule is through an aromatic ring are considered to be aryl or heteroaryl groups, respectively. Bicyclic or tricyclic ring systems where an aryl or a heteroaryl is fused to a carbocyclyl or heterocyclyl and the point of attachment from the ring system to the rest of the molecule is through the non-aromatic ring are considered to be carbocyclyl (e.g., cycloalkyl) or heterocyclyl groups, respectively.
Aryl, heteroaryl, carbocyclyl (including cycloalkyl), and heterocyclyl groups, either alone or a part of a group (e.g., the aryl portion of an aralkyl group), areoptionally substituted at one or more substitutable atoms with, unless specified otherwise, substituents independently selected from: halo, -C≡N, d-C4alkyl,
=0, -ORb, -ORb', -SRb, -SRb', -(Ci-C4alkyl)-N(Rb)(Rb), -(Ci-C4alkyl)-N(Rb)(Rb'),-N(Rb)(Rb), -N( Rb)(Rb'), -0-(Ci-C4alkyl)-N(Rb)(Rb), -0-(Ci-C4alkyl)-N(Rb)(Rb'), -(Ci-C4 alkyl)-0-(Ci-C4 alkyl)-N(Rb)(Rb), -(C1-C4 alkyl)-0-(Ci-C4 alkyl)-N(Rb)(Rb'), -C(0)-N(Rb)(Rb), -(C1-C4 alkyl)-C(0)-N(Rb)(Rb), -(C1-C4 alkyl)-C(0)-N(Rb)(Rb ), -ORb , Rb', -C(0)(Ci-C4
alkyl), -C(0)Rb', -C(0)N(Rb')(Rb), -N(Rb)C(0)(Rb), -N(Rb)C(0)(Rb ), -N(Rb)S02(Rb), -S02N(Rb )(Rb), -N(Rb)S02(Rb'), and -S02N(Rb)(Rb'), wherein any alkyl substituent is optionally further substituted with one or more of -OH, -0-(d-C4 alkyl), halo, -NH2, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
each Rb is independently selected from hydrogen, and -Ci-C alkyl; or two Rbs are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered heterocyclyl optionally comprising one additional heteroatom selected from N, S, and O; and
each Rb is independently selected from C3-C7carbocyclyl, phenyl, heteroaryl, and heterocyclyl, wherein one or more substitutablepositions on said phenyl, cycloalkyl, heteroaryl or heterocycle substituent is optionally further substituted with one or more of -(Ci-C4 alkyl), -(C1 -C4 fluoroalkyl), -OH, -0-(C C4 alkyl), -0-(Ci-C4 fluoroalkyl),
halo, -NH2, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2. Heterocyclyl groups, either alone or as part of a group,are optionally substituted on one or more any substitutable nitrogen atom with oxo,-Ci-C4 alkyl, or fluoro-substituted C1-C4 alkyl.
The term "substituted" refers to the replacement of a hydrogen atom by another group. The term"bodily fluid" includes one or more of amniotic fluid surrounding a fetus, aqueous humour, blood (e.g., blood plasma), serum, Cerebrospinal fluid, cerumen, chyme, Cowper's fluid, female ejaculate, interstitial fluid, lymph, breast milk, mucus (e.g., nasal drainage or phlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal secretion, or vomit.
As used herein, the terms "inhibit" or "prevent" include both complete and partial inhibition and prevention. An inhibitor may completely or partially inhibit the intended target.
The term "treat" means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease/disorder (e.g., a cancer), lessen the severity of the disease/disorder (e.g., acancer) or improve the symptoms associated with the disease/disorder (e.g., a cancer).
As used herein, an amount of a compound effective to treat a disorder, or a "therapeutically effective amount" refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject, in treating a cell, or in curing, alleviating, relieving or improving a subject with a disorder beyond that expected in the absence of such treatment.
As used herein, the term "subject" 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 "non -human animals" 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:
Figure imgf000015_0001
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 R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(Ci- C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-N(R6)-(d-C6 alkylene)-0-(d-C6 alkyl), -(C C6 alkylene)-N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)(R6), -(d-C6 alkylene)-N(R6)-S(0)i-2-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-S(O)i-2-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6
alkylene)-Q, -C(0)N(R6)-(Ci-C6 alkylene)-C(O)- (C0-C6 alkylene)-0-(Ci-C6
alkyl), -C(0)N(R6)-(Ci-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-O-C(O)-(C0-C6 alkyl)-Q, -(Ci-C6
alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-0-(d-C6 alkylene)-Q, -(C0-C6
alkylene)-C(O)-(C0-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6
alkylene)-0-(Ci-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(Ci-C6 alkyl), -(Ci-C6
alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-S(O)0-2-(Ci-C6 alkyl), -(C0-C6 alkylene)-S(0)o-2-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein: any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; wherein:
(i) when X is N and A is optionally substituted phenyl, then (a) 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(0)phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2N(CH3)phenyl,
NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or
NHCH2CH2OC(0)CH3;
(ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, CI or S02CH3, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(0)NH-i-propyl, NHCH(CH3)(CH2)3N(CH2CH3)2, NHCH2CH2OH, NHCH2CH2OCH3, NHCH2CH2OS03H, NHCH2CH2CH2OCH2CH20-phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2OCH3,
NHCH2CH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCH2CH2NHC(0)OCH3,
NHCH2CH2NHC(0)CH3, NHCH2CH2NH2, or NHCH2-phenyl; (iii) when X is CH and A is optionally substituted pyridyl, then neither
N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2-phenyl, NHCH2-(2,4-difluorophenyl), N(CH3)CH2CH2C(0)OH, NHCH2CH2C(0)OH, NHCH2CH2C(0)OCH2CH3,
NHCH2CH2C(0)0-t-butyl, NHCH2CH2C(0)NH2, NHCH2CH2-phenyl, NHCH2CH2OH,
NHCH2CH2NH2, NHCH2CH2N(CH3)2, or NHCH2CH2CH3;
(iv) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1 - pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor
NtR8)^1)^2)^3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH;
(v) when X is N and A is an optionally substituted pyridyl, then (A) neither
N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], N(CH3)2, NHCH2CH2CH2S02CH2CH2C1, NHCH2CH2OCH2CH2S02CH2CH2Cl,or
NHCH2CH2S02CH2CH2C1, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and
NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3;
(vi) when X is N and A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;
(vii) when X is CH and A is unsubstituted 2-pyridinyl, then the ring formed by R4 and R5 is not 5 -methyl- lH-pyrazol-3-yl,
(viii) when A is optionally substituted 1 -pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor NtR8)^1)^2)^3) is N(CH3)2, NHCH3, NHAc, NHisopropyl, NHCH2CH3, NHCH2CH2S03H or N(CH2CH3)2,
(ix) when X is N and A is optionally substituted phenyl, thienyl, or pyridinyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexylC(0)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3,
(x) when X is N, A is an optionally substituted phenyl and R4 and R5 form an optionally substituted phenyl, then N(R8)C(R1)(R2)(R3) is not NHCH2(4-fluorophenyl), NHCH2C02H, NHCH2C(0)C1, NHCH(C02H)(CH2SCH2phenyl), or NHCH2C(0)NHC(0)NHR or NHCH2C(0)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl,
(xi) when X is N, A is an oxadiazole substituted with an optionally substituted pyridinyl, then R4 and R5 do not form an optionally substituted phenyl,
(xii) when A is substituted 1-pyrazolyl, then (A) then N(R7)C(R4)(R5)(R6) and
NtR^CtR1)^2)^3) are not both NHC(CH3)3, and (B) A is not substituted with N=N-R, wherein R is a ring,
(xiii) ring A is not an optionally substituted triazolyl, 3, 5 -dimethyl- lH-pyrazol-l -yl,
(xix) when R1 and R2 are optionally taken together to form an unsubstituted cyclohexyl, and R4 and R5 are 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-lH-inden-2-yl)amino]-6-phenyl-l ,3,5-triazin-2- yl ] amino] methyl] -b enzamide,
(2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4-(methylsulfonyl)- benzamide,
(3) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3-yl]thio]- acetamide,
(4) N2-cyclopropyl-N4-ethyl-6-[3-[(phenylmethyl)thio]-lH-l ,2,4-triazol-l-yl]-l,3,5-triazine-2,4- diamine,
(5) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3-yl]thio]- acetic acid methyl ester,
(6) N- [ [4- [ [ [4-(cyclopropylamino)-6-(2 -pyridinyl)- 1,3,5 -triazin-2-yl]amino]methyl] cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,
(7) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-phenyl-l,3,5-triazine-2,4-diamine,
(8) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]-l,3,5-triazine- 2,4-diamine,
(9) N2,N4-dicyclohexyl-6- [3 -(3 ,4-dimethoxyphenyl)-5 -(methylthio)- 1 H-pyrazol- 1 -yl] -1,3,5- triazine-2,4-diamine,
( 10) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 -yl]- 1 ,3 , 5 - triazine-2,4-diamine,
(1 1) N2,N4-dicyclohexyl-6-phenyl-l,3,5-triazine-2,4-diamine,
(12) 1 ,1 '-[(6^henyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],
(13) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l,l- dimethylethyl)- phenol,
(14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-l,3,5-triazin-2-yl]-glycine,
(15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3- fluorophenyl)-l,3,5-triazin-2-yl]amino]ethyl]- phenol,
(16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4- fluorophenyl)-l,3,5-triazin-2-yl]amino]ethyl]- phenol,
(17) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine,
(18) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l ,3,5-triazine-2,4-diamine,
(19) 4,4'-[[6-[3,5-bis(U-dime lefoy^
3,1 -propanediyl)]bis[2,6-bis(l ,1 -dimethylethyl)-phenol,
(20) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(imino-3,l-propanediyl)]bis[2,6-bis(l,l- dimethylethyl)-phenol,
(21) N-[6-[(2,3-dihydro-lH-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]- alanine,
(22) N4-cyclopentyl-2-phenyl-N6-(phenylmethyl)-4,6-pyrimidinediamine,
(23) 2-[[6-(bicyclo[2.2.1 ]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol,
(24) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l,3,5-triazine-2,4-diamine,
(25) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l,3,5-triazin-2- yl]-benzamide,
(26) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,
(27) [[4-[[[[[4-amino-6-(4^yridinyl)-l,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4- pyridinyl)-l ,3,5-triazin-2-yl]imino]bis-methanol,
(28) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]imi^ methanol, (29) 5-[4,6-bis(diethylamino)-l,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,
(30) N2,N2,N*,N*-tetrae ^
(31) N,A -[6-[4-(acetylamino)-l,2,5-oxadiazol-3^
(32) N-(2-chloro-6-methylphenyl)-5-[[4-(dime lamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]-l ,3,4-Oxadiazole-2-carboxamide,
(33) N4-(5-methyl-lH-pyrazol-3-yl)-2-(2-pyridinyl)-N6-(tetrahydro-2H-pyran-4-yl)-4,6- Pyrimidinediamine,
(34) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(diethylamino)propyl]- 1,3,5 -Triazine-2,4-diamine,
(35) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3- (dimethylamino)propyl]- 1 ,3,5-Triazine-2,4-diamine,
(36) N2-[3,5-bis(trifluorome l)phenyl]-6-(4-chlorophenyl)-N4-[3-(diethylamino)propyl]-1 Triazine-2,4-diamine,
(37) N2,N4-bis[(4-methoxyphenyl)me l]-6-[4-(trifluoromethoxy)phenyl]-l ,3,5-Triazine-2,4- diamine,
(38) N,N"-(6-phenyl-l,3,5-triazine-2,4-diyl)bis[N'-(2-chloroethyl)-Urea,
(39) N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-methyl-3-[[4-phenyl-6-(propylamino)-l ,3,5- triazin-2-yl]amino]phenyl]-urea,
(40) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]-glycine,
(41) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(5-thiazolyl)-l, 3, 5-triazin-2-yl]-L- Valine,
(42) s-Triazine, 2-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) a,a'-[(6-phenyl-l ,3,5-triazine-2,4-diyl)bis[imino(l,l,2,2-tetrafluoro-3-oxo-3,l- propanediyl)]]bis[ro-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)- 1,2-ethanediyl]],
(44) a-[[4-[[(3-chlorophenyl)methyl]amino]-6-(lH-imidazol-l-yl)-l,3,5-triazin-2-yl]amino]-N- [[4-(trifluoromethyl)phenyl]methyl]-, (aR)-Cyclohexanepropanamide, (45) 6-(lH-imidazol-l -yl)-N2,N4-bis(l -methyle l)-l,3,5-Triazine-2,4-diamine, and
(46) N2,N4-bis(l -methylpropyl)-6-phenyl-l ,3,5-Triazine-2,4-diamine.
Provided is a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000021_0001
erein:
ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;
X is N, CH or C-halo;
R1, R3, R4, and R6 are each independently selected from hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein any alkyl portion of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(Ci-Cg alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-N(R6)-(Ci-C6
alkylene)-0-(Ci-C6 alkyl), -(Ci-Cg alkylene)-N(R6)-(C0-C6 alkylene)-Q, -(Ci-Cg
alkylene)-N(R6)(R6X -(Ci-C6 alkylene)-N(R6)-S(0)i-2-(Ci-C6 alkyl), -(d-C6
alkylene)-N(R6)-S(O)i-2-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6 alkylene)-Q, -C(0)N(R6)-(Ci-C6 alkylene)-C(O)- (C0-C6 alkylene)-0-(Ci-C6 alkyl), -C(0)N(R6)-(Ci-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(Ci-Cg alkylene)-0-C(0)-(d-C6 alkyl), -(Ci-Cg alkylene)-O-C(O)-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-0-(Ci-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6
alkylene)-0-(Ci-C6 alkylene)-Q, -(Ci-Cg alkylene)-0-C(0)-(d-C6 alkyl), -(d-C6
alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), -(C0-C6alkylene)-C(0)N(R6)-(Co-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-S(O)0-2-(Ci-C6 alkyl), -(Co-C6 alkylene)-S(0)o-2-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(Ci-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are 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(0)phenyl, NHCH2CH2CH2OH,
NHCH2CH2CH2N(CH3)phenyl, NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or NHCH2CH2OC(0)CH3;
(ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, CI or S02CH3, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(0)NH-i-propyl, NHCH(CH3)(CH2)3N(CH2CH3)2, NHCH2CH2OH, NHCH2CH2OCH3, NHCH2CH2OS03H, NHCH2CH2CH2OCH2CH20-phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2OCH3,
NHCH2CH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCH2CH2NHC(0)OCH3,
NHCH2CH2NHC(0)CH3, NHCH2CH2NH2, or NHCH2-phenyl;
(iii) when X is CH and A is optionally substituted pyridyl, then neither
N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2-phenyl, NHCH2-(2,4-difluorophenyl), N(CH3)CH2CH2C(0)OH, NHCH2CH2C(0)OH, NHCH2CH2C(0)OCH2CH3,
NHCH2CH2C(0)0-t-butyl, NHCH2CH2C(0)NH2, NHCH2CH2-phenyl, NHCH2CH2OH, NHCH2CH2NH2, NHCH2CH2N(CH3)2, or NHCH2CH2CH3;
(iv) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1-pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor NCR^CCR'XR'XR3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH;
(v) when X is N and A is an optionally substituted pyridyl, then (A) neither
N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3;
(vi) when X is N and A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;
(vii) the compound is not selected from the group:
(1 ) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-phenyl-l ,3,5-triazine-2,4- diamine,
(2) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-methoxyphenyl)-l,3,5- triazine-2,4-diamine,
(3) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(3-nitrophenyl)-l,3,5- triazine-2,4-diamine,
(4) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-fluorophenyl)-l ,3,5- triazine-2,4-diamine,
(5) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-trifluoromethoxy- phenyl)-l,3,5-triazine-2,4-diamine,
(6) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-t-butyl-phenyl)-l ,3,5- triazine-2,4-diamine,
(7) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(2-thienyl)-l ,3,5-triazine- 2,4-diamine,
(8) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-lH-inden-2-yl)amino]-6-phenyl-l,3,5- triazin-2-yl]amino]methyl]-benzamide,
(9) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4- (methylsulfonyl)-benzamide,
(10) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-methoxyphenyl)- 1 ,3,5-triazine-2,4-diamine,
(11) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3- yl]thio]-acetamide,
(12) N2-cyclopropyl-N4-ethyl-6-[3-[(phenylme l)thio]-lH ,2,4-triazol-l-yl]-l,3,5- triazine-2,4-diamine,
(13) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3- yl]thio]- acetic acid methyl ester,
(14) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(2,4,6-trimethylphenyl)- l,3,5-triazine-2,4-diamine,
(15) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-phenyl-l ,3,5-triazine- 2,4-diamine,
(16) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-methylphenyl)-l ,3,5- triazine-2,4-diamine,
(17) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-chlorophenyl)-l ,3,5- triazine-2,4-diamine,
(18) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide, (19) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l -yl)-N4-phenyl-l,3,5-triazine-2,4- diamine,
(20) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]- 1 ,3,5-triazine-2,4-diamine,
(21) N2,N4-dicyclohexyl-6-[3-(3,4-dimethoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]- 1 ,3,5-triazine-2,4-diamine,
(22) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 - yl] - 1 ,3 , 5 -triazine-2,4-diamine,
(23) N2,N4-dicyclohexyl-6-phenyl-l,3,5-triazine-2,4-diamine,
(24) 1 ,1 '-[(6^henyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],
(25) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l,l- dimethylethyl)-phenol,
(26) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3- (trifluoromethyl)phenyl] amino ]carbonyl] amino]-2-methylphenyl]-l ,3,5-triazin-2-yl]-glycine,
(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)-l ,3,5-triazine-2,4-diamine,
(30) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l,3,5-triazine-2,4-diamine,
(31) 4,4'-[[6-[3,5-bis(l,l-dimethylethyl)-4- hydroxyphenyl]-l,3,5-triazine-2,4- diyl]bis(imino- 3,l-propanediyl)]bis[2,6-bis(l,l-dimethylethyl)-phenol,
(32) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(imino-3,l-propanediyl)]bis[2,6-bis(l,l- dimethylethyl)-phenol,
(33) N-[6-[(2,3-dihydro-lH-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]- 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)-l,3,5-triazine-2,4-diamine, (37) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l ,3,5- triazin-2-yl]-benzamide,
(38) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,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)-l ,3,5-triazin-2-yl]imino]bis-methanol,
(40) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]i methanol,
(41) 5-[4,6-bis(diethylamino)-l ,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,
(42) N2,N2,N4,N4-tetraethyl-6-(2H-tetrazol-5-yl)-l ,3,5-triazine-2,4-diamine, and
(43) N V-[6-[4-(acetylamino)-l ,2,5-oxadiazol-3-yl]-l ,3,5-triazine-2,4-diyl]bis-acetamide.
Provided is a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000026_0001
(I), wherein:
ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl; X is N or CH;
R1, R3, R4, and R6 are each independently selected from hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein any alkyl portion of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(d-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(Ci-C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(C C6 alkylene)-N(R6)-(Ci-C6
alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6alkylene)-N(R6)(R6), -(Ci-C6 alkylene)-N(R6)-S(0)i-2-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-S(O)i-2-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6 alkylene)-Q, -C(0)N(R6)-(Ci-C6 alkylene)-C(O)- (C0-C6 alkylene)-0-(Ci-C6 alkyl), -C(0)N(R6)-(Ci-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(d-C6 alkyl), -(Ci-C6 alkylene)-O-C(O)-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-0-(Ci-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-0-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6
alkylene)-0-(Ci-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(d-C6 alkyl), -(C C6
alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-S(O)0-2-(Ci-C6 alkyl), -(C0-C6 alkylene)-S(0)o-2-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6 alkyl), -(C0-G alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and d-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are 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(0)phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2N(CH3)phenyl, NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or NHCH2CH2OC(0)CH3;
(ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, CI or S02CH3, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(0)NH-i-propyl, NHCH(CH3)(CH2)3N(CH2CH3)2, NHCH2CH2OH, NHCH2CH2OCH3, NHCH2CH2OS03H, NHCH2CH2CH2OCH2CH20-phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2OCH3,
NHCH2CH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCH2CH2NHC(0)OCH3,
NHCH2CH2NHC(0)CH3, NHCH2CH2NH2, or NHCH2-phenyl;
(iii) when X is CH and A is optionally substituted pyridyl, then neither
N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2-phenyl, NHCH2-(2,4-difluorophenyl), N(CH3)CH2CH2C(0)OH, NHCH2CH2C(0)OH, NHCH2CH2C(0)OCH2CH3,
NHCH2CH2C(0)0-t-butyl, NHCH2CH2C(0)NH2, NHCH2CH2-phenyl, NHCH2CH2OH, NHCH2CH2NH2, NHCH2CH2N(CH3)2, or NHCH2CH2CH3;
(iv) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1 - pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor
NtR8)^1)^2)^3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH;
(v) when X is N and A is an optionally substituted pyridyl, then (A) neither
N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3; (vi) when X is N and A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;
(vii) the compound is not selected from the group:
(1 ) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-phenyl-l ,3,5-triazine-2,4- diamine,
(2) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-methoxyphenyl)-l,3,5- triazine-2,4-diamine,
(3) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(3-nitrophenyl)-l,3,5- triazine-2,4-diamine,
(4) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-fluorophenyl)-l ,3,5- triazine-2,4-diamine,
(5) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-trifluoromethoxy- phenyl)-l,3,5-triazine-2,4-diamine,
(6) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-t-butyl-phenyl)-l ,3,5- triazine-2,4-diamine,
(7) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(2-thienyl)-l ,3,5-triazine- 2,4-diamine,
(8) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-lH-inden-2-yl)amino]-6-phenyl-l,3,5- triazin-2-yl]amino]methyl]-benzamide,
(9) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4- (methylsulfonyl)-benzamide,
(10) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-methoxyphenyl)- l,3,5-triazine-2,4-diamine,
(11) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3- yl]thio]-acetamide,
(12) N2-cyclopropyl-N4-ethyl-6-[3-[(phenylmethyl)thio]-lH-l,2,4-triazol-l-yl]-l,3,5- triazine-2,4-diamine,
(13) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3- yl]thio]- acetic acid methyl ester,
(14) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(2,4,6-trimethylphenyl)- l,3,5-triazine-2,4-diamine,
(15) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-phenyl-l ,3,5-triazine- 2,4-diamine,
(16) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-methylphenyl)-l ,3,5- triazine-2,4-diamine,
(17) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-chlorophenyl)-l ,3,5- triazine-2,4-diamine,
(18) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,
(19) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l -yl)-N4-phenyl-l,3,5-triazine-2,4- diamine,
(20) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]- l,3,5-triazine-2,4-diamine,
(21) N2,N4-dicyclohexyl-6-[3-(3,4-dimethoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]- l,3,5-triazine-2,4-diamine,
(22) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 - yl]-l,3,5-triazine-2,4-diamine,
(23) N2,N4-dicyclohexyl-6-phenyl-l,3,5-triazine-2,4-diamine,
(24) 1 ,1 '-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],
(25) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l,l- dimethylethyl)-phenol,
(26) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3- (trifluoromethyl)phenyl] amino ]carbonyl] amino]-2-methylphenyl]-l ,3,5-triazin-2-yl]-glycine,
(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)-l ,3,5-triazine-2,4-diamine,
(30) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l,3,5-triazine-2,4-diamine,
(31) 4,4'-[[6-[3,5-bis(l,l-dime lethyl)-4- hydroxyphenyl]-l,3,5-triazine-2,4- diyl]bis(imino- 3,l-propanediyl)]bis[2,6-bis(l,l-dimethylethyl)-phenol,
(32) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(imino-3,l-propanediyl)]bis[2,6-bis(l,l- dimethylethyl)-phenol,
(33) N-[6-[(2,3-dihydro-lH-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]- 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)-l,3,5-triazine-2,4-diamine,
(37) 2-chloro-4-(methylsulfonyl)-N-[4 (phenylmethyl)amino]-6-(2-pyridinyl)-l,3,5- triazin-2-yl]-benzamide,
(38) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,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)-l,3,5-triazin-2-yl]imino]bis-methanol,
(40) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-l,3,5-triazin-2-yl]im methanol,
(41) 5-[4,6-bis(diethylamino)-l,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,
(42) N2,N2,N4,N4-tetraethyl-6-(2H-tetrazol-5-yl)-l ,3,5-triazine-2,4-diamine, and
(43) N V'-[6-[4-(acetylamino)-l,2,5-oxadiazol-3-yl]-l,3,5-triazine-2,4-diyl]bis-acetamide.
Also provided is a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000032_0001
(I), wherein:
ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;
X is N or CH;
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-d alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d- C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-N(R6)-(d-C6 alkylene)-0-(d-C6 alkyl), -(d-C6 alkylene)-N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)(R6), -(d-C6 alkylene)-N(R6)-S(0)i-2-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-S(O)i-2-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6
alkylene)-Q, -C(0)N(R6)-(Ci-C6 alkylene)-C(O)- (C0-C6 alkylene)-0-(Ci-C6
alkyl), -C(0)N(R6)-(Ci-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-O-C(O)-(C0-C6 alkyl)-Q, -(Ci-C6
alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-0-(Ci-C6 alkylene)-Q, -(C0-C6
alkylene)-C(O)-(C0-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6
alkylene)-0-(Ci-C6 alkylene)-Q, -(Ci-Ce alkylene)-0-C(0)-(d-C6 alkyl), -(d-C6
alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-S(O)0-2-(Ci-C6 alkyl), -(C0-C6 alkylene)-S(0)o-2-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6 alkyl), -(C0-C6alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(Ci-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; wherein:
(i) when X is N and A is optionally substituted phenyl, then (a) 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(0)phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2N(CH3)phenyl,
NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or
NHCH2CH2OC(0)CH3;
(ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, CI or S02CH3, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(0)NH-i-propyl, NHCH(CH3)(CH2)3N(CH2CH3)2, NHCH2CH2OH, NHCH2CH2OCH3, NHCH2CH2OS03H, NHCH2CH2CH2OCH2CH20-phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2OCH3, NHCH2CH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCH2CH2NHC(0)OCH3,
NHCH2CH2NHC(0)CH3, NHCH2CH2NH2, or NHCH2-phenyl;
(iii) when X is CH and A is optionally substituted pyridyl, then neither
N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2-phenyl, NHCH2-(2,4-difluorophenyl), N(CH3)CH2CH2C(0)OH, NHCH2CH2C(0)OH, NHCH2CH2C(0)OCH2CH3,
NHCH2CH2C(0)0-t-butyl, NHCH2CH2C(0)NH2, NHCH2CH2-phenyl, NHCH2CH2OH, NHCH2CH2NH2, NHCH2CH2N(CH3)2, or NHCH2CH2CH3;
(iv) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1 - pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor
NtR8)^1)^2)^3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH;
(v) when X is N and A is an optionally substituted pyridyl, then (A) neither
N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(0)-[2-chloro-4-(methylsulfonyl)],
N(CH3)2,NHCH2CH2CH2S02CH2CH2C1, NHCH2CH2OCH2CH2S02CH2CH2Cl,or
NHCH2CH2S02CH2CH2C1, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3;
(vi) when X is N and A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;
(vii) when X is CH and A is unsubstituted 2-pyridinyl, then the ring formed by R4 and R5 is not 5 -methyl- lH-pyrazol-3-yl,
(viii) when A is optionally substituted 1 -pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor NtR8)^1)^2)^3) is N(CH3)2, NHCH3, NHAc, NHisopropyl, NHCH2CH3, NHCH2CH2S03H or N(CH2CH3)2,
(ix) when X is N and A is optionally substituted phenyl,thienyl, or pyridinyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexylC(0)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3,
(x) when X is N, A is an optionally substituted phenyl and R4 and R5 form an optionally substituted phenyl, then NCR^CCR1)^2)^3) is not NHCH2(4-fluorophenyl), NHCH2C02H, NHCH2C(0)C1, NHCH(C02H)(CH2SCH2phenyl), or NHCH2C(0)NHC(0)NHR or
NHCH2C(0)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl,
(xi) when X is N, A is an oxadiazole substituted with an optionally substituted pyridinyl, then R4 and R5 do not form an optionally substituted phenyl,
(xii) when A is substituted 1-pyrazolyl, then (A) then N(R7)C(R4)(R5)(R6) and
NtR^CtR1)^2)^3) are not both NHC(CH3)3, and (B) A is not substituted with N=N-R, wherein R is a ring,
(xiii) ring A is not an optionally substituted triazolyl, 3,5-dimethyl-lH-pyrazol-l-yl,
(xix) when R1 and R2 are optionally taken together to form an unsubstituted cyclohexyl, and R4 and R5 are 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-lH-inden-2-yl)amino]-6-phenyl-l,3,5-triazin-2- yl ] amino] methyl] -b enzamide,
(2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4-(methylsulfonyl)- benzamide,
(3) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3-yl]thio]- acetamide,
(4) N2-cyclopropyl-N4-ethyl-6-[3 -[(phenylmethyl)thio]-lH-l ,2,4-triazol-l-yl]-l,3,5-triazine-2,4- diamine,
(5) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3-yl]thio]- acetic acid methyl ester,
(6) N- [ [4- [ [ [4-(cyclopropylamino)-6-(2 -pyridinyl)- 1,3,5 -triazin-2-yl]amino]methyl] cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,
(7) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-phenyl-l,3,5-triazine-2,4-diamine,
(8) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]-l,3,5-triazine- 2,4-diamine,
(9) N2,N4-dicyclohexyl-6- [3 -(3 ,4-dimethoxyphenyl)-5 -(methylthio)- 1 H-pyrazol- 1 -yl] -1,3,5- triazine-2,4-diamine,
( 10) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 -yl]- 1 ,3 , 5 - triazine-2,4-diamine,
(1 1) N2,N4-dicyclohexyl-6-phenyl-l,3,5-triazine-2,4-diamine,
(12) 1 ,1 '-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],
(13) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l,l- dimethylethyl)- phenol,
(14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-l,3,5-triazin-2-yl]-glycine,
(15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3- fluorophenyl)-l,3,5-triazin-2-yl]amino]ethyl]- phenol,
(16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4- fluorophenyl)-l,3,5-triazin-2-yl]amino]ethyl]- phenol,
(17) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine,
(18) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l ,3,5-triazine-2,4-diamine,
(19) 4,4'-[[6-[3,5-bis(l,l-dime lethyl)-4- hydroxyphenyl]-l,3,5-triazine-2,4-diyl]bis(im^ 3,l-propanediyl)]bis[2,6-bis(l,l -dimethylethyl)-phenol,
(20) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(imino-3,l-propanediyl)]bis[2,6-bis(l,l- dimethylethyl)-phenol,
(21) N-[6-[(2,3-dihydro-lH-inden-2-yl)amino]-2-(2-pyridinyl)-4-pyrimidinyl]- alanine,
(22) N4-cyclopentyl-2-phenyl-N6-(phenylmethyl)-4,6-pyrimidinediamine,
(23) 2-[[6-(bicyclo[2.2.1 ]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol,
(24) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l,3,5-triazine-2,4-diamine,
(25) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l,3,5-triazin-2- yl]-benzamide,
(26) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,
(27) [[4-[[[[[4-amino-6-(4-pyridinyl)-l,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4- pyridinyl)-l ,3,5-triazin-2-yl]imino]bis-methanol, (28) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- y 1 ] amino ] methoxy] methyl ] (hydroxy meft^
methanol,
(29) 5-[4,6-bis(diethylamino)-l,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,
(30) N2,N2,N*,N*-tetrae ^
(S ^ N V-^-^^acetylamino^l^^-oxadiazol-S-ylj-l ^^-triazine^^-diyllbis-acetamide,
(32) N-(2-chloro-6-methylphenyl)-5-[[4-(dimethylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]-l ,3,4-Oxadiazole-2-carboxamide,
(33) N4-(5-methyl-lH-pyrazol-3-yl)-2-(2-pyridinyl)-N6-(tetrahydro-2H-pyran-4-yl)-4,6- Pyrimidinediamine,
(34) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(diethylamino)propyl]- 1,3,5 -Triazine-2,4-diamine,
(35) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3- (dimethylamino)propyl]- 1 ,3,5-Triazine-2,4-diamine,
(36) N2-[3,5-bis(trifluoromethyl)phenyl]-6-(4-chlorophenyl)-N4-[3-(diethylamino)propyl]-l ,3,5- Triazine-2,4-diamine,
(37) N2,N4-bis[(4-methoxyphenyl)methyl]-6-[4-(trifluoromethoxy)phenyl]-l ,3,5-Triazine-2,4- diamine,
(38) N,N"-(6-phenyl-l,3,5-triazine-2,4-diyl)bis[N'-(2-chloroethyl)-Urea,
(39) N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-methyl-3-[[4-phenyl-6-(propylamino)-l ,3,5- triazin-2-yl]amino]phenyl]-urea,
(40) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]-glycine,
(41) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(5-thiazolyl)-l, 3, 5-triazin-2-yl]-L- Valine,
(42) s-Triazine, 2-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 ) α,α'- [(6-phenyl- 1,3,5 -triazine-2,4-diyl)bis [imino( 1 , 1 ,2,2-tetrafluoro-3 -oxo-3 , 1 - propanediyl)]]bis[ro-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)- 1,2-ethanediyl]],
(44) a-[[4-[[(3-chlorophenyl)methyl]amino]-6-(lH-imidazol-l -yl)-l,3,5-triazin-2-yl]amino]-N- [[4-(trifluoromethyl)phenyl]methyl]-, (aR)-Cyclohexanepropanamide,
(45) 6-(lH-imidazol-l -yl)-N2,N4-bis(l -methyle l)-l,3,5-Triazine-2,4-diamine, and
(46) N2,N4-bis(l -methylpropyl)-6-phenyl-l ,3,5-Triazine-2,4-diamine.
Also provided is a compound of Formula la, or a pharmaceutically acceptable salt or hydrate thereof:
(la), wherein:
ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein any alkyl portion of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-d alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d-
C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-N(R6)-(d-C6 alkylene)-0-(d-C6 alkyl), -(d-C6 alkylene)-N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)(R6), -(d-C6 alkylene)-N(R6)-S(0)i-2-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-S(O)i-2-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6
alkylene)-Q, -C(0)N(R6)-(Ci-C6 alkylene)-C(O)- (C0-C6 alkylene)-0-(Ci-C6
alkyl), -C(0)N(R6)-(Ci-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-O-C(O)-(C0-C6 alkyl)-Q, -(Ci-C6
alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-0-(d-C6 alkylene)-Q, -(C0-C6
alkylene)-C(O)-(C0-C6 alkylene)-0-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6
alkylene)-0-(Ci-C6 alkylene)-Q, -(Ci-Ce alkylene)-0-C(0)-(d-C6 alkyl), -(Ci-C6alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(d-C6 alkylene)-N(R6)C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-S(O)0-2-(Ci-C6 alkyl), -(Co-Cs alkylene)-S(0)o-2-(Co-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are 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 NCR8)^1)^2)^3) is 4-[[2-[2-(2-aminoethoxy)ethoxy]ethyl]amino] and (b)
N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH2CH2CHO, NHCH2CH2OCH3, NHCH2CH2OH, NHCH2CH(OH)CH3, NHCH2CH2OC(0)phenyl, NHCH2CH2CH2OH,
NHCH2CH2CH2N(CH3)phenyl, NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or NHCH2CH2OC(0)CH3; (ii) when X is N and A is an optionally substituted pyridyl, then (A) neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then Ν^8)^1)^2)^3) is not NHCH2-phenyl or NH-CH2CH3;
(iii) when X is N and A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3; and
(iv) the compound is not selected from the group:
(1) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-phenyl-l ,3,5-triazine-2,4- diamine,
(2) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-methoxyphenyl)-l,3,5- triazine-2,4-diamine,
(3) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(3-nitrophenyl)-l,3,5- triazine-2,4-diamine,
(4) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-fluorophenyl)-l ,3,5- triazine-2,4-diamine,
(5) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-trifluoromethoxy- phenyl)-l,3,5-triazine-2,4-diamine,
(6) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(4-t-butyl-phenyl)-l ,3,5- triazine-2,4-diamine,
(7) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl-6-(2-thienyl)-l ,3,5-triazine- 2,4-diamine,
(8) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-lH-inden-2-yl)amino]-6-phenyl-l,3,5- triazin-2-yl]amino]methyl]-benzamide,
(9) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4- (methylsulfonyl)-benzamide, (10) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-methoxyphenyl)- 1 ,3,5-triazine-2,4-diamine,
(11) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3- yl]thio]-acetamide,
(12) N2-cyclopropyl-N4-ethyl-6-[3-[(phenylme l)thio]-lH ,2,4-triazol-l-yl]-l,3,5- triazine-2,4-diamine,
(13) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3- yl]thio]- acetic acid methyl ester,
(14) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(2,4,6-trimethylphenyl)- l,3,5-triazine-2,4-diamine,
(15) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-phenyl-l ,3,5-triazine- 2,4-diamine,
(16) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-methylphenyl)-l ,3,5- triazine-2,4-diamine,
(17) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl-6-(4-chlorophenyl)-l ,3,5- triazine-2,4-diamine,
(18) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,
(19) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l -yl)-N4-phenyl-l,3,5-triazine-2,4- diamine,
(20) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]- l,3,5-triazine-2,4-diamine,
(21) N2,N4-dicyclohexyl-6-[3-(3,4-dimethoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]- l,3,5-triazine-2,4-diamine,
(22) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 - yl] - 1 ,3 , 5 -triazine-2,4-diamine,
(23) N2,N4-dicyclohexyl-6-phenyl-l,3,5-triazine-2,4-diamine,
(24) 1 ,1 '-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],
(25) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l,l- dimethylethyl)-phenol,
(26) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3- (trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-l ,3,5-triazin-2-yl]-glycine,
(27) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3-fluorophenyl)-l ,3,5-triazin-2-yl]amino]ethyl]- phenol,
(28) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4-fluorophenyl)-l ,3,5-triazin-2-yl]amino]ethyl]- phenol,
(29) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine,
(30) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l ,3,5-triazine-2,4-diamine,
(31) 4,4'-[[6-[3,5-bis(l ,l -dime lethyl)-4-hydroxyphenyl] ,3,5-triazine-2,4- diyl]bis(imino-3,l -propanediyl)]bis[2,6-bis(l ,1 -dimethylethyl)-phenol,
(32) 4,4 (6-phenyl-l ,3,5-triazine-2,4-diyl)bis^
dimethylethyl)-phenol,
(33) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l ,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)-l ,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)-l ,3,5-triazin-2-yl]imino]bis-methanol,
(37) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- yl]amino]methoxy]methyl](hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]i methanol,
(38) 5-[4,6-bis(diethylamino)-l ,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,
(39) N2,N2,N4,N4-tetraethyl-6-(2H-tetrazol-5-yl)-l ,3,5-triazine-2,4-diamine, and
(40) N V-[6-[4-(acetylamino)-l ,2,5-oxadiazol-3-yl]-l ,3,5-triazine-2,4-diyl]bis-acetamide.
Also provided is a compound of Formula la, or a pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000043_0001
(la), wherein:
ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(Ci-Cg alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-N(R6)-(Ci-C6
alkylene)-0-(Ci-C6 alkyl), -(Ci-Cg alkylene)-N(R6)-(C0-C6 alkylene)-Q, -(Ci-Cg
alkylene)-N(R6)(R6), -(Ci-C6 alkylene)-N(R6)-S(0)i-2-(Ci-C6 alkyl), -(d-C6
alkylene)-N(R6)-S(O)i-2-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4
alkylene)-S(0)i-2-N(R6)-(Ci-C6 alkylene)-Q, -C(0)N(R6)-(Ci-C6 alkylene)-C(O)- (C0-C6 alkylene)-0-(Ci-C6 alkyl), -C(0)N(R6)-(Ci-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(Ci-Cg alkylene)-0-C(0)-(d-C6 alkyl), -(Ci-Cg alkylene)-O-C(O)-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-0-(Ci-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6
alkylene)-0-(Ci-C6 alkylene)-Q, -(Ci-Cg alkylene)-0-C(0)-(d-C6 alkyl), -(d-C6
alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-S(O)0-2-(Ci-C6 alkyl), -(C0-C6 alkylene)-S(0)o-2-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(Ci-C4 alkyl), -C02H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; wherein:
(i) when A is optionally substituted phenyl, then (a) neither N(R7)C(R4)(R5)(R6) nor NtR8)^1)^2)^3) is NHCH2CH2OCH2CH2OCH2CH2NH2 or 4-[[2-[2-(2- aminoethoxy)ethoxy]ethyl]amino] and (b) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH2CH2CHO, NHCH2CH2OCH3, NHCH2CH2OH, NHCH2CH(OH)CH3,
NHCH2CH2OC(0)phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2N(CH3)phenyl,
NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or
NHCH2CH2OC(0)CH3;
(ii) when A is an optionally substituted pyridyl, then (A) neither N(R7)C(R4)(R5)(R6) nor NtR8)^1)^2)^3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], N(CH3)2,
NHCH2CH2CH2S02CH2CH2C1, NHCH2CH2OCH2CH2S02CH2CH2Cl,or
NHCH2CH2S02CH2CH2C1, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3; (iii) when A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and
NtR8)^1)^2)^3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;
(iv) when A is optionally substituted 1 -pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor NiR^CiR1)^2)^3) is N(CH3)2, NHCH3, NHAc, NHisopropyl, NHCH2CH3, NHCH2CH2S03H or N(CH2CH3)2,
(v) when A is optionally substituted phenyl,thienyl, or pyridinyl, then neither
N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexylC(0)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3,
(vi) when A is an optionally substituted phenyl and R4 and R5 form an optionally substituted phenyl, then Ν^8)^1)^2)^3) is not NHCH2(4-fluorophenyl), NHCH2C02H, NHCH2C(0)C1, NHCH(C02H)(CH2SCH2phenyl), or NHCH2C(0)NHC(0)NHR or
NHCH2C(0)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl,
(vii) when A is an oxadiazole substituted with an optionally substituted pyridinyl, then R4 and R5 do not form an optionally substituted phenyl,
(viii) when A is substituted 1 -pyrazolyl, then (A) then N(R7)C(R4)(R5)(R6) and
N(R8)C(R1)(R2)(R3) are not both NHC(CH3)3, and (B) A is not substituted with N=N-R, wherein R is a ring,
(ix) ring A is not an optionally substituted triazolyl, 3,5-dimethyl-lH-pyrazol-l -yl,
(x) when R1 and R2 are optionally taken together to form an unsubstituted cyclohexyl, and R4 and R5 are 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-lH-inden-2-yl)amino]-6-phenyl-l,3,5-triazin-2- yl ] amino] methyl] -b enzamide,
(2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4-(methylsulfonyl)- benzamide,
(3) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3-yl]thio]- acetamide,
(4) N2-cyclopropyl-N4-ethyl-6-[3 -[(phenylmethyl)thio]-lH-l ,2,4-triazol-l-yl]-l,3,5-triazine-2,4- diamine,
(5) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3-yl]thio]- acetic acid methyl ester,
(6) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2-yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,
(7) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l -yl)-N4-phenyl-l ,3,5-triazine-2,4-diamine,
(8) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l -yl]-l ,3,5-triazine- 2,4-diamine,
(9) N2,N4-dicyclohexyl-6- [3 -(3 ,4-dimethoxyphenyl)-5 -(methylthio)- 1 H-pyrazol- 1 -yl] -1 ,3,5- triazine-2,4-diamine,
( 10) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 -yl]- 1 ,3 , 5 - triazine-2,4-diamine,
(1 1) N2,N4-dicyclohexyl-6-phenyl-l ,3,5-triazine-2,4-diamine,
(12) 1 ,1 '-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],
(13) 4,4'-[(6-phenyl-l ,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l ,l - dimethylethyl)- phenol,
(14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-l ,3,5-triazin-2-yl]-glycine,
(15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3-fluorophenyl)-l ,3,5-triazin-2-yl]amino]ethyl]- phenol,
(16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4-fluorophenyl)-l ,3,5-triazin-2-yl]amino]ethyl]- phenol,
(17) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine,
(18) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l ,3,5-triazine-2,4-diamine,
(19) 4,4'-[[6-[3,5-bis(l ,l -dime lethyl)-4-hydroxyphenyl]-l ,3,5-triazine-2,4-diyl]bis(imm^ propanediyl)]bis[2,6-bis(l ,l -dimethylethyl)-phenol,
(20) 4,4'-[(6-phenyl-l ,3,5-triazine-2,4-diyl)bis(imino-3,l -propanediyl)]bis[2,6-bis(l J
dimethylethyl)-phenol,
(21) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l ,3,5-triazine-2,4-diamine,
(22) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]-benzamide, (23) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,
(24) [[4-[[[[[4-amino-6-(4^yridinyl)-l,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4- pyridinyl)-l ,3,5-triazin-2-yl]imino]bis-methanol,
(25) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- y 1 ] amino ] methoxy] methyl ] (hydroxy meft^
methanol,
(26) 5-[4,6-bis(diethylamino)-l,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,
(27) N2,N2 -tetraethyl-6-(2H-tetrazol-5-yl)-l,3,5-triazine-2,4-diami^
(28) N V'-[6-[4-(acetylamino)-l,2,5-oxadiazol-3-yl]-l ,3,5-triazine-2,4-diyl]bis-acetamide,
(29) N-(2-chloro-6-methylphenyl)-5-[[4-(dimethylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]-l ,3,4-Oxadiazole-2-carboxamide,
(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]-l ,3,5- Triazine-2,4-diamine,
(33) N2,N4-bis[(4-methoxyphenyl)methyl]-6-[4-(trifluoromethoxy)phenyl]-l ,3,5-Triazine-2,4- diamine,
(34) N,N"-(6-phenyl-l,3,5-triazine-2,4-diyl)bis[N'-(2-chloroethyl)-Urea,
(35) N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-methyl-3-[[4-phenyl-6-(propylamino)-l ,3,5- triazin-2-yl]amino]phenyl]-urea,
(36) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]-glycine,
(37) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(5-thiazolyl)-l, 3, 5-triazin-2-yl]-L- Valine,
(38) s-Triazine, 2-phenyl-4,6-bis[[6-[[4-phenyl-6-[[6-[[4-phenyl-6-(trichloromethyl)-s-triazin-2- yl]amino]hexyl]amino]-s-triazin-2-yl]amino]hexyl]amino]-,
(39) α,α'- [(6-phenyl- 1,3,5 -triazine-2,4-diyl)bis [imino( 1 , 1 ,2,2-tetrafluoro-3 -oxo-3 , 1 - propanediyl)]]bis[ro-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)- 1,2-ethanediyl]],
(40) a-[[4-[[(3-chlorophenyl)methyl]amino]-6-(lH-imidazol-l-yl)-l,3,5-triazin-2-yl]amino]-N^ [[4-(trifluoromethyl)phenyl]methyl]-, (aR)-Cyclohexanepropanamide,
(41) N,A -[6-[4-(acetylamino)-l,2,5-oxadiazol-3-yl] ^
(42) 6-(l H-imidazol- 1 -yl)-N2,N4-bis( 1 -methylethyl)- 1,3,5 -Triazine-2,4-diamine, and
(43) N2,N4-bis(l -methylpropyl)-6-phenyl-l ,3,5-Triazine-2,4-diamine.
In some embodiments, R and R4 are eachindependently selected from
hydrogen, -CH3, -CH2CH3,-CH2OH, -CH(CH3)OH,-C(CH3)2OH, CF3, CN, or R1 and R3 are taken together to form =0; orR4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0).
In some embodiments, R1 and R2 are taken together to form carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, -CN, =0, -OH, and -C(0)Ci-C4 alkyl.In some embodiments, R1 and R2 are taken together to form a carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, Ci-C alkyl, Ci-C haloalkyl, Ci-C alkoxy, -CN, =0, -OH, aryl, heteroaryl- S02Ci-C4 alkyl, -C02Ci-C4 alkyl, -C(0)aryl,and -C(0)d-C4 alkyl. In some embodiments R1 and R2 are taken together to form a carbocyclyl or heterocyclyl, either of which is optionally substituted with aryl or heteroaryl, which is optionally substituted with up to 2 substituents independently selected from halo, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, -CN, and -OH. In some embodiments R1 and R2 are taken together to form a carbocyclyl or heterocyclyl, either of which is optionally substituted with phenyl, pyridinyl or pyrimidinyl, which is optionally substituted with up to 2 substituents independently selected from halo, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, -CN, and -OH.
In some embodiments, R4 and R5 are taken together to form carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, C C4 alkyl, C C4 haloalkyl, C C4 alkoxy, -CN, =0, -OH, and -C(0)Ci-C4 alkyl.In some embodiments, R4 and R5 are 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-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, =0, -OH, aryl, heteroaryl - SO2C1-C4 alkyl, -CO2C1-C4 alkyl, -C(0)aryl, and -C(0)Ci-C4 alkyl. In some embodiments R1 and R2 are taken together to form a carbocyclyl or heterocyclyl, either of which is optionally substituted with aryl or heteroaryl, which is optionally substituted with up to 2 substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, and -OH. In some embodiments R1 and R2 are 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-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, and -OH.
In some embodiments,R2 and R5 are each independently selected from: -(Ci-C6 alkyl), - (Ci-C6 alkyl)-C(0)-NH2, -(Ci-C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6
alkylene)-0-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl),
-(Co-Cg alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), and -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, =0, -C(0)-Ci-C4 alkyl, -CN, and halo.
In some embodiments, R2and R5 are each independently selected from: -(C1-C4 alkyl) optionally substituted with halo, e.g., fluoro or -OH;-(C0-C4 alkylene)-0-(Ci-C4 alkyl), -(C0-C2 alkylene)-N(R6)-(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(O)-NH2,-(C0-C2 alkylene)-Q, -(C0-C6
alkylene)-C(0)-(Ci-C6 alkyl), and -O-(C0-C2 alkylene)-Q, wherein Q is optionally substituted with up to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, =0, -C(0)-Ci-C4 alkyl, -CN, and halo. In one aspect of these embodiments, Q is selected from pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl and oxetanyl, wherein Q is optionally substituted with up to 2 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, =0, fluoro, chloro, and bromo. In another aspect of these embodiments, Q is selected from pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl and oxetanyl, wherein Q is optionally substituted with up to 2
substituents independently selected from -CH3 and =0. In some embodiments, R1 and R2 are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl, oxobicyclo[3.1.0]hexanyl, azetidinyl, any of which is optionally substituted with up to 2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy,C3-C6
cycloalkyl, -OH, -C(0)CH3, fluoro, and chloro.
In some embodiments, R4 and R5 are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl, oxobicyclo[3.1.0]hexanyl, or azetidinyl, any of which is optionally substituted with up to 2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy,C3-C6
cycloalkyl, -OH, -C(0)CH3, fluoro, and chloro. In some embodiments, R4 and R5 are taken together to form phenyl, pyrazolyl, imidazolyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, thiadiazolyl or isothiazolyl,any of which is optionally substituted with up to 2 substituents independently selected from halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C3-C6 cycloalkyl, phenyl,-OH, -C(0)CH3, wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH2, or-CN. In some
embodiments the C3-C6cycloalkyl is
Figure imgf000050_0001
In some embodiments, R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, - NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2; and R2 and R5 are each independently selected
from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d-C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), and -(C0-C6 alkylene)-C(0)-(Ci-C6 alkyl), wherein:any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(Ci-C4 alkyl), -C02H, or halo; and any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H; or R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl; or R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, wherein, when A is an optionally substituted phenyl, 2-pyrrolyl, or 1-imidazolyl, then N(R7)C(R4)(R5)(R6) is not the same as
NCR^CCR'XR'XR3), and the compound is not 2-(l,2-dibromoethyl)-4-phenyl-6-(l, 1,2,2,3,3 ,4,4,5,5,6,6,6- tridecafluorohexyl- 1 ,3 ,5 -Triazine.
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, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(0)2-(Ci-C4
alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(d-C4 alkyl), C1-C4 alkoxy, -NH(Ci-C4
alkyl), -OH, -OCF3, -CN, -NH2, -C(0)NH2, -C(0)NH(Ci-C4 alkyl), -C(0)-N(Ci-C4
alkyl)2, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), azetidinyl, phenyl, and cyclopropyl optionally substituted with OH. In some embodiments, ring A is a substituted 5-6 member monocyclic aryl or monocyclic heteroaryl, which is substituted with up to two substituents independently selected from fluoro, chloro, CF3, CF2, -OH, -OCH3, -OCF3, -CN, -NH2.In some embodiments, ring A is a substituted 6-membered monocyclic aryl. In some embodiments, ring A is a substituted 5-6 membered heteroaryl. In some embodiments, ring A is a substituted 5-membered heteroaryl.
In some embodiments, ring A is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, wherein ring A is optionally substituted with up to two substituents independently selected from halo, -Ci-C alkyl, -Ci-C haloalkyl, -Ci-C hydroxyalkyl, -NH-S(0)2-(Ci-C4 alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(Ci-C4 alkyl), Ci-C4 alkoxy, -NH(Ci-C4 alkyl), -OH, -OCF3, -CN, -NH2, -C(0)NH2, -C(0)NH(Ci-C4 alkyl), - C(0)-N(Ci-C alkyl)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, thiadiazolyland isothiazolyl, wherein ring A is optionally substituted with up to two substituents independently selected from halo, -Ci-C4 alkyl, -Ci-C4 haloalkyl, -Ci-C4 hydroxyalkyl, -NH-S(0)2-(Ci-C4 alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(Ci-C4 alkyl), Ci-C4 alkoxy, -NH(Ci-C4
alkyl), -OH, -CN, and -NH2. In some embodiments, ring A is monocyclic heteroaryl optionally substituted with halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -O-C1-C4 haloalkyl, -OH, -CN, and -NH2; R1, R3, R4, and R6 are each independently selected from hydrogen and C1-C4 alkyl; and R2 and R5 are each independently -(C0-C6 alkylene)-Q; or R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl; orR4 and R5 are 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, -C1-C4 alkyl, -C1-C4 haloalkyl, -O-C1-C4 haloalkyl, -OH, -CN, and -NH2; R1, R3, R4, and R6 are each independently selected from hydrogen and C1-C4 alkyl; and R2 and R5 are each independently -(C0-C6 alkylene)-Q; or R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl oran optionally substituted heterocyclyl; orR4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroar l.
In some embodiments, ring A is:
Figure imgf000052_0001
, wherein R is selected from hydrogen, halo, and -C1-C4 haloalkyl; each Xa is independently N or C-R9a, provided that when one Xa is N, then the other two Xa are both C-R9a; and R9a is selected from hydrogen, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is:
Figure imgf000053_0001
, wherein R9 is selected from hydrogen, halo,
and -C1-C4 haloalkyl. In some embodiments, ring A is:
Figure imgf000053_0002
, wherein R9 is selected from h drogen, halo, and -C1-C4 haloalkyl. In some embodiments, ring A is:
Figure imgf000053_0003
is selected from hydrogen, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is pyridinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyridinyl optionally substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyridi -2-yl substituted with -C1-C4 haloalkyl, e.g., -CHF2 and
CF3. In some embodiments, ring A is:
Figure imgf000053_0004
wherein R is selected from hydn halo, and -C1-C4 haloalkyl. In some embodiments, ring A is:
Figure imgf000054_0001
, wherein each R9 is independently selected from hydrogen, halo, and -C1-C4 haloalkyl. In some embodiments, R9 is chloro or fluoro. In some embodiments, R9 is -CHF2or CF3. In some embodiments, R9 is CF3 or chloro. In some embodiments, R9 is CF3.
In some embodiments, ring A is:
Figure imgf000054_0002
is selected from hydrogen and -C1-C4 alkyl, and wherein R9 is selected from hydrogen, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is:
Figure imgf000054_0003
, wherein R is selected from hydrogen and -C1-C4 alkyl, and wherein R is selected from h drogen, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is:
Figure imgf000054_0004
, wherein R is selected from hydrogen and -C1-C4 alkyl, and wherein R is selected from hydrogen, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is:
Figure imgf000055_0001
, wherein R is selected from hydrogen, halo, and -C1-C4 haloalkyl. In some embodiments, ring A is pyrazolyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrazolyl optionally substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is IH-pyrazol-l- l substituted with -C1-C4
haloalkyl, e.g., -CHF2 and CF3. In some embodiments, ring A is:
Figure imgf000055_0002
, wherein R is selected from hydrogen, halo, and -C1-C4 haloalkyl. In some embodiments, R9 is chloro or fluoro. In some embodiments, R9 is -CHF2 or CF3. In some embodiments, R9 is CF3 or chloro. In some embodiments, R9 is CF3.
g
In some embodiments, ring A is:
Figure imgf000055_0003
, wherein R is selected from hydrogen, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is:
Figure imgf000056_0001
wherein R9 is selected from hydi halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is:
Figure imgf000056_0002
, wherein R is selected from hydrogen, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is:
Figure imgf000056_0003
is selected from hydrogen, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is:
Figure imgf000056_0004
, wherein R is selected from hydrogen, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is:
Figure imgf000057_0001
, wherein R9 is selected from hyd:
halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is:
Figure imgf000057_0002
, wherein R9 is selected from hydrogen, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is pyridinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyridinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyridinyl substituted with -C1-C4 haloalkyl, e.g., -CHF2 and CF3. In some embodiments, ring A is pyrazinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrazinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazinyl substituted with -C1-C4 haloalkyl, e.g., -CF£F2 and CF3. In some embodiments, ring A is pyrimidinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrimidinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrimidinyl substituted with -C1-C4 haloalkyl, e.g., -CF£F2 and CF3. In some embodiments, ring A is pyrazolyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrazolyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazolyl substituted with -C1-C4 haloalkyl, e.g., -CF£F2 and CF3.
In some embodiments, R1, R3, R4, and R6 are each independently selected from hydrogen and C1-C4 alkyl; and R2 and R5 are each independently -(C0-C6 alkylene)-Q. In some embodiments, R1 and R4 are each hydrogen. In some embodiments, R3 and R6 are each C1-C4 alkyl. In some embodiments, R3 and R6 are each C1-C4 haloalkyl. 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, R2 and R5 are each independently unsubstituted cyclopropyl. In some
embodiments, R1 and R4 are each hydrogen, R3 and R6 are each -CH3, and R2 and R5 are each unsubstituted cyclopropyl. In some embodiments, R2 is -(C0-C6 alkylene)-cyclopropyl and R5 is -(C0-C6 alkyl en e)-aryl, e.g., optionally substituted phenyl. In some embodiments, R2 is cyclopropyl and R5 is phenyl substituted with halo, e.g., fluoro.
In some embodiments, ring A is pyridinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyridinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyridinyl substituted with -C1-C4 haloalkyl, e.g., -CHF2 and CF3. In some embodiments, ring A is pyrazinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrazinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazinyl substituted with -C1-C4 haloalkyl, e.g., -CHF2 and CF3. In some embodiments, ring A is pyrimidinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrimidinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrimidinyl substituted with -C1-C4 haloalkyl, e.g., -CHF2 and CF3. In some embodiments, ring A is pyrazolyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrazolyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazolyl substituted with -C1-C4 haloalkyl, e.g., -CF£F2 and CF3.
In some embodiments, R3 and R6 are each independently selected from hydrogen and C1-C4 alkyl; R1 and R2 are taken together to form an optionally substituted carbocyclyl; and R4 and R5 are taken together to form an optionally substituted carbocyclyl.In some embodiments, R1 and R2 are taken together to form a cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted. In some embodiments, R1 and R2 are taken together to form a cyclopentyl or cyclohexyl, each optionally substituted. In some embodiments, R4 and R5 are taken together to form a cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted. In some embodiments, R4 and R5 are taken together to form a cyclopentyl or cyclohexyl, each optionally substituted. In some embodiments, R1 and R2 are taken together to form a cyclopentyl or cyclohexyl, each substituted by one or more halo, e.g., fluoro; and R4 and R5 are taken together to form a cyclobutyl, cyclopentyl or cyclohexyl, each substituted by one or more halo, e.g., fluoro. In some embodiments, R1 and R2 are taken together to form a bicyclo[3.1.OJhexanyl; and R4 and R5 are taken together to form a bic clo[3.1.O hexanyl.In some embodiments, R1 and R2 taken together,
or
Figure imgf000059_0001
1 and R taken together, and R4 and R5 taken
Figure imgf000059_0002
halo, e.g. fluoro, chloro, or bromo. In some embodiments, R1 and R2 taken together, and R4 and R5 taken together form:
Figure imgf000060_0001
.In some embodiments, R1 and R2 are 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 R4 and R5 are 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, R1 and R2or R4 and
R3 are taken together form:
Figure imgf000060_0002
, 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 and R2or R4 and R5 are taken together form:
Figure imgf000060_0003
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 and R2or R4 and R5 are taken
together
Figure imgf000060_0004
phenyl, pyridyl, or pyrimidinyl, which is optionally substituted with cyano or halo, e.g. fluoro, chloro, or bromo.
In som embodiments, ring A is pyridinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyridinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyridinyl substituted with -C1-C4 haloalkyl, e.g., -CHF2 and CF3. In some embodiments, ring A is pyrazinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrazinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazinyl substituted with -C1-C4 haloalkyl, e.g., -CHF2 and CF3. In some embodiments, ring A is pyrimidinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrimidinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrimidinyl substituted with -C1-C4 haloalkyl, e.g., -CF£F2 and CF3. In some embodiments, ring A is pyrazolyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrazolyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazolyl substituted with -C1-C4 haloalkyl, e.g., -CF£F2 and CF3.
In some embodiments, R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, and -CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl; and R2 and R5 are each
independently selected from -(Ci-C6 alkyl) and -(C0-C6 alkylene)-Q. In some embodiments, R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, and -CN; and R2 and R5 are each independently -(Ci-C6 alkyl) and -(C0-C6 alkylene)-Q. In some embodiments, R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, and -CN; R2 is -(Ci-C6 alkyl); and R5 is -(C0-C6 alkylene)-Q, wherein Q is optionally substituted carbocyclyl. In some embodiments, Q is unsubstituted carbocyclyl. In some embodiments, Q is cyclopropyl.
In some embodiments, ring A is pyridinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyridinyl substituted with -C1-C4 haloalkyl, e.g., -CF£F2 and CF3. In some embodiments, ring A is pyrazinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrazinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazinyl substituted with -C1-C4 haloalkyl, e.g., -CF£F2 and CF3. In some embodiments, ring A is pyrimidinyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrimidinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrimidinyl substituted with -C1-C4 haloalkyl, e.g., -CF£F2 and CF3. In some embodiments, ring A is pyrazolyl optionally substituted with halo or -C1-C4 haloalkyl. In some embodiments, ring A is pyrazolyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyrazolyl substituted with -C1-C4 haloalkyl, e.g., -CF£F2 and CF3. In some embodiments, R1, R3, and R6 are each independently selected from hydrogen and C1-C4 alkyl, wherein each said alkyl moiety of R1, R3, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(d-C4 alkyl)2; R2 is -(C0-C6 alkylene)-Q; and R4 and R5 taken together form an optionally substituted carbocyclyl, optionally substituted heterocyclyl or optionally substituted heteroaryl. In some embodiments, R4 and R5 taken together form an optionally substituted carbocyclyl. In some embodiments, the carbocyclyl is selected from cyclopentyl and cyclohexyl optionally substituted
with -OH, -0(Ci-C4 alkyl), -C02H, or halo. In some embodiments, R4 and R5 taken together form an optionally substituted heterocyclyl optionally substituted with -OH, -0(Ci-C4 alkyl), - C02H, or halo. In some embodiments, R4 and R5 taken together form an optionally substituted tetrahydrofuran. In some embodiments, R1, R3, and R6 are each independently selected from hydrogen and C1-C4 alkyl, wherein each said alkyl moiety of R1, R3, and R6 are each
independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl; R2 is -(C0-C6 alkylene)-Q; and R5 is C1-C4 alkyl. In some embodiments, R1, R3, and R6 are each independently selected from hydrogen, C1-C4 alkyl, or carbocyclyl, wherein any alkyl or carbocyclyl portion of R1, R3, and R6are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -S02-Ci-C4 alkyl, -C(0)NH2, -0-R12,-C02R12 or -C(0)R12, wherein R12 is morpholino, piperidinyl, phenyl, pyridyl, or pyrimidinyl. In some embodiments, R1, R3, and R6 are each independently selected from hydrogen and C1-C4 alkyl, wherein each said alkyl moiety of R1, R3, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -O- R12, wherein R12 is phenyl, pyridyl, or pyrimidinyl; R2 is -(C0-C6 alkylene)-Q; and R5 is C1-C4 alkyl.
In some embodiments, R7 is H. In some embodiments, R8 is H. In some embodiments, both R7 and R8 are H.
In some embodiments, ring A, R1, R2, R3, R4, R5, R6, R7, R8 are selected from any one of the preceding embodiments.
Also provided is a compound of Formula B, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000063_0001
(B), wherein:
X isN, CH or C-halo;
Xa is N or C-R9a, provided that when one Xa is N, then the other two Xa are both C-R9a;
R9is halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(0)2-(Ci-C4
alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(d-C4 alkyl), C1-C4 alkoxy, -NH(Ci-C4 alkyl), - N(Ci-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, -C(0)NH2, -C(0)NH(Ci-C4 alkyl), -C(0)-N(d-C4 alkyl)2, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), aryl, and cyclopropyl optionally substituted with OH; each R9a is independently selected from hydrogen, halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(0)2-(Ci-C4 alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(Ci-C4 alkyl), C1-C4 alkoxy, -NH(Ci-C4 alkyl), -N(d-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, -C(0)NH2, - C(0)NH(Ci-C4 alkyl), -C(0)-N(d-C4 alkyl)2, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), aryl, and cyclopropyl optionally substituted with OH;
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(d-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-d alkyl), -(Ci-d alkyl)-C(0)-NH2, -(d- C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl),
-(Co-Cg alkylene)-Q,-(C0-C6 alkylene)-C(0)-(d-C6 alkyl), and-(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, an optionally substituted 5-6 member monocyclic aryl, or an optionally substituted 5-6 member monocyclic heteroaryl;
whereinthe compound is not selected from the group:
(1) 4,6-Pyrimidinediamine, 2-(6-methyl-2-pyridinyl)-N4,N6-dipropyl-;
(2) 4,6-Pyrimidinediamine, N4-ethyl-2-(6-methyl-2-pyridinyl)-N6-propyl-;
(3) 4,6-Pyrimidinediamine, N4,N4-diethyl-2-(6-methyl-2-pyridinyl)-N6-propyl-;
(4) [2,4'-Bipyrimidine]-2',4,6-triamine, N6-[2-(dimethylamino)ethyl]-N2',N2',N4,N4- tetramethyl-; or
(5) [2,4'-Bipyrimidine]-2',4,6-triamine, N6-[2-(dimethylamino)ethyl]-N2',N2',N4,N4- tetramethyl-, phosphate.
In some embodiments, X is N and R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.
Also provided is a compound of Formula lb, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000065_0001
(lb), wherein:
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(Ci-Cg alkyl)-C02H -(Co-Cg alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH, CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl;
R9 is selected from hydrogen, halo, and -C1-C4 haloalkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl;
wherein: (i) neither N(R7)C(R4)(R5)(R6) nor NCR^CCR1)^2)^3) is NHC(0)-[2-chloro-4-(methylsulfonyl)] or N(CH3)2,
(ii) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3,
NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and
(iii) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3; and
wherein the compound is not:
(1) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2-yl]-4-(methylsulfonyl)- benzamide,
(2) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2-yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,
(3) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l ,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 la, or a pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000066_0001
(Ig), wherein: ring A is is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;
R3 and R6 are both hyd: R1 and R4 are each independently selected from C1-C4 alkyl and C1-C4 haloalkyl;and R2 and R5 are each -(Ci-C6 alkyl); or
R1 and R2 are optionally taken together to form an optionally substituted monocyclic carbocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted monocyclic carbocyclyl ;
wherein:
(i) ring A is not an optionally substituted triazolyl, 3,5-dimethyl-lH-pyrazol-l-yl,
(ii) when R1 and R2 are optionally taken together to form an unsubstituted cyclohexyl, and R4 and R5 are 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-(lH-imidazol-l-yl)-N2,N4-bis(l -methylethyl)-l ,3,5-Triazine-2,4-diamine, or
(2) N2,N4-bis(l -methylpropyl)-6-phenyl-l ,3,5-Triazine-2,4-diamine.
Also provided is a compound of Formula C, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000067_0001
(C), wherein:
X is N, CH or C-halo;
each Xb is independently N-R9b, O, S, C-H, or C-R9c, provided that at least one Xb is C-R9c, and when one Xbis C-H or C-R9and the other is C-R9c then Xc is N, and when one Xb is N-R9b, O, or S,then Xc is C;
R9bis hydrogen or -C1-C4 alkyl;
R9c is halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(0)2-(Ci-C4 alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(Ci-C4 alkyl), C1-C4 alkoxy, -NH(Ci-C4 alkyl), - N(Ci-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, -C(0)NH2, -C(0)NH(d-C4 alkyl), -C(0)-N(d-C4 alkyl)2, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), aryl, and cyclopropyl optionally substituted with OH; R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4
haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(Ci- C6 alkyl)-C02H -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), -(C0-C6
alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-d alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, an optionally substituted 5-6 member monocyclic aryl, or an optionally substituted heteroaryl;
wherein:
(i) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1-pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH; and
(ii) when X and Xc are both N, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)2, NHCH3, or N(CH2CH3)2.
Also provided is a compound having Formula Id, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000069_0001
(Id), wherein:
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(Ci-Cg alkyl)-C02H -(Co-Cg alkylene)-Q, -(C0-C6 alkylene)-C(0)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH, CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl;
R9 is halo or-Ci-C4 haloalkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted
carbocyclyl,optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
whereinthe compound is not:
(1) N2,N2,N4-trimethyl-6-[3-(trifluoromethyl)-lH-pyrazol-l -yl]- l,3,5-Triazine-2,4-diamine, or
(2) N4-ethyl-N2,N2-dimethyl-6-[3-(trifluoromethyl H-pyrazol-l -yl]-l ,3,5-Triazine-2,4-diamine.
A com ound having Formula Ie, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000070_0001
(Ie), wherein
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4
haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(Ci-Cg alkyl)-C02H -(Co-Cg alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), -(C0-C6 alkylene)-C(0)-(Co-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH, CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl;
R9 is selected from hydrogen, halo, and -C1-C4 haloalkyl; and Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0);
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.
A com ound having Formula If, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000071_0001
(If), wherein
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(Ci-Cg alkyl)-C02H -(Co-Cg alkylene)-Q, -(C0-C6 alkylene)-C(0)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(0)-(Co-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH, CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H; R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl;
R9 is selected from hydrogen, halo, and -C1-C4 haloalkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0);
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.
Also provided is a compound of Formula Π, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000072_0001
(Π), wherein:
ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(Ci-Cg alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(C C6
alkylene)-N(R6)-(Ci-C6alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-(C0-C6
alkylene)-Q, -(Ci-C6 alkylene)-N(R6)(R6), -(Ci-C6 alkylene)-N(R6)-S(0)i-2-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-S(O)i-2-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6 alkylene)-Q, -C(0)N(R6)-(Ci-C6 alkylene)-C(O)- (C0-C6 alkylene)-0-(Ci-C6 alkyl), -C(0)N(R6)-(Ci-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-O-C(O)-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-0-(Ci-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6
alkylene)-0-(Ci-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(Ci-C6 alkyl), -(Ci-C6
alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-S(O)0-2-(Ci-C6 alkyl), -(C0-C6 alkylene)-S(0)o-2-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH, CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
wherein: (i) when A is phenyl optionally substituted with F, CI or S02CH3, then neither
N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(0)NH-i-propyl,
NHCH(CH3)(CH2)3N(CH2CH3)2, NHCH2CH2OH, NHCH2CH2OCH3, NHCH2CH2OS03H, NHCH2CH2CH2OCH2CH20-phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2OCH3,
NHCH2CH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCH2CH2NHC(0)OCH3,
NHCH2CH2NHC(0)CH3, NHCH2CH2NH2, or NHCH2-phenyl;
(ii) when A is optionally substituted pyridyl, then neither N(R7)C(R4)(R5)(R6) nor
NtR8)^1)^2)^3) is NHCH2-phenyl, NHCH2-(2,4-difluorophenyl), N(CH3)CH2CH2C(0)OH, NHCH2CH2C(0)OH, NHCH2CH2C(0)OCH2CH3, NHCH2CH2C(0)0-t-butyl,
NHCH2CH2C(0)NH2, NHCH2CH2-phenyl, NHCH2CH2OH, NHCH2CH2NH2,
NHCH2CH2N(CH3)2, or NHCH2CH2CH3;
(iii) when A is optionally substituted 1-imidazolyl, optionally substituted 1 -pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is
NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH;
(iv) when A is unsubstituted 2-pyridinyl, then the ring formed by R4 and R5 is not 5 -methyl- 1H- pyrazol-3-yl; and
(v) when A is optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor
NtR8)^1)^2)^3) is N(CH3)2, NHCH3, NHAc, NHisopropyl, NHCH2CH3, NHCH2CH2S03H or N(CH2CH3)2,
(vi) ring A is not an optionally substituted triazolyl, 3, 5 -dimethyl- lH-pyrazol-l-yl,
(vii) when R1 and R2 are optionally taken together to form an unsubstituted cyclohexyl, and R4 and R5 are optionally taken together to form an unsubstituted cyclohexyl, then A is not a disubstituted 1-pyrazolyl or an unsubstituted phenyl; and
(viii) the compound is not selected from the group:
(1) 6-(lH-imidazol-l-yl)-N2,N4-bis(l -methylethyl)-l ,3,5-Triazine-2,4-diamine, or
(2) N2,N4-bis(l -methylpropyl)-6-phenyl-l ,3,5-Triazine-2,4-diamine. Also provided is a compound of Formula Ic, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000075_0001
(Ic), wherein:
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
each R9 is independently selected fromhalo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4
hydroxyalkyl, -NH-S(0)2-(Ci-C4 alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(d-C4 alkyl), C1-C4 alkoxy, -NH(Ci-C4 alkyl), -N(d-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, -C(0)NH2, - C(0)NH(Ci-C4 alkyl), -C(0)-N(d-C4 alkyl)2, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), aryl, and cyclopropyl optionally substituted with OH;
n is 1 to 3 ;
R2 and R5 are each independently selected from: -(Ci-d alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d- C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl),
-(Co-Cg alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), and -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl;
wherein:
(i) neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCH2CH2OCH2CH2OCH2CH2NH2, or 4-[[2-[2-(2-aminoethoxy)ethoxy]ethyl]amino],
(ii) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH2CH2CHO, NHCH2CH2OCH3, NHCH2CH2OH, NHCH2CH(OH)CH3, NHCH2CH2OC(0)phenyl, NHCH2CH2CH2OH,
NHCH2CH2CH2N(CH3)phenyl, NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or NHCH2CH2OC(0)CH3; and
(iii) neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexylC(0)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3.
Also provided is a compound of Formula ΠΙ, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000076_0001
(ΙΠ), wherein:
ring A is an optionally substituted 5-6 member monocyclic heteroaryl;
ring B is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;
R1 and R3are each independently selected from hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(d-C4 alkyl), or -N(d-C4 alkyl)2;
R2is selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d-C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl),-(Co-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), and -(C0-C6
alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 is optionally substituted with one or
more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
wherein when A is an oxadiazole substituted with an optionally substituted pyridinyl, then G is not an optionally substituted phenyl.
In some embodiments, G is substituted with 1 or 2 substituents selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, =0, -OH, aryl, heteroaryl -S02Ci-C4 alkyl, -C02Ci-C4 alkyl, -C(0)aryl, and -C(0)d-C4 alkyl.
Also provided is a compound of Formula nia, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000078_0001
(Ilia), wherein:
ring A is a substituted 5-6 member monocyclic heteroaryl;
Xd is C or N;
each Rb is independently selected from halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -OH, -C(0)CH3, wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH2, or -CN;
p is 1 to 2;
R1 and R3are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(d-C4 alkyl), or -N(d-C4 alkyl)2;
R2is selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(Ci-C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(0)N(R6)-(d-C6 alkyl),
-(Co-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(Ci-C6 alkyl), and -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 is optionally substituted with one or
more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form
C(=0); or R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
wherein when A is an oxadiazole substituted with an optionally substituted pyridinyl, then Xd is not C.
Also provided is a compound of Formula nib, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000079_0001
(nib), wherein:
ring A is a substituted 5-6 member monocyclic heteroaryl;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl;
each Rb is independently selected from halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -OH, -C(0)CH3, wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH2, or -CN;
p is 1 to 2;and
G is an optionally substituted carbocyclyl or heterocyclyl,
wherein A is not an oxadiazole substituted with an optionally substituted pyridinyl.
Also provided is a compound of Formula Hie, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000079_0002
(IIIc), wherein: ring A is a substituted 5-6 member monocyclic heteroaryl;
R1 and R3are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2is selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d-C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl),
-(Co-Cg alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), and -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 is optionally substituted with one or
more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
each Rb is independently selected from halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -OH, -C(0)CH3, wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH2, or -CN; and
p is 1 to 2.
Also provided is a compound of Formula Hid, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000081_0001
ring A is a substituted 5-6 member monocyclic heteroaryl;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl;
each Rb is independently selected from halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -OH, -C(0)CH3, wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH2, or -CN;
p is 1 to 2;and
G is an optionally substituted carbocyclyl or heterocyclyl.
Further embodiments provided herein include combinations of one or more of the particular embodiments set forth above.
In another embodiment, the compound is selected from any one of the compounds set forth in Table 1 , below.
Table 1. Representative Compounds
Figure imgf000081_0002
Figure imgf000081_0003
Figure imgf000081_0004
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
87
Figure imgf000089_0001
88
Figure imgf000090_0001

Figure imgf000091_0001
90
Figure imgf000092_0001
Figure imgf000093_0001
92
Figure imgf000094_0001
93
Figure imgf000095_0001
Figure imgf000096_0001
95
Figure imgf000097_0001
96
Figure imgf000098_0001
97
Figure imgf000099_0001
98
Figure imgf000100_0001
99
Figure imgf000101_0001
100
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
104
Figure imgf000106_0001
105
Figure imgf000107_0001
106
Figure imgf000108_0001
107
Figure imgf000109_0001
108
Figure imgf000110_0001
109
Figure imgf000111_0001
110
Figure imgf000112_0001
111
Figure imgf000113_0001
112
Figure imgf000114_0001
113
Figure imgf000115_0001
114
Figure imgf000116_0001
115
Figure imgf000117_0001
116
Figure imgf000118_0001
117
Figure imgf000119_0001
118
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Included herein are also methods for making compounds of Formula I or a com ound of any one
Figure imgf000123_0002
of the embodiments described herein comprising reacting
Figure imgf000123_0003
embodiments, the preceding methods comprise step (1) reacting
Figure imgf000124_0001
.. I inn o otthheerr e emmbbooddimments, the recedin methods comprise step
Figure imgf000124_0002
(1) reacting (2) reacting
; and step (3) reacting
Figure imgf000124_0003
Also included are methods for making compounds of Formula or a compound of any one of the embodiments described herein comprising reacting
Figure imgf000124_0004
. Also included are methods for making compounds of Formula I or a compound of any
Figure imgf000125_0001
In some embodiments, the preceding methods comprise step (1) reacting
; and step (2) reacting
Figure imgf000125_0002
Also included are methods for making compounds of Formula I or a compound of any one of the embodiments described herein comprising reacting
H
Figure imgf000125_0003
with . In other embodiments, the preceding methods comprise step
(1) converting
Figure imgf000125_0004
0Et under basic conditions to give HO H ;
step (2) reacting
Figure imgf000125_0005
; step (3) reacting step (4) reacting the preceding methods comprise s
Figure imgf000126_0001
tep (1) converting asic conditions to give 3 to give ; step (3) nd step (4) reacting
Figure imgf000126_0002
. In other embodiments, the preceding methods comprise step (1) converti step (2) reacting
Figure imgf000127_0001
I ; step (3) reacting
CI
Figure imgf000127_0002
to give
with R6 .In other embodiments, the method
Figure imgf000127_0003
under basic conditions t
ring Gis a carbocycl l or heteroc cl l rin .In other embodiments, the method comprises the steps of l)reacting
Figure imgf000127_0004
and 2) reacting
Figure imgf000128_0001
to give 5 wherein ring B is an aryl
Figure imgf000128_0002
under basic conditions to give 5 wherein ring B is an aryl or heteroaryl ring, and ring G is a carbocyclyl or heterocyclyl ring. In other
embodiments, the method comprises the step ofreacting ©A H H® with ring A to
Figure imgf000128_0003
The compounds of one aspect of this invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, scalemic mixtures,anddiastereomeric mixtures, as well as single enantiomers or individual stereoisomersthat are substantially free from another possible enantiomer or stereoisomer. The term "substantially free of other stereoisomers" as used herein means a preparation enriched in a compound having a selected stereochemistry at one or more selected stereocentersby at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. The term "enriched" means that at least the designated percentage of a preparation is the compound having a selected stereochemistry at one or more selected stereocenters. Methods of obtaining or synthesizing an individual enantiomer or stereoisomer for a given compound are known in the art and may be applied as practicable to final compounds or to starting material or intermediates.
In certain embodiments, the compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig,n, ΙΠ, Ilia, Illb, Hie, or IIId,is enriched for a structure or structures having a selected stereochemistry at one or more carbon atoms. For example, the compound is enriched in the specific stereoisomer by at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
The compounds of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, Π, ΙΠ, Ilia, Illb, IIIc, or Mdmay also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including ¾ 2H (D or deuterium), and 3H (T or tritium); C may be in any isotopic form, includingnC,12C, 13C, and 14C; N may be in any isotopic form, including13N,14N and 15N; O may be in any isotopic form, including150,160 and 180; F may be in any isotopic form, including18F; and the like. For example, the compound is enriched in a specific isotopic formof H, C, N, O and/or Fby at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
Unless otherwise indicated when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.
The compounds of one aspect of this invention may also be represented in multiple tautomeric forms, in such instances, one aspect of the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented (e.g., alkylation of a ring system may result in alkylation at multiple sites, one aspect of the invention expressly includes all such reaction products; and keto-enol tautomers). All such isomeric forms of such compounds are expressly included herein.
It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of
pharmaceutically acceptable salts are discussed in Berge etal, 1977, "Pharmaceutically
Acceptable Salts." J. Pharm. Sci. Vol. 66, pp. 1-19.
For example, if the compound is anionic, or has a functional group which may be anionic (e.g.,-COOH may be -COO"), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Al3+. Examples of suitable organic cations include, but are not limited to, ammonium ion {i.e., NH4 +) and substituted ammonium ions {e.g., NH3R+, NH2R2+, NHR3+, NR4+). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine,
dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 +.
If the compound is cationic, or has a functional group that may be cationic {e.g.,-NH2 may be -NH3 +), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids:
hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Mesylates of each compound in Table 1 are explicitly included herein. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
The compounds provided herein therefore include the compounds themselves, as well as their salts, hydrates and their prodrugs, if applicable. The compounds provided herein may be modified and converted to prodrugs by appending appropriate functionalities to enhance selected biological properties, e.g., targeting to a particular tissue. Such modifications (i.e., prodrugs) are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion. Examples of prodrugs include esters (e.g., phosphates, amino acid (e.g., valine) esters), carbamates and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active compounds. Calcium and sodium phosphates of each compound in Table 1 , if applicable, are explicitly included herein. Amino acid (e.g., valine) esters of each compound in Table 1, if applicable, are explicitly included herein.
Compositions and routes of administration
The compounds utilized in the methods described herein may be formulated together with a pharmaceutically acceptable carrier or adjuvant into pharmaceutically acceptable compositions prior to be administered to a subject. In another embodiment, such pharmaceutically acceptable compositions further comprise additional therapeutic agents in amounts effective for achieving a modulation of disease or disease symptoms, including those described herein.
The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a subject, together with a compound of one aspect of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the
pharmaceutical compositions of one aspect of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems
(SEDDS) such as d-a-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium
carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and
3-hydroxypropyl- -cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein. The pharmaceutical compositions of one aspect of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of one aspect of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
The pharmaceutical compositions of one aspect of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
The pharmaceutical compositions of one aspect of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of one aspect of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
Topical administration of the pharmaceutical compositions of one aspect of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of one aspect of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of one aspect of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation.
Topically-transdermal patches are also included in one aspect of this invention.
The pharmaceutical compositions of one aspect of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
When the compositions of one aspect of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of one aspect of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of one aspect of this invention in a single composition.
The compounds described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of one aspect of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.
Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the subject's disposition to the disease, condition or symptoms, and the judgment of the treating physician. Upon improvement of a subject's condition, a maintenance dose of a compound, composition or combination of one aspect of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Subjects may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
The pharmaceutical compositions described above comprising a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ilia, nib, IIIc, or Illdor a compound described in any one of the embodiments herein, may further comprise another therapeutic agent useful for treating cancer.
Methods of Use
Provided is a method for inhibiting mutant IDHl activity comprising contacting a subject in need thereof with a compound (including its tautomers and/or isotopologues) of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, ΙΠ, Ilia, Illb, Hie, or Hid, or a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer to be treated is characterized by a mutant allele of IDHl wherein the IDHl mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of a- ketoglutarate to i?(-)-2-hydroxyglutarate in a subject. In one aspect of this embodiment, the mutant IDHl has an R132X mutation. In one aspect of this embodiment, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G. In another aspect, the R132X mutation is R132H or R132C. In yet another aspect, the R132X mutation is R132H. Also provided are methods of treating a cancer characterized by the presence of a mutant allele of IDHl comprising the step of administering to subject in need thereof (a) a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ilia, nib, IIIc, or ind, or a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof, or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.
In one embodiment, the cancer to be treated is characterized by a mutant allele of IDHl wherein the IDHl mutation results in a new ability of the enzyme to catalyze the NAPH- dependent reduction of a-ketoglutarate to i?(-)-2-hydroxyglutarate in a patient. In one aspect of this embodiment, the IDHl mutation is an R132X mutation. In another aspect of this embodiment, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G. In another aspect, the R132X mutation is R132 H or R132C. A cancer can be analyzed by sequencing cell samples to determine the presence and specific nature of (e.g., the changed amino acid present at) a mutation at amino acid 132 of IDH1.
Without being bound by theory, applicants believe that mutant alleles of IDHl wherein the IDHl mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of a-ketoglutarate to i?(-)-2-hydroxyglutarate, and in particular R132H mutations of IDHl, characterize a subset of all types of cancers, without regard to their cellular nature or location in the body. Thus, the compounds and methods of this invention are useful to treat any type of cancer that is characterized by the presence of a mutant allele of IDHl imparting such acitivity and in particular an IDHl R132H or R132C mutation.
In one aspect of this embodiment, the efficacy of cancer treatment is monitored by measuring the levels of 2HG in the subject. Typically levels of 2HG are measured prior to treatment, wherein an elevated level is indicated for the use of the compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ma, mb, IIIc, or Hid, or a compound described in any one of the embodiments described herein to treat the cancer. Once the elevated levels are established, the level of 2HG is determined during the course of and/or following termination of treatment to establish efficacy. In certain embodiments, the level of 2HG is only determined during the course of and/or following termination of treatment. A reduction of 2HG levels during the course of treatment and following treatment is indicative of efficacy. Similarly, a determination that 2HG levels are not elevated during the course of or following treatment is also indicative of efficacy. Typically, the these 2HG measurements will be utilized together with other well- known determinations of efficacy of cancer treatment, such as reduction in number and size of tumors and/or other cancer-associated lesions, improvement in the general health of the subject, and alterations in other biomarkers that are associated with cancer treatment efficacy.
2HG can be detected in a sample by LC MS. The sample is mixed 80:20 with methanol, and centrifuged at 3,000 rpm for 20 minutes at 4 degrees Celsius. The resulting supernatant can be collected and stored at -80 degrees Celsius prior to LC-MS MS to assess 2-hydroxyglutarate levels. A variety of different liquid chromatography (LC) separation methods can be used. Each method can be coupled by negative electrospray ionization (ESI, -3.0 kV) to triple-quadrupole mass spectrometers operating in multiple reaction monitoring (MRM) mode, with MS parameters optimized on infused metabolite standard solutions. Metabolites can be separated by reversed phase chromatography using 10 mM tributyl-amine as an ion pairing agent in the aqueous mobile phase, according to a variant of a previously reported method (Luo etal.J Chromatogr A 1147, 153-64, 2007). One method allows resolution of TCA metabolites: t = 0, 50% B; t = 5, 95% B; t= 7, 95% B; t= 8, 0% B, where B refers to an organic mobile phase of 100% methanol. Another method is specific for 2-hydroxyglutarate, running a fast linear gradient from 50% -95% B (buffers as defined above) over 5 minutes. A Synergi Hydro-RP, 100mm x 2 mm, 2.1 μιτι particle size (Phenomonex) can be used as the column, as described above. Metabolites can be quantified by comparison of peak areas with pure metabolite standards at known concentration. Metabolite flux studies from 13C-glutamine can be performed as described, e.g., in Munger et al. Nat Biotechnol 26, 1179-86, 2008.
In one embodiment 2HG is directly evaluated.
In anotherembodiment a derivative of 2HGformed in process of performing the analytic method is evaluated. By way of example such a derivative can be a derivative formed in MS analysis. Derivatives can include a salt adduct, e.g., a Na adduct, a hydration variant, or a hydration variant which is also a salt adduct, e.g., a Na adduct, e.g., as formed in MS analysis.
In anotherembodiment a metabolic derivative of 2HG is evaluated. Examples include species that build up or are elevated, or reduced, as a result of the presence of 2HG, such as glutarate or glutamate that will be correlated to 2HG, e.g., R-2HG.
Exemplary 2HG derivatives include dehydrated derivatives such as the compounds rovided below or a s lt adduct thereof:
Figure imgf000137_0001
In one embodiment the cancer is a tumor wherein at least 30, 40, 50, 60, 70, 80 or 90% of the tumor cells cany an IDHl mutation, and in particular an IDHl R132H or R132C mutation, at the time of diagnosis or treatment.
IDHl R132X mutations are known to occur in certain types of cancers as indicated in Table 2, below. Table 2. IDH mutations associated with certain cancers
Figure imgf000138_0001
IDH1 R132H mutations have been identified in glioblastoma, acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer, cholangiocarcinomas,
chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer, and angio-immunoblastic non-Hodgkin's lymphoma (NHL). Accordingly, in one embodiment, the methods described herein are used to treat glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer, or angio-immunoblastic non-Hodgkin's lymphoma (NHL) in a patient.
In another embodiment, the methods described herein are used to treat glioma
(glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas (e.g., intrahepatic cholangiocarcinoma (IHCC)),
chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), prostate cancer, chronic myelomonocytic leukemia (CMML), B-acute lymphoblastic leukemias (B-ALL), B-acute lymphoblastic leukemias (B-ALL), myeloid sarcoma, multiple myeloma, lymphoma colon cancer, or angio-immunoblastic non-Hodgkin's lymphoma (NHL) in a patient.
In another embodiment, the advanced hematologic malignancy to be treated is lymphoma (e.g., Non-Hodgkin lymphoma (NHL) such B-cell lymphoma (e.g., Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma) and T-cell lymphoma (e.g., mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma).
Accordingly in one embodiment, the cancer is a cancer selected from any one of the cancer types listed in Table 2, and the IDH R132X mutation is one or more of the IDHl R132X mutations listed in Table 2 for that particular cancer type.
Treatment methods described herein can additionally comprise various evaluation steps prior to and/or following treatment with a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, Π, III, Ilia, nib, Hie, or Illdor a compound described in any one of the embodiments described herein.
In one embodiment, prior to and/or after treatment with a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ma, inb, IIIc, or Illdor a compound described in any one of the embodiments described herein, the method further comprisesthe step of evaluating the growth, size, weight, invasiveness, stage and/or other phenotype of the cancer.
In one embodiment, prior to and/or after treatmentwith a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ma, Mb, IIIc, or Hid or a compound described in any one of the embodiments described herein, the method further comprisesthe step of evaluating the IDHl genotype of the cancer. This may be achieved by ordinary methods in the art, such as DNA sequencing, immuno analysis, and/or evaluation of the presence, distribution or level of 2HG.
In one embodiment, prior to and/or after treatmentwith a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ma, Illb, IIIc, or Illdor a compound described in any one of the embodiments described herein, the method further comprises the step of determining the 2HG level in the subject. This may be achieved by spectroscopic analysis, e.g., magnetic resonance- based analysis, e.g., MRI and/or MRS measurement, sample analysis of bodily fluid, such as serum or spinal cord fluid analysis, or by analysis of surgical material, e.g., by mass- spectroscopy.
Also provided is a method for inhibiting a mutant IDH2 activity comprising contacting a subject in need thereof with a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, Π, III, Ilia, Illb, Hie, or Hid, a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer to be treated is characterized by a mutant allele of IDH2 wherein the IDH2 mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of a-ketoglutarate to i?(-)-2-hydroxyglutarate in a subject. In one aspect of this embodiment, the mutant IDH2 has an R140X mutation. In another aspect of this embodiment, the R140X mutation is a R140Q mutation. In another aspect of this embodiment, the R140X mutation is a R140W mutation. In another aspect of this embodiment, the R140X mutation is a R140L mutation. In another aspect of this embodiment, the mutant IDH2 has an R172X mutation. In another aspect of this embodiment, the R172X mutation is a R172K mutation. In another aspect of this embodiment, the R172X mutation is a R172G mutation. Also provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH2 comprising the step of administering to subject in need thereof (a) a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ilia, nib, IIIc, or ind or a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof, or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.
In one embodiment, the cancer to be treated is characterized by a mutant allele of IDH2 wherein the IDH2 mutation results in a new ability of the enzyme to catalyze the
NAPH-dependent reduction of a-ketoglutarate to i?(-)-2-hydroxyglutarate in a patient. In one aspect of this embodiment, the mutant IDH2 has an R140X mutation. In another aspect of this embodiment, the R140X mutation is a R140Q mutation. In another aspect of this embodiment, the R140X mutation is a R140W mutation. In another aspect of this embodiment, the R140X mutation is a R140L mutation. In another aspect of this embodiment, the mutant IDH2 has an R172X mutation. In another aspect of this embodiment, the R172X mutation is a R172K mutation. In another aspect of this embodiment, the R172X mutation is a R172G mutation. A cancer can be analyzed by sequencing cell samples to determine the presence and specific nature of (e.g., the changed amino acid present at) a mutation at amino acid 140 and/or 172 of IDH2.
Without being bound by theory, applicants believe that mutant alleles of IDH2wherein the IDH2 mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of a-ketoglutarate to i?(-)-2-hydroxyglutarate, and in particular R140Q and/or R172K mutations of IDH2, characterize a subset of all types of cancers, without regard to their cellular nature or location in the body. Thus, the compounds and methods of one aspect of this invention are useful to treat any type of cancer that is characterized by the presence of a mutant allele of IDH2 imparting such acitivity and in particular an IDH2 R140Q and/or R172K mutation.
In one aspect of this embodiment, the efficacy of cancer treatment is monitored by measuring the levels of 2HG as described herein.
In one embodiment the cancer is a tumor wherein at least 30, 40, 50, 60, 70, 80 or 90% of the tumor cells cany an IDH2 mutation, and in particular an IDH2R140Q, R140W, or R140L and/or R172K or R172G mutation, at the time of diagnosis or treatment.
In another embodiment, one aspect of the invention provides a method of treating a cancer selected fromglioblastoma (glioma), myelodysplastic syndrome (MDS),
myeloproliferative neoplasm (MPN), acute myelogenous leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinomas or angioimmunoblastic lymphoma in a patient by administering to the patient a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, ΠΙ, Ma, Illb, IIIc, or Illdin an amount effective to treat the cancer. In a more specific embodiment the cancer to be treated is glioma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myelogenous leukemia (AML), melanoma, chondrosarcoma, or angioimmunoblastic non-Hodgkin's lymphoma (NHL).
2HG is known to accumulate in the inherited metabolic disorder 2-hydroxyglutaric aciduria. This disease is caused by deficiency in the enzyme 2-hydroxyglutarate dehydrogenase, which converts 2HGto a-KG (Struys, E. A. et al. Am J Hum Genet 76, 358-60 (2005)). Patients with 2-hydroxyglutarate dehydrogenase deficiencies accumulate 2HG in the brain as assessed by MRI and CSF analysis, develop leukoencephalopathy, and have an increased risk of developing brain tumors (Aghili, M., Zahedi, F. & Rafiee, J Neurooncol 91, 233-6 (2009); Kolker, S., Mayatepek, E. & Hoffmann, G. F. Neuropediatrics 33, 225-31 (2002); Wajner, M., Latini, A, Wyse, A. T. & Dutra-Filho, C. S. J Inherit Metab Dis 27, 427-48 (2004)). Furthermore, elevated brain levels of 2HG result in increased ROS levels (Kolker, S. et al. Eur J Neurosci 16, 21 -8 (2002); Latini, A. et al. Eur J Neurosci 17, 2017-22 (2003)), potentially contributing to an increased risk of cancer. The ability of 2HG to act as an NMDA receptor agonist may contribute to this effect (Kolker, S. et al. Eur J Neurosci 16, 21-8 (2002)). 2HG may also be toxic to cells by competitively inhibiting glutamate and/or aKG utilizing enzymes. These include
transaminases which allow utilization of glutamate nitrogen for amino and nucleic acid biosynthesis, and aKG-dependent prolyl hydroxylases such as those which regulate FflFl -alpha levels.
Thus, according to another embodiment, one aspect of the invention provides a method of treating 2-hydroxyglutaric aciduria, particularly D-2-hydroxyglutaric aciduria, in a patient by administering to the patient a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, Π, III, Ilia, Illb, IIIc, or indor a compound described in any one of the embodiments described herein.
Also provided are methods of treating a disease selected from Maffucci syndrome and Oilier disease, characterized by the presence of a mutant allele of IDH1 comprising the step of administering to subject in need thereof (a) a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, ΠΙ, Ma, Illb, IIIc, or Hid, or a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof, or (b) a pharmaceutical composition comprising (a) and a pharmaceutically acceptable carrier.
Treatment methods described herein can additionally comprise various evaluation steps prior to and/or following treatment with a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, Π, III, Ilia, nib, Hie, or Illdor a compound described in any one of the embodiments described herein.
In one embodiment, prior to and/or after treatment with a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ma, Mb, IIIc, or Mdor a compound described in any one of the embodiments described herein, the method further comprisesthe step of evaluating the growth, size, weight, invasiveness, stage and/or other phenotype of the cancer.
In one embodiment, prior to and/or after treatmentwith a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, III, Ma, Illb, IIIc, or Illdor a compound described in any one of the embodiments described herein, the method further comprisesthe step of evaluating the IDH2 genotype of the cancer. This may be achieved by ordinary methods in the art, such as DNA sequencing, immuno analysis, and/or evaluation of the presence, distribution or level of 2HG. In one embodiment, prior to and/or after treatmentwith a compound of Formula I, la, lb, B, C, Ic, Id, Ie, If, Ig, II, ΠΙ, Ma, b, IIIc, or Illdor a compound described in any one of the embodiments described herein, the method further comprises the step of determining the 2HG level in the subject. This may be achieved by spectroscopic analysis, e.g., magnetic resonance-based analysis, e.g., MRI and/or MRSmeasurement, sample analysis of bodily fluid, such as serum or spinal cord fluid analysis, or by analysis of surgical material, e.g., by mass-spectroscopy.
Combination therapies
In some embodiments, the methods described herein comprise the additional step of co -administering to a subject in need thereof a second therapy e.g., an additional cancer therapeutic agent or an additional cancer treatment. Exemplary additional cancer therapeutic agents include for example, chemotherapy, targeted therapy, antibody therapies,
immunotherapy,and hormonal therapy. Additional cancer treatments include, for example: surgery, and radiation therapy. Examples of each of these treatments are provided below.
The term "co-administering" as used herein with respect to an additional cancer therapeutic agents means that the additional cancer therapeutic agent may be administered together with a compound of one aspect of this invention as part of a single dosage form (such as a composition of one aspect of this invention comprising a compound of one aspect of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional cancer therapeutic agent may be administered prior to, consecutively with, or following the administration of a compound of one aspect of this invention. In such combination therapy treatment, both the compounds of one aspect of this invention and the second therapeutic agent(s) are administered by conventional methods. The administration of a composition of one aspect of this invention, comprising both a compound of one aspect of the invention and a second therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of one aspect of this invention to said subject at another time during a course of treatment. The term "co -administering" as used herein with respect to an additional cancer treatment means that the additional cancer treatment may occurprior to, consecutively with, concurrently with or following the administration of a compound of one aspect of this invention. In some embodiments, the additional cancer therapeutic agent is a chemotherapy agent.
Examples of chemotherapeutic agents used in cancer therapy include, for example,
antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives), alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others), and hypomethylating agents(e.g., decitabine (5-aza-deoxycytidine), zebularine, isothiocyanates, azacitidine (5- azacytidine), 5-flouro-2'-deoxycytidine, 5,6-dihydro-5-azacytidine and others). Exemplary agents include Aclarubicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin,
Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, bendamustine, Bleomycin, Bortezomib, Busulfan,
Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Crisantaspase,
Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin, Estramustine, Etoglucid, Etoposide, Floxuridine, Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine, Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin, Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine, Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine, Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin, Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine, Tioguanine, Tipifarnib, Topotecan,
Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine,
Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein. Because some drugs work better together than alone, two or more drugs are often given at the same time. Often, two or more chemotherapy agents are used as combination chemotherapy. In some embodiments, the additional cancer therapeutic agent is a differentiation agent. Such differentiation agent includes retinoids (such as all-trans-retinoic acid (ATRA), 9-cis retinoic acid, 13 -cz's -retinoic acid (13-cRA) and 4-hydroxy-phenretinamide (4-HPR)); arsenic trioxide; histone deacetylase inhibitors HDACs (such as azacytidine (Vidaza) and butyrates (e.g., sodium phenylbutyrate)); hybrid polar compounds (such as hexamethylene bisacetamide ((HMBA)); vitamin D; and cytokines (such as colony-stimulating factors including G-CSF and GM-CSF, and interferons).
In some embodiments the additional cancer therapeutic agent is a targeted therapy agent.
Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and also cyclin-dependent kinase inhibitors such as Alvocidib and Seliciclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the
anti-HER2/neu antibody trastuzumab (HERCEPTIN®) typically used in breast cancer, and the anti-CD20 antibody rituximab and Tositumomab typically used in a variety of B-cell
malignancies. Other exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab. Exemplary fusion proteins include Aflibercept and Denileukin diftitox. In some embodiments, the targeted therapy can be used in combination with a compound described herein, e.g., a biguanide such as metformin or phenformin, preferably phenformin. Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. An example of such therapy includes BEXXAR®.
In some embodiments, the additional cancer therapeutic agent is an immunotherapy agent.
Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the subject's own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma subjects.
Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a graft-versus-tumor effect. In some embodiments, the immunotherapy agents can be used in combination with a compound or composition described herein.
In some embodiments, the additional cancer therapeutic agent is a hormonal therapy agent. The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial. In some embodiments, the hormonal therapy agents can be used in combination with a compound or a composition described herein.
Other possible additional therapeutic modalities include imatinib, gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies.
EXAMPLES
General experimental notes:
In the following examples, the reagents (chemicals) were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company), and used without further purification. Nuclear magnetic resonance (NMR) spectra were obtained on a Brucker AMX-400 NMR (Brucker, Switzerland). Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were given with electrospray ionization (ESI) from a Waters LCT TOF Mass Spectrometer (Waters, USA) or Shimadzu LCMS-2020 Mass Spectrometer (Shimadzu, Japan). Microwave reactions were run on an Initiator 2.5 Microwave Synthesizer (Biotage, Sweden).
For exemplary compounds disclosed in this section, the specification of a stereoisomer (e.g., an (R) or (S) stereoisomer) indicates a preparation of that compound such that the compound is enriched at the specified stereocenter by at least about 90%, 95%, 96%, 97%, 98%, or 99%. The chemical name of each of the exemplary compound described below is generated by ChemDraw software.
Abbreviations list:
General
anhy. anhydrous
aq. aqueous
min minute(s)
hrs hours
mL milliliter
mmol millimole(s)
mol mole(s)
MS mass spectrometry
NMR nuclear magnetic resonance
TLC thin layer chromatography
HPLC high-performance liquid chromatography
satd. saturated
Spectrum
Hz hertz
δ chemical shift J coupling constant s singlet
d doublet
t triplet
q quartet
m multiplet
br broad
qd quartet of doublets dquin doublet of quintets dd doubletof doublets dt doublet of triplets
Solvents and Reagents
DAST diethylaminosulfurtri fluoride
CHCls chloroform
DCM dichloromethane
DMF dimethylformamide
Et20 diethyl ether
EtOH ethyl alcohol
EtOAc ethyl acetate
MeOH methyl alcohol
MeCN acetonitrile
PE petroleum ether
THF tetrahydrofuran
DMSO dimethyl sulfoxide
AcOH acetic acid
HC1 hydrochloric acid
H2S04 sulfuric acid
NH4CI ammonium chloride
KOH potassium hydroxide NaOH sodium hydroxide
K2C03 potassium carbonate
Na2C03 sodium carbonate
TFA trifluoroacetic acid
Na2S04 sodium sulfate
NaBH4 sodium borohydride
NaHC03 sodium bicarbonate
NaHMDS sodium hexamethyldisilylamide
LiHMDS lithium hexamethyldisilylamide
LAH lithium aluminum hydride
NaBH4 sodium borohydride
LDA lithium diisopropylamide
Et3N triethylamine
Py pyridine
DMAP 4-(dimethylamino)pyridine
DIPEA NN-diisopropylethylamine
Xphos 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl
BINAP 2,2'-bis(diphenylphosphanyl)-l ,1 '-binaphthyl dppf 1 ,1 '-bis(diphenylphosphino)ferrocene
TBTU 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate
DPPA diphenylphosphoryl azide
NH4OH ammonium hydroxide
EDCI 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide
HOBt 1 -hydroxybenzotriazole
Py Pyridine
Dppf 1 , 1 '-bis(diphenylphosphino)ferrocene
HATU 0-(7-azabenzotriazol- 1 -yl)-NNN',N'-tetra-methyluronium
BINAP 2,2'-bis(diphenylphosphanyl)-l ,1 '-binaphthyl Preparation of Intermediates
Preparation of 1-phenylcyclopropanamine.
Figure imgf000150_0001
Ethylmagnesium bromide (48.5 mL, 146 mmol) was added dropwise over 30 min to a solution of benzonitrile (5 g, 48 mmol, 3 eq) and titanium tetraisopropanolate (21.5 mL, 73 mmol, 1.5 eq) in dry THF (140 mL) at -70°C. The solution was stirred at r.t. for 1.5 hr, followed by dropwise addition of boron trifluorideetherate (15 mL, 121 mmol, 2.5 eq) over 15 min. The mixture was stirred at r.t. for another 1.5 hr followed by addition of IN aq. HC1 and Et20. The resulting mixture was poured into 10% aq. NaOH, and extracted with Et20. Combined organic layers were dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography using PE/EtOAc/NH3.H20 (4:1 :0.1%) to afford the desired product. LC-MS: m/z 134.1 (M+H)+.
Preparation of 2-amino-2-methylpropanenitrile
Figure imgf000150_0002
To a mixture of NH4CI (4.9 g, 92.3 mmol) and acetone (7 mL, 92.3 mmol) in ammonium hydroxide (40 mL, 230.7 mmol) was added KCN (5 g, 76.9 mmol) at r.t. The reaction mixture was stirred at r.t for 3 days. The mixture was extracted with DCM (2 x 30 mL). Combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated to afford the desired product which was used directly in the next step without any further purification.
Preparation of 2-aminopropanenitrile
Figure imgf000150_0003
To a mixture of NH4CI (981 mg, 18.5mmol), acetaldehyde (1 mL, 18.5mmol) in ammonium hydroxide (3 mL) was added KCN (1 g, 15.4mmol) at room temperature. The reaction mixture was stirred at r.t for 2 days. The mixture was extracted with DCM (2 x 30 mL). Combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated to afford the desired product which was used directly in the next step without any further purification.
Preparation ofdicyclopropylmethanamine
Figure imgf000151_0001
Stepl. Preparation of dicyclopropylmethanoneoxime. To a mixture of dicyclopropylmethanone (500 mg, 4.5 mmol) in pyridine (5 mL) was added hydroxylamine hydrochloride (469 mg, 6.75 mmol). The reaction mixture was stirred at 100°C for 4 hr and cooled to r.t followed by addition of EtOAc. The resulting mixture was washed with 1 N aq. HCl and brine, dried over anhydrous Na2S04, andconcentrated under reduced pressure to give the desired product which was used directly in the next step without any further purification.
Figure imgf000151_0002
LC-MS : m/z 124.1 (M-H)".
Step 2.Preparation of dicyclopropylmethanamine. To a cooled solution of dicyclopropylmethanoneoxime (550 mg, 4.4 mmol) in THF (5 mL) was added LiAlH4 (200 mg, 5.3 mmol). The mixture was then stirred at 80°C for 6 hr and cooled to room temperature. The mixture was quenched by IN aq.NaOH until gas evolution ceased and then filtered. The filtrate was extracted with EtOAc. Combined organic layers were dried over anhydrous Na2S04, and concentrated under reduced pressure to give the desired product which was used directly in the next step without any further purification.
Figure imgf000151_0003
LC-MS : m/z 112.1 (M+Hf.
Preparation of bicyclo[3.1.0]hexan-3-amine
Figure imgf000152_0001
Step 1: Preparation of benzyl cycIopent-3-en /carbamate. To a solution of cyclopent-3- enecarboxylic acid (5 g, 44.6 mmol, l eq) and DPPA (13.5 g, 49 mmol, 1.1 eq) in toluene (80 mL) was added Et3N (7.4 mL, 53.5 mmol, 1.2 eq) at r.t. The mixture was then stirred at reflux for 2hr during which period a larger amount of nitrogen evolved. After BnOH (7 mL, 66.9 mmol, 1.5 eq) was added, the resulting mixture was stirred at 100°C overnight and cooled to room temperature. After quenched with saturated aqueous NaHC03. The resulting mixture was extracted with EtOAc. Combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by flash chromatography using
1) as eluent to give the desired product.
Figure imgf000152_0002
LC-MS: m/z 218.0 (M+H)+.
Step 2: Preparation ofbemyl bicyclo[3.1.0]hexan-3-ylcarbamate. To a solution of benzyl cyclopent-3-enyl carbamate (1 g, 4.6 mmol, 1 eq) in anhydrous DCM at 0°C under an atmosphere of nitrogen was added ZnEt2 (9.7 mL, 9.7 mmol, 2.1 eq), followed by dropwise addition of CH2I2 (0.78 mL, 9.7 mmol, 2.1 eq). The reaction mixture was warmed to room temperature and stirred for 4 hr. The resulting reaction mixture was quenched with brine and extracted with DCM. The organic layer was dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography using PE/EtOAc (5:1) as eluent to give the desired product.
Figure imgf000152_0003
LC-MS: m/z 232.1 (M+H)+.
Step 3: Preparation ofl>icyclo[3.1.0]hexan-3-amine. To a solution of benzyl bicyclo [3.1.0]hexan-3-yl carbamate (2 g) in MeOH (20 mL) at r.t. under an atmosphere of nitrogen was added Pd/C (0.2 g)in one portion. The resulting mixture was then stirred under a hydrogen balloon overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the desired product which was used directly in the next step without any further purification.
Figure imgf000153_0001
LC-MS: m/z 98.1 (M+H)+.
Preparation of 2-(l,l-difluoroethyl)pyridin
Figure imgf000153_0002
Step 1: Preparation of 4-chloro-N-methox -N-methylpicolinamide. To a solution of 4- chloropicolinic acid (10 g, 63.5 mmol) in DMF (150 mL) was added TBTU (30.6 g, 95.2 mmol), N,0-dimethylhydroxylamine(9.3 g, 95.2 mmol) and DIPEA (24.6 g, 190.4 mmol) at 0°C.The mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous NH4C1 and extracted with EtOAc. The organic layer was dried over Na2S04and concentrated. The residue was purified by flash chromatography to give the desired product.
Figure imgf000153_0003
LC-MS: lz 201.0 (M+H) .
Step 2: Preparation of l-(4-chloropyridin-2-yl)ethanone. To a solution of 4-chloro-N-methoxy- N-methylpicolinamide (11.25 g, 56.08 mmol) in THF (50 mL) at 0°Cwas added MeMgBr (28.04mL, 84.12 mmol). The mixture was then stirred at r.t. overnight and quenched with saturated aqueous NH4C1. The resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2S04 and concentrated. The residue was purified by flash chromatography to give the desired product,
Figure imgf000154_0001
1H NMR (400 MHz, CDC13): 58.52(d, J = 5.2 Hz, 1H), 7.96 (s, 1H), 7.40 (d, J = 5.2 Hz, 1H), 2.64 (s, 3H).LC-MS: m/z 156.0 (M+H)+.
Step 3: 4-chloro-2-(l,l-difluoroethyl)pyridine. To a solution of 1 -(4-chloropyridin-2- yl)ethanone (6.3 g, 40.5 mmol) in DCM (30 mL)was added DAST (65.2 g, 405 mmol) at 0°C. The mixture was then stirred at r.t. overnight and quenched with saturated aqueous NaHC03. The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous Na2S04 and concentrated. The residue was purified by flash chromatography to give the desired product.
Figure imgf000154_0002
Ή NMR (400 MHz, CDC13):58.48 (d, J = 5.2 Hz, lH), 7.60 (s, 1H), 7.31 (d, J = 5.2 Hz, 1H) , 1.90-1.99 (m, 3H).LC-MS: m/z 178.0 (M+H)+.
Step 4:Preparation of tert-butyl (2-(l,l-difluoroethyl)pyridin-4-yl)carbamate. To a solution of 4-chloro-2-(l,l-difluoroethyl)pyridine (6.0 g, 33.8 mmol) in dioxane(20 mL)was added BocNH2(4.74 g, 40.5 mmol), X-phos (1.14 g, 1.7 mmol), CsC03 (16.5 g, 50.7 mmol) and Pd(OAc)2 (1.32 g, 2.7 mmol) at room temperature. The mixture was then stirred at 80 °C overnight and then cooled to room temperature. The reaction mixture was diluted with Sat. aq. NH4CI and extracted with EtOAc. The organic layer was dried over anhydrous Na2S04andconcentrated. The residuewas purified by flash chromatography to give the desired product.
Figure imgf000154_0003
LC-MS: m/z 259.1 (M+H) .
Step 5:Preparation of 2-(l,l-difluoroethyl)pyridin-4-amine. A solution of tert-butyl (2-(l,l- difluoroethyl)pyridin-4-yl)carbamate (7.97 g, 30.86 mmol) in DCM (30 mL) was cooled under ice-water bath. TFA (10 mL) was then added dropwise. The reaction mixture was stirred at room temperature for 4 hrs and monitored by TLC. Once the reaction completed, the mixture was diluted with water and adjusted pH>7by saturated aqueous NaHC03. The resulting mixture was extracted with DCM. Combined organic layers were dried over anhydrous Na2S04 and concentrated to give the desired product which was used in the next step without further purification.
Figure imgf000155_0001
LC-MS: m/z 159.1 (M+H) .
Preparation of -(4-aminopyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000155_0002
Step 1: Preparation ofl- (4-broinopyridin -2-yl)cycloprop n ec rbon itrile. L iHMD S (1M in toluene, 17.6 mL, 17.6 mmol, 3.1 eq) was added dropwise to a cold (-5°C) mixture of 4-bromo- 2-fluoropyridine (1 g, 5.7 mmol), cyclopanecarbonitrile (1.25 mL, 17 mmol, 3 eq) and4A MS in toluene (20 mL). The reaction mixture was allowed to warm to room temperature and stirred for 16 hr. After it was poured into water, the mixture was filtered. The filtrate was diluted with EtOAc and H20, and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography using PE/EtOAc (9:1) as eluent to give the desired product.
Figure imgf000156_0001
LC-MS: m/z 223.0 (M+H)+.
Step 2: Preparation ofl-(4-(diphenylmethyleneamino)pyridin-2- yl)cyclopropanecarbonitrile.To a mixture of l -(4-bromopyridin-2-yl)cyclopropanecarbonitrile (0.45g, 2.1 mmol), BINAP (0.04 g, 0.063 mmol), Pd2(dba)3 (0.019g, 0.021 mmol) and NaO'Bu (0.282 g, 2.94 mmol) in toluene (6 mL) at r.t. under an atmosphere of nitrogen was added diphenylmethanimine (0.45 g, 2.51 mmol). The reaction mixture was stirred at reflux for 2 hr and then cooled to room temperature. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography to give the desired product.
Figure imgf000156_0002
LC-MS: m/z 324.1 (M+H) .
Step 3: Preparation ofl-(4-aminopyridin-2-yl)cyclopropanecarbonitrile.A mixture of l-(4- (diphenylmethyleneamino)pyridin-2-yl)cyclopropanecarbonitrile (0.48 g, 1.49 mmol), THF (10 mL) and aq. HCl (2N, 2.0 mL)was stirred at room temperature for lhour. The mixture was then partitioned between EtOAc (15 mL) and water (15 mL). The aqueous phase was extracted with EtOAc (2 x 25 mL). Combined organic layers were dried over anhydrous Na2S04 and concentrated. The residue was purified by column chromatography to give the desired product.
Figure imgf000156_0003
LC-MS: m/z 160.1 (M+H) .
Example 1 Preparation of Di-aliphatic Triazine Compounds of Formula DWherein Ring A is substituted Pyridin-2-yl or Phenyl. The compounds of this Example are prepared by general Scheme 1, set forth below. Scheme 1
Figure imgf000157_0001
Formula D
Step 1: Preparation of 6-trifluomethyl-pyridine-2-carboxylic acid methyl ester (2). To a solution of 2-chloro-6-trifluoromethyl-pyridine (2 g, 1 1.1 mmol, 1.0 eq) in MeOH (20 mL) was add Pd(OAc)2 (124 mg, 0.05eq) and dppf (600 mg, 0.1 eq) under an atmosphere of nitrogen. Et3N
(2.3 mL, 1.5eq) was then added to the resulting orange solution. The reaction solution was then stirred under an atmosphere of carbon monoxide (40 psi) at 60°C for 22 hr. Once the reaction completed, the mixture was filtered and the filtrate was concentrated in high vacuum. The residue was purified by column chromatography to afford the desired product.
Figure imgf000157_0002
1HNMR (400 MHz, CDC13): δ 8.32 (d, J = 8 Hz, 1H), 8.06 (t, J = 8 Hz, 1H), 8.88 (d, J = 8 Hz, 1H), 4.04 (s, 3H).LC-MS: m/z 206 (M+H)+.
Step 2:Preparation of 6-(6- trifluomethylpyridin-2-yl)-l,3,5-triazine-2,4-dione. To a solution of freshly prepared NaOEt from Na (3.84 g, 0.16 mol, 3 eq) in ethanol (500 mL) was added methyl
6-trifluoromethylpicolinate (33 g, 0.16 mol, 3eq) and biuret (5.3 g, 0.052 mol). Theresulting mixture was heated to reflux for 1 hr and then concentrated. The residue was poured into water and treated with Sat. aq. NaHC03 to adjust pH to 7. The precipitated solid was collected by filtration and dried under air to give the desired compound.
Figure imgf000158_0001
1H NMR (400 MHz, DMSO-d6): δ 10.88 (s, 1H), 8.46 (d, J= 7.4 Hz, 1H), 8.28 (t, J= 7.3 Hz, 1H), 8.11 (d, J= 7.4 Hz, 1H).LC-MS: m/z 259 (M+H)+.
Step 3: Preparation of 2,4-dichloro-6-(6-trifluomethyl-pyridin-2-yl)-l,3,5-triazine. To a solution of 6-(6-trifluomethyl-pyridin-2-yl)-l,3,5-triazine-2,4(lH,3H)-dione (3.37 g, 0.013mol) in POCl3 (48 mL) was added PC15 (23 g, 0.1 mol). The mixture was stirred at 100°C for 2 hr and then concentrated. The residue was dissolved inEtOAc and then washed with Sat. aq. NaHC03. The organic layer was dried over anhydrous Na2S04 and thenconcentrated to give the desired roduct.
Figure imgf000158_0002
Ή NMR (400 MHz, CDC13): δ 8.76 (d, J= 7.9 Hz, 1H), 8.19 (t, J = 7.9 Hz, 1H), 7.97 (d, J= 7.8 Hz, 1H).LC-MS: m/z 294.9 (M+H)+.
Step 4: Preparation of N2 ,N* -bis((R)-l -cyclopropylethyl)-6-(6-(trifluoroinethyl) -pyridin-2-yl)- l,3,5-triazine-2,4-diamine. To a mixture of 2,4-dichloro-6-(6-(trifluoromethyl)pyridine-2-yl)- 1,3,5-triazine (600 mg, 2.0mmol, 1.0 eq) and (R)-l-cyclopropylethanamine hydrochloride salt (536 mg, 4.4mmol, 2.2eq) in THF (12 mL) were added CsF (1.2 g, 8.0mmol, 2eq) and DIPEA (1.4 mL, 8.0mmol, 4eq) at room temperature. The mixture was stirred at 60°C overnight and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a standard method to give the desired product.
Figure imgf000159_0001
Ή NMR (400 MHz, CD3OD): δ 8.70-8.68 (m, 1 H), 8.34-8.32 (m, 1 H), 8.16-8.14 (m, 1 H), 3.61 -3.57 (m, 2 H), 1.36-1.32 (m, 6 H), 1.06-1.01 (m, 2 H), 0.61 -0.39 (m, 8 H).LC-MS: m/z 393.2 (M+H)+.
The procedure set forth in Example lwas used to produce the following compounds using the appropriate starting materials.
CompoundN' !,7V (-bis((S)-l-cychpropylethyl)-6-(6-(trifluoromethyl)pyridin-2-yl)- 1,3,5-tr zine- 2,4-diamine
Figure imgf000159_0002
Ή NMR (400 MHz, CDC13): δ 8.50 (s, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 5.44 - 5.18 (m, 2H), 3.66 - 3.57 (m, 2H), 1.27 (d, J = 5.4 Hz, 6H), 0.93 - 0.88 (m, 2H), 0.52 - 0.27 (m, 8H).LC-MS: m/z 393.2 (M+H)+.
Compound N2-((R)-l-cyclopropylethyl)-N*-((S)-l-cycfapropytethyl)-6-(6-(trifluoro methyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000160_0001
1H NMR (400 MHz, CDC13): δ 8.51 (s, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.77 (d, J = 7.3 Hz, 1H), 5.46 - 5.19 (m, 2H), 3.67 - 3.54 (m, 2H), 1.32 - 1.22 (m, 6H), 0.95 - 0.83 (m, 2H), 0.59 - 0.23 (m, 8H).LC-MS: m/z 393.2(M+H)+.
CornpoundN1 ',Ν (-bis(l-cyclopropylethyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5 -triazine- 2,4-diamine
Figure imgf000160_0002
1HNMR (400 MHz, CD3OD): 58.6 (m, 1H), 8.2-8.1 (m, 1H), 8.0-7.9 (m, 1H), 4.0-3.52 (m, 2H), 1.4-1.2 (m, 6H), 1.0 (m, 2H), 0.6-0.35 (m, 6H), 0.35-0.2 (m, 2H).LC-MS: m/z 393.2 (M+H)+.
CornpoundN,N '-bisfcyclobuiylmethyty-d-fd-ftrifluoromethytypyridin^-yl)-!^^ -triazine-2,4- diamine
Figure imgf000160_0003
Ή NMR (400 MHz, CDC13): δ 8.54 (m, 1H), 8.00 (m, 1H), 7.78 (d, J = 5.9 Hz, 1H), 5.27 (m, 2H), 3.69 - 3.32 (m, 4H), 2.59 (m, 2H), 2.10 (m, 4H), 1.92 (m, 4H), 1.84 - 1.62 (m, 4H).LC-MS: m/z 393.2 (M+H)+.
CompoundN' ',Ν (-bis((R)-l-cyclobutytethyl)-6-(6-(trifluoromethyl)pyridin-2-yl)- 1,3, 5-tr zine- 2,4-diamine
Figure imgf000161_0001
'H NMR (400 MHz, CDC13): δ 8.71 - 8.41 (m, 1H), 7.99 (d, J = 1.4 Hz, 1H), 7.77 (d, J= 7.7 Hz, 1H), 5.34 - 4.84 (m, 2H), 4.30 - 3.96 (m, 2H), 2.44 - 2.28 (m, 2H), 2.09 - 1.96 (m, 4H), 1.93 - 1.78 (m, 8H), 1.14 (d, J = 5.9 Hz, 6H).LC-MS: m/z 421.2
(M+H)+.
CompoundN2, rf-bis(2-methylcyclopropyl)-6-(6-(trifluoromethyl)pyrM -triazine- 24-diamine
Figure imgf000161_0002
1HNMR (400 MHz, CD3OD): 68.65-8.4 (m, 1H), 8.1-7.75 (m, 2H), 2.55-2.25 (m, 2H), 1.2-1.0 (m, 6H), 0.9-0.8 (m, 2H), 0.7-0.6 (m, 2H), 0.5-0.38 (m, 2H).LC-MS: m/z 365.3 (M+H)+.
CompoundN ',Ν '-bis(cyclopropylmethyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5 -triazine-2,4- diamine
Figure imgf000162_0001
1H NMR (400 MHz, CD3OD): δ 8.60-8.68 (m, 1H), 8.21 (t, J = 8.0 Hz, 1H), 7.93-8.00 (m, 1H), 3.26-3.42 (m, 4H), 1.08-1.19 (m, 2H), 0.51 -0.58 (m, 4H), 0.25-0.34 (m, 4H).LC-MS: m/z 365.2 (M+H)+.
CompoundN !,7V (-bis((l-methyl(yclopropyl)methyl)-6-(6-(trifluoromethyl)pyridin-2 -yl)-l,3, 5- tria ine-2 ,4-diamine
Figure imgf000162_0002
1HNMR (400 MHz, CD3OD): δ 8.61-8.59 (m, 1 H), 8.17-8.15 (m, 1H), 7.94-7.92 (m, 1H), 3.43- 3.33 (m, 4H), 1.14 (s, 6H), 0.55-0.53 (m, 4H), 0.34-0.32 (m, 4H).LC-MS: m/z 393.2 (M+H)+.
Compound N2,rf-dicyclobutyl-6-(6-(trifluoromethyl)pyridin-2-yl)-l,^ 2,4-diamine
Figure imgf000162_0003
Ή NMR (400 MHz, CDC13): δ 8.67 - 8.38 (m, 1H), 7.99 (d, J= 6.8 Hz, 1H), 7.78 (d, J= 7.5 Hz, 1H), 5.52 (m 2H), 4.80 - 4.32 (m, 2H), 2.41 (s, 4H), 2.20 (s, 1H), 2.06 - 1.62 (m, 8H).LC-MS: m/z 365.2 (M+H)+. CompoundN2 ,Ν4 -di(bicyclo[3.1.0Jhexan-3-yl)-6-(6-(trifluoromethyl)pyridin-2-yl) -1,3, 5- triazine-2 ,4-diamine
Figure imgf000163_0001
H NMR (400 MHz, CD3OD): δ 8.66 - 8.57 (m, 1H), 8.14 (t, J= 8.0 Hz, 1H), 7.92 (d, J= 7.5 Hz, 1H), 4.60 -4.44 (m, 2H), 2.44 - 2.21 (m, 4H), 1.80 - 1.69 (m, 4H), 1.35 (d, J= 3.4 Hz, 4H), 0.69 - 0.53 (m, 2H), 0.32 (d, J= 4.3 Hz, 2H).LC-MS: m/z 417.2 (M+H)+.
Com ound N,N'-dicyclopentyl-6-(6-trifluoromethyl-pyridin-2-yl)-[l, 3, 5]triazine- 2,4-diamine
Figure imgf000163_0002
1HNMR (400 MHz, CD3OD): δ 8.60-8.68 (m, lH), 8.20 (t, J = 7.6 Hz, 1H), 7.95-8.01 (m, 1H), 4.29-4.55 (m, 2H), 2.00-2.15 (m, 4H), 1.75-1.84 (m, 4H), 1.51-1.74 (m, 8H).LC-MS : m/z 393.5 (M+H)+.
CompoundN2, N4 -bis (3, 3-difluorocyclopentyl)-6-(6-(trifluoromethyl)pyridin-2-yl)- triazine-2 ,4-diamine
Figure imgf000164_0001
Ή NMR (400 MHz, CDC13): δ 8.53 (m, 1H), 8.08 - 8.02 (m, 1H), 7.85 - 7.80 (m, 1H), 5.78 - 5.18 (m, 2H), 4.82 - 4.38 (m, 2H), 2.82 - 2.50 (m, 2H), 2.31 - 2.05 (m, 8H), 1.93 - 1.80 (m, 2H).LC-MS: m/z 465.2 (M+H)+.
CompoundN2 ,l^-bh(4,4-dijluorocyclohexyl)-6-(6-(trty 1,3,5- triazine-2 ,4-diamine
Figure imgf000164_0002
1H NMR (400 MHz, CDC13): δ 8.64 - 8.42 (m, 1H), 8.05 (t, J = 7.8 Hz, 1H), 7.84 (d, J = 6.6 Hz, 1H), 6.24 - 5.25 (m, 2H), 4.18 - 4.01 (m, 2H), 2.43 - 1.48 (m, 16H).LC-MS: m/z 493.2 (M+H)+.
Co^oundN,N'-bis-(tetrahydro-pyran-4-yl)-6-(6-trifluoromethyl-pyridin- 2-yl)-fl ,3,5Jtr zine- -diamine
Figure imgf000164_0003
1HNMR (400 MHz, DMSO-d6): δ 7.43-8.55 (m, 5H), 3.82-4.15 (m, 6H), 3.48-3.50 (m, 4H), 1.75-1.87 (m, 4H), 1.46-1.60 (m, 4H).LC-MS : m/z 425.1 (M+H)+. CompoundN ',Ν (-diisopropyl-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-tr zine -2,4-diamine
Figure imgf000165_0001
¾ NMR (400 MHz, CDC13): δ 8.67 - 8.41 (m, 1H), 7.99 (s, 1H), 7.77 (d, J = 7.7 Hz, 1H), 5.18 (m, 2H), 4.45 - 4.03 (m, 2H), 2.15 (m, 1H), 1.26 (d, J = 4.5 Hz, 12H).LC-MS: m/z 341.2 (M+H)+.
Compound N2,N*-di-tert-butyl-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-trmzine -2,4-diamine
Figure imgf000165_0002
'H NMR (400 MHz, DMSO-d6): δ 8.44 - 8.31 (m, 1H), 8.19 - 8.12 (m, 1H), 7.93 (d, .7 = 7.3 Hz, 1H), 7.16 - 6.77 (m, 2H), 1.35 (s, 18H).LC-MS: m/z 369.2 (M+H)+.
CompoundN,N'-di-sec-bufyl-6-(6-trifluoromethyl-pyrMin-2-yl)-fl,3,5Jtr zine- 2,4-diamine
Figure imgf000165_0003
1HNMR (400 MHz, CD3OD): δ 8.42-8.68 (m, 1H), 8.15-8.21 (m, 1H), 7.94 (d, J = 8.0 Hz, 1H), 4.01 -4.29 (m, 2H), 1.55-1.69 (m, 4H), 1.19-1.30 (m, 6H), 0.95-1.05 (m, 6H).LC-MS : m/z 369.5 (M+H)+.
CompoundN,N'-Di-sec-butyl-6-(6 rifluoromethyl^yridin-2-yl)-[l,3,5]triaz
Figure imgf000166_0001
1HNMR (400 MHz, CD3OD): δ 8.72-8.79 (m, 1H), 8.38-8.43 (m, 1 H), 8.20-8.23 (m, 1H), 4.13- 4.45 (m, 2H), 1.67-1.74 (m, 4H), 1.29-1.33 (m, 6H), 1.01-1.05 (m, 6H).LC-MS: m/z 369.2 (M+H)+.
CompoundN' !,7V (-di-sec-buiyl-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000166_0002
1HNMR (400 MHz, CD3OD): δ 8.72-8.79 (m, 1H), 8.38-8.43 (m, 1 H), 8.20-8.23 (m, 1H), 4.13- 4.45 (m, 2H), 1.67-1.74 (m, 4H), 1.29-1.33 (m, 6H), 1.01-1.05 (m, 6H).LC-MS: m/z 369.2 (M+H)+.
CompoundN2-((R)-sec-butyl)-rf-((S)-sec-butyl)-6-(6-(trifluorome 2-yl)-l,3,5- triazine-2 ,4-diamine
Figure imgf000167_0001
¾ NMR (400 MHz, CD3OD): δ 8.59-8.65 (m, lH), 8.15-8.19 (m, 1 H), 7.94-7.95 (m, 1H), 4.06- 4.24 (m, 2H), 1.58-1.65 (m, 4H), 1.21 -1.26 (m, 6H), 0.98-1.01 (m, 6H).LC-MS: m/z 369.2 (M+H)+.
CompoundN2 ,Ν4 -bis (3-methylbutan-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)- 1,3, 5-triazine- -diamine
Figure imgf000167_0002
1H NMR (400 MHz, CDC13): δ 8.58 - 8.47 (m, 1H), 7.99 (t, J = 7.2 Hz, 1H), 7.77 (d, J= 7.7 Hz, 1H), 5.30 - 5.03 (m, 2H), 4.16 - 3.97 (m, 2H), 1.93 - 1.75 (m, 2H), 1.16 (d, J = 6.6 Hz, 6H), 0.97 - 0.93 (m, 12H).LC-MS: m/z 397.2 (M+H)+.
CompoundN' ',Ν (-bis((R)-3-methylbutan-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)- 1,3,5- triazine-2 ,4-diamine
Figure imgf000167_0003
Ή NMR (400 MHz, DMSO-d6): δ 8.46 (m, 1H), 8.21 (m, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.36 (m, 2H), 3.90 (m 2H), 1.79 (m, 2H), 1.05 (t, J = 7.6 Hz, 6H), 0.87 (t, J = 7.6 Hz, 12H).LC-MS: m/z 397.2 (M+H)+.
CompoundN1 ',Ν (-bis((S)-3-methylbutan-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)- 1,3, 5- triazine-2 ,4-diamine
Figure imgf000168_0001
1H NMR (400 MHz, DMSO-d6): δ 8.46 (d, J = 7.9 Hz, 1H), 8.24 (d, J = 6.9 Hz, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.55 (m, 2H), 4.25 - 3.78 (m, 1H), 1.93 - 1.65 (m, 1H), 1.15 - 1.00 (m, 6H), 0.89 (t, J = 7.8 Hz, 12H).LC-MS: m/z 397.2 (M+H)+.
CompoundN2, TV '-bis ((R)-l-cyclopropylethyl)-6-(4-(trifluoromethyl)pyrimidin -2-yl)-l,3,5- triazine-2 ,4-diamine
Figure imgf000168_0002
1H NMR (400 MHz, CDC13): δ 9.20 (s, 1H), 7.74 (s, 1H), 5.46 (m, 2H), 3.59 (m, 2H), 1.26 (m, 8H), 0.91 (s, 2H), 0.65 - -0.27 (m, 8H).LC-MS: m/z 394.2 (M+H)+.
Compound ^-((RJ-l-phenylethyfy-rf-ffSJ-l-phenytethyfy-e-fe-ftrifluoromethyl) pyridin-2-yl)- 1,3, 5-triazine-2 ,4-diamine
Figure imgf000169_0001
1H NMR (400 MHz, CDC13): δ 8.52 - 8.33 (m, 1H), 8.05 - 7.86 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.52 - 7.18 (m, 10H), 5.82 - 5.40 (m, 2H), 5.37 - 4.92 (m, 2H), 1.65 - 1.39 (m, 6H).LC-MS: m/z 465.2 (M+H)+.
Cotnpound6-(6-chloropyridin-2-yl)-N' !,7V '-bisffRj-l-cyclopropylethyfy-l^^-tria -zine-2,4- diamine
Figure imgf000169_0002
1H NMR (400 MHz, CD3OD): δ 8.37 (t, J = 7.8 Hz, 1H), 8.02 (t, J = 7.8 Hz, 1H), 7.71 - 7.65 (m, 1H), 3.74 - 3.54 (m, 2H), 1.32 (d, J = 6.6 Hz, 6H), 1.08 - 0.94 (m, 2H), 0.63 - 0.21 (m, 8H).LC-MS: m/z 359.2 (M+H)+.
Figure imgf000169_0003
'HNMR (400 MHz, CD30D): 58.5-8.38 (m, 1H), 8.0-7.9 (m, 1H), 7.6-7.5 (m, 1H), 3.35-3.16 (m, 4H), 2.0-1.9 (m, 2H), 1.0-0.9 (m, 12H).LC-MS: m/z 335.1 (M+H)+. Compound6-(6-chloropyridin-2-yl)- j2 ,N*-diisopropyl-l,3,5-triazine-2,4-diamine
Figure imgf000170_0001
1HNMR (400 MHz, CD3OD): δ 8.25-8.19 (m, 1H), 7.81 (brs, 1 H), 7.46 (d, J
4.26-4.11 (m, 2H), 1.15 (d, J = 6.0 Hz, 12H).LC-MS: m/z 307.1 (M+H)+.
Compound N2,N*-di(but-3-en-l-yl)-6^henyl-l,3,5Jriazine-2,4-dwmine
Figure imgf000170_0002
'HNMR (400 MHz, CD3OD): 58.19-8.13 (m, 2H), 7.77-7.61 (m, 3H), 5.95-5.85 (m, 2H), 5. 5.11 (m, 4H), 3.72-3.59 (m, 4H), 2.49-2.44 (m, 4H).LC-MS: m/z 296.3 (M+H)+.
Compound N2 ,N* -di(3-oxabicyclo[3.1.0Jhexan-6-yl)-6-phenyl-l,3,5-triazine-2,4- diamine
Figure imgf000170_0003
1HNMR (400 MHz, CD3OD): δ 8.35-8.1 (m, 2H), 8.3-8.2 (m, 1H), 7.7-7.6 (m, 2H), 4.1-4.0 (m, 4H), 3.85-3.7 (m, 4H), 2.9-2.55 (m, 2H), 2.1-2.0 (m, 2H).LC-MS: m/z 352.2 (M+H)+.
Compound N2 ,N* -bis((lS,3S)-3-(4-fluorophenyl)cyclobutyl)-6-(6- (triflu oromethyl )pyridin -2- yl)-l,3,5-triazine-2,4-diamine To a mixture of 2,4-dichloro-6-(6-(trifluoromethyl)pyridine-2-yl)- 1,3,5-triazine (600 mg, 2.0 mmol, 1.0 eq) and (ls,3s)-3-(4-fluorophenyl)cyclobutanamine (726 mg, 4.4 mmol, 2.2 eq) in THF (12 mL) at r.t.were added CsF (0.6 g, 2.0 mmol, 1 eq.) and DIPEA (0.7 mL, 4.0 mmol, 2 eq). The resulting mixture was stirred at 60°C overnight and then filtered. The filtrate was concentrated and purified via standard techniques to afford the desired product.
Figure imgf000171_0001
¾ NMR (400 MHz, CDC13) δ 8.48 (m, 1H), 7.95 (m, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.16 - 7.04 (m, 4H), 6.93 (t, J = 8.5 Hz, 4H), 6.46 - 5.32 (m, 2H), 4.47 (m, 2H), 3.28 - 3.02 (m, 2H), 2.81 (d, J= 7.6 Hz, 4H), 2.01 (m, 4H).LC-MS: m/z 553.2 (M+H)+.
Compound N2 ,N* -bis((l R,3R)-3-(4-fluorophenyl)cyclobutyl)-6-(6-(trifluor
-l,3,5-triazine-2,4-diamine
Figure imgf000171_0002
Ή NMR (400 MHz, CDC13) δ 8.56 (m, 1H), 8.01 (s, 1H), 7.80 (s, 1H), 7.25 - 6.93 (m, 8H), 5.64 (m, 2H), 4.82 - 4.37 (m, 2H), 3.68 (s, 1H), 3.24 (s, 1H), 2.89 (m, 2H), 2.54 (m, 4H), 2.09 - 1.98 (m, 2H).LC-MS: m/z 553.2 (M+H)+.
Compound 6-(6-(Trifluoromethyl)pyridin-2-yl)-N N '-bisffRj-lfl -trifluoropropan^-yl)- 1,3, 5-triazine-2,4-diamine
Figure imgf000172_0001
IH NMR (400 MHz, CDC13) δ 8.62 (m, IH), 8.03 (d, J = 7.8 Hz, IH), 7.83 (d, J
5.59 (d, J= 9.4 Hz, IH), 5.34 (m, 3H), 1.42 (m, 6H); LC-MS: m/z449 (M+H)+.
Compound N' ' ,l^-bh((S)A,l,l-tvijluorobutan-2-yl)-6-(6-(trijfa
Figure imgf000172_0002
¾ NMR( 400MHz, CDC13)58.55 (d, J=8 Hz, IH), 8.06 - 8.02(m, IH), 7.83 (d, J=8Hz, IH), 5.64 - 5.15(m, 2H), 4.93 - 4.71(m, 2H),2.0 - 1.94(m, 2H),1.69- 1.57 (m, 2H), 1.08 - 1.02(m, 6H). LCMS: m/z 477(M+H)+.
Compound N l^-bis((2,2-difluorocyclopropyl)methyl)-6-(6-(tri
-triazine-2,4-diamine
Figure imgf000172_0003
Ή NMR (400 MHz, CDC13) 58.59-8.51 (m, 1H), 8.02 (bs, 1H), 7.80 (d, J=7.6 Hz, 1H), 5.70- 5.38 (m, 2H), 3.81- 3.41 (m, 4H), 2.04-1.92 (m, 2H), 1.73-1.59(m, 2H), 1.28-1.23 (m, 2H). LC-MS: m/z 437 (M+H)+.
Compound N2,rf-bis((3,3-difluorocyclobutyl)methyl)-6-(6-(triflu^
triazine-2 ,4-diamine
Figure imgf000173_0001
Ή NMR (400 MHz, CDC13) δ 8.54 (m, 1H), 8.02 (m, 1H), 7.80 (d, J = 7.2 Hz, 1H), 5.84 - 5.11 (m, 2H), 3.95 - 3.27 (m, 4H), 2.94 - 1.99 (m, lOH). LC-MS: m/z 465 (M+H)+.
Compound N2,rf-bis(3,3-difluorocyclobutyl)-6-(6-(trifluoromethyl)pyrM^
-diamine
Figure imgf000173_0002
1H NMR (400 MHz, CDC13) 58.56 - 8.48 (m, 1H), 8.04 - 8.02 (m, 1H), 7.82 - 7.80 (m, 1H), 5.76 - 5.41 (m, 2H), 4.52 - 4.37 (m, 2H), 3.06 (bs, 4H), 2.63 - 2.61 (m, 4H). LC-MS: m/z 437.1 (M+H)+.
Compound N2,]^-bis((S)-3,3-difluorocyclopentyl)-6-(6-(trifluoromethyl)pyridm^ triazine-2 ,4-diamine
Figure imgf000174_0001
Ή NMR (400 MHz, CDC13) 58.54 - 8.38 (m, 1H), 7.95 (m 1H), 7.73 (m, 1H), 5.60 - 5.25 (m, 2H), 4.63 - 4.42 (m, 2H), 2.68 - 2.52 (m, 2H), 2.16 - 1.77 (m, 10H). LCMS: m/z 465.1 (M+H)+.
Compound N l^-bis((R)-3,3-difluorocyclopentyl)-6-(6-(trijluorom^
triazine-2 ,4-diamine
Figure imgf000174_0002
1H NMR (400 MHz, CDCl3)557-8.48 (m, 1H), 8.02-8.01 (m, 1H),7.80 (s,lH), 5.66-5.32 (m, 2H),4.71-4.49 (m, 2H),2.64-2.61 (m, 2H),2.31-2.05 (m, 8H), 1.86-1.79 (m, 2H). LC-MS: m/z 465 (M+H)+.
Compound N2-((R)-3,3-difluorocyclopentyl)-N4-((S)-3,3-difluorocyclopentyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000174_0003
H NMR (400 MHz, CDC13) 58.56-8.48 (m, 1H), 8.02(d, J=8 Hz, 1H),7.80-7.81 (m,lH), 5.66- 5.32 (m, 2H),4.71-4.54 (m, 2H),2.65-2.60 (m, 2H), 2.31-2.05 (m, 8H), 1.86-1.81 (m, 2H).
LC-MS: m/z 465 (M+H)+.
Compound N2,]S4-bis(4,4-difluorocyclohexyl)-6-(4-(trifluoromethyl)pyridin^
Figure imgf000175_0001
Ή NMR (400 MHz, CDC13) δ 8.70-8.62 (m, 2H), 7.62 (d, 1H), 6.70-6.43 (m, 1H), 5.22-3.95 (m, 3H), 2.11-1.69 (m, 16H). LCMS: m/z 493(M+H) +.
N N '-bisffRJ-l-cycfapropylethyfy-e-fe-methoxypyridin^-yfy-l^ -Mazine^^-
Figure imgf000175_0002
1H NMR (400 MHz, CDC13) δ 8.18 - 7.65 (m, 2H), 7.15 - 6.98 (m, 1H), 6.34 - 5.67 (m, 2H), 4.15 (s, 3H), 3.71 -3.48 (m, 2H), 1.33 - 1.25 (m, 6H), 0.98 - 0.86 (m, 2H), 0.62 - 0.26 (m, 8H). LCMS: m/z 355.2 (M+H)+.
Compound N2,N4-bis(3,3-difluorocyclobutyl)-6-(6-(trifluoromethoxy)pyrMin^ triazine-2 ,4-diamine
Figure imgf000176_0001
1H NMR (400 MHz, CDC13) δ 8.34 - 8.27 (m, 1H), 7.96 - 7.92 (m, 1H), 7.22 (d,J = 8 Ηζ,ΙΗ), 5.83 - 5.41 (m, 2H), 4.49 - 4.35 (m, 2H), 3.05 (d, J = 4 Hz, 4H), 2.63 - 2.54 (m, 4H).LCMS: m/z 453 (M+H)+.
N2,]S4-bis(3,3-difluorocyclopentyl)-6-(6-(trifluoromethoxy)pyridin^
Figure imgf000176_0002
Ή NMR (400 MHz, CDC13) δ 8.33 - 8.26 (m, 1H), 7.95 - 7.92 (m, 1H), 7.22(d, J = 8 Hz, 1H), 5.65 - 5.28 (m, 2H), 4.67 - 4.52 (m, 2H),2.64 - 2.59 (m, 2H), 2.30 - 1.79 (m, 10H) .LCMS: m/z 481 (M+H)+.
Compound N2,Nt-bis(4,4-difluorocyclohexyl)-6-(6-(trifluoroinethoxy)py M
tria ine-2 ,4-diamine
Figure imgf000176_0003
1H NMR (400 MHz, CDC13) δ 8.31 (d, J = 8 Hz, 1H), 7.98 - 7.92 (m, 1H), 7.24 (d, J = 12 Hz, 1H), 5.44 - 5.08 (m, 2H), 4.16 - 3.98 (m, 2H), 2.15 - 1.65 (m, 16H).LCMS: m/z 509(M+H). + Compound N2,rf-bis(4,4-difluorocyclohexyl)-6-(3-fluoro-6-methoxypyridin^ triazine-2 ,4-diamine
Figure imgf000177_0001
Ή NMR (400 MHz, CDC13) δ 7.45-7.41 (t, IH), 6.84 (d, IH), 5.43-5.07 (m, 2H), 4.08-3.98 (m, 5H), 2.11-2.01 (m, 8H), 1.96-1.89 (m, 4H), 1.87-1.83 (m, 4H). LCMS : m/z 473(M+H)+.
Table 1: The followingcompounds were prepared by following theprocedure described in Scheme 1 above.
Figure imgf000177_0002
Figure imgf000178_0001
diamine
Example 2 Preparation of Di-aliphatic Triazine Compounds of Formula EWherein Ring A is substituted Pyridin-2-yl or Phenyl. The compounds of this Example are prepared by general Scheme 2, set forth below.
Figure imgf000178_0002
Formula E
Step l:Preparationof(R)-4-chloro-N-(l-cyclopropylethyl)-6-(6-(trifluorom^
l,3,5-triazin-2-amine.To a mixture of 2,4-dichloro-6-(6-(trifluoromethyl)pyridine -2-yl)-l,3,5- triazine (600 mg, 2.0mmol, 1.0 eq) and (R)-l-cyclopropylethanamine hydrochloride salt (268 mg, 2.2mmol, 1.1 eq) in THF (6 mL) were added CsF (608 mg, 4.0mmol, 2eq) and DIPEA (0.7 mL, 4.0mmol, 2 eq) at room temperature. The mixture was stirred at 40°C overnight and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a standard method to give the desired product.
Figure imgf000179_0001
LC-MS: m/z 344.1 (M+Hf .
Step2: Preparation N2-((R)-l-cyclopropylethyl)-N4-(pentan-2-yl)-6- (6-
(trifluoromethyl)pyridin-2-yl) -l,3,5-triazine-2,4-diamine. To a mixture of (R)-4-chloro-N-(l- cyclopropylethyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazin-2-amine (80 mg, 0.23 mmol, 1.0 eq) and pentan-2 -amine (25 mg,0.28mmol, 1.2eq) in THF (2 mL) were added CsF (70 mg, 0.46mmol, 2eq) and DIPEA (0.08 mL, 0.46 mmol, 2 eq) at room temperature. The mixture was stirred at 60°C ovemight and filtered. The filtrate was concentrated under reduced pressure and then purified by a standard method to give the desired product.
Figure imgf000179_0002
¾ NMR (400 MHz, DMSO-d6): δ 8.54 - 8.42 (m, 1H), 8.23 (t, J = 7.8 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 9.5 Hz, 1H), 4.27 - 3.96 (m, 1H), 3.65 - 3.47 (m, 1H), 1.60 - 1.46 (m, 1H), 1.41 - 1.29 (m, 3H), 1.22 (d, 6.5 Hz, 3H), 1.12 (d, J = 6.1 Hz, 3H), 1.01 - 0.96 (m, 1H), 0.88 (t, J = 7.1 Hz, 3H), 0.50 - 0.29 (m, 3H), 0.26 - 0.07 (m, 1H).LC-MS: m/z 395.2 (M+H)+.
The procedure set forth in Example 2was used to produce the following compounds using the appropriate starting materials.
Figure imgf000180_0001
Ή NMR (400 MHz, CDC13): δ 8.52 (m, 1H), 8.00 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 5.63 (m, 2H), 3.73 (m, 9H), 2.66 (d, J = 5.9 Hz, 2H), 1.29 (m, 3H), 1.01 - 0.79 (m, 1H), 0.60 - 0.17 (m, 4H).LC-MS: m/z 411.2 (M+H)+.
Compound (R)-N2-(l-cyclopropylethyl)-N*-(4,4-difluorocyclohexyl)-6-(6-(trifluoro methyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000180_0002
1H NMR (400 MHz, CDC13): δ 8.66 - 8.39 (m, 1H), 8.02 (t, J = 7.7 Hz, 1H), 7.80 (d, J= 7.7 Hz, 1H), 5.34 (m, 2H), 4.11 (m, 1H), 3.63 (m, 1H), 2.32 - 1.54 (m, 9H), 1.29 (m, 3H), 0.95 (s, 1H), 0.70 - 0.16 (m, 4H).LC-MS: m/z 443.2 (M+H)+.
Compound N2-((R)-l-cyclopropylethyl)-N*-(6,6-difluorospiro[3.3]heptan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000181_0001
1H NMR (400 MHz, CDC13): δ 8.54 - 8.49 (m, IH), 8.01 (t, J = 7.3 Hz, 1H), 7.78 (d, J= 7.7 Hz, 1H), 5.60 - 5.27 (m, 2H), 4.57 - 4.37 (m, 1H), 3.67 - 3.57 (m, 1H), 2.70 - 2.65 (m, 2H), 2.57 (m, 3H), 2.22 - 1.92 (m, 4H), 1.30 (d, J = 5.8 Hz, 2H), 0.93 (s, 1H), 0.54 - 0.29 (m, 4H).LC-MS: m/z 455.2 (M+H)+.
Compound
Figure imgf000181_0002
(trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000181_0003
Ή NMR (400 MHz, CDC13): δ 8.63 - 8.34 (m, IH), 8.00 (t, J = 7.8 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 5.57 (m, 2H), 4.21 (m, IH), 3.85 - 3.32 (m, IH), 2.22 - 1.57 (m, 15H), 1.25 (m, 4H), 0.90 (m, IH), 0.66 -0.24 (m, 4H).LC-MS: m/z 459.2 (M+H)+.
Compound (R)-N2-(l-cyclopropylethyl)-N*-(di(yclopropylmethyl)-6-(6-(trifluoro methyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000182_0001
Ή NMR (400 MHz, CDC13): δ 8.49 (d, J = 7.5 Hz, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.77 (d, J= 7.7 Hz, 1H), 5.71 - 5.05 (m, 2H), 3.59 (m, 2H), 1.25 (m, 3H), 1.07 - 0.80 (m, 3H), 0.64 - 0.19 (m, 12H).LC-MS: m/z 419.2 (M+H)+.
Compound rf-fffy-l-cyclopropylethyfy-d-fd-ftrifluoromethytypyridin^-yfy-N4- (1,1,1- trifluoropropan-2-yl)-l,3,5-triazine-2,4-d mine
Figure imgf000182_0002
1H NMR (400 MHz, CDC13): δ 8.53 (s, 1H), 8.01 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 5.91 - 4.65 (m, 3H), 3.67 (m, 1H), 1.51 - 1.15 (m, 6H), 0.93 (s, 1H), 0.74 - 0.10 (m, 4H).LC-MS: m/z 421.1 (M+H)+.
Compound (RJ-rf-fl-cyclopropylethyfy-N'-fi^-dihydro-lH-inden^-yfy-e-fe
(trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000183_0001
Ή NMR (400 MHz, CDC13): δ 8.61 - 8.46 (m, 1H), 7.99 (t, J = 8.1 Hz, 1H), 7.77 (d, J= 7.7 Hz, 1H), 7.26 - 7.17 (m, 4H), 5.75 - 5.30 (m, 2H), 5.11 - 4.75 (m, 1H), 3.78 - 3.54 (m, 1H), 3.46 - 3.31 (m, 2H), 2.94 - 2.88 (m, 2H), 1.32 (d, J= 6.4 Hz, 3H), 1.24 - 1.19 (m, 1H), 0.98 - 0.86 (m, 1H), 0.52 - 043(m, 3H), 0.29 (s, 1H).LC-MS: m/z 441.2 (M+H)+.
Compound (R)-N2-(l-cycfapropylethyl)-N*^rop-2-yn-l-yl)-6-(6-(trifluoromethyl) pyridin-2- yl)-l,3,5-triazine-2,4-diamine
Figure imgf000183_0002
Ή NMR (400 MHz, CDC13): δ 8.55 (m, 1H), 8.01 (t, J = 7.8 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 5.94 - 5.12 (m, 2H), 4.30 (m 2H), 3.59 (m, 1H), 2.23 (s, 1H), 2.01 (s, 3H), 0.90 (m, 1H), 0.59 - 0.16 (m, 4H).LC-MS: m/z 363.1 (M+H)+.
Compound (R)-N '-(l-cyclopropylethyl)-N 1-(2-phenoxyethyl)-6-(6-(trifluoromethyl)pyridin-2- yl)-l,3,5-triazine-2,4-diamine
Figure imgf000184_0001
¾ NMR (400 MHz, CDC13): δ 8.43 (d, J = 8.0 Hz, 1H), 7.93 (t, J = 7.6 Hz, 1H), 7.71 (d, J= 7.7 Hz, 1H), 7.34 - 7.18 (m, 2H), 7.00 - 6.69 (m, 3H), 6.03 - 5.08 (m, 2H), 4.07 (s, 2H), 3.94 - 3.71 (m, 2H), 3.53 (d, J= 6.8 Hz, 1H), 1.34 - 1.04 (m, 4H), 0.35 (m, 4H).LC-MS: m/z 445.2 (M+H)+.
Compound N2-((R)-l-cyclopropylethyl)-rf-(l-m thoxypropan-2-yl)-6-(6-(trifluoro methyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000184_0002
Ή NMR (400 MHz, CDC13): δ 8.51 (m, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 5.55 - 5.33 (m, 2H), 4.45 - 4.29 (m, 2H), 3.68 - 3.39 (m, 4H), 1.85 (s, 3H), 1.28 - 0.93 (m, 6H), 0.60 - 0.27 (m, 3H).LC-MS: m/z 397.2 (M+H)+.
Compound (RJ-rf-fl-cyclopropylethyfy-N'-fl^-dimethoxypropan^-yfy-e-fe- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000184_0003
¾ NMR (400 MHz, CDC13): 8.47 (m, 1H), 8.05 - 7.80 (m, 1H), 7.71 (d, J = 7.7 Hz, 1H), 5.90 - 5.06 (m, 2H), 4.57 - 4.05 (m, 1H), 3.65 - 3.38 (m, 4H), 3.33 (m, 6H), 1.23 (m, 4H), 0.84 (m, 1H), 0.61 - 0.05 (m, 4H).LC-MS: m/z 427.2 (M+H)+.
Compound 2-((4-(((R)-l-cyclopropykthyl)amino)-6-(6-(trifluoromethyl)pyridine -2-yl)-l,3,5- triazin-2-yl)amino)propanenitrile
Figure imgf000185_0001
Ή NMR (400 MHz, CDC13): δ 8.56 (m, 1H), 8.03 (t, J = 7.8 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 5.52 (m, 2H), 5.16 - 4.85 (m, 1H), 3.76 - 3.44 (m, 1H), 1.72 - 1.55 (m, 3H), 1.39 - 1.21 (m, 3H), 0.95 (s, 1H), 0.65 - 0.16 (m, 4H).LC-MS: m/z 378.2 (M+H)+.
Compound (R)-2-(4-(l-cycfapropytethylamino)-6-(6-(trifluoromethyl)pyrMin-2-yl)- 1,3,5- tria in-2-ylamino)-2-methylpropanenitrile
Figure imgf000185_0002
13): δ 8.56 (d, J = 8.2 Hz, 1H), 8.03 (t, J = 7.7 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 5.71 - 5.54 (m, 2H), 3.70 (m, 1H), 1.82 (s, 6H), 1.36 - 1.25 (m, 4H), 0.97 (d, J = 7.7 Hz, 1H), 0.62 - 0.26 (m, 4H).LC-MS: m/z 392 (M+H)+.
CompoundN2-((R)-l-cyc^propylethyl)-l^-(tetrahydrofuran-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000186_0001
1HNMR(400 MHz, CDC13): δ 8.57-8.47 (m, 1H), 7.99 (t,J=7.2Hz, 1H), 7.78 (d,J=7.6Hz, 1H), 5.73 - 5.32 (m, 2H), 4.79 - 4.60 (m, 1H), 3.99 - 3.49 (m, 5H), 2.29 (m, 2H), 1.91 (m, 1H), 1.30 (m, 3H), 0.56 - 0.23 (m, 4H).LC-MS: m/z 395.2 (M+H)+.
Compound(lS,2S)-2-(4-((R)A-cyclopropylethylandno)-6-(6-(t¥ifl^
l3,5-triazin-2-ylamino)cyclohexanol
Figure imgf000186_0002
'H MR (400 MHz, CDCI3): δ 8.48 (d, J= 7.4 Hz, 1H), 8.01 (t, J= 7.8 Hz, 1H), 7.79 {A, J =1.1 Hz, 1H), 5.67 - 5.28 (m, 2H), 3.65 (m, 4H), 2.09 (s, 3H), 1.47 - 1.23 (m, 8H), 0.92 (s, 1H), 0.62 - 0.40 (m, 3H), 0.30 (s, 1H).LC-MS: m/z 423.2 (M+H)+.
Compound(lR,2S)-2-(4-((R)-l-cyclopropylethylamino)-6-(6-(trifluoromethyl) -pyridin-2-yl)- l,3,5-triazin-2-ylamino)cyclopentanol
Figure imgf000186_0003
Ή NMR (400 MHz, CDC13): δ 8.51 (m, 1H), 8.01 (t, J= 7.6 Hz, 1H), 7.80 (t, J= 6.4 Hz, 1H), 5.40-5.31 (m, 1H), 4.10 - 3.97 (m, 2H), 3.69 - 3.52 (m, 1H), 2.25 -2.09 (m, 2H), 1.95-1.55 (m, 7H), 1.29 (d, J = 6.0 Hz, 2H), 0.93 (d, J = 7.5 Hz, 1H), 0.66 - 0.16 (m, 4H).LC-MS: m/z 409.2 (M+H)+.
Compound (R)-N2-benzyl-]^-(l-cyclopropylethyl)-6-(6-(trifluoromethyl)pyridin- 2-yl)-l,3,5- triazine-2 ,4-diamine
Figure imgf000187_0001
Ή NMR (400 MHz, CDC13): δ 8.49 (d, J = 7.2 Hz, lH), 7.98 (t, J= 7.7 Hz, 1H), 7.77 (d, J= 7.7 Hz, 1H), 7.31 (m, 5H), 5.51 (m, 2H), 4.67 (m, 2H), 3.63 (m, 1H), 1.27 (m, 3H), 0.91 (s, 1H), 0.38 (m, 4H).LC-MS: m/z 415.2 (M+H)+.
Compound N2-((R)-l-cyclopropylethyl)-rf-((S) ^henylethyl)-6-(6-(trifluoromethyl) pyridin- -yl)-l,3,5-triazine-2,4-diamine
Figure imgf000187_0002
Ή NMR (400 MHz, CDC13): δ 8.45 (t, J= 10.4 Hz, lH), 7.98 (t, J= 7.7 Hz, 1H), 7.77 (d, J= 7.7 Hz, 1H), 7.54 - 7.03 (m, 5H), 5.70 (d, J= 6.9 Hz, 1H), 5.45 (m, 1H), 5.15 (m, 1H), 3.50 (m, 1H), 1.55 (m, 3H), 1.28 (m, 1H), 0.96 (m, 3H), 0.64 - 0.18 (m, 4H).LC-MS: m/z 429.2 (M+H)+.
Compound N2-((R)-l-cyclopropylethyl)-rf-((R)-l^henylethyl)-6-(6-(trifluoro methyl) pyridin- 2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000188_0001
Ή NMR (400 MHz, CDC13): δ 8.47 (d, J = 8.3 Hz, 1H), 7.98 (t, J = 7.7 Hz, 1H), 7.76 (d, J= 7.7 Hz, 1H), 7.50 - 7.02 (m, 5H), 5.78 - 5.07 (m, 3H), 3.55 (m, 1H), 1.72 (m, 1H), 1.56 (d, J = 6.7 Hz, 3H), 0.97 (m, 3H), 0.58 - 0.15 (m, 4H).LC-MS: m/z 429.2 (M+H)+.
Compound N2-((ltyA-cyctopropylethyl)-l^-(l-(3-fluorophenyl)ethyl)-6-(6
(trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000188_0002
1H NMR (400 MHz, CDC13): δ 8.55 - 8.36 (m, 1H), 8.00 (t, J = 7.7 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.27 (d, J = 7.8 Hz, 2H), 7.18 - 6.90 (m, 3H), 5.71 - 5.06 (m, 3H), 3.78 - 3.32 (m, 1H), 1.54 (d, J = 6.8 Hz, 3H), 1.34 - 1.22 (m, 3H), 1.00 (d, J = 6.3 Hz, 1H), 0.94 - 0.72 (m, 1H), 0.54 - 0.37 (m, 2H), 0.31 - 0.20 (m, 1H).LC-MS: m/z 447.2 (M+H)+.
Compound N2-((R)-l-cycfapropylethyl)-N*-(l-(3-(trifluoromethyl)phenyl)ethyl)
(trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000189_0001
¾ NMR (400 MHz, CDC13): δ 8.42 (m, 1H), 8.08 - 7.93 (m, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.67 - 7.38 (m, 4H), 5.84 - 5.49 (m, 1H), 5.49 - 5.03 (m, 2H), 3.72 - 3.16 (m, 1H), 1.57 (d, J = 6.9 Hz, 3H), 1.26 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 6.4 Hz, 1H), 0.73 (m, 1H), 0.53 - 0.41 (m, 1H), 0.37 (m, 1H), 0.25 (m, 1H).LC-MS: m/z 497.2 (M+H)+.
Compound^-ffR^l-cyclopropylethy^-N^-fflR^S^-phenyliyclopropy^-e-fe
(Mfluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000189_0002
1H NMR (400 MHz, CDC13): δ 8.47 (d, J = 8.3 Hz, 1H), 7.98 (t, J = 7.7 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.37 (m, 4H), 7.23 (m, 1H), 5.81 - 5.05 (m, 3H), 3.55 (m 1H), 1.72 (s, 1H), 1.56 (d, J = 6.7 Hz, 3H), 0.97 (m 3H), 0.63 - 0.18 (m, 4H).LC-MS: m/z 441.2 (M+H)+.
Compound (R)-N2-(l-cyclopropylethyl)-N*-(l^henyl(yclopropyl)-6-(6-(trifluoro methyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000190_0001
1H NMR (400 MHz, DMSO-d6): δ 8.53 - 8.13 (m, 3H), 7.99 (m, 1H), 7.70 (m, 1H), 7.45 - 7.04 (m, 5H), 3.30 - 3.19 (m, 1H), 1.38 - 1.09 (m, 5H), 1.07 - 0.75 (m, 3H), 0.43 - -0.09 (m, 4H).LC-MS: m/z 441.2 (M+H)+.
Compound (Rj-d-fd-chloropyridin^-ylj-^-fl-cyclopropylethylj-N^^-diethyl- 1,3,5-triazine- 24-diamine
Figure imgf000190_0002
Ή NMR (400 MHz, CDC13): δ 8.32 (d, J = 6.6 Hz, 1H), 7.75 (s, 1H), 7.42 (s, 1H), 5.51 (s, 1H), 3.62 (m, 5H), 1.42 - 1.03 (m, 9H), 0.92 (d, J = 7.7 Hz, 1H), 0.63 - 0.17 (m, 4H). LC-MS: m/z 347.2 (M+H)+.
Compound (R)-methyl 3-((4-((l-cyclopropylethyl)amino)-6-(6-(trifluoromethyl)pyri -din-2-yl)- -triazin-2-yl)amino)propanoate
Figure imgf000190_0003
Ή NMR (400 MHz, CDC13): δ 8.52 (m, 1H), 8.00 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 5.63 (m, 2H), 3.73 (m, 9H), 2.66 (d, J = 5.9 Hz, 2H), 1.29 (m, 3H), 1.01 - 0.79 (m, 1H), 0.60 - 0.17 (m, 4H).LC-MS: m/z 411.2 (M+H)+.
Compound (R)-N2-(l-cyclopropylethyl)-]^-(2^henoxyethyl)-6-(6-(trifluoromethyl) pyridin-2- yl)-l,3,5-triazine-2,4-diamine
Figure imgf000191_0001
Ή NMR (400 MHz, CDC13): δ 8.43 (d, J = 8.0 Hz, 1H), 7.93 (t, J = 7.6 Hz, 1H), 7.71 A, J = 1.1 Hz, 1H), 7.34 - 7.18 (m, 2H), 7.00 - 6.69 (m, 3H), 6.03 - 5.08 (m, 2H), 4.07 (s, 2H), 3.94 - 3.71 (m, 2H), 3.53 (d, J = 6.8 Hz, 1H), 1.34 - 1.04 (m, 4H), 0.35 (m, 4H).LC-MS: m/z 445.2 (M+H)+.
Compound (lR,2S)-2-((4-(cyclopentylamino)-6-(6-(trifluoromethyl)pyridin-2 -yl)-l,3,5-triazin- -yl)amino)cyclopentanol
Figure imgf000191_0002
1HNMR (400 MHz, CD3OD): 68.63-8.57 (m, 1H), 8.17-8.14 (m, 1 H), 7.94-7.92 (m, 1H), 4.48- 4.23 (m, 3H), 2.05-1.91 (m, 5H), 1.78-1.59 (m, 9H).LC-MS: m/z 409.3 (M+H).
Compound N2-(3,3-difluorocycfapentyl)-N*-(tetrahydrofuran-3-yl)-6-(6-(trifluoro methyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000192_0001
Ή NMR (400 MHz, CD3OD): δ 8.68-8.56 (m, 1H), 8.15 (t, J = 8.3 Hz, 1H), 7.93 A, J = 1.5 Hz, 1H), 4.81 - 4.43 (m, 2H), 4.11 - 3.92 (m, 2H), 3.86 (m, 1H), 3.78 - 3.66 (m, 1H), 2.74 - 2.50 (m, 1H), 2.38 - 1.75 (m, 7H).LC-MS: m/z 431.2 (M+H)+.
Compound tert-butyl 3-((4-((3,3-difluorocyclopentyl)amino)-6-(6-(trifluoromethyl) pyridin-2- -l,3,5-triazin-2-yl)amino)pyrrolidine-l-carboxylate
Figure imgf000192_0002
1H NMR (400 MHz, CDC13): δ 8.62 - 8.46 (m, 1H), 8.03 (d, J= 6.9 Hz, 1H), 7.81 (d, J= 7.7 Hz, 1H), 5.91 - 5.19 (m, 2H), 4.61 (m, 2H), 3.82 - 3.59 (m, 1H), 3.50 (s, 1H), 3.29 (m, 1H), 2.65 (m, 1H), 2.43 - 2.06 (m, 5H), 1.97 (s, 1H), 1.47 (s, 9H). LC-MS: m/z 530.2 (M+H)+.
Compound ^-isobufyl-N^-ftetrahydro^H^yran^-y^-e-fe-fMfluoromethyl^yrMin^-yl)- 1,3, 5-triazine-2,4-diamine
Figure imgf000192_0003
1HNMR (400 MHz, CD3OD): 68.7-8.6 (m, 1H), 8.25-8.15 (m, 1H), 8.0-7.9 (m, 1H), 4.4-4.1 (m, 1H), 4.05-3.96 (m, 2H), 3.3-3.2 (m, 2H), 2.1 -1.9 (m, 3H), 1.63-1.5 (m, 2H), 1.05-0.9 (m, 6H). LC-MS: m/z 397.3 (M+H)+.
Compound N2-((R)-l-cyclopropylethyl)-N4-(l-(2-methoxyethoxy)propan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000193_0001
Ή NMR (400 MHz, CDC13) δ 8.61 - 8.42 (m, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 5.78 - 5.37 (m, 2H), 4.52 - 4.22 (m, 1H), 3.79 - 3.47 (m, 7H), 3.40 (s, 3H), 1.29 (d, J = 5.7 Hz, 6H), 0.99 - 0.80 (m, 1H), 0.61 - 0.21 (m, 4H). LC-MS: m/z 441 (M+H)+.
Compound 2-((4-(((R) -cyclopropylethyl)amino)-6-(6-(trifluoromethyl)pyridin-2
triazin-2-yl)amino)propan-l -ol
Figure imgf000193_0002
1H NMR (400 MHz, CDC13) δ 8.57 - 8.47 (m, 1H), 8.01 (t, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 5.62- 5.20 (m, 2H), 4.23 (m, 1H), 3.82 - 3.49 (m, 3H), 1.35 - 1.22 (m, 6H), 0.93 (m, 1H), 0.58 - 0.29 (m, 4H). LCMS: m/z 383.2 (M+H)+.
Compound N2-((R)-l-cyclopropylethyl)-N4-(l-isopropoxypropan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000194_0001
1H NMR (400 MHz, CDC13) δ 8.65 - 8.42 (m, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 5.92 - 5.08 (m, 2H), 4.44 - 4.13 (m, 1H), 3.73 - 3.27 (m, 4H), 1.27 (m, 6H), 1.17 (d, J = 6.1 Hz, 6H), 1.04 - 0.84 (m, 1H), 0.63 - 0.16 (m, 4H). LC-MS: m/z 425 (M+H)+.
Compound N2 -((R)-l-cyclopropylethyl)- '-(4-methoxybutan-2-y i)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000194_0002
1H NMR (400MHz, CDC13)5 8.63 - 8.48 (m, 1H), 8.01 - 7.97(m, 1H), 7.77 (d,J=7.6Hz, 1H), 5.54 - 5.25 (m, 2H), 4.44 - 4.22 (m, 1H), 3.64 - 3.49 (m, 3H), 3.33(d,J=2.4Hz, 3H), 1.89 - 1.78 (m, 2H), 1.30 - 1.25 (m, 5H), 0.93 - 0.83(m, 2H), 0.53 - 0.28 (m, 4H). LCMS: m/z 411(M+H)+.
Compound N2-((R)-l-cyclopropylethyl)-N4-(l-phenylpropan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000194_0003
Ή NMR (400 MHz, CDC13) δ 8.41 (d, J = 7.6 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.25 - 7.14 (m, 5H), 5.50 - 4.92 (m, 2H), 4.25 (m, 1H), 3.68 - 3.39 (m, 1H), 2.99 (m, 1H), 2.61 (m, 1H), 1.26 - 1.06 (m, 8H), 0.52 - 0.28 (m, 3H).LC-MS: m/z 443 (M+H)+.
Compound N2-((R)-l-cyclopropylethyl)-N4-(l-morpholinopropan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000195_0001
Ή NMR (400MHz, CDC13)5 8.51 - 8.50 (m, 1H), 8.22(s, 1H), 8.03 - 7.99(m, 1H), 7.83 - 7.79 (m, 1H), 6.39- 5.86 (m, 2H), 4.44 (m, 7H), 3.79 - 3.52 (m, 5H), 3.25 - 2.53 (m, 5H), 0.95(s, 1H), 0.54 - 0.26 (m, 4H). LCMS: m/z 452(M+H)+.
Compound N2-((R)-l-cyclopropylethyl)-N4-(l-(piperidin-l-yl)propan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000195_0002
1H NMR (400MHz, CDC13): δ 8.54 - 8.51 (m , 2H), 8.01 -7.98 (m, 1H), 7.77 (d, J=7.6Hz , 1H), 6.66 - 6.17 (m, 1H), 5.72 - 5.54 (m, 1H), 4.84 - 4.44 (m, 1H), 4.21(s, 5H), 3.67- 2.63 (m, 7H), 1.77 (d,J=5.2Hz, 4H), 1.53(s, 2H), 0.93(d,J=4Hz, 1H), 0.52 - 0.27 (m, 4H). LCMS: m/z 450(M+H)+.
Compound (R)-3-((4-((l-cyclopropylethyl)amino)-6-(6-(trifluoromethyl)pyridm^
triazin-2-yl)amino)-2,2-dimethylpropanamide
Figure imgf000196_0001
Ή NMR (400MHz, CDC13)5 8.52 - 8.37 (m, 1H), 8.00 - 7.96(m, 1H), 7.87 - 7.75 (m, 1H),6.01- 5.22 (m, 2H), 4.26- 3.53(m, 3H), 2.32 - 1.45(m, 2H), 1.41 - 1.29 (m, 8H), 1.23 - 1.21 (m, 1H), 0.97 - 0.28 (m, 5H). LCMS: m/z 424(M+H)+.
Compound 3-((4-(((R)-l-cyclopropylethyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5- triazin-2-yl)amino)butanenitrile
Figure imgf000196_0002
1H NMR (400MHz, CDC13)5 8.50 (d,J=7.6Hz, 1H), 8.03 - 7.99(m, 1H), 7. 80(d,J=7.6Hz, 1H), 5.64 - 5.17 (m, 2H), 4.55 - 4.32 (m, 1H), 3.70 - 3.51 (m, 1H), 2.87 - 2.69 (m, 2H), 1.46(d,J=6.8Hz, 3H), 1.33 - 1.25 (m, 3H), 0.96 - 0.89 (m, 1H), 0.55- 0.30 (m, 4H). LCMS: m/z 392(M+H)+.
Compound (R)-3-((4-((l-cyclopropylethyl)amino)-6-(6-(trifluoromethyl)pyrM
triazin-2-yl)amino)-2,2-dimethylpropanenitrile
Figure imgf000196_0003
Ή NMR (400MHz, CDC13) δ 8.55(s, 1H), 8.1 l(s, 1H), 7.91 (d,J=8Hz, 1H), 3.73 - 3.62 (m, 4H), 1.47 - 1.42 (m, 7H), 1.37 - 1.35 (m, 3H), 0.75 - 0.69 (m, 1H), 0.58(m, 2H), 0.40 - 0.34 (m, 2H). LCMS: m/z 406(M+H)+.
Compound l-((4-((3,3-Difluorocyclopentyl)amino)-6-(6-(trifluoromethyl)pyridm^
triazin-2-yl)amino)-2-methylpropan-2-ol
Figure imgf000197_0001
Ή NMR (400 MHz, CDC13) δ 8.50 (s, 1H), 8.03 (d, J = 7.3 Hz, 1H), 7.80 (d, J = 7.4 Hz, 1H), 5.68 (m, 2H), 4.60 (m, 1H), 3.83 - 3.03 (m, 3H), 2.74 - 2.56 (m, 1H), 2.31 (s, 2H), 2.19 - 1.97 (m, 2H), 1.83 (m, 1H), 1.30 (s, 6H).LCMS: m/z 433 (M+H)+.
Compound N '-(3, 3-difluorocyclopentyl)-Nt-(l-(4-fluorophenyl)azetidin-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000197_0002
1H NMR (400 MHz, CDC13) δ 10.05 - 8.37 (m, 1H), 8.31 - 7.54 (m, 2H), 7.60 - 6.68 (m, 4H), 5.49 - 4.41 (m, 4H), 3.80 - 3.35 (m, 2H), 2.55 - 2.12 (m, 6H). LC-MS: m/z 510 (M+H)+.
Compound TV' '-(3 ,3-difluorocyclopeniyl)-N*-(l- yridin-2-yl)azetidin-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000198_0001
¾ NMR (400 MHz, CDC13) δ 8.50 (s, 1H), 8.09 (m, 2H), 7.80 (s, 1H), 7.49 (s, 1H), 6.66 (s, 1H), 6.26 (m, 2H), 5.77 (m, 1H), 4.99 - 4.34 (m, 4H), 3.96 (m, 2H), 2.42 - 1.71 (m, 6H).LCMS: m/z 493(M+H)+.
Compound ' N '-(3 ,3-difluorocyclopeniyl)-N*-(l- yridin-3-yl)azetidin-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000198_0002
1H NMR (400MHz, CDC13): δ 8.50 (d,J=8Hz, 1H), 8.07 - 8.01 (m, 2H), 7.92(s, 1H), 7.80 (d,J=8Hz, 1H), 7.17 - 7.14 (m, 1H), 6.80 - 6.79 (m, 1H), 6.15 - 5.34 (m, 2H), 5.14 - 4.51 (m, 2H), 4.39 - 4.35 (m , 2H), 3.89 - 3.78 (m, 2H), 2.62 - 2.57 (m, 1H), 2.30 - 2.11 (m, 5H).LCMS: m/z 493(M+H)+.
Compound rf-fi^-difluorocyclopentyfy-N'-fflr^rJ-S-ft-fluorophenyfycyclobutyfy-e-fe- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000198_0003
Ή NMR (400 MHz, CDC13) δ 8.55 (d, J = 7.6 Hz, 1H), 8.21 - 8.01 (m, 1H), 7.88 (m, 1H), 7.26 - 7.15 (m, 2H), 7.04 (t, J= 8.4 Hz, 2H), 4.89 - 4.35 (m, 2H), 3.88 - 3.40 (m, 1H), 3.00 - 1.75 (m, 11H). LC-MS: m/z 509 (M+H)+.
Compound ' N l-(3 ,3-difluorocyclopentyl)-N '-((Is, 3s)-3-(4-fluorophenyl)cyclobutyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000199_0001
Ή NMR (400 MHz, CDC13) δ 8.65 - 8.42 (m, 1H), 8.02 (t, J = 7.3 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.20 - 7.12 (m, 2H), 7.01 (t, J= 8.6 Hz, 2H), 5.82 - 5.20 (m, 2H), 4.83 - 4.37 (m, 2H), 3.40 - 3.11 (m, 1H), 3.00 - 1.75 (m, 10H). LC-MS: m/z 509 (M+H)+.
Compound N2-(3,3-difluorocyclopentyl)-N4-(3-phenylcyclobutyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000199_0002
Ή NMR (400 MHz, CDC13) δ 8.65 - 8.42 (m, 1H), 8.01 (t, J = 7.8 Hz, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.42 - 7.29 (m, 3H), 7.23 (t, J= 6.4 Hz, 1H), 6.07 - 5.20 (m, 2H), 4.90 - 4.40 (m, 2H), 4.13 - 3.56 (m, 1H), 2.75 - 1.75 (m, 10H). LC-MS: m/z 491 (M+H)+.
Compound N2-(3,3-difluorocyclopeniyl)-N*-(l-methylpyrrolidin-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000200_0001
Ή NMR (400 MHz, CDC13) δ 8.62 - 8.48 (m, 1H), 8.09 - 7.94 (m, 1H), 7.80 (t, J= 7.4 Hz, 1H), 4.91 - 4.27 (m, 2H), 3.42 - 2.56 (m, 9H), 2.44 - 2.22 (m, 4H), 2.00 - 1.57 (m, 4H). LC-MS: m/z 444 (M+H)+.
Compound (3-((4-((3,3-Difluorocycfapentyl)amino)-6-(6-(trifluoromethyl)pyrMin-2-y^ triazin-2-yl)amino)pyrrolidin-l-yl)(phenyl)methanone
Figure imgf000200_0002
Ή NMR (400 MHz, CDC13) δ 8.76 - 8.35 (m, lH), 8.10 - 7.91 (m, 1H), 7.84 (s, 1H), 7.53 (d, J = 7.4 Hz, 2H), 7.43 (d, J = 6.5 Hz, 3H), 5.75 - 5.29 (m, 2H), 4.86 - 3.77 (m, 4H), 3.70 - 3.23 (m, 2H), 2.79 - 1.74 (m, 8H). LC-MS: m/z 534 (M+H)+.
Compound N2-(l-benzylpyrrolidin-3-yl)-N*-(3,3-difluorocyclopentyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000200_0003
Ή NMR (400 MHz, CDC13) δ: 8.62 - 8.40 (m, 1H), 8.12 - 7.93 (m, 1H), 7.79 (d, J = 7.3 Hz, 1H), 7.57 - 7.28 (m, 5H), 6.23 - 5.45 (m, 2H), 5.07 - 3.75 (m, 4H), 3.06 - 2.40 (m, 4H), 2.38 - 1.60 (m,8H). LC-MS: m/z 520 (M+H)+.
Compound (4S)-4-((4-((3,3-difluorocyclopentyl)amino)-6-(6-(trifluoromethyl)pyrM
-triazin-2-yl)amino)A-(pyrulin-2-yl)pyrrolidin-2-one
Figure imgf000201_0001
Ή NMR (400 MHz, CDC13) δ 8.66 - 8.29 (m, 3H), 8.00 (s, 1H), 7.73 (m, 2H), 7.12 - 7.01 (m, 1H), 5.73 (m, 2H), 5.00 - 4.40 (m, 3H), 4.24 - 4.05 (m, 1H), 3.15 (m, 6.3 Hz, 1H), 2.85 - 2.51 (m, 2H), 2.21 (m, 5H). LCMS: m/z 521 (M+H)+.
Compound N2 -(3, 3-difluorocyclopentyl)-T^-(3-phenylcyclopentyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000201_0002
Ή NMR (400MHz, CDC13)5 8.59 - 8.48 (m, 1H), 8.03 - 7.99 (m, 1H), 7.80 (d, J=4Hz, 1H), 7.34 - 7.30 (m, 3H), 7.23 - 7.19 (m, 2H), 5.63 - 5.31 (m, 2H), 4.70 - 4.56 (m, 2H), 3.29 - 3.17 (m, 1H), 2.65 - 2.04 (m, 9H), 1.81 (m, 3H). LCMS: m/z 505(M+H)+.
Compound N2-(3,3-difluorocyclopentyl)-Nt-(2,3-dihydro-lH-inden-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000202_0001
IH NMR (400MHz, CDC13): δ 8.64 - 8.46 (m, IH), 8.01 (d,J=12.8Hz , IH), 7.78 (d, J=7.6Hz , IH), 7.21(m, 3H), 5.76 - 5.31 (m, 2H), 5.02 - 4.44 (m, 2H), 3.45 - 3.36 (m, 2H), 2.97 - 2.91 (m, 2H), 2.68 - 2.58(m, IH), 2.31 - 2.09 (m, 4H), 1.85 - 1.84 (m, IH), 1.25(m, IH). LCMS: m/z 477(M+H)+.
Compound ^-(S-chloro^^-dihydro-lH^den^-y^-N^-fS^-difluoroiyclopeniy^-e-fe- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000202_0002
Ή NMR (400 MHz,CDCl3) δ 8.57 - 8.48 (m, 1H),8.01 (d, J = 8 Hz, IH), 7.81 (d, J = 8 Ηζ,ΙΗ), 7.26 - 7.18 (m, 3H), 6.02 - 5.36 (m, 2H), 5.05 - 4.43(m, 2H), 3.48 - 3.32 (m, 2H), 3.04 - 2.87 (m, 2H), 2.70 - 2.58 (m, IH), 2.36 - 2.10 (m, 4H), 1.99 - 1.82 (m, 1H).LCMS: m/z 511 (M+H)+.
Compound N2-(3, 3-difluorocyclopentyl)-]^-(5-fluoro-2, 3-dihydro^H-inden-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000202_0003
Ή NMR (400MHz, CDC13)5 8.59 - 8.47 (m, 1H), 8.04 - 7.97 (m, 1H), 7.79 (d,J=7.2Hz, 1H), 7.26 - 7.17 (m, 1H), 6.96 - 6.87 (m, 2H), 5.75 - 5.30 (m, 2H), 5.06 -4.44 (m, 2H), 3.39 - 3.32 (m, 2H), 2.95 - 2.62 (m, 3H), 2.33 - 2.05 (m, 4H), 1.87 - 1.82 (m, 1H). LCMS: m/z 495(M+H)+.
Compound N2-(5-bromo-2,3-dihydro-lH-inden-2-yl)-N' '-(3, 3-difluorocyclopentyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000203_0001
Ή NMR (400 MHz, CDC13) δ 8.57 - 8.47 (m, 1H), 8.04 - 7.99 (m, 1H), 7.82 - 7.78 (m, 1H), 7.52 - 7.29 (m, 2H), 7.18 - 7.00 (m, 1H), 5.70 - 5.30 (m, 2H), 5.03 - 4.48 (m, 2H) , 3.40 - 3.30 (m, 2H), 2.96 - 2.63 (m, 3H), 2.35 - 2.07 (m, 4H), 1.87 - 1.25 (m, 1H).LCMS: m/z 556 (M+H)+ .
Compound 2-((4-((3,3-Difluorocyclopentyl)amino)-6-(6-(trifluoromethyl)pyridm^
triazin-2-yl)amino)-2,3-dihydro-lH-indene-5-carbonitrile
Figure imgf000203_0002
Ή NMR (400 MHz, CDC13) δ 8.57 - 8.47 (m, 1H), 8.01 (d, J= 8 Hz, 1H), 7.80 (d, J= 4 Hz, 1H), 7.54 - 7.50 (m, 2H), 7.37 - 7.33 (m, 1H), 5.77 - 5.34 (m, 2H), 5.07 - 4.56 (m, 2H), 3.43 (m, 2H), 3.03 - 2.99 (m, 2H), 2.70 - 2.58 (m, 1H), 2.32 - 2.04 (m, 5H).LCMS: m/z 502 (M+H)+.
Compound TV '-(3, 3-difluorocyclopentyl)-]^-(5-methoxy-2,3-dihydro-lH-inden-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Ή NMR (400 MHz, CDC13) δ 8.69 - 8.46 (m, lH),8.00(d, J = 8 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.14 (s, 1H), 6.81 - 6.75 (m, 2H), 5.76 - 5.33 (m, 2H), 5.02 - 4.78 (m, 1H), 4.58 - 4.47 (m, 1H), 3.80 (s, 3H), 3.39 - 3.33 (m, 2H), 2.93 - 2.62 (m, 4H), 2.31 - 2.10 (m, 4H).LCMS: m/z 507 (M+H)+.
Compound N '-(3, 3-difluorocyclopentyl)-N '-(6, 7-dihydro-5H-cyclopenta[b]pyridin-6-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000204_0002
1H NMR (400 MHz, CDC13) δ: 8.64 - 8.35 (m, 2H), 8.07 - 7.76 (m, 2H), 7.53 (m, 1H), 7.11 (m, 1H), 5.86 - 5.30 (m, 2H), 5.01 - 4.54 (m, 2H), 3.62 - 2.60 (m, 5H), 2.40 - 1.86 (m, 5H). LCMS: m/z 478.2 (M+H)+.
Compound N2-(4,6-dibromo-2,3-dihydro-lH-inden-2-yl)-N' '-(3, 3-difluorocyclopentyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000204_0003
Ή NMR (400 MHz, CDC13) δ 8.55 - 8.46 (m, 1H), 8.07 - 7.99 (m, 1H), 7.80(d, J = 8 Ηζ,ΙΗ), 7.51 - 7.44 (m, 2H), 7.09 - 7.04 (m, 2H), 6.03 - 5.38 (m, 2H), 5.03 - 4.43 (m, 2H), 3.48 - 3.25 (m, 2H), 3.06 - 2.88 (m, 2H), 2.69 - 2.58 (m, 1H), 2.31- 2.29 (d, J = 8 Hz, 2H) ,2.17 - 2.01 (m, 2H), 1.90 - 1.77 (m, 1H).LCMS: m/z 635(M+H)+.
Compound rf-fi^-difluorocyclopentyfy-N'-fl-phenylpyrrolidin-S-yfy-e-fe- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000205_0001
Ή NMR (400 MHz, CDC13) δ 8.61-8.49 (m, 1H), 8.04-7.98 (m, 1H), 7.80-7.78 (m, 1H), 7.27- 7.23 (m, 2H), 6.74-6.70 (t, 1H), 6.59 (d, 2H), 5.73-5.33 (m, 2H), 4.91-4.48 (m, 2H) , 3.75-3.28 (m, 4H), 2.62-1.87(m, 8H). LCMS: m/z 506 (M+H) +.
Compound TV' '-(3 ,3-difluorocyclopeniyl)-N*-(l^yridin-2-yl)pyrrolidin-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000205_0002
Ή NMR (400 MHz, CDC13) δ 8.67 - 8.44 (m, 1H), 8.17 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 6.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, IH), 6.59 (t, J = 5.9 Hz, 1H), 6.39 (d, J = 8.1 Hz, 1H), 5.84 - 4.30 (m, 4H), 4.07 - 3.51 (m, 4H), 2.83 - 1.97 (m, 8H). LC-MS: m/z 507 (M+H)+. Compound N2-(3,3-difluorocyclopentyl)-]^-(l^yrimidin-2-yl)pyrrolidin-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000206_0001
1H NMR (400 MHz, CDC13) δ 8.64 - 8.48 (m, 1H), 8.34 - 8.33 (m, 2H), 8.04 - 7.38 (m, 1H), 7.80 - 7.79 (m, 1H), 6.54 - 6.52 (m, 1H), 5.73 - 5.35 (m, 2H), 4.61 - 4.58 (m, 2H), 4.00 - 3.93 (m, 1H), 3.79 - 3.58 (m, 3H), 2.90 - 2.61 (m, 1H), 2.38 - 2.12 (m, 6H), 1.88 - 1.82 (m, 1H). LCMS: m/z 508(M+H)+.
Compound N2-(3, 3-difluorocyclopentyl)-]^-(6,6-difluorospiro[3.3]heptan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000206_0002
Ή NMR (400 MHz, CDC13) δ 8.66 - 8.39 (m, lH), 8.02 (d, J= 7.2 Hz, 1H), 7.80 (d, J = 6.6 Hz, 1H), 5.73 - 5.20 (m, 2H), 4.80 - 4.30 (m, 2H), 2.83 - 1.78 (m, 14H). LC-MS: m/z 491 (M+H)+.
Compound l-((4-((4,4-Difluorocyclohexyl)amino)-6-(6-(trifluoroinethyl)py M
triazin-2-yl)amino)-2-methylpropan-2-ol
Figure imgf000206_0003
Ή NMR (400 MHz, DMSO-d6) δ 8.63 - 8.45 (m, 1H), 8.24 (t, J = 7.7 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.57 - 7.10 (m, 1H), 4.62 (m, 1H), 4.03-4.04 (m, 1H), 3.37 (s, 2H), 2.08 (s, 2H), 1.93-1.85 (m, 4H), 1.62 (d, J = 12.2 Hz, 2H), 1.12 (s, 6H). LC-MS: m/z 447 (M+H)+.
Compound ' N '-(4, 4-difluorocyclohexyl)-Nt-(tetrahydro-2H-pyran-4-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000207_0001
Ή NMR (400 MHz, CDC13) δ 8.55 - 8.48 (m, 1H), 8.05 - 7.99 (m, 1H), 7.80 (d, J= 7.6 Hz, 1H), 5.44 - 5.12 (m, 2H), 4.26 - 4.01 (m, 4H), 3.74 - 3.52 (m, 2H), 2.20 - 1.83 (m, 8H), 1.73 - 1.50 (m, 4H); LCMS: m/z 459.2 (M+H)+.
Compound Tert-butyl 4-((4-((4,4-difluorocyclohexyl)amino)-6-(6-(ti,ifluoromethyl)pyridin -2- -l,3,5-triazin-2-yl)amino)piperidine-l-carboxylate
Figure imgf000207_0002
1H NMR (400 MHz, CDC13) δ 8.48 - 8.40 (m, 1H), 7.97 - 7.91 (m, 1H), 7.74 - 7.69 (m, 1H), 5.56 - 5.15 (m, 2H), 4.18 - 3.85 (m, 4H), 2.95 - 2.82 (m, 2H), 2.10 - 1.54 (m, 9H), 1.40 (m, 12H). LCMS: m/z 558.3 (M+H)+.
Compound l-(4-((4-((4,4-Difluorocyclohexyl)amino)-6-(6-(trifluoromethyl)pyrid
triazin-2-yl)amino)piperidin-l-yl)ethanone
Figure imgf000208_0001
Ή NMR (400 MHz, CDC13) δ 8.54 - 8.48 (m, 1H), 8.06 - 7.97 (m, 1H), 7.81 (d, J= 7.2 Hz, 1H), 5.57 - 5.14 (m, 2H), 4.54 - 3.83 (m, 4H), 3.25 - 2.83 (m, 4H), 2.24 - 2.05 (m, 7H), 1.77 - 1.44 (m, 6H). LCMS: m/z 500.2 (M+H)+.
Compound N '-(4, 4-difluorocyclohexyl)-rf-(l-(methylsulfonyl)piperidin-4-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000208_0002
1H NMR (400 MHz, CDC13) δ 8.58 - 8.48 (m, 1H), 8.05 - 7.96 (m, 1H), 7.80 (d, J = 6.8 Hz, 1H), 5.56 - 5.18 (m 2H), 4.25 - 3.95 (m, 4H), 3.64 - 3.45 (m, 2H), 2.26 - 1.55 (m, 15H). LCMS: m/z 536.2 (M+H)+.
Compound N2- (4,4-diflu orocyclohexyfy-N*- ( 6, 6-difluorospiro[3.3]heptan-2-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000208_0003
Ή NMR (400 MHz, CDC13) δ 8.66 - 8.39 (m, 1H), 8.14 - 7.94 (m, 1H), 7.81 (d, J= 7.7 Hz, 1H), 6.04 - 5.01 (m, 2H), 4.74 - 3.74 (m, 2H), 2.79 - 2.42 (m, 6H), 2.31 - 1.96 (m, 6H), 1.85 - 1.50 (m, 4H). LC-MS: m/z 505 (M+H)+.
Compound N2-(3 ,3-difluorocyclobutyl)-N' '-(4,4-difluorocyclohexyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000209_0001
Ή NMR (400MHz, CDC13)5 8.54 - 8.48 (m, 1H), 8.02 (d, J=8Hz, 1H), 7.81 (d, J=4Hz, 1H), 5.77 - 5.14 (m, 2H), 4.53 - 3.96 (m, 2H), 3.11 - 3.03 (m, 2H), 2.70 - 2.54 (m, 2H), 2.15 - 2.09 (m, 4H), 1.93(m, 2H), 1.69(m, 2H).LCMS: m/z 465(M+H)+
Compound N2 -(4, 4-difluorocyclohexyl)-Nt -(3, 3-difluorocyclopentyl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000209_0002
Ή NMR (400MHz, CDC13)5 8.48 - 8.56(m, 1H), 8.01(d, J=4Hz, 1H), 7.80(d, J=4Hz, 1H), 5.63 - 5.13(m, 2H), 4.72 - 3.97 (m, 2H), 2.62(m, 1H), 2.31(m, 2H), 2.14 - 1.86 (m, 9H), 1.74(m, 2H). LCMS: m/z 479(M+H)+.
Compound (Rj-d-fd-chloropyridin^-ylj-^-fl ^^^-hex fluoropropan^-ylj-N^-fl,!,!- trifluoropropan-2-yl)-l,3,5-triazine-2,4-d mine
Figure imgf000210_0001
1H NMR (400 MHz, CDC13) 58.40-8.34 (m, 1H), 7.87 - 7.84 (m, 1H), 7.53 (d, J = 8 Hz, 1H), - 6.15-5.83 (m, 1H), 5.77-5.31 (m, 2H), 5.17-4.76 (m, 1H), 1.51- 1.43 (m, 3H) ; LC-MS: m/z 469 (M+H)+.
Compound (R)-6-( 6-chloropyridin-2-yl)-N2- (4,4-difluorocyclohexyl)-Nt-(l, 1,1- trifluoropropan-2-yl)-l,3,5-triazine-2,4-d mine
Figure imgf000210_0002
1H NMR (400 MHz, DMSO-d6) δ 8.33 (m, 2H), 8.13 - 7.92 (m, 2H), 7.78 - 7.59 (m, 1H), 5.21 4.76 (m, 1H), 4.06 (m, 1H), 2.23 - 1.45 (m, 8H), 1.42 - 1.25 (m, 3H). LCMS: m/z 437 (M+H)+.
Table 2: The following targets were prepared by the procedure described in Scheme 2 above.
Figure imgf000210_0003
Figure imgf000211_0001
Figure imgf000212_0001
triazine-2,4 -diamine H H
Example 3 Preparation of Di-aliphatic Triazine Compounds of Formula F. The compounds of this Example are prepared by general Scheme 3, set forth below.
Figure imgf000212_0002
9
Step 1: Preparation ofe-chloro-^^-bisff^-l-cychpropylethy^-l^^^ zine^^-diamine.
To a mixture of 2,4,6-trichloro-l ,3,5-triazine (2g, 10.9 mmol, 1 eq) and (R)-l- cyclopropylethanamine hydrochloride (2.7 g, 22.8 mmol, 2.1 eq)in acetone (50 mL) was added DIPEA (4.5 mL, 27.3 mmol, 2.5 eq) and CsF (3.3 g, 21.8 mmol, 2.0 eq). The mixture was stirred at 40°C for 3 hr and then at 50°C for another 3 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by a standard method to afford the desired product.
Figure imgf000212_0003
LC-MS: m/z 282.1 (M+H)+ Step 2: Preparation of N2 ,N* -bis((R)-l -cyclopropylethyl)-6-(pyridin-4-yl)- l,3,5-triazine-2,4- diamine.To a mixture of 6-chloro-N2,N4-bis((R)-l-cyclo -propylethyl)-l,3,5-triazine-2,4-diamine (100 mg, 0.36 mmol), pyridin-4-ylboronic acid (66 mg, 0.52 mmol), and K2C03 (99 mg, 0.72 mmol) in 1,4-dioxane (3 mL) and water (1 mL) stirred at r.t. under the atmosphere of nitrogenwas added Pd(PPh3)4 (42 mg, 0.036 mmol) in one portion. The reaction mixture was stirred at 80°C ovemight. The mixture was partitioned between water and EtOAc. The organic layer was dried over anhydrous Na2S04 and concentrated. The residue was purified by a standard method to ive the desired product.
1H NMR (400 MHz, DMSO-d6): δ 7.61 - 7.28 (m, 6H), 3.58 - 3.39 (m, 2H), 1.23 - 1.10 (m, 3H), 1.02 - 0.89 (m, 2H), 0.48 - 0.26 (m, 6H), 0.20 - 0.10 (m, 2H). LC-MS: m/z 325.2 (M+H)+.
The procedure set forth above was used to produce the following compounds using the appropriate starting materials.
Com ound6-(3-chlorophenyl)-N -bh((R)A-cyclopropylethyl)A,3,54riazine -2,4-diatnine
Figure imgf000213_0002
Ή NMR (400 MHz, DMSO-d6):5 8.30 - 8.14 (m, 2H), 7.58 (d, J = 7.7 Hz, 1H), 7.52 (t, J
Hz, 1H), 7.41 (d, J= 8.2 Hz, 1H), 7.35 - 7.26 (m, 1H), 3.70 - 3.43 (m, 2H), 1.26 - 1.15 (m 1.02 - 0.92 (m, 2H), 0.49 - 0.30 (m, 6H), 0.26 - 0.11 (m, 2H).LC-MS: m/z 358.2 (M+H)+. Compound3-(4,6-bis((R)-l-cyclopropylethylamino)-l,3,5-triazin-2-yl)phenol
Figure imgf000214_0001
1H NMR (400 MHz, CDC13): δ 7.99 - 7.64 (m, 2H), 7.29 (d, J= 7.9 Hz, 1H), 6.96 (d, J= 7.8 Hz, 1H), 5.78 - 5.04 (m, 2H), 4.07 (s, 1H), 3.60 (m, 2H), 1.27 (d, J= 4.3 Hz, 6H), 0.89 (d, J= 3.6 Hz, 2H), 0.43 (m, 8H). LC-MS: m/z 340.2 (M+H)+.
Table 3: The following targets were prepared by the procedure described in Scheme 3 above.
Figure imgf000214_0002
Figure imgf000215_0001
Example 4 Preparation of Di-aliphatic Triazine Compounds of Formula G. The compounds of this Example are prepared by general Scheme 4, set forth below.
Scheme 4
Figure imgf000216_0001
12 13
Formula G
Step 1. Preparation of N2-(3,3-difluorocyclopentyl)-Nt-(pyrroHdin-3-yl)-6-(6- (trifluoro methyl)pyridin-2-yl)-l,3,5-triazine-2,4-diarnine. To a solution of tert-butyl 3-(4-(3,3- difluorocyclopentylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l ,3,5-triazin-2- ylamino)pyrrolidine-l-carboxylate (160 mg, 0.3 mmol) in DCM (3 mL) at 0°C was added TFA (1 mL). The mixture was stirred at room temperature for 2hrs and then concentrated. The residue was extracted with EtOAc. Combined organic layerswere washed with saturated aqueous NaHC03 and brine, dried over anhydrous Na2S04 and then concentrated to afford the desired product which was used in the next step without any further purification.
Figure imgf000216_0002
LC-MS: m/z 430.2 (M+H)+.
Step 2. Preparation of N' ~-(3,3-difluorocyclopentyl)-N ' -(l-(methylsulfonyl)pyrroli -din-3-yl)-6- (6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine. A mixture of N2-(3,3- difluorocyclopentyl)-N4-(pyrrolidin-3-yl)-6-(6-(trifluoromethyl) pyridin-2-yl)-l,3,5-triazine-2,4- diamine (20 mg, 0.05 mmol), Et3N (9.4 mg, 0.09 mmol), MsCl (6 mg, 0.06 mmol) in DCM (2 mL) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by a standard method to afford the desired product.
Figure imgf000217_0001
1H NMR (400 MHz, CDC13): δ 8.62 - 8.46 (m, 1H), 8.04 (d, J= 7.5 Hz, 1H), 7.81 (d, J= 7.6 Hz, 1H), 5.79 - 5.38 (m, 2H), 4.80 - 4.53 (m, 2H), 3.76 - 3.52 (m, 2H), 3.39 - 3.23 (m,lH), 2.91 (s, 3H), 2.69 - 2.57 (m, 1H), 2.45 - 2.25 (m, 3H), 2.20 - 1.98 (m, 3H), 1.95 - 1.81 (m, 1H), 1.22 - 1.18 (m, 1H).LC-MS: m/z 508.1 (M+H)+.
The procedure set forth above was used to produce the following compoundsusing the appropriate starting material.
Coumpound methyl 3-((4-((3,3-difluorocyclopentyl)amino)-6-(6-(trifluoro methyl)pyridin-2- yl)-l,3,5-triazin-2-yl)amino)pyrrolidine-l-carboxylate.
Figure imgf000217_0002
1H NMR (400 MHz, CDC13): δ 8.58-8.48 (m, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 5.94 - 5.18 (m, 2H), 4.72 - 4.47 (m, 2H), 3.83 - 3.74 (m, 1H), 3.72 (s, 3H), 3.65 - 3.51 (m, 2H), 3.44 - 3.28 (m, 1H), 2.45 - 1.80 (m, 7H).LC-MS: m/z 488.2 (M+H)+. Compound! -(3-((4-((3,3-difluorocyc1openty1)amino)-6-(6-(trifl -2-yl)-l ,3,5- triazin-2-yl)amino)pyrrolidin-l-yl)ethanone
Figure imgf000218_0001
1H NMR (400 MHz, CDC13): δ 8.55 (m, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.85 (t, J = 6.7 Hz, 1H), 4.84 - 4.30 (m, 2H), 3.97 - 3.52 (m, 4H), 2.62 (m, 1H), 2.50 - 2.22 (m, 3H), 2.22 - 1.98 (m, 3H), 1.25 (s, 3H).LC-MS: m/z 472.2 (M+H)+.
Compound N' '-(3,3-difluorocyclopeniyl)-N" ' -(l-methylpyrrolidin-3-yl) -6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine.To a solution of tert-butyl 3-(4-(3,3- difluorocyclopentylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l ,3,5-triazin-2- ylamino)pyrrolidine-l-carboxylate (25 mg, 0.05mmol) in THF (3 mL) at 0°C was added LiAlH4(5 mg, 0.14 mmol). The mixture was stirred at 0°Cfor 2hr, then at r.t for 30 min, and finally at 60 °C for 2hr. The reaction mixture was quenched with water and extracted by EtOAc. Combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by a standard method to give the desired product.
Figure imgf000218_0002
Ή NMR (400 MHz, CDC13): δ 8.55 (m, 1H), 8.08 - 7.93 (m, 1H), 7.80 (t, J = 7.4 Hz, 1H), 4.63 (m, 2H), 3.47 - 2.87 (m, 3H), 2.69 (m, 6H), 2.28 (m, 4H), 1.84 (m, 4H).LC-MS: m/z 444.2 (M+H)+. Example SPreparation of Di-aliphatic Triazine Compounds. The compounds of this Example are prepared by general Scheme 5, set forth below.
Scheme 5
Figure imgf000219_0001
14
Step 1: Preparation of 6-(6-(azetidin-l-yl)pyridin-2-yl)-N2,N*-bis((R)-l-cyclopropyl -ethyl) - l,3,5-triazine-2,4-diatnine. A mixture of 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-l- cyclopropylethyl) -l ,3,5-triazine-2,4-diamine (40 mg, 0.11 mmol), azetidine (7.6 mg, 0.13 mmol), 2,2'-bis-(diphenylphosphino)-l,r-binaphthyl (6.9 mg, 0.01 mmol), sodium tert-butoxide (15 mg, 0.16 mmol) and tris(dibenzylideneacetone) -dipalladium (10.2 mg, 0.01 mmol) in toluene (3 mL) was stirred at 100°C under an atmosphere of nitrogen ovemight. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressureand the residue was purified by a standard method to afford the desired product.
Figure imgf000219_0002
Ή NMR (400 MHz, CD3OD): δ 8.49 (s, 1H), 7.72 - 7.53 (m, 2H), 6.56 (d, J=7.4, 1H), 4.11 (t, J=7.4, 4H), 3.59 (m, 2H), 2.42 (p, J=7.4, 2H), 1.30 (d, J=6.5, 6H), 0.98 (s, 2H), 0.67 - 0.13 (m, 8H). LC-MS: m/z 380.2 (M+H)+.
Step 2: Preparation of ^^-bisffR^l-cychpropykthy^-e^yridin^-y^-l^^-tr zine^^- diamine. To a solution of 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-l-cyclopropylethyl)-l,3,5- triazine-2,4-diamine (20 mg, 0.05 mmol) in methanol (2 mL) was added Pd/C (2 mg) under an atmosphere of nitrogen. The mixture was then stirred at room temperature under ahydrogen balloon overnight. The mixture was filtered and the filtrate was concentrated. The residue was purified by a standard method to afford the desired product.
Figure imgf000220_0001
1H NMR (400 MHz, DMSO-d6): δ 8.82 - 8.03 (m, 4H), 7.75 (m, 2H), 3.79 - 3.45 (m, 2H), 1.21 (d, J= 6.3 Hz, 6H), 1.07 - 0.84 (m, 2H), 0.55 - 0.05 (m, 8H). LC-MS: m/z 325.2 (M+H)+.
Example 6 Preparation of Di-aliphatic Triazine Compounds of Formula ELThe compounds of this Example are prepared by general Scheme 6, set forth below.
6
Figure imgf000220_0002
18 Formula H
Step 1: Preparationof 2-((4-(2-fluoro-5-hydroxyphenyl)-6-(isopropylamino)-l, 3,5-triazin-2- yl)amino)-2-methylpropanenitrile.To a solution of 2-((4-(2-fluoro-5-methoxyphenyl)-6- (isopropylamino)-l ,3,5-triazin-2-yl)amino)-2-methylpropanenitrile (200 mg, 0.6 mmol) in anhydrous DCM (3 mL) at -65°C was added dropwise BBr3 (0.6 mL) and the reaction mixture was stirred at this temperature for 20 min. The mixture was slowly warmed up to 0°C and stirred for 10 min. and then stirred at room temperature for 1 hr. The reaction was quenched with icy Sat. aq. NaHC03 till pH = 8. The resulting mixture was extracted with EtOAc(2 x 10 mL). Combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. Theresidue was purified by a standard method to afford the desired product.
Figure imgf000221_0001
Ή NMR (400 MHz, CDC13): δ 7.20 (s, 1H), 6.96 (t, J = 9.6 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 5.72 (m, 2H), 4.26 (s, 1H), 1.79 (s, 6H), 1.26 (d, J= 6.1 Hz, 6H). LC-MS: m/z 331.2 (M+H)+.
Example 7Preparation of Di-aliphatic Pyrimidine Compounds of Formula J.The compounds of this Example are prepared by general Scheme 7, set forth below.
Scheme 7
Figure imgf000221_0002
Figure imgf000221_0003
Step 1: Preparation of6-(trifluoromethyl)picolinirnidarnide. To a solution of6- (trifluoromethyl)picolinonitrile (50 mg, 0.3 mmol, 1 eq) in EtOH (3 mL) was added NaOMe (1.6 mg, 0.03 mmol, 0.1 eq) at 0°C. The mixture was stirred at r.t. for 1 hr, followed by addition of NH4C1 (21 mg, 0.39 mmol, 13 eq). The resulting mixture was stirred at 90°C for 1 hr and cooled to room temperature. The mixture was adjusted pH to 9 with saturated aqueous NaHC03 and then extracted with EtOAc. Combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by a standard method to afford the desired product.
Figure imgf000222_0001
LC-MS: m/z 190.1 (M+H)+.
Step 2: Preparation of2-(6-(trifluoromethyl)pyridin-2-yl)pyrimidine-4,6-diol. To a solution of sodium (366 mg, 15.9 mmol, 5.0 eq) in anhydrous EtOH (6 mL) was added dropwise a solution of 6-(trifluoromethyl)picolinimidamide (600 mg, 3.2 mmol) in EtOH. The reaction mixture was stirred at r.t. for 1 hr, followed by addition of diethyl malonate (1 mL, 6.4 mmol, 2.0 eq). The mixture was stirred at reflux overnight and then cooled to room temperature. The resulting mixture was adjusted pH to 7 by 1 N aq. HClsolution. The suspension was filtered and the filter cake was washed with water. The solid was suspended in MeOH and filtered. The filtrate was concentrated under reduced pressure to give the desired product which was used directly in the next step without any further purification.
Figure imgf000222_0002
LC-MS: m/z 256.0 (M-H)".
Step 3: Preparation of4,6-dichloro-2-(6-(trifluoromethyl)pyridin-2-yl)pyrimidine. A solution of 2-(6-(trifluoromethyl)pyridin-2-yl)pyrimidine-4,6-diol (1 g, 3.9 mmol) in POCl3 (6 mL) was stirred at 90°C overnight and then concentrated to remove the volatile. The residue was purified by a standard method to afford the desired product.
Figure imgf000223_0001
LC-MS: m/z 294.0 (M+H)+.
Step 4: Preparation of(R)-6-chloro-N-(l-cyclopropylethyl)-2-(6-(trifluoromethyl) -pyridin-2- yl)pyrimidin-4-amine. To a solution of 4,6-dichloro-2-(6-(trifluoromethyl) pyridin-2- yl)pyrimidine (80 mg, 0.27 mmol, 1 eq) in THF (3 mL) was added (R)-l- - cyclopropylethanamine (0.06 mL, 0.6 mmol, 2.2 eq) and EtsN (0.07 mL, 0.54 mmol, 2 eq). The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified by a standard method to give the desired product.
Figure imgf000223_0002
LC-MS: m/z 343.1 (M+H) .
Step 5 : Preparation ofiV4,N6-bis((R)-l-cyclopropylethyl)-2-(6-(trifluoromethyl)pyri din-2- yl)pyrimidine-4,6-diamine.To a solution of (R)-6-chloro-N-(l-cyclopro pylethyl)-2-(6- (trifluoromethyl) -pyridin-2-yl)pyrimidin-4-amine (50 mg, 0.15 mmol, 1 eq) in DMSO (2 mL) was added (R)-l -cyclopropylethanamine hydrochloride (22 mg, 0.18 mmol, 1.2 eq) and DIPEA (0.08 mL, 0.45 mmol, 3 eq). The mixture was irradiated under microwave at 160 °C for 1.5 hr. After addition of (R)-l -cyclopropylethanamine (0.18 mmol, 1.2 eq),the resulting mixture was stirred and irradiated under microwave at 160 °C for another 2 hr. The mixture was cooled to r.t. and then partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by a standard method to give the desired product.
Figure imgf000224_0001
Ή NMR (400 MHz, CDC13): δ 8.40 (d, J = 7.9 Hz, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.62 (d, J= 7.8 Hz, 1H), 5.19 (m, 3H), 3.13 (d, J = 6.3 Hz, 2H), 1.19 (d, J = 6.4 Hz, 6H), 0.96 - 0.72 (m, 2H), 0.52 - 0.33 (m, 4H), 0.33 - 0.10 (m, 4H).LC-MS: m/z 392.2 (M+H)+.
The procedure set forth above was used to produce the following compounds using the appropriate starting materials.
CompoundN1 ',Ν* ^-bis((S) -cyclopropylethyl)-2-(6-(trifluoromethyl)pyridin-2-yl) pyrimidine-
Figure imgf000224_0002
Ή NMR (400 MHz, CDC13): δ 8.49 (d, J = 7.8 Hz, 1H), 7.95 (t, J = 7.9 Hz, 1H), 7.71 (d, J= 7.8 Hz, 1H), 5.22 (m, 3H), 3.22 (d, J = 6.5 Hz, 2H), 1.40 - 1.15 (m, 6H), 0.95 (m, 2H), 0.61 - 0.44 (m, 4H), 0.31 (m, 4H).LC-MS: m/z 392.2 (M+H)+.
Co^oundNi-((R)-l-cychpropylethyl)-N6-((S)-l-(yclopropylethyl)-2-(6-(t^^
methyl)pyridin-2-yl)pyrimidine-4,6-diamine
Figure imgf000224_0003
Ή NMR (400 MHz, CDC13): δ 8.49 (d, J = 7.8 Hz, 1H), 7.97 (t, J = 7.9 Hz, 1H), 7.72 (d, J= 7.8 Hz, 1H), 5.22 (m, 3H), 3.22 (d, J = 6.5 Hz, 2H), 1.68 - 1.25 (m, 6H), 0.97 (m 2H), 0.61 - 0.44 (m, 4H), 0.31 (m, 4H).LC-MS: m/z 392.2 (M+H)+.
Table 7: The following compounds were prepared by the procedure described in Scheme 7 above.
Figure imgf000225_0002
Example 9. Preparation of Symmetric Di-aliphatic Triazine Compounds of Formula K.
The compounds of this Example are prepared by general Scheme 9, set forth below.
Figure imgf000225_0001
Formula K Step 1: Preparation of 2-bromo-6-(l,l-difluoroethyl)pyridine.
To a solution of l-(6-bromopyridin-2-yl)ethanone (26 g, 130 mmol) in dry DCM (150 mL) at 0 °C was added dropwise DAST (84 mL, 650 mmol) over 30 min. The reaction mixture was then slowly allowed to warm up to r.t, and stirred until the reaction was complete. The resulting mixture was slowly poured into ice (300 g) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by standard methods to afford 2-bromo-6-(l,l- difluoroethyl)pyridine.LC-MS: m/z 222.0 (M+H)+.
Step 2:Preparation of methyl 6-(l,l-difluoroethyl)picolinate.
To a solution of 2-bromo-6-(l ,l -difluoroethyl)pyridine (30.2 g, 136 mmol) in MeOH (300 mL) were added l ,l '-bis(diphenylphosphino)-ferrocene (7.5 g, 13.6 mmol), triethylamine (28.4 mL, 204 mmol), and Pd(OAc)2(1.52 g, 6.7 mmol). The mixture was stirred at 60°C under CO atmosphere (60 psi) for 16 hr. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified bystandard methods to afford methyl 6-(l,l-difluoroethyl) picolinate.LC-MS: m/z 202.2 (M+H)+.
Step 3: Preparation of6-(6-(l,l-difluoroethyl)pyridin-2-yl)-l,3,5-triazine-2,4(lH,3H)-dione. To a solution of NaOEt in EtOH (freshly prepared from sodium (1.9 g, 82.6 mmol and EtOH (150 mL)) was added methyl 6-(l,l-difluoroethyl)picolinate(2.8 g, 28 mmol) and biuret(14.0 g, 70 mmol). The mixture was stirred at 90°C for 16 hr and concentrated under reduced pressure. To the residue was added water (50 mL). The resulting mixture was adjusted the pH to 7 with IN HCl, and then filtered. The filter cake was washed with water, and dried under high vacuum to afford 6-(6-(l,l-difluoroethyl)pyridin-2-yl) ,3,5-triazine-2,4(lH,3H)-dione.LC-MS: m/z 255.1 (M+H)+.
Step 4: Preparation of2,4-dichloro-6-(6-(l,l-difluoroethyl)pyridin-2-yl)-l,3,5-triazine.
To a solution of6-(6-(l,l -difluoroethyl)pyridin-2-yl)-l,3,5-triazine-2,4(lH,3H)-dione (6 g, 25 mmol) in POCl3 (60 mL) was added PC15 (26 g, 125 mmol). The mixture was stirred at 100°C for 16 hr and concentrated under reduced pressure. The residue was purified by standard methods to afford 2,4-dichloro-6-(6-(l,l-difluoroethyl)pyridin-2-yl)-l,3,5-triazine. Ή NMR (400MHz, CDCI3) 58.62 (d, 1H), 8.07 (t, 1H), 7.94 (d, 1H), 2.16 (q, 3H). LC-MS: m/z 292.1 (M+H)+.
Step 5: Preparation of N2,Nt-bis(4,4-difluorocyclohexyl)-6-(6-(l,l-difluoroethyl) pyridin-2-yl)- l,3,5-triazine-2,4-diamine To a mixture of 2,4-dichloro-6-(6-(l,l-difluoroethyl)pyridin-2-yl)- 1,3,5-triazine (582 mg, 2.0 mmol, 1.0 eq) and 4,4-difluorocyclohexanamine hydrochloride (752 mg, 4.4 mmol, 2.2 eq) in THF (12 mL) at r.t.were added CsF (1.2 g, 8.0 mmol, 2eq) and DIPEA (1.4 mL, 8.0 mmol, 4 eq). The mixture was stirred at 60°C overnight and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by standard methods to give the desired product.
Figure imgf000227_0001
Ή NMR (400 MHz, CDC13) δ 8.32-8.40 (m, 1H), 7.94 (bs, 1H), 7.78 (bs, 1H), 5.07-5.46 (m, 2H), 3.99-4.18 (m, 2H), 1.71-2.17 (m, 19H). LC-MS: m/z 489.2 (M+H)+.
The procedure set forth in Example 9 was used to produce the following compounds using the appropriate starting materials.
Compound N2,N4-bis(3,3-difluorocyclopentyl)-6-(6-(l,l-difluoroethyl)pyridin-2-yl)-l,3,5-
Figure imgf000227_0002
Ή NMR (400 MHz, CDC13) δ 8.32-8.43 (m, 1H), 7.93-7.95 (m, 1H), 7.78 (bs, 1H), 5.28-5.70 (m, 2H), 4.54-4.71 (m, 2H), 1.72-2.65(m, 15H). LC-MS: m/z 461.2 (M+H)+.
Compound N2J\4-bis(3,3-difluorocyclobutyl)-6-(6-(l,l-difluoroethyl)pyridin-2-yl)-l,3,5-
Figure imgf000228_0001
1H NMR (400 MHz, CDC13) δ 8.35-8.42 (m, 1H), 7.95 (bs, 1H), 7.80 (bs, 1H), 5.42-5.85 (m, 2H), 4.35-4.52 (m, 2H), 3.04 (bs, 4H), 2.62 (bs, 4H), 2.04-2.16(m, 3H). LC-MS: m/z 433.2 (M+H)+.
Example 10. Preparation of Symmetric Di-aliphatic Triazine Compounds of Formula L.
The compounds of this Example are prepared by general Scheme 10, set forth below.
Scheme 10
Figure imgf000228_0002
Formula L
Step 1: Preparation of 6-(6-chloropyridin-2-yl)-l,3,5-triazine-2,4(lH,3H)-dione.To a dried three-necked round bottom flask were added biuret (14.8 g, 0.14 mol), methyl 6-chloropicolinate (21 g, 0.12 mol) and EtOH (250 mL). The mixture was degassed with N2 three times and then stirred at 25°C for 20 min. Then the temperature was allowed to rise to 50°C, followed by addition of HC(OMe)3 (17 mL, 0.14 mol) and TFA (1.37 g, 0.01 mol). The reaction mixture (pale yellow slurry) was stirred at this temperature for 30 min, followed by drop wise addition of a solution of NaOEt in EtOH (20%wt, 163 g, 0.48 mol). The resulting yellowish thick slurry was heated to reflux for 2hr until the reaction was complete. The mixture was cooled to r.t. and concentrated under reduced pressure. The residue was treated with water (200 mL) and concentrated under reduced pressure to remove the remaining ethanol. Then water (300 mL) was added to the residue (while stirring) to form a clear brown solution. The solution was cooled to 10°C and slowly adjusted to pH 1 by 6N HC1. The resulting mixture was stirred for another 2 hr and filtered. The filter cake was washed with aq. HC1 (pH=l), collected and suspended in DCM (300 mL). The suspension was stirred at r.t. for 2hr, filtered and dried to afford the desired product. LC-MS: m/z 225.0 (M+H)+.
Step 2: Preparation of 2,4-dichloro-6-(6-chloropyridin-2-yl)-l,3,5-triazine. The procedure is the same as Example 1 Step 3 described above.LC-MS: m/z 260.9 (M+H)+.
Step 3 : Preparation of 6-(6-chloropyridin-2-yl)-N2,N*-bis((R)-l -trifluoropropan-2-yl)- l,3,5-triazine-2,4-diamine. A mixture of 2,4-dichloro-6-(6-chloro -pyridin-2-yl)-l,3,5-triazine (0.27 g, 1.04 mol), (R)-l,l,l-trifluoropropan-2-amine hydrochloride (0.39 g, 2.6 mol), and potassium carbonate (0.43 g, 3.1 mol) in dry 1,4-dioxane (2.5 mL) was stirred under the atmosphere of N2 at 50°C for 36 hr then at 100°C for another 36 hr until the reaction was complete. The resulting mixture was filtered through Celite and the cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by standard methods to give the desired roduct.
Figure imgf000229_0001
Ή NMR (400 MHz, CDC13) δ 8.32 (m, 1H), 7.80 (m, 1H), 7.48 (d, J = 7.9 Hz, 1H), 5.61 (m, 1.5H), 5.25 (m, 0.5H), 5.09 (m, 0.5H), 4.88 (m, 1.5H), 1.54 - 1.26 (m, 6H). LC-MS: m/z 415 (M+H)+.
The procedure set forth in Example 10 was used to produce the following compounds using the appropriate starting materials.
6-(6-Chloropyridin-2-yl)-N2,N4-bis((S)-l,l,l-trifluoropropan-2-yl)-l,3,5-
Figure imgf000230_0001
1H NMR (400 MHz, CDC13)5 8.29 - 8.16 (m, 1H), 7.72 (d, J= 7.6 Hz, 1H), 7.41 (d, J= 7.9 Hz, 1H), 5.70 - 5.13 (m, 2H), 5.09 - 4.71 (m, 2H), 1.34 (m, 6H).LC-MS: m/z 415 (M+H)+.
Compound6-(6-Chloropyridin-2-yl)-N2-((R)-l,l,l-trifluoropropan-2-yl)-N4-((S)-l,l,l- rifluoro ropan-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000230_0002
XH NMR (400 MHz, CDC13) δ 8.41 - 8.23 (m, 1H), 7.83 (s, 1H), 7.51 (d, J= 6.2 Hz, 1H), 5.68 5.20 (m, 2H), 5.18 - 4.81 (m, 2H), 1.48 - 1.39 (m, 6H).LC-MS: m/z 415 (M+H)+.
Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(l,1 -trifluoropropan-2-yl)-l,3,5-triazine- 2,4-diamine
Figure imgf000231_0001
1H NMR (400 MHz, CDC13) δ 8.29 - 8.16 (m, IH), 7.72 (d, J = 7.6 Hz, IH), 7.41 (d, J= 7.9 Hz, IH), 5.70 - 5.13 (m, 2H), 5.09 - 4.71 (m, 2H), 1.34 (m, 6H).LC-MS: m/z 415 (M+H)+.
Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(l,1 -trifluorobutan-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000231_0002
1H NMR (400 MHz, CDC13) δ 8.39 - 8.31 (m, IH), 7.86 - 7.79 (m, IH), 7.50 (d, J= 7.8 Hz, IH), 5.67 - 5.12 (m, 2H), 4.98 - 4.65 (m, 2H), 2.07 - 1.91 (m, 2H), 1.70 - 1.55 (m, 2H), 1.06 (dd, J = 8.6, 6.0 Hz, 6H).LC-MS: m/z443 (M+H)+.
Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis((S)-l,1 -trifluorobutan-2-yl)-l,3,5-triazine- -diamine
Figure imgf000231_0003
H NMR (400 MHz, CDC13) δ 8.30-8.35 (t, IH), 7.78-7.82 (t, IH), 7.47-7.52 (m, IH), 5.49-5.63 (m, 2H), 4.72-4.89 (m, 2H), 1.95-1.99 (m, 2H), 1.59 (m, 2H), 1.02-1.08 (t, 6H).LC-MS: m/z 443 (M+H)+. Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis((R)-l,1 -trifluorobutan-2-yl)-l,3,5-triazine- 2,4-diamine
Figure imgf000232_0001
¾ NMR (400 MHz, CDC13) δ 8.31-8.35 (t, IH), 7.78-7.82 (t, IH), 7.47-7.49 (m, IH), 5.16-5.71 (m, 2H), 4.72-4.74 (m, 2H), 1.94-2.01 (m, 2H), 1.62-1.64 (m, 2H), 1.02-1.08 (t, 6H).LC-MS: m/z 443 (M+H)+.
Compound6-(6-Chloropyridin-2-yl)-N2-((R)-l,l,l-trifluorobutan-2-yl)-N4-((S)-l,l,l- trifluorobutan-2-yl)-l,395-triazine-2,4-diamine
Figure imgf000232_0002
1HNMR (400MHz, CDC13) 58.30-8.35 (m, IH), 7.81 (s, IH), 7.47-7.49 (d, IH), 5.35-5.66 (m, 2H), 4.91-5.13 (d, IH), 4.72 (s, IH), 2.00-2.23 (d, 3H), 1.31-1.42 (d, IH), 1.03-1.07 (m, 6H).LC- MS: m/z 443 (M+H)+.
Compound3,3'-((6-(6-Chloropyridin-2-yl)-l,395-triazine-2,4- diyl)bis(azanediyl))dibutanenitrile
Figure imgf000232_0003
Ή NMR (400 MHz, CDC13) δ 8.21 (s, lH), 7.73 (t, J= 7.6 Hz, 1H), 7.41 (d, J= 7.8 Hz, 1H), 5.61 - 5.18 (m, 2H), 4.59 - 4.20 (m, 2H), 2.85 - 2.60 (m, 4H), 1.44 - 1.36 (m, 6H).LC-MS: m/z 357 (M+H)+.
Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(l-cyclopropylpropyl)-l,395-triazine-2,4- diamine
Figure imgf000233_0001
1H NMR (400 MHz, CDC13) δ 8.26 (d, J = 7.3 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 5.37 - 5.08 (m, 2H), 3.48 - 3.37 (m, 2H), 1.73 - 1.56 (m, 4H), 0.98 (t, J = 7.3 Hz, 6H), 0.92 - 0.80 (m, 2H), 0.66 - 0.20 (m, 8H). LC-MS (m/z): 387.2 (M+H)+.
Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(dicyclopropylmethyl)-l,3,5-triazine-2,4- diamine
Figure imgf000233_0002
Ή NMR (400 MHz, CDC13) δ 8.18 (d, J= 7.6 Hz, 1H), 7.69 (t, J= 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 5.50 - 5.01 (m, 2H), 3.30 (s, 2H), 0.89 (m, 4H), 0.50 - 0.21 (m, 16H). LC-MS: m/z 411.2 (M+H)+.
Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(4,4-difluorocyclohexyl)-l,3,5-triazine-2,4- diamine
Figure imgf000234_0001
1H NMR (400 MHz, CDC13) δ 8.28 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 6.64-6.12 (m, 2H), 4.17-3.98 (m, 2H), 2.17-1.70 (m, 16H). LC-MS: m/z 459 (M+H)+.
Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(3,3-difluorocyclopentyl)-l,3,5-triazine-2,4- diamine
Figure imgf000234_0002
1H NMR (400 MHz, CDC13) δ 8.41 - 8.25 (m, IH), 7.85 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 5.78 - 5.37 (m, 2H), 4.69 - 4.53 (m, 2H), 2.65 - 2.55 (m, 2H), 2.51 - 1.98 (m, 8H), 1.85 - 1.76 (m, 2H). LCMS: m/z 431.1 (M+H)+.
Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(2,2-difluorocyclopentyl)-l,3,5-triazine-2,4- iamine
Figure imgf000234_0003
Ή NMR (400 MHz, CDC13) δ 8.48 - 8.26 (m, IH), 7.82 (s, IH), 7.49 (s, IH), 5.63 (m, 2H), 4.70 (m, 2H), 2.41-2.08 (m, 6H), 1.83 (m, 4H), 1.66 (s, 2H). LCMS: m/z 431(M+H)+.. Compound2,2'-((6-(6-Chloropyridin-2-yl)-l,3,5-triazine-2,4- diyl)bis(azanediyl))dicyclopentanol
Figure imgf000235_0001
Ή NMR (400 MHz, CDC13) δ 8.27 - 8.17 (m, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 6.30 - 5.83 (m, 1H), 5.52 (m, 2H), 5.00 (m, 1H), 4.05 - 3.88 (m, 2H), 2.32 - 2.17 (m, 2H), 2.10 (m, 1H), 2.01 (s, 1H), 1.88 - 1.65 (m, 6H), 1.51 (m, 2H). LCMS: m/z 391(M+H)+.
Compound6-(6-Chloropyridin-2-yl)-N2,N4-bis(6,6-difluorospiro[3.3]heptan-2-yl)-l,3,5- triazine-2,4-diamine
Figure imgf000235_0002
1H NMR (400MHz, CDC13) 58.25 - 7.78 (m, 4H), 7.64 (m, 1H), 4.45 - 4.24 (m, 2H), 2.72- 2.66 (m, 4H), 2.61 - 2.50 (m, 4H), 2.46 - 2.41 (m, 4H), 2.22 - 2.19 (m, 4H). LCMS: m/z 483(M+H)+.
Compound6-(4-Chloropyridin-2-yl)-N2J\4-bis(4,4-difluorocyclohexyl)-l,3,5-triazine-2,4- diamine
Figure imgf000235_0003
Ή NMR (400 MHz, CDC13) δ 8.68 (d, J = 8.0 Hz, 1H), 8.48 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 5.28 (d, J = 8.0 Hz, 2H), 4.20-4.02 (m, 2H), 1.98-1.61 (m, 16H). LC-MS: m/z 459.1 (M+H)+. Compound6-(5-Chloropyridin-3-yl)-N2,N4-bis((R)-l-cyclopropylethyl)-l,3,5-triazine-2,4- iamine
Figure imgf000236_0001
1H NMR (400 MHz, CDC13) δ 9.36 (m, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.54 (t, J = 1.9 Hz, 1H), 5.46 - 5.06 (m, 2H), 3.78 - 3.40 (m, 2H), 1.29 (s, 6H), 0.95 - 0.87 (m, 2H), 0.56 - 0.38 (m, 6H), 0.29 (s, 2H).LC-MS: m/z 359 (M+H)+.
Example 11 The compounds of this Example are prepared by general Scheme 11, set forth below.
Scheme 11
Figure imgf000236_0002
Step 1. Preparation of N2 ,1^ -bh((ltyA-cyclopropylethyl)-6-(6-((4-methoxybenzyl) arnino)pyridin-2-yl)-l,3,5-triazine-2,4-diamine. To a solution of 6-(6-chloropyridin-2-yl)- N2,N4-bis((R)-l-cyclopropylethyl)-l,3,5-triazine-2,4-diamine (120 mg, 0.33 mmol), (4- methoxyphenyl)methanamine (69 mg, 0.51 mmol), ΒΓΝΑΡ (42 mg, 0.66 mmol) and t-BuONa (63 mg, 0.66 mmol) in anhydrous dioxane (2 mL) at r.t. under N2 atmospherewas added Pd2(dba)3 (30 mg, 0.033 mmol) in one portion. The reaction mixture was then stirred at 100 °C overnight then concentrated under reduced pressure to afford the desired product.
Figure imgf000236_0003
LCMS: m/z 460 (M+Hf.
Step 2. Preparation of 6-(6-aminopyridin-2-yl)-N l,N '-bisfflty-l-cyclopropyl ethyl)-l,3,5- triazine-2,4-diamine. N2,N4-bis((R)-l-cyclopropylethyl)-6-(6-(4-methoxybenzylamino) pyridin- 2-yl)-l,3,5-triazine-2,4-diamine (80 mg, 0.17 mmol) was dissolved in TFA (0.5 mL) under N2 atmosphere. The solution mixture was then stirred at r.t. overnight then concentrated under reduced pressure. The residue was purified by standard methods to afford the desired product.
Figure imgf000237_0001
1H NMR (400 MHz, CDC13) δ 7.71 - 7.54 (m, 2H), 6.74 - 6.69 (m, 1H), 6.24 - 5.30 (m, 2H), 3.70 - 3.54 (m, 2H), 1.29 - 1.25 (m, 6H), 0.95 - 0.90 (m, 2H), 0.58 - 0.26 (m, 8H). LCMS: m/z 340.2 (M+H)+.
Example 12 The compounds of this example are prepared by general Scheme 12, set forth below.
Scheme 12
Figure imgf000237_0002
Step 1. Preparation of 6-(4,6-bis((R)-l-cyclopropylethylamino)-l,3,5 riazin-2-yl)pyridin-2-oL
To a mixture of N2,N4-bis((R)-l-cyclopropylethyl)-6-(6-methoxypyridin-2-yl)- 1,3,5-triazine- 2,4-diamine (50 mg, 0.14 mmol) and Nal (63 mg, 0.42 mmol) in anhydrous CH3CN (1 mL) at r.t. was added TMSC1 (46 mg, 0.42 mmol) in one portion. The reaction mixture was stirred 80 °C for 6 hr then concentrated under reduced pressure. The residue was purified by standard methods to afford the desired product. ¾ NMR (400 MHz, CDC13) δ 10.24 (br s, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.29 - 7.20 (m, 1H), 6.71 (d, J = 8.0 Hz, 1H), 5.42 - 5.31 (m, 2H), 3.63 - 3.52 (m, 2H), 1.30 - 1.25 (m, 6H), 0.98 - 0.87 (m, 2H), 0.62 - 0.21 (m, 8H).LCMS: m/z 341.2 (M+H)+.
Example 13 The compounds of this Example are prepared by general Scheme 13, set forth below.
Scheme 13
Figure imgf000238_0001
Step 1. Preparation ofN2,N*-bis((R)-l-cycfapropytethyl)-6-(6-vinylpyridin-2-yl)- 1,3,5-triazine- 2,4-diamine. To a suspension of 6-(6-chloropyridin-2-yl)-N2,N4-bis ((R)-l-cyclopropylethyl)- l,3,5-triazine-2,4-diamine (200 mg, 0.56 mmol), 2,4,6-trivinyl-l ,3,5,2,4,6-trioxatriborinane (135 mg, 0.84 mmol) and K2CO3 (154 mg, 1.11 mmol) in dioxane (2 mL) and H20 (0.8 mL) under an atmosphere of N2 was added Pd(dppf)Cl2 (41 mg, 0.06 mmol) in one portion. The reaction mixture was stirred at 100 °C overnight then cooled to r.t. and quenched with water. The resulting mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by standard methods to afford the desired product. H NMR
(400 MHz, CDCI3) δ 8.28 - 8.15 (m, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.05 - 6.99 (m, 1H), 6.15 (d, J = 17.6 Hz, 1H), 5.42 (d, J = 17.6 Hz, 1H), 5.44 - 5.16 (m, 2H), 3.72 - 3.52 (m, 2H), 1.35 - 1.22 (m, 6H), 0.98 - 0.86 (m, 2H), 0.58 - 0.21 (m, 8H). LCMS: m/z 351.1
(M+H)+.
Example 14 The compounds of this Example are prepared by general Scheme 14, set forth below. Scheme 14
Figure imgf000239_0001
Step 1. Preparation of 6-(4,6-bis(((R)-l-c clopropylethyl)amino)-l,3,5-triazin-2-yl) picolinaldehyde. Ozone was bubbled into a solution of N2, N4-bis((R)-l-cyclopropylethyl)-6-(6- vinylpyridin-2-yl)-l ,3,5-triazine-2,4-diamine (120 mg, 0.34 mmol) in DCM (2 mL) at -78 °C for lhr. After excess ozone was purged by N2, Me2S (0.2 mL) was added into the reaction mixture at 0 °C. The resulting mixture was concentrated and the residue was purified by standard methods to afford the desired product. LCMS: m/z 353 (M+H)+.
Step 2. Preparation of N2 ,Ν4 -kis((R)-1 -cyclopropylethyl)-6-(6-(difluoroinethyl) pyridin-2-yl)- l,3,5-triazine-2,4-diamine. To a solution of 6-(4,6-bis((R)-l -cyclo propylethylamino)-l,3,5- triazin-2-yl)picolinaldehyde (50 mg, 0.14 mmol) in anhydrous DCM (2 mL) at 0 °C was added dropwise DAST (68 mg, 0. 43 mmol). The reaction mixture was stirred at r.t overnight. The resulting mixture was slowly quenched with satd. aq. NaHC03 (5 mL) at 0°C, then extracted with DCM (40 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2S04, concentrated, and purified by standard methods to afford the desired product. 1H NMR (400 MHz, CDC13) δ 8.46 (s, 1H), 7.97 (t, J = 7.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 6.98 - 6.70 (m, 1H), 5.47 - 5.21 (m, 2H), 3.67 - 3.50 (m, 2H), 1.32 - 1.25 (m, 6H), 0.92 - 0.86 (m, 2H), 0.58 - 0.21 (m, 8H). LCMS: m/z 375 (M+H)+.
The procedure set forth in Example 14 was used to produce the following compounds using the appropriate starting materials.
CompoundN2,N4-bis(4,4-difluorocyclohexyl)-6-(6-(difluoromethyl)pyridin-2-yl)-l,3,5- triazine-2,4-diamine
Figure imgf000240_0001
1H NMR (400 MHz, CDC13) δ 8.48 (, 1H), 8.01 (br s., 1H), 7.81 (d, J = 8.0 Hz, 1H), 6.67 - 7.01 (m, 1H), 5.02 - 5.55 (m, 2H), 3.95 - 4.20 (m, 2H), 2.14 (m, 8H), 1.86 - 1.98 (m, 4H), 1.77 (m, 4H). LC-MS: m/z 475 (M+H)+.
CompoundN2J\4-bis(3,3-difluorocyclobutyl)-6-(6-(difluoromethyl)pyridin-2-yl)-l,395- triazine-2,4-diamine
Figure imgf000240_0002
1H NMR (400 MHz, CDC13) δ 8.64 - 8.35 (m, 1H), 8.10 - 7.92 (m, 1H), 7.81 (d, J= 7.7 Hz, 1H), 6.82 (m, 1H), 5.98 - 5.29 (m, 2H), 4.70 - 4.16 (m, 2H), 3.24 - 2.92 (m, 4H), 2.79 - 2.44 (m, 4H). LC-MS: m/z 419 (M+H)+.
Example 15 The compounds of this Example are prepared by general Scheme 15, set forth below.
Scheme 15
Figure imgf000241_0001
Step 1: Preparation of methyl 6-(4,6-bis((R)-l-cyclopropylethylamino)-l,3,5-triazin-2- yl)picolinate. To a mixture of 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-l-cyclopropylethyl)-l,3,5- triazine-2,4-diamine (0.25g, 0.7mmol) in MeOH (l OmL) were added dppf (80mg, 0.15mmol), Pd(OAc)2 (60mg, 0. 27 mmol) and EtsN (150mg, 1.5 mmol). The reaction mixture was degassed and back-filled with CO three times and then stirred under an atmosphere of CO (60 psi) at 70°C for 12hr. The resulting mixture was cooled to r.t. and concentrated under reduced pressure. The residue was triturated with EtOAc (lOOmL) and filtered. The filtrate was concentrated and purified by standard methods to afford methyl 6-(4,6-bis((R)-l-cyclopropylethylamino)-l,3,5- triazin-2-yl)picolinate. Ή NMR (400 MHz, CDC13) δ 8.50 (m, 1H), 8.24-8.22 (dd, 1H), 7.99- 7.95 (t, 1H), 5.49 (m, 2H), 4.02 (s, 3H), 3.57 (m, 2H), 1.92 (s,6H) , 0.96-0.87 (m, 2H) , 0.52-0.26 (m,8H). LCMS: m/z 383(M+H)+.
Step 2: Preparation of6-(4,6-bis(((R)-l-cyclopropylethyl)amino)-l,3,5-triazin-2-yl) picolinic acid. To a mixture of methyl 6-(4,6-bis((R)-l -cyclopropylethylamino)-l,3,5-triazin-2- yl)picolinate (150 mg, 0.40 mmol) in water(2.0mL) and THF(3.0mL) was added lithium hydroxide(47 mg, 2.0 mmol). The reaction mixture was stirred at r.t. overnight then acidified withaq.HCl (1 N) to pH5-6 and extracted with EtOAc. The combined organic layers weredried over anhydrous Na2S04, and concentrated under reduced pressure to give the desired product.LCMS: m/z 367 (M-H)". Step 3: Preparation of 6-(4,6-bis((R)-l-cyclopropylethylamino)-l,3,5-triazin-2-yl)picolinami
To an ice cold mixture of 6-(4,6-bis(((R)-l-cyclopropylethyl)amino)-l ,3,5-triazin-2-yl)picolinic acid (120mg, 0.32mmol) in dry DCM(5.0mL) and DMF(O.lmL) was added dropwise oxalyl chloride(65mg, 0.5mmol). The reaction mixture was stirred at r.t. for 2 hr then treated with ammonia. The resulting mixture wasstirred for lOmin at 0°C, and then concentrated and purified by standard methods to give 6-(4,6-bis((R)-l-cyclopropylethylamino)- l,3,5-triazin-2- yl)picolinamide. ¾ NMR (400 MHz, CDC13) δ 13.59 (s, 1H), 9.30-9.14 (m, 3H), 8.58-8.30 (m, 3H), 7.95 (s, 1H), 3.77-3.54 (m, 2H), 1.29 (d, 6H), 1.02 (m,2H) , 0.50-0.30 (m,8H). LCMS: m/z 368(M+H)+.
Step 4: Preparation of 6-(4,6-bis((R)-l-cyclopropylethylamino)-l,3,5-triazin-2- yl)picolinonitrile. To a mixture of 6-(4,6-bis((R)-l -cyclopropylethylamino)-l,3,5-triazin-2- yl)picolinamide(36mg, O. lmmol) in dry pyridine(3.0mL) was added phosphorous trichloride (0.1 mL). The reaction mixture was stirred at r.t. for 2 hr then concentrated under reduced pressure. The residue was purified by standard methods to give 6-(4,6-bis((R)-l- cyclopropylethylamino)-l,3,5-triazin-2-yl)picolinonitrile. H NMR (400 MHz, CDC13) δ 8.50- 8.48 (m, 1H), 8.24-8.22 (t, 1H), 7.73-7.71 (dd, lH), 5.46-5.14 (m, 2H), 3.62-3.50 (m, 2H), 1.22- 1.18 (m, 6H), 0.89-0.84 (m, 2H), 0.46-0.20 (m,8H). LCMS: m/z 350(M+H)+.
Example 16 The compounds of this Example are prepared by general Scheme 16, set forth below.
Scheme 16
Figure imgf000242_0001
Step 1: Preparation of 3,6-difluoro-2-hydrazinylpyridine. To an ice-cold solution of 2,3,6- trifluoropyridine(1.0 g, 7.5 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.75 g, 15.0 mmol). The reaction mixture was warmed up to r.t. and then heated at reflux for 2 hr. After it was cooled to r.t., the reaction mixture was diluted with water (10 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to afford 3,6-difluoro-2-hydrazinylpyridine.LC-MS (m/z): 146 (M+H)+.
Step 2: Preparation of 2-bromo-3,6-difluoropyridine. To a stirred solution of 3,6-difluoro-2- hydrazinylpyridine(l .l g, 7.0 mmol) in chloroform (20 mL) at r.t. was added dropwise bromine (1.8 g, 11.2 mmol). The reaction mixture was heated to 60°C for 1.5 hr. The resulting mixture was cooled to r.t., quenched with satd. aq. NaHC03, and extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over anhydrous Na2S04and concentrated and purified by standard methods to afford 2-bromo-3,6-difluoropyridine. LC-MS: m/z 194 (M+H)+.
Step 3.'Preparation of methyl 3,6-difluoropicolinate. To a solution of 2-bromo-3,6- difluoropyridine (0.8 g, 4.1mmol) in MeOH (10 mL) were added dppf (0.3 g, 0.56 mmol), Pd(OAc)2 (0.1 g, 0. 45 mmol) and EtsN (1.6 mL, 8.2 mmol). The suspension was degassed and back-filled with CO atmosphere three times. The resulting mixture was stirred under CO atmosphere (60 psi) at 70°C for 12 hr, then cooled to r.t. and concentrated under reduced pressure. The residue was triturated with EtOAc (150 mL) and filtered. The filtrate was concentrated and purified by standard methods to afford methyl 3,6-difluoropicolinate.LC-MS: m/z 174 (M+H)+.
Step 4:Preparation of N2,N4-bis(4,4-difluorocyclohexyl)-6-(3,6-difluoropyrMin-2-yl)-l,3,5- triazine-2,4-diamine. To a suspension of N1,N5-bis(4,4-difluorocyclo hexyl)-biguanide (167 mg, 0.50 mmol) and methyl 3,6-difluoropicolinate (130 mg, 0.75 mmol) in MeOH (5 mL) was added NaOMe (81 mg, 1.5 mmol). The reaction mixture was stirred at r.t. overnight, then poured into water, and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by standard methods to afford N2, N4-bis (4,4-difluorocyclohexyl)-6-(3,6-difluoropyridin-2-yl)-l,3,5-triazine-2,4- diamine. ¾ NMR (400 MHz, CDC13) δ 7.67-7.61 (m, 1H), 7.07-7.03 (m, lH), 5.46-5.10 (m, 2H), 4.08-3.97 (m, 2H), 2.17-2.09 (m, 8H), 1.96-1.83 (m, 4H), 1.73-1.63 (m, 4H). LC-MS: m/z 461 (M+H)+.
Example 17 The compounds of this Example are prepared by general Scheme 17, set forth below.
Scheme 17
Figure imgf000244_0001
Step 1: Preparation of N2,Ni-bis(4,4-difluorocyclohexyl)-6-(3-fluoro-6-hydrazinylpyridin-2- yl)-l,3,5-triazine-2,4-diamine. To a solution of N2,N4-bis(4,4-difluoro -cyclohexyl)-6-(3,6- difluoropyridin-2-yl)-l ,3,5-triazine-2,4-diamine (230 mg, 0.50 mmol) in THF(20 mL) was added hydrazine hydrate(150 mg, 3.0 mmol). The reaction mixture was stirred at 60°C for 2.5 hr. After cooling to r.t., the reaction mixture was diluted with DCM and washed with water. The organic phase was separated,dried over anhydrous Na2S04, and concentrated under reduced pressure to give the desired product. LC-MS (m/z): 473.2 (M+H)+.
Step 2: Preparation of 6-(6-amino-3-fluoropyridin-2-yl)-N2,N4-bis(4,4-difluorocyclohexyl)- l,3,5-triazine-2,4-diamine. To a solution of N2,N4-bis(4,4-difluoro -cyclohexyl)-6-(3-fluoro-6- hydrazinylpyridin-2-yl)-l,3,5-triazine-2,4-diamine (47 mg, 0.1 mmol) in methanol (5.0 mL) was added Raney Ni (100 mg).The reaction mixture was stirred under H2 atmosphere overnight at r.t. then filtered. The filtrate was concentrated and purified by standard methodsto afford the desired product. ¾ NMR (400 MHz, CDC13) δ 7.43-7.39 (m, 1H), 7.03-7.01 (m, 1H), 4.59 (s, 2H), 4.10-4.05 (m, 2H), 2.09-1.93 (m, 12H), 1.76-1.68 (m, 4H). LC-MS: m/z 458.2 (M+H)+.
Example 18 The compounds of this Example are prepared by general Scheme 18, set forth below. Scheme 18
Figure imgf000245_0001
Step 1: Preparation of 6-(4,6-bis((4,4-difluorocyclohexyl)amino)-l,3,5-triazin- 2-yl)-5- fluoropyridin-2-ol. A mixture of N2,N4-bis(4,4-difluorocyclohexyl)-6-(3,6-difluoropyridin-2- yl)-l,3,5-triazine-2,4-diamine (100 mg, 0.22 mmol) in cone. HC1 (5.0 mL) was stirred at 100°C overnight. The resulting mixture was concentrated and purified by standard methods to afford the desired product. ¾ NMR (400 MHz, CDC13) δ 9.96 (m, 1H), 7.40-7.27 (m, 2H), 6.73-6.67 (m, 1H), 5.47-5.17 (m, 2H), 4.02-3.92 (m, 2H), 2.11-1.66 (m, 16H). LCMS: m/z 459(M+H)+.
Example 19 The compounds of this Example are prepared by general Scheme 19, set forth below.
Figure imgf000245_0002
Step 1: Preparation of NJ l,N'-bis(3,3-difluorocyclopentyl)-biguanide. A mixture of 3,3- difluorocyclopentanamine hydrochloride (3 g, 19.1 mmol) and sodium dicyanamide (1.7 g, 19.1 mmol) was heated at 160°C for 1 hr. The resulting product was dissolved in MeOH then filtered. The filtrate was concentrated to afford the desired product. LC-MS: m/z 310.2 (M+H)+.
Step 2: Preparation of ethyl 6-cyclopropylpicolinate. To a mixture of ethyl 6-bromopicolinate (200 mg, 0.87 mmol) andcyclopropylboronic acid (149 mg, 1.74 mmol) in toluene (15 mL) were addedK3P04 (369 mg, 1.74 mmol) anddichloro(diphenylphosphinoferrocene)palladium (11 mg, 0.017 mmol). The resulting mixture was stirred under N2 atmosphere at 100 C overnight, then cooled to r.t. and filtered. The filtrate was concentrated and purified by standard methodsto afford the desired product. LC-MS: m/z 192.1 (M+H)+.
Step 3: 6-(6-cyclopropylpyridin-2-yl)-N: ' ,T^-bis(3^-difluorocyclopentyl)A,3,5-triazine-2,4- diamine. To a mixture of N\N5-bis(3,3-difluorocyclopentyl)-biguanide (50 mg,0.16 mmol) and ethyl 6-cyclopropylpicolinate (62 mg, 0.33 mmol) in methanol (5 mL) was added NaOMe (44 mg , 0.80 mmol). The reaction mixture was stirred at r.t. overnight, and then concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was separated, washed with brine, and dried over anhydrous Na2S04,concentrated, and purified by standard methods to afford the desired product. XH NMR (400 MHz, CDC13) 58.43-8.33 (m, 1H), 8.06-7.99 (m, 1H), 7.25-7.23 (d, J=8 Hz, 1H), 6.66-6.52 (m, 1H), 5.90-5.79 (m, 1H), 4.74-4.45 (m, 2H), 2.66-2.54 (m, 2H), 2.38-2.16 (m, 8H), 1.90-1.88 (m, 2H), 1.42-1.40 (m, 2H), 1.29-1.25 (m, 1H), 1.25-1.01 (m, 2H). LC-MS: m/z 437.2 (M+H)+.
The procedure set forth in Example 19 was used to produce the following compounds using the appropriate starting materials.
Compound 6-(6-Cyclopropylpyridin-2-yl)-N2,N4-bis(4,4-difluorocyclohexyl)-l,3,5-triazine- -diamine
Figure imgf000246_0001
1H NMR (400 MHz, CDC13) δ 8.21 (s, 1H) , 7.87 (s, 1H) , 7.14 (s, 1H), 5.16 (s, 1H), 4.17 - 4.01 (m, 2H) , 2.43 (s, 1H), 2.16 - 1.74 (m, 16H), 1.25 (s, 2H), 1.02 (s, 2H), 0.87 (m, 1H).LCMS: m/z 465(M+H)+ . Compound N2,N4-bis(4,4-difluorocyclohexyl)-6-(6-methylpyridin-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000247_0001
Ή NMR (400MHz, CDC13)5 8.181 - 8.11 (m, 1H), 7.71(s, 1H), 7.29(s, 1H), 5.46 - 5.07 (m, 2H), 4.19 - 3.99 (m, 2H), 2.69(s, 3H), 2.17 - 2.12 (m, 9H), 1.97 - 1.84 (m, 4H), 1.63 - 1.55 (m, 3H).LCMS: m/z 439(M+H)+.
Example 20 Preparation of Symmetric Di-aliphatic Triazine Compounds of Formula M.
The compounds of this Example are prepared by general Scheme 20, set forth below.
Scheme 20 iuret, EtONa, EtOH
HC(OMe)3, TFA
Figure imgf000247_0002
Formula M
Step 1: Preparation of methyl 6-(trifluoromethyl)pyrazine-2-carboxylate. To a mixture of 2- chloro-6-(trifluoromethyl)pyrazine (1 g,5.5 mol) in MeOH (5.5 mL) was added dppf (0.16 g, 0.29 mmol), Pd(OAc)2 (0.1 g, 0.44 mmol) and Et3N (0.12 mL, 8.2 mmol). The suspension was degassed under vacuum and then backfilled with CO three times. The resulting mixture was stirred under CO atmosphere (80 psi) at 70°C for 2 days until the reaction was completed. The mixture was cooled to r.t. and concentrated under reduced pressure at 30°C. To the residue was added EtOAc (150 mL). The suspension was filtered and the filtrate was concentrated and purified by standard methods to afford the desired product.LC-MS: m/z 207 (M+H)+.
Step 2: Preparation of 6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazine-2,4(lH,3H) -dione.
The procedure is the same as Example 1 Step 2 described above. LC-MS: m/z 260 (M+H)+.
Step 3: Preparation of 2,4-dichloro-6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazine. To a solution of 6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazine-2,4(lH,3H)-dione (2.8 g, 0.011 mol) in POCl3 (30 mL) was added Et3N (0.3 mL). The mixture was stirred at 100°C for 16 hr until the reaction was completed. The resulting mixture was concentrated and purified by standard methods to afford the desired product. LC-MS: m/z 296 (M+H)+.
Step 4: Preparation of N2 ,Ν4 -kis(4,4-difluorocyclohexyl)-6-(6-(trifluoroinethyl) pyrazin-2 -yl)- l 3,5-triazine-2,4-diamine.T\\Q procedure is the same as Example 1 Step 4.
Figure imgf000248_0001
1H NMR (400 MHz, CDC13) δ 9.73 (m, 1H), 9.07 (s, 1H), 5.49-5.15 (m, 2H), 4.17-3.99 (m, 2H), 2.17-1.58 (m, 16H). LC-MS: m/z 494 (M+H)+.
The procedure set forth in Example 20 above was used to produce the following compounds using the appropriate starting materials.
N2^4-bis(3 -difluorocyclopentyl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000249_0001
Ή NMR (400 MHz, CDC13) δ 9.74 (m, 1H), 9.07 (d, J = 3.2 Hz, 1H), 5.68 - 5.37 (m, 2H), 4.71 - 4.53 (m, 2H), 2.66 - 2.61 (m, 2H), 2.32 - 1.85 (m, 10H).LC-MS: m/z 466 (M+H)+.
N2J\4-bis((R)-3,3-difluorocyclopentyl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazine- -diamine
Figure imgf000249_0002
1H NMR (400 MHz, CDC13) δ 9.77-9.71 (m, 1H), 9.06 (s, 1H), 5.68-5.37 (m, 2H), 5.54-4.72 (m, 2H), 3.12 (m, 1H), 2.64 (m, 1H), 2.32 (m, 3H), 2.17-2.13 (m, 6H).LC-MS: m/z 466 (M+H)+.
N2^4-bis((S)-3,3-difluorocyclopentyl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazine- -diamine
Figure imgf000249_0003
1H NMR (400 MHz, CDC13) δ 9.74 (m, 1H), 9.07 (d, J= 3.6 Hz, 1H), 5.70 -5.38 (m, 2H), 4.83 - 4.38 (m, 2H), 2.80 - 1.76 (m, 12H). LC-MS: m/z 466 (M+H)+. N2-((R)-3,3-difluorocyclopentyl)-N4-((S)-3,3-difluorocyclopentyl)-6-(6- (trifluoromethyl)pyrazin-2-yl)-l,395-triazine-2,4-diamine
Figure imgf000250_0001
NMR (400 MHz, CDC13) δ 9.74 (m, 1H), 9.07 (d, J= 3.3 Hz, 1H), 5.68 -5.37 (m, 2H), 4.81 4.40 (m, 2H), 2.79 - 1.73 (m, 12H). LC-MS: m/z 466 (M+H)+.
N2J\4-bis(3,3-difluorocyclobutyl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000250_0002
NMR MHz, CDC13) δ 9.74 (m, 1H), 9.08 (s, 1H), 5.84 - 5.49 (m, 2H), 4.53 - 4.37 (m, 2H), 3.12 - 3.02 (m, 4H), 2.70 - 2.57 (m, 4H). LC-MS: m/z 438 (M+H)+.
6-(6-(Trifluoromethyl)pyrazin-2-yl)-N2,N4-bis((R)-l,l,l-trifluoropropan-2-yl)-l,3,5- triazine-2 4-diamine
Figure imgf000250_0003
1H NMR (400 MHz, CD3OD) δ 9.80 (s, 1H), 9.17 (s, 1H), 5.22-4.88 (m, 2H), 1.43-1.38 (m, 6H).LC-MS: m/z 450.1 (M+H)+. N2^4-bis((S)-1 -trifluorobutan-2-yl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-1 95-triazine- -diamine
Figure imgf000251_0001
1HNMR(400MHz,DMSO-d6) 59.86-9.69 (m, 1H), 9.37 (d, 1H), 8.68-8.28 (m, 2H), 5.04-4.71 (m, 2H), 1.81-1.68 (m,4H), 0.97-0.90, 6H).LC-MS: m/z 478.1 (M+H)+.
Example 21 Preparation of Symmetric Di-aliphatic Triazine Compounds of Formula N.
The compounds of this Example are prepared by general Scheme 21, set forth below.
Scheme 21
Figure imgf000251_0002
Formula N
Step 1: Preparation of l-(6-chloropyrazin-2-yl)ethanol. To a solution of methyl 6- formylpyrazine-2-carboxylate (590 mg, 4.15 mmol) in anhydrous THF (5 mL) at -5°C was added dropwise CH3MgBr (2.1 mL, 6.2 mmol). The reaction mixture was stirred at r.t. for 1 hr, then quenched with satd. a.q. NH4C1 at 0°C and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated to afford the desired product.LC-MS: m/z 159.0 (M+H)+.
Step 2: Preparation of l-(6-chloropyrazin-2-yl)ethanone. To a solution of l-(6-chloropyrazin-2- yl)ethanol (370 mg, 2.3 mmol) in DCM (5 mL) at r.t. was added DMP (1.5 g, 3.5 mmol).The reaction mixture was stirred at r.t. for 3 hr then filtered. The filtrate was concentrated and purified by standard methods to afford the desired product.1H NMR (400 MHz, CDC13) δ 9.12(s, 1H), 8.78(s, 1H), 2.72(s, 3H). LC-MS: m/z 157.1 (M+H)+.
Step 3: Preparation of methyl 6-acetylpyrazine-2-carboxylate. To a solution of l-(6- chloropyrazin-2-yl)ethanone (260.0 mg, 1.7 mmol) in MeOH (3 mL) were added dppf (94.0 mg, 0.17 mmol), Pd(OAc)2 (20 mg, 0.1 mmol) and Et3N (0.4 mL, 2.6 mmol). The mixture was stirred under CO (60 psi) atmosphere at 60°C overnight. The resulting mixture was cooled to r.t. and filtered. The filtrate was concentrated and purified by standard methods to afford the desired product. LC-MS: m/z 181.0 (M+H)+.
Step 4: Preparation of methyl 6-(l,l-difluoroethyl)pyrazine-2-carboxylate. To a solution of methyl 6-acetylpyrazine-2-carboxylate(240 mg, 1.3 mmol) in anhydrous DCM (3 mL) at 0 °C was slowly added DAST (0.86 mL, 6.5 mmol). The reaction mixture was stirred at r.t. for 3 hr, then quenched with coldsatd. aq. NaHC03 at 0 °C and extracted with DCM (3 xl 0 mL). The combined organic layers were dried over anhydrous Na2S04 and concentratedto afford the desired product. LC-MS: m/z 203.1 (M+H)+.
Step 5: Preparation of6-(6-(l,l-difluoroethyl)pyrazin-2-yl)-l,3,5-triazine-2,4 (lH,3H)-dione.
The procedure is the same as Example 1 Step 2 described above. LC-MS: m/z 256.1 (M+H)+.
Step 6: Preparation of 2,4-dichloro-6-(6-(l,l-difluoroethyl)pyrazin-2-yl) -1,3,5-triazine. The procedure is the same as Example 1 Step 3 described above. LC-MS: m/z 292.0 (M+H)+. Step 7: Preparation ofN2,N*-bis(4,4-difluorocycfahexyl)-6-(6-(l,l-difluoroethyl) pyrazin-2-yl)- -triazine-2,4-diatnine. The procedure is the same as Example 1 Step 4 described above.
Figure imgf000253_0001
1H NMR (400 MHz, CDC13) δ 9.59 (m, 1H), 9.05 (s, 1H), 5.46 (s, 1H), 5.06 (m, 1H), 4.07 (m, 2H), 2.17 (s, 3H), 2.09 (s, 4H), 1.93 (m, 4H), 1.79 - 1.55 (m, 8H).LC-MS: m/z 490.2 (M+H)+.
The procedure set forth in Example 21 was used to produce the following compounds using the appropriate starting materials.
N2^4-bis(3,3-difluorocyclopentyl)-6-(6-(l,l-difluoroethyl)pyrazin-2-yl)-l,395-triazine-2,4- diamine
Figure imgf000253_0002
1H NMR (400 MHz, CDC13) δ 9.60 (m, 1H), 9.04 (d, J = 6.0 Hz, 1H), 5.66 - 5.34 (m, 2H), 4.70 4.52 (m, 2H), 2.65 - 2.60 (m, 2H), 2.32 - 2.08 (m, 10H), 1.90 - 1.74 (m, 3H). LC-MS: m/z 462.2 (M+H)+.
N2J\4-bis(3,3-difluorocyclobutyl)-6-(6-(l,l-difluoroethyl)pyrazin-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000254_0001
¾ NMR (400 MHz, CDC13) δ 9.62-9.57 (m, 1H), 9.05 (s, 1H), 5.75-5.44 (m, 2H), 4.51-4.37 (m, 2H), 3.07(s, 4H), 2.65-2.61 (m, 4H), 2.17-2.08 (m, 3H). LC-MS: m/z 434.2 (M+H)+.
Example 22 Preparation of Symmetric Di-aliphatic Triazine Compounds of Formula O.
The compounds of this Example are prepared by general Scheme 22, set forth below.
Scheme 22
Figure imgf000254_0002
Step 1: Preparation of 2-(methoxycarbonyl)pyrazine 1-oxide. To a solution of methyl pyrazine- 2-carboxylate (10.0 g, 70 mmol) in 1 ,2-dichloroethane (120 mL) was added 3- chloroperoxybenzoic acid (25.0 g, 140 mmol). The reaction mixture was stirred at 60°C overnight. The resulting mixture was cooled to r.t. and filtered. The filtrate was dried over anhydrous K2C03and concentrated under reduced pressure. The residue was triturated with hexane and filtered and dried to afford 2-(methoxycarbonyl)pyrazine 1-oxide.LC-MS: m/z 155.0 (M+H)+. Step 2: Preparation of methyl 6-chloropyrazine-2-carboxylate. A mixture of 2- (methoxycarbonyl)pyrazine 1 -oxide (4.8 g, 30 mmol) in SOCl2 (50 mL) was stirred at 85°C overnight. The mixture was cooled to r.t. and concentrated under reduced pressure. The residue was neutralized by satd.aq. NaHCC and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated and purified by standard methods to afford methyl 6-chloropyrazine-2-carboxylate.1H NMR (600 MHz, CDCls) δ 8.59 (s, 1H), 8.53 (s, 1 H), 4.84 (s, 2H), 3.01 (s, 1H).LC-MS: m/z 173.0 (M+H)+.
Step 3: Preparation of (6-chloropyrazin-2-yl)methanol. To a solution of methyl 6- chloropyrazine-2-carboxylate (2.0 g, 11.6 mmol) in water (20 mL) at 0 °C was added NaBH4 (2.3 g, 58.0 mmol) portionwise. The reaction mixture was warmed to r.t. and stirred for 30 min, followed by addition of satd. aq. K2C03 (40 mL) and EtOH (20 mL). The resulting mixture was stirred for another 1 hr and extracted with EA (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SC>4and concentrated and purified by standard methods to afford (6- chloropyrazin-2-yl)methanol. LC-MS: m/z 145.0 (M+H)+.
Step4: Preparation of6-chloropyrazine-2-carbaldehyde. To a solution of (6-chloropyrazin-2- yl)methanol(600mg, 4.2 mmol) in DCM (10 mL) was added Dess-Martin reagent (2.6 g, 6.3 mmol). The reaction mixture was stirred at r.t. for 3 hr, and then filtered. The filtrate was concentratedand purified by standard methods to afford 6-chloropyrazine-2- carbaldehyde.LC-MS: m/z 143.0 (M+H)+.
Step5: Preparation of methyl 6-formylpyrazine-2-carboxylate. To a mixture of 6- chloropyrazine-2-carbaldehyde (1.0 g, 7.0 mmol) in MeOH (10 mL) were added dppf (388 mg, 0.7 mmol), Pd(OAc)2 (90 mg, 0.4 mmol) and Et3N (1.5 mL, 10.5 mmol). The suspension was stirred under CO atmosphere (60 psi) at 60°C overnight. The resulting mixture was cooled to r.t. and filtered. The filtrate was concentrated and purified by standard methods to afford methyl 6- formylpyrazine-2-carboxylate.LC-MS: m/z 167.0 (M+H)+. Step6: Preparation of methyl 6- (diflu oroincthyl )pyrazin e-2-c rboxyhite. To a mixture of methyl 6-formylpyrazine-2-carboxylate (4.1 g, 24.7 mmol) in anhydrous DCM (40 mL) at 0 °C was slowly added DAST (16.3 mL, 123.5 mmol). The reaction mixture was stirred at r.t. for 3 hrs, then quenched with cold satd. aq.NaHC03 at 0 °C and extracted with DCM (2 x 20 mL). Combined organic layers were dried over anhydrous Na2S04 and concentratedto afford the desired product. LC-MS: m/z 189.0 (M+H)+.
Step?: Preparation of 6-(6-(difluoromethyl)pyrazin-2-yl)-l,3,5-tr zine-2,4(lH,3H)-dione. To a flame-dried three necked round bottom flask was added biuret (659 mg, 6.4 mmol) andmethyl 6- (difluoromethyl)pyrazine-2-carboxylate (1.0 g, 5.3 mmol), followed by addition of EtOH (12 mL). The mixture was degassed and back-filled with N2three times. The mixture was stirred at 25°C for 20 min, and then heated to 50°C. Then HC(OMe)3 (0.7 mL, 6.4 mmol) and TFA (0.04 mL, 0.53 mmol) were added to the above mixture. The mixture(pale yellow slurry )was stirred at this temperature for 30 min, followed by dropwise addition of a solution of NaOEt in EtOH (20% wt, 7.2 g, 21.2 mmol). The resulting mixture was heated at reflux for 2 hr, then cooled to r.t. and concentrated under reduced pressure. The residue was treated with water (10 mL) and concentrated again to remove the remaining ethanol. The final residue was suspended in water (30 mL), cooled to 10°C when the acidity was adjusted to pH=l by slow addition of 6N HC1 (solid precipitated out), and then stirred for 2hr. The mixture was filtered and the filter cake was washed withaq. HC1 (pH=l). The solid was collected and suspended in DCM (30 mL). The suspension was stirred at r.t. for 2 hr and then filtered again. The filtercake was collected and dried to afford the desired product.LC-MS: m/z 242.0 (M+H)+.
Step 8: Preparation of 2,4-dichloro-6-(6-(difluoromethyl)pyrazin-2-yl)-l,3,5-triazine. The procedure is the same as Example 1 Step 3 described above.LC-MS: m/z 2782.0 (M+H)+.
Step 8: Preparation ofN2 ,Ν4 -bis(4,4-difluorocyclohexyl)-6-(6-(difluoromethyl) pyrazin -2-yl)- l,3,5-triazine-2,4-diamine. The procedure is the same as Example 1 Step 4 described above.
Figure imgf000257_0001
1H NMR (400 MHz, CDC13) δ 9.69 (m, 1H), 9.07 (s, 1H), 6.89 (m, 1H), 5.53 - 5.12 (m, 2H), 4.08 (m, 2H), 2.23 - 1.67 (m, 16H).LC-MS: m/z 476.2 (M+H)+.
The procedure set forth in Example 22 was used to produce the following compounds using the appropriate starting materials.
N2^4-bis(3^-difluorocyclopentyl)-6-(6-(difluoromethyl)pyrazin-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000257_0002
1H NMR (400 MHz, CDC13) δ 9.73-9.67 (m, 1H), 9.07 (s, 1H), 7.03-6.76 (m, 1H), 5.63-5.35 (m, 2H), 4.73-4.55 (m, 2H), 2.66-2.61 (m, 2H), 2.32 (s, 4H), 2.13-1.57 (m,6H). LC-MS: m/z 448.2 (M+H)+.
N2J\4-bis(3,3-difluorocyclobutyl)-6-(6-(difluoromethyl)pyrazin-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000257_0003
¾ NMR (400 MHz, CDC13) δ 9.72-9.67 (m, 1H), 9.07 (s, 1H), 6.85 (d, 1H), 5.76-5.48 (m, 2H), 4.54-4.38 (m, 2H), 3.08 (s, 4H), 2.66-2.61 (m, 4H). LC-MS: m/z 420.1 (M+H)+.
N2^4-bis(3 -difluorocyclobutyl)-6-(4-(difluoromethyl)pyrimidin-2-yl)-l,395-triazine-2,4- diamine
Figure imgf000258_0001
1H NMR (400 MHz, CDC13) δ 9.17 (d, J = 4.9 Hz, lH), 7.77 (d, J = 4.9 Hz, 1H), 6.77 (m, 1H), 5.76 (m, 2H), 4.55 (m, 2H), 3.07 m, 4H), 2.61 (m, 4H).LC-MS: m/z420 (M+H)+.
N2^4-bis(3 -difluorocyclopentyl)-6-(4-(difluoromethyl)pyrimidin-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000258_0002
1H NMR (400 MHz, DMSO-d6) δ 9.19 (m, 1H), 8.16 (m, 1H), 7.88 (m, 1H), 7.04 (m, 1H), 4.47 (m, 2H), 2.63 (m, 1H), 2.25 (m, 9H), 1.83 (m, 2H). LC-MS: m/z448 (M+H)+.
N2^4-bis(4,4-difluorocyclohexyl)-6-(4-(difluoromethyl)pyrimidin-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000259_0001
Ή NMR (400 MHz, CDC13) 5(m, 1Η),7.79-7.78 (m, 1H), 6.91-6.64 (m, 1H), 5.72-5.20 (m, 2H), 4.26-4.02 (m, 2H), 2.13-2.10 (m, 8H), 1.98-1.87 (m, 4H), 1.76-1.73 (m, 4H). LC-MS: m/z 476 (M+H)+.
Example 23 The compounds of this Example are prepared by general Scheme 23, set forth below.
Scheme 23
Figure imgf000259_0002
Step 1.'Preparation of6-(6-chloropyrazin-2-yl)-N2,Ni-bis(4,4-difluorocyclohexyl)-l,3,5- triazine-2 ,4-diamine. To a mixture of methyl 6-chloropyrazine-2-carboxylate (300mg,1.74mmol) and N1,N5-di-(4,4-difluorocyclohexanamine)- biguanide (700 mg, 2.10 mmol)in MeOH (8 mL) was added MeONa (340 mg, 6.28 mmol).The reaction mixture was stirred at r.t. overnight, and then partitioned between EtOAc (30 mL) and H2O(30mL). The organic layerwas separated, washed with brine (30 mL), dried over anhydrous Na2S04, and concentrated and purified by standard methods to afford the desired product. 1H NMR (400MHz, DMSO-d6)5 9.48 - 9.32 (m,
1H), 8.93 (d,J=8Hz, 1H), 7.92 - 7.59 (m, 2H), 4.15 -3.95(m, 2H), 2.08 - 1.60(m, 16H).LCMS: m/z 460(M+H)+.
The procedure set forth in Example 23 was used to produce the following compounds using the appropriate starting materials. 6-(6-Chloropyrazin-2-yl)-N ,N -bis(3,3-difluorocyclopentyl)-l,3,5-triazine-2,4-diamine
Figure imgf000260_0001
1HNMR (400MHz, CDC13) δ 9.45 (d, 1H), 8.72(s,lH), 5.65 (d, 2H), 4.53-4.37 (m, 2H), 3.07- 2.60 (m, 8H). LC-MS: m/z 432 (M+H)+.
6-(6-Chloropyrazin-2-yl)-N ,N -bis(3,3-difluorocycloburyl)-l,395-triazine-2,4-diamine
Figure imgf000260_0002
Ή NMR (400 MHz, CDC13) δ 9.45 (d, 1H), 8.71 (s, 1H), 5.69-5.36 (m, 2H), 4.70-4.52 (m, 2H), 2.65-2.05 (m, 12H). LC-MS: m/z 404 (M+H)+.
6-(6-chloropyrazin-2-yl)-N2,N4-bis(1 -trifluoropropan-2-yl)-l,355-triazine-2,4-diamine
Figure imgf000260_0003
XH NMR (400 MHz, CDC13) δ 9.42 (d, 1H), 8.66 (s, 1H), 5.61-5.24 (m, 2H), 5.01 -4.78(m, 2H), 1.41 -1.34(m, 6H). LCMS: m/z 416(M+H)+.
Example 24 Preparation of SymmetricDi-aliphatic Triazine Compounds of Formula P. The compounds of this Example are prepared by general Scheme 24, set forth below.
Figure imgf000261_0001
Formula P
Step 1: Preparation of methyl 2-(trifluoromethyl)pyrimidine-4-carboxylate. To a solution of 4- chloro-2-(trifluoromethyl)pyrimidine (10 g, 54.9 mmol) in MeOH (60 mL) was added dppf (3.0 g, 5.5 mmol), Pd(OAc)2 (630 mg, 2.8 mmol) and Et3N (11.4 mL, 41.2 mmol). The mixture was stirred under CO atmosphere (60 psi) at 60 °C overnight. The resulting mixture was cooled to r.t. and filtered. The filtrate was concentrated and purified by standard methods to afford the desired product. LC-MS: m/z 207.0 (M+H)+.
Step2: Preparation of 6-(2-(trifluoromethyl)pyrimidin-4-yl)-l,3,5-triazine-2,4(lH,3H)- dione.T e procedure is the same as Example 1 Step 2 described above.LC-MS: m/z 260.0 (M+H)+.
Step 3: Preparation of 2,4-dichhro-6-(2-(trifluoromethyl)pyrimMin-4-yl)-l,3,5-triazine. The procedure is the same as Example 1 Step 3 described above. LC-MS: m/z 296.0 (M+H)+.
Step 4: Preparation of N2,N*-bis(4,4-difluorocyclohexyl)-6-(2-(trifluoromethyl)pyri midin-4- yl)-l,3,5-triazine-2,4-diamine.T e procedure is the same as Example 1 Step 4 described above.
Figure imgf000262_0001
' H MR (400 MHz, CDC13) δ 9.08 (m, 1H), 8.42 (m, 1H), 5.54 - 5.19 (m, 2H), 4.16 - 3.99 (m, 2H), 2.29 - 1.73 (m, 16H). LC-MS: m/z 494.2 (M+H)+.
The procedure set forth in Example 24 was used to produce the following compounds using the appropriate starting materials.
N2^4-bis(3,3-difluorocyclopentyl)-6-(2-(trifluoromethyl)pyrimidin-4-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000262_0002
Ή NMR (400 MHz, CDC13) δ 9.06-9.10 (m, 1H), 8.39-8.45 (m, 1H), 5.66-5.68 (d, J=8.0 Hz, 2H), 4.52-4.70 (m, 2H), 2.60-2.65 (m, 2H), 2.13-2.32 (m, 8H), 1.67-1.87 (m, 2H). LC-MS: m/z 466.2 (M+H)+.
N2^4-bis(3 -difluorocyclobutyl)-6-(2-(trifluoromethyl)pyrimidin-4-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000262_0003
¾ NMR (400 MHz, CDC13) δ 9.10 (m, 1H), 8.51 - 8.37 (m, 1H), 5.93 - 5.48 (m, 2H), 4.44 (m, 2H), 3.07 (m, 4H), 2.75 - 2.49 (m, 4H).LC-MS: m/z 438.1 (M+H)+.
6-(2-(Trifluoromethyl)pyrimidin-4-yl)-N2J\4-bis((R)-l,l,l-trifluoropropan-2-yl)-l,3,5- triazine-2,4-diamine
Figure imgf000263_0001
1H NMR (400 MHz, CDC13) 5 9.1 1 (m, 1H), 8.45 (t, J= 5.6 Hz, 1H), 5.74 - 5.32 (m, 2H), 5.16 4.79 (m, 2H), 1.43 (m, 6H).LC-MS: m/z 450.1 (M+H)+.
N2^4-bis((S)-l,l,l-trifluorobutan-2-yl)-6-(2-(trifluoromethyl)pyrimidin-4-yl)-l,3,5- triazine-2,4-diamine
Figure imgf000263_0002
1H NMR (400 MHz, CDC13) δ 9.1 1 (m, 1H), 8.46 (d, J = 5.0 Hz, 1H), 5.78 - 5.22 (m, 2H), 4.97 - 4.63 (m, 2H), 2.12 - 1.90 (m, 2H), 1.61-1.69 (m, 2H), 1.05 (t, J= 7.5 Hz, 6H).LC-MS: m/z 478.1 (M+H)+.
N2J\4-bis(4,4-difluorocyclohexyl)-6-(4-(trifluoromethyl)pyri midin-2-yl)-l,3,5- triazine-2,4- diamine.
Figure imgf000264_0001
1 H NMR (400 MHz, CDC13) δ 9.22 (d, J = 4.9 Hz, IH), 7.77 (d, J= 4.9 Hz, IH), 5.64 - 5.16 (m, 2H), 4.21 - 4.01 (m, 2H), 2.28 - 1.52 (m, 16H). LC-MS: m/z 494.2 (M+H)+.
N2^4-bis(3 -difluorocyclopentyl)-6-(4-(trifluoromethyl)pyrimidin-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000264_0002
1HNMR (400MHz, CDC13) δ 9.22 (d, IH), 7.77 (d, IH), 5.87 (d, 2H), 4.58-4.53 (m, 2H), 2.69- 2.56 (m, 2H), 2.31-2.29 (m, 4H), 2.17-2.08 (m, 4H), 1.87-1.68 (m, 2H).LC-MS: m/z 466.2 (M+H)+.
N2^4-bis(3 -difluorocyclobutyl)-6-(4-(trifluoromethyl)pyrimidin-2-yl)-l,395-triazine-2,4- diamine
Figure imgf000264_0003
Ή NMR (400 MHz, DMSO-d6) δ 9.34 (m, IH), 8.64 - 8.00 (m, 3H), 4.46 - 4.10 (m, 2H), 3.07 - 2.83 (m, 4H), 2.74 - 2.62 (m, 4H). LC-MS: m/z 438.1 (M+H)+. N2^4-bis((R)-l-cyclopropylethyl)-6-(4-(trifluoromethyl)pyrimidin-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000265_0001
1H NMR (400 MHz, CDC13) δ 9.19 (s, 0.6H), 7.74-7.73 (m, 0.6H), 5.63-5.43 (m, 2H),3.61-3.58 (m, 2H), 1.27-1.26 (m, 8H), 0.90 (m, 2H), 0.50-0.26(m, 8H). LCMS: m/z 394(M+H)+.
N2^4-bis(4,4-difluorocyclohexyl)-6-(4-(2-methoxyethyl)pyrimidin-2-yl)-l,395-triazine-2,4- diamine
Figure imgf000265_0002
Ή NMR (400 MHz, CDC13) 58.83-8.82(m, 1Η),7.40-7.39 (m, lH),5.60-5.58(m,2H), 4.26-4.01 (m, 2H), 3.81 -3.77 (t, J=8Hz, 2H), 3.35 (s, 3H), 3.21-3.18 (m, J=8Hz,2 H), 2.11-2.05 (m, 8H), 1.94-1.86 (m, 4H), 1.74-1.69 (m, 4H). LC-MS: m/z 484 (M+H)+.
Example 25 The compounds of this Example are prepared by general Scheme 25, set forth below.
Scheme 25
Figure imgf000266_0001
Step 1: Preparation of ethyl 2-(trifluoromethyl)thiazole-4-carboxylate. To a solution of 2,2,2- trifluoroacetamide(1.42 g, 12.6 mmol) in dry THF(60 mL) was added Lawesson's reagent (3.06 g,7.56 mmol). The reaction mixture was heated atreflux for 18 hr and then cooled, followed by addition ofethyl 3-bromo-2-oxopropanoate (1.6 mL, 12.6 mmol). The mixture was refluxed for another 18 hr and then cooled to r.t.. The resulting mixture was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous Na2S04 and concentrated andpurified by standard methods to afford ethyl 2-(trifluoromethyl)thiazole-4-carboxylate.1H NMR (400MHz,CDCl3) 58.42 (s, 1H) 4.47 (q, J=7.1 Hz, 2H), 1.45 (t, J= 7.2 Hz, 3H). LC-MS: m/z 226 (M+H)+.
Step 2: Preparation of
Figure imgf000266_0002
(3,3-difluorocyclobutyl)-biguanide. A mixture of 3,3- difluorocyclobutanamine hydrochloride^.024 g, 0.021 mol) and NaN(CN)2 (890 mg,0.01 mol) was vigorously stirred at 160°C for 2 hr then cooled to r.t.. The resulting mixture was dissolved in MeOH and filtered. The filtrate was concentrated to afford the desired product.LC-MS: m/z 282 (M+H)+.
Step 3: Preparation of N l^-bis(3,3-difluorocyclobutyl)-6-(4-(trifluorom^
l,3,5-triazine-2,4-diamine. To a mixture of N^N^bis^^-difluorocyclobuty^-biguanide (60 mg, 0.22 mmol) in MeOH (5 mL) were added ethyl 2-(trifluoromethyl)thiazole-4-carboxylate (58.5 mg, 0.26 mmol) and NaOMe (23.7 mg, 0.44 mmol). The reaction mixture was then stirred at r.t. for 48 hr then partitioned between EtOAc and H2O.The organic layer was separated, washed with brine, dried over anhydrous Na2S04, and concentrated and purified by standard methods to afford the N^N4-bis(3,3-difluorocyclobutyl)-6-(4-(trifluoromethyl)thiazol-2-yl) ,3,5 riazine- 2 4-diamine.
Figure imgf000267_0001
1H NMR (400 MHz, CDC13) 57.83 (d, J = 5.2 Hz, 1H), 7.01-6.74 (m, 1H), 5.74-5.43 (m, 2 H) , 4.45-4.32 (m, 2H), 3.11-3.04 (m, 4H), 2.63-2.48 (m, 4H). LC-MS: m/z 443 (M+H)+.
The procedure set forth in Example 25 was used to produce the following compounds using the appropriate starting materials.
N2JV4-bis(4,4-difluorocyclohexyl)-6-(4-(trifluoromethyl)thiazol-2-yl)-l,3,5-triazine-2,4- iamine
Figure imgf000267_0002
Ή NMR (400MHz, CDC13)5 7.84(s, 1H), 5.42 - 5.07 (m, 2H), 3.89 - 3.79 (m, 2H), 2.06 - 1.79(m, 13H), 1.67 - 1.57 (m, 3H). LCMS: m/z 499(M+H)+.
N2JV -bis(3 -difluorocyclopentyl)-6-(4-(trifluoromethyl)thiazol-2-yl)-l,3,5-triazine-2,4- diamine F XNAN N F F
H H
Ή NMR (400MHz, CDC13)5 7.91 (d,J=4Hz, 1H), 5.66 - 5.34 (m, 2H), 4.64 - 4.51 (m
2.59 (m, 2H), 2.31 - 2.04 (m, 8H), 1.86 - 1.80 (m, 2H).LCMS: m/z 471(M+H)+.
6-(4-(trifluoromethyl)thiazol-2-yl)-N ,N -bis(l,1 -trifluoropropan-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000268_0001
XH NMR (400MHz, CDC13)5 7.94 (s, 1H), 5.81 - 5.31(m, 2H), 5.01 - 4.83(m, 2H), 1.47 - 1.39 (m, 6H).LCMS: m/z 455(M+H)+.
N2 J\4-bis(4,4-difluorocyclohexyl)-6-(2-(trifluoromethyl)thiazol-4-yl)-l,3,5-triazine-2,4- iamine
Figure imgf000268_0002
Ή NMR (400 MHz, CDC13) δ 8.48 (m, 1H), 5.41-5.09 (m, 2H), 4.16-3.99 (m, 2H), 2.28 - 1.66 (m, 16H).LC-MS: m/z 499 (M+H)+. N2J\4-bis(3,3-difluorocyclobutyl)-6-(2-(trifluoromethyl)thiazol-4-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000269_0001
!H NMR (400 MHz, CDC13) δ 8.50 (m, 1H), 6.73-6.38 (m, 2H), 4.46-4.36 (m, 2H), 3.06 (s, 4H), 2.61 (s, 4H).LC-MS: m/z 443 (M+H)+.
6-(2-(trifluoromethyl)thiazol-4-yl)-N2,N4-bis((R)-l,1 -trifluoropropan-2-yl)-l,3,5-triazine- -diamine
Figure imgf000269_0002
Ή NMR (400 MHz, CDC13) δ 8.49 (d, 1H), 5.57-5.12 (m, 2H), 4.97-4.49 (m, 2H), 1.36- 1.25(m,6H). LCMS: m/z 455(M+H)+. 2J\4-bis(4,4-difluorocyclohexyl)-6-(2-methyloxazol-4-yl)-l,395-triazine-2,4-diamine
Figure imgf000269_0003
1H NMR (400MHz, CDC13)5 8.11(s, 1H), 5.27 - 4.92(m, 2H), 4.02 - 3.81 (m, 2H),2.47(s, 3H), 2.03 - 1.79 (m, 12H), 1.63 - 1.54(m, 4H).LCMS: m/z 429(M+H)+. -bis(3 -difluorocyclobutyl)-6-(2-methyloxazol-4-yl)-l,395-triazine-2,4-diamine
Figure imgf000270_0001
Ή NMR (400 MHz, CDC13) δ 8.24 (m, 1H), 5.66 (m, 2H), 4.31 (s, 2H), 3.13 - 2.95 (m, 4H), 2.60 (m, 7H).LC-MS: m/z 373 (M+H)+. 2J\4-bis(4,4-difluorocyclohexyl)-6-(5-methylisoxazol-3-yl)-l,355-triazine-2,4-diamine
Figure imgf000270_0002
Ή NMR (400MHz, CDC13)5 6.52 - 6.48 (m, 1H), 5.44- 5.09 (m, 2H), 4.15- 3.96 (m, 2H), 2.49(s, 3H), 2.11 - 1.89(m, 13H), 1.70 - 1.63 (m, 3H).LCMS: m/z 429(M+H)+. 2J\4-bis(3,3-difluorocyclobutyl)-6-(5-methylisoxazol-3-yl)-l,355-triazine-2,4-diamine
Figure imgf000270_0003
Ή NMR (400 MHz, DMSO-d6) δ 6.51 (m, 1H), 5.86 - 5.33 (m, 2H), 4.65 - 4.13 (m, 2H), 3.04 (dd, J= 6.2, 5.4 Hz, 4H), 2.70 - 2.55 (m, 4H), 2.50 (s, 3H). LC-MS: m/z 373 (M+H)+.
Example 26 The compounds of this Example are prepared by general Scheme 26, set forth below.
Figure imgf000271_0001
Figure imgf000271_0002
Step 1: Preparation of ethyl 2-bromothiazole-4-carboxylate. To a solution of ethyl 2- aminothiazole-4-carboxylate (15.0 g, 87.1 mmol) in MeCN (100 mL) was added isoamyl nitrite (24.5 g, 209 mmol) and CuBr2 (27.5 g, 122 mmol). The mixture was stirred at 70°C overnight, then cooled to r.t, diluted with water (200 mL), and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over anhydrous Na2S04 and concentrated and purified by standard methodsto afford ethyl 2-bromothiazole-4-carboxylate. LC-MS: m/z 236 (M+H)+.
Step 2: Preparation of 2-bromothiazole-4-carboxylic acid. To a solution of ethyl 2- bromothiazole-4-carboxylate (18.0 g, 76.0 mmol) in THF (90 mL) and H20 (90 mL) was added LiOH (4.8 g, 114 mmol). The mixture was stirred at r,t for 3 hr and extracted with EtOAc (2 x 150 mL).The aqueouslayer was separated, adjusted to pH 2-3 with satd. aq. NH4C1, and filtered. The solid was collected and dried under high vacuum to afford 2-bromothiazole-4-carboxylic acid. LC-MS: m/z 206 (M-H)".
Step 3: Preparation of 2-bromo-N-methoxy-N-methylthiazole-4-carboxamide.To a solution of 2-bromothiazole-4-carboxylic acid (11.4 g, 55.0 mmol) in DCM (100 mL) were added Ν,Ο- dimethylhydroxylamine (6.9 g, 71.0 mmol), HATU (27.0 g, 71.0 mmol) and DIPEA (21.2 g, 164.0 mmol). The mixture was stirred at r,t. overnight, then quenched with water (200 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were dried over anhydrous Na2S04, and concentrated and purified by standard methods to afford 2-bromo-N-methoxy-N- methylthiazole- 4-carboxamide.LC-MS: m/z 251 (M+H)+.
Step 4: Preparation of l-(2-bromothiazol-4-yl)ethanone. To a solution of 2-bromo-N-methoxy- N-methylthiazole-4-carboxamide (6.8 g, 27.0 mmol) in THF (60 mL) under N2 atomsphere at 0°C was slowly added dropwise MeMgBr (9.9 mL, 29.7 mmol, 3M in THF). The mixture was slowly warmed to r,t and stirred at this temperature for 30 min. The reaction mixture was quenched with satd. aq. NH4C1 (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2S04, and concentrated and purified by standard methods to afford l -(2-bromothiazol-4-yl)ethanone. LC-MS: m/z 206 (M+H)+.
Step 5:Preparation of methyl 4-acetylthiazole-2-carboxylate. To a solution of l-(2- bromothiazol-4-yl)ethanone (340 mg, 1.65 mmol) in MeOH (10 mL) were added Pd(OAc)2 (20.0 mg, 0.08 mmol), dppf (95.0 mg, 0.16 mmol) and Et3N (250 mg, 2.5 mmol). The mixture was heated at 60°C under CO atmosphere (0.4 mPa) overnight. The resulting mixture was cooled to r.t. and filtered. The filtrate was concentrated and the residue purified by standard methods to afford methyl 4-acetylthiazole-2-carboxylate. LC-MS: m/z 186 (M+H)+.
Step 6: Preparation of methyl 4-(l,l-difluoroethyl)thiazole-2-carboxylate. To a solution of 4- acetylthiazole-2-carboxylate (200 mg, 1.07 mmol) in DCM (10 mL) at 0°C was slowly added dropwise DAST (1.64 g, 10.2 mmol). The mixture was then warmed to r,t and stirred at r.t. overnight. The mixture was slowly quenched with satd. aq. NaHC03 (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2S04, and concentrated and purified by standard methods to give methyl 4-(l,l -difluoroethyl)thiazole-2- carboxylate.LC-MS: m/z 208 (M+H)+.
Step 7: Preparation of N2 ,N* -bis(4,4-difluorocyclohexyl)-6-(4-(l ,1-difluoroethyl) thiazol-2-yl)- l,3,5-triazine-2,4-diamine. To a mixture of N\N5-bis(3,3-difluorocyclobutyl)-biguanide (60 mg, 0.22 mmol) in MeOH (5 mL) were added ethyl 4-(l,l-difluoroethyl)thiazole-2-carboxylate (50 mg, 0.26 mmol) and NaOMe (23.7 mg, 0.44 mmol). The reaction mixture was then stirred at r.t. for 48 hr, and then partitioned between EtOAc and H2O.The organic layer was separated, washed with brine, dried over anhydrous Na2S04, concentrated and purified by standard methods to afford N^N4-bis(4,4-difluorocyclohexyl)-6-(4-(l ,l-difluoroethyl)thiazol-2-yl) ,3,5-triazine-2,4 diamine
Figure imgf000273_0001
Ή NMR (400 MHz, CDC13) δ 7.75 (d, J = 3.7 Hz, 1H), 5.30 (m, 2H), 4.05 (d, J = 49.4 Hz, 2H), 2.30 - 2.01 (m, 11H), 1.94 (d, J= 9.2 Hz, 4H), 1.81 - 1.68 (m, 3H). LC-MS: m/z 495 (M+H)+.
The procedure set forth in Example 26 was used to produce the following compounds using the appropriate starting materials.
N2J\4-bis(4,4-difluorocyclohexyl)-6-(2-(l,l-difluoroethyl)thiazol-4-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000273_0002
Ή NMR (400 MHz, DMSO-d6) δ 8.59 (d, 1H), 7.52 (m, 2H), 4.09 (m, 2H), 3.25 (m, 3H), 2.34 (m, 1H), 1.58 (m, 16H). LC-MS: m/z494 (M+H)+.
N2J\4-bis(3,3-difluorocyclopentyl)-6-(2-(l,l-difluoroethyl)thiazol-4-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000274_0001
1H NMR (400 MHz, CDC13) δ 8.44 - 8.36 (m, 1H), 5.54 - 5.24 (m, 2H), 4.67 - 4.53 (m, 2H), 2.63 - 2.60 (m, 2H), 2.31 - 2.02 (m, 1 1H), 1.82 - 1.75 (m, 2H) .LCMS: m/z 467(M+H)+.
N2J\4-bis(3,3-difluorocyclobutyl)-6-(2-(l,l-difluoroethyl)thiazol-4-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000274_0002
Ή NMR (400 MHz, CDC13) δ 8.45 - 8.36 (m, 1H), 5.71 - 5.36 (m, 2H),4.47 - 4.35 (m, 2H), 3.05 (s, 4H), 3.6 l(s, 4H), 2.24 - 2.03 (m, 3H). LCMS: m/z 439(M+H)+:
Example 27 The compounds of this Example are prepared by general Scheme 27, set forth below.
Scheme 27
Figure imgf000274_0003
Step 1: Preparation of 2-bromothiazole-4-carbaldehyde. To a mixture of 2-bromo-N-methoxy- N-methylthiazole-4-carboxamide (10 g, 0.04 mol) in THF (80 mL) at -78 °C was slowly added DIBAL-H (7.35 g, 0.052 mol). The reaction mixture wasstirred at -78 °C for 2 hr, then adjusted pH to 5-6. The mixture was partitioned between EtO Ac (80 mL) and H20 (60 mL). The organic layer was separated, washed with brine(40 mL), dried over anhydrous Na2S04, concentrated and purified by standard methods to afford the desired product.LC-MS: m/z 192 (M+H)+.
Step 2: Preparation of 2-bromo-4-(difluoromethyl)thiazole. To a mixture of 2-bromothiazole-4- carbaldehyde (0.764 g, 0.004 mol) in DCM (7 mL) at 0 °C was added dropwise DAST (3.22 g, 0.02 mol). The mixture was stirred at 25 °Cfor 48 hr, then quenched withsatd. aq. NaHC03 and adjusted pH to 8 - 10. The resulting mixture was extracted with DCM (2 x 40 mL). The combined organic layers were washed with brine(30 mL), dried over anhydrous Na2S04 and concentrated and purified by standard methods to afford the desired product. LC-MS: m/z 214 (M+H)+.
Step 3: Preparation of methyl 4-(difluoromethyl)thiazole-2-carboxylate. A mixture of 2-bromo- 4-(difluoromethyl)thiazole (0.6 g, 2.82 mmol), dppf (0.14 g, 0.28 mmol), Et3N (0.43 g, 4.23 mmol) and Pd(OAc)2 (0.13 g, 0.56 mmol) in MeOH (10 mL) was stirred at 60 °Cunder an atmosphere of CO for 16 hr. The resulting mixture was filtered, the filtrate was concentrated and the residue was partitioned between DCM (30 mL) and H20. The organic layer was separated, washed with brine(30 mL), dried over anhydrous Na2S04, and concentrated and purified by standard methodsto afford the desired product.LC-MS: m/z 194 (M+H)+.
Step 4: Preparation of N2,Ni-bis(4,4-difluorocyclohexyl)-6-(4-(difluoromethyl)thiazol-2-yl)- l,3,5-triazine-2,4-diamine.To a suspension of N\N5-bis(3,3-difluorocyclobutyl)-biguanide (45 mg, 13.3 mmol) and methyl 4-(difluoromethyl)thiazole-2-carboxylate (40 mg, 20.7 mmol) in MeOH (lOmL) was added NaOMe (20 mg, 37.0 mmol). The reaction mixture was stirred at r.t. overnight, then poured into water and extracted with EtO Ac. Combined organic layers were over anhydrous Na2S04, concentrated and purified by standard methods to afford the desired product.
Figure imgf000276_0001
Ή NMR (400 MHz, CDC13) δ 7.75 (s, 1H), 6.94-6.67 (t, 1H), 5.40-5.08 (m, 2H), 4.04-3.90 (m, 2H), 2.05-1.84 (m, 8H), 1.79-1.64 (m, 4H), 1.62-1.54 (m, 4H). LC-MS: m/z 481(M+H)+.
The procedure set forth in Example 27 was used to produce the following compounds using appropriate starting materials.
N2J\4-bis(3,3-difluorocyclobutyl)-6-(4-(difluoromethyl)thiazol-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000276_0002
Ή NMR (400MHz, CDC13)5 7.84 (d, J=8Hz, 1H), 7.02 - 6.74(m, 1H), 5.74 - 5.44(m, 2H), 4.46 - 4.36(m, 2H), 3.06 (d, J=8Hz, 4H), 2.63 - 2.59 (m, 4H).LCMS: m/z 425(M+H)+.
N2J\4-bis(3,3-difluorocyclopentyl)-6-(4-(difluoromethyl)thiazol-2-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000276_0003
Ή NMR (400MHz, CDC13)5 7.84(s, 1H), 7.04 - 6.76(m, 1H), 5.65 - 5.36 (m, 2H), 4.66 - 4.55 (m, 2H), 2.66 -1.85(m, 12H).LCMS: m/z 453(M+H)+.
Example 28 The compounds of this Example are prepared by general Scheme 28, set forth below.
Scheme 28
Figure imgf000277_0001
Step 1: Preparation of 5-phenyl-l,3,4-oxathiazol-2-one. To a solution of benzamide (200 mg, 1.65 mmol) in toluene (2 mL) under N2atmospherewas added carbonyl chloride thiohypochlorite(0.16 mL, 1.98 mmol). The mixture was stirred at 120°C for 3 hr. The resulting mixture was cooled to r.t, then quenched with H20 and extracted with EtOAc(2 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04, concentrated and purified by standard methods to afford the desired product.LC-MS: m/z 180 (M+H)+.
Step 2: Preparation of 3 -phenyl- J , 2, 4-th iadiazole-5-carboxylate A mixture of 5-phenyl-l,3,4- oxathiazol-2-one (270 mg, 1.5 mmol) and ethyl carbonocyanidate (790 mg, 6.0 mmol) in DCE (2 mL) was stirred in a sealed vial under microwave irradiation at 160°C for 0.5 hr. The resulting mixture was concentrated and purified by standard methods to afford the desired product.LC-MS: m/z 235 (M+H)+.
Step 3: Preparation of N2,rf-bis(4,4-difluorocyclohexyl)-6-(3-phenyl-l,2,4-thiadiazol -5-yl)- l,3,5-triazine-2,4-diamine. To a mixture of N1,N5-bis(4,4-difluorocyclohexyl)-biguanide (90 mg, 0.27 mmol) and ethyl 3 -phenyl- l,2,4-thiadiazole-5-carboxylate (75 mg, 0.32 mmol) in MeOH (2 mL) was added NaOMe (43 mg, 0.8 mmol). The reaction mixture was then stirred at r.t. overnight. The resulting mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2S04and concentrated and purified by standard methods to afford the desired product.
Figure imgf000278_0001
Ή NMR (400 MHz, CDC13) δ 8.40 (d, J = 3.3 Hz, 2H), 7.48 (s, 3H), 5.68 - 5.01 (m, 2H), 4.27 - 3.87 (m, 2H), 2.26 - 1.63 (m, 8H). LC-MS: m/z 508.2 (M+H)+.
The procedure set forth in Example 28was used to produce the following compounds using appropriate starting materials.
N2J\4-bis(4,4-difluorocyclohexyl)-6-(3-methyl-l,2,4-thiadiazol-5-yl)-l,3,5-triazine-2,4- diamine
Figure imgf000278_0002
1H NMR (400 MHz, CDC13) δ 5.58 - 5.10 (m, 2H), 4.20 - 3.84 (m, 2H), 2.77 (s, 3H), 2.23 - 1.63 (m, 16H). LC-MS: m/z 446 (M+H)+.
Example 29 The compounds of this Example are prepared by general Scheme 29, set forth below. Scheme 29
Figure imgf000279_0001
Step 1. Preparation of 6-chloro-N2, IS4 -bis((R)-l-cyclopropylethyl)-l, 3, 5-triazine-2, 4- diamine.To a solution of 2,4,6-trichloro-l ,3,5-triazine (2 g, 10.9 mmol) in acetone (35 mL) were added (S)-l-cyclopropylethanamine hydrochloride^.7 mg, 22.8 mmol), DIPEA (3.5 mg, 27 mmol) and CsF (3.3 mg, 21.8 mmol). The mixture was stirred at 50°C overnight, and then filtered. The filtrate was concentrated and purified by standard methods to give the desired product. LC-MS: m/z 282 (M+H)+.
Step B.Preparation of N2,N*-bis((R)-l-cycfapropylethyl)-6-(4-methyl-lH-pyrazol-l-yl)-l,3,5- triazine-2 ,4-diamine. To an ice-cold solution of4-methyl-lH-pyrazole (207 mg, 1.07 mmol)in dry THF (5 mL) was slowly added NaH (34 mg, 1.42 mmol) over 30 min, followed by addition of a solution of 6-chloro-N2,N4-bis((R)-l-cyclo -propylethyl)-l,3,5-triazine-2,4-diamine (200 mg, 0.71 mmol) in THF (3 mL). The reaction mixture was stirred at r.t. overnight, and then concentrated and purified by standard methods to afford N2,N4-bis((R)-l-cyclopropylethyl)-6-(4- methyl-lH-pyrazol-1 -yl)-l ,3,5-triazine-2,4-diamine.
Figure imgf000279_0002
1H NMR (400 MHz, CDC13) δ 8.17 (s, 1H), 7.56 (s, 1H), 5.50 - 5.12 (m, 2H), 3.56 (d, J = 6.0 Hz, 2H), 2.12 (s, 3H), 1.25 (s, 6H), 0.94 - 0.84 (m, 2H), 0.54 - 0.32 (m, 6H), 0.26 (d, J = 4.1 Hz, 2H).LC-MS: m/z 328 (M+H)+.
The procedure set forth in Example 29 was used to produce the following compounds using the appropriate starting materials. CompoundN2,N4-bis((R)- 1 -cyclopropylethyl)-6-(4-iodo- IH-pyrazol- 1-yl)- 1 ,3,5-triazine-2,4- diamine
Figure imgf000280_0001
Ή NMR (400 MHz, CDC13) δ 8.51 (s, 1H), 7.73 (s, 1H), 5.49 - 5.20 (m, 2H), 3.56 (d, J= 6.8 Hz, 2H), 1.26 (d, J = 6.5 Hz, 6H), 0.90 (s, 2H), 0.55 - 0.24 (m, 8H).LC-MS: m/z 440 (M+H)+.
Compound6-(4-Chloro-lH-pyrazol-l-yl)-N2,N4-bis(4,4-difluorocyclohexyl)-l,3,5-triazine- -diamine
Figure imgf000280_0002
Ή NMR (400MHz, CDC13)5 8.43 - 8.38 (m, 1H), 7.68 (d, J=9.2Hz, 1H), 5.41 - 5.18 (m, 2H), 4.10 - 3.98 (m, 2H), 2.14 - 1.91(m, 13H), 1.86 - 1.73(m, 1.2H), 1.68 - 1.61 (m, 1.8H). LCMS: m/z 448 (M+H)+.
CompoundN2,N4-bis((R)-l-cyclopropylethyl)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-l,395- triazine-2,4-diamine
Figure imgf000280_0003
Ή NMR (400 MHz, CDC13) δ 8.53 (d, J= 10.0 Hz, 1H), 6.66 (d, J= 2.5 Hz, 1H), 5.63 - 5.23 (m, 2H), 3.63 - 3.45 (m, 2H), 1.27 (d, J = 6.5 Hz, 6H), 0.91 (d, J = 7.6 Hz, 2H), 0.58 - 0.26 (m, 8H).LC-MS: m/z 382 (M+H)+.
Compound6-(3-(Trifluoromethyl)-lH-pyrazol-l-yl)-N2,N4-bis(l,1 -trifluoropropan-2-yl)- mine
Figure imgf000281_0001
Ή NMR (400 MHz, CDC13)5 8.55 (m, 1H), 6.70 (d, J= 2.7 Hz, 1H), 5.77 - 5.30 (m, 2H), 5.05 - 4.78 (m, 2H), 1.49 - 1.37 (m, 6H).LC-MS: m/z 438.1(M+H)+.
CompoundN2,N4-bis((S)-l,1 -trifluorobutan-2-yl)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)- -triazine-2,4-diamine
Figure imgf000281_0002
1H NMR(400MHz, CDC13)5 8.60 - 8.57 (m, 1H ), 7.80 -5.29 (m, 3H), 4.76 -4.69 (m, 2H),2.03 - 1.95(m, 2H), 1.72 - 1.63 (m, 2H),1.09 - 1.02 (m, 6H). LCMS: m/z 466(M+H)+.
CompoundN2,N4-bis(3,3-difluorocyclopentyl)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-l,395- t riazine-2,4-diamine
Figure imgf000282_0001
Ή NMR (400MHz, CDC13)5 8.57 - 8.50 (m, 1H), 6.68(d,J=4Hz, 1H), 5.74 - 5.44(m, 2H), 4.76 - 4.47 (m, 2H), 2.66 - 2.57 (m, 2H), 2.08 - 2.3 l(m, 8H), 1.81 - 1.86(m, 2H). LCMS: m/z 454(M+H)+.
CompoundN2,N4-bis(4,4-difluorocyclohexyl)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-l,3,5- triazine-2,4-diamine
Figure imgf000282_0002
1H NMR (400 MHz, DMSO-d6) δ 8.86 - 8.50 (m, 1H), 8.13 - 7.76 (m, 2H), 7.00 (d, J = 9.7 Hz, 1H), 4.18 - 3.92 (m, 2H), 2.14 - 1.82 (m, 12H), 1.62 (s, 4H).LC-MS: m/z 482 (M+H)+.
CompoundN2,N4-bis(3,3-difluorocyclobutyl)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-l,3,5- triazine-2,4-diamine
Figure imgf000282_0003
Ή NMR (400MHz, CDC13)5 8.56 - 8.50 (m, 1H), 6.69 (d,J=6Hz, 1H), 5.85 - 5.52 (m, 2H), 4.37 (m, 2H), 3.05 - 3.12 (m, 4H), 2.50 - 2.67 (m, 4H).LCMS: m/z 426(M+H)+. Example 30 The compounds of this Example are prepared by general Scheme 30, set forth below.
COO OMe
Figure imgf000283_0001
Step 1: Preparation ofmethyl l-methyl-lH-pyrazole-3-carboxylate. To a solution of l -methyl- lH-pyrazole-3-carboxylic acid (504 mg, 4 mmol) in MeOH (5 mL) was added SOCl2 (1.4 mL, 20 mmol) at 0°C. The mixture was stirred at r.t overnight then concentrated under reduced pressure. The residue was dissolved in EtOAc, washed withsatd. aq. NaHCC and concentrated to afford methyl l -methyl-lH-pyrazole-3-carboxylate.LC-MS: m/z 141 (M+H)+.
Step 2: Preparation ofN2,N*-bis(4,4-difluorocyclohexyl)-6-(l-methyl-lH-pyrazol-3-yl) -1,3,5- triazine-2,4-diamine. To a solution of N1,N5-bis(4,4-difluorocyclohexyl)-biguanide (120 mg, 0.36 mmol) and methyl l-methyl-lH-pyrazole-3-carboxylate (60 mg, 0.43 mmol) in MeOH (2 mL) was added NaOMe (28 mg, 1.07 mmol). The reaction mixture was stirred at r.t. overnight, then poured into water and extracted with EtOAc. Combined organic layers were dried over anhydrous Na2S04,and concentrated and purified by standard methods to afford N2,N4-bis(4,4- difluorocyclohexyl)-6-(l -methyl-lH-pyrazol-3-yl)-l,3,5-triazine-2,4-diamine.
Figure imgf000283_0002
1H NMR (400 MHz, CDC13) δ 7.40 (d, J = 2.1 Hz, 1H), 6.92 (s, 1H), 5.75 - 4.94 (m, 2H), 4.28 3.85 (m, 5H), 2.26 - 1.54 (m, 16H).LC-MS: m/z 428 (M+H)+. The procedure set forth in Example 30was used to produce the following compounds using the appropriate starting materials.
CompoundN2,N4-bis(4,4-difluorocyclohexyl)-6-(lH-pyrazol-3-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000284_0001
¾ NMR (400 MHz, CDC13) δ 7.57 (s, 1H), 6.89 (s, 1H), 5.55 - 4.84 (m, 2H), 4.15 - 3.80 (m, 2H), 2.05 - 1.56 (m, 16H).LC-MS: m/z 414 (M+H)+.
CompoundN2,N4-bis(3,3-difluorocyclopentyl)-6-(2-methyl-lH-imidazol-4-yl)-l,395-triazine- -diamine
Figure imgf000284_0002
¾ NMR (400 MHz, CDC13) δ 7.71 (s, 1H), 5.65-5.07 (m, 2H), 4.63-4.61 (m, 2H), 2.61-2.49 (m, 3H), 2.29(s, 3H), 2.09-1.92 (m, 9H). LC-MS: m/z 400.1 (M+H)+.
CompoundN2,N4-bis(3,3-difluorocyclobutyl)-6-(2-methyl-lH-imidazol-4-yl)-l,3,5-triazine- 2,4-diamine
Figure imgf000284_0003
1H NMR (400 MHz, CDC13) δ 7.62 (s, 1H), 6.49-6.34 (m, 2H), 4.36-4.33 (m, 2H), 3.04 (s, 3H), 2.69-2.49 (m, 8H). LC-MS: m/z 372 (M+H)+. CompoundN2,N4-bis(4,4-difluorocyclohexyl)-6-(2-methyl-lH-imidazol-4-yl)-l,3,5-triazine- -diamine
Figure imgf000285_0001
1H NMR (400 MHz, CDC13) δ 8.67-7.66 (m, 1H), 6.26-5.84 (m, 1H), 5.1 1-4.81 (m, 1H), 3.49- 3.11 (m, 7H), 2.48 (s, 2H), 2.10-1.66 (m, 12H). LC-MS: m/z 428.3 ( +H)+.
Example 31 The compounds of this Example are prepared by general Scheme 31, set forth below.
Scheme 31
Figure imgf000285_0002
Step 1: Preparation of 4-iodo-3-(trifluoromethyl)-lH-pyrazole. To a solution of 3- (trifluoromethyl)-lH-pyrazole (500 mg, 3.7 mmol) in 50% H2S04 at 0 °C was added S (992 mg, 4.4 mmol). The suspension was stirred at 0°C for 10 min and then at r.t. for 3 hr. The resulting mixture was quenched with water (50 mL), and then stirred overnight. The precipitate was collected by filtration and dried to afford 4-iodo-3-(trifluoromethyl)-lH-pyrazole.LC-MS: m/z 263 (M+H)+.
Step 2: Preparation of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3 - (triflu oroinethyl)-! H- pyrazole. To a mixture of 4-iodo-3-(trifluoro methyl)- lH-pyrazole (100 mg, 0.38 mmol) and (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l ,3,2-dioxaborolane) (397 mg, 0.57 mmol) in DMF (3 mL) were added Ι ,Γ-bis -(diphenylphosphino)ferrocene-palladium(n)dichloride dichloromethane complex (31 mg, 0.04 mmol) and potassium acetate (509 mg, 0.76).The reaction mixture was stirred at 90 °C for 2 hr, then quenched with water and extracted with Et20. The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated to afford 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3 -(trifluoromethyl)-lH-pyrazole.LC-MS: m/z 263 (M+H)+.
Step 3: Preparation of N2,]S4-bis(4,4-difluorocyclohe yl)-6-(3-(trifluoromethyl)-lH^yrazol-4- yl)-l,3,5-triazine-2,4-diamine. To a solution of 6-chloro-N2,N4-bis(4,4-difluorocyclohexyl)- l,3,5-triazine-2,4-diamine (145 mg, 0.38 mmol) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-3-(trifluoromethyl)-lH-pyrazole (100 mg, 0.38 mmol) in DME (3 mL) and H20 (1 mL) were added K2C03 (158 mg, 1.15 mmol) and Pd(PPh3)4 (44 mg, 0.04 mmol) under N2 atmosphere. The mixture was stirred at 90°C for 16 hr, and then filtered. The filtrate was partitioned between EtOAc and H20. The aqueous layer was separated and extracted with EtOAc. The combined organic layerswere washed with brine, dried over anhydrous Na2S04, and concentrated and purified by standard methods to afford N2,N4-bis(4,4-difluorocyclohexyl)-6-(3- (trifluoromethyl)-lH-pyrazol-4-yl)-l ,3,5-triazine-2,4-diamine.
Figure imgf000286_0001
1H NMR (400 MHz, DMSO-d6) δ 8.09 - 7.47 (m, 3H), 7.29 - 7.00 (m, 1H), 4.11 - 3.76 (m, 2H), 2.19 - 1.46 (m, 16H).LC-MS: m/z 482 (M+H)+. The procedure set forth Example 31 was used to produce the following compounds using the appropriate starting materials.
CompoundN2,N4-bis(4,4-difluorocyclohexyl)-N2-methyl-6-(3-(trifluoromethyl)-lH-pyrazol- 4-yl)- 1 ,3,5-triazine-2,4-diamine
Figure imgf000287_0001
Ή NMR (400 MHz, CDC13) δ 7.75 (s, 1H), 6.90 (s, 1H), 5.45 (d, J= 7.1 Hz, 1H), 4.94 - 4.44 (m, 1H), 4.09 - 3.84 (m, 1H), 3.07 (d, J = 11.0 Hz, 3H), 2.35 - 2.02 (m, 6H), 2.03 - 1.66 (m, 10H). LC-MS: m/z 496 (M+H)+.
CompoundN2,N4-bis(4,4-difluorocyclohexyl)-6-(l-methyl-3-(trifluoromethyl)-lH-pyrazol-4- yl)-l,3,5-triazine-2,4-diamine
Figure imgf000287_0002
1H NMR (400 MHz, CDC13) δ 7.57 - 7.37 (m, 1H), 5.18 - 4.88 (m, 2H), 4.01 - 3.79 (m, 5H), 2.21 - 1.46 (m, 16H).LC-MS: m/z 496 (M+H)+.
CompoundN2,N4-bis((R)-l-cyclopropylethyl)-6-(5-(trifluoromethyl)pyridin-3-yl)-l,3,5- triazine-2,4-diamine
Figure imgf000288_0001
1H NMR (400 MHz, DMSO- d6) δ 9.60 (s, 1H), 9.13 (s, 1H), 8.75 (s, 1H), 7.60 (s, 1H), 7.46 (s, 1H), 3.64 - 3.50 (m, 2H), 1.21 (d, J = 4 Hz, 6H), 0.96 (s, 2H), 0.43 - 0.33 (m, 6H), 0.14 (s, 2H).LCMS: m/z 393 (M+H)+.
CompoundN2,N4-bis((R)-l-cyclopropylethyl)-6-(2-(trifluoromethyl)pyridin-4-yl)-l,3,5- triazine-2,4-diamine
Figure imgf000288_0002
Ή NMR (400 MHz, CDC13) δ 9.04 - 8.82 (m, 1H), 8.68 - 8.28 (m, 2H), 3.83 - 3.64 (m, 1H), 3.60 - 3.51 (m, 1H), 1.36 (m, 6H), 0.91 - 0.85 (m, 2H), 0.67 - 0.48 (m, 4H), 0.34 (m, 4H).LCMS: m/z 393 (M+H)+.
CompoundN2,N4-bis((R)-l-cyclopropylethyl)-6-(2,5-difluorophenyl)-l,3,5-triazine-2,4- diamine
Figure imgf000288_0003
Ή NMR (400 MHz, CDC13) δ 7.76 - 7.55 (m, 1H), 7.08 (dd, J = 7.6, 5.8 Hz, 2H), 5.43 - 5.02 (m, 2H), 3.55 (s, 2H), 1.27 (d, J = 5.8 Hz, 6H), 0.90 (d, J = 7.4 Hz, 2H), 0.55 - 0.37 (m, 6H), 0.30 - 0.23 (m, 2H).LC-MS: m/z 360 (M+H)+.
CompoundN2,N4-bis((R)-l-cyclopropylethyl)-6-(3-(trifluoromethoxy)phenyl)-l,3,5-triazine- 2 4-diamine
Figure imgf000289_0001
Ή NMR (400MHz, CDC13): δ 8.25 - 8.18 (m, 2H), 7.46 - 7.42 (m, 1H), 7.32 - 7.26 (m, 1H), 5.28 - 5.13 (m, 2H), 3.68 - 3.55 (m, 2H), 1.29 - 1.25 (m, 6H), 0.95 - 0.88 (m, 2H), 0.56- 0.41 (m, 6H), 0.28(s, 2H). LCMS: m/z 408(M+H)+. -l-cyclopropylethyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000289_0002
Ή NMR (400 MHz, CDC13) δ 8.63 - 8.55 (m, 2H), 7.75 (d, J = 8 Hz, 1H), 7.57 - 7.53 (m, 1H), 5.53 - 5.21 (m, 2H), 3.69 - 3.55 (m, 2H), 1.25 (s, 2H), 0.90 - 8.86 (m, 2H), 0.57 - 0.30 (m, 1H).LCMS: m/z 349(M+H)+ .
Example 32. Preparation of Aromatic-Aliphatic Triazine Compounds of Formula Q. The compounds of this Example are prepared by general Scheme 32, set forth
eme 32
Figure imgf000290_0001
below. Formula Q
Step 1: Preparation of 4-chloro-N-(6-(l,l-difluoroethyl)pyridin-3-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5 riazin-2-amine. To a mixture of 2,4-dichloro-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine (188 mg, 0.64 mmol) and 2-(l ,1 - difluoroethyl)pyridin-4-amine (50 mg, 0.32 mmol) in 1, 4-dioxane (4 mL) were added 'BuONa (61 mg, 0.64 mmol) and Pd(dppf)Cl2 (22 mg, 0.03 mmol) under an atmosphere of nitrogen. The reaction mixture was then stirred at 80°C overnight, and then filtered. The filtrate was concentrated and urified by standard methods to afford the desired product.
Figure imgf000290_0002
LC-MS: m/z 417.1 (M+H) .
Step 2:Preparation of N2-(3,3-difluorocyclopentyl)-T^-(2-(l,l-difluoroethyl)pyridin-4^ (trifluoromethyl)pyridin-2-yl)-l,3,5 riazine-2,4-diamine To a mixture of 4-chloro-N-(6-(l,l- difluoroethyl)pyridin-3-yl)-6-(6-(trifluoromethyl)pyridine-2-yl)-l,3,5-triazin-2-amine (35 mg, 0.08 mmol) and 3,3-difluorocyclopentanamine (16 mg, 0.13 mmol) in THF (2 mL) were added CsF (24 mg, 0.16 mmol) and DIPEA (0.03 mL, 0.16 mmol). The reaction mixture was then stirred at 50°C overnight. The mixture was filtered and the filtrate was concentrated and purified by standard methods to afford the desired product.
Figure imgf000291_0001
1H NMR (400 MHz, CDC13) δ 8.61 (m, 1H), 8.52 (d, J = 5.4 Hz, 1H), 8.43 (s, 1H), 8.08 (d, J = 7.7 Hz, 1H), 8.03 - 7.73 (m, 2H), 7.73 - 7.34 (m, 1H), 6.08 - 5.52 (m, 1H), 4.88 - 4.55 (m, 1H), 2.82 - 2.64 (m, 1H), 2.46 - 2.12 (m, 4H), 2.1 1 - 1.98 (m, 3H), 1.94 - 1.81 (m, 1H). LC-MS: m/z 502 (M+H)+.
The procedure set forth in Example 32 was used to produce the following compounds using the appropriate starting materials.
(S)-N2-(3,3-difluorocyclopentyl)-N4-(2-(l,l-difluoroethyl)pyridin-4-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000291_0002
Ή NMR (400 MHz, CDC13) δ 8.61 (m, 1H), 8.53 (d, J = 5.4 Hz, 1H), 8.46 - 7.94 (m, 2H), 7.91 - 7.32 (m, 3H), 5.77 (m, 1H), 4.70 (m, 1H), 2.79 - 2.60 (m, 1H), 2.50 - 2.11 (m, 4H), 2.04 (m, 3H), 1.87 (m, 1H).LC-MS: m/z 502 (M+H)+.
(R)-N2-(3,3-difluorocyclopentyl)-N4-(2-(l,l-difluoroethyl)pyridin-4-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000292_0001
Ή NMR (400 MHz, CDC13) δ 8.62 (m, 1H), 8.53 (d, J = 5.4 Hz, 1H), 8.47 - 7.94 (m, 2H), 7.93 - 7.33 (m, 3H), 5.90 - 5.60 (m, 1H), 4.96 - 4.46 (m, 1H), 2.80 - 2.61 (m, 1H), 2.50 - 2.10 (m, 4H), 2.04 (m, 3H), 1.87 (m, 1H). LC-MS: m/z 502 (M+H)+.
N2-(4,4-difluorocyclohexyl)-N4-(2-(l,l-difluoroethyl)pyridin-4-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000292_0002
Ή NMR (400 MHz, CDC13) δ 8.69 - 8.43 (m, 3H), 8.07 (t, J= 7.8 Hz, 1H), 8.01 - 7.73 (m, 21 7.49 (m, 1H), 5.61 (m, 1H), 4.19 (m, 1H), 2.24 - 2.13 (m, 4H), 2.12 - 1.93 (m, 5H), 1.76 - 1. (m, 2H).LC-MS: m/z 516 (M+H)+.
N2-(3,3-difluorocyclobutyl)-N4-(2-(l,l-difluoroethyl)pyridin-4-yl)-6-(6- (trifluoromethyl)pyridin-2-yl)-l,395-triazine-2,4-diamine
Figure imgf000292_0003
Ή NMR (400 MHz, CDC13) δ 8.72 - 8.26 (m, 3H), 8.18 - 7.75 (m, 3H), 7.72 - 7.33 (m, 1H), 6.03 (m, 1H), 4.53 (m, 1H), 3.16 (d, J = 8.2 Hz, 2H), 2.59 (m, 2H), 2.05 (m, 3H).LCMS: m/z 488 (M+H)+.
2-((4-((2-(1 -Difluoroethyl)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5- triazin-2-yl)amino)propanenitrile
Figure imgf000293_0001
Ή NMR (400 MHz, DMSO-d6) δ 11.25 -10.25 (m, 1H), 9.16 - 8.47 (m, 3H), 8.41 - 8.19 (m, 2H), 8.15 - 7.80 (m, 2H), 5.40 - 4.80 (m, 1H), 2.00 (t, J= 19.0 Hz, 3H), 1.63 (d, J= 7.2 Hz, 3H). LCMS: m/z 451 (M+H)+.
2-((4-((2-(1 -Difluoroethyl)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5- triazin-2-yl)amino)-2-methylpropanenitrile
Figure imgf000293_0002
Ή NMR (400 MHz, CDC13) δ 8.88 - 8.43 (m, 2H), 8.03 (m, 4H), 7.67 (s, 1H), 5.97 (m, 1H), 2.02 (m, 3H), 1.86 (s, 6H). LCMS: m/z 465 (M+H)+.
3-((4-((2-(1 -Difl oroethyl)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5- triazin-2-yl)amino)-2,2-dimethylpropanenitrile
Figure imgf000294_0001
Ή NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.91 - 8.38 (m, 4H), 8.33 (t, J = 7.9 Hz, 1H), 8.21 - 7.51 (m, 2H), 3.80 - 3.60 (m, 2H), 2.00 (m, 3H), 1.40 (d, J = 3.9 Hz, 6H). LCMS: m/z 479 (M+H)+.
3-((4-((2-(1 -Difl oroethyl)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5- triazin-2-yl)amino)butanenitrile
Figure imgf000294_0002
1H NMR (400 MHz, DMSO-d6) δ: 10.90 - 10.25 (m, 1H), 8.75 - 8.52 (m, 2H), 8.52 - 8.20 (m, 3H), 8.18 - 7.75 (m, 2H), 4.67 - 4.26 (m, 1H), 3.09 - 2.72 (m, 2H), 2.00 (m, 3H), 1.35 (t, J= 5.5 Hz, 3H). LCMS: m/z 465 (M+H)+.
3-((4-((2-(1 -Difl oroethyl)pyridin-4-yl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5- triazin-2-yl)amino)-3-methylbutanenitrile
Figure imgf000294_0003
Ή NMR (400 MHz, DMSO-d6) δ 8.65 - 8.44 (m, 2H), 8.42 - 7.96 (m, 3H), 7.92 - 7.35 (m, 2H), 6.00 - 5.60 (m, 1H), 3.40 - 3.10 (m, 2H), 2.10 - 1.90 (m, 3H), 1.75 - 1.50 (m, 6H). LCMS: m/z 479 (M+H)+.
N2-(3,3-difluorocyclopentyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000295_0001
Ή NMR (400 MHz, CDC13) δ 8.67 - 8.57 (m, 2H), 8.53 (d, J= 1.7 Hz, 1H), 8.19 - 7.38 (m, 4H), 6.03 - 5.53 (m, 1H), 4.85 - 4.55 (m, 1H), 2.81 - 2.58 (m, 1H), 2.51 - 2.07 (m, 4H), 1.98 - 1.81 (m, 1H), 1.32 - 1.16 (m, 1H).LC-MS: m/z 506 (M+H)+.
(R)-N2-(3,3-difluorocyclopentyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000295_0002
Ή NMR (400 MHz, CDCl3)58.65-8.52 (m, 3H), 8.10-8.06 (m, 2H),7.86-7.85 (m, 1H), 7.48-7.42 (m, lH),6.00-5.86 (m, 1H), 4.81 -4.60 (m , 1H), 2.77-2.62 (m, 1H), 2.41-2.32 (m, 2H), 2.12-2.19 (m, 2H), 1.93-1.86 (m, 1H). LCMS: m z 506 (M+H)+.
(S)-N2-(3,3-difluorocyclopentyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000296_0001
Ή NMR (400 MHz, CDC13) δ 8.67 - 8.56 (m, 2H), 8.53 (d, J= 1.8 Hz, 1H), 8.20 - 7.82 (m, 3H), 7.77 - 7.40 (m, 1H), 6.09 - 5.51 (m, 1H), 4.92 - 4.46 (m, 1H), 2.80 - 2.59 (m, 1H), 2.46 - 2.29 (m, 2H), 2.29 - 2.08 (m, 2H), 1.97 - 1.85 (m, 1H).LC-MS: m/z 506 (M+H)+.
N2-(4,4-difluorocyclohexyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000296_0002
1H NMR (400 MHz, CDC13) 58.57-8.62 (m, 3H), 7.85-8.17 (m, 3H), 7.37-7.72 (m, 1H), 5.45- 5.82 (m, 1H), 4.10-4.26 (m, 1H), 2.17-2.19 (d, J=9.2Hz, 4H), 1.88-2.04 (m, 2H), 1.66-1.81 (m, 2H); LC-MS : m/z 520 (M+H)+.
N2-(3,3-difluorocyclobutyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000296_0003
1H NMR (400 MHz, CDC13) δ 8.65 - 8.55 (m, 2H), 8.51 - 8.32 (m, 1H) 8.11 - 8.04 (m, 1H), 7.86 - 7.83 (m, 1H), 7.68 - 7.47 (m, 1H), 6.33 - 6.06 (m, 1H), 4.58 - 4.42 (m, 1H), 3.17- 3.10 (m, 2H), 2.75 - 2.53 (m, 2H), 2.29 (s, 1H). LCMS: m/z 492(M+H)+.
N2-(6,6-difluorospiro[3.3]heptan-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000297_0001
1H NMR (400 MHz, CDC13) 58.55-8.70 (m, 3H), 7.84-8.20 (m, 3H), 7.31-7.66 (m, 1H), 5.68- 6.00 (m, 1H), 4.49-4.55 (m, 1H), 2.57-2.76 (m, 6H), 1.83-2.27 (m, 2H). LC-MS : m/z 532 (M+H)+.
6-(6-(Trifluoromethyl)pyridin-2-yl)-N2-(2-(trifluoromethyl)pyridin-4-yl)-N4-(l,l,l- trifluoropropan-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000297_0002
Ή NMR (400 MHz, CDC13) δ 8.62 - 8.59 (m, 1H), 8.44 (s, 1H), 8.16- 8.07 (m, 1H), 7.87 (d, J = 8 Hz, 1H), 7.75 - 7.50 (m, 1H), 1.53 - 1.49 (m, 3H) .LCMS: m/z 498(M+H)+.
N2-(2,2,2-trifluoroethyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(2-(trifluoromethyl)pyridin- 4-yl)- 1 ,3,5-triazine-2,4-diamine
Figure imgf000298_0001
Ή NMR (400MHz, DMSO-d6)5 10.91(s, 1H), 8.75 - 8.71 (m, 2H), 8.61 - 8.57 (m, 2H), 8.36 - 8.33 (m, 1H), 8.21 - 7.83 (m, 2H), 4.41 - 4.24 (m, 2H).LCMS: m/z 484(M+H)+.
N2-((3,3-difluorocyclobutyl)methyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000298_0002
1H NMR (400 MHz, CDC13) δ 8.70 - 8.41 (m, 3H), 7.96 (m, 4H), 7.52 (m, 1H), 5.95 - 1H), 3.67 (m, 2H), 2.77 - 2.13 (m, 5H).LCMS: m/z 506 (M+H)+.
N2-((2,2-difluorocyclopropyl)methyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000298_0003
1H NMR (400 MHz, DMSO-d6) δ 10.76 - 10.69 (m, 1H), 8.74 - 8.66 (m, 2H), 8.58 - 8.55 (m, 2H), 8.34 - 8.30 (m, 1H), 8.11 (d, J = 8 Hz, lH), 7.96 - 7.86 (m, 1H), 3.61 - 3.43 (m, 2H), 2.17 - 2.09 (m, 1H), 1.67 - 1.32 (m, 2H). LCMS: m/z 492(M+H)+. N2-(3,3-difluorocyclopentyl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(5- (trifluoromethyl)pyridin-3-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000299_0001
Ή NMR (400 MHz, CDC13) δ 8.86 (t, J= 6.0 Hz, 1H), 8.83 - 8.73 (m, 1H), 8.64 - 8.55 (m, 2H), 8.09 - 8.03 (m, 1H), 7.89 - 7.83 (m, 1H), 6.00 - 5.88 (m, 1H), 4.80 - 4.55 (m, 1H), 2.74 - 2.57 (m, 1H), 2.47 - 2.05 (m, 4H), 1.94 - 1.82 (m, 1H). LC-MS:m/z 506 (M+H)+.
1- (4-((4-((3 -Difl orocyclopentyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,395-triazin-
2- yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000299_0002
Ή NMR (600 MHz, CDC13) δ 8.67 (s, 2H), 8.29 (t, J = 5.9 Hz, 1H), 8.07 (t, J = 7.6 Hz, 1H), 7.91 - 7.79 (m, 2H), 7.05 (s, 1H), 5.97 (d, J = 7.9 Hz, 1H), 5.06 - 4.61 (m, 1H), 2.81 - 2.66 (m, 1H), 2.43 - 1.36 (m, 1H), 2.34 - 2.18 (m, 2H), 2.14 - 2.04 (m, 1H), 1.87 - 1.77 (m, 3H), 1.72 (m, 2H). LC-MS: m/z 503 (M+H)+
(R)-l-(4-((4-((3,3-difluorocyclopentyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000300_0001
1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.77 - 8.59 (m, 2H), 8.49 (s, 1H), 8.36 - 8.20 (m, 2H), 8.11 (d,J=7.8Hz, 1H), 7.55 (d,J=4.6Hz, 1H), 4.86-4.47 (m, 1H), 2.75 - 2.57 (m, 1H), 2.29-2.06 (m, 4H), 1.97- 1.82 (m, 1H), 1.80- 1.74 (m, 2H), 1.71 - 1.63 (m, 2H). LC-MS: m/z 503 (M+H)+.
(S)-l-(4-((4-((3,3-difluorocyclopentyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,395- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000300_0002
Ή NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.79 - 8.60 (m, 2H), 8.49 (s, 1H), 8.38 - 8.19 (m, 2H), 8.11 (d,J=7.7Hz, 1H), 7.55 (d, J =4.4 Hz, 1H), 4.80-4.54 (m, 1H), 2.75 - 2.55 (m, 1H), 2.37- 2.06 (m, 4H), 1.96 - 1.82 (m, 1H), 1.76- 1.67 (m, 4H).LC-MS:m/z 503(M+H)+. l-(4-((4-((4,4-Difluorocyclohexyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazin-2- yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000300_0003
¾ NM (400 MHz, CDC13) δ 8.83 - 8.65 (m, lH), 8.58 (m, 1H), 8.32 (d, J = 5.4 Hz, 1H), 8.10 (t, J = 7.8 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.62 (m, 1H), 7.09 (s, 1H), 5.65 (m,lH), 4.29 (s, 1H), 2.12 (m, 6H), 1.89-1.91 (m, 2H), 1.82 - 1.63 (m, 4H). LC-MS: m/z 517 (M+H)+. l-(4-((4-((3 -Difl orocyclobutyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazin-2- yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000301_0001
1H NMR (400 MHz, DMSO-d6) δ 10.48 (brs, 1H), 8.89 (d, J= 6.5 Hz, 1H), 8.78 - 8.56 (m, 1 8.42 (s, 1H), 8.37 - 8.24 (m, 2H), 8.10 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 4.1 Hz, 1H), 4.45 (s, 1 3.13 - 2.97 (m, 2H), 2.71 - 2.56(m, 2H), 1.83 - 1.59 (m, 4H).LC-MS: m/z 489 (M+H)+. l-(4-((4-((6,6-Difluorospiro[3.3]heptan-2-yl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)- -triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000301_0002
H NMR (400 MHz, CDC13) δ 8.70 - 8.53 (m, 2H), 8.31 - 8.28 (m, 1H), 8.10 - 8.06 (m, 1H), 7.85 - 7.83 (d, J= 8 Hz, 1H), 7.66 - 7.52 (m, 1H), 7.20 - 7.07 (m, 1H), 5.94 - 5.66 (m, 1H), 4.67 - 4.63 (m, 1H), 2.75 - 2.55 (m, 6H), 2.25 - 2.10 (m, 2H), 1.89 - 1.83 (m, 2H), 1.74 - 1.71 (m, 2H) LCMS: m/z 529 (M+H). + l-(4-((4-(((2,2-Difluorocyclopropyl)methyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)- l,395-triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000302_0001
1H NMR (400 MHz, CDC13) δ 8.72 (m, 2H), 8.31 (d, J= 5.5 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.58 (m, 1H), 7.05 (m, 1H), 5.92 (m, 1H), 4.00 (s, 1H), 3.61 (m, 1H), 2.08 (m, 1H), 1.83 (m, 2H), 1.72 (m, 2H), 1.52 (m, 2H). LC-MS: m/z489 (M+H)+. l-(4-((4-((2,2,2-Trifluoroethyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazin-2- yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000302_0002
1H NMR (400 MHz, CDC13) δ 8.93-8.42 (m, 2H), 8.34-8.29 (m, 1H), 8.10 (t, J = 7.8 Hz, 1H), 8.03-7.58 (m, 2H), 7.13 (d, J = 4.2 Hz, lH), 6.34-6.03 (m, 1H), 4.36-4.29 (m, 2H), 1.74(s, 4H). LC-MS: m/z 481.2 (M+H)+. l-(4-((4-((2-Hydroxy-2-methylpropyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000302_0003
Ή NMR (400 MHz, CDC13) δ 8.77 - 8.44 (m, 2H), 8.29 (d, J= 5.5 Hz, 1H), 8.07 (t, J= 7.7 Hz, 1H), 7.77 (m, 2H), 6.96 (s, 1H), 6.14 (m, 1H), 3.79 - 3.55 (m, 2H), 1.91 - 1.84 (m, 2H), 1.73 - 1.69 (m, 2H), 1.35 (s, 6H). LC-MS: m/z471 (M+H)+.
(R)-l-(4-((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((l,1 -trifluoropropan-2-yl)amino)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000303_0001
Ή NMR (400 MHz, CDC13) δ 8.73 (m, 2H), 8.36 (m, 1H), 8.11 (d, J = 7.3 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.07 (m, 1H), 5.82 (m, 1H), 5.09 (s, 1H), 4.81 (m, 4H), 1.50 (m, J = 8.5 Hz, 3H). LC-MS: m/z495 (M+H)+.
(S)-l-(4-((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((l,1 -trifluoropropan-2-yl)amino)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000303_0002
1H NMR (400 MHz, CDC13) δ 8.77 (d, J = 9.2 Hz, 2H), 8.66 (m, J = 8 Hz, 1H), 8.57 (s, 1H), 8.10 (m, 1H),7.52 (m, 1H), 7..10 (d, J = 4 Hz, 1H), 5.86 (m, 1H), 5.05 (m, 1H), 1.8 (m, 4H), 1.62 (m, 3H). LC-MS: m/z495 (M+H)+.
4-((4-(Tert-butylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazin-2- yl)amino)picolinonitrile
Figure imgf000304_0001
Ή NMR (400 MHz, DMSO-d6) δ 8.66 - 8.41 (m, 3H), 8.12 - 8.00 (m, 1H), 7.91 - 7.80 (m, 1H), 7.65 - 7.55 (m, 1H), 5.80 - 5.20 (m, 1H), 1.58 (m, 9H). LCMS: m/z 415 (M+H)+.
4-((4-((3,3-Difluorocyclobutyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,395-triazin-2- yl)amino)picolinonitrile
Figure imgf000304_0002
Ή NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.97 - 8.52 (m, 4H), 8.38 - 8.25 (m, 1H), 8.13 (d, J = 7.8 Hz, 1H), 8.01 - 7.80 (m, 1H), 4.56 - 4.24 (m, 1H), 3.17 - 2.95 (m, 2H), 2.80 - 2.60 (m, 2H). LCMS: m/z 449 (M+H)+.
4-((4-((3,3-Difluorocyclopentyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazin-2- yl)amino)picolinonitrile
Figure imgf000304_0003
Ή NMR (400 MHz, CDC13) δ 8.07-8.66 (m, 4H), 7.86 (d, J = 8.0 Hz, 2H), 7.53-7.68 (m, 5.85-6.03 (m, 1H), 4.58-4.79 (m, 1H), 2.66-2.75 (m, 1H), 1.95-2.47 (m, 1H), 1.88-1.93(m, LC-MS: m/z 463 (M+H)+. 4-((4-((4,4-Difluorocyclohexyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,395-triazin-2- yl)amino)picolinonitrile
Figure imgf000305_0001
Ή NMR (400 MHz, DMSO-d6) δ 10.72-10.76 (m, 1H), 7.93-8.72 (m, 5H), 4.03-4.23 (m, 1H), 1.94-2.16 (m, 6H), 1.64-1.73 (m, 2H). LC-MS: m/z 477 (M+H)+.
4-((4-((2-Hydroxy-2-methylpropyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazin- -yl)amino)picolinonitrile
Figure imgf000305_0002
Ή NMR (400 MHz, CDC13) δ 8.57 - 8.50 (m, 2H), 8.43 - 8.36 (m, 1H), 8.22 - 8.02 (m, 2H), 7.85 (m,lH), 7.60 (s, 1H), 6.32 - 6.23 (m, 1H), 3.74 - 3.58 (m, 2H), 1.37 (s, 6H). LCMS: m/z 431 (M+H)+.
3-((4-((3,3-Difluorocyclopentyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazin-2- yl)amino)-5-fluorobenzonitrile
Figure imgf000305_0003
Ή NMR (400MHz, CDC13)5 8.64 - 8.55 (m, 1H), 8.16 - 7.74 (m, 5H), 7.08 - 7.02 (m, 1H),5.97 - 5.71 (m, 1H), 4.79 - 4.55 (m, 1H), 2.69 - 2.64 (m, 1H), 2.41 - 2.14 (m, 4H), 2.01(s, 1H). LCMS: m/z 480(M+H)+.
3-((4-((4,4-Difluorocyclohexyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,395-triazin-2- yl)amino)-5-fluorobenzonitrile
Figure imgf000306_0001
Ή NMR (400MHz, CDC13): δ 8.60 - 8.54 (m, 1H), 8.08 - 8.07 (m, 1H), 7.85 - 7.81 (m, 4H), 7.08 - 7.03 (m, 1H), 5.76 - 5.48 (m, 1H), 4.22 - 4.04 (m, 1H), 2.21 - 2.18 (m, 4H), 2.02 - 1.92(m, 2H), 1.78 - 1.71 (m, 2H). LCMS: m/z 494(M+H)+.
3-((4-((3,3-Difluorocyclobutyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,395-triazin-2- yl)amino)-5-fluorobenzonitrile
Figure imgf000306_0002
1H NMR (400MHz, DMSO-d6)5 10.50(s, 1H), 8.81 - 8.67 (m, 1H), 8.55 (d, J=8Hz, 1H), 8.24 - 8.09 (m, 3H), 7.46 - 7.42 (m, 1H), 4.45 - 4.28(m, 2H), 3.05 - 3.01 (m, 2H), 2.77 (d, J=8Hz, 2H).LCMS: m/z 466(M+H)+.
3-((4-((Cyclopropylmethyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazin-2- yl)amino)-5-fluorobenzonitrile
Figure imgf000307_0001
Ή NMR (400MHz, CDC13)5 8.59 - 8.49(m, 1H), 8.01 - 7.97 (m, 1H), 7.83 - 7.74 (m, 3H), 7.56(s, 1H), 6.99 - 6.96 (m, 1H), 5.83 - 5.62 (m, 1H), 3.43 -3.30 (m, 2H), 1.07(d, J=4Hz, 1H), 0.57 - 0.52 (m, 2H), 0.29 - 0.24 (m, 2H).LCMS: m/z 430(M+H)+.
3-Fluoro-5-((4-((2-hydroxy-2-methylpropyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)- -triazin-2-yl)amino)benzonitrile
Figure imgf000307_0002
1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.61 (m, 1H), 8.24 (m, 5H), 7.43 (t, J
1H), 4.61 (m, 1H), 3.45 (m, 2H), 1.18 (d, J = 4.4 Hz, 6H). LCMS: m/z 448 (M+H)+. l-((4-((3-Chlorophenyl)amino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,395-triazin-2- yl)amino)-2-methylpropan-2-ol
Figure imgf000307_0003
1H NMR (400 MHz, DMSO-d6) δ 10.11 (m 1H), 8.67 - 8.52 (m, 1H), 8.40 - 8.20 (m, 2H), 8.09 (d, J = 7.8 Hz, 1H), 7.90 (s, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.40 - 7.22 (m, 1H), 7.05 (t, J = 7.2 Hz, 1H), 4.75 - 4.40 (m, 1H), 3.44 (m 2H), 1.17 (d, J = 6.4 Hz, 6H). LCMS: m/z 439 (M+H)+. 3-((4-(Tert-butylamino)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5-triazin-2- yl)amino)benzonitrile
Figure imgf000308_0001
Ή NMR (400 MHz, DMSO-d6) δ 10.80 - 10.20 (m, 1H), 9.50 - 9.25 (m, 1H), 8.36 - 7.96 (m, 4H), 7.50 - 7.40 (m, 1H), 1.47 (s, 9H). LCMS: m/z 414 (M+H)+.
N2-(3,3-difluorocyclopentyl)-N4-(3,5-difluorophenyl)-6-(6-(trifluoromethyl)pyridin-2-yl)- -triazine-2,4-diamine
Figure imgf000308_0002
Ή NMR (400 MHz, CDC13) δ 8.59 (m, 1H), 8.06 (t, J = 7.8 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.41 (m, 3H), 6.56 (t, J = 8.8 Hz, 1H), 5.74 (m, 1H), 4.83 - 4.53 (m, 1H), 2.79 - 2.60 (m, 1H), 2.46 - 2.06 (m, 4H), 1.95 - 1.81 (m, 1H).LC-MS: m/z 473 (M+H)+.
N2-(4,4-difluorocyclohexyl)-N4-(3,5-difluorophenyl)-6-(6-(trifluoromethyl)pyridin-2-yl)- -triazine-2,4-diamine
Figure imgf000308_0003
Ή NMR (400 MHz, CDC13) δ 8.50 (d, J= 10.5 Hz, lH), 7.98 (t, J= 7.7 Hz, 1H), 7.76 (d, J= 7.7 Hz, 1H), 7.25 (d, J = 7.6 Hz, 2H), 6.48 (t, J = 8.9 Hz, 1H), 5.67-5.34 (m, 1H), 4.14-3.96 (m, 1H), 2.13-2.11 (m, 4H), 2.00-1.74 (m, 5H). LC-MS: m/z 487.2 (M+H)+.
N2-(4,4-difluorocyclohexyl)-N4-(2-phenylpyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)- -triazine-2,4-diamine
Figure imgf000309_0001
Ή NMR (400 MHz, CDCl3)58.59-8.58 (m, 2H), 8.30 (s,lH), 8.08-7.81 (m, 5H), 7.50-7.42 (m,4H), 5.87-5.85 (m, 1H), 4.22-4.10 (m, 1H), 2.15-1.68 (m, 8H). LC-MS: m/z 528 (M+H)+.
N2-(3,3-difluorocyclopentyl)-N4-(2-phenylpyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)- -triazine-2,4-diamine
Figure imgf000309_0002
Ή NMR (400 MHz, CDC13) δ 8.61 (m, 2H), 8.31 - 7.69 (m, 6H), 7.69 - 7.40 (m, 4H), 5.87 (m, 1H), 4.72 (m, 1H), 2.69 (m, 1H), 2.34 (m, 2H), 2.14 (m, 2H), 1.86 - 1.80 (m, 1H).LC-MS: m/z 514 (M+H)+.
N2-(2-phenylpyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(l,1 -trifluoropropan-2- yl)-l,3,5-triazine-2,4-diamine
Figure imgf000310_0001
Ή NMR (400 MHz, CDC13) δ 8.63 (m, 2H), 8.04 (m, 6H), 7.62 - 7.30 (m, 5H), 5.81 (d, J Hz, 1H), 5.39 (m, 1H), 5.00 (m, 1H), 1.50 (d, J = 7.0 Hz, 3H).LC-MS: m/z 506 (M+H)+.
(R)-N2-(2-phenylpyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(l,l,l- trifluoropropan-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000310_0002
1H NMR (400 MHz, CDC13) δ 8.67 - 8.58 (m, 2H), 8.14 (m, 2H), 8.01 (d, J = 7.0 Hz, 2H), 7.88 (d, J = 7.6 Hz, 1H), 7.71 - 7.34 (m, 5H), 5.69 (m, 1H), 5.22 - 4.92 (m, 1H), 1.49 (d, J = 7.1 Hz, 3H).LC-MS: m/z 506 (M+H)+.
(R)-4-(4-((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((l,l,l-trifluoropropan-2-yl)amino)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)benzonitrile
Figure imgf000310_0003
Ή NMR (400 MHz, CDC13) δ 8.87-8.53 (m, 2H), 8.42 (s, 1H), 8.11 (d, J = 8.0 Hz, 3H), 7.96- 7.76 (m, 4H), 7.40 (s, 1H), 5.86-5.67 (m, 1H), 5.18-4.91(m, 1H), 1.62-1.47 (m, 3H). LC-MS: m/z 531 (M+H)+.
(R)-N2-(2-(4-fluorophenyl)pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(l,l,l- trifluoropropan-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000311_0001
Ή NMR (400 MHz, CDC13) δ 8.61 (d, J = 8.0 Hz, 2H), 8.27 (s, 1H), 8.13-7.64 (m, 5H), 7.36 (s, 1H), 7.17 (t, J = 8.6 Hz, 2H), 6.83-6.64 (m, 1H), 6.16-4.96 (m, 1H), 1.50 (d, J = 7.5 Hz, 3H). LC-MS: m/z 524.1 (M+H)+.
(R)-N2-(2-(4-chlorophenyl)pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N4-(l,l,l- trifluoropropan-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000311_0002
Ή NMR (400 MHz, CDC13) δ 8.61 (t, J = 6.4 Hz, 2H), 8.31 - 8.05 (m, 2H), 7.95 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 6.10 - 5.91 (m, 1H), 5.22 - 4.91 (m, 1H),1.51 (t, J = 7.7 Hz, 3H). LC-MS: m/z 540 (M+H)+.
N2-(3,3-difluorocyclopentyl)-N4-(lH-indol-2-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-l,3,5- triazine-2,4-diamine
Figure imgf000312_0001
Ή NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.82 - 8.55 (m, 1H), 8.16 (m, 4H), 7.68 (m, 2H), 7.02 (m, 3H), 4.98 (m, 1H), 2.68 (s, 1H), 2.23 (m, 4H), 1.97 (m, 1H). LC-MS: m/z 476 (M+H)+.
N2-(3,3-difluorocyclopentyl)-N4-(l-methyl-lH-indol-2-yl)-6-(6-(trifluoromethyl)pyridin-2- -l,3,5-triazine-2,4-diamine
Figure imgf000312_0002
Ή NMR (400 MHz, CDC13) δ 8.54 (s, 1H), 8.35 (d, J = 6.8 Hz, 1H), 8.10 (s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.17 (m, 4H), 5.57 (m, 1H), 4.83 (m, 1H), 3.59 (s, 3H), 2.94 - 2.06 (m, 7H). LCMS: m/z 490 (M+H)+.
1- (4-((4-((4,4-difluorocyclohexyl)amino)-6-(6-(l,l-difluoroethyl)pyridin-2-yl)-l,395-triazin- - yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000312_0003
Ή NMR (400 MHz, CDC13) δ 8.54 (m, 2H), 8.32 (d, J = 5.5 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.59 (m, 1H), 7.20 (s, lH), 5.71 (d, J = 7.9 Hz, 1H), 4.34 (m, 1H), 2.15 (m, 9H), 1.85 (m, 2H), 1.23 (m, 1H). LC-MS: m/z513 (M+H)+. 1- (4-((4-((3 -Difluorocyclopentyl)amino)-6-(6-(l,l-difluoroethyl)pyridin-2-yl)-l,395-triazin- - yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000313_0001
Ή NMR (400MHz, CDC13)5 8.61 (s, 1H), 8.53(s, 1H), 8.30(d, J=4Hz, 1H), 8.02 - 7.98 (m, 1H) , 7.82 (d, J=8Hz, 1H), 7.52 - 7.10 (m, 2H), 5.93 - 5.60 (m, 1H), 4.87 - 4.75 (m, 1H), 2.74 - 2.71 (m, 1H), 2.44(m, 1H), 2.18 - 2.04 (m, 5H),1.89 - 1.85 (m, 3H), 1.72(m, 3H).LCMS: m/z 499(M+H)+.
1- (4-((4-((3 -Difluorocyclobutyl)amino)-6-(6-(l,l-difluoroethyl)pyridin-2-yl)-l,3,5-triazin- - yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000313_0002
Ή NMR (400 MHz, CDC13) 510.43 (m, 1H), 8.78 (d, J = 4.1 Hz, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.32 (d, J = 5.6 Hz, 2H), 8.12 (m, 1H), 7.9 (m, 1H), 7.88 (m, 1H), 4.45 (s, 1H), 3.03 (m, 2H), 2.78 (m, 2H), 2.13 (m, 3H), 1.43 (m, 4H). LC-MS: m/z485 (M+H)+.
(R)-l-(4-((4-(6-(l,l-difluoroethyl)pyridin-2-yl)-6-((l,l,l-trifluoropropan-2-yl)amino)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000314_0001
Ή NMR (400 MHz, CDC13) δ 8.59 - 8.52 (m, 1H), 8.46 - 8.45 (d, J = 4 Hz, 1H), 8.32 - 8.25 (m, 1H), 8.02 - 7.98 (m, 1H), 7.82 (d, J = 8 Hz, lH), 7.69 - 7.50 (m, 1H), 7.21 - 7.00 (m, 1H), 5.83 - 5.56 (m, 1H), 5.18 - 5.07 (m, 1H), 2.18 - 2.07 (m, 3H), 1.87 - 1.85 (m, 2H), 1.73 - 1.71 (m, 2H), 1.50 - 1.46 (m, 3H) .LCMS: m/z 491 (M+H)+.
(S)-l-(4-((4-(6-(l,l-difluoroethyl)pyridin-2-yl)-6-((l,l,l-trifluoropropan-2-yl)amino)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000314_0002
1H NMR (400 MHz, CDC13) δ 8.59 - 8.52 (m, 1H), 8.46 (s, 1H), 8.33 - 8.32 (d, J = 4 Hz, 1H) 8.03 - 7.99 (m, 1H), 7.92 - 7.84 (m, 1H), 7.52 (s, 1H), 7.26 - 7.22 (d, J = 16 Hz, 1H), 5.85 - 5.59 (m, 1H), 5.18 - 5.09 (m, 1H), 2.18 - 2.09 (m, 3H), 1.88 - 1.85 (m, 4H), 1.51 - 1.48 (m, 3H). LCMS: m/z 491 (M+H)+.
1- ((4-((3-Chloro-5-fluorophenyl)amino)-6-(6-(l,l-difluoroethyl)pyridin-2-yl)-l,395-triazin- - yl)amino)-2-methylpropan-2-ol
Figure imgf000314_0003
Ή NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.43 (m, 1H), 8.17 (m, 1H), 7.88 (m, 3H), 7.00 (d, J = 7.9 Hz, 1H), 4.54 (s, 1H), 3.45 (m, 2H), 2.10 (m, 3H), 1.17 (m, J = 7.0 Hz, 6H). LC-MS: m/z453 (M+H)+.
3-((4-(6-(l,l-Difluoroethyl)pyridin-2-yl)-6-((2-hydroxy-2-methylpropyl)amino)-l,3,5- triazin-2-yl)amino)-5-fluorobenzonitrile
Figure imgf000315_0001
1H NMR (400 MHz, CDC13) 58.40-8.42 (d, J = 8 Hz, 1H), 7.74-7.99 (m, 5H), 7.03 (m, 1H), 6.16-6.25 (m, 1H), 3.49-3.64 (m, 2H), 2.05-2.21 (m, 3H), 1.33 (s, 6H); LC-MS : m/z 444 (M+H)+. l-((4-(6-(l,l-Difl oroethyl)pyridin-2-yl)-6-((3-fluoro-5-(trifluoromethyl)phenyl)amino)- -triazin-2-yl)amino)-2-methylpropan-2-ol
Figure imgf000315_0002
1H NMR (400 MHz, CDC13) δ 8.42 (bs, 1H), 7.57-7.96 (m, 5H), 6.99-7.03 (m, 1H), 6.16-6.28 (m, 1H), 3.54-3.62(m, 2H), 2.00-2.21 (m, 3H), 2.07-2.22 (m, 3H), 1.28(s, 6H). LC-MS: m/z 487 (M+H)+. l-(4-((4-(6-Chloropyridin-2-yl)-6-((3,3-difluorocyclopentyl)amino)-l,3,5-triazin-2- yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000316_0001
1H NMR (400 MHz, CDC13) δ 8.68 (s, 1H), 8.53 - 8.43 (m, 1H), 8.30 (d, J = 4 Ηζ,ΙΗ), 7.86 - 7.72 (m, 1H), 7.59 - 7.49 (m, 2H), 7.27- 6.99 (m, 1H), 5.96 - 5.71 (m, 1H), 4.96 - 4.88 (m, 1H), 2.76 - 2.70 (m, 1H), 2.43 - 2.07 (m, 4H), 1.89 - 1.79 (m, 3H), 1.75 - 1.72 (m, 2H).LCMS: m/z 469(M+H)+ .
(R)-l-(4-((4-(6-chloropyridin-2-yl)-6-((l-cyclopropylethyl)amino)-l,3,5-triazin-2- yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000316_0002
1H NMR (400 MHz, CDC13) δ 8.43 (s, 2H), 8.23 (d, J = 8 Hz, lH), 7.80 - 7.76 (m, 1H), 7.43 (d, J= 8 Hz, 2H), 7.05 - 7.03 (m, 1H), 5.79 - 5.50 (m, 1H), 3.70 - 3.67 (m, 1H), 1.80 - 1.77 (m, 2H), 1.66 - 1.59 (m, 2H), 1.29 - 1.18 (m, 4H), 0.93 - 0.78 (m, 1H), 0.48 - 0.33 (m, 4H).LCMS: m/z 433(M+H)+. l-(4-((4-(6-Chloropyridin-2-yl)-6-((2,2,2-trifluoroethyl)amino)-l,3,5-triazin-2- yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000316_0003
Ή NMR (400 MHz, CDC13) δ 8.54 - 8.42 (m, 2H), 8.33 - 8.29 (m, 1H), 7.88 - 7.50 (m, 3H), 7.14 - 7.08 (m, 1H), 6.19 - 5.99 (m, 1H), 4.31 (s, 2H), 1.88 - 1.71 (m, 4H) .LCMS: m/z 447 (M+H)+. l-(4-((4-(6-Chloropyridin-2-yl)-6-((l,1 -trifluoropropan-2-yl)amino)-l,395-triazin-2- yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000317_0001
1H NMR (400 MHz, CDC13) δ 8.56 - 8.43 (m, 2H), 8.32 (d, J = 4 Hz, 1H), 7.88 - 7.84 (m, 1H), 7.73 - 7.50 (m, 2H), 7.07 - 7.00 (m, 1H), 5.85 - 5.57 (m, 1H), 5.30 - 5.07 (m, 1H), 1.90 - 1.73 (m, 4H), 1.50 - 1.46 (m, 3H). LCMS: m/z 461 (M+H)+.
6-(6-Chloropyridin-2-yl)-N2-(3,3-difluorocyclopentyl)-N4-(2-(trifluoromethyl)pyridin-4-yl)- -triazine-2,4-diamine
Figure imgf000317_0002
Ή NMR (400 MHz, CDC13) δ 8.61 - 8.53 (m, 2H), 8.41 - 8.33 (m, 1H), 8.13 - 7.78 (m, 2H), 7.68 - 7.27 (m, 2H), 5.95 - 5.61 (m, 1H), 4.79 - 4.60 (m, 1H), 2.74 - 2.65 (m, 1H), 2.44 - 2.29 (m, 2H), 2.25 - 2.09 (m, 2H), 1.92 - 1.83 (m, 1H).LCMS: m/z 472 (M+H)+.
6-(6-Chloropyridin-2-yl)-N2-(cyclopropylmethyl)-N4-(2-(trifluoromethyl)pyridin-4-yl)- -triazine-2,4-diamine
Figure imgf000317_0003
Ή NMR (400MHz, CDC13)5 8.60 - 8.57 (m, 1H), 8.52 - 8.42(m, 1H), 8.36 - 8.19 (m, 1H), 7.86 - 7.68 (m, 2H), 7.51 (d, J=8Hz, 2H), 5.96 - 5.65 (m, 1H), 3.51 - 3.39 (m, 2H), 1.16 (d, J=8Hz, 1H), 0.63 - 0.60 (m, 2H) , 0.35 - 0.30 (m, 2H). LCMS: m/z 422(M+H)+. l-(4-((4-((3,3-Difl orocyclobutyl)amino)-6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazin-2- yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000318_0001
Ή NMR (400 MHZz, CDC13) δ 9.84 (s, 1H), 9.12 (s, 1H), 8.49 - 8.31 (m, 2H), 7.78 - 7.68 (m, 1H), 7.15 (s, 1H), 6.16 - 5.98 (m, 1H), 4.73 - 4.58 (m, 1H), 3.22 (d, J= 8 Hz, 2H), 2.62 - 2.54 (m, 2H), 1.89 - 1.79 (m, 4H). LCMS: m/z 490 (M+H)+. l-(4-((4-((4,4-Difluorocyclohexyl)amino)-6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5-triazin-2- yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000318_0002
Ή NMR (400MHz, CDC13)5 9.84 (d, J=4Hz, 1H), 9.12(s, 1H), 8.49(s, 1H), 8.34 - 8.31 (m, 1H), 7.72 - 7.63 (m, 1H), 7.27 - 7.13 (m, lH), 5.79 - 5.58 (m, 1H), 4.36 - 4.26(m, 1H), 2.20 - 2.13(m, 4H), 1.90 - 1.72 (m, 8H). LCMS: m/z 518(M+H)+. l-(4-((4-((6,6-Difluorospiro[3.3]heptan-2-yl)amino)-6-(6-(trifluoromethyl)pyrazin-2-yl)- l,395-triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000319_0001
Ή NMR (400MHz, DMSO-d6)5 10.53(s, 1H), 9.84 - 9.75 (m, 1H), 9.39 (d, J=8Hz, 1H), 8.80 (d, J=8Hz, 1H), 8.41 - 8.21 (m, 2H), 7.83 - 7.56 (m, 1H), 4.57 (d, J=8Hz, 1H), 2.71 - 2.57 (m, 6H), 2.27 - 2.22 (m, 2H), 1.81 - 1.67 (m, 4H). LCMS: m/z 530(M+H)+.
(R)-l-(4-((4-((3,3-difluorocyclopentyl)amino)-6-(6-(trifluoromethyl)pyrazin-2-yl)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000319_0002
1H NMR(400MHz,DMSO-d6)5 10.58(s, 1H), 9.87 - 9.77(m, 1H), 9.39 (d, J=4Hz, 1H), 8.77 (d, J=4Hz, 1H), 8.42 - 8.32(m, 2H), 7.82 - 7.57 (m, 1H), 4.67(m, 1H), 2.67 - 1.69 (m, 10H).LCMS: m/z 504(M+H)+.
(S)-l-(4-((4-((3,3-difluorocyclopentyl)amino)-6-(6-(trifluoromethyl)pyrazin-2-yl)-l,395- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000319_0003
Ή NMR (400MHz, CDC13)5 9.85(s, 1H), 9.12(s, 1H),8.61 - 8.44 (m, 1H), 8.33 (d, J = 8Hz, 1H), 7.52(s, 1H), 7.00(s, 1H), 5.97 - 5.75 (m, 1H), 4.94 - 4.75 (m, 1H), 2.75 - 1.73 (m, 10H).LCMS: m/z 504(M+H)+.
(R)-l-(4-((4-(6-(trifluoromethyl)pyrazin-2-yl)-6-((l,1 -trifluoropropan-2-yl)amino)-l,395- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000320_0001
Ή NMR (400MHz, CDC13)5 9.90 - 9.84 (m, 1H), 9.14(s, 1H), 8.43 - 8.35 (m, 2H), 7.52 - 7.15 (m, 2H), 5.86 - 5.60 (m, 1H), 5.14 - 4.80 (m, 1H), 1.87 (d, J=8Hz, 2H), 1.74(m, 2H ) , 1.50 - 1.57 (m, 3H).LCMS: m/z 496(M+H)+.
(R)-N2-(3,3-difluorocyclopentyl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000320_0002
Ή NMR (400 MHz, CDC13) 5 9.81 (m 1H), 9.14 (d, J= 3.6 Hz, 1H), 8.81 - 8.14 (m, 2H), 8.07 - 7.37 (m, 2H), 6.30 - 5.59 (m, 1H), 4.82 - 4.62 (m, 1H), 2.70 (m, 1H), 2.57 - 2.09 (m, 4H), 2.01 - 1.84 (m, 1H). LC-MS: m/z 507 (M+H)+.
(S)-N2-(3,3-difluorocyclopentyl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000321_0001
¾ NM (400 MHz, CDC13) δ 9.81 (m, 1H), 9.14 (d, J = 3.1 Hz, 1H), 8.74 - 8.08 (m, 2H), 8.06 - 7.29 (m, 2H), 6.22 - 5.58 (m, 1H), 4.85 - 4.50 (m, 1H), 2.70 (m, 1H), 2.52 - 2.09 (m, 4H), 2.01 - 1.82 (m, 1H).LC-MS: m/z 507 (M+H)+.
N2-(3,3-difluorocyclobutyl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000321_0002
H NMR (400 MHz, CDC13) δ 9.81 (d, J= 13.8 Hz, 1H), 9.14 (d, J= 3.5 Hz, 1H), 8.80 - 8.19 (m, 2H), 7.99 - 7.41 (m, 2H), 6.31 - 5.71 (m, 1H), 4.70 - 4.39 (m, 1H), 3.29 - 3.06 (m, 2H), 2.88 - 2.47 (m, 2H). LC-MS: m/z 493 (M+H)+.
N2-(4,4-difluorocyclohexyl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000321_0003
¾ NMR (400 MHz, CDC13) δ 9.80 (d, J = 8.8 Hz, 1H), 9.14 (d, J = 3.4 Hz, 1H), 8.62 (d, J = 5.5 Hz, 1H), 8.59-8.20 (m, 1H), 5.83-5.49 (m, 1H), 4.25-4.11 (m, 1H), 2.33 - 1.71 (m, 6H). LC-MS: m/z 521 (M+H)+.
N2-(cyclopropylmethyl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-N4-(2-(trifluoromethyl)pyridin- -yl)- 1 ,3,5-triazine-2,4-diamine
Figure imgf000322_0001
Ή NMR (400 MHz, DMSO-d6) 82 (s, 4H), 9.20 (s, 4H), 8.73 (s, 3H), 8.49 (t, J = 6.2 Hz, 4H), 8.37 (s, 1H), 8.13 (s, 1H), 7.79 (d, J = 4.4 Hz, 3H), 3.45-3.30 (m, 8H), 1.29 - 1.16 (m, 5H), 0.57 (m 8H), 0.39 - 0.30 (m, 8H). LC-MS:m/z 457 (M+H)+.
N2-(6,6-difluorospiro[3.3]heptan-2-yl)-6-(6-(trifluoromethyl)pyrazin-2-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000322_0002
Ή NMR (400 MHz, CD3OD) 59.84 (d, J = 9.0 Hz, 1H), 9.22 (d, J = 5.1 Hz, 1H), 8.93 - 8.35 (m, 2H), 8.14 - 7.72 (m, 2H), 4.77 - 4.35 (m, 1H), 2.67 (m, 6H), 2.43 - 2.15 (m, 2H). LC-MS: m/z 533 (M+H)+.
(S)-N2-(3,3-difluorocyclopentyl)-N4-(3,5-difluorophenyl)-6-(6-(trifluoromethyl)py yl)-l,3,5-triazine-2,4-diamine
Figure imgf000323_0001
Ή NMR (400 MHz, CDC13) δ 9.80 (m, 1H), 9.12 (d, J = 3.1 Hz, 1H), 7.71 - 7.27 (m, 3H), 6.73 - 6.44 (m, 1H), 5.98 - 5.48 (m, 1H), 4.68 (m, 1H), 2.81 - 2.59 (m, 1H), 2.50 - 2.02 (m, 4H), 1.97 - 1.78 (m, 1H).LC-MS: m/z 474 (M+H)+.
(R)-N2-(3,3-difluorocyclopentyl)-N4-(3,5-difluorophenyl)-6-(6-(trifluoromethyl)pyrazin-2- -l,3,5-triazine-2,4-diamine
Figure imgf000323_0002
1H NMR (400 MHz, CDC13) δ 9.80 (m, 1H), 9.12 (d, J = 3.1 Hz, 1H), 7.71 - 7.27 (m, 3H), 6.73 - 6.44 (m, 1H), 5.98 - 5.48 (m, 1H), 4.68 (m, 1H), 2.81 - 2.59 (m, 1H), 2.50 - 2.02 (m, 4H), 1.97 - 1.78 (m, 1H). LC-MS: m/z 474 (M+H)+.
N2-(4,4-difluorocyclohexyl)-N4-(3,5-difluorophenyl)-6-(6-(trifluoromethyl)pyrazin-2-yl)- 1 ,3?5-triazine-2,4-diamine
Figure imgf000323_0003
Ή NMR (400 MHz, CDC13) δ 9.78 (d, J = 7.6 Hz, 1H), 9.11 (s, 1H), 7.39 (m, 3H), 6.58 (t, J = 8.8 Hz, 1H), 5.76 - 5.39 (m, 1H), 4.22 - 4.06 (m, 1H), 2.21 (m, 4H), 1.95 (m, 2H), 1.80 - 1.68 (m, 2H).LC-MS: m/z 488 (M+H)+. l-(4-((4-((4,4-Difluorocyclohexyl)amino)-6-(6-(difluoromethyl)pyrazin-2-yl)-l,3,5-triazin-2- yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000324_0001
1H NMR (400 MHz, CDC13) δ 9.79 (d, J = 7.0 Hz, 1H), 9.12 (s, 1H), 8.54 (m, 1H), 8.32 (d, J = 6.0 Hz, 1H), 7.52 (d, J = 6.1 Hz, 1H), 7.14 (m, 1H), 6.85 (m, 1H), 5.68 (m, 1H), 4.30 (m, 1H), 2.18 (m, 6H), 1.85 (m, 2H), 1.73 (m, 4H). LC-MS: m/z 500 (M+H)+.
(S)-l-(4-((4-(6-(difluoromethyl)pyrazin-2-yl)-6-((l,1 -trifluoropropan-2-yl)amino)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000324_0002
Ή NMR (400 MHz, CDC13) δ 9.83 (m, 1H), 9.16 (s, 1H), 8.42 (m, 2H), 7.60 (s, 1H), 7.13 (m, 1H), 6.88 (m, 1H), 5.88 (m, J = 9.5 Hz, 1H), 5.16 (s, 1H), 1.89 (m, J = 4.5 Hz, 2H), 1.76 (s, 2H), 1.52 (d, J = 7.0 Hz, 3H). LC-MS: m/z478 (M+H)+.
(R)-l-(4-((4-(6-(difluoromethyl)pyrazin-2-yl)-6-((l,1 -trifluoropropan-2-yl)amino)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000325_0001
Ή NMR (400 MHz, CDC13) δ 9.81 (m, 1H), 9.12 (d, J= 10.5 Hz, 1H), 8.34 (m, 2H), 7.54 (d, J = 13.1 Hz, 1H), 7.08 (m, 1H), 6.86 (m, 1H), 5.85 (d, J = 9.8 Hz, 1H), 5.14 (s, 1H), 1.92 (m, 2H), 1.71 (m, 2H), 1.51 (m, J = 7.7 Hz, 3H). LC-MS: m/z478 (M+H)+.
6-(6-Chloropyrazin-2-yl)-N2-(3,3-difluorocyclopentyl)-N4-(3,5-difluorophenyl)-l,395- triazine-2,4-diamine
Figure imgf000325_0002
1H NMR (400 MHz, CDCI3) δ 9.51 (d, J = 17.3 Hz, 1H), 8.76 (s, 1H), 7.64 - 7.11 (m, 3H), 6.57 (t, J = 8.8 Hz, 1H), 5.95 - 5.50 (m, 1H), 4.86 - 4.50 (m, 1H), 2.85 - 1.80 (m, 6H). LC-MS: m/z 440 (M+H)+.
6-(6-Chloropyrazin-2-yl)-N2-(3,3-difluorocyclobutyl)-N4-(3,5-difluorophenyl)-l,3,5-triazine- 2,4-diamine
Figure imgf000325_0003
XH NMR (400MHz, CDC13)5 9.53 - 9.49 (m, 1H), 8.76(s, 1H), 7.60 - 7.50 (m, 1H), 7.29(s, 1H), 7.26(s, 1H), 6.61 - 6.56 (m, 1H), 6.01 - 5.74 (m, lH), 4.59 - 4.42 (m, 1H), 3.16(s, 2H), 3.16 - 2.55 (m, 2H).LCMS: m/z 426(M+H)+. (S)-N2-(3,3-difluorocyclopentyl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-6-(2- (trifluoromethyl)pyrimidin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000326_0001
Ή NMR (400 MHz, CDC13) δ 9.16 (t, J= 6.1 Hz, 1H), 8.68 - 7.76 (m, 4H), 7.72 - 7.45 (m, 1H), 5.86 (m, 1H), 4.70 (m, 1H), 2.86 - 1.84 (m, 6H). LCMS: m/z 507 (M+H)+.
(R)-N2-(3,3-difluorocyclopentyl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-6-(2- (trifluoromethyl)pyrimidin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000326_0002
Ή NMR (400 MHz, CDC13) δ 9.18 - 9.15 (m, 1H), 8.64 - 8.61 (m, 1H), 8.53 - 8.51 (m, 1H), 8.48 (d, J=4 Hz, 1H), 8.17 - 7.80 (m, 1H) 7.72 - 7.48 (m, 1H), 6.02 - 5.71 (m, 1H), 4.80 - 4.61 (m, 1H), 2.76 - 2.63 (m, 4H), 1.95 - 1.88 (m, 1H). LCMS: m/z 507(M+H)+.
(S)-l-(4-((4-((3,3-difluorocyclopentyl)amino)-6-(2-(trifluoromethyl)pyrimidin-4-yl)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000326_0003
1H NMR (400 MHz, CDC13) δ 9.15 (d, J = 5.4 Hz, 1H), 7.62 (m, 2H), 8.33 (d, J = 5.5 Hz, 1H), 7.57 (s, 1H), 7.00 (s, 1H), 6.00 (d, J = 8.0 Hz, lH), 4.76 (d, J = 8.6 Hz, 1H), 2.71 (s, 1H), 2.32 (m, 4H), 1.83 (m, 5H). LC-MS: m/z504 (M+H)+.
(R)-l-(4-((4-((3 -difluorocyclopentyl)amino)-6-(2-(trifluoromethyl)pyrimidin-4-yl)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000327_0001
Ή NMR (400 MHz, CDC13) δ 9.14 (d, J = 5.1 Hz, lH), 8.35 (m, 2H), 8.33 (d, J = 5.5 Hz, 1H), 7.56 (s, 1H), 7.00 (s, 1H), 5.99 (d, J = 8.0 Hz, lH), 4.76 (d, J = 7.1 Hz, 1H), 2.73 (m, 1H), 2.23 (m, 4H), 1.78 (m, 5H). LC-MS: m/z504 (M+H)+. l-(4-((4-((3,3-Difl orocyclopentyl)amino)-6-(4-(trifluoromethyl)pyrimidin-2-yl)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000327_0002
Ή NMR (400 MHz, CDC13) δ 9.27 (d, J = 4.8 Hz, 1H), 8.67 (s, 1H), 8.29 (d, J = 5.2 Hz, 1H), 8.06 (s, 1H), 7.81 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 6.19 (d, J= 7.6 Hz, 1H), 2.85 - 2.69 (m, 1H), 2.53 - 2.05 (m, 5H), 1.92 - 1.68 (m, 5H). LCMS: m/z 504 (M+H)+.
(S)-l-(4-((4-((3,3-difluorocyclopentyl)amino)-6-(4-(trifluoromethyl)pyrimidin-2-yl)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000328_0001
Ή NMR (400 MHz, CDC13) δ 9.29 (d, J = 4.9 Hz, IH), 8.58 (m, 1H), 8.33 (d, J = 5.5 Hz, 1H), 7.82 (t, J = 14.2 Hz, 2H), 7.00 (d, J = 13.0 Hz, IH), 6.14 (d, J = 8.0 Hz, IH), 4.94 (m, IH), 2.89 - 2.69 (m, IH), 2.51 (m, IH), 2.34 - 2.07 (m, 3H), 1.94 - 1.72 (m, 5H). LCMS: m/z 504 (M+H)+.
(R)-l-(4-((4-((3 -difluorocyclopentyl)amino)-6-(4-(trifluoromethyl)pyrimidin-2-yl)-l,3,5- triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000328_0002
1H NMR (400 MHz, CDC13) δ 9.27 (d, J = 4.9 Hz, IH), 8.68 (s, IH), 8.31 (d, J = 5.5 Hz, IH), 7.80 (dd, J = 20.2, 12.7 Hz, 2H), 6.95 (s, IH), 6.12 (d, J = 8.1 Hz, IH), 5.02 (s, IH), 2.77 (m, IH), 2.56 - 2.41 (m, IH), 2.32 - 2.05 (m, 3H), 1.95 - 1.69 (m, 5H). LCMS: m/z 504 (M+H)+.
N2-(tert-butyl)-N4-(2-(1 -difluoroethyl)pyridin-4-yl)-6-(4-(trifluoromethyl)pyrimidin-2-yl)- -triazine-2,4-diamine
Figure imgf000328_0003
¾ NMR (400 MHz, CDC13) δ 9.24 (d, J = 5.0 Hz, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.38 (d, J = 1.4 Hz, 1H), 7.97 (s, 1H), 7.80 (d, J = 5.0 Hz, 1H), 7.37 (s, 1H), 6.05 (s, 1H), 2.04 (d, J = 18.6 Hz, 3H), 1.55 (s, 9H). LCMS: m/z 455(M+H)+.
N2-(2-(l,l-difluoroethyl)pyridin-4-yl)-N4-isopropyl-6-(4-(trifluoromethyl)pyrimidin-2-yl)- -triazine-2,4-diamine
Figure imgf000329_0001
H NMR (400 MHz, CDC13) δ 9.26 (d, J = 5.0 Hz, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.41 (d, J = 1.5 Hz, 1H), 7.84 (m, 2H), 7.41 (s, 1H), 5.86 (d, J = 7.5 Hz, 1H), 4.32 (m, 1H), 2.04 (m, 3H), 1.36 (d, J = 6.5 Hz, 6H). LCMS: m/z 441 (M+H)+.
3-((4-(Tert-butylamino)-6-(4-(trifluoromethyl)pyrimidin-2-yl)-l,395-triazin-2-yl)amino)-5- fluorobenzonitrile
Figure imgf000329_0002
Ή NMR (400 MHz, DMSO-d6) δ 10.80 - 10.20 (m, 1H), 9.50 - 9.25 (m, 1H), 8.36 - 7.96 (m, 4H), 7.50 - 7.40 (m, 1H), 1.47 (s, 9H). LCMS: m/z 433 (M+l)+. l-((4-((3,5-Difluorophenyl)amino)-6-(4-(trifluoromethyl)pyrimidin-2-yl)-l,3,5-triazin-2- yl)amino)-2-methylpropan-2-ol
Figure imgf000330_0001
1H NMR (400 MHz, DMSO-d6) δ 10.70 - 10.20 (m, 1H), 9.50 - 9.27 (m, 1H), 8.37 - 7.94 (m, 2H), 7.80 - 7.50 (m, 2H), 6.98 - 6.71 (m, 1H), 4.75 - 4.48 (m, 1H), 3.47 - 3.38 (m, 2H), 1.14 (s, 6H). LCMS: m/z 442 (M+H)+.
Example 33. Preparation of Aromatic-aliphatic Triazine Compounds. The compounds of this Example are prepared by general Scheme 33, set forth below.
Scheme 33
Figure imgf000330_0002
Step 1: Preparation of NJ l-(3,5-difluorophenyl)-N ^-nitrile-guanidine. To a solution of NaN(CN)2 (4.1 g, 46.5 mmol) in water (34 mL) at 80°C was added a solution of 3,5- difluoroaniline (3 g, 23.2 mmol) in a mixed solvent of water and cone. HCl (2M, 2 mL). The reaction mixture was then stirred at 90°C for 16 hours. The resulting mixture was cooled to r.t. and quenched by satd. aq. NaHCC and adjusted topH 7-8. The mixture was filtered and the filter cake was collected and dried to afford the desired product. LC-MS: m/z 197 (M+H)+. Step 2: Preparation of N1 -(3,5-difluorophenyl)-N5-(4,4-difluorocyclohexyl) -guanidine. A mixture of N1-(3,5-difluorophenyl)-N3-nitrile-guanidine (300 mg, 1.53 mmol) and 4,4- difluorocyclohexanamine hydrochloride (262 mg, 1.53 mmol) was well mixed together and then stirred at 160°C for lhr. The resulting mixture was cooled to r.t. and then trituratedwith a mixed solvent of EtOAc and PE. The solid was collected by filtration and dried to afford the desired product. LC-MS: m/z 332 (M+H)+.
Step 3: Preparation of 3,6-difluoro-2-hydrazinylpyridine. To an ice-cold mixture of 2,3,6- trifluoropyridine (1.0 g, 7.5 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.75 g, 15.0 mmol). The reaction mixture was warmed to r.t. then heated to reflux for 2 hr. After cooling to r.t., the reaction mixture was diluted with water (10 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to afford 3,6-difluoro-2-hydrazinylpyridine. LC-MS: m/z 146 (M+H)+.
Step 4:Preparation of2-bromo-3,6-difluoropyridine. To a stirred solution of 3,6-difluoro-2- hydrazinylpyridine(l .l g, 7.0 mmol) in chloroform (20 mL) at r.t. was added dropwise bromine (1.8 g, 11.2 mmol).The reaction mixture was then stirred at 60°C for 1.5 hr. The resulting mixture was cooled to r.t.,then quenched with satd. aq. NaHC03, and extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over anhydrous Na2S04, and concentrated and purified by standard methods to afford 2-bromo-3,6-difluoropyridine. LC-MS: m/z 194 (M+H)+.
Step 5:Preparation of methyl 3,6-difluoropicolinate. To a solution of 2-bromo-3,6- difluoropyridine (0.8 g, 4.1mmol) in MeOH (10 mL) were added dppf (0.3 g, 0.56 mmol), Pd(OAc)2 (0.1 g, 0. 45 mmol) and Et3N (1.6 mL, 8.2 mmol). The suspension was degassed and back-filled with CO atmosphere three times. The mixture was then stirred under CO atmosphere (60 psi) at 70°C for 12 hr. The resulting mixture was cooled to r.t. and concentrated under reduced pressure. The residue was triturated with EtOAc (150 mL). The solid was filtered off and the filtrate was concentrated and purified by standard methods to afford methyl 3,6- difluoropicolinate. LC-MS: m/z 174 (M+H)+.
Step 6: Preparation ofN2-(4,4-difluoroc clohexyl)-T^-(3,5-difluorophenyl)-6-(3,6 difluoropyridin -2-yl)-l,3, 5-triazin e-2, 4-diamin e. To a suspension of N1-(3,5-difluorophenyl)- N5-(4,4-difluorocyclohexyl)-guanidine (191 mg, 0.58 mmol) and methyl 3,6-difluoropicolinate (100 mg, 0.58 mmol) in MeOH (3 mL) was added NaOMe (94 mg, 1.73 mmol). The reaction mixture was stirred at r.t. overnight, then poured into water and extracted with EtOAc. Combined organic layers were dried over anhydrous Na2S04, and concentrated and purified by standard methods to afford N2-(4,4-difluorocyclohexyl)-N4-(3,5-difluorophenyl)-6-(3,6-difluoropyridin-2- -l,3,5-triazine-2,4-diamine.
Figure imgf000332_0001
Ή NMR (400 MHz, CDC13) δ 7.70 (td, J= 8.8, 5.8 Hz, 1H), 7.49 - 7.38 (m, 1H), 7.37 - 7.17 (m, 2H), 7.17 - 7.05 (m, 1H), 6.55 (t, J = 8.9 Hz, 1H), 5.67 - 5.37 (m, 1H), 4.13 - 4.02 (m, 1H), 2.18 (d, J = 8.3 Hz, 4H), 2.03 - 1.87 (m, 2H), 1.73 - 1.70 (d, J = 11.2 Hz, 2H). LC-MS: m/z 455 (M+H)+.
The procedure set forth in Example 33 was used to produce the following compounds using the appropriate starting materials.
Compound N2-(3,3-difluorocyclopentyl)-N4-(3,5-difluorophenyl)-6-(3,6-difluoropyridin-2- -l,3,5-triazine-2,4-diamine
Figure imgf000332_0002
Ή NMR (400 MHz, CDC13) δ 7.77 - 7.62 (m, 1H), 7.47 - 7.27 (m, 2H), 7.24 (d, J= 7.7 Hz, 1H), 7.11 (ddd, J = 8.8, 3.9, 2.7 Hz, 1H), 6.55 (t, J = 8.7 Hz, 1H), 5.94 - 5.29 (m, 1H), 4.76 - 4.48 (m, 1H), 2.90 - 1.72 (m, 6H). LC-MS: m/z 441 (M+H)+.
Comound N2-(3,3-difluorocyclobutyl)-N4-(3,5-difluorophenyl)-6-(3,6-difluoropyridin-2-yl)- -triazine-2,4-diamine
Figure imgf000333_0001
Ή NMR (400 MHz, CDC13) δ 7.70 (m, 1H), 7.58 - 7.28 (m, 2H), 7.25 - 7.19 (m, 1H), 7.16 - 7.06 (m, 1H), 6.73 - 6.30 (m, 1H), 6.18 - 5.37 (m, 1H), 4.63 - 4.31 (m, 1H), 3.40 - 2.93 (m, 2H), 2.88 - 2.19 (m, 2H). LC-MS: m/z 427 (M+H)+.
Example 34. The compounds of this Example are prepared by general Scheme 34, set forth below.
Scheme 34
Figure imgf000333_0002
Step 1: Preparation of N2-(4,4-difluorocyclohexyl)-rf-(3,5-difluorophenyl)-6-(3-fluoro-6- hydrazinylpyridin-2-yl)-l,3,5-triazine-2,4-diarnine. To a solution of N2-(4,4- difluorocyclohexyl)-N4-(3,5-difluorophenyl)-6-(3,6-difluoropyridin-2-yl)-l,3,5-triazine-2,4- diamine(225 mg, 0.49 mmol) in THF(20 mL) was added hydrazine hydrate(150 mg, 3.0 mmol). The reaction mixture was thenstirred at 60°C for 2.5 hr. After cooling to r.t., the reaction mixture was diluted with DCM (20 mL) and washed with brine (2 x 10 mL). The organic phase was separated, dried over anhydrous Na2S04and concentrated under reduced pressure to give the desired product.
Figure imgf000334_0001
LC-MS: m/z 467 (M+H)
Step 2: Preparation of d-fd-amino-S-fluoropyrMin^-yfy-rf- ^-difluorocyclohexyfy-N^-fSfS- difluorophenyl)-l,3,5-triazine-2,4-diamine. To a solution of N2-(4,4-difluorocyclohexyl)-N4- (3,5-difluorophenyl)-6-(3-fluoro-6-hydrazinylpyridin-2-yl)-l ,3,5-triazine-2,4-diamine(46 mg,0.1 mmol) in methanol(5.0 mL) was added Raney Ni (100 mg). The mixture was stirred at r.t. under H2 atmosphere overnight. The resulting mixture was filtered and the filtrate was concentrated and purified by standard methods to afford 6-(6-amino-3-fluoropyridin-2-yl)-N2-(4,4- difluorocyclohexyl)-N4-(3,5-difluorophenyl)-l,3,5-triazine-2,4-diamine.
Figure imgf000334_0002
1H NMR (400 MHz, CDC13) δ 7.52-7.50 (m, 2H), 7.45-7.39 (m, 1H), 7.02-6.97 (m, 1H), 6.63- 6.54 (m, 1H), 4.60 (s, 1H), 4.26-4.05 (m, 1H), 1.73-2.21 (m, 8H). LC-MS: m/z 452(M+H)+.
The procedure set forth in Example 34was used to produce the following compounds using the appropriate starting materials. Compound 6-(6-Amino-3-fluoropyridin-2-yl)-N2-(3,3-difluorocyclopentyl)-N4-(3,5- difluorophenyl)-l,3,5-triazine-2,4-diamine
Figure imgf000335_0001
Ή NMR (400 MHz, CDC13) δ 7.50-7.36 (m, 3H), 6.96-6.95 (m, 1H), 6.59-6.53 (m, 1H), 4.89- 4.51 (m, 2H), 2.66-2.60 (m, 1H), 2.35-2.11 (m, 4H), 1.92-1.58 (m, 2H). LCMS: m/z 438 (M+H)+.
Example 35: Preparation of N4,N6-bis(4,4-difluorocyclohexyl)-2-(6-(trifluoromethyl) pyrazin-2-yl) pyrimidine-4, 6-diamine
Scheme 35
Figure imgf000335_0002
Step A: 6-(Trifluoromethyl)pyrazine-2-carboxamide.To a solution of methyl 6-(trifluoromethyl) pyrazine-2-carboxylate (15 g, 72.8 mmol) in EtOH (20 mL) was added NH4OH (6 mL, 156 mmol).The reaction mixture was stirred at r.t. for 4hr then concentrated under reduced pressure. The residue was triturated with H20(10 mL) and then filtered to afford 6- (trifluoromethyl)pyrazine-2-carboxamide.LC-MS: m/z 192 ( +H)+. Step B:6-(Trifluoromethyl)pyrazine-2-carbonitrile. A mixture of 6-(trifluoromethyl) pyrazine-2- carboxamide (10 g, 52 mmol) in POCl3 (80 mL) was stirred at 100°Covernight. The reaction mixture was cooled to r.t. and concentrated under reduced pressure. The residue was partitioned between DCM and ice water. The organic layer was separated, washed with brine, dried over anhydrous Na2S04,concentrated, andpurified by standard methods to afford 6- (trifluoromethyl)pyrazine-2-carbonitrile.LC-MS: m/z 174 ( +H)+.
Step C: 6-(Trifluoromethyl)pyrazine-2-carboximidamide hydrochloride.^ Ό a solution of 6- (trifluoromethyl) pyrazine-2-carbonitrile (3.4 g, 15 mmol) in MeOH (5 mL) was added a solution of sodium metal (35 mg, 1.5 mmol) in MeOH. The reaction mixture was stirred at r.t. for 12 hr, followed by addition of NH4C1 (1.5 g, 30 mmol). The mixture was stirred at 70°C for 3 hr, then cooled to r.t. and concentrated under reduced pressure. The residue was diluted with EtOH (10 mL) and stirred at reflux for 0.5 hr. The resulting mixture was cooled to r.t. and filtered. The filtrate was concentrated under reduced pressure to afford 6-(trifluoromethyl) pyrazine-2- carboximidamide hydrochloride. LC-MS: m/z 191 (M +H)+.
Step D: 2-(6-(trifluoromethyl)pyrazin-2-yl)pyrirmdine-4,6(lH,5H)-dione. To a mixture of 6- (trifluoromethyl) pyrazine-2-carboximidamide hydrochloride (1.6 g, 7.0 mmol) in diethyl malonate (3.2 g, 21.2 mmol) was added potassium carbonate (3.0 g, 21.2 mmol). The reaction mixture was stirred at 120 °C for 8 hr. The resulting mixture was cooled to r.t. and trituratedwith petroleum ether. The solid was collected by filtration, washed with petroleum ether then treated with MeOH to form a suspension. The suspension was filtered and the filtrate was concentrated under reduced pressure to afford 2-(6-(trifluoromethyl)pyrazin-2-yl)pyrimidine-4,6-(lH,5H)- dione. LC-MS: m/z 259 ( +H)+.
Step E: 4, 6-Dichloro-2-(6-(trifluoromethyl) pyrazin-2-yl)pyrimidine. A mixture of 2-(6- (trifluoromethyl) pyrazin-2-yl) pyrimidine-4, 6(1H, 5H)-dione (1.4 g, 5.4 mmol) in POCl3 (10 mL) was stirred at 100°C overnight then cooled to r.t. and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA = 20/1 to 10/1) to afford 4, 6- dichloro-2-(6-(trifluoromethyl) pyrazin-2-yl)pyrimidine.LC-MS: m/z 295 ( +H)+. Step F: N4, iV'-bis (4,4-difluorocyclohexyl)-2-(6-(trifluoromethyl) pyrazin-2-yl) pyrimidine-4, 6-diamine. To a mixture of 4, 6-dichloro-2-(6-(trifluoromethyl) pyrazin-2-yl)pyrimidine (100 mg, 0.34 mmol), CsF(103 mg, 0.68 mmol) and 4,4-difluorocyclohexanamine hydrochloride (116 mg, 0.68 mmol) in DMSO (1 mL) was added DIPEA (220 mg, 0.17 mmol). The reaction mixture was stirred at 80°C for 4 hr under nitrogen,and then stirred at 150°C for 6 hr under microwave irradiation. The resulting mixture was cooled to r.t, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by standard methods to afford N4,N6-bis (4,4-difluorocyclohexyl)-2-(6-(trifluoromethyl) pyrazin-2-yl) pyrimidine-4, 6-diamine.
Figure imgf000337_0001
Ή ΝΜΡν (400 MHz, CDC13) δ 9.73 (s, lH), 9.00 (s, 1H), 5.31 (s, 1H), 4.95 (m, 2H), 3.76 (m, 2H), 2.20-2.09 (m, 8H), 1.98-1.85 (m, 4H), 1.72-1.63 (m, 4H).LC-MS: m/z 493 (M+H)+.
Example 36. Preparation of Aromatic-aliphatic Triazine Compounds. The compounds of this Example are prepared by general Scheme 36, set forth below.
Sheme 36
Figure imgf000338_0001
Step 1: Preparation of l-(4-bromopyridin-2-yl)cyclopropanecarbonitrile. To a solution of 4- bromo-2-fluoropyridine (30 g, 170.47 mmol) and cyclopropane carbonitrile (22.9 g, 340.94 mmol) in THF (400 mL) below -10°C was slowly added dropwise LiHMDS (1.2 mmol L, 284 mL). The reaction mixture was then stirred at r.t. for 12 hr. The resulting mixture was cooled to 0°C, then quenched with brine (200 mL). The mixture was concentrated under reduced pressure. The residue was extracted with EtOAc (3x200 trsL).The combined layers were dried over anhydrous Na2S04 andconcentrated and purified by standard methods to afford the desired product.LC-MS: m/z 223 (M+H)+.
Step 2: Preparation of l-(4-(diphenylmethyleneandno)pyridin-2-yl)cyclopropanecarbonitrile.
To a solution of l -(4-bromopyridin-2-yl)cyclopropanecarbonitrile (30 g, 134.48 mmol) and diphenyl methanimine (29.3 g, 161.38 mmol) in dioxane (150 mL) were added t-BuONa (19.4 g, 201.73 mmol), Binap (5.0 g, 8.1 mmol) and Pd2(dba)3 (2.5 g, 2.69 mmol). The mixture was heated tol00°C for 1 hr under N2 atmosphere, then cooled andfiltered The filtrate was concentrated to give the desired product.LC-MS: m/z 324 (M+H)+. Step 3: Preparation of l-(4-aminopyridin-2-yl)cyclopropanecarbonitrile. A mixture of l-(4- (diphenylmethyleneamino)pyridin-2-yl)cyclopropanecarbonitrile (42.1 g crude, 130 mmol) and THF/ aq. HCl (2N) (200 mL, V:V=2:1) was stirred at r.t. for 1 hr and concentrated under reduced pressure. The aqueouslayer was extracted with PE (3x100 mL), then adjusted to pH 8-9 with satd. aq. Na2C03, and extracted with EtOAc (3x100 mL).The combined organic layers were dried over anhydrous Na2S04, and concentrated concentrated and purified by standard methods to afford the desired product.1HNMR (CDCl3)58.04-8.05 (d, J=4Hz, 1H), 6.95-6.96 (d, J=4Hz), 6.37-6.39 (m, 1H), 4.23 (br, 2H), 1.17-1.80 (m, 2H), 1.61-1.63 (m, 2H).LC-MS: m/z 160 (M+H)+.
Step 4: Preparation ofl-(4-(4, 6-dichloro-l,3,5-triazin-2-ylamino)pyridin-2-yl)cyclopropane carbonitrile.To a solution of l -(4-aminopyridin-2-yl)cyclopropanecarbonitrile (2.5 g, 15.7 mmol), 2,4,6-trichloro-l,3,5-triazine (3.5 g, 18.8 mmol) in THF (40 mL) was added NaHC03 (2.64 g, 31.4 mmol). The reaction mixture was stirred at r.t. overnight thenfiltered. The filtrate was concentrated and purified by standard methods to afford the desired product.LC-MS: m/z 307 (M+H)+.
Step 5: Preparation of l-(4-(4-chloro-6-(3,3-difluorocyclopentylamino)-l,3,5-triazin-2-yl amino) pyridin-2-yl)cyclopropanecarbonitrile.To a solution of l-(4-(4,6-dichloro-l,3,5-triazin- 2-ylamino)pyridin-2-yl)cyclopropanecarbonitrile (0.75 g, 2.44mmol) and 3,3- difluorocyclopentanamine hydrochloride (0.39 g, 2.44 mmol) in THF (10 mL) at 0 °C was slowly added dropwise DIPEA (0.63 g, 4.88 mmol). The reaction mixture was stirred at r.t. for 8hr, and then concentrated under reduced pressure. The residue was partitioned between EtOAc (20mL) and HCl solution (10 %wt, 3 mL). The aqueous layer was separated and extracted with EtOAc (2x5 mL).The combined organic layers were dried over anhydrous Na2S04 and concentrated and purified by standard methods to afford the desired product.LC-MS: m/z 392 (M+H)+.
Step 6: Preparation ofl-(4-(4-(3,3-difluoro(yclopentylamino)-6-(3-(trifluoromethyl)-lH- pyrazol-l-yl)-l,3,5 rmzin-2-yfamino)pyrMin-2-yl)cycfapropanecarbonitrile.To a solution of 1- (4-(4-chloro-6-(3,3-difluorocyclopentylamino)-l,3,5-triazin-2-ylamino) pyridin-2- yl)cyclopropanecarbonitrile (0.6 g, 1.53 mmol) in DMF (600 mL) were added 3- (trifluoromethyl)-lH-pyrazole (0.2 g, 1.53 mmol) andK2C03 (0.42 g, 3.06 mmol). The mixture was stirred at 35°C overnight then concentrated under reduced pressure. The residue was dissolved in EtOAc (20mL) then washed in sequence withaq. 10% LiCl solution (2x5 mL), 5% HCl solution(2x5 mL), and satd. aq. NaHC03 (2x5 mL). The organic layer was separated, dried over anhydrous Na2S04, and concentrated and purified by standard methods to afford the desired product. Ή NMR (400 MHz, CDC13) δ 8.81 - 8.21 (m, 3H), 7.75 - 7.43 (m, 1H), 7.17 - 6.88 (m, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.05 - 5.76 (m, 1H), 5.12 - 4.41 (m, 1H), 2.86 - 2.61 (m, 1H), 2.57 - 2.00 (m, 4H), 1.97 - 1.78 (m, 3H), 1.76 - 1.68 (m, 2H). LC-MS: m/z 492 (M+H)+.
The procedure set forth in Example 36was used to produce the following compounds using the appropriate starting materials.
Compound (S)-l-(4-(4-(3,3-Difluorocyclopentylamino)-6-(3-(trifluoromethyl)-lH-pyrazol- l-yl)-l,3,5-triazin-2-ylamino)pyridin-2-yl)cyclopropanecarbonitrile.
1HNMR (400 MHz, CDC13)58.51-8.64 (m, 2H), 8.30-8.32 (m, 1H), 7.70-7.87 (m, 1H), 7.96-7.14 (m, 1H), 6.66-6.75 (m, 1H), 5.86-6.07 (m, 1H), 4.64-4.93 (m, 1H), 2.44-2.76 (m, 1H), 2.04-2.30 (m, 4H), 1.72-1.94 (m, 5H). LC-MS: m/z 492 (M+H)+.
Compound (R)-l-(4-(4-(3,3-Difluorocyclopentylamino)-6-(3-(trifluoromethyl)-lH-pyrazol- l-yl)-l,3,5-triazin-2-ylamino)pyridin-2-yl)cyclopropanecarbonitrile.
Figure imgf000341_0001
Ή NMR (400 MHz, CDC13) δ 8.59 (m, 2H), 8.32 (d, J = 5.5 Hz, 1H), 7.52 (s, 1H), 6.95 (m, 1H), 6.74 (d, J = 2.7 Hz, 1H), 5.91 (m, 1H), 4.83 (m, 1H), 2.69 (m, 1H), 2.31 (m, 4H), 1.76 (m, 5H). LC-MS: m/z492 (M+H)+.
Compound l-(4-((4-((4,4-Difluorocyclohexyl)amino)-6-(3-(trifluoromethyl)-lH-pyrazol-l- -l,3,5-triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000341_0002
1H NMR (400 MHz, CDC13) δ 8.80 - 8.11 (m, 3H), 7.63 (m, 1H), 7.17 - 6.97 (m, 1H), 6.76 (t, J = 3.4 Hz, 1H), 5.75 (m, 1H), 4.21 (m, 1H), 2.14 (m, 6H), 1.93 - 1.83 (m, 2H), 1.77 - 1.61 (m, 4H). LCMS: m/z 506 (M+H)+.
Compound l-(4-((4-((3,3-Difluorocyclobutyl)amino)-6-(3-(trifluoromethyl)-lH-pyrazol-l- -l,3,5-triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000341_0003
Ή NMR (400 MHz, CDC13) δ: 8.78 - 8.50 (M, 2H), 8.32 (m, 1H), 7.86 - 7.56 (m, 1H), 7.13 - 6.98 (M, 1H), 6.74 (t, J = 3.9 Hz, 1H), 6.18 (d, J = 6.9 Hz, 1H), 4.85 - 4.42 (M, 1H), 3.28 - 3.05 (m, 2H), 2.83 - 2.47 (m, 2H), 1.91 - 1.85 (m, 2H), 1.76 - 1.69 (m, 2H). LCMS: m/z 478 (M+H)+.
Compound l-(4-((4-(3-(Trifluoromethyl)-lH-pyrazol-l-yl)-6-((l,1 -trifluoropropan-2- yl)amino)-l,3,5-triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000342_0001
1H NMR (400 MHz, CDC13) δ 8.84 - 8.27 (m, 3H), 7.71 (m, 1H), 7.11 (m, 1H), 6.76 (d, J= 2.6 Hz, 1H), 5.91 (d, J = 9.6 Hz, 1H), 5.03 (s, 1H), 1.87 (m, 2H), 1.76 - 1.72 (m, 2H), 1.49 (t, J = 8.4 Hz, 3H). LCMS: m/z 484 (M+H)+.
Compound (R)-l-(4-((4-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-6-((l,1 -trifluoropropan-2- yl)amino)-l,3,5-triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000342_0002
Ή NMR (400 MHz, CDC13) δ 8.65 (s, 1H), 8.48 (d, J = 1.7 Hz, 1H), 8.35 (d, J = 5.5 Hz, 1H), 7.59 (m, 1H), 7.14 (m, 1H), 6.76 (d, J = 2.7 Hz, 1H), 5.75 (m, 1H), 5.02 (s, 1H), 1.93 - 1.76 (m, 2H), 1.69 (m, 2H), 1.49 (t, J = 8.7 Hz, 3H). LCMS: m/z 484 (M+H)+.
Compound (S)-l-(4-((4-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-6-((l,l9l-trifluoropropan-2- yl)amino)-l,3,5-triazin-2-yl)amino)pyridin-2-yl)cyclopropanecarbonitrile
Figure imgf000343_0001
1H NMR (400 MHz, CDC13) δ 8.67 (s, 1H), 8.50 (d, J = 1.4 Hz, 1H), 8.38 (m, 1H), 7.64 (m, 1H), 7.07 (s, 1H), 6.77 (d, J = 2.6 Hz, 1H), 5.82 (m, 1H), 5.34 - 4.85 (m, 1H), 1.97 - 1.85 (m, 2H), 1.77 (m, 2H), 1.57 - 1.44 (m, 3H). LCMS: m/z 484 (M+H)+.
Compound N2-(3,3-difluorocyclopentyl)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000343_0002
Ή NMR (400 MHz, CDC13) δ 8.52 (m, 3H), 8.01 - 7.37 (m, 2H), 6.76 (t, J = 3.7 Hz, 1H), 5.92 (m, 1H), 4.79 - 4.53 (m, 1H), 2.67 (m, 1H), 2.47 - 2.09 (m, 4H), 1.93 - 1.86 (m, 1H).LCMS: m/z 495(M+H)+.
Compound (S)-N2-(3,3-difluorocyclopentyl)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000343_0003
Ή NMR (400MHz, CDC13)5 8.64 - 8.55 (m, 2H), 8.48 - 8.1 1 (m, 1H), 7.75 - 7.41 (m, 2H), 6.77 - 6.75 (m, 1H), 5.97 - 5.73 (m, 1H), 4.71 - 4.61 (m, 1H), 2.74 - 2.61 (m, 1H), 2.42 - 2.36 (m, 2H), 2.30 - 2.16 (m, 2H), 1.93 - 1.86 (m, 1H).LCMS: m/z 495(M+H)+.
Compound N2-(3,3-difluorocyclobutyl)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000344_0001
Ή NMR (400MHz, CD3OD)5 8.69 - 8.62 (m, 1H), 8.51 - 7.67 (m, 3H), 6.84 - 6.834(i
4.51 - 4.29 (m, 1H), 3.09 - 3.02 (m, 2H), 2.68 - 2.64 (m, 2H).LCMS: m/z 481(M+H)+.
Compound N2-(cyclopropylmethyl)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-N4-(2- (trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000344_0002
1H NMR (400 MHz, CDC13) δ 8.87 - 8.36 (m, 3H), 8.27 - 7.44 (m, 2H), 7.01 - 6.54 (m, 1H), 6.17 - 5.80 (m, 1H), 3.43 (m, 2H), 1.35 - 1.01 (m, 1H), 0.75 - 0.56 (m, 2H), 0.43 - 0.24 (m, 2H).LC-MS: m/z 445 (M+H)+.
Compound 6-(3-(Trifluoromethyl)-lH-pyrazol-l-yl)-N2-(2-(trifluoromethyl)pyridin-4-yl)- N4-(l,1 -trifluoropropan-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000345_0001
1H NMR (400 MHz, CDC13) δ 8.69 - 8.08 (m, 3H), 7.68 (m, 2H), 6.77 (d, J= 2.7 Hz, 1H), 5.86 (m, 1H), 4.93 (m, 1H), 1.52 (dd, J = 7.1 Hz, 3H).LC-MS: m/z 487 (M+H)+.
Compound (R)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-N2-(2-(trifluoromethyl)pyridin-4- -N -(l,1 -trifluoropropan-2-yl)-1 ?5-triazine-2,4-diamine
Figure imgf000345_0002
Ή NMR (400 MHz, CDC13) δ 8.74 - 8.48 (m, 2H), 8.46 - 7.74 (m, 2H), 7.72 - 7.34 (m, 1H), 6.77 (d, J = 2.7 Hz, 1H), 6.08 - 5.53 (m, 1H), 5.11 - 4.77 (m, 1H), 1.52 (m, 3H).LC-MS: m/z 487 (M+H)+.
Compound (S)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-N2-(2-(trifluoromethyl)pyridin-4- -N4-(l,1 -trifluoropropan-2-yl)-l^,5-triazine-2,4-diamine
Figure imgf000345_0003
Ή NMR (400 MHz, CDC13) 5 8.65 - 8.61 (m, 1H), 8.56 (d, J = 4 Hz, 1H), 8.37 (m, 1H), 8.08 - 7.81 (m, 1H), 7.70 - 7.44 (m, 1H), 6.76 - 6.68 (m, 1H), 5.97 - 5.78 (m, 1H), 5.05 - 4.82 (m, 1H), 1.53 - 1.49 (m, 3H) .LCMS: m/z 487(M+H)+.
Compound 3-((4-((3,3-Difluorocyclobutyl)amino)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)- -triazin-2-yl)amino)-5-fluorobenzonitrile
Figure imgf000346_0001
1H NMR (400 MHz, CDC13) δ 8.61 -8.54 (m, 1H), 7.86 - 7.78 (m, 1H), 7.69 (s, 1H) 7.60 (d, J = 8 Hz, 1H), 7.13 - 7.08 (m, 1H), 6.76 - 6.74(m, 1H), 6.01 - 5.94 (m, 1H), 4.58 - 4.42 (m, 1H), 3.20 - 3.10 (m, 2H), 2.80 - 2.54 (m, 2H). LCMS: m/z 455 (M+H)+.
Compound 3-Fluoro-5-((4-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-6-((l,1 -trifluoropropan- -yl)amino)- 1 ,395-triazin-2-yl)amino)benzonitrile
Figure imgf000346_0002
1H NMR (400 MHz, CDC13) δ 8.60 - 8.53 (m, 1H), 7.99 - 7.62 (m, 3H),7.14 - 7.09 (m, 1H), 6.76 (d, J = 4 Hz, 1H), 5.90 - 5.82 (m, 1H), 5.04 - 4.98 (m, 1H), 4.87 - 4.81 (m, 3H). LCMS: m/z 461(M+H)+.
Compound 3-((4-((3,3-Difluorocyclopentyl)amino)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)- l,395-triazin-2-yl)amino)-5-fluorobenzonitrile
Figure imgf000347_0001
1H NMR (400 MHz, CDC13) δ 8.63 - 8.55 (m, 1H), 7.83 - 7.66 (m, 3H), 7.12 - 7.08 (m, 1H), 6.77
- 6.75 (m, 1H), 6.68 (d, J = 4 Hz, 1H),6.21 - 5.79 (m, 1H), 5.56 - 4.69 (m, 1H), 2.74-2.50 (m, 1H),2.40-2.15 (m, 4H), 1.94 - 1.89 (m, 1H). LCMS: m/z 469 (M+H)+.
Compound 4-((4-((3,3-Difluorocyclopentyl)amino)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)- l,395-triazin-2-yl)amino)picolinonitrile
Figure imgf000347_0002
H NMR (400 MHz, CDC13) δ 8.74 - 8.31 (m, 4H), 7.83 - 7.51 (m, 1H), 6.76 - 6.67 (m, 1H), 6.24
- 6.19 (m, 1H), 4.70 - 4.55 (m, 1H), 2.78 - 2.62 (m, 1H), 2.45 - 2.13 (m, 4H), 1.98 - 1.91 (m, 1H). LCMS: m/z 452(M+H)+.
Compound (S)-4-((4-((3,3-difluorocyclopentyl)amino)-6-(3-(trifluoromethyl)-lH-pyrazol-l- -l,3,5-triazin-2-yl)amino)picolinonitrile
Figure imgf000347_0003
Ή NMR (400 MHz, DMSO- d6) δ 10.89 (s, 1H), 8.90 (d, J = 8 Hz, 1H), 8.70 - 8.66 (m, 1H), 8.58 - 8.42 (m, 2H), 8.00 - 7.95 (m, 1H), 7.09 (s, 1H), 4.65 - 4.43 (m, 1H), 2.69 - 2.57 (m, 1H), 2.36 - 2.08 (m, 4H), 1.91 - 1.80 (m, 1H) .LCMS: m/z 452 (M+H)+.
Compound 4-((4-((3,3-Difluorocyclobutyl)amino)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)- -triazin-2-yl)amino)picolinonitrile
Figure imgf000348_0001
Ή NMR (400 MHz, CDC13) δ 10.12 (s, 1H), 8.28 - 7.58 (m, 4H), 7.09 - 7.14 (m, 1H), 6.25 (s, 1H), 3.61 - 3.48 (m, 1H), 2.29 - 1.88 (m, 4H). LCMS: m/z 438 (M+H)+.
Compound (R)-4-((4-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-6-((l,1 -trifluoropropan-2- yl)amino)-l,3,5-triazin-2-yl)amino)picolinonitrile
Figure imgf000348_0002
1H NMR (400 MHz, CDC13) δ 8.64 (d, J= 8 Hz, 1H), 8.61 - 8.57 (m, 1H), 8.45 - 8.32 (m, 1H), 8.14 - 7.84(m, 1H), 7.78 - 7.48 (m, 1H), 6.78 - 6.68 (m, 1H), 6.05 - 5.96 (m, 1H), 5.26 - 4.70 (m, 1H),1.57 - 1.51 (m, 3H).LCMS: m/z 444 (M+H)+.
Compound N2-(3,3-difluorocyclopentyl)-N4-(3,5-difluorophenyl)-6-(3-(trifluoromethyl)-lH- pyrazol-l-yl)-l,395-triazine-2,4-diamine
Figure imgf000349_0001
1H NMR (400 MHz, CDC13) δ 8.65 - 8.51 (m, 1H), 7.65 - 7.40 (m, 1H), 7.23 (m, 2H), 6.78 - 6.69 (m, 1H), 6.64 - 6.50 (m, 1H), 5.95 - 5.70 (m, 1H), 4.74 - 4.51 (m, 1H), 2.78 - 2.58 (m, 1H), 2.44 - 2.06 (m, 4H), 1.87 (d, J= 3.8 Hz, 1H). LC-MS: m/z 462 (M+H)+.
Compound N2-(3,3-difluorocyclobutyl)-N4-(3,5-difluorophenyl)-6-(3-(trifluoromethyl)-lH- pyrazol-l-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000349_0002
Ή NMR (400 MHz, CDC13) δ 8.73 - 8.40 (m, 1H), 7.61 (m, 1H), 7.22 (m, 2H), 6.73 (dd, J = 6.7, 2.7 Hz, 1H), 6.61 - 6.43 (m, 1H), 6.00 (m, 1H), 4.44 (m, 1H), 3.29 - 3.02 (m, 2H), 2.85 - 2.38 (m, 2H). LC-MS: m/z 448 (M+H)+.
Compound N2-(3,5-difluorophenyl)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)-N4-(l,1 - trifluoropropan-2-yl)-l,3,5-triazine-2,4-diamine
Figure imgf000349_0003
Ή NMR (400 MHz, CDC13) δ 8.62 - 8.51 (m, 1H), 7.78 - 7.35 (m, 1H), 7.25 - 7.12 (m, 2H), 6.74 (d, J = 2.0 Hz, 1H), 6.65 - 6.52 (m, 1H), 5.85 - 5.62 (m, 1H), 5.06 - 4.80 (m, 1H), 1.48 (m, 3H). LC-MS: m z 454 (M+H)+.
Compound l-((4-((3,5-Difluorophenyl)amino)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl)- -triazin-2-yl)amino)-2-methylpropan-2-ol
Figure imgf000350_0001
1H NMR (400 MHz, CDC13) δ 8.53 (d, J = 4 Hz, 1H), 7.70 - 7.53 (m, 1H), 7.23 - 7.19 (m, 2H), 6.71 - 6.67 (m, 1H), 6.57 - 6.51 (m, 1H), 6.28 - 6.08 (m, 1H), 3.73 - 3.56 (m, 2H), 2.46 - 1.49 (m, 6H), 1.24 (m,lH). LCMS: m/z 430 (M+H)+ .
Example 37. Preparation of Aromatic-aliphatic Triazine Compounds of Formula Ic. The compounds of this Example are prepared by general Scheme 37, set forth below.
Scheme 37
Figure imgf000351_0001
Step 1: Preparation of 4,6-dichloro-N-(2-(trifluoromethyl)pyridin^-yl)-l,3,5-triazin-2-amine.
To a solution of 2-(trifluoromethyl)pyridin-4-amine (3 g, 18.7 mmol) and 2,4,6-trichloro-l,3,5- triazine (3.6 g, 19.5 mmol) in THF (40 mL) was added NaHC03(3.1 g,37.5 mmol). The reaction mixture was stirred at r.t. for 16 hr and filtered. The filtrate was concentrated concentratedand purified by standard methodsto affordthe desired product.LC-MS: m/z 310 (M+H)+.
Step 2: Reparation of d-chloro-^-fS^-difluorocyclobutylj-N^^-ftrifluoromethyljpyridin^- yl)-l,3,5-triazine-2,4-diamine. To a solution of 4,6-dichloro-N-(2-(trifluoromethyl)pyridin-4-yl)- l,3,5-triazin-2-amine (4 g, 12.9 mmol) and 3,3-difluorocyclobutanamine hydrochloride (1.9 g, 13.5 mmol) in THF (40 mL) was added DIPEA (4.8 g, 37.2 mmol). The reaction mixture was stirred at r.t. for 15 hr then concentrated under reduced pressure The residue was partitioned between EtOAc (200 mL) and aq. HCl (10%wt, 50 mL). The aqueous layer was separated and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2S04,concentratedand purified by standard methodsto affordthe desired product.
LC-MS: m/z 381 (M+H)+. Step ^.'Preparation of 4-(3,3-difluorocyclobutylamino)-6-(2-(trifluoromethyl)pyridin-4- ylamino)-l,3,5-triazine-2-carbonitrile. To a solution of 6-chloro-N2-(3,3-difluorocyclobutyl)- N4-(2-(trifluoromethyl)pyridin-4-yl)-l,3,5-triazine-2,4-diamine (2.2 g, 5.77 mmol) in MeCN (30 mL) and DMSO (10 mL) at r.t. was added NaCN (2.9 g, 60 mmol). The reaction mixture was stirred at 60°C overnight then partitioned between EtOAc (50 mL) and H20 (20 mL).The organic layer was separated, washed with brine, dried over anhydrous Na2S04, concentratedand purified by standard methodsto affordthe desired product.LC-MS: m/z 372 (M+H)+.
Step 4: Preparation of 4-(3,3-difluorocyclobutylamino)-6-(2-(trifluoromethyl) pyridin-4- ylamino)-l,3,5-triazine-2-carbothioamide. To a solution of 4-(3,3-difluorocyclobutylamino)-6- (2-(trifluoromethyl)pyridin-4-ylamino)-l,3,5-triazine-2-carbonitrile (0.7 g, 1.88 mmol) in DMF (15 mL) were added NaHS (0.5 g, 9.0 mmol) and MgCl2 (0.85 g, 9.0 mmol). The reaction mixture was stirred at r.t. for 0.5 hr then partitioned between EtOAc (30 mL) and H20 (10 mL).The organic layer was separated, washed with brine, dried over anhydrous Na2SC>4, and concentratedand purified by standard methodsto affordthe desired product.LC-MS: m/z 406 (M+H)+.
Step 5: Preparation of 2-(4-(3,3-difluorocyclobutylamino)-6-(2-(trifluoromethyl)pyridin-4- ylamino)-l, 3, 5-triazin-2-yl)-4-(trifluoromethyl)-4,5-dihydrothiazol-4-ol A mixture of 4-(3,3- difluorocyclobutylamino)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-l,3,5-triazine-2- carbothioamide (350 mg, 0.86 mmol) and 3-bromo-l,l,l -trifluoropropan-2-one (180 mg, 0.95 mmol) in MeCN (10 mL) was stirred at 60°C for 2 hr then partitioned between EtOAc (20 mL) and H20 (10 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2S04, and concentratedand purified by standard methodsto affordthe desired product.
Ή NMR (400 MHz, DMSO-d6) δ 10.94 - 10.86 (m, 1H), 9.08 (d, J = 6.0 Hz, 1H), 8.69 - 8.48 (m, 2H), 7.86 - 7.78 (m, 2H), 4.30 - 4.21 (m, 1H), 3.76 - 3.71 (m, 1H), 3.53 - 3.41 (m, 1H), 3.11 - 2.93 (m, 2H), 2.87 - 2.66 (m, 2H). LC-MS: m/z 516 (M+H)+.
Step 6: Preparation of N2-(3,3-difluorocyclobutyl)-]^-(2-(trifluoromethyl)pyridin-4-yl)-6-(4- (trifluoromethyl)thiazol-2-yl)-l,3,5-triazine-2,4-diamine. To a solution of 2-(4-(3,3- difluorocyclobutylamino)-6-(2-(trifluorom
(trifluoromethyl)-4,5-dihydrothiazol-4-ol (250 mg, 0.48 mmol) and TEA (0.4 mL, 2.4 mmol) in DCM (20 mL) at 0°C was added dropwise a solution of triphosgene (290 mg, 0.96 mmol) in DCM (5 mL). The reaction mixture was stirred at 0°C for 0.5 hr, and then partitioned between DCM (20 mL) and H20 (10 mL).The organic layer was separated, washed with brine, dried over anhydrous Na2S04, and concentratedand purified by standard methodsto affordthe desired product. XH NMR (400 MHz, DMSO-d6) δ 11..05 -10.94 (m, 1H), 9.10 (d, J = 6.1 Hz, 1H), 8.82 (s, 1H), 8.70 (s, 1H), 8.64 (t, J = 5.4 Hz, 1H), 7.83 (d, J = 5.4 Hz, 1H), 4.52 - 4.22 (m, 1H), 3.18 - 2.99 (m, 2H), 2.82 (dt, J= 32.2, 14.2 Hz, 2H).LC-MS: m/z 498 (M+H)+.
The procedure set forth above in Example 37 used to produce the following compounds using the appropriate starting materials.
Compound N2-(cyclopropylmethyl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-6-(4- (trifluoromethyl)thiazol-2-yl)-l,395-triazine-2,4-diamine
Figure imgf000353_0001
H NMR (400 MHz, CDC13) δ 8.61 (t, J = 5.7 Hz, 1H), 8.52 - 8.15 (m, 1H), 7.99 (s, 1H), 7.77 - 7.41 (m, 2H), 6.09 - 5.70 (m, 1H), 3.50 - 3.34 (m, 2H), 1.20 - 1.11 (m, 1H), 0.67 - 0.57 (m, 2H), 0.40 - 0.28 (m, 2H). LC-MS: m/z 462 (M+H)+.
Compound N2-(3,3-difluorocyclopentyl)-N4-(2-(trifluoromethyl)pyridin-4-yl)-6-(4- (trifluoromethyl)thiazol-2-yl)-l,395-triazine-2,4-diamine
Figure imgf000354_0001
1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.83 (d, J = 6.9 Hz, 1H), 8.75 (s, 1H), 8.62 (s, 1H), 8.57 (d, J = 5.5 Hz, 1H), 7.79 (d, J = 5.5 Hz, 1H), 4.61 - 4.32 (m, 1H), 2.59 - 2.51 (m, 1H), 2.41 - 1.99 (m, 4H), 1.95 - 1.74 (m, 1H). LC-MS: m/z 512 (M+H)+.
Compound N2-(3,3-difluorocyclopentyl)-N4-(3,5-difluorophenyl)-6-(4- (trifluoromethyl)thiazol-2-yl)-l,395-triazine-2,4-diamine
Figure imgf000354_0002
Ή NMR (400MHz, CDC13)5 7.97(s, 1H), 7.45 - 7.26 (m, 4H), 7.25 - 7.23 (m, 1H), 6.60 - 6.56 (m, 1H), 5.92 - 5.34 (m, 1H), 4.68 - 4.57 (m, 1H), 2.70 - 2.64 (m, 1H), 2.37 - 2.16 (m, 4H), 1.87(s, 1H).LCMS: m/z 479(M+H)+.
Compound N2-(3,3-difluorocyclobutyl)-N4-(3,5-difluorophenyl)-6-(4- (trifluoromethyl)thiazol-2-yl)-l,395-triazine-2,4-diamine
Figure imgf000354_0003
Ή NMR (400MHz, CDC13)5 7.97(d,J=4Hz, 1H), 7.60 - 7.47 (m, 1H), 7.26(m, 1H), 7.26 - 7.22 (m, 1H), 6.61 - 6.53 (m, 1H), 6.00 - 5.74 (m, 1H), 4.52 - 4.41 (m, 1H), 3.15(s, 2H), 2.70 - 2.57 (m, 2H). LCMS: m/z 465(M+H)+.
Compound 3-((4-((3,3-Difluorocyclobutyl)amino)-6-(4-(trifluoromethyl)thiazol-2-yl)-l,3,5- triazin-2-yl)amino)-5-fluorobenzonitrile
Figure imgf000355_0001
1H NMR (400MHz, CDC13)5 8.01(s, 1H), 7.87 - 7.797(m, 2H), 7.66 (d,J=8Hz, 1H), 7.14 - 7.10 (m, 1H), 5.99 - 5.75 (m, 1H), 4.72 - 4.58 (m, 1H), 2.79 - 2.65 (m, 1H), 2.40 - 2.18 (m, 3H).LCMS: m/z 472(M+H)+.
Compound 3-((4-((3,3-Difluorocyclopentyl)amino)-6-(4-(trifluoromethyl)thiazol-2-yl)-l,395- triazin-2-yl)amino)-5-fluorobenzonitrile
Figure imgf000355_0002
Ή NMR (400MHz, CDC13)5 8.00(s, 1H), 7.28 - 7.02 (m, 3H), 6.61 (s, 1H), 6.01 - 5.76 (m, 1H), 4.51 . 4.44 (m5 m), 3.18(s, 1H), 2.63(m, 2H), 1.60 - 1.50(m, 1H), 1.27 -1.10 (m, 2H).LCMS: m/z 486(M+H)+.
Example 38.Preparation of Dialiphatic Pyrimidine Compounds of Formula S. The compounds of this Example are prepared by general Scheme 32, set forth below. Scheme 32
Figure imgf000356_0001
Formula S
Step 1: Preparation of methyl 6-chloropicolinimidate. To a solution of 6-chloropicolinonitrile (3 g, 22 mmol) in MeOH (25 mL) was added a freshly prepared solution of sodium metal (55 mg, 2.4 mol) in MeOH (5 mL). The reaction mixture was stirred at r.t. for 16 hr, and then concentrated under reduced pressure to afford the desired product. LC-MS: m/z 171 (M+H)+.
Step 2: Preparation of 6-chloropicolinimidamide. A mixture of ammonium chloride (2.18 g, 40mmol) and methyl 6-chloropicolinimidate (3.5 g, 20mmol) in MeOH (30 mL) was a stirred at 70°C for 3 hr, then cooled to r.t. and concentrated under reduced pressure. The residue was diluted with EtOH (40 mL) and stirred at reflux for 0.5 hr. The resulting mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to give thedesired product.LC-MS: m/z l56 (M+H)+.
Step 3: Preparation of 2-(6-chloropyridin-2-yl)pyrimidine-4,6-dioL To a solution of sodium metal (0.9 g, 40mmol) in MeOH (10 mL) was added 6-chloropicolinimid -amide (2 g, 13 mmol) and dimethyl malonate (1.7 g, 13 mmol).The reaction mixture was stirred at 85°C overnight, and then concentrated under reduced pressure. The residue was triturated with EtOAc (30 mL) and filtered. The solid was collected and dried under high vacuum to give the desired product.LC-MS: m/z 224 (M+H)+. Step 4: Preparation of 4,6-dichloro-2-(6-chloropyridin-2-yl)pyrimidine. A mixture of 2-(6- chloropyridin-2-yl)pyrimidine-4,6-diol (2 g, 9 mmol) in POCl3 (20 mL) was stirred at 90 °C overnight then concentrated under reduced pressure. The residue was slowly poured into satd. aq. NaHC03 at 0°C. The resulting mixture was extracted with EtOAc (2 x 30 mL). Combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2S04and concentrated under reduced pressure. The residue was purified by standard methods to give the desired product.LC-MS: m/z 260 (M+H)+.
Step 5: Preparation of (R)- 6-chloro-2- ( 6-ch loropyridin -2-yl)-N- (J, J, J -trifluoropropan -2- yl)pyrimidin-4-amine. A mixture of 4,6-dichloro-2-(6-chloropyridin-2-yl)pyrimidine ( 200 mg, 0.77 mmol ), l ,l ,l -trifluoropropan-2-amine hydrochloride (255 mg, 1.7 mmol), CsF ( 258 mg, 1.7 mmol), and DIPEA (497 mg, 3.85 mmol) in DMSO (3 mL) was stirred at 100°C overnight. The resulting mixture was quenched with H20 (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified bystandard methods to give the desired product.1H NMR (400 MHz, DMSO-d6) δ 8.37 (m, 2H), 8.04 (m, 1H), 7.68 (d, J= 8 Hz, 1H), 6.89 (m, 1H), 5.02 (m, 1H), 1.38 (d, J= 8 Hz, 3H).LC-MS: m/z 337 (M+H)+.
Step 6: Preparation of (R)-2-(6-chloropyridin-2-yl)-Nt-(4,4-difluorocyclohexyl)-I A-(1,1,1- trifluoropropan-2-yl)pyrimidine-4,6-diamine. A mixture of (R)-6-chloro-2-(6-chloropyridin-2- yl)-N-(l ,l ,l -trifluoropropan-2-yl)pyrimidin-4-amine (100 mg, 0.3 mmol ) , 4,4- difluorocyclohexanamine hydrochloride ( 114 mg, 0.66 mmol), CsF (100 mg, 0.66 mmol), and DIPEA (194 mg, 1.5 mmol) in DMSO (3 mL) was stirred at 100°C overnight.The resulting mixture was quenched with H20 (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (30 mL) , dried over anhydrous Na2S04, concentrated, andpurified bystandard methods to give the desired product.
Figure imgf000358_0001
1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 8 Hz, 1H), 8.15 (s, 1H), 7.96 (m, 1H), 7.56 (d, J = 8 Hz, 1H), 7.31 (m, 1H), 7.06 (d, J= 8 Hz, 1H), 5.62 (m, 1H), 5.30 - 4.84 (m, 1H), 2.33 (m, 1H), 2.14 - 1.90 (m, 5H), 1.65 (m, 2H), 1.32 (d, J= 8 Hz, 3H).LCMS: m/z 436 (M+H)+
Example 8.Enzymatic and Cell Assays
In Vitro Assays for IDHlm (R132H or R132C)Inhibitors
The following describes the experimental procedures that can be used to obtain data on columns 2 and 4 of Table 4 and column 2 of Table 5.
In the primary reaction, the reduction of a-KG acid to 2-HG is accompanied by a concomitant oxidation of NADPH to NADP. The amount of NADPH remaining at the end of the reaction time is measured in a secondary diaphorase/resazurin reaction in which the NADPH is consumed in a 1 :1 molar ratio with the conversion of resazurin to the highly fluorescent resorufin. Uninhibited reactions exhibit a low fluorescence at the end of the assay, while reactions in which the consumption of NADPH by R132H IDH1 has been inhibited by a small molecule show a high fluorescence.
The primary reaction is performed in a volume of 50 μϋ, IX Buffer (150 raM NaCl, 20 mM Tris 7.5, 10 mM MgCl2, 0.05% (w/v) bovine serum albumin), contained 0.25 ug/mL (2.7 nM) IDH1 wt / IDH1 R132H heterodimer, 0.3 mM alpha-ketoglutarate, 4 μΜ NADPH, and either 300 μΜ ΝΑΟΡ (saturated) or 30 μΜ NADP (without saturation), and 1 uL of 5 OX compound in DMSO. The mixture of compound, enzyme, and cofactor is pre-incubated at room temperature for 1 hr prior to the addition of alpha-ketoglutarate. To perform the secondary reaction, 10 uL of IX buffer containing 36 μg/ml diaphorase and 30 mM resazurin is added to the primary reaction and incubated for a further 5 minutes at 25°C. Florescence is read on a Spectramax platereader at Ex 544 Em 590. Compounds or compound dilutions are prepared in 100% DMSO concentration and diluted 1 :50 into the final reaction. IDH1 wt / IDH1 R132C is assayed under similar conditions except that IX Buffer is 50 mM K2HP04, pH 6.5; 10 raM MgCl2; 10% glycerol; 0.03% (w/v) bovine serum albumin and final concentrations are 0.4 ug/mL (4.3 nM) IDH1 wt / IDH1 R132C heterodimer, 0.02 mM alpha-ketoglutarate, 4 uM NADPH, and either 300 μΜ NADP (saturated) or 30 μΜ NADP (without saturation). IC50s are determined.
IDH1 or IDH2 wildtype (wt) and mutant heterodimers are expressed and purified by methods known in the art. For example, IDH1 wt R132m heterodimer is expressed and purified as follows. Co-expression of IDHlwt-his and IDHlR132C-flagis carried out in sf9 insect cells.
Cells (25g) are resuspended in 250 ml of 50mM Tirs, 500mM NaCl, pH7.4, at 4°C with stirring.
Cells are disrupted with 4 passes through an M-Yl 10 Micro fluidizer (Microfluidics) set to 500 psi, and then centrifuged at 22,000 rcf for 20min at 4°C. The supernatant is harvested and loaded
at 15cm/h on a Histrap FF 5*lml column (GE) which is equilibrated with 50mM Tirs, 500mM NaCl, pH7.4. Host cell contaminants are removed by washing the column with equilibration buffer followed by equilibration buffer containing 20mM imidazole and 60mM imidazole to baseline. IDHlwt-his homodimer and IDHlwt-his / IDHlR132C-flag are eluted by equilibration buffer containing 250mM imidazole. Fractions eluted by 250mM imidazole are pooled together and loaded at 15cm/h onto a column pre-packed with 10ml ANTI-FLAG® M2 Affinity Gel (Sigma), the column is equilibrated with 50mM Tris, 500mM NaCl, pH7.4. After washing with equilibration buffer, IDHlwt-his/IDHlR132C-flag heterodimer is eluted by equilibration buffer containing flag peptide (0.2mg/ml). Aliquots of IDHlwt-his/IDHlR132C-flag are flash frozen in liquid N2 and stored at -80°C.Same conditions are used for the purification of IDHlwt-
his/IDHlR132H-flag.
In Vitro Assays for IDHlm (R132H or R132C) Inhibitors
The following describes the experimental procedures that can be used to obtain data on columns 3 and 6 of Table 4.
A test compound is prepared as 10 mM stock in DMSO and diluted to 50X final concentration in DMSO, for a 50 μΐ reaction mixture. IDH enzyme activity converting alpha- ketoglutarate to 2-hydroxyglutaric acid is measured using a NADPH depletion assay. In the assay the remaining cofactor is measured at the end of the reaction with the addition of a catalytic excess of diaphorase and resazurin, to generate a fluorescent signal in proportion to the amount of NADPH remaining. IDH1-R132 homodimer enzyme is diluted to 0.125 μg/ml in 40 μΐ of Assay Buffer(l 50 mM NaCl, 20 mM Tris-Cl pH 7.5, 10 mM MgCl2, 0.05% BSA, 2 mM b- mercaptoethanol); 1 μΐ of test compound dilution in DMSO is added and the mixture is incubated for 60 minutes at room temperature. The reaction is started with the addition of 10 μΐ of
Substrate Mix (20 μΐ NADPH, 5 mM alpha-ketoglutarate, in Assay Buffer) and the mixture is incubated for 90 minutes at room temperature. The reaction is terminated with the addition of 25 μΐ of Detection Buffer (36 μg/ml diaphorase, 30 mM resazurin, in IX Assay Buffer), and is incubated for 1 minute before reading on a SpectraMax platereader at Ex544/Em590.
Compounds are assayed for their activity against IDH1 R132C following the same assay as abovewith the following modifications: Assay Buffer is (50 mM potassium phosphate, pH 6.5; 40 mM sodium carbonate, 5 mM MgCl2, 10% glycerol, 2 mM b-mercaptoethanol, and0.03% BSA). The concentration of NADPH and alpha-ketoglutarate in the Substrate Buffer is 20 μΜ and 1 mM, respectively.
In Vitro Assays for IDHlm (R132H or R132C) Inhibitors The following describes the experimental procedures that can be used to obtain data oncolumns 3 and 5 of Table 5.
A test compound is prepared as 10 mM stock in DMSO and diluted to 50X final concentration in DMSO, for a 50 μΐ reaction mixture. IDH enzyme activity converting alpha- ketoglutarate to 2-hydroxyglutaric acid is measured using a NADPH depletion assay. In the assay the remaining cofactor is measured at the end of the reaction with the addition of a catalytic excess of diaphorase and resazurin, to generate a fluorescent signal in proportion to the amount of NADPH remaining. IDH1-R132H homodimer enzyme is diluted to 0.125 μg/ml in 40 μΐ of Assay Buffer(l 50 mM NaCl, 20 mM Tris-Cl pH 7.5, 10 mM MgCl2, 0.05% BSA, 2 mM b- mercaptoethanol) containing 5 μΜ NADPH and 37.5 μΜ ΝΑΟΡ; 1 μΐ of test compound dilution in DMSO is added and the mixture is incubated for 60 minutes at room temperature. The reaction is started with the addition of 10 μΐ of Substrate Mix (20 μΐ NADPH, 5 mM alpha- ketoglutarate, in Assay Buffer) and the mixture is incubated for 60 minutes at room temperature. The reaction is terminated with the addition of 25 μΐ of Detection Buffer (36 μg/ml diaphorase, 30 mM resazurin, in IX Assay Buffer), and is incubated for 1 minute before reading on a SpectraMax platereader at Ex544 Em590.
Compounds are assayed for their activity against IDH1 R132C following the same assay as abovewith the following modifications: IDH1-R132C homodimer enzyme is diluted to 0.1875 μg/ml in 40 μΐ of Assay Buffer (50 mM potassium phosphate, pH 6.5; 40 mM sodium carbonate, 5 mM MgCl2, 10% glycerol, 2 mM b-mercaptoethanol, and0.03% BSA) containing 5 uM NADPH and 28.75 uM NADP. The concentration of alpha-ketoglutarate in the Substrate Buffer is 1 mM.
In Vitro Assays for IDH2m R140QInhibitors
The following describes the experimental procedures used to obtain data on column 7 of Table 4.
Compounds are assayed for IDH2 R140Qinhibitory activity through a cofactor depletion assay. Compounds are preincubated with enzyme, then the reaction is started by the addition of NADPH and a-KG, and allowed to proceed for 60 minutes under conditions previously demonstrated to be linear with respect for time for consumption of both cofactor and substrate. The reaction is terminated by the addition of a second enzyme, diaphorase, and a corresponding substrate, resazurin. Diaphorase reduces resazurin to the highly fluorescent resorufin with the concomitant oxidation of NADPH to NADP, both halting the IDH2 reaction by depleting the available cofactor pool and facilitating quantitation of the amount of cofactor remaining after a specific time period through quantitative production of an easily detected fluorophore.
Specifically, into each of 12 wells of a 384-well plate, 1 μΐ of ΙΟΟχ compound dilution series is placed, followed by the addition of 40 μΐ of buffer (50 mM potassium phosphate (K2HPO4), pH 7.5; 150 mM NaCl; 10 mM MgCl2, 10% glycerol, 0.05% bovine serum albumin, 2 mM beta-mercaptoethanol) containing 0.25 μg/ml IDH2 R140Q protein. The test compound is then incubated for one hour at room temperature with the enzyme; before starting the IDH2 reaction with the addition of 10 μΐ of substrate mix containing 4 μΜ NADPH and 1.6 mM a-KG in the buffer described above. After a further 16hours of incubation at room temperature, the reaction is halted and the remaining NADPH measured through conversion of resazurin to resorufin by the addition of 25 μΐ Stop Mix (36 μg/ml diaphorase enzyme and 60 μΜ resazurin; in buffer). After one minute of incubation the plate is read on a plate reader at Ex544 Em590.
For determination of the inhibitory potency of compounds against IDH2 R140Q in an assay format similar to the above, a similar procedure is performed, except that the final testing concentration is 0.25 ^πιΐ IDH2 R140Q protein, 4 μΜ NADPH and 1.6 mM a-KG.
For determination of the inhibitory potency of compounds against IDH2 R140Q in a high throughput screening format, a similar procedure is performed, except that 0.25 μg/ml IDH2 R140Q protein is utilized in the preincubation step, and the reaction is started with the addition of 4 μΜ NADPH and 8 μΜ α-KG.
In Vitro Assays for IDH2m R140Q Inhibitors
The following describes the experimental procedures used to obtain data on column 6 of Table 5.
Compounds are assayed for IDH2 R140Q inhibitory activity through a cofactor depletion assay. Compounds are preincubated with enzyme and cofactor, then the reaction is started by the addition ofa-KG, and allowed to proceed for 60 minutes under conditions previously demonstrated to be linear. The reaction is terminated by the addition of a second enzyme, diaphorase, and a corresponding substrate, resazurin. Diaphorase reduces resazurin to the highly fluorescent resorufin with the concomitant oxidation of NADPH to NADP, both halting the IDH2 reaction by depleting the available cofactor pool and facilitating quantitation of the amount of cofactor remaining after a specific time period through quantitative production of an easily detected fluorophore.
Specifically, into each of 12 wells of a 384-well plate, 1 μΐ of 50x compound dilution series is placed, followed by the addition of 40 μΐ of buffer (50 mM potassium phosphate (K2HP04), pH 7.5; 150 mM NaCl; 10 mM MgCl2, 10% glycerol, 0.05% bovine serum albumin, 2 mM beta-mercaptoethanol) containing 0.39 ^πιΐ IDH2 R140Q protein, 5 uM NADPH and 750 uM NADP. The test compound is then incubated for 16 hrs at room temperature with the enzyme and cofactors before starting the IDH2 reaction with the addition of 10 μΐ of substrate mix containing 8 mM a-KG (final concentration 1.6 mM) in the buffer described above. After a further 1 hour of incubation at room temperature, the reaction is halted and the remaining NADPH measured through conversion of resazurin to resorufin by the addition of 25 μΐ Stop Mix (36 μg/ml diaphorase enzyme and 60 μΜ resazurin; in buffer). After one minute of incubation the plate is read on a plate reader at Ex544 Em590.
Cellular Assays for IDHlm (R132H or R132C) Inhibitors
The following describes the experimental procedures that can be used to obtain data on column 5 of Table 4.
Cells (HT1080 or U87MG) are grown in T125 flasks in DMEM containing 10% FBS, lx penicillin/streptomycin and 500ug/mL G418 (present in U87MG cells only). They are harvested by trypsin and seeded into 96 well white bottom plates at a density of 5000 cell/well in 100 ul/well in DMEM with 10% FBS. No cells areplaced in columns 1 and 12. Cells are incubated overnight at 37°C in 5% C02. The next day test compounds aremade up at 2x the final concentration and lOOul are added to each cell well. The final concentration of DMSO is 0.2% and the DMSO control wells areplated in row G. The plates arethen placed in the incubator for 48 hours. At 48 hours, lOOul of media isremoved from each well and analyzed by LC-MS for 2- HG concentrations. The cell plate isplaced back in the incubator for another 24 hours. At 72 hours post compound addition, 10 mL/plate of Promega Cell Titer Glo reagent is thawed and mixed. The cell plate is removed from the incubator and allowed to equilibrate to
roomtemperature. Then lOOul of Promega Cell Titer Glo reagent is added to each well of media. The cell plate is then placed on an orbital shaker for 10 minutes and then allowed to sit at room temperature for 20 minutes. The plate is then read for luminescence with an integration time of 500ms.
U87MG pLVX-IDH2 R140Q-neo and HT1080 Cell Based Assays
The following describes the experimental procedures that are used to obtain data on column 8 of Table 4.
U87MGpLVX-IDH2R140Q-neo cells aremaintained in DMEM containing 10% FBS, lx penicillin/streptomycin and 500μg/uL G418. HT1080 cells aremaintained in RPMI containing 10% FBS, lx penicillin/streptomycin. Cells are seeded at a density of 5,000 (U87MGR140Q) or 2,500 (HT1080) cells/well into 96-well microtiter plates and incubated overnight at 37°C and 5% C02. The next day compounds are prepared in 100% DMSO and then diluted in media for a final concentration of 0.2% DMSO. Media is removed from the cell plates and 200 \xL of the compound dilutions are added to each well. After 48 hours of incubation with compound at 37°C, 100 μΐ. of media areremoved from each well and analyzed by LC-MS for 2-HG concentrations as described in Dang, L. et al. Nature, 2009, 462, 739-744. The cell plates arethen allowed to incubate another 24 hours. At 72 hours post compound addition, Promega Cell Titer Glo reagent is added to each well and the plates are read for luminescence to determine any compound effects on growth inhibition (GI5o).
Cellular Assay for IDHlm R132H Inhibitors
The following describes the experimental procedures that can be used to obtain data in column 4 of Table 5.
Neurosphere cells (TS603) are grown at 37C in 5% C02 in Stem Cell Technologies NeuroCult™ NS-A media supplemented with 1% Primocin, 1% Normocin, 0.0002% Heparin, 20ng/mL EGF and lOng/mL bFGF. Cells are harvested, pelleted and resuspended in Accumax for cell dissociation and counting. Cells are counted and then resuspended in NeuroCult media with 2x heparin, EGF and bFGF at 4 million cells/1 OmL media. 1 ΟΟμΙ of cell solution are plated in each well of a 96 well with the exception of columns 1 and 12. Columns 1 and 12 contain 200μί PBS. Compound dose responses are set up at a 2x concentration in Neurocult media without heparin, EGF and bFGF. The final concentration of DMSO is 0.25%. DMSO only control wells are plated in row H. The plates are then placed in the incubator for 48 hours. At 48 hours, ΙΟΟμΙ of media is removed from each well and analyzed by LC-MS for 2-HG concentrations. The cell plate is placed back in the incubator for another 24 hours. At 72 hours post compound addition, 10 mL/plate of Promega Cell Titer Glo reagent is thawed and mixed. The cell plate is removed from the incubator and allowed to equilibrate to room temperature. Then ΙΟΟμΙ of Promega Cell Titer Glo reagent is added to each well of
media. The cell plate is then placed on an orbital shaker for 10 minutes and then allowed to sit at room temperature for 20 minutes. The plate is then read for luminescence with an integration time of 500ms.
The data for various compounds of one aspect of the invention in the R132Henzymatic assay, R132Cenzymatic assay, R140Q enzymatic assay, R132C cell-based assay, and R140Q cell-based assay as described above or similar thereto are presented below in Tables 2 and 3. For each assay, values indicated as "A" represent an IC50 of less than 50 nM; values indicated as "B" represent an IC50 of between 50 nM and 100 nM; values indicated as "C" represent an IC50 of greater than 100 nM and less than 1 μΜ; values indicated as "D" represent an IC50 of greater than or equal to 1 μΜ; values indicated as "no fit" are inactives and blank values represent that the compound was either inactive or not tested in that particular assay.
Table 4. Inhibitory Activities of Representative Compounds of formula I
IDHl
wt/R132H IDHl
NADPH / IDHl wt/R132C IDHl IDH2
Compound HT1080 U87MG
NADP R132H NADPH / R132C R140Q
No. IC50 IC50
IC50 IC50 NADP IC50 IC50
not IC50
saturated
1 D D A A
2 A A A A A
3 C B B B B A
D No Fit
D C
C D A
No Fit D B
B C A
D D B
C B B A
D D B
A A B
D D D
D D
D D A
B A B
A B B
B B B
A B B A
D D A
B C A
B B
D D
D D
C D A
B C
A B B B
C D
B C B
A A A A
D D
A A B
A A B
D D
A A B
B D
B C
A B B
B B
B D
B C
C D C D
A B
D D
D No Fit
D No Fit
D D
A A B
D D
B A
C B
D D
C B
B A
D D
A A
A
A
D
B
B
B
Fit
D
D
C
B
B
D B
A B
A B
B A
B B B A
D C
No Fit D B
D D B
C B B A
D D B
D D A
D D
D D 85 B C B
86 B D D
87 B D
88 D D
89 D D
90 C B
91 D D
92 D D
93 D
94 D
95 D
96 D
100 A A A
101 A A A A A
102 A A A A
103 A A A A
104 A A A A
105 A A A A A
106 A C A A
107 A C A A
108 A B A A
109 A A A
110 A A B A A
111 A A A A
112 A C A A
113 A A A A A
114 A A A A
115 A A C A A
116 A C A A
117 A A D A A
118 A A A A
119 A B A A
120 A A A
121 A A A A A
122 A B A A
123 A A C A A
124 A A A A
125 A A A A
126 A A A A
127 A A B A A 128 A A A A A
129 A A A
130 A A A A A
131 A A A A
132 A C A A
133 A C A A
134 A A A A A
135 A
136 A A A A A
137 A B A A
138 A A A A
139 A A A
140 A C A A
141 A A A A
142 A A A A A
143 A B A A
144 A A A A
145 A A C A A
146 A A A A
147 A A C A A
148 A A A
149 A A B A A
150 A A A
151 A A B A A
152 A A A A
153 A B A A
154 A C A A
155 A B A A
156 A A A A
157 A A B B
158 A C A A
159 A C A A
160 A A A A
161 A A A A
162 A A A A
163 A C A A
164 A A A A
165 A C A A
166 A C
167 A A A A
A A A A 169 A A A A
170 A A A A
171 A C A A
172 A B A A
173 A B A A
174 A B A A
175 A C A A
176 A A C A A
177 A B A A
178 A A C A A
179 A C A A
180 A A B C
181 A A C A A
182 A A A A
183 A B A A
184 A A A
185 A B A A
186 A C A A
187 A A A A
188 A A
189 A A C A A
190 A C A A
191 A A C A A
192 A A C A A
193 A A A A
194 A B B B
195 A C A A
196 A B B C
197 A C A A
198 A A A
199 A A A A
200 A D A A
201 A B A A
202 A C A A
203 A A A A A
204 A A A
205 A B A A
206 A
207 A C A A
208 A
209 A C A A 210 A C A A
211 A C A A
212 A B A A
213 A A A A
214 A A A A
215 A C A A
216 A C A A
217 A C A A
218 A C A A
219 A
220 A C B B
221 A D A A
222 A B C C
223 A B A A
224 A A C A A
225 A
226 A B A A
227 A B C C
228 A A A
229 A B C A A
230 A A A
231 A B D A A
232 A D A A
233 A
234 A
235 A C A A
236 A D A A
237 A A C A A
238 A C
239 A C
240 A
241 A C
242 B B
243 B c
244 B C D A A
245 B C A A
246 B B B B
247 B B A A
248 B C C A
249 B C A C 25Q B C C 251 B C A C
252 B c A A
253 B c A A
254 B
255 C c C
256 C B A A
257 C C A A
258 C D A
259 C A A
260 C B D A A
261 C B A A
262 C C
263 C C C
264 C C
265 C C
266 C C D
267 C C A A
268 C A C B B
269 C
270 C C C C
271 C C
272 C C C C C
273 C C D
274 C C
275 C
276 C C
277 C B B
278 C D D
279 C C C C
280 C D D
281 c
282 c
283 c C C
284 c
285 c D D
286 c
287 c D C C
288 c C C
289 c D A A
290 c
291 G 292 C D
293 C C B B
294 c
295 c
296 c D
297 c C
298 c D A A
299 c
300 c
301 c D
302 c C C C
303 D
304 D
305 D
306 D
307 D
308 D C C
309 D
310 D
311 D D
312 D
313 D
314 D
315 D
316 D
317 D
318 D
319 D
320 D
321 D D
322 D
323 D
324 D
325 D D A A
326 D D D
327 D
328 D
329 D
330 D
331 D
352 S 333 D
334
335
336
337
338
339 A A
340 A A
341 A A
342 A A
343 A A
344 B B
345 C C
346 A A
347 A A
348 A A
349 A A
350 B A A
351 A A
352 A A
353 A A
354 A A
355 A A
356 A A
357 A A
358 A A
359 A A
360 A A
361 A A
362 A
363 B B
364 A A
365 A A
366 A A
367 A A
368 A A
369 A A
370 A A
371 A A
372 A A m 375 A A
376 A A
377 C A A
378 B A A
379 A A
380 A A
381 C A A
382 C A A
383 A A
384 C A A
385 C A A
386 A A A
387 A A
388 B A A
389 C A A
390 C A A
391 C A A
392 B A A
393 C A A
394 C A A
395 A A
396 B B
397 A A
398 A A
399 A A A
400 A A
401 C A A
402 A A A
403 A A A
404 A A A
405 B A A
406 A A A
407 C A A
408 A A A
409 A A A
410 A A A
411 C B B
412 C B
413 C A 444 A G G 415 C C
416 A C D
417 c D
418 B
419 D C
420 C C B
421 C
Table 5. Inhibitory Activities of Representative Compounds of formula I
Figure imgf000376_0001
126 B A
127 A A A
128 A A
129 A
130 A
131 B A
132 A A
133 B A C
134 A A
135 A
136 A A
137 A A C
138 A A
139 A
140 A A
141 A A
142 A A
143 A A
144 A A
145 A A
146 A A
147 B A
148 A
149 A A
150 A
151 A A
152 A A
153 A
154 A A
155 A A
156 A A
157 A A
158 B A C
159 A A
160 B A C
161 A A B
162 A A
163 B A
164 B A
165 B A
A 167 A A A
168 A A B
169 A A
170 C A
171 B A
172 A A
173 A A
174 A A B
175 B A
176 C A
177 B A
178 B A A
179 A A
180 A A
181 A A
182 C A
183 C A
184 A
185 A A
186 C A
187 C A
188 A
189 C A C
190 C A D
191 C A
192 C A
193 B A A
194 C A
195 B A
196 A A
197 C A
198 A
199 C A
200 B A
201 B A
202 C A
203 A A A
204 A
205 C A
206 A
A
207 B 208 A
209 C A
210 B A
211 C A
212 C A
213 B A
214 C A
215 B A
216 C A
217 B A
218 A
219 A
220 B A
221 C A
222 C A
223 C A
224 C A
225 A
226 C A
227 C A
228 A
229 C A
230 A
231 C A
232 C A
233
234 C C
235 A
236 C
237 C A
238 C A
239 C A
240
241 C B
242 C
243 D A
244 A B
245 A A
246 C A
247 C A
A
248 249 D B
250 C A B
251 C A
252 D B
253 C A
254 B
255 C C
256 D A
257 C
258
259
260
261 D B
262 D C
263 C C
264 C B
265 D C
266 D A C
267 D B
268 D A B
269
270 D
271 C C
272 D
273 D D
274 D C
275 D
276 D
277
278
279 D
280 D C
281
282
283 D
284
285
286
287 D
288
B
289 D 290
291
292
293 D D
294
295
296 D
297 D
298 D B
299
300
301 D
302 D
303
304
305 C
306
307
308 D C
309 D
310
311 D
312
313
314
315 D
316
317 D
318 D
319 D
320
321 D
322
323
324
325 B
326
327
328 D
329
35Θ 331
332 D
333 D
334
335 A A
336 A A
337 A A
338 B A
339 A A
340 C B
341 C A
342 C A
343 C
344 B A
345 A A
346 A A
347 A A
348 A A
349 A A
350 A A A B
351 A A
352 A A
353 A A
354 B A
355 A A
356 A A
357 B A
358 A A
359 A A
360 A A
361 B A
362 B
363 A A
364 B A
365 B A
366 A A
367 A A
368 A A A
369 A A
370 A A
A A
334 372 A A
373 A A
374 B A
375 C A
376 D
377 A A
378 A A
379 B A
380 C A
381 A A
382 B C A
383 C A
384 A A
385 B A
386 A A
387 C A
388 A A
389 A B A C
390 B A
391 A B A C
392 A A
393 A B A C
394 A A
395 A A
396 D
397 C
398 C
399 A A
400 A C A C
401 A A A C
402 B A
403 A A
404 A A
405 B A
406 A A
407 C A
408 A A
409 A A
410 A A A A
411 C A
C
443 413 A A
414 B C A
415
416 C
417 C
418 A
419 C
421 C
Having thus described several aspects of several embodiments, it is to be appreciated various alterations, modifications, and improvements will readily occur to those skilled in the art. Such alterations, modifications, and improvements are intended to be part of this disclosure, and are intended to be within the spirit and scope of the invention. Accordingly, the foregoing description and drawings are by way of example only.

Claims

Claims
1. A compound having Formula I or a pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000385_0001
:
ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;
X is N, CH or C-halo;
R1, R3, R4, and R6 are each independently selected from hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-d alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d- C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-N(R6)-(d-C6 alkylene)-0-(d-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)(R6), -(Ci-C6 alkylene)-N(R6)-S(0)i-2-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-S(O)i-2-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4 alkylene)-S(0)i-2-N(R6)-(Ci-C6
alkylene)-Q, -C(0)N(R6)-(Ci-C6 alkylene)-C(O)- (C0-C6 alkylene)-0-(Ci-C6
alkyl), -C(0)N(R6)-(Ci-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-O-C(O)-(C0-C6 alkyl)-Q, -(Ci-C6
alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-0-(d-C6 alkylene)-Q, -(C0-C6
alkylene)-C(O)-(C0-C6 alkylene)-0-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6
alkylene)-0-(Ci-C6 alkylene)-Q, -(Ci-Ce alkylene)-0-C(0)-(d-C6 alkyl), -(d-C6
alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)C(0)-(Ci-C6 alkyl), -(Ci-d alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-S(O)0-2-(Ci-C6 alkyl), -(C0-C6 alkylene)-S(0)o-2-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6 alkyl), -(C0-C6alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(Ci-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; wherein:
(i) when X is N and A is optionally substituted phenyl, then (a) 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(0)phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2N(CH3)phenyl,
NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or
NHCH2CH2OC(0)CH3;
(ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, CI or S02CH3, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(0)NH-i-propyl,
NHCH(CH3)(CH2)3N(CH2CH3)2, NHCH2CH2OH, NHCH2CH2OCH3, NHCH2CH2OS03H, NHCH2CH2CH2OCH2CH20-phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2OCH3, NHCH2CH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCH2CH2NHC(0)OCH3,
NHCH2CH2NHC(0)CH3, NHCH2CH2NH2, or NHCH2-phenyl;
(iii) when X is CH and A is optionally substituted pyridyl, then neither N(R7)C(R4)(R5)(R6) nor NtR8)^1)^2)^3) is NHCH2-phenyl, NHCH2-(2,4-difluorophenyl), N(CH3)CH2CH2C(0)OH, NHCH2CH2C(0)OH, NHCH2CH2C(0)OCH2CH3, NHCH2CH2C(0)0-t-butyl,
NHCH2CH2C(0)NH2, NHCH2CH2-phenyl, NHCH2CH2OH, NHCH2CH2NH2,
NHCH2CH2N(CH3)2, or NHCH2CH2CH3;
(iv) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1 -pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH;
(v) when X is N and A is an optionally substituted pyridyl, then (A) neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], N(CH3)2,
NHCH2CH2CH2S02CH2CH2C1, NHCH2CH2OCH2CH2S02CH2CH2Cl,or
NHCH2CH2S02CH2CH2C1, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3;
(vi) when X is N and A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;
(vii) when X is CH and A is unsubstituted 2-pyridinyl, then the ring formed by R4 and R5 is not 5 -methyl- 1 H-pyrazol-3 -yl,
(viii) when A is optionally substituted 1 -pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N R8)^1)^2)^3) is N(CH3)2, NHCH3, NHAc, NHisopropyl, NHCH2CH3, NHCH2CH2S03H or N(CH2CH3)2,
(ix) when X is N and A is optionally substituted phenyl, thienyl, or pyridinyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexylC(0)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3,
(x) when X is N, A is an optionally substituted phenyl and R4 and R5 form an optionally substituted phenyl, then Ν^8)^1)^2)^3) is not NHCH2(4-fluorophenyl), NHCH2C02H, NHCH2C(0)C1, NHCH(C02H)(CH2SCH2phenyl), or NHCH2C(0)NHC(0)NHR or
NHCH2C(0)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl,
(xi) when X is N, A is an oxadiazole substituted with an optionally substituted pyridinyl, then R4 and R5 do not form an optionally substituted phenyl,
(xii) when A is substituted 1-pyrazolyl, then (A) then N(R7)C(R4)(R5)(R6) and
NtR^CtR1)^2)^3) are not both NHC(CH3)3, and (B) A is not substituted with N=N-R, wherein R is a ring,
(xiii) the compound is not selected from the group:
(1) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-lH-inden-2-yl)amino]-6-phenyl-l,3,5-triazin-2- yl ] amino] methyl] -b enzamide,
(2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4-(methylsulfonyl)- benzamide,
(3) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3-yl]thio]- acetamide,
(4) N2-cyclopropyl-N4-ethyl-6-[3 -[(phenylmethyl)thio]-lH-l ,2,4-triazol-l-yl]-l,3,5-triazine-2,4- diamine,
(5) 2-[[l-[4-(cyclopropylamino)-6-(ethylamino)-l,3,5-triazin-2-yl]-lH-l,2,4-triazol-3-yl]thio]- acetic acid methyl ester,
(6) N- [ [4- [ [ [4-(cyclopropylamino)-6-(2 -pyridinyl)- 1,3,5 -triazin-2-yl]amino]methyl] cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,
(7) N2-cyclopropyl-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-phenyl-l,3,5-triazine-2,4-diamine,
(8) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l-yl]-l,3,5-triazine- 2,4-diamine,
(9) N2,N4-dicyclohexyl-6- [3 -(3 ,4-dimethoxyphenyl)-5 -(methylthio)- 1 H-pyrazol- 1 -yl] -1,3,5- triazine-2,4-diamine,
( 10) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 -yl]- 1 ,3 , 5 - triazine-2,4-diamine,
(11) N2,N4-dicyclohexyl-6-phenyl-l,3,5-triazine-2,4-diamine, (12) 1 ,1 '-[(6^henyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],
(13) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l,l- dimethylethyl)- phenol,
(14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-l,3,5-triazin-2-yl]-glycine,
(15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3- fluorophenyl)-l,3,5-triazin-2-yl]amino]ethyl]- phenol,
(16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4- fluorophenyl)-l,3,5-triazin-2-yl]amino]ethyl]- phenol,
(17) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine,
(18) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l ,3,5-triazine-2,4-diamine,
(19) 4,4 [6-[3,5-bis(l,l-dime lethyl)-4- hydro^^
3,1 -propanediyl)]bis[2,6-bis(l ,1 -dimethylethyl)-phenol,
(20) 4,4'-[(6-phenyl-l,3,5-triazine-2,4- diyl)bis(imino-3,l-propanediyl)]bis[2,6-bis(l,l- dimethylethyl)-phenol,
(21) N-[6-[(2,3-dihydro-lH-inden-2-yl)amino]-2-(2^yridinyl)-4-pyrimidinyl]- alanine,
(22) N4-cyclopentyl-2-phenyl-N6-(phenylmethyl)-4,6-pyrimidinediamine,
(23) 2-[[6-(bicyclo[2.2.1 ]hept-2-ylamino)-2-phenyl-4-pyrimidinyl]amino]-ethanol,
(24) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l,3,5-triazine-2,4-diamine,
(25) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l,3,5-triazin-2- yl]-benzamide,
(26) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,
(27) [[4-[[[[[4-amino-6-(4^yridinyl)-l,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4- pyridinyl)-l ,3,5-triazin-2-yl]imino]bis-methanol,
(28) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- yl]amino]methoxy]methyl](hydroxymethyl)am
methanol,
(29) 5-[4,6-bis(diethylamino)-l,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,
(30) N2,N2,N*,N*-tetrae ^ (31) N,A -[6-[4-(acetylamino)-l,2,5-oxadiazo
(32) N-(2-chloro-6-me lphenyl)-5-[[4-(dimethylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]-l ,3,4-Oxadiazole-2-carboxamide,
(33) N4-(5-methyl-lH-pyrazol-3-yl)-2-(2-pyridinyl)-N6-(tetrahydro-2H-pyran-4-yl)-4,6- Pyrimidinediamine,
(34) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(diethylamino)propyl]- 1,3,5 -Triazine-2,4-diamine,
(35) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3- (dimethylamino)propyl]- 1 ,3,5-Triazine-2,4-diamine,
(36) N2-[3,5-bis(trifluorome l)phenyl]-6-(4-chlorophenyl)-N4-[3-(diethylamino)propyl]-l ,3,5- Triazine-2,4-diamine,
(37) N2,N4-bis[(4-methoxyphenyl)me l]-6-[4-(trifluoromethoxy)phenyl]-l ,3,5-Triazine-2,4- diamine,
(38) N,N"-(6-phenyl-l,3,5-triazine-2,4-diyl)bis[N'-(2-chloroethyl)-Urea,
(39) N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-methyl-3-[[4-phenyl-6-(propylamino)-l ,3,5- triazin-2-yl]amino]phenyl]-urea,
(40) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]-glycine,
(41) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(5-thiazolyl)-l, 3, 5-triazin-2-yl]-L- Valine,
(42) s-Triazine, 2^henyl-4,6-bis[[6-[[4-phenyl-6-[[6-[[4^henyl-6-(trichloromethyl)-s-triazin-2- yl]amino]hexyl]amino]-s-triazin-2-yl]amino]hexyl]amino]-,
(43) a,a'-[(6^henyl ,3,5 riazine-2,4-diyl)bis[imino(l,l,2,2-tetrafluoro-3-oxo-3,l- propanediyl)]]bis[ro-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)- 1,2-ethanediyl]], and
(44) a-[[4-[[(3-chlorophenyl)methyl]amino]-6-(lH-imidazol-l-yl)-l,3,5-triazin-2-yl]amino]-N- [[4-(trifluoromethyl)phenyl]methyl]-, (aR)-Cyclohexanepropanamide.
2. A compound having Formula la or a pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000391_0001
(la), wherein:
ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;
R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(Ci-C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(d-C6 alkylene)-N(R6)-(Ci-C6
alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6
alkylene)-N(R6)(R6), -(Ci-C6 alkylene)-N(R6)-S(0)i-2-(Ci-C6 alkyl), -(C C6
alkylene)-N(R6)-S(O)i-2-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-S(0)i-2-N(R6)(R6), -(C1-C4
alkylene)-S(0)i-2-N(R6)-(Ci-C6 alkylene)-Q, -C(0)N(R6)-(Ci-C6 alkylene)-C(O)- (C0-C6 alkylene)-0-(Ci-C6 alkyl), -C(0)N(R6)-(Ci-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-O-C(O)-(C0-C6 alkyl)-Q, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), -(Ci-C6 alkylene)-0-(Ci-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6
alkylene)-0-(Ci-C6 alkylene)-Q, -(Ci-C6 alkylene)-0-C(0)-(Ci-C6 alkyl), -(Ci-C6
alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)C(0)-(Ci-C6 alkyl), -(Ci-C6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-S(O)0-2-(Ci-C6 alkyl), -(C0-C6 alkylene)-S(0)o-2-(C0-C6 alkylene)-Q, -(Ci-C6 alkylene)-N(R6)-C(0)-N(R6)-(Ci-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein: any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH, CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl;
wherein:
(i) when A is optionally substituted phenyl, then (a) neither N(R7)C(R4)(R5)(R6) nor
NtR8)^1)^2)^3) is NHCH2CH2OCH2CH2OCH2CH2NH2 or 4-[[2-[2-(2- aminoethoxy)ethoxy]ethyl]amino] and (b) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH-[(4- methoxyphenyl)methyl], NHCH2CH2CHO, NHCH2CH2OCH3, NHCH2CH2OH, NHCH2CH(OH)CH3,
NHCH2CH2OC(0)phenyl, NHCH2CH2CH2OH, NHCH2CH2CH2N(CH3)phenyl,
NHCH2C(0)OCH3, NHCH2C(0)OCH2CH3, NHCH2phenyl, NHCH(CH3)CH2CH3, or
NHCH2CH2OC(0)CH3;
(ii) when A is an optionally substituted pyridyl, then (A) neither N(R7)C(R4)(R5)(R6) nor NiR^CiR1)^2)^3) is NHC(0)-[2-chloro-4-(methylsulfonyl)], N(CH3)2,
NHCH2CH2CH2S02CH2CH2C1, NHCH2CH2OCH2CH2S02CH2CH2Cl,or
NHCH2CH2S02CH2CH2C1, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(0)C(CH3)3, NHC(0)CH=CH2, NHC(0)C(CH3)=CH2, NHCH2CH2OH, NH-cyclohexyl, NHCH2-phenyl, NHC(0)phenyl, NHC(0)(CH2)5NH2, NHC(0)OCH3, NHC(0)CH3, and NHC(0)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2-phenyl or NH-CH2CH3;
(iii) when A is an optionally substituted heteroaryl, then N(R7)C(R4)(R5)(R6) and
NtR8)^1)^2)^3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl, NHCH2CH(CH3)2, and NHC(0)CH3;
(iv) when A is optionally substituted 1 -pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor
NtR8)^1)^2)^3) is N(CH3)2, NHCH3, NHAc, NHisopropyl, NHCH2CH3, NHCH2CH2S03H or N(CH2CH3)2,
(v) when A is optionally substituted phenyl, thienyl, or pyridinyl, then neither
N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexylC(0)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3,
(vi) when A is an optionally substituted phenyl and R4 and R5 form an optionally substituted phenyl, then N(R8)C(R1)(R2)(R3) is not NHCH2(4-fluorophenyl), NHCH2C02H, NHCH2C(0)C1, NHCH(C02H)(CH2SCH2phenyl), or NHCH2C(0)NHC(0)NHR or NHCH2C(0)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl,
(vii) when A is an oxadiazole substituted with an optionally substituted pyridinyl, then R4 and R5 do not form an optionally substituted phenyl,
(viii) when A is substituted 1 -pyrazolyl, then (A) then N(R7)C(R4)(R5)(R6) and
N(R8)C(R1)(R2)(R3) are not both NHC(CH3)3, and (B) A is not substituted with N=N-R, wherein R is a ring,
(ix) the compound is not selected from the group:
(1) N-(2-aminophenyl)-4-[[[4-[(2,3-dihydro-lH-inden-2-yl)amino]-6-phenyl-l,3,5-triazin-2- yl ] amino] methyl] -b enzamide,
(2) 2-chloro-N-[4-(cyclopropylamino)-6-(2-pyridinyl)-l,3,5-triazin-2-yl]-4-(methylsulfonyl)- benzamide,
(3 ) 2- [[ 1 - [4-(cyclopropylamino)-6-(ethylamino)- 1,3,5 -triazin-2-yl] - 1 H- 1 ,2,4-triazol-3 -yl]thio] - acetamide,
(4) N2-cyclopropyl-N4-ethyl-6-[3 -[(phenylmethyl)thio]-lH-l ,2,4-triazol-l-yl]-l,3,5-triazine-2,4- diamine, (5) 2-[[l -[4-(cyclopropylamino)-6-(ethylamino)-l ,3,5 riazin-2-yl]-lH-l ,2,4-triazol-3-yl]thio]- acetic acid methyl ester,
(6) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5 riazin-2-yl]amino]methyl]cyclohexyl] methyl]-4-fluoro-benzenesulfonamide,
(7) N2-cyclopropyl-6-(3,5-dimethyl-lH^yrazol-l -yl)-N4-phenyl-l ,3,5-triazine-2,4-diamine,
(8) N2,N4-dicyclohexyl-6-[3-(4-methoxyphenyl)-5-(methylthio)-lH-pyrazol-l -yl]-l ,3,5-triazine- 2,4-diamine,
(9) N2,N4-dicyclohexyl-6- [3 -(3 ,4-dimethoxyphenyl)-5 -(methylthio)- 1 H-pyrazol- 1 -yl] -1 ,3,5- triazine-2,4-diamine,
( 10) N2,N4-dicyclohexyl-6- [5 -(methylthio)-3 -(3,4,5 -trimethoxyphenyl)- 1 H-pyrazol- 1 -yl]- 1 ,3 , 5 - triazine-2,4-diamine,
(1 1) N2,N4-dicyclohexyl-6-phenyl-l ,3,5-triazine-2,4-diamine,
(12) 1 ,1 '-[(6-phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone],
(13) 4,4'-[(6-phenyl-l ,3,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(l ,l - dimethylethyl)- phenol,
(14) N-[4-[(4-aminobutyl)amino]-6-[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]-2-methylphenyl]-l ,3,5-triazin-2-yl]-glycine,
(15) 4-[2-[[4-[(5-aminopentyl)amino]-6-(3-fluorophenyl)-l ,3,5-triazin-2-yl]amino]ethyl]- phenol,
(16) 4-[2-[[4-[(5-aminopentyl)amino]-6-(4-fluorophenyl)-l ,3,5-triazin-2-yl]amino]ethyl]- phenol,
(17) 6-(4-aminopyridin-3-yl)-N2-benzyl-N4-(tert-butyl)-l ,3,5-triazine-2,4-diamine,
(18) N2,N4-bis(cyclohexylmethyl)-6-phenyl-l ,3,5-triazine-2,4-diamine,
(19) 4,4'-[[6-[3,5-bis(l ,l -dime lethyl)-4-hydroxyphenyl]-l ,3,5-triazine-2,4-diyl]bis(imm^ propanediyl)]bis[2,6-bis(l ,l -dimethylethyl)-phenol,
(20) 4,4'-[(6-phenyl-l ,3,5-triazine-2,4-diyl)bis(imino-3,l -propanediyl)]bis[2,6-bis(l ,l ^ dimethylethyl)-phenol,
(21) N2-isopropyl-6-phenyl-N4-(tetrahydro-2H-pyran-4-yl)-l ,3,5-triazine-2,4-diamine,
(22) 2-chloro-4-(methylsulfonyl)-N-[4-[(phenylmethyl)amino]-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]-benzamide,
(23) N-[[4-[[[4-(cyclopropylamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]methyl]cyclohexyl]methyl]-4-fluoro-benzenesulfonamide,
(24) [[4-[[[[[4-amino-6-(4^yridinyl)-l,3,5-triazin-2-yl]amino]methoxy]methyl]amino]-6-(4- pyridinyl)-l ,3,5-triazin-2-yl]imino]bis-methanol,
(25) [[4-[[[[[4-[bis(hydroxymethyl)amino]-6-(4-pyridinyl)-l ,3,5-triazin-2- yl]amino]methoxy]methyl](hydroxymethyl)amm^
methanol,
(26) 5-[4,6-bis(diethylamino)-l,3,5-triazin-2-yl]- 2H-tetrazole-2 -acetic acid ethyl ester,
(27) N2,N2 -tetraethyl-6-(2H-tetrazol-5-yl)-l,3,5-triazine-2,4-diam^
(28) N V'-[6-[4-(acetylamino)-l,2,5-oxadiazol-3-yl]-l ,3,5-triazine-2,4-diyl]bis-acetami^^
(29) N-(2-chloro-6-methylphenyl)-5-[[4-(dime lamino)-6-(2-pyridinyl)-l ,3,5-triazin-2- yl]amino]-l ,3,4-Oxadiazole-2-carboxamide,
(30) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3-(diethylamino)propyl]- 1,3,5 -Triazine-2,4-diamine,
(31) 6-(4-chlorophenyl)-N2-[4-chloro-3-(trifluoromethyl)phenyl]-N4-[3- (dimethylamino)propyl]- 1 ,3,5-Triazine-2,4-diamine,
(32) N2-[3,5-bis(trifluorome l)phenyl]-6-(4-chlorophenyl)-N4-[3-(diethylamino)propyl]-l ,3,5- Triazine-2,4-diamine,
(33) N2,N4-bis[(4-methoxyphenyl)methyl]-6-[4-(trifluoromethoxy)phenyl]-l ,3,5-Triazine-2,4- diamine,
(34) N,N"-(6-phenyl-l,3,5-triazine-2,4-diyl)bis[N'-(2-chloroethyl)-Urea,
(35) N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-methyl-3-[[4-phenyl-6-(propylamino)-l ,3,5- triazin-2-yl]amino]phenyl]-urea,
(36) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(4-pyridinyl)-l ,3,5-triazin-2-yl]-glycine,
(37) N-[4-[[5-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-2- methylphenyl]amino]-6-(5-thiazolyl)-l, 3, 5-triazin-2-yl]-L- Valine,
(38) s-Triazine, 2-phenyl-4,6-bis[[6-[[4-phenyl-6-[[6-[[4-phenyl-6-(trichloromethyl)-s-triazin-2- yl]amino]hexyl]amino]-s-triazin-2-yl]amino]hexyl]amino]-,
(39) α,α'- [(6-phenyl- 1,3,5 -triazine-2,4-diyl)bis [imino( 1 , 1 ,2,2-tetrafluoro-3 -oxo-3 , 1 - propanediyl)]]bis[ro-[tetrafluoro(trifluoromethyl)ethoxy]-Poly[oxy[trifluoro(trifluoromethyl)- 1,2-ethanediyl]], and
(40) a-[[4-[[(3-chlorophenyl)methyl]amm^
[[4-(trifluoromethyl)phenyl]methyl]-, (aR)-Cyclohexanepropanamide.
3. The compound of claim 2, wherein
R1, R3, R4, and R6 are each independently selected from hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2; and
R2 and R5 are each independently selected from: -(Ci-Ce alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d- C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl), and -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo; and
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, wherein, when A is an optionally substituted phenyl, 2-pyrrolyl, or 1-imidazolyl, then
N(R7)C(R4)(R5)(R6) is not the same as N(R8)C(R1)(R2)(R3), and the compound is not 2-(l,2- dibromoethyl)-4-phenyl-6-(l, 1,2,2,3,3,4,4,5 ,5 ,6,6 ,6-tridecafluorohexyl-l,3,5-Triazine.
4. The compound of claim 2, wherein ring A is a substituted 5-6 member monocyclic aryl or monocyclic heteroaryl, which is substituted with up to two substituents independently selected from halo, -C C4 alkyl, -C1-C4 haloalkyl, -C1 -C4 hydroxyalkyl, -NH-S(0)2-(Ci-C4 alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(d-C4 alkyl), C1-C4 alkoxy, -NH(Ci-C4
alkyl), -OH, -OCF3, -CN, -NH2, -C(0)NH2, -C(0)NH(Ci-C4 alkyl), -C(0)-N(Ci-C4
alkyl)2, -(C1-C6 alkylene)-0-(Ci-C6 alkyl), azetidinyl, phenyl, and cyclopropyl optionally substituted with OH.
5. A com ound having Formula B, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000397_0001
wherein:
X isN, CH or C-halo;
Xa is N or C-R9a, provided that when one Xa is N, then the other two Xa are both C-R9a;
R9 is halo, -Ci-C4 alkyl, -C C4 haloalkyl, -Ci-C4 hydroxyalkyl, -NH-S(0)2-(Ci-C4
alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(Ci-C4 alkyl), Ci-C4 alkoxy, -NH(Ci-C4 alkyl), - N(Ci-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, -C(0)NH2, -C(0)NH(Ci-C4 alkyl), -C(0)-N(Ci-C4 alkyl)2, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), aryl, and cyclopropyl optionally substituted with OH; each R9a is independently selected from hydrogen, halo, -Ci-C alkyl, -Ci-C haloalkyl, -Ci-C hydroxyalkyl, -NH-S(0)2-(Ci-C4 alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(Ci-C4 alkyl), Ci-C4 alkoxy, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, -C(0)NH2, - C(0)NH(Ci-C4 alkyl), -C(0)-N(Ci-C4 alkyl)2, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), aryl, and cyclopropyl optionally substituted with OH;
R1, R3, R4, and R6 are each independently selected from hydrogen, Ci-C alkyl, Ci-C
haloalkyl, -0-Ci-C alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -0-Ci-C alkyl, -NH(Ci-C alkyl), or -N(Ci-C4 alkyl)2; R2 and R5 are each independently selected from: -(Ci-Ce alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d- C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(0)N(R6)-(Ci-C6 alkyl),
-(Co-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(Ci-C6 alkyl), and -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(Ci-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, an optionally substituted 5-6 member monocyclic aryl, or an optionally substituted 5-6 member monocyclic heteroaryl;
whereinthe compound is not selected from the group:
(1) 4,6-Pyrimidinediamine, 2-(6-methyl-2-pyridinyl)-N4,N6-dipropyl-;
(2) 4,6-Pyrimidinediamine, N4-ethyl-2-(6-methyl-2-pyridinyl)-N6-propyl-;
(3) 4,6-Pyrimidinediamine, N4,N4-diethyl-2-(6-methyl-2-pyridinyl)-N6-propyl-;
(4) [2,4'-Bipyrimidine]-2',4,6-triamine, N6-[2-(dimethylamino)ethyl]-N2',N2',N4,N4- tetramethyl-; or
(5) [2,4'-Bipyrimidine]-2',4,6-triamine, N6-[2-(dimethylamino)ethyl]-N2',N2',N4,N4- tetramethyl-, phosphate.
6. The compound of claim 5, wherein R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl.
7. A compound having Formula C, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000399_0001
(C), wherein:
X is N, CH or C-halo;
each Xb is independently N-R9b, O, S, C-H, or C-R9c, provided that at least one Xb is C-R9c, and when one Xb is C-H or C-R9c and the other is C-R9c then X° is N, and when one Xb is N-R9b, O, or S,then Xc is C;
R9bis hydrogen or -C1-C4 alkyl;
R9c is halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(0)2-(Ci-C4 alkyl), -S(0)2NH(Ci-C4 alkyl), -CN, -S(0)2-(d-C4 alkyl), C1-C4 alkoxy, -NH(Ci-C4 alkyl), - N(Ci-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, -C(0)NH2, -C(0)NH(Ci-C4 alkyl), -C(0)-N(d-C4 alkyl)2, -(Ci-C6 alkylene)-0-(Ci-C6 alkyl), aryl, and cyclopropyl optionally substituted with OH; R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4
haloalkyl, -O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2;
R2 and R5 are each independently selected from: -(Ci-Ce alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d- C6 alkyl)-C02H -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(Ci-C6 alkyl), -(C0-C6
alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(d-C4 alkyl), -C02H, or halo;
any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H; R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; or
R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, an optionally substituted 5-6 member monocyclic aryl, or an optionally substituted heteroaryl;
wherein:
(i) when X is CH and A is optionally substituted 1-imidazolyl, optionally substituted 1-pyrrolyl or optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NH(CH2)7CH3, NHCH2-(o-chloro-phenyl), or NHCH2CH2OH; and
(ii) when X and Xc are both N, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)2, NHCH3, or N(CH2CH3)2.
8. The compound of claim 7 wherein:
R9c is halo, -OH, CN, -NH2, -O-C1-C4 alkyl, -NH(d-C4 alkyl), -N(d-C4 alkyl)2, -C1-C4 alkyl, -C1-C4 haloalkyl, and -(Ci-C6 alkylene)-0-(d-C6 alkyl);
R and R4are each hydrogen;
R3 and R6 are each independently selected from C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN; and
R2 and R5 are each -(Ci-C6 alkyl), wherein:
the alkyl moiety present in R2 and R5 is optionally substituted with one or more -OH, -0(Ci-C4 alkyl), -C02H, or halo; and any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH, CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H.
9. The compound of claim 7 wherein R1 and R4 are each independently selected from Ci-C4 alkyl and Ci-C4 haloalkyl,and R2 and R5 are each -(Ci-C6 alkyl).
10. The compound of claim 1 or 2 whereinR3 and R6 are both hydrogen, R1 and R4 are each independently selected from Ci-C4 alkyl and C1-C4 haloalkyl,andR2 and R5 are each -(Ci-C6 alkyl).
11. A compound having Formula ΠΙ, or pharmaceutically acceptable salt or hydrate thereof:
Figure imgf000401_0001
(ΙΠ), wherein:
ring A is an optionally substituted 5-6 member monocyclic heteroaryl;
ring B is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl;
R1 and R3are each independently selected from hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, -0-Ci-C4 alkyl, and CN, wherein each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -0-Ci-C4 alkyl, -NH(C C4 alkyl), or -N(Ci-C4 alkyl)2;
R2is selected from: -(Ci-C6 alkyl), -(Ci-C6 alkyl)-C(0)-NH2, -(d-C6 alkyl)-C02H -(C2-C6 alkenyl or alkynyl), -(Ci-C6 alkylene)-0-(d-C6 alkyl), -(C0-C6 alkylene)-C(0)N(R6)-(d-C6 alkyl),-(Co-C6 alkylene)-Q, -(C0-C6 alkylene)-C(0)-(d-C6 alkyl), and -(C0-C6
alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein:
any alkyl or alkylene moiety present in R2 is optionally substituted with one or
more -OH, -0(Ci-C4 alkyl), -C02H, or halo; any terminal methyl moiety present in R2 is optionally replaced with -CH2OH,
CF3, -CH2F, -CH2C1, C(0)CH3, C(0)CF3, CN, or C02H;
R7 and R8 are each independently selected from hydrogen and Ci-C6 alkyl; and
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein
R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=0); or
R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;
wherein when A is an oxadiazole substituted with an optionally substituted pyridinyl, then G is not an optionally substituted phenyl.
12. The compound of claim 11 , wherein G is substituted with 1 or 2 substituents selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, =0, -OH, aryl, heteroaryl - S02Ci-C4 alkyl, -C02Ci-C4 alkyl, -C(0)aryl, and -C(0)d-C4 alkyl.
13. A pharmaceutical composition comprising a compound of claim 1 , and a
pharmaceutically acceptable carrier.
14. The composition of claim 13, further comprising a second therapeutic agent useful in the treatment of cancer.
15. A method of treating a cancer characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in a new ability of the enzyme to catalyze the
NAPH-dependent reduction of a-ketoglutarate to i?(-)-2-hydroxyglutarate in a patient, comprising the step of administering to the patient in need thereof a composition of claim 13.
16. The method of claim 15, wherein the IDH1 mutation is an IDH1 R132H or R132C mutation.
17. The method of claim 16, wherein the cancer is selected from from glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer,or angio-immunoblastic non-Hodgkin's lymphoma (NHL) in a patient.
18. The method of claims 16, further comprising administering to the patient in need thereof a second therapeutic agent useful in the treatment of cancer.
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