NZ715717B2 - Therapeutically active compounds and their methods of use - Google Patents

Therapeutically active compounds and their methods of use Download PDF

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NZ715717B2
NZ715717B2 NZ715717A NZ71571714A NZ715717B2 NZ 715717 B2 NZ715717 B2 NZ 715717B2 NZ 715717 A NZ715717 A NZ 715717A NZ 71571714 A NZ71571714 A NZ 71571714A NZ 715717 B2 NZ715717 B2 NZ 715717B2
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alkyl
alkylene
compound
optionally substituted
halo
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NZ715717A
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NZ715717A (en
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Zhenwei Cai
Zenon D Konteatis
Muller Janeta Popovici
Jeremy M Travins
Robert Zahler
Ding Zhou
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Les Laboratoires Servier Sas
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Priority claimed from PCT/CN2013/079200 external-priority patent/WO2015003360A2/en
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Priority to NZ754946A priority Critical patent/NZ754946A/en
Publication of NZ715717A publication Critical patent/NZ715717A/en
Publication of NZ715717B2 publication Critical patent/NZ715717B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • 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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    • 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
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    • C07—ORGANIC CHEMISTRY
    • 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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    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D401/14—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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • 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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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • 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
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    • 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
    • C07D417/02—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

Abstract

Provided are compounds of formula (Ia), (B), (C), or (Ig) useful for treating cancer and methods of treating cancer comprising administering to a subject in need thereof a compound described herein. The compounds are inhibitors of IDH1 and/or IDH2 mutants having alpha hydroxyl neoactivity.

Description

Attorney Docket Number: C2081 - THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE CLAHVI OF PRIORITY This application claims priority from International Application Serial No.
PCT/CN20l3/O792OO filed July 11, 2013, which is incorporated herein by nce in its entirety.
BACKGROUND OF H‘IVENTION Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate , d-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 ze to the ondrial matrix, and two NADP(+)—dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer.
IDHl (isocitrate dehydrogenase l (NADP+), cytosolic) is also known as IDH; IDP; IDCD; IDPC or PICD. The protein encoded by this gene is the NADP(+)-dependent isocitrate ogenase found in the asm and peroxisomes. It contains the PTS-l peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes ts 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 e 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 k entries NM_OOS 896.2 and NP_OOS 887.2 respectively. The tide and amino acid sequences for IDHl are also described in, e.g., Nekrutenko et al., Mol. Biol. Evol. 15:1674-1684(1998); Geisbrecht et al., J.
Biol. Chem. 274:30527-30533(1999); Wiemann et al., Genome Res. 11:422-435(2001); The MGC Project Team, Genome Res. 14:2121-2127(2004); Lubec et al., Submitted (DEC-2008) to UniProtKB; Kullmann et al., ted 996) to the EMBL/GenBank/DDBJ databases; and Sjoeblom et al., Science 314:268-274(2006).
Non-mutant, e.g., wild type, IDH1 catalyzes the ive decarboxylation of isocitrate to α-ketoglutarate thereby reducing NAD+ (NADP+) to NADH (NADPH), e.g., in the forward reaction: Isocitrate + NAD+ (NADP+) → α-KG + CO2 + NADH (NADPH) + H+.
It has been discovered that ons of IDH1 present in certain cancer cells result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)hydroxyglutarate (2HG). The production of 2HG is ed 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 )-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 te 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 (α-KG) thereby reducing NAD+ (NADP+) to NADH ), e.g., in the forward reaction: Isocitrate + NAD+ (NADP+) → α-KG + CO2 + NADH (NADPH) + H+.
It has been discovered that mutations of IDH2 t in certain cancer cells result in a new ability of the enzyme to catalyze the NADPH-dependent ion of α-ketoglutarate to R(-)hydroxyglutarate (2HG). 2HG is not formed by ype 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 IDHl and/or mutant IDH2 and their neoactiVity is therefore a potential therapeutic treatment for cancer. Accordingly, there is an ongoing need for inhibitors of IDHl and/orIDHZ mutants having alpha hydroxyl iVity.
SUNflVIARY OF INVENTION Described herein are compounds of Formula I, or a pharmaceutically acceptable salt or hydrate R7 R8 (I), wherein: ring A is an optionally substituted 5-6 member clic aryl or monocyclic heteroaryl; X is N, CH or C-halo; R1, R3, R4, and R6 are each independently ed 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(C1-C4 alkyl), or -N(C1-C4 alkyl); R2 and R5 are each independently selected from: -(C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-NH2, -(C1- C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(C1-C6 alkylene)-N(R6)-(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 ne)-N(R6)-(Co-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)(R6), -(C1-C6 alkylene)-N(R6)-S(O)1.2-(C1-C6 alkyl), -(C1-C6 ne)-N(R6)-S(O)1(C0-C6 alkyl)-Q, -(C1-C6 alkylene)-S(O)1N(R6)(R6), 4 alkylene)-S(0)1N(R6)-(C1-C6 alkylene)-Q, -C(O)N(R6)-(C1-C6 alkylene)-C(O)- (C0-C6 alkylene)-O-(C1-C6 alkyl), -C(O)N(R6)-(C1-C6 ne)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-O-C(O)-(C1-C6 alkyl), -(C1-C6 alkylene)-O-C(O)-(C0-C6 alkyl)-Q, -(C1-C6 alkylene)-O-(C1-C6 , 6 alkylene)-O-(C1-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(Co-C6 alkylene)-O-(C1-C6 alkyl), -(Co-C6 alkylene)-C(O)-(C0-C6alkylene)-O-(C1-C6 alkylene)-Q, -(C1-C6 ne)-O-C(O)-(C1-C6 alkyl), -(C1-C6 alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)N(R6)-(C1-C6 alkyl), —(c0—c6 ne)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)C(O)-(C1-C6 alkyl), -(C1-C6 ne)-N(R6)C(O)-(Co-C6 alkylene)-Q, -(Co-C6 alkylene)-S(O)o(C1-C6 alkyl), -(C0-C6 alkylene)-S(O)0.2-(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)-C(O)-N(R6)-(C1-C6 alkyl), -(C0-C6 alkylene)-Q, 6 ne)-C(O)-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 ne)-Q, wherein: any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -O(C1-C4 alkyl), -C02H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH20H, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN, or COZH; 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 er with the carbon atom to which they are ed to form C(=O); or R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=O); or R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or optionally tuted 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 , then (a) r N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCHZCHZOCHZCHZOCHZCHZNHZA-[[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], NHCHZCHZCHO, NHCHZCHZOCHg, NHCHZCHZOH, NHCHZCH(OH)CH3, NHCHZCH20C(O)phenyl, NHCH2CH2CH20H, NHCHZCHZCH2N(CH3)phenyl, NHCH2C(O)OCH3, NHCH2C(O)OCH2CH3, NHCHzphenyl, NHCH(CH3)CH2CH3, or NHCHZCH20C(O)CH3; (ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, C1 or $02CH3, then neither N(R7)C(R4)(R5)(R6) net N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(O)NH-i-propyl, H3)(CH2)3N(CH2CH3)2, NHCH2CH20H, NHCHzCH20CH3, NHCHzCH20803H, NHCHZCHZCHZOCHZCHZO-phenyl, HZCHZOH, NHCHZCHZCHZOCHg, NHCHZCH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCHZCHZNHC(O)OCH3, HzNHC(O)CH3, NHCHzCHzNHz, or NHCHz-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 NHCHz-phenyl, NHCHZ-(2,4-difluorophenyl), CH2CH2C(O)OH, NHCHZCH2C(O)OH, NHCHZCH2C(O)OCH2CH3, NHCHZCH2C(O)O-t-butyl, NHCHZCH2C(O)NH2, Hz-phenyl, NHCHZCHZOH, NHCHZCHZNHZ, NHCHZCH2N(CH3)2, or NHCHZCHZCHg; (iv) when X is CH and A is optionally substituted azolyl, optionally substituted 1- pyrrolyl or ally substituted l-pyrazolyl, then r N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NH(CH2)7CH3, (o-chloro-phenyl), or NHCHZCHZOH; (V) when X is N and A is an optionally substituted pyridyl, then (A) neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(O)-[2-chloro(methylsulfonyl)], N(CH3)2, NHCHZCHZCHZSOzCHzCHzCl,NHCH2CH20CHzCHZSOzCHzCHzCl,or NHCHZCHZSOZCHZCHZCI, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not bothNHC(O)C(CH3)3, NHC(O)CH=CH2, NHC(O)C(CH3)=CH2, NHCHZCHZOH, NH- cyclohexyl, NHCHz-phenyl, NHC(O)phenyl, NHC(O)(CH2)5NH2, NHC(O)OCH3, NHC(O)CH3, and NHC(O)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCHz-phenyl or NH-CHZCHg; (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, NHCHZCHz-i-propyl, NHCHZCH(CH3)2, and NHC(O)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) whenA is optionally substituted l-pyrazolyl, then r N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)2, NHCH3,NHAc, NHisopropyl, NHCHZCHg, NHCHZCHZS03H 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 ohexle(O)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, chloro, or CF3; (X) when X is N, A is an optionally substituted phenyl and R4 and R5 form an optionally substituted phenyl, then N(R8)C(R1)(R2)(R3) is not NHCH2(4-fluorophenyl), NHCHZCOZH, NHCH2C(O)C1, NHCH(C02H)(CH28CHzphenyl), (O)NHC(O)NHR or NHCH2C(O)NHC(S)NHR, wherein R is ally 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 l-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; (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 exyl, then A is not a disubstituted l-pyrazolyl or an unsubstituted phenyl; and (xx) the compound is not selected from the group: (1) N—(2-aminophenyl)[[[4-[(2,3 -dihydro-l H—indenyl)amino]phenyl-l ,3 ,5- triazinyl]amino]methyl]-benzamide; (2) ro-N-[4-(cyclopropylamino)(2-pyridinyl)-l riazinyl]—4- (methylsulfonyl)-benzamide; (3) 2-[[l yclopropylamino)(ethylamino)-l ,3 azinyl]— l H—l ,2,4-triazol-3 - yl]thio]-acetamide; (4) N2-cyclopropyl-N4-ethyl[3 -[(phenylmethyl)thio]- l H—l ,2,4-triazol-l -yl]-l ,3,5- triazine-2,4-diamine; (5) 2-[[l -[4-(cyclopropylamino)(ethylamino)-l ,3 ,5-triazinyl]— l H—l ,2,4-triazol-3 - yl]thio]- acetic acid methyl ester; (6) N—[[4-[[[4-(cyclopropylamino)(2-pyridinyl)- l ,3 ,5-triazin yl]amino]methyl]cyclohexyl] methyl]fluoro-benzenesulfonamide; (7) N2-cyclopropyl(3 ,5-dimethy1-1H—pyrazoly1)-N4-pheny1-1,3 ,5-triazine-2,4- diamine; (8) N2,N4-dicyclohexyl[3 -(4-methoxypheny1)(methy1thio)-1H—pyrazol-l -y1]-1 ,3 ,5- triazine-2,4-diamine; (9) N2,N4-dicyclohexyl[3 -(3 ,4-dimethoxyphenyl)-5 -(methy1thio)-1H—pyrazol-l -y1] - 1,3 ,5-triazine-2,4-diamine; (10) N2,N4-dicyclohexyl[5 y1thio)-3 -(3 ,4, 5 -trimethoxyphenyl)-1 H—pyrazol y1]-1,3 ,5-triazine-2,4-diamine; (1 1) N2,N4-dicyclohexy1phenyl-1 ,3 ,5 -triazine-2,4-diamine; (12) 1 ,1 '- [(6 -pheny1-s—triazine-2,4-diy1)diimino]bis [dodecahydro-anthraquinone]; (13) 4,4'-[(6-pheny1—1,3 ,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(1,1- dimethylethyl)—phenol; (14) N—[4-[(4-aminobutyl)amino][5 -[ [[ oro-3 - (trifluoromethyl)pheny1]amino]carbonyl] amino]—2-methylphenyl]-1 ,3 ,5-triazinyl]-g1ycine; (15) 4-[2-[[4-[(5-aminopenty1)amino]—6-(3 - fluorophenyl)—1 ,3 ,5-triazin yl]amino]ethy1]— phenol; (16) 4-[2-[[4-[(5-aminopenty1)amino]—6-(4- fluorophenyl)—1 ,3 ,5-triazin no]ethy1]— phenol; (17) 6-(4-aminopyridin-3 -y1)-N2-benzyl-N4-(tert-buty1)-1 ,3 ,5-triazine-2,4-diamine; (1 8) N2,N4-b is(cyclohexylmethyl)pheny1—1 ,3 ,5-triazine-2,4-diamine; (19) 4,4'-[[6-[3 ,5-bis(1,1-dimethy1ethy1) hydroxyphenyl]—1,3 ,5-triazine-2,4- is(imino- 3,1 -propanediy1)]bis[2,6-bis(1,1-dimethy1ethy1)—phenol; (20) 4,4'-[(6-pheny1—1,3 ,5-triazine-2,4- diy1)bis(imino-3 ,1 -propanediy1)]bis[2,6-bis(1 ,1 - ylethyl)—phenol; (21) N—[6-[(2,3 -dihydro-1H—indeny1)amino](2-pyridiny1)pyrimidiny1]—Balanine; (22) lopenty1pheny1-N6-(pheny1methyl)-4,6-pyrimidinediamine; (23) 2-[[6-(bicyclo[2.2. 1 ]hept—2-y1amino)pheny1pyrimidiny1]amino]-ethanol; (24) NZ-isopropylphenyl-N4-(tetrahydro-2H-pyrany1)-1,3 ,5-triazine-2,4-diamine; (25) 2-chloro(methylsu1fonyl)-N-[4-[(pheny1methy1)amino](2-pyridiny1)—1,3,5- triaziny1]—benzamide; (26) N—[[4-[[[4-(cyclopropylamino)(2-pyridiny1)-1 ,3 ,5-triazin yl]amino]methy1]cyclohexy1]methy1]fluoro-benzenesu1fonamide; (27) [[[4-amino(4-pyridinyl)—1,3,5-triazinyl]amino]methoxy]methyl]amino]- 6-(4-pyridiny1)-1,3 ,5-triaziny1]imino]bis-methanol; (28) [[4-[[[[[4-[bis(hydroxymethyl)amino](4-pyridiny1)-1,3 ,5-triazin yl]amino]methoxy]methyl](hydroxymethyl)amino] (4-pyridiny1)— 1 ,3 , 5 -triazinyl]imino]bis- methanol; (29) 5-[4,6-bis(diethy1amino)—1,3,5-triaziny1]— 2H-tetrazoleacetic acid ethyl ester; (3 O) N2,N2,N4,N4-tetraethy1(2H-tetrazol-5 -y1)-1,3 ,5 -triazine-2,4-diamine; (31) NN—[6-[4-(acety1amino)-1,2,5-oxadiazoly1]—1,3,5-triazine-2,4-diy1]bis-acetamide; (3 2) N—(2-chloromethy1pheny1)-5 -[ [4-(dimethy1amino)—6-(2-pyridiny1)-1 ,3 ,5 -triazin y1]amino]-1,3,4-Oxadiazolecarboxamide; (3 3) N4-(5-methy1—1H—pyrazol-3 -y1)(2-pyridiny1)—N6-(tetrahydro-2H-pyrany1)-4,6- dinediamine; (3 4) 6-(4-chlorophenyl)-N2- [4-chloro-3 -(trifluoromethyl)phenyl]-N4- [3 - ylamino)propy1]—1,3 ,5-Triazine-2,4-diamine; (3 5) 6-(4-chlorophenyl)-N2- [4-chloro-3 -(trifluoromethyl)phenyl]-N4- [3 - (dimethylamino)propyl]— 1 ,3 ,5 -Triazine-2,4-diamine; (3 6) N2-[3 (trifluoromethyl)phenyl](4-chlorophenyl)-N4-[3 - (diethylamino)propy1]—1,3 ,5-Triazine-2,4-diamine; (3 7) N2,N4-bis[(4-methoxyphenyl)methyl][4-(trifluoromethoxy)pheny1]-1 ,3 ,5 - Triazine-2,4-diamine; (3 8) N,N"-(6-pheny1—1,3,5-triazine-2,4-diy1)bis[N'-(2-chloroethy1)-Urea; (3 9) N—[4-chloro-3 uoromethyl)phenyl]-N'-[4-methy1-3 -[[4-phenyl(propy1amino)- 1,3 ,5-triazinyl]amino]phenyl]-urea; (40) N—[4-[[5-[[[[4-chloro-3 -(trifluoromethyl)phenyl]amino]carbonyl]amino]—2- methylphenyl]amino](4-pyridiny1)-1 ,3 ,5-triaziny1]-glycine; (41) N—[4-[[5-[[[[4-chloro-3 -(trifluoromethyl)phenyl]amino]carbonyl]amino]—2- 2014/081957 methylphenyl]amino](5 -thiazolyl)-l ,3 ,5 inyl]-L-Valine; (42) zine, 2-phenyl-4,6-bis[[6-[[4-phenyl[[6-[[4-phenyl(trichloromethyl)-s- triazinyl]amino]hexyl]amino] -s-triazinyl]amino]hexyl]amino] -; (43) 0c,0c'- [(6-phenyl-l ,3 ,5-triazine-2,4-diyl)bis [imino(l ,l ,2,2-tetrafluoro-3 -oxo-3 ,l - propanediyl)] ]bis [03- [tetrafluoro(trifluoromethyl)ethoxy] -Poly[oxy[trifluoro(trifluoromethyl)- l,2-ethanediyl] ]; (44)0c-[[4-[[(3 -chlorophenyl)methyl]amino](lH—imidazol-l -yl)-l ,3 ,5 -triazin yl]amino]—N—[[4-(trifluoromethyl)phenyl]methyl]-, (ocR)-Cyclohexanepropanamide; (45)6-(l H—imidazol-l -yl)-N2,N4-bis(l -methylethyl)-l ,3 ,5-Triazine-2,4-diamine;and (46) N2,N4-bis(l -methylpropyl)phenyl-l ,3 , 5 -Triazine-2,4-diamine.
The compounds of Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, and IIId, or as described in any one of the embodiments herein inhibits mutant IDHl or mutant IDH2.
Also described herein are pharmaceutical compositions sing a compound of Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, lIIb, lIIc, and IIId, 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 ption or illustrated in the drawings are not meant to be ng. 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,3, ‘6 comprising," or "having,3, ‘6containing3, ‘6 , involving", and variations thereof , is meant to encompass the items listed fter and equivalents thereof as well as additional items.
Definitions: The term "halo" or "halogen" refers to any l 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 lkyl" 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 yl" include benzyl, 2-phenylethyl, ylpropyl, 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 arbon 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 l 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 tuent.
The term y" refers to an -O-alkyl radical. The term "haloalkoxy" refers to an alkoxy in which one or more en atoms are ed by halo, and includes alkoxy moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkoxy).
Unless ise specified, the term "aryl" refers to a fully aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system. Examples of aryl es are , 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., lkyls), and partially ted ring systems. Carbocyclyl groups also include spirocyclic es. Examples of spirocyclic moieties include, but are not limited to, bicyclo [3.1 .O]hexanyl, spiro[2.2]pentanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, 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 le is through the non-aromatic ring are considered to be yclyl (e.g., cycloalkyl). Examples of such carbocyclyl moieties include, but are not d to, 2,3-dihydro-lH—indene and l,2,3,4-tetrahydronaphthalene.
The term alkyl" 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 norbomyl.
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 atoms 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 W-O', 8(0) and S(O)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 ed 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 ed from O, N, or S(or the oxidized formssuch as W-O', 8(0) and . The heteroatom may optionally be the point of attachment of the heterocyclyl substituent. Examples of heterocyclyl include, but are not limited to, ydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino, pyrrolinyl, pyrimidinyl, and pyrrolidinyl. Heterocyclyl groups include fully saturated ring systems, and partially saturated ring systems.
Bicyclic and lic ring systems containing one or more heteroatoms and both aromatic and non-aromatic rings are considered to be heterocyclyl or heteroaryl groups. Bicyclic or lic 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 , respectively. Bicyclic or lic 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 cyclyl groups, either alone or a part of a group (e.g., the aryl portion of an l group), areoptionally tuted at one or more substitutable atoms with, unless ed otherwise, substituents independently selected from: halo, -CEN, C1-C4alkyl, =0, -0Rb, —0Rb’, -SRb, -SRb’, -(C1-C4alkyl)-N(Rb)(Rb), -(C1-C4alkyl)-N(Rb)(Rb’),-N(Rb)(Rb), -N( Rb)(Rb’), -O-(C1-C4alkyl)-N(Rb)(Rb), -O-(C1-C4alkyl)-N(Rb)(Rb’), —(c1—c4 alkyl)-O-(C1-C4 alkyl)-N(Rb)(Rb), 4 alkyl)-O-(C1-C4 alkyl)-N(Rb)(Rb’), -C(O)—N(Rb)(Rb), -(C1-C4 alkyl)-C(O)-N(Rb)(Rb), -(C1-C4 alkyl)-C(O)-N(Rb)(Rb’), —0Rb’, Rb’, -C(O)(C1-C4 alkyl), -C(0)Rb’, -C(0)N(Rb’)(Rb), -N(Rb)C(0)(Rb), -N(Rb)C(0)(Rb’), -N(Rb)SOz(Rb), -802N(Rb )(Rb), SOZ(Rb’), and -SOZN(Rb)(Rb’), wherein any alkyl substituent is optionally further substituted with one or more of -OH, -O-(C1-C4 alkyl), halo, -NH2, -C4 alkyl), or -N(C1-C4 alkyl)2; each Rb is independently selected from hydrogen, and -C1-C4 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 arbocyclyl, 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 -(C1-C4 alkyl), -(C1-C4 fluoroalkyl), -OH, -O-(C1-C4 alkyl), -O-(C1-C4 lkyl), halo, -NH2, -NH(C1-C4 alkyl), or -N(C1-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,—C1-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 ate, interstitial fluid, lymph, breast milk, mucus (e. g., nasal drainage or phlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal ion, or vomit.
As used herein, the terms "inhibit" or "prevent" include both complete and partial inhibition and tion. An inhibitor may completely or partially inhibit the intended target.
The term "treat" means se, 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 ofthe 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 ent.
As used herein, the term "subject" is ed to include human and non-human s.
Exemplary human subjects include a human patient red to as a t) having a disorder, e.g., a disorder described herein or a normal subject. The term "non-human animals" of one aspect of the ion includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human es, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.
Compounds Provided is a compound ofFormula I, or a pharmaceutically acceptable salt or hydrate thereof: R7 R8 (I), wherein: ring A is an optionally substituted 5-6 member monocyclic aryl or monocyclic heteroaryl; X is N, CH or ; 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(C1-C4 alkyl), or C4 alkyl)2; R2 and R5 are each independently selected from: -(C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-NH2, -(C1- C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(C1-C6 alkylene)-N(R6)-(C1-C6 ne)-O-(C1-C6 alkyl), —(c1—c6 alkylene)-N(R6)-(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)(R6), -(C1-C6 alkylene)-N(R6)-S(O)1(C1-C6 alkyl), -(C1-C6 alkylene)-N(R6)-S(O)1(C0-C6 alkyl)-Q, -(C1-C6 alkylene)-S(O)1N(R6)(R6), -(C1-C4 alkylene)-S(0)1N(R6)-(C1-C6 alkylene)-Q, (R6)-(C1-C6 alkylene)-C(O)- (C0-C6 ne)-O-(C1-C6 alkyl), -C(O)N(R6)-(C1-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, 6 alkylene)-O-C(O)-(C1-C6 , -(C1-C6 alkylene)-O-C(O)-(Co-C6 alkyl)-Q, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C1-C6 alkyl), 6 ne)-C(O)-(C0-C6 alkylene)-O-(C1-C6 alkylene)-Q, -(C1-C6 alkylene)-O-C(O)-(C1-C6 alkyl), -(C1-C6 alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)N(R6)-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)C(O)-(C1-C6 alkyl), -(C1-C6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, 6 alkylene)-S(O)0(C1-C6 alkyl), -(C0-C6 alkylene)-S(O)0(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)-C(O)-N(R6)-(C1-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein: any alkyl or ne moiety present in R2 and R5 is ally substituted with one or more -OH, -O(C1-C4 alkyl), -C02H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH20H, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN, or COzH; R7 and R8 are each ndently selected from hydrogen and C1-C6 alkyl; and Q is selected from aryl, heteroaryl, carbocyclyl and cyclyl, 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(=O); or R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=O); 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 tuted 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 NHCHZCHZOCHZCHZOCHZCHZNHZ, [2— (2-aminoethoxy)ethoxy]ethyl]amino] and (b) N(R7)C(R4)(R5)(R6) and (R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), NH—[(4- methoxyphenyl)methyl], NHCHZCHZCHO, NHCHZCHZOCHg, NHCHZCHZOH, NHCHZCH(OH)CH3, NHCHZCH20C(O)phenyl, NHCH2CH2CH20H, NHCHZCHZCH2N(CH3)phenyl, NHCH2C(O)OCH3, NHCH2C(O)OCH2CH3, NHCHzphenyl, NHCH(CH3)CH2CH3, or NHCHzCHzOC(O)CH3; (ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, C1 or $02CH3, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(O)NH-i-propyl, H3)(CH2)3N(CH2CH3)2, NHCHzCHon, NHCHzCHzOCH3, NHCHzCH20803H, NHCHZCHZCHZOCHZCHZO-phenyl, HZCHZOH, HZCHZOCHg, NHCHZCH(OH)CH3, N(CH2CH3)2, NH—i-propyl, NHCHZCHZNHC(O)OCH3, NHCHZCHZNHC(O)CH3, NHCHZCHZNHZ, or NHCHz-phenyl; (iii) when X is CH and A is optionally substituted l, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCHz-phenyl, NHCHZ-(2,4-difluorophenyl), N(CH3)CH2CH2C(O)OH, NHCHzCH2C(O)OH, NHCHzCH2C(O)OCH2CH3, NHCHzCH2C(O)O-t-butyl, NHCHzCH2C(O)NH2, Hz-phenyl, NHCHZCHZOH, NHCHZCHZNHZ, NHCHZCH2N(CH3)2, or NHCHZCHZCHg; (iv) when X is CH and A is optionally substituted l-imidazolyl, optionally substituted 1- pyrrolyl or optionally substituted l-pyrazolyl, then r N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NH(CH2)7CH3, NHCHz-(o-chloro-phenyl), or NHCHZCHZOH; (V) when X is N and A is an optionally substituted pyridyl, then (A) neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(O)-[2-chloro(methylsulfonyl)], N(CH3)2, NHCHZCHZCHZSOZCHZCHZCI, HZOCHZCHZSOzCHzCHzCl,or NHCHZCHZSOZCHZCHZCI, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(O)C(CH3)3, NHC(O)CH=CH2, C(CH3)=CH2, NHCHzCHZOH, NH-cyclohexyl, NHCHz-phenyl, NHC(O)phenyl, NHC(O)(CH2)5NH2, OCH3, NHC(O)CH3, and NHC(O)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCHz-phenyl or NH-CHZCH3; (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, NHCHzCHz-i-propyl, NHCHZCH(CH3)2, and 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 zol-3 -yl, (Viii) when A is optionally substituted l-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)2, NHCH3, NHAc, NHisopropyl, NHCHZCHg, NHCHZCH2803H 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 (R1)(R2)(R3) is NHcyclohexle(O)NHCH2R, wherein R is phenyl or pyridinyl which is tuted with one or more of OCF3, OCH3, chloro, or CF3, (X) when X is N, A is an ally 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(O)Cl, NHCH(C02H)(CH28CHzphenyl), or NHCH2C(O)NHC(O)NHR or NHCH2C(O)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl, (Xi) when X is N, A is an oxadiazole tuted with an optionally substituted pyridinyl, then R4 and R5 do not form an optionally substituted phenyl, (xii) when A is substituted l-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, (xiii) ring A is not an optionally tuted 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 tituted cyclohexyl, then A is not a disubstituted zolyl or an unsubstituted phenyl; and (XX) the compound is not selected from the group: (1) N—(2-aminophenyl)—4-[[[4-[(2,3 -dihydro-l H—indenyl)amino]phenyl-l ,3 ,5-triazin yl]amino]methyl]-benzamide, (2) 2-chloro-N- [4-(cyclopropylamino)(2-pyridinyl)-l ,3 , 5 -triazinyl] (methylsulfonyl)- benzamide, (3) 2-[[l -[4-(cyclopropylamino)(ethylamino)-l ,3 ,5-triazinyl]— l H—l ,2,4-triazol-3 -yl]thio]- acetamide, (4) N2-cyclopropyl-N4-ethyl[3 -[(phenylmethyl)thio]- l H—l ,2,4-triazol-l -yl]-l ,3 ,5-triazine-2,4- diamine, (5) 2-[[l yclopropylamino)(ethylamino)-l ,3 ,5-triazinyl]— l H—l ,2,4-triazol-3 -yl]thio]- acetic acid methyl ester, (6) N—[[4-[[[4-(cyclopropylamino)(2-pyridinyl)-l ,3,5-triazinyl]amino]methyl]cyclohexyl] methyl]fluoro-benzenesulfonamide, (7) N2-cyclopropyl(3 ,5-dimethyl-l H—pyrazol-l -yl)-N4-phenyl-l ,3 ,5-triazine-2,4-diamine, (8) N2,N4-dicyclohexyl[3 -(4-methoxyphenyl)-5 -(methylthio)-lH—pyrazol-l -yl]-l ,3 ,5-triazine- 2,4-diamine, (9) dicyclohexyl[3 -(3 ,4-dimethoxyphenyl)-5 ylthio)-lH—pyrazol-l -yl] -l ,3 ,5- ne-2,4-diamine, (l O) N2,N4-dicyclohexyl[5-(methylthio)-3 -(3 ,4,5-trimethoxyphenyl)-l H—pyrazol-l -yl]-l ,3 ,5- triazine-2,4-diamine, (1 1) N2,N4-dicyclohexylphenyl-1,3 ,5-triazine-2,4-diamine, (12) 1,1 '- [(6-phenyl-s-triazine-2,4-diyl)diimino]bis [dodecahydro-anthraquinone], (13) 4,4'-[(6-phenyl-1,3 ,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(1,1- dimethylethyl)- phenol, (14) N—[4- [(4-aminobutyl)amino]—6- [5 -[ [[ [4-chloro-3 -(trifluoromethyl)phenyl]amino]carbonyl] amino]—2-methylphenyl]—1 ,3 ,5-triazinyl] -glycine, (15) 4-[2-[[4-[(5-aminopentyl)amino]—6-(3 - fluorophenyl)—1 ,3 ,5-triazinyl]amino]ethyl]— phenol, (16) 4-[2-[[4-[(5-aminopentyl)amino]—6-(4- fluorophenyl)—1 ,3 ,5-triazinyl]amino]ethyl]— phenol, (17) minopyridin-3 2-benzyl-N4-(tert-butyl)-1 ,3 ,5-triazine-2,4-diamine, (1 8) N2,N4-b is(cyclohexylmethyl)phenyl-1 ,3 , 5-triazine-2,4-diamine, (19) 4,4'-[[6-[3 (1,1-dimethylethyl) hydroxyphenyl]—1,3 ,5-triazine-2,4-diyl]bis(imino- 3 ,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol, (20) 4,4'-[(6-phenyl-1,3 azine-2,4- diyl)bis(imino-3 ,1-propanediyl)]bis[2,6-bis(1,1- dimethylethyl)—phenol, (21) N—[6-[(2,3 -dihydro-1H—indenyl)amino](2-pyridinyl)pyrimidinyl]—Balanine, (22) N4-cyclopentylphenyl-N6-(phenylmethyl)-4,6-pyrimidinediamine, (23) 2-[[6-(bicyclo[2.2.1]heptylamino)phenylpyrimidinyl]amino]-ethanol, (24) NZ-isopropylphenyl-N4-(tetrahydro-2H-pyranyl)-1,3 azine-2,4-diamine, (25) 2-chloro(methylsulfonyl)—N— [4-[(phenylmethyl)amino](2-pyridinyl)—1 ,3 azin yl]—benzamide, (26) N—[[4-[[[4-(cyclopropylamino)(2-pyridinyl)-1 ,3 ,5 -triazin yl]amino]methyl]cyclohexyl]methyl]fluoro-benzenesulfonamide, (27) [[4-[[[[[4-amino(4-pyridinyl)—1,3 ,5-triazinyl]amino]methoxy]methyl]amino](4- pyridinyl)-1 ,3 ,5 -triazin-2 -yl] imino]bis-methanol, (28) [[4-[[[[[4-[bis(hydroxymethyl)amino](4-pyridinyl)-1,3 ,5 -triazin yl]amino]methoxy]methyl](hydroxymethyl)amino] (4-pyridinyl)— 1 ,3 , 5 -triazinyl]imino]bis— methanol, (29) 5-[4,6-bis(diethy1amino)—1,3,5-triaziny1]— 2H-tetrazoleacetic acid ethyl ester, (3 O) N4,N4-tetraethy1(2H-tetrazol-5 -y1)-1,3 ,5 -triazine-2,4-diamine, (31) NN—[6-[4-(acety1amino)—1,2,5-oxadiazolyl]—1,3,5-triazine-2,4-diy1]bis—acetamide, (3 2) N—(2-chloromethy1phenyl)-5 -[ [4-(dimethylamino)(2-pyridiny1)-1 ,3 ,5 -triazin y1]amino]-1,3,4-Oxadiazolecarboxamide, (3 3) N4-(5-methy1—1H—pyrazol-3 -y1)(2-pyridiny1)—N6-(tetrahydro-2H-pyrany1)-4,6- Pyrimidinediamine, (3 4) 6-(4-chlorophenyl)-N2- [4-chloro-3 -(trifluoromethyl)phenyl]-N4- [3 -(diethylamino)propyl]- 1,3 ,5-Triazine-2,4-diamine, (3 5) 6-(4-chlorophenyl)-N2- oro-3 -(trifluoromethyl)phenyl]-N4- [3 - (dimethylamino)propyl]— 1 ,3 ,5 -Triazine-2,4-diamine, (3 6) N2-[3 ,5-bis(trifluoromethyl)phenyl](4-chlorophenyl)-N4-[3 -(diethy1amino)propy1]—1,3 ,5 - Triazine-2,4-diamine, (3 7) bis[(4-methoxyphenyl)methyl][4-(trifluoromethoxy)pheny1]-1 ,3 ,5 ine-2,4- diamine, (3 8) N,N"-(6-pheny1—1,3,5-triazine-2,4-diy1)bis[N'-(2-chloroethy1)-Urea, (3 9) N—[4-chloro-3 -(trifluoromethyl)phenyl]-N'-[4-methy1-3 -[[4-phenyl(propy1amino)-1,3 ,5 - triaziny1]amino]pheny1] -urea, (40) N—[4-[[5-[[[[4-chloro-3 -(trifluoromethyl)phenyl]amino]carbonyl]amino]—2- methylphenyl]amino](4-pyridiny1)-1 ,3 ,5-triaziny1]—g1ycine, (41) N—[4-[[5-[[[[4-chloro-3 -(trifluoromethyl)phenyl]amino]carbonyl]amino]—2- methylphenyl]amino]—6-(5 -thiazoly1)—1,3 ,5 -triaziny1]—L-Valine, (42) s-Triazine, y1-4,6-bis[[6-[[4-phenyl[[6-[[4-pheny1(trichloromethy1)-s-triazin yl]amino]hexyl]amino]-s-triazinyl]amino]hexyl]amino]-, (43) 0c,0c'-[(6-pheny1-1,3 ,5 -triazine-2,4-diyl)bis[imino(1,1,2,2-tetrafluoro-3 -oxo-3 ,1 - propanediy1)] ]bis [03- [tetrafluoro(trifluoromethy1)ethoxy] -Poly[oxy[trifluoro(trifluoromethy1)- 1,2-ethanediy1] ], (44) 0c-[[4-[[(3 -chlorophenyl)methyl]amino](1H—imidazol-l -y1)-1 ,3 ,5-triazinyl]amino]-N- [[4-(trifluoromethyl)phenyl]methyl]-, (ocR)-Cyclohexanepropanamide, (45)6-(l H—imidazol-l -yl)-N2,N4-bis(l -methylethyl)-l ,3 ,5-Triazine-2,4-diamine, and (46) N2,N4-bis(l -methylpropyl)phenyl-l ,3 , 5 -Triazine-2,4-diamine.
Provided is a compound ofFormula I, or a pharmaceutically acceptable salt or hydrate f: Ru N." NAXANJ Provided is a compound ofFormula I, or a ceutically acceptable salt or hydrate thereof: R4 N \ N R1 R‘PkryixANkR3R5 R2 R7 R8 (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 kyl, 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(C1-C4 alkyl), or -N(C1-C4 alkyl)2; R2 and R5 are each independently ed from: -(C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-NH2, -(C1-C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(C1-C6 alkylene)-N(R6)-(C1-C6 alkylene)-O-(C1-C6 alkyl), 6 alkylene)-N(R6)-(Co-C6 alkylene)-Q, 6alkylene)-N(R6)(R6), -(C1-C6 alkylene)-N(R6)-S(0)1(C1-C6 alkyl), -(C1-C6 alkylene)-N(R6)-S(O)1.2-(C0-C6 alkyl)-Q, 6 alkylene)-S(O)1.2-N(R6)(R6), -(C1-C4 alkylene)-S(O)1.2-N(R6)-(C1-C6 alkylene)-Q, -C(O)N(R6)-(C1-C6 alkylene)-C(O)- (Co—C6 alkylene)-O-(C1-C6 alkyl), -C(O)N(R6)-(C1-C6 alkylene)-C(O)-(Co-C6 alkylene)-O-(Co-C6 alkylene)-Q, -(C1-C6 alkylene)-O-C(O)-(C1-C6 alkyl), -(C1-C6 alkylene)-O-C(O)-(C0-C6 -Q, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(Co-C6 alkylene)-O-(C1-C6 alkyl), -(Co-C6 alkylene)-C(O)-(Co-C6 alkylene)-O-(C1-C6 alkylene)-Q, -(C1-C6 alkylene)-O-C(O)-(C1-C6 alkyl), -(C1-C6 alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 ne)-C(O)N(R6)-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)C(O)-(C1-C6 alkyl), -(C1-C6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-S(O)0(C1-C6 , -(C0-C6 alkylene)-S(O)0(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)-C(O)-N(R6)-(C1-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein: any alkyl or ne moiety present in R2 and R5 is optionally substituted with one or more -OH, -O(C1-C4 , -C02H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH20H, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN, or COZH; R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl; and Q is selected from aryl, heteroaryl, yclyl and heterocyclyl, any of which is optionally tuted; wherein R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=O); or R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=O); or R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl or ally substituted heterocyclyl; or R4 and R5 are optionally taken together to form an optionally substituted carbocyclyl or ally 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], NHCHzCHzCHO, NHCHzCHzOCH3, NHCHZCHZOH, NHCHZCH(OH)CH3, NHCHZCH20C(O)phenyl, NHCHZCHZCHZOH, NHCHZCHZCH2N(CH3)phenyl, NHCH2C(O)OCH3, (O)OCH2CH3, NHCHzphenyl, NHCH(CH3)CH2CH3, or NHCHzCHzOC(O)CH3; (ii) when X is CH or C-Cl and A is phenyl optionally substituted with F, C1 or , then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(O)NH-i-propyl, NHCH(CH3)(CH2)3N(CH2CH3)2, NHCHZCHZOH, NHCHZCHZOCHg, NHCHZCH20803H, NHCHzCHzCHZOCHzCHZO-phenyl, NHCHZCHZCHZOH, HZCHZOCHg, NHCHZCH(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCHZCHZNHC(O)OCH3, NHCHZCHZNHC(O)CH3, NHCHZCHZNHZ, or NHCHz-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 NHCHz-phenyl, NHCHZ-(2,4-difluorophenyl), N(CH3)CH2CH2C(O)OH, H2C(O)OH, NHCHZCH2C(O)OCH2CH3, NHCHzCH2C(O)O-t-butyl, NHCHzCH2C(O)NH2, NHCHzCHz-phenyl, NHCHZCHZOH, NHCHZCHZNHZ, NHCHZCH2N(CH3)2, or HZCHg; (iv) when X is CH and A is ally substituted l-imidazolyl, ally substituted 1- pyrrolyl or optionally substituted l-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NH(CH2)7CH3, NHCHz-(o-chloro-phenyl), or NHCHZCHZOH; (V) when X is N and A is an optionally substituted pyridyl, then (A) neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHC(O)-[2-chloro(methylsulfonyl)], (B) (R4)(R5)(R6) and (R1)(R2)(R3) are not both NHC(O)C(CH3)3, NHC(O)CH=CH2, NHC(O)C(CH3)=CH2, NHCHZCHZOH, NH-cyclohexyl, NHCHz-phenyl, NHC(O)phenyl, NHC(O)(CH2)5NH2, NHC(O)OCH3, NHC(O)CH3, and NHC(O)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCHz-phenyl or NH-CHZCH3; (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 H3)2, NHCHZCHz-i-propyl, NHCHZCH(CH3)2, and NHC(O)CH3; (Vii) the compound is not ed from the group: (1 ) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopenty1pheny1-1,3 ,5-triazine-2,4- diamine, (2) N2-[2- [2-(2-aminoethoxy)ethoxy] ethyl] -N4-cyclopenty1(4-methoxypheny1)—1 ,3 , 5 - triazine-2,4-diamine, (3) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopenty1(3-nitropheny1)-1,3,5- ne-2,4-diamine, (4) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopenty1(4-fluoropheny1)-1 ,3 ,5 - triazine-2,4-diamine, (5) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopenty1(4-trifluoromethoxypheny1 )-1,3 ,5-triazine-2,4-diamine, (6) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl(4-t-buty1—pheny1)-1 ,3 ,5 - triazine-2,4-diamine, (7) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopenty1(2-thieny1)-1 ,3 ,5 -triazine- 2,4-diamine, (8) N—(2-aminopheny1)[ [[4-[(2,3 -dihydro-1H—indenyl)amino]pheny1-1,3 ,5- triaziny1]amino]methy1]-benzamide, (9) 2-chloro-N-[4-(cyclopropy1amino)(2-pyridiny1)-1,3,5-triaziny1]—4- (methylsulfony1)-benzamide, (10) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropy1(4-methoxypheny1)— 1,3 ,5-triazine-2,4-diamine, (1 1) 2-[[1-[4-(cyclopropylamino)(ethy1amino)-1,3 ,5 -triaziny1]—1H—1,2,4-triazol-3 - y1]thio]-acetamide, (12) N2-cyclopropy1-N4-ethy1[3 -[(pheny1methy1)thio]-1H—1,2,4-triazoly1]—1,3 ,5- ne-2,4-diamine, (13) 2-[[1-[4-(cyclopropylamino)(ethy1amino)-1,3 ,5 -triaziny1]—1H—1,2,4-triazol-3 - yl]thio]- acetic acid methyl ester, (14) N2-[2- [2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl(2,4,6-trimethylphenyl) 1,3 ,5-triazine-2,4-diamine, (1 5) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropylphenyl-1,3 ,5-triazine- 2,4-diamine, (16) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl(4-methylphenyl)—1,3 ,5- triazine-2,4-diamine, (17) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropyl(4-chlorophenyl)-1,3 ,5 - triazine-2,4-diamine, (18) N—[ [4-[ [[4-(cyclopropylamino)(2-pyridinyl)-1 ,3 ,5-triazin yl]amino]methyl]cyclohexyl] ]fluoro-benzenesulfonamide, (19) N2-cyclopropyl(3 ,5-dimethyl-1H—pyrazolyl)-N4-phenyl-1,3 ,5-triazine-2,4- diamine, (20) N2,N4-dicyclohexyl [3 -(4-methoxyphenyl)-5 -(methylthio)-1H—pyrazol-l -yl]— 1,3 ,5-triazine-2,4-diamine, (21) N2,N4-dicyclohexyl[3 -(3 ,4-dimethoxyphenyl)—5-(methylthio)-1H—pyrazol-l -yl]— 1,3 ,5-triazine-2,4-diamine, (22) N2,N4-dicyclohexyl[5 -(methylthio)-3 -(3 ,4, 5 -trimethoxyphenyl)-1 H—pyrazol yl]—1,3 azine-2,4-diamine, (23) N2,N4-dicyclohexylphenyl-1,3 ,5-triazine-2,4-diamine, (24) 1 ,1 phenyl-s-triazine-2,4-diyl)diimino]bis[dodecahydro-anthraquinone], (25) 4,4'-[(6-phenyl-1,3 ,5-triazine-2,4- diyl)bis(iminomethylene)]bis[2,6-bis(1,1- ylethyl)—phenol, (26) N—[4-[(4-aminobutyl)amino]—6-[5 -[ [[ [4-chloro-3 - (trifluoromethyl)phenyl]amino]carbonyl] amino]—2-methylphenyl]—1 ,3 azinyl] -glycine, (27) 4-[2-[[4-[(5-aminopentyl)amino]—6-(3 - fluorophenyl)—1 ,3 ,5-triazin yl]amino]ethyl]— phenol, (28) 4-[2-[[4-[(5-aminopentyl)amino]—6-(4- fluorophenyl)—1 ,3 ,5-triazin yl]amino]ethyl]— phenol, (29) 6-(4-aminopyridin-3 -y1)-N2-benzyl-N4-(tert-buty1)-1 ,3 ,5-triazine-2,4-diamine, (3 O) N2,N4-bis(cyclohexylmethy1)pheny1-1,3 ,5-triazine-2,4-diamine, (31) [6-[3 ,5-bis(1,1-dimethy1ethy1) hydroxyphenyl]—1,3 ,5-triazine-2,4- diyl]bis(imino- 3 ,1-propanediy1)]bis[2,6-bis(1,1-dimethy1ethy1)—phenol, (3 2) 4,4'-[(6-pheny1—1,3 ,5-triazine-2,4- diy1)bis(imino-3 ,1 -propanediy1)]bis[2,6-bis(1 ,1 - dimethylethyl)—phenol, (3 3) N—[6-[(2,3 -dihydro-1H—indeny1)amino](2-pyridiny1)pyrimidiny1]—Balanine, (34) N4-cyclopenty1pheny1-N6-(pheny1methyl)-4,6-pyrimidinediamine, (3 5) 2-[[6-(bicyclo[2.2.1]hepty1amino)pheny1pyrimidinyl]amino]-ethanol, (3 6) NZ-isopropylphenyl-N4-(tetrahydro-2H-pyrany1)-1,3 ,5-triazine-2,4-diamine, (3 7) 2-chloro(methylsu1fony1)-N-[4-[(pheny1methy1)amino](2-pyridiny1)—1,3 ,5- triaziny1]—benzamide, (3 8) N—[[4-[[[4-(cyclopropylamino)(2-pyridiny1)-1 ,3 ,5 -triazin y1]amino]methyl]cyclohexyl]methy1]fluoro-benzenesu1fonamide, (3 9) [[4-[[[[[4-amino(4-pyridiny1)—1,3 ,5-triaziny1]amino]methoxy]methyl]amino]- 6-(4-pyridiny1)-1,3 aziny1]imino]bis-methanol, (40) [[4-[[[[[4-[bis(hydroxymethyl)amino](4-pyridiny1)-1,3 azin yl]amino]methoxy]methyl](hydroxymethyl)amino] (4-pyridiny1)— 1 ,3 , 5 iny1]imino]bis— methanol, (41) 5-[4,6-bis(diethy1amino)—1,3,5-triaziny1]— 2H-tetrazoleacetic acid ethyl ester, (42) N2,N2,N4,N4-tetraethy1(2H-tetrazoly1)-1 ,3 ,5-triazine-2,4-diamine, and (43) NN—[6-[4-(acety1amino)—1,2,5-oxadiazol-3 -y1]-1,3,5-triazine-2,4-diy1]bis—acetamide.
Also provided is a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof: R7 R8 (I), wherein: ring A is an optionally substituted 5-6 member clic 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(C1-C4 alkyl), or -N(C1-C4 alkyl)2; R2 and R5 are each independently selected from: -(C1-C6 , -(C1-C6 alkyl)-C(O)-NH2, -(C1- C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(C1-C6 alkylene)-N(R6)-(C1-C6 alkylene)-O-(C1-C6 alkyl), —(c1—c6 alkylene)-N(R6)-(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)(R6), -(C1-C6 alkylene)-N(R6)-S(O)1(C1-C6 alkyl), -(C1-C6 alkylene)-N(R6)-S(O)1(C0-C6 alkyl)-Q, 6 alkylene)-S(O)1N(R6)(R6), -(C1-C4 alkylene)-S(0)1N(R6)-(C1-C6 alkylene)-Q, -C(O)N(R6)-(C1-C6 alkylene)-C(O)- (C0-C6 alkylene)-O-(C1-C6 , -C(O)N(R6)-(C1-C6 ne)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-O-C(O)-(C1-C6 alkyl), -(C1-C6 alkylene)-O-C(O)-(C0-C6 alkyl)-Q, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 ne)-O-(C1-C6 alkylene)-Q, -(Co-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C1-C6 alkylene)-Q, -(C1-C6 alkylene)-O-C(O)-(C1-C6 alkyl), 6 alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)N(R6)-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)C(O)-(C1-C6 alkyl), -(C1-C6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 ne)-S(O)0(C1-C6 alkyl), 6 alkylene)-S(O)0(C0-C6 ne)-Q, -(C1-C6 alkylene)-N(R6)-C(O)-N(R6)-(C1-C6 alkyl), -(C0-C6alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein: any alkyl or alkylene moiety t in R2 and R5 is optionally substituted with one or more -OH, -O(C1-C4 alkyl), -C02H, or halo; any terminal methyl moiety present in R2 and R5 is optionally ed with -CH20H, CF3, -CH2F, -CH2C1, C(O)CH3, C(O)CF3, CN, or COZH; 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(=O); or R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=O); 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 ally substituted yclyl, 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 NHCHZCHZOCHZCHZOCHZCHZNHZ, 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, ropyl), NH(n-butyl), NH(n-docecyl), NH—[(4- yphenyl)methyl], NHCHZCHZCHO, NHCHZCHZOCHg, NHCHZCHZOH, NHCHZCH(OH)CH3, NHCHzCHzOC(O)phenyl, HzCHzOH, NHCHzCHzCH2N(CH3)phenyl, NHCH2C(O)OCH3, (O)OCH2CH3, NHCHzphenyl, NHCH(CH3)CH2CH3, or NHCHZCH20C(O)CH3; (ii) when X is CH or C-Cl and A is phenyl optionally tuted with F, C1 or SOzCH3, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(O)NH-i-propyl, NHCH(CH3)(CH2)3N(CH2CH3)2, NHCHZCHZOH, NHCHZCHZOCHg, NHCHZCH20803H, NHCHZCHZCHZOCHZCHZO-phenyl, NHCHZCHZCHZOH, NHCHZCHZCHZOCHg, H(OH)CH3, N(CH2CH3)2, NH-i-propyl, NHCHzCHzNHC(O)OCH3, NHCHZCHZNHC(O)CH3, NHCHZCHZNHZ, or NHCHz-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 NHCHz-phenyl, NHCHZ-(2,4-difluorophenyl), N(CH3)CH2CH2C(O)OH, NHCHZCH2C(O)OH, NHCHzCH2C(O)OCH2CH3, NHCHzCH2C(O)O-t-butyl, NHCHZCH2C(O)NH2, Hz-phenyl, NHCHZCHZOH, NHCHzCHzNHz, NHCHzCH2N(CH3)2, or NHCH2CH2CH3; (iv) when X is CH and A is optionally substituted azolyl, optionally substituted 1- pyrrolyl or optionally substituted zolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NH(CH2)7CH3, (o-chloro-phenyl), or NHCHZCHZOH; (V) when X is N and A is an optionally substituted pyridyl, then (A) neither N(R7)C(R4)(R5)(R6) nor (R1)(R2)(R3) is NHC(O)-[2-chloro(methylsulfonyl)], N(CH3)2,NHCH2CH2CHZSOzCHzCHzCl, HZOCHZCHZSOzCHzCHzCl,or NHCHzCHzSOzCHzCHzCl, (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(O)C(CH3)3, NHC(O)CH=CH2, NHC(O)C(CH3)=CH2, NHCHzCHZOH, NH-cyclohexyl, NHCHz-phenyl, NHC(O)phenyl, (CH2)5NH2, NHC(O)OCH3, NHC(O)CH3, and NHC(O)NH-optionally substituted phenyl, and (C) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCHz-phenyl or NH-CHZCH3; (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, NHCHzCHz-i-propyl, NHCHZCH(CH3)2, and NHC(O)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 l-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)2, NHCH3, NHAc, NHisopropyl, Hg, NHCHZCH2803H 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 NHcyclohexle(O)NHCH2R, wherein R is phenyl or pyridinyl which is substituted with one or more of OCF3, OCH3, , or CF3, (X) when X is N, A is an optionally substituted phenyl and R4 and R5 form an optionally WO 03640 substituted phenyl, then N(R8)C(R1)(R2)(R3) is not NHCH2(4-fluorophenyl), NHCH2C02H, (O)C1, NHCH(C02H)(CH28CHzphenyl), or NHCH2C(O)NHC(O)NHR or NHCH2C(O)NHC(S)NHR, wherein R is optionally substituted phenyl or naphthyl, (Xi) when X is N, A is an oxadiazole substituted with an ally substituted pyridinyl, then R4 and R5 do not form an optionally substituted phenyl, (xii) when A is tuted l-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, (xiii) ring A is not an ally 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 exyl, then A is not a disubstituted l-pyrazolyl or an unsubstituted phenyl; and (XX) the compound is not selected from the group: (1) N—(2-aminophenyl)[[[4-[(2,3 -dihydro-l H—indenyl)amino]phenyl-l ,3 ,5-triazin yl]amino]methyl]-benzamide, (2) 2-chloro-N- [4-(cyclopropylamino)(2-pyridinyl)-l ,3 , 5 -triazinyl] (methylsulfonyl)- benzamide, (3) 2-[[l -[4-(cyclopropylamino)(ethylamino)-l ,3 ,5-triazinyl]— l H—l ,2,4-triazol-3 -yl]thio]- acetamide, (4) lopropyl-N4-ethyl[3 -[(phenylmethyl)thio]- l H—l ,2,4-triazol-l -yl]-l ,3 ,5-triazine-2,4- diamine, (5) 2-[[l -[4-(cyclopropylamino)(ethylamino)-l ,3 ,5-triazinyl]— l H—l ,2,4-triazol-3 -yl]thio]- acetic acid methyl ester, (6) N—[[4-[[[4-(cyclopropylamino)(2-pyridinyl)-l ,3,5-triazinyl]amino]methyl]cyclohexyl] methyl]fluoro-benzenesulfonamide, (7) N2-cyclopropyl(3 ,5-dimethyl-l H—pyrazol-l -yl)-N4-phenyl-l ,3 ,5-triazine-2,4-diamine, (8) N2,N4-dicyclohexyl[3 thoxyphenyl)-5 -(methylthio)-lH—pyrazol-l -yl]-l ,3 ,5-triazine- 2,4-diamine, (9) N2,N4-dicyclohexyl[3 -(3 ,4-dimethoxyphenyl)-5 -(methylthio)-lH—pyrazol-l -yl] -l ,3 ,5- 2014/081957 triazine-2,4-diamine, (10) N2,N4-dicyclohexyl[5 -(methylthio)-3 -(3 ,4,5-trimethoxyphenyl)-1H—pyrazol-l -yl]—1 ,3 ,5- ne-2,4-diamine, (1 1) N2,N4-dicyclohexylphenyl-1,3 ,5-triazine-2,4-diamine, (12) 1,1 '- [(6-phenyl-s-triazine-2,4-diyl)diimino]bis [dodecahydro-anthraquinone], (13) 4,4'-[(6-phenyl-1,3 ,5-triazine-2,4- is(iminomethylene)]bis[2,6-bis(1,1- dimethylethyl)- phenol, (14) N—[4- [(4-aminobutyl)amino]—6- [5 -[ [[ [4-chloro-3 uoromethyl)phenyl]amino]carbonyl] amino]—2-methylphenyl]—1 ,3 ,5-triazinyl] -glycine, (15) 4-[2-[[4-[(5-aminopentyl)amino]—6-(3 - fluorophenyl)—1 ,3 ,5-triazinyl]amino]ethyl]— phenol, (16) 4-[2-[[4-[(5-aminopentyl)amino]—6-(4- fluorophenyl)—1 ,3 ,5-triazinyl]amino]ethyl]— phenol, (17) 6-(4-aminopyridin-3 -yl)-N2-benzyl-N4-(tert-butyl)-1 ,3 azine-2,4-diamine, (1 8) N2,N4-b is(cyclohexylmethyl)phenyl-1 ,3 , 5-triazine-2,4-diamine, (19) 4,4'-[[6-[3 ,5-bis(1,1-dimethylethyl) hydroxyphenyl]—1,3 ,5-triazine-2,4-diyl]bis(imino- 3 ,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol, (20) 4,4'-[(6-phenyl-1,3 ,5-triazine-2,4- diyl)bis(imino-3 ,1-propanediyl)]bis[2,6-bis(1,1- dimethylethyl)—phenol, (21) N—[6-[(2,3 -dihydro-1H—indenyl)amino](2-pyridinyl)pyrimidinyl]—Balanine, (22) lopentylphenyl-N6-(phenylmethyl)-4,6-pyrimidinediamine, (23) 2-[[6-(bicyclo[2.2.1]heptylamino)phenylpyrimidinyl]amino]-ethanol, (24) NZ-isopropylphenyl-N4-(tetrahydro-2H-pyranyl)-1,3 ,5-triazine-2,4-diamine, (25) 2-chloro(methylsulfonyl)—N— [4-[(phenylmethyl)amino](2-pyridinyl)—1 ,3 ,5-triazin yl]—benzamide, (26) N—[[4-[[[4-(cyclopropylamino)(2-pyridinyl)-1 ,3 ,5 -triazin yl]amino]methyl]cyclohexyl]methyl]fluoro-benzenesulfonamide, (27) [[4-[[[[[4-amino(4-pyridinyl)—1,3 ,5-triazinyl]amino]methoxy]methyl]amino](4- pyridinyl)-1 ,3 ,5 -triazin-2 -yl] imino]bis-methanol, (28) [[[4-[bis(hydroxymethyl)amino](4-pyridiny1)-1,3 ,5-triazin yl]amino]methoxy]methyl](hydroxymethyl)amino] (4-pyridiny1)— 1 ,3 , 5 -triazinyl]imino]bis- methanol, (29) 5-[4,6-bis(diethy1amino)—1,3,5-triaziny1]— 2H-tetrazoleacetic acid ethyl ester, (3 O) N2,N2,N4,N4-tetraethy1(2H-tetrazol-5 -y1)-1,3 ,5 -triazine-2,4-diamine, (31) NN—[6-[4-(acety1amino)—1,2,5-oxadiazolyl]—1,3,5-triazine-2,4-diy1]bis—acetamide, (3 2) N—(2-chloromethy1pheny1)-5 -[ [4-(dimethylamino)(2-pyridiny1)-1 ,3 ,5 -triazin y1]amino]-1,3,4-Oxadiazo1ecarboxamide, (3 3) N4-(5-methy1—1H—pyrazol-3 -y1)(2-pyridiny1)—N6-(tetrahydro-2H-pyrany1)-4,6- Pyrimidinediamine, (3 4) 6-(4-chlorophenyl)-N2- [4-chloro-3 -(trifluoromethyl)phenyl]-N4-[3 -(diethy1amino)propy1]— 1,3 azine-2,4-diamine, (3 5) 6-(4-chlorophenyl)-N2- [4-chloro-3 -(trifluoromethyl)phenyl]-N4- [3 - (dimethylamino)propyl]— 1 ,3 ,5 -Triazine-2,4-diamine, (3 6) N2-[3 ,5-bis(trifluoromethyl)phenyl](4-chlorophenyl)-N4-[3 -(diethy1amino)propy1]—1,3 ,5 - ne-2,4-diamine, (3 7) N2,N4-bis[(4-methoxyphenyl)methyl][4-(trifluoromethoxy)pheny1]-1 ,3 ,5 -Triazine-2,4- diamine, (3 8) N,N"-(6-pheny1—1,3,5-triazine-2,4-diy1)bis[N'-(2-chloroethy1)-Urea, (3 9) N—[4-chloro-3 -(trifluoromethyl)phenyl]-N'-[4-methy1-3 -[[4-phenyl(propy1amino)-1,3 ,5 - triaziny1]amino]pheny1] -urea, (40) N—[4-[[5-[[[[4-chloro-3 -(trifluoromethyl)phenyl]amino]carbonyl]amino]—2- methylphenyl]amino](4-pyridiny1)-1 ,3 ,5-triaziny1]—g1ycine, (41) N—[4-[[5-[[[[4-chloro-3 -(trifluoromethyl)phenyl]amino]carbonyl]amino]—2- phenyl]amino]—6-(5 -thiazoly1)—1,3 ,5 -triaziny1]—L-Va1ine, (42) s-Triazine, 2-pheny1-4,6-bis[[6-[[4-phenyl[[6-[[4-pheny1(trichloromethy1)-s-triazin yl]amino]hexyl]amino]-s-triaziny1]amino]hexyl]amino]-, (43) 0c,0c'-[(6-pheny1—1,3 azine-2,4-diy1)bis[imino(1 ,1 ,2,2-tetrafluoro-3 -oxo-3 ,1 - ediy1)] ]bis [03- [tetrafluoro(trifluoromethy1)ethoxy] -Poly[oxy[trifluoro(trifluoromethy1)- l,2-ethanediyl] ], (44) 0c-[[4-[[(3 -chlorophenyl)methyl]amino](l H—imidazol-l -yl)-l ,3 ,5-triazinyl]amino]-N- [[4-(trifluoromethyl)phenyl]methyl]-, (ocR)-Cyclohexanepropanamide, (l H—imidazol-l -yl)-N2,N4-bis(l -methylethyl)-l ,3 ,5-Triazine-2,4-diamine, and (46) N2,N4-bis(l lpropyl)phenyl-l ,3 , 5 -Triazine-2,4-diamine.
Also provided is a compound of Formula Ia, or a pharrnaceutically acceptable salt or hydrate thereof: R4 N \N R1 R5RANANANkWI R2 R7 R8 (Ia), 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(C1-C4 , or -N(C1-C4 alkyl); R2 and R5 are each independently selected from: -(C1-C6 , -(C1-C6 alkyl)-C(O)-NH2, -(C1- C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(C1-C6 alkylene)-N(R6)-(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-N(R6)-(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)(R6), -(C1-C6 alkylene)-N(R6)-S(O)1.2-(C1-C6 alkyl), -(C1-C6 alkylene)-N(R6)-S(O)1(C0-C6 alkyl)-Q, -(C1-C6 alkylene)-S(O)1N(R6)(R6), -(C1-C4 alkylene)-S(0)1N(R6)-(C1-C6 alkylene)-Q, -C(O)N(R6)-(C1-C6 alkylene)-C(O)- (C0-C6 alkylene)-O-(C1-C6 alkyl), -C(O)N(R6)-(C1-C6 ne)-C(O)-(Co-C6 alkylene)-O-(Co-C6 alkylene)-Q, -(C1-C6 alkylene)-O-C(O)-(C1-C6 alkyl), 6 ne)-O-C(O)-(C0-C6 -Q, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(Co-C6 alkylene)-O-(C1-C6 alkyl), 6 alkylene)-C(O)-(Co-C6 alkylene)-O-(C1-C6 alkylene)-Q, -(C1-C6 alkylene)-O-C(O)-(C1-C6 alkyl), 6alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)N(R6)-(C1-C6 alkyl), —(c0—c6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)C(O)-(C1-C6 , 6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-S(O)0(C1-C6 , —(c0—c6 alkylene)-S(O)o.2-(Co-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)-C(O)-N(R6)-(C1-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-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, -O(C1-C4 alkyl), -C02H, or halo; any terminal methyl moiety present in R2 and R5 is ally replaced with -CH20H, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN, or COZH; R7 and R8 are each ndently 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(=O); or R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=O); 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 tuted carbocyclyl or optionally substituted heterocyclyl; wherein: (i) when A is optionally substituted phenyl, then (a) neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is 4-[[2-[2-(2-aminoethoxy)ethoxy]ethyl]amino] and (b) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHEt, NH(n-propyl), NH(n-butyl), NH(n-docecyl), - methoxyphenyl)methyl], NHCHZCHZCHO, NHCHzCHzoCHg, NHCHzCHzOH, NHCHzCH(OH)CH3, NHCHzCHzOC(O)phenyl, NHCHzCHzCHzOH, NHCHZCHZCH2N(CH3)phenyl, NHCH2C(O)OCH3, NHCH2C(O)OCH2CH3, NHCHzphenyl, NHCH(CH3)CH2CH3, or NHCHZCH20C(O)CH3; 2014/081957 (ii) when X is N and A is an optionally substituted pyridyl, then (A) r (R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is -[2-chloro(methylsulfonyl)], (B) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(O)C(CH3)3, NHC(O)CH=CH2, NHC(O)C(CH3)=CH2, NHCHzCHon, NH—cyclohexyl, NHCHz-phenyl, NHC(O)phenyl, NHC(O)(CH2)5NH2, NHC(O)OCH3, NHC(O)CH3, and NHC(O)NH—optionally substituted phenyl, and (C) when (R4)(R5)(R6) is 3)3, then N(R8)C(R1)(R2)(R3) is not NHCHz-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, NHCHZCHz-i-propyl, NHCHZCH(CH3)2, and NHC(O)CH3; and (iV) the compound is not selected from the group: (1) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentylphenyl-l ,3 ,5 -triazine-2,4- diamine, (2) N2-[2- [2-(2-aminoethoxy)ethoxy] ethyl] -N4-cyclopentyl(4-methoxyphenyl)—l ,3 , 5 - triazine-2,4-diamine, (3) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl(3 -nitrophenyl)-l ,3,5- triazine-2,4-diamine, (4) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl(4-fluorophenyl)-l ,3 ,5 - triazine-2,4-diamine, (5) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl(4-trifluoromethoxyphenyl )-l ,3 ,5-triazine-2,4-diamine, (6) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl(4-t-butyl-phenyl)-l ,3 ,5 - triazine-2,4-diamine, (7) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopentyl(2-thienyl)-l ,3 ,5 -triazine- 2,4-diamine, (8) N—(2-aminophenyl)[ [[4-[(2,3 -dihydro-l H—indenyl)amino]phenyl-l ,3 ,5- triazinyl]amino]methyl]-benzamide, (9) 2-chloro-N-[4-(cyclopropylamino)(2-pyridinyl)—l ,3,5-triazinyl]—4- (methylsulfonyl)-benzamide, (10) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropy1(4-methoxypheny1)— 1,3 ,5-triazine-2,4-diamine, (1 1) 2-[[1-[4-(cyclopropylamino)(ethy1amino)-1,3 ,5 iny1]—1H—1,2,4-triazol-3 - y1]thio]-acetamide, (12) N2-cyclopropy1-N4-ethy1[3 -[(pheny1methy1)thio]—1H—1,2,4-triazoly1]—1,3 ,5- triazine-2,4-diamine, (13) 2-[[1-[4-(cyclopropylamino)(ethy1amino)-1,3 ,5 -triaziny1]—1H—1,2,4-triazol-3 - y1]thio]- acetic acid methyl ester, (14) N2-[2- [2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropy1(2,4,6-trimethy1pheny1)— 1,3 ,5-triazine-2,4-diamine, (1 5) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropy1pheny1-1 ,3 ,5-triazine- 2,4-diamine, (16) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropy1(4-methy1pheny1)—1,3 ,5- triazine-2,4-diamine, (17) N2-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-N4-cyclopropy1(4-chlorophenyl)-1,3 ,5 - triazine-2,4-diamine, (18) N—[ [4-[ [[4-(cyclopropylamino)(2-pyridiny1)-1 ,3 ,5-triazin y1]amino]methyl]cyclohexyl] methyl]fluoro-benzenesu1fonamide, (19) N2-cyclopropyl(3 ,5-dimethy1—1H—pyrazol-1 -y1)-N4-pheny1-1,3 ,5-triazine-2,4- diamine, (20) N2,N4-dicyclohexy1 [3 thoxypheny1)—5 -(methy1thio)-1H—pyrazol-l -y1]- 1,3 ,5-triazine-2,4-diamine, (21) N2,N4-dicyclohexy1[3 -(3 ,4-dimethoxypheny1)—5-(methy1thio)-1H—pyrazol-l -y1]- 1,3 ,5-triazine-2,4-diamine, (22) N2,N4-dicyclohexyl[5 -(methy1thio)-3 -(3 ,4, 5 -trimethoxypheny1)-1H—pyrazol-l - y1]-1,3 azine-2,4-diamine, (23) N2,N4-dicyclohexy1pheny1—1,3 ,5-triazine-2,4-diamine, (24) 1 ,1 pheny1-s-triazine-2,4-diy1)diimino]bis[dodecahydro-anthraquinone], (25) 4,4'-[(6-pheny1—1,3 ,5-triazine-2,4- diyl)bis(iminomethy1ene)]bis[2,6-bis(1,1- dimethylethyl)-phenol, (26) N—[4-[(4-aminobutyl)amino]—6-[5 -[ [[ [4-chloro-3 - (trifluoromethyl)phenyl]amino]carbonyl] amino]—2-methylphenyl]-1 ,3 ,5-triazinyl] -glycine, (27) 4-[2-[[4-[(5-aminopentyl)amino]—6-(3 -fluorophenyl)-1 ,3 ,5-triazinyl]amino]ethyl]- phenol, (28) 4-[2-[[4-[(5-aminopentyl)amino]—6-(4-fluorophenyl)—1 ,3 ,5-triazinyl]amino]ethyl]- phenol, (29) 6-(4-aminopyridin-3 -yl)-N2-benzyl-N4-(tert-butyl)-1 ,3 ,5-triazine-2,4-diamine, (3 O) N2,N4-bis(cyclohexylmethyl)phenyl-1,3 ,5-triazine-2,4-diamine, (31) 4,4'-[[6-[3 ,5-bis(1,1-dimethylethyl)hydroxyphenyl]-1,3 azine-2,4- diyl]bis(imino-3 ,1-propanediyl)]bis[2,6-bis(1,1-dimethylethyl)-phenol, (3 2) 4,4'-[(6-phenyl-1,3 ,5-triazine-2,4-diyl)bis(imino-3 ,1 -propanediyl)]bis[2,6-bis(1,1- dimethylethyl)-phenol, (3 3) propylphenyl-N4-(tetrahydro-2H-pyranyl)-1,3 ,5-triazine-2,4-diamine, (3 4) 2-chloro(methylsulfonyl)—N— [4-[(phenylmethyl)amino](2-pyridinyl)-1 ,3 ,5- triazinyl]-benzamide, (3 5) N—[[4-[[[4-(cyclopropylamino)(2-pyridinyl)-1 ,3 ,5 -triazin yl]amino]methyl]cyclohexyl]methyl]fluoro-benzenesulfonamide, (3 6) [[4-[[[[[4-amino(4-pyridinyl)—1,3 azinyl]amino]methoxy]methyl]amino]- 6-(4-pyridinyl)-1,3 ,5-triazinyl]imino]bis-methanol, (3 7) [[4-[[[[[4-[bis(hydroxymethyl)amino](4-pyridinyl)-1,3 ,5-triazin yl]amino]methoxy]methyl](hydroxymethyl)amino] pyridinyl)- 1 ,3 , 5 -triazinyl]imino]bis- methanol, (3 8) 5-[4,6-bis(diethylamino)—1,3,5-triazinyl]— 2H-tetrazoleacetic acid ethyl ester, (3 9) N2,N2,N4,N4-tetraethyl(2H-tetrazolyl)-1,3,5-triazine-2,4-diamine, and (40) NN—[6-[4-(acetylamino)—1,2,5-oxadiazol-3 -yl]—1,3,5-triazine-2,4-diyl]bis-acetamide.
Also provided is a nd of Formula Ia, or a ceutically acceptable salt or hydrate thereof: N \N R1 R55|\ ANAI R2 N NJ In some embodiments, Rland R4 are eachindependently selected from hydrogen, -CH3, -CH2CH3,-CH20H, -CH(CH3)OH,-C(CH3)20H, CF3, CN, or R1 and R3 are taken er to form =0; orR4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=O).
In some embodiments, R1 and R2 are taken together to form carbocyclyl or heterocyclyl, either of which is optionally substituted with up to 3 tuents independently selected from halo, e.g., fluoro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, =0, -OH, and -C(O)C1-C4 alkyl.In some embodiments, R1 and R2 are taken together to form a yclyl 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- SOzCl-C4 alkyl, -C02C1-C4 alkyl, -C(O)aryl,and -C(O)C1-C4 alkyl. In some embodiments R1 and R2 are taken together to form a yclyl 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 ments R1 and R2 are taken together to form a carbocyclyl or heterocyclyl, either of which is optionally tuted 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 ments, R4 and R5 are taken together to form yclyl 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, and -C(O)C1-C4 alkyl.In some embodiments, R4 and R5 are taken together to form a carbocyclyl or heterocyclyl, either of which is optionally tuted 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 - SOzCl-C4 alkyl, -C02C1-C4 alkyl, -C(O)aryl, and -C(O)C1-C4 alkyl. In some embodiments R1 and R2 are taken er to form a carbocyclyl or heterocyclyl, either of which is optionally substituted with aryl or heteroaryl, which is optionally substituted with up to 2 tuents 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, nyl or pyrimidinyl, which is optionally tuted 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: -(C1-C6 alkyl), - (C1-C6 alkyl)-C(O)-NH2, -(C1-C6 alkyl)-COZH, 6 alkenyl or alkynyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl), 6 alkylene)-C(O)N(R6)-(C1-C6 alkyl), -(C0-C6 alkylene)-Q, 6 ne)-C(O)-(C1-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(O)-C1-C4 alkyl, -CN, and halo.
In some embodiments, Rzand R5 are each independently ed from: -(C1-C4 alkyl) optionally substituted with halo, e.g., fluoro or C0-C4 alkylene)-O-(C1-C4 alkyl), -(C0-C2 alkylene)-N(R6)-(C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-NH2,-(C0-C2 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-C6 alkyl), and -O-(C0-C2 alkylene)-Q, wherein Q is optionally substituted with up to 3 tuents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, =0, -C(O)—C1-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, n 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, utyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.l]heptanyl, oxobicyclo[3.l.O]hexanyl, azetidinyl, any of which is optionally substituted with up to 2 substituents ndently ed from C1-C4 alkyl, C1-C4 alkoxy,C3-C6 cycloalkyl, -OH, -C(O)CH3, fluoro, and .
In some embodiments, R4 and R5 are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.l]heptanyl, oxobicyclo[3.l.O]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 lkyl, -OH, -C(O)CH3, fluoro, and .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 tuted with up to 2 substituents independently selected from halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C3-C6 lkyl, phenyl,-OH, -C(O)CH3, wherein any alkyl, cycloalkyl, or phenyl moiety is ally substituted with fluoro, chloro, -OH, -NH2, or—CN. In some 55) CNi: J‘F‘JJ CN embodiments the C3-C6cycloalkyl is U or firfib , , .
In some ments, 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(C1-C4 alkyl), or -N(C1-C4 alkyl); and R2 and R5 are each ndently selected from: -(C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-NH2, -(C1-C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C1-C6 alkyl), and 6 alkylene)-C(O)-(C1-C6 , whereinzany alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -O(C1-C4 alkyl), -C02H, or halo; and any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH20H, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN, or COzH; or R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=O); or R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=O); 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 tuted carbocyclyl, n, when A is an optionally substituted phenyl, 2-pyrrolyl, or l-imidazolyl, then N(R7)C(R4)(R5)(R6) is not the same as N(R8)C(R1)(R2)(R3), and the compound is not -dibromoethyl)phenyl(l,l,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, O)2-(C1-C4 alkyl), -S(O)2NH(C1-C4 alkyl), -CN, -S(O)2-(C1-C4 alkyl), C1-C4 alkoxy, -NH(C1-C4 alkyl), -OH, -OCF3, -CN, -NH2, -C(O)NH2, -C(O)NH(C1-C4 alkyl), N(C1-C4 alkyl)2, -(C1-C6 alkylene)-O-(C1-C6 alkyl), azetidinyl, phenyl, and cyclopropyl ally substituted with OH. In some ments, ring A is a substituted 5-6 member monocyclic aryl or monocyclic aryl, which is substituted with up to two substituents independently selected from fluoro, chloro, CF3, CFZ, -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 ed from halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(O)2-(C1-C4 alkyl), -S(O)2NH(C1-C4 alkyl), -CN, -S(O)2-(C1-C4 , C1-C4 alkoxy, -NH(C1-C4 alkyl), -OH, -OCF3, -CN, -NH2, -C(O)NH2, -C(O)NH(C1-C4 , - C(O)—N(C1-C4 alkyl)2, and cyclopropyl optionally substituted with OH.
In some ments, ring A is selected from phenyl, pyrazolyl, imidazolyl, idinyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl,thiazolyl, thiadiazolyland azolyl, n ring A is optionally substituted with up to two substituents independently selected from halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(O)2—(C1-C4 alkyl), -S(O)2NH(C1-C4 alkyl), -CN, -S(O)2-(C1-C4 alkyl), C1-C4 alkoxy, -NH(C1-C4 alkyl), -OH, -CN, and -NH2.
In some embodiments, ring A is monocyclic heteroaryl ally 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 -(Co-C6 alkylene)-Q; or R1 and R2 are optionally taken together to form an optionally substituted carbocyclyl, an ally substituted heterocyclyl or an optionally substituted heteroaryl; orR4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, an ally substituted heterocyclyl or an optionally substituted heteroaryl.
In some embodiments, ring A is clic 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 6 alkylene)-Q; or R1 and R2 are optionally taken er to form an optionally substituted carbocyclyl oran ally substituted heterocyclyl; orR4 and R5 are optionally taken together to form an optionally substituted carbocyclyl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl.
Xa R9 xa/ Y lay/N In some embodiments, ring A 1s: | wherein R9 is selected from hydrogen, halo, and -C1-C4 haloalkyl; each X3 is independently N or C-R9a, proVided that when one X3 is N, then the other two X3 are both C-R9a; and R93 is selected from en, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A 1s:. . . . 9 . | ,where1n R is selected from hydrogen, halo, N/Y| and -C1-C4 haloalkyl. In some embodiments, ring A is:. . . | wherein R. 9 . selected from hydrogen, halo, and -C1-C4 haloalkyl. In some embodiments, ring A is: N R9 | where1n R, 9 , is selected from hydrogen, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is nyl optionally tuted with halo or -C1-C4 kyl.
In some embodiments, ring A is pyridinyl optionally 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 1s: | where1n R91s selected from hydrogen, halo, and -C1-C4 haloalkyl. In some embodiments, ring A is: | wherein each R9 is independently ed from hydrogen, halo, and -C1-C4 haloalkyl. In some embodiments, R9 is chloro or fluoro. In some embodiments, R9 is -CHonr CF3. In some embodiments, R9 is CF3 or chloro. In some embodiments, R9 is CF3.
In some embodiments, ring A is: | n R9b 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 1s: | where1n R9b is selected from hydrogen and -C1-C4 alkyl, and wherein R9 is selected from hydrogen, halo, and -C1-C4 haloalkyl.
\ N\R9b In some embodiments, ring A 1s: | where1n R9b is selected from en and -C1-C4 alkyl, and wherein R9 is selected from hydrogen, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A 1s:. . . . . | wherein R9 is selected from en, halo, and -C1-C4 haloalkyl. In some embodiments, ring A is pyrazolyl ally tuted 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 lH—pyrazol-l-yl substituted with -C1-C4 haloalkyl, e.g., -CHF2 and CF3. . . . . 9 In some embodiments, ring A is: | wherein R . 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.
In some embodiments, ring A is: | wherein R9 is selected from hydrogen, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is: | wherein R9 is selected from hydrogen, halo, and -C1-C4 haloalkyl.
SY/ N In some embodiments, ring A is: | wherein R9 is selected from hydrogen, halo, and -C1-C4 haloalkyl.
/N:< JVVV‘ In some embodiments, ring A 1s:. . . | wherein R. 9 . is selected from en, halo, and -C1-C4 haloalkyl.
JVVV‘ In some embodiments, ring A 1s:. . . | wherein R. 9 . is selected from hydrogen, halo, and -C1-C4 haloalkyl.
In some ments, ring A is: | wherein R9 is ed from hydrogen, halo, and -C1-C4 haloalkyl.
O / N In some embodiments, ring A is: X wherein R9 is selected from hydrogen, halo, and -C1-C4 haloalkyl.
In some embodiments, ring A is nyl 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 ments, ring A is pyrazinyl optionally substituted with halo or -C1-C4 haloalkyl. In some ments, ring A is pyrazinyl substituted with halo, e.g., chloro or fluoro. In some ments, ring A is nyl 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., -CHF2 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 ments, 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 tituted 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 -(Co-C6 alkylene)-cyclopropyl and R5 is -(C0-C6 alkylene)-aryl, e.g., optionally substituted phenyl. In some ments, R2 is cyclopropyl and R5 is phenyl tuted with halo, e.g., fluoro.
In some embodiments, ring A is pyridinyl optionally substituted with halo or -C1-C4 kyl.
In some embodiments, ring A is pyridinyl substituted with halo, e.g., chloro or fluoro. In some embodiments, ring A is pyridinyl tuted 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 nyl substituted with halo, e.g., chloro or fluoro. In some ments, 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 dinyl substituted with halo, e.g., chloro or fluoro. In some ments, 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., -CHF2 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 er 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 ments, R1 and R2 are taken together to form a entyl or cyclohexyl, each substituted by one or more halo, e.g., fluoro; and R4 and R5 are taken together to form a utyl, 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.l.0]hexanyl; and R4 and R5 are taken together to form a bicyclo[3.l.0]hexanyl.In some embodiments, R1 and R2 taken together, F F Ffl F and R4 and R5 taken er form: 93‘, ‘6: ,or ii. In some F é embodiments, R1 and R2 taken together, and R4 and R5 taken together form: or Flog: . In some embodiments, R1 and R2 taken together, and R4 and R5 taken together form: .In some embodiments, R1 and R2 taken together, and R4 and R5 taken together form: 21‘ . In some embodiments, R1 and R2 taken together, and R4 and R5 taken together form: which is ally substituted with cyano or halo, e. g. fluoro, chloro, or bromo. In some embodiments, R1 and R2 taken together, and R4 and R5 taken together form: A .In some embodiments, R1 and R2 are taken together to form a utyl, entyl or exyl, 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 utyl, cyclopentyl or cyclohexyl, each substituted by one or more 6-member monocyclic aryl, e.g., , which is optionally substituted with halo, e.g. fluoro, chloro, or bromo. In some embodiments, R1 and Rzor R4 and R5 are taken together form: :77- 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 Rzor R4 and R5 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.In some embodiments, R1 and Rzor R4 and R5 are taken .777- together form: wherein Ring C is phenyl, pyridyl, or dinyl, 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 ments, ring A is pyrimidinyl optionally substituted with halo or -C1-C4 kyl.
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., -CHF2 and CF3.
In some embodiments, R1, R3, R4, and R6 are each independently ed 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, C4 alkyl; and R2 and R5 are each independently selected from -(C1-C6 alkyl) and -(C0-C6 ne)-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 ndently -(C1-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 -(C1-C6 ; and R5 is -(C0-C6 alkylene)-Q, wherein Q is optionally substituted carbocyclyl. In some embodiments, Q is unsubstituted yclyl. 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 tuted 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 ments, 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 ally 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., -CHF2 and CF3.
In some embodiments, R1, R3, and R6 are each independently ed 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, -C4 alkyl), or -N(C1-C4 alkyl)2; R2 is -(C0-C6 alkylene)-Q; and R4 and R5 taken together form an ally substituted carbocyclyl, optionally substituted heterocyclyl or optionally substituted heteroaryl. In some embodiments, R4 and R5 taken together form an ally substituted carbocyclyl. In some embodiments, the carbocyclyl is selected from cyclopentyl and cyclohexyl optionally substituted with -OH, -O(C1-C4 alkyl), -C02H, or halo. In some embodiments, R4 and R5 taken together form an optionally substituted heterocyclyl optionally substituted with -OH, -O(C1-C4 alkyl), - COzH, or halo. In some embodiments, R4 and R5 taken er 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 en, 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, -SOz-C1-C4 alkyl, H2, -O-R12,—C02R12 or —C(O)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, n each said alkyl moiety of R1, R3, and R6 are each independently optionally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, R12, wherein R12 is , pyridyl, or dinyl; R2 is -(C0-C6 alkylene)-Q; and R5 is C1-C4 alkyl.
In some embodiments, R7 is H. In some ments, 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 pharrnaceutically acceptable salt or hydrate thereof: R4 N R1 R§\ 1}]AXA 1}]kR3[\i R2 R7 R8 (B), wherein: X isN, CH or C-halo; X3 is N or C-R9a, provided that when one X3 is N, then the other two X3 are both C-R9a; R9is halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(O)2-(C1-C4 alkyl), -S(O)2NH(C1-C4 alkyl), -CN, -S(O)2-(C1-C4 alkyl), C1-C4 , -NH(C1-C4 , - N(C1-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, -(C1-C6 alkylene)-O-(C1-C6 alkyl), aryl, and cyclopropyl optionally substituted with OH; each R93 is independently ed from en, halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(O)2-(C1-C4 alkyl), -S(O)2NH(C1-C4 alkyl), -CN, -S(O)2-(C1-C4 , C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, H2, - C(O)NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, -(C1-C6 alkylene)-O-(C1-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(C1-C4 alkyl), or -N(C1-C4 alkyl)2; R2 and R5 are each independently selected from: -(C1-C6 , -(C1-C6 alkyl)-C(O)-NH2, -(C1- C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C1-C6 alkyl), -(C0-C6 alkylene)-Q,-(C0-C6 alkylene)-C(O)-(C1-C6 alkyl), and-(Co-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein: any alkyl or ne moiety present in R2 and R5 is optionally substituted with one or more -OH, -O(C1-C4 alkyl), -C02H, or halo; any terminal methyl moiety t in R2 and R5 is optionally replaced with , CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN, or COZH; R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl; and Q is selected from aryl, aryl, 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(=O); or R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=O); or R1 and R2 are optionally taken together to form an optionally substituted yclyl or ally 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-methylpyridinyl)-N4,N6-dipropyl-; (2) rimidinediamine, N4-ethyl(6-methylpyridinyl)-N6-propyl-; (3) 4,6-Pyrimidinediamine, N4,N4-diethyl(6-methylpyridinyl)-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, (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 a lb, or pharrnaceutically acceptable salt or hydrate thereof: R4 N \ N R1 RANJLNANkR3R5 R2 R7 R8 (Ib), wherein: R1, R3, R4, and R6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -O-C1-C4 alkyl, and CN, n each said alkyl moiety of R1, R3, R4, and R6 are each independently optionally substituted with -OH, -NH2, -CN, C4 alkyl, -NH(C1-C4 alkyl), or -N(C1-C4 alkyl)2; R2 and R5 are each independently ed from: -(C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-NH2, -(C1-C6 -C02H, -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-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, -O(C1-C4 alkyl), -C02H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH20H, CF3, -CH2F, -CH2C1, C(O)CH3, 3, CN, or COZH; R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl; R9 is selected from en, 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 ed to form C(=O); or R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=O); 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 ally substituted carbocyclyl, optionally substituted heterocyclyl; wherein: (i) neither (R4)(R5)(R6) nor (R1)(R2)(R3) is NHC(O)-[2-chloro(methylsulfonyl)] or N(CH3)2, (ii) N(R7)C(R4)(R5)(R6) and (R1)(R2)(R3) are not both NHC(O)C(CH3)3, NHC(O)CH=CH2, NHC(O)C(CH3)=CH2, NHCHzCHzOH, NH-cyclohexyl, NHCHz-phenyl, NHC(O)phenyl, NHC(O)(CH2)5NH2, NHC(O)OCH3, NHC(O)CH3, and NHC(O)NH—optionally substituted phenyl, and (iii) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCHz-phenyl or NH-CH2CH3; and wherein the compound is not: (1) 2-chloro-N-[4-(cyclopropylamino)(2-pyridinyl)-l ,3 ,5-triazinyl](methylsulfonyl)- benzamide, (2) N—[[4-[[[4-(cyclopropylamino)(2-pyridinyl)- l ,3 ,5 -triazinyl]amino]methyl]cyclohexyl] methyl]fluoro-benzenesulfonamide, (3) 2-chloro(methylsulfonyl)-N—[4-[(phenylmethyl)amino](2-pyridinyl)-l ,3 ,5 -triazinyl] - benzamide, or (4) N—[[4-[[[4-(cyclopropylamino)(2-pyridinyl)- l ,3 ,5-triazin yl]amino]methyl]cyclohexyl]methyl]fluoro-benzenesulfonamide.
Also provided is a compound of Formula Ia, or a pharmaceutically acceptable salt or hydrate thereof: 4‘ l1 R1 R2 R6 N N N R3 H H (Ig), n: ring A is is an optionally substituted 5-6 member monocyclic aryl or monocyclic aryl; R3 and R6 are both hydrogen; R1 and R4 are each independently selected from C1-C4 alkyl and C1-C4 haloalkyl;and R2 and R5 are each -(C1-C6 ; 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 tuted 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 l-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 ine-2,4-diamine, or (2) N2,N4-bis(l -methylpropyl)phenyl-l ,3 ,5-Triazine-2,4-diamine.
Also proVided is a compound of Formula C, or pharrnaceutically able salt or hydrate thereof: b-Xb R4 NkN R1 Rik JL x J Also provided is a compound having Formula Id, or pharmaceutically acceptable salt or hydrate thereof: R7 R8 (Id), wherein: R1, R3, R4, and R6 are each ndently 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(C1-C4 alkyl), or -N(C1-C4 alkyl)2; R2 and R5 are each independently selected from: -(C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-NH2, -(C1-C6 alkyl)-C02H, -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-C6 , -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein: any alkyl or alkylene moiety present in R2 and R5 is optionally tuted with one or more -OH, C4 alkyl), -C02H, or halo; any terminal methyl moiety present in R2 and R5 is optionally ed with -CH20H, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN, or COZH; R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl; R9 is halo or-C1-C4 haloalkyl; and Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is ally substituted; wherein R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=O); or R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=O); R1 and R2 are optionally taken together to form an ally 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[3 -(trifluoromethyl)-lH—pyrazol-l -yl]- l,3,5-Triazine-2,4-diamine, or (2) N4-ethyl-N2,N2-dimethyl[3 -(trifluoromethyl- l H—pyrazol-l -yl] -l ,3 ,5 -Triazine-2,4-diamine.
A compound having Formula Ie, or pharrnaceutically acceptable salt or e thereof: 5i i1 J: R6 1}] N/ 1}] R3 R7 R8 (Ie), wherein R1, R3, R4, and R6 are each ndently 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(C1-C4 alkyl), or -N(C1-C4 alkyl)2; R2 and R5 are each independently selected from: -(C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-NH2, -(C1-C6 alkyl)-C02H, -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)-(Co-C6 ne)-Q, wherein: any alkyl or ne moiety present in R2 and R5 is optionally substituted with one or more -OH, -O(C1-C4 alkyl), -C02H, or halo; any terminal methyl moiety t in R2 and R5 is optionally replaced with -CH20H, CF3, -CH2F, -CH2C1, C(O)CH3, C(O)CF3, CN, or COZH; R7 and R8 are each ndently selected from hydrogen and C1-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 tuted; wherein R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=O); or R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=O); 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 compound haVing Formula If, or ceutically acceptable salt or hydrate thereof: R7 R8 (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(C1-C4 alkyl), or C4 alkyl)2; R2 and R5 are each independently selected from: -(C1-C6 alkyl), -(C1-C6 alkyl)-C(O)-NH2, -(C1-C6 alkyl)-C02H, -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)-(Co-C6 ne)-Q, wherein: any alkyl or alkylene moiety present in R2 and R5 is ally substituted with one or more -OH, -O(C1-C4 , -C02H, or halo; any terminal methyl moiety present in R2 and R5 is ally replaced with -CH20H, CF3, -CH2F, -CH2Cl, 3, C(O)CF3, CN, or COZH; R7 and R8 are each independently selected from hydrogen and C1-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 ally substituted; wherein R1 and R3 are optionally taken er with the carbon atom to which they are attached to form C(=O); or R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=O); R1 and R2 are optionally taken together to form an optionally tuted carbocyclyl or optionally substituted cyclyl; 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 H, or pharrnaceutically acceptable salt or e thereof: R4 \ [\i N R1 Wax/x,R5 R2 R7 R8 (11), 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(C1-C4 alkyl), or -N(C1-C4 alkyl)2; R2 and R5 are each independently selected from: -(C1-C6 alkyl), -(C1-C6 -C(O)-NH2, -(C1-C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(C1-C6 alkylene)-N(R6)-(C1-C6alkylene)-O-(C1-C6 alkyl), -(C1-C6 ne)-N(R6)-(C0-C6 alkylene)-Q, —(c1—c6 alkylene)-N(R6)(R6), -(C1-C6 alkylene)-N(R6)-S(O)1(C1-C6 alkyl), —(C1-C6 alkylene)-N(R6)-S(O)1.2-(C0-C6 alkyl)-Q, -(C1-C6 alkylene)-S(O)1.2-N(R6)(R6), -(C1-C4 ne)-S(O)1.2-N(R6)-(C1-C6 alkylene)-Q, -C(O)N(R6)-(C1-C6 alkylene)-C(O)- (Co—C6 alkylene)-O-(C1-C6 alkyl), -C(O)N(R6)-(C1-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-O-C(O)-(C1-C6 alkyl), -(C1-C6 alkylene)-O-C(O)-(Co-C6 -Q, 6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 ne)-O-(C1-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)-(C0-C6 alkylene)-O-(C1-C6 alkylene)-Q, -(C1-C6 alkylene)-O-C(O)-(C1-C6 , -(C1-C6 alkylene)-O-C(O)-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)N(R6)-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)C(O)-(C1-C6 , -(C1-C6 alkylene)-N(R6)C(O)-(C0-C6 alkylene)-Q, 6 ne)-S(O)0(C1-C6 alkyl), 6 alkylene)-S(O)0(C0-C6 alkylene)-Q, -(C1-C6 alkylene)-N(R6)-C(O)-N(R6)-(C1-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-C6 , -(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, -O(C1-C4 alkyl), -C02H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH20H, CF3, -CH2F, -CH2C1, C(O)CH3, C(O)CF3, CN, or COzH; R7 and R8 are each independently selected from en 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(=O); or R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=O); 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 ally substituted aryl, or an optionally substituted heteroaryl; wherein: (i) when A is phenyl optionally substituted with F, C1 or , then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)CH2C(O)NH-i-propyl, NHCH(CH3)(CH2)3N(CH2CH3)2, NHCHZCHZOH, NHCHZCHZOCHg, NHCHZCH20803H, NHCHzCHzCHzoCHzCHzo-phenyl, NHCHzCHzCHon, NHCHZCHZCHZOCHg, NHCHZCH(OH)CH3, N(CH2CH3)2, NH—i-propyl, NHCHZCHZNHC(O)OCH3, NHCHZCHZNHC(O)CH3, NHCHZCHZNHZ, or NHCHz-phenyl; (ii) when A is optionally tuted pyridyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHCHz-phenyl, NHCHz-(2,4-difluorophenyl), N(CH3)CH2CH2C(O)OH, H2C(O)OH, NHCHZCH2C(O)OCH2CH3, NHCHZCH2C(O)O-t-butyl, NHCHZCH2C(O)NH2, Hz-phenyl, NHCHZCHZOH, NHCHZCHZNHZ, NHCHZCH2N(CH3)2, or NHCHZCHZCHg; (iii) when A is optionally substituted l-imidazolyl, optionally substituted l-pyrrolyl or optionally substituted l-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) net N(R8)C(R1)(R2)(R3) is )7CH3, NHCHz-(o-chloro-phenyl), or NHCHZCHon; (iV) when A is tituted 2-pyridinyl, then the ring formed by R4 and R5 is not 5-methyl-1H- pyrazolyl; and (V) when A is optionally substituted l-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is N(CH3)2, NHCHg, NHAc, NHisopropyl, NHCHZCHg, NHCHZCstogH 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 l-pyrazolyl or an unsubstituted phenyl; and (Viii) the nd is not selected from the group: (1)6-(lH-imidazol-l 2,N4-bis(l -methylethyl)-l ,3 ,5 -Triazine-2,4-diamine, or (2) N2,N4-bis(l -methylpropyl)phenyl-l ,3 ,5-Triazine-2,4-diamine.
Also provided is a compound of Formula Ic, or pharrnaceutically acceptable salt or hydrate | /—(R)n9 5C 11 J2 R6 1}] N/ 1}] R3 R7 R8 (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, C4 alkyl, -NH(C1-C4 alkyl), or -N(C1-C4 2; each R9 is independently selected fromhalo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(O)2-(C1-C4 , -S(O)2NH(C1-C4 alkyl), -CN, -(C1-C4 , C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, -C(O)NH2, - C(O)NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, -(C1-C6 alkylene)-O-(C1-C6 , aryl, and cyclopropyl optionally tuted with OH; 11 is l to 3; R2 and R5 are each independently selected from: -(C1-C6 alkyl), -(C1-C6 -C(O)-NH2, -(C1- C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(Co-C6 ne)-C(O)N(R6)-(C1-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-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, -O(C1-C4 alkyl), -C02H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH20H, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN, or COZH; R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl; and Q is selected from carbocyclyl and heterocyclyl, any of which is optionally substituted; wherein R1 and R3 are ally taken er with the carbon atom to which they are attached to form C(=O); or R4 and R6 are optionally taken together with the carbon atom to which they are ed to form C(=O); 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 NHCHZCHZOCHZCHZOCHZCHZNHZ, 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], NHCHZCHZCHO, NHCHzCHzoCHg, NHCHzCHzOH, NHCHzCH(OH)CH3, NHCHzCHzOC(O)phenyl, NHCHzCHzCHzOH, NHCHZCHZCH2N(CH3)phenyl, NHCH2C(O)OCH3, NHCH2C(O)OCH2CH3, NHCHzphenyl, NHCH(CH3)CH2CH3, or NHCHZCH20C(O)CH3; and (iii) neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHcyclohexle(O)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 111, or ceutically acceptable salt or e thereof: XNANXRB R7 R8 (111), wherein: ring A is an optionally tuted 5-6 member monocyclic heteroaryl; ring B is an ally substituted 5-6 member monocyclic aryl or 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(C1-C4 alkyl), or -N(C1-C4 Rzis selected from: -(C1-C6 alkyl), -(C1-C6 -C(O)-NH2, -(C1-C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), 6 alkylene)-O-(C1-C6 alkyl), -(Co-C6 alkylene)-C(O)N(R6)-(C1-C6 ,-(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-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, -O(C1-C4 alkyl), -C02H, or halo; any terminal methyl moiety present in R2 is optionally replaced with , CF3, -CH2F, -CH2Cl, 3, C(O)CF3, CN, or COZH; 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 ally substituted; n R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=O); 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 l or 2 substituents selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 , -CN, =0, -OH, aryl, heteroaryl -SOzC1-C4 alkyl, -C02C1-C4 alkyl, -C(O)aryl, and -C(O)C1-C4 alkyl.
Also proVided is a compound of Formula HIa, or pharrnaceutically acceptable salt or hydrate thereof: (R—-I M i)p \ , 1}] N 1}] R3 R7 R8 (IIIa), wherein: ring A is a substituted 5-6 member monocyclic heteroaryl; Xd is C or N; each Rb is independently ed from halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -OH, -C(O)CH3, wherein any alkyl, cycloalkyl, or phenyl moiety is ally tuted 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, -C4 alkyl), or -N(C1-C4 alkyl)2; Rzis selected from: -(C1-C6 , -(C1-C6 alkyl)-C(O)-NH2, -(C1-C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C0-C6 ne)-C(O)N(R6)-(C1-C6 alkyl), -(Co-C6 alkylene)-Q, -(Co-C6 alkylene)-C(O)-(C1-C6 alkyl), and -(Co-C6 alkylene)-C(O)-(Co-C6 alkylene)-Q, wherein: any alkyl or alkylene moiety present in R2 is optionally substituted with one or more -OH, -O(C1-C4 , -C02H, or halo; any terminal methyl moiety present in R2 is optionally replaced with -CH20H, CF3, -CH2F, -CH2C1, C(O)CH3, C(O)CF3, CN, or COZH; 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(=O); or R1 and R2 are optionally taken together to form an optionally tuted 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 HIb, or pharrnaceutically acceptable salt or hydrate thereof: R7 R8 (HIb), n: ring A is a tuted 5-6 member monocyclic heteroaryl; R7 and R8 are each independently selected from en and C1-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(O)CH3, n any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH2, or —CN; p is l 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 HIc, or pharrnaceutically acceptable salt or hydrate thereof: p \ NANAN R3 R7 R8 (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, C4 alkyl, -NH(C1-C4 alkyl), or -N(C1-C4 alkyl)2; Rzis selected from: 6 alkyl), -(C1-C6 alkyl)-C(O)-NH2, -(C1-C6 alkyl)-C02H, -(C2-C6 alkenyl or alkynyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(Co-C6 alkylene)-C(O)N(R6)-(C1-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-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, -O(C1-C4 alkyl), -C02H, or halo; any terminal methyl moiety present in R2 is optionally replaced with -CH20H, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN, or COzH; 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 er with the carbon atom to which they are ed to form C(=O); or R1 and R2 are ally 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(O)CH3, wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH2, or —CN; and p is l to 2.
Also proVided is a compound of a HId, or pharrnaceutically acceptable salt or hydrate thereof: R7 R8 (HId), wherein: ring A is a tuted 5-6 member monocyclic heteroaryl; R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl; each Rb is independently ed from halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, -OH, -C(O)CH3, wherein any alkyl, cycloalkyl, or phenyl moiety is optionally substituted with fluoro, chloro, -OH, -NH2, or —CN; p is l to 2;and G is an optionally substituted carbocyclyl or heterocyclyl. r embodiments proVided herein include combinations of one or more of the particular embodiments set forth above.
In another embodiment, the compound is ed from any one ofthe compounds set forth in Table 1, below.
Table 1. Representative Compounds Com oundp Com oundp Structure Structure Number Number F F Chiral F F / F \ I F \ N I 1 2 N \N CH N \N CH JL A UL A 3 N N N Compound nd Structure Structure Number Number O‘CH3 Chiral |\ F CH N \N HCHSCXNANAN 3 3| / H CH3 H CH3 F Chiral \ F N \N OH Chiral \ F N \N ANAN/YCHSH Compound nd Structure Structure Number Number Chiral F Chiral F Chiral Chiral \ CF3 CF3 Chiral CH Chiral \ CF3 Chiral 2014/081957 Compound Compound Structure Structure Number Number F Chiral \ F 23 28 VF?"wail\ \\.
N "W; \ CF3 Chiral 24 CH3 N’JN\ VAFN \N N \ H H I F Chiral \ CF3 CH N’ N CH 3* L 3 N \ R N N H H | F Chiral \ F I 31 WO 03640 Compound Com oundp Structure Structure Number Number / CF3 Chiral F | / F \ N I 33 gm N/JN\ CH3 CH3 N/JN\ CH3 V; \N NJSVH V/VRW \N NJ\/\CH3 H H CF3 Chiral / HC N N N I 3 \ N Y. \Y CN N /N H3 34 gHsl/j: c_:H3 Wm N NW | N / CF3 CN N CH I 7< Y \Y Y 3 \ N HaC CHsN /N CH3 F F 41 Fm 1’ v OF N \NAN H H / CF3 Chiral — / CF3 \ N CH3 N’JN\ U "’i J7 V/RLH \N NH N \N N 42 H H @w Chiral \ CF3 c 1/ IN CHéN V/g CF3 Chiral N /I INI CH3 \ N CF CH3 N’ N / 43 38 c N’ N V5 "AN| Do Com oundp Com oundp Structure Structure Number Number / CF3 \ \ 'N F I H30 F /N 49 N/ 44 CH3 N/JN\ CH3 I ac CH3 VAN] \ / \N NJVO‘CH3 N H H g g Cl Chiral \ \f Y | F N /N H3 /N F 45 CH3 N’ N C_>H3 I H H/W I: Chiral Cl Chiral N \ \ | | /N /N 46 CH3 N’ N 9H3 | V/RLHCHSJNLW VA?" / \NAN/EH3 N NW CF3 Chiral.
/ \ F N I \ /N CH N’ N 47 CH 52 vflwfirw A1F " E Co, R R H H N \N N H H CF Chiral F \ 3 | \ F /N I 48 CHM W V/EN = ECL "’l 0-B N/ F 00 N R N‘CH3 N \NAN H H H H Com oundp Compound ure Structure Number Number \ F 54 59 F3CL Ii J3NH\ N N N H H F F F Chiral \ F 55 FACL x L EHF N/ N o 60 N N N CH H H a Chiral F \ \ F /N 61 F N/ N ,9 N \NJ\N N§'S=O H H CH3 CF3 Chiral Chiral 57 CH3 N’ IN 9H3 V/LNAxNAN ' R H H/W Cl Chiral / CF3 Chiral \ IN 58 CH N/ N 3x I DBL R N N N H H WO 03640 Compound Compound Structure Structure Number Number CI Chiral CH3 N; N c_:H3 66 72 N Chiral 67 73 69 74 70 75 Compound Compound ure fl m N umber N umber /N CN 76 81 N/ N Ax k N IN NHA 77 82 N/IN N NJ\\NJ\N"‘ H H NIANH I \N/ N/ 83 | NIA \ WAN N NH /N I \N/ 79 / N \NL 84 NIAWAN 80 NE/ \N/ xNx 85 NIAWAN WO 03640 Compound Compound Structure Structure Number Number 86 91 N/IN N’ N *N xNx \ ‘N | | /N / 87 92 N/IN N/ N *N J\\ ' I I / /N 88 93 NJ\\N M\N /N CI 89 94 E N/ N N/IN xxNx \NA 90 95 nd mmD.Ound Wmmre 5ummm Number mmber w \ \N 3 I I 96 104 aF /I\ANN NHA E C: F NA/ N 3 F 1 N- NH NH NH \N NH I \N \ / I 100 105 F CF NIA/ NI F F£3 NH \N NH CB NA \N/ NH N NH /\N / 101 106 F / If 9%3 NIA NHA a NA/ N \N ck \ NH NH F 1N NH NH I \N / / \N, / 107 51 F F El . NIA NHA Q NHA ,,NH \N . F NI/A MH F NH N I W3 103 F CF3 NIA/ NHA ca 108 /N|A NH \N NH NA1 F NH N NH Compound C Structure wbMy Structure Number N #8 109 EN 1 14 \ f/ / | N FF N 110 1 1 5 / / N \N \ N 111 1 16 i" / N \N N N 112 k 1 1 7 N/ Ax ' N N N N H / /N 113 1 1 8 N FF \NA| WO 03640 CoNm D.oUNnd COmpomd mt.u.e St .0.u re m r Nmmr / \ , I CN N 1 19 N|A\ 124 F N um" N| N I IA F N NH NH 120 F \VIA 125 F F N \ N NH N NH NH /N NH CF3 F \,N \ N N p. 1 \ 126 NIA/ /NIA F\/ N NH IANI N NH N p.2 I \NI/A F F N NH N W F IA NHA NH NH F F p.3 _ \NIA N 8 F NH N n8 F \v|A\ Fy NIA N NH N Compound Compound ure Structure Number Number NIWC\ / N 129 134 N / N \ N CF N \N 3 | NANJ35F \ )L / N N N N H H CN H H CI \ | /N 130 135 Ax NI #NH / N Nof | \ N N A | CF / IN N N E H N F}FF \ IN 137 / / |N CN JLN/A 3F NAIN \ N N H H \ CF3 F3 | N N/ 138 IN / |N CN i" *NAN {1 \N H / J3 WO 03640 Compound COmpound am mmw e Number N ummr F N \ F F 139 144 N \ x N F FW F /N F NH NH /N NH flNIA\N, \ F 140 F F 145 NI/A F F NIA \ N F F NH N NH NH /N NH N Ema 141 ,NIA / \N, NI CEma 146 NIA F F N NH F NHA \NI/A N F NH N NH / N C I NI \ 142 N NHA C..."F3 147 F IVIA F F NI \ F N NH / M NH N NH / Ema F F \ IN F 143 _ / NHA 8 N/ F 148 VIA NH \N NH Fw F F NHA \ I/A W F NH N NH WO 03640 Compound ComD.ou nd 5trucm8 Structure Number N um ber \ 3 I \ 149 F F F \ 154 N N \N F F "A F / NAN NH N NH NH H \ 3 I SX 150 155 F EN QNIA x N .I F / N 1 NH N NH F NH N/ N \ cw "(C 151 156 N- \ \ i" NA N CEma / UF NH /N NH F 1/ NH N N \ two I /N 152 157 F / \N F NIA\ NHA / NH N NH N F NH / 2 |N /N \ W3 F F 153 F 158 N / \N NHA \/NNIA I \ / N N El NH NH NH 2014/081957 Compound Compound Structure flwame Number Number /_ / N / \N/ / / FF N N CN N 202 I NHA 207 \ \ NH N NH N / I 3 \ NHA /IA N Wk NH NH \ F3 F NIA/ F I F I \NNIA A N NH NH NH w NH md COmD.omd 5uuCwW Summre N umba N umw F / \ \ N 209 214 F F / NIA x NI fl N F F Viv NIA\ C / N NH,v NH N NH NH C Ema \ / \ N/ 21 0 5 F NIA 21 \ \ / Nc N| Nl \N FfinNIA I N| / / A /NIA N N NH CN NH NH F \ F \ | l / N 21 1 216 N//N3 F \ N / NIA| \NI/A GF NHA / NH N NH NH N NH F F C Ema C| \ / I N \ IN / 212 F F 21 7 m / F / N NIA F \ NHA | \ NHA \ N NH N G /N NH NH NH C F \ cm. cN | 213 F 21 8 F F N / / I F F \ N \ leA NHA H aNHA / NH N NH NH N NH nd Compound Structure amdWe Number N umber \ CF3 / /N \ IN 219 224 ’I" fl N / F \NAN \ NHA H NH N F F |\ I /N /\N N \N )L/ NA \N/ Br N N N N H H NH NH F F |\ F FF / /N N \ M/ \ N / N N \N H NH |\ F 227 \ N \NNHANH NH \NI/AN NH WO 03640 COmpound COmp0und 5umm m.0..u.e N umbe r N ummr \ 3 I / N 229 F 234 / NA, NHA \ N I I NH \N / NH C NH \N NIA N NH CEma \/:N F / I N F N 230 235 N N| Ffl NnA / NH «NH F N NH OH cw0 F I \ F N\ I 23 1 2 6 N| \ I / / NHAN m NI F NH NH NIA F O \N NH W CF \ 3 \ 3 I N / caF F 232 237 VIA/ N NHA \ N F NIA NHA / F \N VB NH N NH Ca NH W F 3 F IN \ F 233 238 N / Viv N/\:N NHA / \ F N NH NH /o F NH \N NHA LNH 2014/081957 Compound C StmCWm wb Stm .u.
Number ONmuPm .0. e e.mr FF II I \/ F 239 o 244 N/\ NI NIA IAN MN N N\—/ // /\N NHA N NH NH 240 245 241 246 242 ON 247 243 248 2014/081957 CoNmPm0bmd COmD.ou nd Structure flruCtu re u a N ummr W F \ 2 I \ | F /N / N 249 Ffi F 254 NHA \ F N F N \N F Br )LN/ F / NH N NH CF3 C \ / a F IN \ 250 g 2 5 N \N / I F N O \ )LN/A CN \ NHA NH NH N NH CF3 F \ F N N FFfl F 256 _._I I F N N NH NH _._Ifl NH N NH OCEM. \ 3 252 FFug F I F / N CF3 F \ F N / N NH NH I \ NIA| / NH N NH F \ 253 / N /N\ I IA 258 F F F NH NH w UN I / FVD NH N NH Compound umnd Structure flm re N umber u r \ \ / N / N 1/ N / N NI NH MN / N C| 260 \ IN / 265 FF N VIAA NH NH 1’" W / 3 261 \ IN l 266 N FF NIA/ fl NH \N NH N \ 262 / N | 267 N \ N NHA N NH m NH /N \ 263 N6N L 268 H N N IAEN NH NH WO 03640 Compound ComD.ou nd Structure s .0.m Number N um ber | W 1 IN 269 274 F N F JL NHA N mNHIN NH N / l N,_N RV / C 270 %\ 275 F N / F *N i/ N | NH N NH / F \ I 271 276 F N / F N \ x m l N NH /N NH 272 277 F N / F J\\N NA / NH N 273 278 NA \ 'f N NH /N NH WO 03640 Compound C0mD.ou nd amc e ru re N umber N um ber / I 279 284 l/ :. N| NH N NH NH F N \ F I I / N 280 / 2 5 F N F MIA NH \N \Q I F C two \ F I F / 286 NHA \ N I. NH / W NH N NH F I N / 287 282 0 F N F 1 \ F N| NH N NH IANH F l \ N F / F l F NH NH N NH Compound nd Structure Structure Number Number 289 294 290 295 291 296 292 297 293 298 WO 03640 Compound Compound Structure Structure N umber N umber 299 304 300 305 301 306 302 307 303 308 C0mD.ou nd m S.N .0.U re flm m N umbe r N um ba \ / / N \ IN 309 314 F O NA \ N F G: F /I\A /N UN 1N NH NH I \ / N N 31 0 31 5 F \ W NA N F V NIANIN1N/ NH NH / \N I 31 1 \ \ M 316 F F NA N / N- N Fa N|\A/ NH NN N NH \ \ N 12 ,N|A\ 3 F 3 1 7 NHA N NIA N F3 NIA /NIA NH ,N NH % F aC \ F | I N 313 LNG 31 8 F F NIA NI FWNHIN NH N NH NH Compound Compound ure Structure Number N umber 319 324 320 325 321 326 322 327 323 328 nd Compound Structure Structure Number Number 329 334 330 335 2014/081957 Compound Compound Structure Structure Number Number "VFF 3/N 339 344 Csti/ IN 9F3 \AN \N N/\/ H H I 529 340 CF3 F 345 N/ N/ | I" ,6 H H | 52% 341 346 "ll 11 (CV CF3 N/ N g3 N N N \ANXNkN/V H H | \%F 342 NC 347 \ Jill: N N/ N".O I \N, /\N% N NIA 3 CF _ 3 I NIA \NIA/ .
NH N N/\/ NH H \ CF3 364 N / NIA/ : \ \ JN\ 359 /\ NH N N/\CF3 | H NH6 O 1 F \ F l N 365 W3 N / N N NA//\N F I | F \ / F NH NH \VLF l \ IN /\N 366 F F 361 N N NA F F I / Di NH N N NH H N \ F 362 INI /\N 367 NIA/ NHA IANH F N F NH NH pmmD.ou nd C Suud.um ure N umbe r oNmuPmobue.mr F F N| \ V / N / N 368 373 NHA xNI/A \ N F NH N N N‘ N| \ | / N N F 374 NHA \NI/A / N N F NH N NH H F M N / / N IN 375 \ IN NI \ NAN"- N H NH /N NH F | 376 / N IN 37 1 N / \ N | NAN \ NnA H NH /N NIA \ NI / NH N NH Compound Co Structure mN ure Number uPmobue.mr NI3 | F 383 378 F H \ I N 1 AN| H NH m CF3 \ 379 //N /\ N \ | A / F3 N 385 N F N 380 /\ Cl N F J\ W3 N C."a. \ 381 _.
FF NH N 387 W3 382 N / /\ NI NC \ NH NH Compound COmD.ou nd ure flm u re Number N um ber PEIF CEma 388 IN 393 F x NIA :1NI F F C NAN 3 NH NH \ cm. 3 4 El F 389 Y" 9 \N F F NI N NAN EZN H NH NCcm. NW3 i" 395 F 390 F F F UNI\A :1 NA NH NH C F \ cm. 397 F 391 i" F N NA NI NH F Q cwC EN NH NH / \ I N :1N / N 398 F 392 NA N J\\NNHA :. Q NI A NC CEma NH NH nd ComD.wnd 5md.u re ww.ure N umba N um ba F F W‘IVIAC F3 F NI _ 8 / N 399 404 w NI N F F F . ,1 I/AN x x QF N C NH NH MM a IA Nl NH /N NH CF3 C \ EM.
/ F I N F F / N 400 fiNIA 05 / F 4 / l I \ NHA /NIA i N \ N|\A NHA NH N NH CEma NH N NH N| F Ctwo N N 40 1 m \KVIAx F 406 / N \IVIA N N l N| F NIANH N F F \ / F v .u /N F NH N NH NH _ / \N, N S \lex 407 CF3 402 F F FF NIAx VB N / N N| NIA I \ NHA NI/A NH /N NH NH NH F N F _ |N N \ S 408 F F 4 i 03 F F F NHA xNIA F FVQ NHA NI/A FD / N N NH NH NH NH Cargotgd nd Structure Structure Number ECI /N 415 412 I 413 N/IIN/ F FL 1 ANA Compound Compound ure Structure Number Number \ F 419 422 WNMNW|NH H / CF3 420 423 N/ N 421 424 Included herein are also methods for making compounds ofFormula I or a compound of any one of the embodiments described herein comprising reacting R5§—NH2 R6 .Insome embodiments, the preceding s comprise step (1) reacting N \N R 1 RZR NI j: R1R 2 ' / / CIAN N Cl N Cl With, 7L; 3 R3 , , 2 to give H ; and step (2) reacting ; and step (3) reacting one ofthe embodiments described herein sing reacting Also included are methods for making nds ofFormula I or a compound of any R4 NJ§N R1 R5R?|\NJ\N/)\N| R2 H H With, one ofthe embodiments described herein comprising reacting ®B(OH)2. In some embodiments, the preceding methods compr1se step (1) react1ng. . . .
CI CI N N )g R1 4 R4 N N R1 | R2 5R R5 | R2 R ?_NH2 R3 R64\NJ\N/)\N R3 H w1th. R , . to give H H ; and step (2) ng R4 N \ N R1 Rik A A J In certain embodiments, the compound ofFormula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig,]I, III, IIIa, IIIb, IIIc, 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, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIIdmay also comprise one or more isotopic substitutions. For example, H may be in any ic form, including 1H, 2H (D or ium), and 3H (T or tritium); C may be in any ic form, includingllC,12C, 13C, and 14C; N may be in any isotopic form, including13N,14N and 15N; 0 may be in any isotopic form, ing150,160 and 18O; F may be in any isotopic form, includinngF; 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 eric forms, in such instances, one aspect of the invention sly 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 e, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge eta], 1977, "Pharmaceutically Acceptable Salts." J. Pharrn. Sci. Vol. 66, pp. l-l9.
For e, 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 e, 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., NHI) and substituted ammonium ions (e.g., NH3R+, NH2R2+, NHRH, NR"). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, zine, benzylamine, phenylbenzylamine, e, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary um ion is N(CH3)4+.
If the compound is cationic, or has a functional group that may be ic (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 d to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
Examples of suitable c anions include, but are not limited to, those derived from the following c acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, ic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, esulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, acetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Mesylates of each compound in Table l are explicitly included herein. Examples of suitable polymeric organic anions include, but are not d 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 ed herein may be modified and converted to prodrugs by appending riate functionalities to enhance selected biological ties, e.g., targeting to a particular tissue. Such modifications (i.e., prodrugs) are known in the art and e 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 gs include esters (e.g., phosphates, amino acid (e.g.,valine) esters), carbamates and other ceutically acceptable derivatives, which, upon administration to a subject, are capable of ing active nds. 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 nds utilized in the methods described herein may be formulated together with a pharmaceutically acceptable carrier or adjuvant into ceutically acceptable compositions prior to be administered to a subject. In another ment, such pharmaceutically acceptable compositions r comprise additional therapeutic agents in amounts effective for achieving a modulation of disease or disease symptoms, including those described herein.
The term "pharmaceutically acceptable r or adjuvant" refers to a carrier or nt that may be administered to a subject, together with a compound of one aspect of this invention, and which does not destroy the pharmacological ty 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-oc-tocopherol hyleneglycol 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, l 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, ium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium ymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. extrins such as d-, [3-, and y-cyclodextrin, or chemically modified tives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-B-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 stration or administration by injection. The pharmaceutical compositions of one aspect of this invention may contain any conventional xic pharmaceutically-acceptable carriers, adjuvants or es. 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, ynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion ques.
The pharmaceutical itions may be in the form of a e 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 sing or wetting agents (such as, for e, Tween 80) and suspending agents. The sterile inj ectable preparation may also be a sterile injectable solution or suspension in a xic parenterally acceptable diluent or solvent, for example, as a solution in l,3-butanediol. Among the able vehicles and solvents that may be employed are mannitol, water, ’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 inj ectables, as are l 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 ymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or sions. 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 13 l aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used e lactose and corn starch. Lubricating agents, such as ium 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 ons 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 stered 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 ritating 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 als e, 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 y accessible by l application. For application topically to the skin, the pharmaceutical composition should be formulated with a le ointment containing the active components suspended or dissolved in a carrier. Carriers for topical stration 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 le 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 earate, 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 ofthis invention.
The ceutical compositions of one aspect of this invention may be stered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of ceutical 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 sing 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 n, 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 ition.
The compounds described herein can, for example, be stered by ion, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, ly, 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 nd or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of one aspect of this invention will be stered from about 1 to about 6 times per day or atively, 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 e a single dosage form will vary depending upon the host d and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations n 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 stration, rate of excretion, drug combination, the severity and course of the e, condition or symptoms, the subject’s disposition to the disease, condition or symptoms, and the judgment ofthe 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 ittent ent on a long-term basis upon any ence of disease symptoms.
The pharmaceutical compositions described above comprising a compound of Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId or a compound described in any one of the embodiments herein, may r comprise another therapeutic agent useful for ng cancer.
Methods of Use Provided is a method for inhibiting mutant IDH1 activity comprising contacting a subject in need thereof with a compound (including its tautomers and/or isotopologues) of Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId, or a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer to be treated is characterized by a mutant allele of IDH1 wherein the IDH1 mutation results in a new ability of the enzyme to catalyze the NADPH-dependent ion of glutarate to R(-)hydroxyglutarate in a subject. In one aspect of this embodiment, the mutant IDH1 has an R132X mutation. In one aspect of this embodiment, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G. In another aspect, the R132X mutation is R132H or R132C. In yet another aspect, the R132X mutation is R132H.
Also provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1 comprising the step of administering to subject in need thereof (a) a compound of Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId, or a compound described in any one of the ments herein, or a pharmaceutically acceptable salt thereof, or (b) a ceutical composition comprising (a) and a pharmaceutically acceptable carrier.
In one embodiment, the cancer to be treated is characterized by a mutant allele of IDH1 wherein the IDH1 mutation s in a new ability of the enzyme to catalyze the NADPH-dependent ion of α-ketoglutarate to R(-)hydroxyglutarate in a patient. In one aspect of this embodiment, the IDH1 mutation is an R132X mutation. In another aspect of this embodiment, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G. In another aspect, the R132X mutation is R132 H or R132C. A cancer can be analyzed by cing 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 IDH1 wherein the IDH1 mutation results in a new ability of the enzyme to catalyze the NADPH- dependent ion of α-ketoglutarate to R(-)hydroxyglutarate, and in particular R132H mutations of IDH1, characterize a subset of all types of cancers, without regard to their cellular nature or on 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 IDH1 imparting such acitivity and in particular an IDH1 R132H or R132C mutation.
In one aspect of this embodiment, the efficacy of cancer treatment is red 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, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId, or a compound described in any one of the ments described herein to treat the cancer. Once the elevated levels are established, the level of 2HG is determined during the course of and/or ing termination of treatment to establish efficacy. In certain embodiments, the level of 2HG is only determined during the course of and/or following ation of ent. A reduction of 2HG levels during the course of treatment and following ent 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 er with other well-known determinations of cy 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) tion 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 (MRIVI) mode, with MS parameters zed on d lite standard solutions. lites can be separated by ed phase chromatography using 10 mM tributyl-amine as an ion pairing agent in the aqueous mobile phase, according to a variant of a usly reported method (Luo et alJ ChromatogrA 1147, , 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 >< 2 mm, 2.1 pm 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 rembodiment 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 of2HG is evaluated. Examples e 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 nds provided below or a salt adduct thereof: 0 O O H '2' O O HO O HO .nO HO : O W o o O HO OH and 7 7 7 .
In one embodiment the cancer is a tumor wherein at least 30, 40, 50, 60, 70, 80 or 90% of the tumor cells carry an IDH1 mutation, and in particular an IDH1 R132H or R132C mutation, at the time of diagnosis or treatment.
IDH1 R132X mutations are known to occur in n types of cancers as indicated in Table 2, below.
Table 2. IDH mutations associated with certain cancers Cancer Type IDH1 R132X Tumor Type Mut4ti0n brain tumors R132H primary tumor R132C primary tumor R132S primary tumor R132G primary tumor R132L primary tumor R132V primary tumor R132C HT1080 fibrosarcoma cell line Acute Myeloid Leukemia R132H primary tumor (AML) Acute lymphoblastic ia R132C primary tumor (ALL) IDH1 R132H mutations have been identified in glioblastoma, acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer, cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative sm (MPN), colon cancer, and angio-immunoblastic dgkin’s lymphoma (NHL). Accordingly, in one embodiment, the methods described herein are used to treat glioma (glioblastoma), acute myelogenous ia, sarcoma, melanoma, non-small cell lung cancer (NSCLC), giocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon , or angio-immunoblastic non-Hodgkin’s lymphoma (NHL) in a patient.
In another embodiment, the s bed herein are used to treat glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, all cell lung cancer (NSCLC), cholangiocarcinomas (e.g., intrahepatic cholangiocarcinoma (lHCC)), chondrosarcoma, myelodysplastic syndromes (MD S), myeloproliferative sm (MPN), prostate cancer, c 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 dgkin’s lymphoma (NHL) in a patient.
In another embodiment, the advanced hematologic malignancy to be treated is lymphoma (e.g., dgkin lymphoma (NHL) such B-cell lymphoma (e.g., Burkitt ma, 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 ma) 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 ofFormula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIIdor a compound described in any one of the embodiments bed herein.
In one embodiment, prior to and/or after treatment with a compound ofFormula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, lIIa, IIIb, IIIc, or IIIdor a compound described in any one of the ments described herein, the method further comprisesthe step of evaluating the growth, size, weight, invasiveness, stage and/or other phenotype ofthe cancer.
In one embodiment, prior to and/or after treatmentwith a compound ofFormula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, lIIa, IIIb, IIIc, or IIId 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 tion of the presence, distribution or level of 2HG.
In one embodiment, prior to and/or after ent with a compound of Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId or a nd 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 al, e.g., by mass-spectroscopy.
Also provided is a method for inhibiting a mutant IDH2 activity comprising contacting a t in need thereof with a compound of Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId, a compound described in any one of the embodiments herein, or a pharmaceutically acceptable salt f. 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 NADPH-dependent ion of α-ketoglutarate to R(-)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, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId or a compound described in any one of the embodiments , or a pharmaceutically acceptable salt f, or (b) a pharmaceutical composition sing (a) and a pharmaceutically acceptable carrier.
In one embodiment, the cancer to be treated is characterized by a mutant allele of IDH2 n the IDH2 mutation results in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)hydroxyglutarate in a patient. In one aspect of this ment, the mutant IDH2 has an R140X mutation. In another aspect of this embodiment, the R140X mutation is a R140Q mutation. In r 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 on is a R172G mutation. A cancer can be analyzed by sequencing cell samples to determine the ce and specific nature of (e.g., the changed amino acid t at) a on at amino acid 140 and/or 172 of IDH2.
Without being bound by theory, applicants e that mutant s of IDH2 wherein the IDH2 mutation results in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)hydroxyglutarate, and in particular R140Q and/or R172K ons 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 carry an IDH2 mutation, and in particular an IDH2 R140Q, R140W, or R140L and/or R172K or R172G mutation, at the time of diagnosis or treatment.
In another embodiment, one aspect of the invention provides a method of treating a cancer selected from glioblastoma (glioma), myelodysplastic me (MDS), myeloproliferative sm (MPN), acute myelogenous leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinomas or mmunoblastic lymphoma in a patient by administering to the patient a compound of Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIId in an amount effective to treat the cancer. In a more specific embodiment the cancer to be treated is glioma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myelogenous leukemia (AML), melanoma, chondrosarcoma, or angioimmunoblastic non-Hodgkin’s lymphoma (NHL). 2HG is known to accumulate in the inherited metabolic disorder 2-hydroxyglutaric aciduria. This e is caused by deficiency in the enzyme 2-hydroxyglutarate dehydrogenase, which converts 2HG to d-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 sed 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 of2HG 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 ), potentially buting to an increased risk of cancer. The ability of2HG to act as an NIVIDA 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 dKG utilizing enzymes. These include transaminases which allow utilization of glutamate nitrogen for amino and nucleic acid biosynthesis, and dKG—dependent prolyl hydroxylases such as those which regulate HJFl -alpha levels.
Thus, according to another embodiment, one aspect of the invention provides a method of treating 2-hydroxyglutaric aciduria, particularly Dhydroxyglutaric aciduria, in a patient by administering to the t a compound of Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIIdor a compound described in any one of the ments described herein.
Also provided are s of treating a disease selected from Maffucci syndrome and Ollier disease, terized by the presence of a mutant allele of IDHl sing the step of administering to subject in need f (a) a compound of Formula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, lIIa, IIIb, IIIc, or IIId, or a nd described in any one of the embodiments herein, or a pharrnaceutically acceptable salt f, or (b) a pharmaceutical composition comprising (a) and a pharrnaceutically acceptable carrier.
Treatment methods described herein can additionally comprise s evaluation steps prior to and/or following ent with a compound ofFormula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIIdor a compound described in any one of the embodiments described In one embodiment, prior to and/or after treatment with a compound ofFormula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, lIIa, IIIb, IIIc, or IIIdor a compound described in any one of the embodiments described herein, the method r comprisesthe step of evaluating the , size, weight, invasiveness, stage and/or other phenotype of the cancer.
In one embodiment, prior to and/or after entwith a compound ofFormula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, lIIa, IIIb, IIIc, or IIIdor a compound described in any one of the embodiments described herein, the method further comprisesthe step of evaluating the IDH2 genotype ofthe 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 ment, prior to and/or after treatmentwith a compound ula I, Ia, Ib, B, C, Ic, Id, Ie, If, Ig, II, III, IIIa, IIIb, IIIc, or IIIdor a compound described in any one of the embodiments described herein, the method further comprises the step of ining the ZHG level in the subject. This may be achieved by spectroscopic analysis, e.g., ic resonance-based analysis, e. g., MRI and/or MRSmeasurement, sample analysis of bodily fluid, such as serum or spinal cord fluid analysis, or by is of al 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 y e.g., an additional cancer therapeutic agent or an additional cancer treatment. Exemplary additional cancer eutic agents include for example, herapy, 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 ion. 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 ition of one aspect of this invention, comprising both a nd 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 herapy agent.
Examples of chemotherapeutic agents used in cancer therapy include, for example, tabolites (e. g., folic acid, purine, and pyrimidine derivatives), alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, ines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others), and hypomethylating agents(e.g., decitabine (5-aza-deoxycytidine), zebularine, isothiocyanates, azacitidine (5- azacytidine), o-2'-deoxycytidine, 5,6-dihydroazacytidine and others). Exemplary agents include bicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, tene, bendamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur, stine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin, bine, Clofarabine, Crisantaspase, Cyclophosphamide, bine, Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin, Estramustine, Etoglucid, ide, Floxuridine, Fludarabine, uracil (5FU), Fotemustine, Gemcitabine, Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, Masoprocol, lan, Mercaptopurine, Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin, bicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine, Procarbazine, Raltitrexed, Ranimustine, can, Sapacitabine, Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin, Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide, Tesetaxel, Testolactone, itrate, 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 ments, the additional cancer therapeutic agent is a differentiation agent. Such differentiation agent includes retinoids (such as all-trans-retinoic acid , 9-cis retinoic acid, l3-cz's-retinoic acid (l3-cRA) and oxy-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 -stimulating factors including G—CSF and GM-CSF, and interferons).
In some embodiments the additional cancer therapeutic agent is a targeted y 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. ent examples are the tyrosine kinase inhibitors such as ib, Bosutinib, Cediranib, dasatinib, erlotinib, imatinib, gefitinib, nib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and also cyclin-dependent kinase inhibitors such as Alvocidib and Seliciclib. Monoclonal antibody therapy is another gy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the ERZ/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 mab, Panitumumab, Trastuzumab, Alemtuzumab, Bevacizumab, lomab, and Gemtuzumab. Exemplary fusion proteins include Aflibercept and Denileukin diftitox. In some ments, the ed therapy can be used in combination with a compound described herein, e.g., a biguanide such as min or rmin, preferably phenforrnin.
Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected ellular 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 ®.
In some embodiments, the additional cancer eutic agent is an immunotherapy agent.
Cancer immunotherapy refers to a e set of therapeutic gies designed to induce the subj ect's own immune system to fight the tumor. porary 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 poietic 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 ments, 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 ts, such as togens 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 mental notes: In the following examples, the ts (chemicals) were purchased from cial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company), and used without further cation. Nuclear magnetic resonance (NIVIR) spectra were obtained on a Brucker AMX-400 NlVIR (Brucker, Switzerland). Chemical shifts were reported in parts per million (ppm, 5) downfield from tetramethylsilane. Mass spectra were given with electrospray ionization (ESI) from a Waters LCT TOF Mass Spectrometer s, 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 isomer (e.g., an (R) or (S) stereoisomer) tes a preparation of that nd such that the compound is enriched at the specified center by at least about 90%, 95%, 96%, 97%, 98%, or 99%. The chemical name of each ofthe 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 NlVIR nuclear magnetic nce TLC thin layer chromatography HPLC high-performance liquid chromatography satd. saturated Spectrum Hz hertz chemical shift coupling constant singlet doublet triplet quartet multiplet broad quartet of doublets dquin doublet of quintets dd doubletof doublets dt doublet of triplets Solvents and Reagents DAST diethylaminosulfithrifluoride CHC13 chloroform DCM dichloromethane DMF dimethylformamide EtzO diethyl ether EtOH ethyl alcohol EtOAc ethyl acetate MeOH methyl alcohol MeCN acetonitrile PE petroleum ether THF tetrahydrofuran DMSO dimethyl sulfoXide AcOH acetic acid HCl hloric acid H2804 sulfuric acid NH4Cl ammonium chloride KOH ium hydroxide NaOH sodium hydroxide K2C03 potassium carbonate Na2C03 sodium carbonate TFA roacetic acid NaZSO4 sodium sulfate NaBH4 sodium borohydride NaHC03 sodium bicarbonate NaHMDS sodium hexamethyldisilylamide LiHMDS lithium hexamethyldisilylamide LAH lithium aluminum hydride NaBH4 sodium borohydride LDA m diisopropylamide Et3N triethylamine pyridine DMAP 4-(dimethylamino)pyridine DIPEA N,N—diisopropylethylamine Xphos 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl BINAP 2,2 ’ -bis(diphenylphosphanyl)-l ,l ’ hthyl dppf l ,l '-bis(diphenylphosphino)ferrocene TBTU 2-( l H—benzotriazole-l -yl)-l , l ,3 ,3 -tetramethyluronium tetrafluoroborate DPPA diphenylphosphoryl azide NH4OH ammonium hydroxide EDCI l -3 -(3 -dimethylaminopropyl)carbodiimide HOBt l -hydroxybenzotriazole Pyridine Dppf l ,l '-bis(diphenylphosphino)ferrocene HATU 0-(7-azabenzotriazol-l -yl)-N,N,N’,N’-tetra-methyluronium BINAP 2,2 ’ -bis(diphenylphosphanyl)-l ,l ’ -binaphthyl Preparation of Intermediates Preparation of 1-phenylcyclopropanamine.
©/ W9N EtMgBr Ethylmagnesium bromide (48.5 mL, 146 mmol) was added dropwise over 30 min to a on 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 d 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 1N aq. HCl and EtZO. The resulting mixture was poured into 10% aq. NaOH, and extracted with EtZO. Combined organic layers were dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography using PE/EtOAc/NH3H20 (4:1 :0.1%) to afford the desired product. LC-MS: m/z 134.1 (M+H)+.
Preparation of 2-aminomethylpropanenitrile KCN, NH3HZO NH4C| CN To a mixture of NH4C1 (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 ted 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 opropanenitrile KCN, NH3H20 0 CN )LH NH4CI XNHz To a mixture of NH4Cl (981 mg, ol), acetaldehyde (1 mL, 18.5mmol) in ammonium hydroxide (3 mL) was added KCN (1 g, ol) at room temperature. The on 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 NaZSO4 and concentrated to afford the desired product which was used ly in the next step without any further cation.
Preparation ofdicyclopropylmethanamine o N NH2 H NHZOH 1 LiAIH4 pyridine fl THF m Step1.Preparati0n 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 l N aq. HCl and brine, dried over ous Na2804, andconcentrated under d pressure to give the desired product which was used directly in the next step without any further purification.
LC-MS : m/z 124.1 (M—H)‘.
Step 2.Preparati0n of opropylmethanamine. To a cooled solution of opropylmethanoneoxime (550 mg, 4.4 mmol) in THF (5 mL) was added LiAlH4 (200 mg, .3 mmol). The mixture was then stirred at 80°C for 6 hr and cooled to room temperature. The mixture was quenched by 1N aq.NaOH until gas evolution ceased and then filtered. The te was extracted with EtOAc. Combined organic layers were dried over anhydrous Na2804, and concentrated under reduced pressure to give the desired product which was used directly in the next step without any further purification.
LC-MS : m/z 112.1 (M+H)+.
Preparation of bicyclo[3.1.0]hexanamine Zn Et2 D DPPA CH2'2 £y—»Pd/C HOOC CszNJ:> CszN Step 1: Preparation of benzyl cyclopent-3—enylcarbamate.2To a solution of cyclopent boxylic acid (5 g, 44.6 mmol, 1eq) and DPPA (13.5 g, 49 mmol, 1.1 eq) in e (80 mL) was added Et3N (7.4 mL, 53.5 mmol, 1.2 eq) at r.t.. The mixture was then d at reflux for 2hr during which period a larger amount of nitrogen evolvedAfter 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 Na2804, and concentrated under reduced pressure. The residue was d by flash chromatography using PE/EtOAc (5:1) as eluent to give the desired product.
CszN LC-MS: m/z 218.0 (M+H)+.
Step 2: Preparation ofbenzyl bicyclo[3.1.0]hexanylcarbamate. To a on of benzyl cyclopentenylcarbamate (1 g, 4.6 mmol, 1 eq) in anhydrous DCM at 0°C under an atmosphere of nitrogen was added ZnEtz (9.7 mL, 9.7 mmol, 2.1 eq), followed by dropwise addition of CHzIz (0.78 mL, 9.7 mmol, 2.1 eq). The on mixture was warmed to room temperature and stirred for 4 hr. The resulting reaction mixture was quenched with brine and extracted with DCM. The c layer was dried over anhydrous NaZSO4, and concentrated. The residue was purified by column chromatography using PE/EtOAc (5:1) as eluent to give the desired product.
CszN LC-MS: m/z 232.1 (M+H)+.
Step 3: Preparation clo]3.1.0]hexanamine. To a solution of benzyl bicyclo[3.1.0]hexanylcarbamate (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 d pressure to give the desired product which was used directly in the next step without any further purification. 1 LC-MS: m/z 98.1 (M+H)+.
Preparation of -diflu0roethyl)pyridinamine OTBTU MgBrMe \ DAST H—>| —> DIPEA DMF N/ DCM CI 4: l BocNH2 0%NH N/ F —> F Pd(OAc)2 \ X-phos,CsZCO3 | Step 1: Preparation of 4-chloro-N-methoxy-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,O-dimethylhydroxylamine(9.3 g, 95.2 mmol) and DIPEA (24.6 g, 190.4 mmol) at O°C.The e 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 NaZSO4and concentrated. The residue was purified by flash chromatography to give the desired product.
LC-MS: m/z 201.0 (M+H)+.
Step 2: Preparation of1-(4-chl0r0pyridin-2—yl)ethanone. To a on of 4-chloro-N-methoxy- N—methylpicolinamide (11.25 g, 56.08 mmol) in THF (50 mL) at O°Cwas added MeMgBr (28.04mL, 84.12 mmol). The mixture was then stirred at r.t. overnight and quenched with saturated aqueous NH4Cl. The ing mixture was extracted with EtOAc. The organic layer was dried over anhydrous NaZSO4 and concentrated. The residue was purified by flash chromatography to give the desired product. 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 .
Step 3: 4-chl0r0-2—(1,1-diflu0r0ethyl)pyridine. To a on of 1-(4-chloropyridin anone (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 NaZSO4 and concentrated. The residue was purified by flash chromatography to give the desired product.
N/ F 1H NMR (400 MHz, CDC13):58.48 (d, J: 5.2 Hz, 1H), 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.°Preparati0n of tert-butyl (2-(1,1-diflu0r0ethyl)pyridin-4—yl)carbamate. To a on of 4-chloro(1,1-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 mol) 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.
NH4C1 and extracted with EtOAc. The organic layer was dried over anhydrous Na2804andconcentrated. The residuewas purified by flash chromatography to give the d product.
LC-MS: m/z 259.1 (M+H)+.
Step 5.°Preparati0n of 2—(1,1-diflu0r0ethpryridinamine. A solution of tert-butyl (2-(1,1- difluoroethyl)pyridinyl)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 ature 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 Na2804 and concentrated to give the desired product which was used in the next step without further purification.
/ F LC-MS: m/z 159.1 .
Preparation ofl-(4-aminopyridin-Z-yl)cyclopropanecarbonitrile _ N Br F [>——N \\ N\\ / Br —> O 1 / N l \ \ N LiHMDS, 4A BuONa, Pd2dba3 \ N I toluene BINAP,dioxane / N 100 °C 2 N HCI in THF H2N r.t. I Step 1: Preparation br0m0pyridin-2—yl)cyclopropanecarbonitrile.LiHMDS (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 d for 16 hr. After it was poured into water, the mixture was filtered. The e was diluted with EtOAc and H20, and ted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous NaZSO4, and concentrated. The residue was purified by column chromatography using PE/EtOAc (9:1) as eluent to give the desired product.
LC-MS: m/z 223.0 (M+H)+.
Step 2: Preparation ofl-(4-(diphenylmethyleneamin0)pyridin yl)cyclopropanecarbonitrile.To a mixture of 1-(4-bromopyridinyl)cyclopropanecarbonitrile (0.45g, 2.1 mmol), BINAP (0.04 g, 0.063 mmol), Pd2(dba)3 g, 0.021 mmol) and NaOtBu (0.282 g, 2.94 mmol) in toluene (6 mL) at r.t. under an atmosphere of nitrogen was added ylmethanimine (0.45 g, 2.51 mmol). The reaction mixture was stirred at reflux for 2 hr and then cooled to room temperature. The e was concentrated under reduced pressure and the residue was purified by column tography to give the desired product.
LC-MS: m/z 324.1 (M+H)+.
Step 3: Preparation ofl-(4-amin0pyridinyl)cyclopropanecarbonitrile.A mixture of 1-(4- (diphenylmethyleneamino)pyridinyl)cyclopropanecarbonitrile (0.48 g, 1.49 mmol), THF (10 mL) and aq. HCl (2N, 2.0 mL)was stirred at room temperature for 1hour. 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 Na2804 and concentrated. The residue was purified by column chromatography to give the desired t.
H2N \ LC-MS: m/z 160.1 (M+H)+.
Example 1 Preparation of Di-aliphatic Triazine Compounds of Formula DWherein Ring A is substituted Pyridin-Z-yl or Phenyl.The compounds of this Example are ed by general Scheme 1, set forth below. o o KR HZNJkNJkNH2 I j" | v? co | x? H PCI5,POCI3 /N /N HN \N CI Swim)» SOOC'HOOC pp / N OEt EtOHa o 0 , CAN)», 1 2 H RA RZR NH21 | % l /]\l\ /N —> R1 N \N R1 N \N R2 | R2 CIANACI. A A J< R3 H N H R3 4 FormulaD Step 1: ation of 6-triflu0methyl-pyridine—Z-carboxylic acid methyl ester (2). To a solution of 2-chlorotrifluoromethyl-pyridine (2 g, 11.1 mmol, 1.0 eq) in MeOH (20 mL) was add Pd(OAc)2 (124 mg, 0.05eq) and dppf (600 mg, 0.1eq) 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 d t. 1HNMR (400 MHz, CDC13): 5 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.°Preparati0n of 6-(6- trifluomethylpyridin-Z—yD-I,3,5-triazine-2,4-di0ne. 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 d compound.
HN \N CAN/g0 1H NMR (400 MHz, DMSO-d6): 5 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-triflu0methyl-pyridin-2—yl)—1,3,5-triazine. To a solution of rifluomethyl-pyridinyl)-1,3,5-triazine-2,4(1H,3H)-dione (3.37 g, 0.013mol) in POC13 (48 mL) was added PC15 (23 g, 0.1 mol). The mixture was d 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 NaZSO4 and thenconcentrated to give the desired N. ‘N CIANACI 1HNMR (400 MHz, CDC13): 5 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 ofN2,N4-bis((R)cyclopr0pylethyl)—6—(6—(trifluoromethyl) -pyridinyl)- 1,3,5-triazine-2,4-diamine. To a mixture of 2,4-dichloro(6-(trifluoromethyl)pyridineyl)- 1,3,5-triazine (600 mg, 2.0mmol, 1.0 eq) and (R)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 2014/081957 filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a standard method to give the d product.
\ F gfiNkNANN/ IN = H H 1H NMR (400 MHz, CD30D): 5 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 ng materials.
CompoundN2,N4-bis((S)cyclopr0pylethyl)—6—(6—(trifluoromethpryridin-Z-yb- 1,3, 5-triazine— 2,4-diamine E I" (:9) NJ\\NJ\N7~!W H H 1H NMR (400 MHz, CDClg): 5 8.50 (s, 1H), 7.99 (t, J: 7.9 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), .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 )cyclopr0pylethyl)-N4-((S)cyclopr0pylethyl)—6-(6-(triflu0r0 methpryridin-Z—yD-1,3,5-triazine—2,4—diamine /| F EN/NE . | .
(S) NJ\\NJ\N (R) H H 1H NMR (400 MHz, CDC13): 5 8.51 (s, 1H), 7.99 (t, J: 7.9 Hz, 1H), 7.77 (d, J: 7.3 Hz, 1H), .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)+. ndN2,N4-bis l0pr0pylethyl)—6—(6—(trifluoromethpryridin-Z-yD-I,3,5 -triazine- 2,4-diamine 1HNMR (400 MHz, CDgOD): 58.6 (m, 1H), 8.2-8.1 (m, 1H), 8.0-7.9 (m, 1H), 40—352 (m, 2H), 1.4—1.2 (m, 6H), 1.0 (m, 2H), 06-035 (m, 6H), 0.3 5—02 (m, 2H).LC-MS: m/z 393.2 (M+H)+.
CompoundN2,N4-bis(cyclobuwlmethyD(6-(trifluoromethpryridin-Z-yD-I,3,5 -triazine-2,4— diamine \ F N \N 1H NMR (400 MHz, CDC13): 5 8.54 (m, 1H), 8.00 (m, 1H), 7.78 (d, J: 5.9 Hz, 1H), 5.27 (m, 2H), 3.69 4 3.32 (m, 4H), 2.59 (m, 2H), 2.10 (m, 4H), 1.92 (m, 4H), 1.84 4 1.62 (m, 4H).LC-MS: m/z 393.2 (M+H)+.
CompoundN2,N4-bis((R)cycl0butylethyl)(6-(triflu0r0methyl)pyridin-2—yl)— 1,3, 5-triazine— 2,4-diamine D/(IgNANANmN. ‘N - H H 1H NMR (400 MHz, CDC13): 5 8.71 4 8.41 (m, 1H), 7.99 (d, J : 7.4 Hz, 1H), 7.77 (d, J: 7.7 Hz, 1H), 5.34 4 4.84 (m, 2H), 4.30 4 3.96 (m, 2H), 2.44 4 2.28 (m, 2H), 2.09 4 1.96 (m, 4H), 1.93 4 1.78 (m, 8H), 1.14 (d, J : 5.9 Hz, 6H).LC-MS: m/z 421.2 (M+H)*.
CompoundN2,N4-bis(Z-methylcyclopropyl)(6-(triflu0r0methyl)pyridin-2—yl)—1,3,5 -triazine- amine )L A 1HNMR (400 MHz, CD30D): 58.65484 (m, 1H), 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)+.
CompoundN2,N4-bis(cyclopropylmethyD(6-(trifluoromethpryridin-Z-yD-I,3,5 -triazine-2,4— diamine )N'x \JNx/ WHN N NH/W 1H NMR (400 MHz, CD30D): 5 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), .34 (m, 4H).LC-MS: m/z 365.2 (M+H)+.
CompoundN2,N4-bis((1-methylcyclopr0pyl)methyl)—6-(6-(trifluoromethpryridin-Z -yl)-1,3, 5- triazine—2,4-diamine |\ F VuiNfi$ 1HNMR (400 MHz, CD30D): 5 .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,N4-dicyclobutyl(6-(trifluaromethpryridin-Z-yD-I,3,5-triazine— 2,4-diamine \ F aNxNAN"I \N D H H 1H NMR (400 MHz, CDC13): 5 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,N4-di(bicycl0[3. 1. 0]hexan-3—yl)—6—(6—(try‘luoromethybpyridin-Z-yl) -1,3, 5- triazine—2,4-diamine / F 1HNMR (400 MHz, CD30D): 5 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)+.
Compound N,N'—dicycl0pent:vl—6—(6-trifluoromethyl-pyridin-Z-yl)-[1,3,5]triazine— 2,4-diamine 1HNMR (400 MHz, CD30D): 5 8.60-8.68 (m, 1H), 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 CompoundN2,N4-bis(3,3-diflu0r0cycl0pemjyl)—6-(6-(trifluoromethpryridin-Z-yb- 1,3, 5- triazine—2,4-diamine 1H NMR (400 MHz, CDC13): 5 8.53 (m, 1H), 8.08 — 8.02 (m, 1H), 7.85 — 7.80 (m, 1H), 5.78 — .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,N4-bis(4,4-diflu0r0cyclohexyl)—6—(6-(triflu0r0methyl)pyridin-2—yl)— 1,3, 5- triazine—2,4-diamine /| F F F FUi/fifijq\ N N N H H 1H NMR (400 MHz, CDC13): 5 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)+.
CompoundN,N'-bis-(t‘etrahydropyran-4—y0(6-triflu0r0methyl—pyridin- 2—yl)—[1,3,5]triazine— 2,4-diamine H H 1HNMR (400 MHz, DMSO-d6): 5 7.43-8.55 (m, 5H), 3.82-4.15 (m, 6H), 3.48-3.50 (m, 4H), .87 (m, 4H), 1.46-1.60 (m, -MS : m/z 425.1 (M+H)+.
WO 03640 CompoundN2,N4-diis0propyl(6—(trifluoromethpryridin-Z—yl)-1,3,5-triazine -2,4-diamine |\ F 4 "P" kNANAN H H 1H NMR (400 MHz, CDC13): 5 8.67 4 8.41 (m, 1H), 7.99 (s, 1H), 7.77 (d, J: 7.7 Hz, 1H), 5.18 (m, 2H), 4.45 4 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,N4-di-tert-butyl(6—(trifluoromethpryridin-Z-yD-I,3,5-triazine -2,4-diamine |\ F A ANVN J< N NAN H H 1H NMR (400 MHz, DMSO-d6): 5 8.44 4 8.31 (m, 1H), 8.19 4 8.12 (m, 1H), 7.93 (d, J: 7.3 Hz, 1H), 7.16 4 6.77 (m,2H), 1.35 (s, 18H).LC-MS: m/z 369.2 (M+H)+.
CompoundN,N'-di-sec-but:vl—6—(6—triflu0r0methyl—pyridinyl)-[1,3,5]triazine— 2,4-diamine \ F \J\ N/IN JV NkNAN H H 1HNMR (400 MHz, CD30D): 5 .68 (m, 1H), 8.15-8.21 (m, 1H), 7.94 (d, J: 8.0 Hz, 1H), .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-trifluoromethyl-pyridin-Z-yD-[I,3,5]triazine-2,4 —diamine 3 N \N WNJLNAN/(Sk/ H H 1HNMR (400 MHz, CDgOD): 5 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), .74 (m, 4H), 1.29—1.33 (m, 6H), 1.01—1.05 (m, 6H).LC-MS: m/z 369.2 (M+H)+.
CompoundN2,N4-di-sec-buljyl(6-(trifluoromethpryridin-Z-yD-I,3,5-triazine—2,4— diamine \/(ngJ\N/J\N{R)\/N| : H H 1HNMR (400 MHz, CDgOD): 5 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)+.
CompoundNZ-((R)-sec—buwD-N4-((S)-sec-but:vl)—6—(6—(t‘rifluoromethpryridin- 2-yl)-1,3,5- triazine—2,4-diamine N/ N H H 1HNMR (400 MHz, CD30D): 5 8.59-8.65 (m, 1H), 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 CompoundN2,N4-bis(3—methylbutan-2—yl)—6-(6—(trifluaromethpryridin-Z-yb- 1,3,5-triazine— amine W/LNAN/ANJY1 \N 1H NMR (400 MHz, CDC13): 5 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)+.
CompoundN2,N4-bis((R)methylbutan-2—yl)—6-(6—(trifluoromethyDpyridin-Z-yb- 1,3,5- triazine—2,4-diamine (R) \ J\ (R) 1H NMR (400 MHz, 6): 5 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)+.
CompoundN2,N4-bis((S)methylbutan-2—yl)—6-(6—(triflu0r0methyl)pyridin-2—yl)— 1,3, 5- triazine—2,4-diamine E NI ‘N (:5) NxNANJsff H H 1H NMR (400 MHz, DMSO-d6): 5 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)+. ndN2,N4-bis((R)cyclopr0pylethyl)—6—(4—(trifluoromethpryrimidin yl)-1,3,5- triazine—2,4-diamine >9,I F VJURFNANANN. ‘N (R) H H 1H NMR (400 MHz, CDC13): 5 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 NZ-((R)phenylethyl)-N4-((S)phenylethyl)—6-(6-(triflu0r0methyl) pyridin-Z-yD- 1,3, 5-triazine—2,4—diamine |\ F E N\N E ©®NANAmfi©: I : 1H NMR (400 MHz, CDC13): 5 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)+.
Compound6—(6—chloropyridin-Z-yD-NZ,N4-bis((R)cycl0pr0pylethyl)—1,3, 5-tria -zine-2,4- diamine %N \NAN1%" 2 H H 1H NMR (400 MHz, CD30D): 8 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)+.
Compound6—(6—chloropyridin-Z-yD-NZ,N4-diis0buljyl-1,3,5-triazine—2,4—diamine N. ‘N 1HN1\/[R (400 1V1HZ, CD3OD): 8 (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), 9 (m, 12H).LC-MSZ m/z 335.1 (M+H)+.
Compound6-(6-chloropyridin-Z-yD-NZ,N4-diisopropyl-1,3,5-triazine-2,4—diamine A N'W kNANAN H H 1HNMR (400 MHz, : 5 8.25-8.19 (m, 1H), 7.81 (hrs, 1 H), 7.46 (d, J = 7.6 Hz, 1H), 4.26-4.11 (m, 2H), 1.15 (d, J: 6.0 Hz, C-MS: m/z 307.1 (M+H)+.
Compound N2,N4-di(butenyl)phenyl-1,3,5-triazine-2,4-diamine 1HNMR (400 MHz, : 5819-813 (m, 2H), 7.77-7.61 (m, 3H), 5.95-5.85 (m, 2H), 5.20— .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,N4-di(3-oxabicyclo[3.1. 0]hexanyl)phenyl—1,3,5-triazine-2,4- diamine @NlNiNfi H H 1HNMR (400 MHz, CD30D): 5 835-81 (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), 29—255 (m, 2H), 2.1—2.0 (m, 2H).LC-MS: m/z 352.2 (M+H)+.
Compound N2,N4-bis((1S,3S)(4-fluorophenyl)cyclobut:vl)—6—(6— (trifluoromethpryridin-Z— yl)—1,3,5-triazine—2,4-diamine To a mixture of 2,4-dichloro(6-(trifluoromethyl)pyridineyl)- 1,3,5-triazine (600 mg, 2.0 mmol, 1.0 eq) and (1s,3s)(4-fluoropheny1)cyclobutanamine (726 mg, 4.4 mmol, 2.2 eq) in THF (12 mL) at re added CsF (0.6 g, 2.0 mmol, 1 eq.) and DIPEA (0.7 mL, 4.0 mol, 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. 1%919N(S) 1H NMR (400 MHz, CDC13) 5 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: rn/z 553.2 .
Compound N2,N4-bis((1R,3R)(4-fluorophenyl)cyclobutyl)(6-(t‘rifluoromethpryridin-Z— yl)—1,3,5-triazine—2,4-diamine J\N(r) 1H NMR (400 MHz, CDC13) 5 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: rn/z 553.2 (M+H)+.
Compound 6-(6-(Trifluoromethpryridin-Z—yD-NZ,N4-bis ((R)-1,1,1-trifluoropropan-2—yl)— 1,3, 5-triazine—2,4—diamine \ F N\N AAAL 1H NMR (400 MHz, CDC13) 5 8.62 (m, 1H), 8.03 (d, J: 7.8 Hz, 1H), 7.83 (d, J: 7.7 Hz, 1H), .59 (d, J: 9.4 Hz, 1H), 5.34 (m, 3H), 1.42 (m, 6H); LC-MS: m/z449 (M+H)+.
Compound N2,N4-bis((S)-1,1,1-trifluorobutan-2—yl)—6—(6—(trifluoromethpryridinyl)-1,3,5- triazine—2,4-diamine \ F CF3 N/ IN 9F3 1H NMR( 400MHz, CDC13)68.55 (d, J=8 Hz, 1H), 8.06 — , 1H), 7.83 (d, J=8Hz, 1H), 5.64 — 5.15(m, 2H), 4.93 — 4.71(m, 2H),2.o — 1.94(m, 2H),1.69- 1.57 (m, 2H), 1.08 — 1.02(m, 6H).
LCMS: m/z 477(M+H)+.
Compound N2,N4-bis((2,2-difluorocyclopropmeethyD-6—(6—(trifluoromethpryridin-Z—yb- 1,3, 5-triazine—2,4—diamine 1H NMR (400 MHz, CDC13) 8859—851 (m, 1H), 8.02 (bs, 1H), 7.80 (d, J=7.6 Hz, 1H), 5.70— .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 bis((3,3-difluorocyclobutj/DmethyD(6-(trifluoromethpryridin-Z-yD-I,3,5- triazine—2,4-diamine |\ F 1H NMR (400 MHz, CDC13) 5 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, 10H). LC-MS: m/z 465 (M+H)+.
Compound N2,N4-bis(3,3-difluorocyclobugzl)(6-(trifluoromethpryridin-Z—yD-I,3,5-triazine- 2,4-diamine F F N \N Ffl 1N2 MF H H 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,N4-bis((S)-3,3-difluorocyclopen021)—6—(6—(trifluoromethpryridin-Z-yD-I,3,5- triazine—2,4-diamine |\ F X](S) | F "II/HJ\\NJ\H(S)IVF 1H 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 .
Compound bis((R)-3,3-difluorocyclopen02l)—6—(6—(trifluoromethpryridin-Z-yD-I,3,5- triazine—2,4-diamine Ffl Ii @F(R)F .
H \N "W F 1H NMR (400 MHz, CDC13)557-8.48 (m, 1H), 8.02-8.01 (m, 1H),7.80 (s,1H), 5.66-5.32 (m, 2H),4.71—4.49 (m, 2H),2.64—2.61 (m, 2H),2.31—2.05 (m, 8H), 1.86-1.79 (m, 2H). LC-MS: m/z 465 (M+H)+.
Compound N2—((R)-3,3-difluorocyclopemjyl)—N4—((S)-3,3-difluorocyclopemjyl)—6—(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine |\ F F8:(S) | F .© LC-MS: m/z 465 (M+H)+.
Compound N2,N4-bis(4,4-difluorocyclohexyl)(4-(trifluoromethyl)pyridinyl)-1,3,5- triazine—2,4-diamine 1H NMR (400 MHz, CDC13) 5 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)+.
Compound N2,N4-bis((R)cyclopropylethyl)—6-(6-methoxypyridin-2—yl)—1,3,5-triazine-2,4— 1H NMR (400 MHz, CDC13) 5 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 .
Compound N2,N4-bis(3,3-difluorocyclobutyl)(6-(trifluoromethoxy)pyridinyl)-1,3,5- triazine—2,4-diamine OCF3 F F N \N F F JL A N N N H H 1H NMR (400 MHz, CDC13) 5 8.34 — 8.27 (m, 1H), 7.96 — 7.92 (m, 1H), 7.22 (d,J= 8 Hz,1H), .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)+.
Compound bis(3,3-difluorocyclopentyl)(6-(trifluoromethoxy)pyridinyl)-1,3,5- triazine—2,4-diamine / OCF3 FF>CL kNJKNN/ N D Compound N2,N4-bis(4,4—difluorocyclohexyD(6-(trifluoromethoxy)pyridinyl)-1,3,5- triazine—2,4-diamine / OCF3 F F PU "W" GPNJ\\NJ\N H H 1H NMR (400 MHz, CDC13) 5 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,N4-bis(4,4-diflu0r0cyclohexyl)—6-(3—fluorometh03qypyridin-2—yD-1,3,5- triazine—2,4-diamine F F Ffiliflq/ 1H NMR (400 MHz, CDC13) 5 7.45—7.41 (t, 1H), 6.84 (d, 1H), .07 (m, 2H), 4.08-3.98 (m, 5H),2.11-2.01 (m, 8H), 1.96-1.89 (m, 4H), .83 (m, 4H). LCMS : m/z 473(M+H)+.
Table 1: The followingcompounds were prepared by following theprocedure described in Scheme 1 above.
LCMS Compound Structure Expected Found MW (M+1)+ di((1R,5S) 0xabicyclo[3. 1. 0]hexa n-6—y )l 6-( 3 86. 1 3 87. 1 chloropyridin- 2-yl)- 1,3,5—triazine—2,4— diamine 6-(6-amin0pyridin-2— yl)—N2,N4- dineopemjyl—L3,5- 343 .2 344.2 triazine—2,4-diamine WO 03640 6-(6—amin0pyridin-2— yl)—N2,N4-diisobmjyl- 1,3,5-triazine—2,4— 3 15.2 3 16.2 diamine 6-(6-amin0pyridin-2— yl)-N2,N"-bis (3- methylbutan-Z—yy- 343.2 344.2 1,3,5-triazine- 2,4- diamine Example 2 Preparation of Di—aliphatic ne Compounds of Formula EWherein Ring A is substituted Pyridin-Z-yl or Phenyl.The compounds of this Example are ed by general Scheme 2, set forth below.
SchemeZ R9 R9 R2 NH2 4 R5 NH2 R3 5 J\ 6 4 k \ 1 R 7 R N N R1 —> N R 2 R5 R2 N \N )L A R fix )L A J< 3 A A R3 R fl N CI N N fl R CI N CI 4 6 FormulaE Step 1.°Preparati0n0f(R)—4-chloro-N-(1-cycl0pr0pylethyl)—6—(6—(triflu0r0methyl)pyridin-2—yl)— 1,3,5-triazin-2—amine.To a mixture of 2,4-dichloro(6-(trifiuoromethy1)pyridine y1)-1,3,5- triazine (600 mg, 2.0mmol, 1.0 eq) and (R)cyclopropy1ethanamine 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 e was concentrated under reduced pressure and the residue was purified by a standard method to give the desired product.
%MJ\\NJ\CIIN LC-MS: m/z 344.1 (M+H)+.
Step2: Preparation of NZ-((R)cyclopr0pylethyl)—N4—@entan-Z—yD (6- (trifluoromethpryridin-Z-yl) -1,3,5-triazine—2,4—diamine. To a mixture of (R)chloro-N—(lcyclopropylethyl )(6-(trifluoromethyl)pyridinyl)-l,3,5-triazinamine (80 mg, 0.23mmol, 1.0 eq) and pentanamine (25 mg,0.28mmol, l.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 overnight and filtered. The filtrate was concentrated under reduced pressure and then purified by a standard method to give the d product. figNkaijNH H 1H NMR (400 MHz, DMSO-d6): 5 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 .
The procedure set forth in e 2was used to produce the ing compounds using the appropriate starting materials.
WngNANVLO/IN 0 H H 1H NMR (400 MHz, CDC13): 5 8.52 (m, 1H), 8.00 (t, J: 7.6 Hz, 1H), 7.78 (d, J: 7.7 Hz, 1H), .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-(1-cyclopropylethyl)—N4-(4,4-difluorocyclohexyl)—6-(6-(trifluoro methpryridin-Z—yD-I,3,5-triazine—2,4—diamine 5111:1110H H 1H NMR (400 MHz, CDC13): 5 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)+. nd NZ-((R)cyclopropylethyl)—N4-(6, 6-difluorospiro[3.3]heptanyl)—6—(6— (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine /| F W15"!1H\N N H H 1H NMR (400 MHz, CDC13): 5 8.54 — 8.49 (m, 1H), 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 NZ-((1R,3R,5R, 7R)—adamantanyl)-N4-((R)cyclopropylethyl)—6-(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine \ 'l'l NkNXNN (R:@IH H (R) 1H NMR (400 MHz, CDC13): 5 8.63 — 8.34 (m, 1H), 8.00 (t, J: 7.8 Hz, 1H), 7.78 (d, J: 7.7 Hz, 1H), 5.57 (m, 2H), 4.21 (m, 1H), 3.85 — 3.32 (m, 1H), 2.22 — 1.57 (m, 15H), 1.25 (m, 4H), 0.90 (m, 1H), 0.66 —0.24 (m, 4H).LC-MS: m/z 459.2 (M+H)+.
Compound (R)—N2-(1-cyclopropylethyl)—N4-(dicyclopropylmethyb(6-(trifluoro methpryridin-Z—yD-1,3,5-triazine—2,4—diamine 1H NMR (400 MHz, CDC13): 5 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 )cyclopropylethyl)—6-(6-(trifluoromethpryridin-Z-yD-M- (1,1,1- trifluoropropan-Z—yl)—1,3, 5-triazine—2,4—diamine 1H NMR (400 MHz, CDC13): 5 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 (R)—N2-(1-cyclopropylethyl)—N4-(2,3-dihydro—1H—inden-Z-yD-6—(6 - (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine V/('R7NJ\\NJ\NIN Si}H H 1H NMR (400 MHz, CDC13): 5 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)+. nd (R)—N2-(1-cyclopropylethyl)—N4—@rop—Z-yn-I-yl)(6-(trifluoromethyl) pyridin-Z— yl)—1,3,5-triazine—2,4—diamine |\ F VJMIi\N u\ 1H NMR (400 MHz, CDC13): 5 8.55 (m, 1H), 8.01 (t, J: 7.8 Hz, 1H), 7.79 (d, J: 7.7 Hz, 1H), .94 — 5.12 (m, 2H), 4.30 (m 2H), 3.59 (m, 1H), 2.23 (s, 1H), 2.01 (s, 3H), 0.90 (m, 1H), 0.59 — 0.16 (m, 4H).LC-MS: m/z 363.1 (M+H)+.
Compound (R)—N2-(1-cyclopropylethyl)—N4-(Z-phenoxyethyD-6—(6—(trifluoromethpryridin-Z- yl)—1,3,5-triazine—2,4—diamine $139000IN 1H NMR (400 MHz, CDC13): 5 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 NZ-((R)cyclopropylethyl)—N4-(1-methoxypropan-2—yl)—6-(6—(trifluoro methpryridin-Z—yD-I,3,5-triazine—2,4—diamine /| F %NJ\\NJ\HH N/IN J\/O\ 1H NMR (400 MHz, CDC13): 5 8.51 (m, 1H), 7.99 (t, J: 7.9 Hz, 1H), 7.77 (d, J: 7.7 Hz, 1H), .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 .
Compound (R)—N2-(1-cyclopropylethyl)—N4-(1,3-dimethoxypropan-2—yl)—6-(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine / F W'RTHkNXNHIN 1H NMR (400 MHz, CDC13): 8.47 (m, 1H), 8.05 — 7.80 (m, 1H), 7.71 (d, J: 7.7 Hz, 1H), 5.90 — .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)+. nd 2-((4-(((R)cyclopropylethyl)amino)—6-(6-(trifluoromethyl)pyridine yl)-1,3,5- triazin-Z-yDamino)propanenitrile WgNkNANxN / IN ON H H 1H NMR (400 MHz, : 5 8.56 (m, 1H), 8.03 (t, J: 7.8 Hz, 1H), 7.81 (d, J: 7.7 Hz, 1H), .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—(1-cyclopropylethylamino)—6—(6—(trifluoromethpryridin-Z-yb- 1,3,5- triazin-Z—ylamino)methylpropanenitrile \ CF3 VJUSNkNANH N 1 J Compounsz-((R)cyclopropylethyl)—N4-(tetrahydrofuran-3—yl)—6-(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine /| F WgNkNxHW 0H 1H NMR (400 MHz, CDC13): 5 8.57 4 8.47 (m, 1H), 7.99 (t, J: 7.2 Hz, 1H), 7.78 (d, J: 7.6 Hz, 1H), 5.73 4 5.32 (m, 2H), 4.79 4 4.60 (m, 1H), 3.99 4 3.49 (m, 5H), 2.29 (m, 2H), 1.91 (m, 1H), 1.30 (m, 3H), 0.56 4 0.23 (m, 4H).LC-MS: m/z 395.2 (M+H)+.
Compound(1S,2S)(4-((R)cyclopr0pylethylamin0)(6-(triflu0r0-methyl)pyridin-2—yl)— 1,3, 5-triazin-2—ylamino)cyclohexanol v%NJ\NJ\N"©N/ N (S) H H(S) 1H NMR (400 MHz, CDC13): 5 8.48 (d, J: 7.4 Hz, 1H), 8.01 (t, J : 7.8 Hz, 1H), 7.79 (d, J : 7.7 Hz, 1H), 5.67 4 5.28 (m, 2H), 3.65 (m, 4H), 2.09 (s, 3H), 1.47 4 1.23 (m, 8H), 0.92 (s, 1H), 0.62 4 0.40 (m, 3H), 0.30 (s, 1H).LC-MS: m/Z 423.2 (M+H)+. ndflR,2S)(4-((R)—1-cyclopr0pylethylamin0)—6-(6-(triflu0r0methyl) -pyridin-2—yl)— 1,3, 5-triazin-2—ylamino)cyclopentanol /| F N’ N "0419 %NJ\\NJ\N"{‘S)O|H H 1H NMR (400 MHz, CDC13): 5 8.51 (m, 1H), 8.01 (t, J = 7.6 Hz, 1H), 7.80 (t, J = 6.4 Hz, 1H), .40 4 5.31 (m, 1H), 4.10 4 3.97 (m, 2H), 3.69 4 3.52 (m, 1H), 2.25 4 2.09 (m, 2H), 1.95 41.55 (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-N4-(1-cyclopropylethyl)—6—(6—(trifluoromethyl)pyridin- 2—yl)—1,3,5- triazine—2,4-diamine 1H NMR (400 MHz, CDC13): 5 8.49 (d, J: 7.2 Hz, 1H), 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 NZ-((R)cyclopropylethyl)—N4-((S)phenylethyl)(6-(trifluoromethyl) pyridin- 1,3,5-triazine-2,4-diamine V/(IgNkNAN|N (S) H H 1H NMR (400 MHz, CDC13): 5 8.45 (t, J: 10.4 Hz, 1H), 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)+. nd NZ-((R)cyclopropylethyl)—N’-((R)phenylethyl)—6-(6—(trifluoro methyl) pyridin- 2—yl)—1,3,5-triazine-2,4-diamine \ 'l'l %NJ\\NJ\N®©IN _ H H 1H NMR (400 MHz, CDC13): 5 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, -MS: m/z 429.2 (M+H)+.
Compound NZ-((R)cyclopropylethyl)—N4-(1-(3-fluorophenyl)ethyl)—6—(6 - (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine 1H NMR (400 MHz, CDC13): 5 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 NZ-((R)cyclopropylethyl)—N4-(1-(3-(trifluoromethyl)phenyl)ethyl) (6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine WngN/AH1 \N CF, 1H NMR (400 MHz, CDC13): 5 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 .
Compounsz-((R)cyclopr0pylethyl)—N4-((1R,2S)phenylcyclopropyl)(6 - (trifluoromethybpyridin-Z-yl)-1,3,5-triazine-2,4—diamine %NJN: j: (S) \ ‘.
N N\(R) H H 1H NMR (400 MHz, CDC13): 5 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-(1-cyclopr0pylethyl)—N4-(1-phenylcycl0pr0pyl)—6-(6-(triflu0r0 methpryridin-Z—yD-1,3,5-triazine—2,4—diamine W'I‘SNANAN1 \NH H 1H NMR (400 MHz, DMSO-d6): 5 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 (R)—6-(6-chloropyridin-Z-yD-NZ-(1-cyclopropylethyl)-N4,N4-diethyl- 1,3,5-triazine— 2,4-diamine V/(gNkNAFIN 1H NMR (400 MHz, CDC13): 5 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-((1-cyclopropylethyl)amino)(6-(t‘rifluoromethpryri -yl)- 1,3, 5-triazin-2—yl)amino)propanoate 1H NMR (400 MHz, CDC13): 5 8.52 (m, 1H), 8.00 (t, J: 7.6 Hz, 1H), 7.78 (d, J: 7.7 Hz, 1H), .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-(1-cyclopropylethyl)—N4-(2-phenoxyethyl)—6—(6-(trifluoromethyl) pyridin-Z- yl)—1,3,5-triazine—2,4-diamine figwxmwfig|N 1H NMR (400 MHz, CDC13): 5 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 .
Compound (1R,2S)((4-(cyclopentylamino)(6-(trifluoromethyl)pyridin-2 -yl)-1,3,5-triazin- 2—yl)amino)cyclopentanol |\ F N aIR < K NANAN‘VS)| I > H H 1HNMR (400 MHz, CD30D): 5863—857 (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 NZ-(3,3-difluorocyclopenljyl)—N’-(tetrahydrofuran-3—yl)—6-(6-(trifluoro methpryridin-Z—yD-1,3,5-triazine—2,4—diamine 1H NMR (400 MHz, CDgOD): 5 8.68-8.56 (m, 1H), 8.15 (t, J: 8.3 Hz, 1H), 7.93 (d, J: 7.5 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 ((3,3—difluorocyclopemjyl)amino)(6-(trifluoromethyl) pyridin-Z— yl)—1,3,5-triazin-2—yl)amino)pyrrolidine—1-carboxylate FQNHNHNJCMWF N / N H H 1H NMR (400 MHz, CDC13): 5 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 NZ-isobutyl-N4-(tetrahydro—ZH—pyran-4—yl)—6-(6-(trifluoromethyD-pyridin-Z—yD- 1,3, 5-triazine—2,4—diamine \ F "P" O YNANANH H 1HNMR (400 MHz, : 58.7-86 (m, 1H), 8.25-8.15 (m, 1H), 8.0-7.9 (m, 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—09 (m, 6H).
LC-MS: m/z 397.3 (M+H)+.
Compound NZ-((R)cyclopropylethyl)—N4-(1-(Z-methoxyethoxy)propan-2—yl)(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine |\ F «LN N/N o/ H H 1H NMR (400 MHz, CDC13) 5 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-(trifluoromethyl)pyridinyl)-1,3,5- triazin-Z-yl)amino)propanol "1 \ N VLNxN/AN)VOHH H 1H NMR (400 MHz, CDC13) 5 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 NZ-((R)cyclopropylethyl)—N4-(1-isopropoxypropan-Z-yD-6—(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine NI \N 1H NMR (400 MHz, CDC13) 5 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 NZ-((R)cyclopropylethyl)—N4-(4-methoxybutan-2—yl)—6—(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine flo/NH H 1H NMR (400MHz, CDC13)6 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 — O.83(m, 2H), 0.53 — 0.28 (m, 4H). LCMS: m/z 411(M+H)+.
Compound NZ-((R)cyclopropylethyl)—N4-(1-phenylpropan-2—yl)—6—(6— (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine WO 03640 1H NMR (400 MHz, CDC13) 5 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 NZ-((R)cyclopropylethyl)—N4-(1-morpholinopropan-2—yl)—6-(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine «LNANKNJVN¢N O 1H NMR (400MHz, CDC13)6 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), O.95(s, 1H), 0.54 — 0.26 (m, 4H). LCMS: m/z 452(M+H)+.
Compound Nz-((R)cyclopr0pylethyl)-N4-(1-(piperidinyl)propanyl)—6-(6- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine 1H NMR (400MHz, CDC13): 5 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), O.93(d,J=4Hz, 1H), 0.52 — 0.27 (m, 4H). LCMS: m/z 450(M+H)+.
Compound (R)—3—((4-((1-cyclopropylethyl)amino)(6-(trifluoromethpryridin-Z-yD-I,3,5- triazin-Z-yl)amino)-2,2-dimethylpropanamide WO 03640 %NJ\\NJ\N%NH2N/ IN H H 1H NMR (400MHz, CDC13)5 8.52 — 8.37 (m, 1H), 8.00 — 7.96(m, 1H), 7.87 — 7.75 (m, 1H),6.01- .22 (m, 2H), 4.26- 3.53(m, 3H), 2.32 — , 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)cyclopr0pylethyl)amin0)—6-(6-(triflu0r0methyl)pyridinyl)-1,3,5- triazin-Z-yl)amin0)butanenitrile «LNLNENMNH H 1H NMR (400MHz, CDC13)6 8.50 (d,J=7.6Hz, 1H), 8.03 — 7.99(m, 1H), 7. 80(d,J=7.6Hz, 1H), .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-((1-cyclopr0pylethyl)amino)(6-(trifluaromethpryridin-Z-yD-I,3,5- triazin-Z-yDamino)—2,2-dimethylpr0panenitrile WO 03640 1H NMR z, CDC13) 5 8.55(s, 1H), 8.11(s, 1H), 7.91 (d,J=8Hz, 1H), 3.73 — 3.62 (m, 4H), 1.47 — 1.42 (m, 7H), 1.37 — 1.35 (m, 3H), 0.75 — 0.69 (m, 1H), 0.58(m, 2H), 0.40 — 0.34 (m, 2H).
LCMS: m/z 406(M+H)+.
Compound 1-((4-((3,3-Difluorocyclopentyl)amino)—6-(6-(trifluoromethpryridin-Z-yl)-1,3,5- triazin-Z-yl)amino)methylpropan-2—ol Ffl WF NkaN/YH H OH 1H NMR (400 MHz, CDC13) 5 8.50 (s, 1H), 8.03 (d, J: 7.3 Hz, 1H), 7.80 (d, J: 7.4 Hz, 1H), .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 NZ-(3,3-difluorocyclopenwD-N'-(1-(4-fluorophenyDazetidinyl)—6-(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine \ F F81F NHNAMLNW" 1H NMR (400 MHz, CDC13) 5 10.05 — 8.37 (m, 1H), 8.31 — 7.54 (m, 2H), 7.60 — 6.68 (m, 4H), .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 NZ-(3,3-difluorocyclopenljyl)—N4-(1-@yridin-Z-yDazetidinyD(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine \ F F81" ~\ F WNAML 1H NMR (400 MHz, CDC13) 5 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 NZ-(3,3-difluorocyclopenwD-M-(1-@yridin-3—yDazetidin-3—yD(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine |\ F /N N F8113" ~\ F "kW/L 1H NMR (400MHz, CDC13): 5 8.50 Hz, 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 3.89 — 3.78 (m, 2H), 2.62 — 2.57 (m, 1H), 2.30 — 2.11 (m, 5H).LCMS: , 2H), m/z 493(M+H)+.
Compound N2-(3,3-difluorocyclopeng2l)-N4-((1r,3r)(4-fluorophenyDcyclobulij(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine |\ F /N F Ffl N/IN F N \NAN" H H 2014/081957 1H NMR (400 MHz, CDC13) 5 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 N2-(3,3-difluorocyclopen020-N4-((1s,3s)(4-fluorophenyl)cyclobuljyl)—6-(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine 1H NMR (400 MHz, CDC13) 5 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—phenylcyclobuljyl)—6—(6— (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine 1H NMR (400 MHz, CDC13) 5 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-difluorocyclopenlij-N4-(1-methylpyrrolidin-3—yl)—6—(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine '30 N \N F Jlx A E \ H N H 1H NMR (400 MHz, CDC13) 5 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)+. nd (3-((4-((3,3-Difluorocyclopentyl)amino)—6—(6—(t‘rifluoromethpryridin-Z—yl)-1,3,5- triazin-Z—yl)amino)pyrrolidinyl)@henybmethanone 1H NMR (400 MHz, CDC13) 8 8.76 — 8.35 (m, 1H), 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 NZ-(I-benzylpyrrolidin-3—yl)—]\fl-(3,3-difluorocyclopengzl)(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine 1H NMR (400 MHz, CDC13) 5: 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-((3,3-difluorocyclopentyl)amino)(6-(trifluoromethpryridin-Z—yl)- 1,3, 5-triazin-2—yl)amino)@yridinyl)pyrrolidin-2—one \ F Ffl N/ I" 5N N‘ F \N @ H H 1H NMR (400 MHz, CDC13) 6 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 NZ-(3,3-difluorocyclopenljyl)—N4-(3-phenylcyclopenwD(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine ||:>O\NJ\\NJ\NJ3N©N/ N 1H 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), , 3H). LCMS: m/z 505(M+H)+.
Compound NZ-(3,3-difluorocyclopenljyl)—N4-(2,3-dihydro-1H-inden-Z-yD-6—(6— (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine F>CLW1MF N/ N /@ 1H NMR (400MHz, CDC13): 5 8.64 — 8.46 (m, 1H), 8.01 (d,J=12.8Hz, 1H), 7.78 (d, J=7.6Hz, 1H), 7.21(m, 3H), 5.76 — 5.31 (m, 2H), 5.02 — 4.44 (m, 2H), 3.45 — 3.36 (m, 2H), 2.97 — 2.91 (m, 2H), 2.68 — 2.58(m, 1H), 2.31 — 2.09 (m, 4H), 1.85 — 1.84 (m, 1H), 1.25(m, 1H). LCMS: m/z H)+.
Compound NZ-(5—chloro-2,3-dihydro—1H—inden-Z—yD-N4-(3,3-difluorocyclopenljyl)—6-(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine FF>O\NJ\\NJ\N N @CI H H 1H NMR (400 MHz,CDC13) 8 8.57 — 8.48 (m, 1H),8.01 (d, J: 8 Hz, 1H), 7.81 (d, J: 8 Hz,1H), 7.26 — 7.18 (m, 3H), 6.02 — 5.36 (m, 2H), 5.05 — 4.43(m, 2H), 3.48 — 3.32 (m, 2H), 3.04 — 2.87 (m, 2H), 2.70 — 2.58 (m, 1H), 2.36 — 2.10 (m, 4H), 1.99 — 1.82 (m, MS: m/z 511 (M+H)+.
Compound NZ-(3,3-difluorocyclopemjyl)—N4-(5—fluoro-2,3-dihydro-1H—inden-Z-yD-6—(6— (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine 1H NMR (400MHz, 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 NZ-(5-bromo-2,3-dihydro-1H-inden-Z-yD-N4-(3,3—difluorocyclopenljyl)—6-(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine F>CLN)\\NJ\NI H H 1H NMR (400 MHz, CDC13) 8 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-(trifluoromethpryridin-Z-yl)-1,3,5- triazin-Z—yDamino)—2,3—dihydro-1H-indenecarbonitrile NJ\\NJ\N N @CN H H 1H NMR (400 MHz, CDC13) 5 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 NZ-(3,3-difluorocyclopenljyl)—N4-(5—methoxy-2,3-dihydro—1H-inden-Z-yD-6—(6— (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine 2014/081957 F NJ\\NJ\N H H 1H NMR (400 MHz, CDC13) 5 8.69 = 8 Hz, 1H), 7.79 — 8.46 (m, 1H),8.00(d, J — 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 NZ-(3,3-difluorocyclopengzD-N4-(6, 7-dihydro-5H-cyclopentalbjpyridinyl)(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine Ffl 1/1 \ 1 N \N N 1H NMR (400 MHz, CDC13) 5: 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 NZ-(4,6-dibromo-2,3-dihydro—1H-inden-Z—yD-N4-(3,3-difluorocyclopenljyl)—6-(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine Ffl MkF N/ N Br 1H NMR (400 MHz, CDC13) 5 8.55 — 8.46 (m, 1H), 8.07 — 7.99 (m, 1H), 7.80(d, J: 8 Hz,1H), 7.51 — 7.44 (m, 2H), 7.09 — 7.04 (m, 2H), 6.03 — 5.38 (m, 2H), 5.03 — 4.43 (m, 2H), 3.48 — 3.25 (m, 2H), 3.06 — 2.88 (m, 2H), 2.69 — 2.58 (m, 1H), 2.31— 2.29 (d, J: 8 Hz, 2H) ,2.17 — 2.01 (m, 2H), 1.90 — 1.77 (m, 1H).LCMS: m/z 635(M+H)+.
Compound N2-(3,3-difluorocyclopenlij-N4-(1-phenylpyrrolidin-3—yl)—6—(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine |\ F gal/JED 3F N\N N H H 1H NMR (400 MHz, CDC13) 5 .49 (m, 1H), 8.04-7.98 (m, 1H), 7.80-7.78 (m, 1H), 7.27— 7.23 (m, 2H), .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 N2-(3,3-difluorocyclopenlij-N4-(1-@yridinyl)pyrrolidin-3—yl)—6—(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine $03,041:) 1H NMR (400 MHz, CDC13) 5 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, 1H), 6.59 (t, J: 5.9 Hz, 1H), 6.39 (d, J: 8.1 Hz, 1H), .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-difluorocyclopenlij-N4-(1-@yrinzidin-Z-ybpyrrolidinyl)(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine \ F Ffl "P" QF "XNA" #1}N5 1H NMR (400 MHz, CDC13) 5 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)+. nd N2-(3,3-difluorocyclopengzD-N4-(6,6-difluorospiro[3.3]heptanyl)—6—(6— (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine |\ F F>QJNLUBLDQLFF N N/N H H 1H NMR (400 MHz, CDC13) 8 8.66 — 8.39 (m, 1H), 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 1-((4-((4,4-DifluorocyclohexyDamino)—6—(6-(trifluoromethpryridin-Z—yD-I,3,5- triazin-Z-yl)amino)methylpropan-2—ol \ F PU "/ I" NHNANAKOHH H 1H NMR (400 MHz, DMSO-d6) 5 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)+. nd NZ-(4,4-difluorocyclohexyD-M—(tetrahydro—ZH-pyran-4—yl)—6-(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine 1:1 F flux/N103 1H NMR (400 MHz, CDC13) 5 8.55 — 8.48 (m, 1H), 8.05 — 7.99 (m, 1H), 7.80 (d, J: 7.6 Hz, 1H), .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)+. nd Tert-buljyl 4-((4-((4,4-difluorocyclohexyl)amino)(6-(trifluoromethyl)pyridin yl)—1,3,5-triazinyl)amino)piperidine—1-carboxylate \ F FA[ ] N/IN O’BOC N/KNxHH 1H NMR (400 MHz, CDC13) 5 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 1-(4—((4-((4,4-Difluorocyclohexyl)amino)(6-(trifluoromethpryridin-Z-yD-I,3,5- triazin-Z—yl)amino)piperidinyl)ethanone \ E F 11 FfiHMHO 1H NMR (400 MHz, CDC13) 5 8.54 — 8.48 (m, 1H), 8.06 — 7.97 (m, 1H), 7.81 (d, J: 7.2 Hz, 1H), .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 N2-(4,4—difluorocyclohexyD-N4-(1-(methylsulfonyl)piperidin-4—yl)—6—(6— (trifluoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine |\ F F \‘/ FfiNxx)?»/ N N/§\ 1H NMR (400 MHz, CDC13) 5 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 NZ-(4,4-difluorocyclohexyD-M—(6,6-difluorospirol3.3]heptanyl)—6—(6— uoromethpryridin-Z-yl)-1,3,5-triazine—2,4—diamine |\ F PU "1‘" HFNAN/AN H H 1H NMR (400 MHz, CDC13) 8 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-difluorocyclobulij-N4-(4,4-difluorocyclohexyD-6—(6— (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine 1H NMR (400MHz, CDC13)5 8.54 — 8.48 (m, 1H), 8.02 (d, J=8Hz, 1H), 7.81 (d, J=4Hz, 1H), .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-difluorocyclohexyD-M—(3,3-difluorocyclopen020(6- (trifluoromethpryridin-Z-yl)-1,3,5-triazine-2,4—diamine |\ F Ff) "myNXNKN F H H 1H NMR (400MHz, CDC13)5 8.48 — , 1H), , J=4Hz, 1H), 7.80(d, J=4Hz, 1H), 5.63 — .13(m, 2H), 4.72 — 3.97 (m, 2H), 2.62(m, 1H), 2.31(m, 2H), 2.14 — 1.86 (m, 9H), , 2H).
LCMS: m/z 479(M+H)+.
Compound (R)(6-chloropyridin-Z—yD-NZ-(1,1,1,3,3,3-hexafluoropropan-Z-yD-N4-(1,1,1- trifluoropropan-Z—yl)—1,3, 5-triazine-2,4-diamine N / IN CF3 F3C (R) "*NANACF3 1H NMR (400 MHz, CDC13) 5840—834 (m, 1H), 7.87 — 7.84 (m, 1H), 7.53 (d, J = 8 Hz, 1H), — 6.15-5.83 (m, 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-chloropyridin-Z—yD-NZ-(4,4-diflu0rocyclohexVD-N4-(1,1,1- trifluoropropan-Z—yl)—1,3, 5-triazine—2,4-diamine F3C7IgMJLNAMN \N E 3LF 1H NMR (400 MHz, DMSO-d6) 5 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 ing targets were prepared by the procedure described in Scheme 2 above.
LCMS Compound Name Structure Expected Found MW (M+1)+ 1-(4-((R) cyclopropylethylamin 0)(6- (trifluoromethpryrid in-Z-yl) -triazin- 2-ylamin0)pr0pan-2— 1-(4-(1 - cyclopropylethylamin 0)(6- (trifluoromethpryrid l) -1,3,5-triazin- 2-ylamin0)—2— methylpropan-Z-ol (R)-N2-(1- cyclopropylethyD-N4- @yridin-Z—ylmethyb- 6-(6-(triflu0r0 methpryridin-Z-yb- 1,3,5-triazine—2,4— diamine N -((R) cyclopropylethyD-N4- (1-@yridin-2— yDethyD(6- (trifluoro yridin-Z-yb- 1,3,5-triazine—2,4— diamine NZ-cyclohexyl-N4- isopropyl—6—phenyl— 1,3,5-triazine—2,4— NZ-isopropyl phenyl-N4- (tetrahydro—ZH- pyranyl)—1,3,5— triazine—2,4 -diamine Example 3 ation of Di—aliphatic Triazine Compounds of a F. The compounds of this Example are prepared by general Scheme 3, set forth below.
Scheme 3 (A) CI R1 CI NJ§N R2 NH2 R4-B(OH)2 N2\N NAN )L / R R5R4 R1R 11 R5R4 R1R 6 Js L J< 3 6i Js J\ J< 3 CI N CI R N N N THF R2 R N N N R2 H H H H 9 10 Formula F Step 1: Preparation 0f6—chlor0-N2,N4-bis((R)cyclopr0pylethyl)—1,3,5-triazine—2,4—diamine.
To a mixture of 2,4,6-trichloro-1,3,5-triazine (2g, 10.9 mmol, 1 eq) and (R) 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 trated under reduced pressure. The residue was purified by a standard method to afford the desired product.
(R) )\NA| (R) N N\" H H LC-MS: m/z 282.1 (M+H)+.
Step 2: Preparation of N2,N4-bis((R)cyclopr0pylethyl)@yridinyl)— 1,3,5-triazine—2,4— e.To a mixture of 6-chloro-N2,N4-bis((R)-l-cyclo lethyl)-l,3,5-triazine-2,4-diamine (100 mg, 0.36 mmol), pyridinylboronic 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 NaZSO4 and concentrated. The residue was purified by a standard method to give the desired product.
VLWNKHWN ; 1H NMR (400 MHz, DMSO-d6): 5 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 ng materials.
Compound6—(3-chlor0phenyl)—N2,N4-bis((R)cyclopr0pylethyl)—1,3,5-triazine -2,4-diamine «(SWWN E 1H NMR (400 MHz, DMSO-d6):6 8.30 — 8.14 (m, 2H), 7.58 (d, J: 7.7 Hz, 1H), 7.52 (t, J: 7.8 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, 6H), 1.02 — 0.92 (m, 2H), 0.49 — 0.30 (m, 6H), 0.26 — 0.11 (m, 2H).LC-MS: m/z 358.2 (M+H)+.
Compound3—(4,6—bis((R)cyclopr0pylethylamin0)—1,3,5-triazin-2—yl)phenol (R) )L A (R) H H 1H NMR (400 MHz, CDC13): 5 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.
LCMS Compound Structure N2,N4-bis((R) ropylethyD @yridin-3—yl)—1,3,5— triazine—2,4- diamine , -bis((R) ropylethyD (2—flu0r0-5— methoxyphenyD- 1,3, 5-triazine—2,4- diamine 6-(2-chlor0phenyl)- N2,N4-bis ((R)_1- ropylethyb- 1,3,5—triazine -2,4— diamine 6-(2-flu0r0phenyl)- N2,N4-bis - cyclopropylethyb- 1,3,5—triazine -2,4— diamine (3-(4, 6-bis((R)—1- cyclopropylethylamin 0)—1,3,5-triazin prhenyl) methanol N2,N4-bis(1- cyclopropylethyD (1H-indolyl)-1,3,5- triazine—2,4- diamine N2,N4-bis((R) cyclopropylethyD (1H-indolyl)-1,3,5- triazine—2,4- diamine Example 4 Preparation of Di—aliphatic ne Compounds of Formula G. The compounds of this Example are prepared by general Scheme 4, set forth below.
Scheme 4 F F F F F F \ F \ F \ I F CF COOH | | ’N 3—, IN ’N Et3N,DCM X1 V N J: F N’ N F F A A We N N N 90 A L ENH Ffl A L ,CwN" N N N N N N N H H H H H H 12 13 FormulaG Step 1. Preparation of NZ-(3,3-diflu0r0cyclopentyl)—N4-0)yrr0lidinyl)(6- (trifluoro yridin-Z-yD-I,3,5-triazine-2,4—diamine. To a solution of utyl 3-(4-(3,3- rocyclopentylamino)(6-(trifluoromethy1)pyridiny1)-1 ,3 ,5 -triazin ylamino)pyrrolidinecarboxy1ate (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 NaZSO4 and then concentrated to afford the desired product which was used in the next step without any further purification.
|\ F N1F N/N NAxNAN. 0H H H LC-MS: m/z 430.2 (M+H)+.
Step 2. Preparation ofNZ-(3,3-diflu0r0cyclopentvl)—N4-(1-(methylsulf0nyl)pyrroli -dinyl) (6-(triflu0r0methyl)pyridin-2—yl)—1,3,5-triazine-2,4—diamine. A mixture of 3- difluorocyclopentyl)-N4-(pyrrolidiny1)(6-(trif1uoromethy1) pyridinyl)-1,3,5-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.
|\ F Ffl 2 O ~ I N\S:O H H 1H NMR (400 MHz,CDC13):5 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 , 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 ndsusing the appropriate starting material.
Coumpound methyl 3-((4-((3,3-diflu0r0cyclopentyl)amin0)(6-(trifluoro methpryridin-Z— yl)-1,3,5-triazin-2—yl)amin0)pyrrolidinecarb0x;ylate.
BO N/ N J3 O NJ\\NJ\NI N F fi\ H H 1H NMR (400 MHz, CDC13): 5 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, -MS: m/z 488.2 (M+H)+.
Compoundl-(3-((4-((3,3-diflu0r0qyclopemjyl)amin0)—6-(6—(triflu0r0methyl)pyridin yl)-1,3,5- triazin-Z—yl)amin0)pyrrolidinyl)ethan0ne :81 1’1 of\ 1H NMR (400 MHz, CDC13): 5 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 3-diflu0r0cyclopen920-ZW-(1-methylpyrrolidinyl) (6- (trifluoromethybpyridin-Z-yl)-1,3,5-triazine—2,4—diamine.To a solution of tert-butyl 3-(4-(3,3- difluorocyclopentylamino)(6-(trifluoromethyl)pyridinyl)-1 ,3 ,5 -triazin 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 O°Cfor 2hr, then at r.t for 30 min, and finally at 60 °C for 2hr. The on mixture was quenched with water and extracted by EtOAc.
Combined organic layers were washed with brine, dried over anhydrous NaZSO4, and concentrated. The residue was purified by a rd method to give the desired product.
F81F N/ N NkNAN. 13 \ H H 1H NMR (400 MHz, CDC13): 6 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 Pd2(dba)3,,B|NAP N / IN _ E NaOBut, toluene,100 00 N / N 5 N N "W N N "W H H H H CI \ | | / N 2 MeOH N/ N/ N : VN g V/LNkaN/W|H H H H Step 1: Preparation of 6-(6-(azetidinyl)pyridin-2—yl)—N2,N4-bis((R)cycl0pr0pyl -ethyl) - 1,3, 5-triazine—2,4-diamine. A mixture of 6-(6-chloropyridinyl)—N2,N4-bis((R)-1 - cyclopropylethyl) -1,3,5-triazine-2,4-diamine (40 mg, 0.11 mmol), azetidine (7.6 mg, 0.13 mmol), 2,2'-bis-(diphenylphosphino)-1,1'-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 d at 100°C under an here of nitrogen ovemight. The mixture was cooled to room temperature and filteredThe filtrate was concentrated under reduced pressureand the residue was purified by a standard method to afford the desired product. 1H NMR (400 MHz, CD30D): 5 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 bis((R)cyclopr0pylethyl)—6-@yridin-2—yl)—1,3,5-triazine—2,4— diamine. To a solution of 6-(6-chloropyridinyl)—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 d at room ature 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. #0"kaN E 1H NMR (400 MHz, DMSO-d6): 5 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 .
Example 6 Preparation of Di-aliphatic Triazine Compounds of Formula H.The compounds of this Example are prepared by general Scheme 6, set forth below.
Scheme 6 F/E \j F BBI’3 Refit" U E; —> MM 18 FormulaH Step 1: Preparationof 2—((4-(2—flu0r0-5—hydr0xyphenyl)—6-(is0pr0pylamin0)—1, 3,5—triazin-2— yl)amin0)methylpr0panenitrile.To a solution of 2-((4-(2-fluoromethoxyphenyl) (isopropylamino)-l,3,5-triazinyl)amino)methylpropanenitrile (200 mg, 0.6 mmol) in anhydrous DCM (3 mL) at -65°C was added dropwise BBr3 (0.6 mL) and the on 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 ature 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 NaZSO4 and concentrated under reduced pressure. Theresidue was purified by a standard method to afford the desired product.
ANANANN \N| J Example 7Preparation ofDi—aliphatic Pyrimidine Compounds of a J.The compounds of this Example are prepared by general Scheme 7, set forth below.
Scheme 7 RA ii pl \A] \/\ NaOMe | 7 EtO OEt / N | PCI5, POCI3 / N 21 NH Cl \ 4 N N 80°C-110°C CN NaOEt, EtOH HN NH2 HOMOH 19 20 22 RA RA RA N|\N 2R1 N \N 2R1 N \N R4 CIMCI 5 R39\NJI\/\CIR RR3g\NJ\%\NJ HN NH2 LC-MS: m/z 190.1 (M+H)+.
Step 2: Preparation 0f2-(6-(triflu0r0methyl)pyridinyl)pyrimidine—4,6-diol. To a on of sodium (3 66 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 ed pH to 7 by l 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 trated under reduced pressure to give the desired product which was used directly in the next step without any further purification.
LC-MS: m/z 256.0 (M-H)'.
Step 3: Preparation 0f4,6-dichlor0-2—(6—(trifluoromethpryridinyl)pyrimidine. A solution of 2-(6-(trifluoromethyl)pyridinyl)pyrimidine-4,6-diol (l g, 3.9 mmol) in POC13 (6 mL) was stirred at 90°C ght and then concentrated to remove the volatile. The residue was purified by a standard method to afford the desired product.
LC-MS: m/z 294.0 (M+H)+.
Step 4: Preparation 6-chlor0-N-(1-cyclopr0pylethyl)—2—(6—(trifluoromethyl) -pyridin pryrimidin-4—amine. To a solution of 4,6-dichloro(6-(trifluoromethyl) pyridin 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 Et3N (0.07 mL, 0.54 mol, 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.
\ F N/ IN (R) NMCI LC-MS: m/z 343.1 (M+H)+.
Step 5 .° Preparation 0fN4,N6-bis((R)cyclopr0pylethyl)—2—(6—(t‘rifluoromethybpyri din pryrimidine—4,6—diamine.To a on of (R)chloro-N—(l-cyclopro pylethyl)(6- (trifluoromethyl) -pyridinyl)pyrimidinamine (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 ave 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 n EtOAc and water. The organic layer was washed with water and brine, dried over anhydrous , and concentrated. The residue was purified by a standard method to give the desired product.
N/ N : (R) MMNW 1H NMR (400 MHz, CDC13): 5 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 .
The procedure set forth above was used to produce the following compounds using the appropriate starting materials.
ConzpoundN4,N6-bis((S)cyclopr0pylethyl)(6—(trifluaromethpryridin-Z-yl) pyrimidine- 4, 6-diamine /| F : N/N | 1H NMR (400 MHz, : 5 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)+.
CompoundN’-((R)—1-cyclopr0pylethyl)—N6-((S)cyclopr0pylethyl)—2—(6—(trifluoro methyDpyridin-Z-yDpyrimidine—4,6-diamine N/ IN 1H NMR (400 MHz, CDC13): 5 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.
LCMS Compound Name Structure Expected Found MW (M+1)+ N4,N6-bis( cyclopropylethyD-Z- (trifluoromethpryrid in-Z-yl) dine- 4, 6-diamine Example 9. Preparation of Symmetric Di-aliphatic Triazine Compounds of Formula K.
The compounds of this Example are prepared by l Scheme 9, set forth below.
Scheme9 F o o o F F / 00 d f Pd OA) / / H NJLNJLNH DAST ' pp' ( C2 I I | 2_H_2, \ N DCM \ N \ N TEA, CH30H,6000 Na’EtOHygooc Br Br 0 O/ F 1 F F F RZR NH2 | \ /N PCI5 POCI3 I HN \N 100°C N \N 2 0 fl 0 CIANXCI AMER FormulaK Step 1: Preparation 0f2-br0m0(1,1-diflu0r0ethyl)pyridine.
To a solution of 1-(6-bromopyridinyl)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 (3 00 g) and extracted with DCM (2 x 50 mL). The ed organic layers were washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by standard methods to afford o(1,1- difluoroethyl)pyridine.LC-MS: m/z 222.0 (M+H)+.
Step 2.°Preparati0n ofmethyl 6-(1,1-diflu0r0ethyl)picolinate.
To a solution of 2-bromo(1,1-difluoroethyl)pyridine (30.2 g, 136 mmol) in MeOH (300 mL) were added 1,1’-bis(diphenylphosphino)-ferrocene (7.5 g, 13.6 mmol), triethylamine (28.4 mL, 204 mmol), and Pd(OAc)2(1.52 g, 6.7 mmol).The mixture was stirred at 60°C under CO atmosphere (60 psi) for 16 hr. The resulting mixture was filtered and concentrated under reduced pressure. The e was purified bystandard methods to afford methyl 6-(1,1-difluoroethyl) picolinate.LC-MS: m/z 202.2 (M+H)+.
Step 3: Preparation 0f6-(6-(1,1-diflu0r0ethyl)pyridinyl)-1,3,5-triazine-2,4(1H,3H)-di0ne. To a solution of NaOEt in EtOH ly prepared from sodium (1.9 g, 82.6 mmol and EtOH (150 mL)) was added methyl 6-(1,1-difluoroethyl)picolinate(2.8 g, 28 mmol) and biuret(14.0 g, 70 mmol). The mixture was stirred at 90°C for 16 hr and concentrated under reduced pressure. To the residue was added water (50 mL). The ing mixture was adjusted the pH to 7 with 1N HCl, and then filtered. The filter cake was washed with water, and dried under high vacuum to afford 1,1-difluoroethyl)pyridinyl)-1,3,5-triazine-2,4(1H,3H)-dione.LC-MS: m/z 255.1 Step 4: Preparation 0f2,4-dichlor0—6—(6—(1,1-diflu0r0ethyl)pyridin-2—yl)—1,3,5-triazine.
To a solution of6-(6-(1,1-difluoroethyl)pyridinyl)-1,3,5-triazine-2,4(1H,3H)-dione (6 g, 25 mmol) in POC13 (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 WO 03640 afford chloro(6-(1,1-difluoroethyl)pyridinyl)—1,3,5-triazine. 1H N1VIR (400MHz, CDCl3) 5862 (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 ofN2,N4-bis(4,4-diflu0r0cycl0he3qyl)—6-(6-(1,1-diflu0r0ethyl) pyridin-Z-yD- 1,3,5-triazine—2,4—diamine To a mixture of 2,4-dichloro(6-(1,1-difluoroethyl)pyridinyl)- 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 mol, 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.
F F Ff) M OFN N/ N H H 1H NMR (400 MHz, CDC13) 5 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 ng materials.
Compound N2,N4-bis(3,3-diflu0r0cyclopentyl)—6-(6-(1,1-difluor0ethyl)pyridinyl)—1,3,5- triazine-2,4-diamine FFtLN'WJjFF NANAN H H WO 03640 1H NMR (400 MHz, CDC13) 5 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 N2,N4-bis(3,3-difluorocyclobutyl)—6-(6-(1,1-difluoroethyl)pyridinyl)-1,3,5- triazine-2,4-diamine F F F F N N N H H 1H NMR (400 MHz, CDC13) 5 8.3 5-8.42 (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 ric Di-aliphatic Triazine Compounds of Formula L.
The compounds of this Example are prepared by general Scheme 10, set forth below.
CI CI 1 \ \ R2R NH2 0 | | /N /N CI N biuret,EtONa,EtOH R3 o/ pool3 \ —> _> I 100°C / HC(OMe)3,TFA 11:1 )NL j:/\ o N 0 CI N CI 2R1 N\N R1 RRAMAN/AMXRSI R2 Formula L Step 1: Preparation of 6-(6-chloropyridin-Z-yD-1,3,5-triazine—2,4(1H,3H)-di0ne.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 e 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 2014/081957 addition of HC(OMe)3 (17 mL, 0.14 mol) and TFA (1.37 g, 0.01 mol). The reaction e (pale yellow slurry) was d at this temperature for 30 min, followed by dropwise addition of a solution of NaOEt in EtOH (20%wt, 163 g, 0.48 mol). The ing yellowish thick slurry was heated to reflux for 2hr until the reaction was complete. The mixture was cooled to r.t. and trated under reduced re. The residue was treated with water (200 mL) and concentrated under d 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 °C and slowly adjusted to pH 1 by 6N HCl. The resulting mixture was stirred for another 2 hr and filtered. The filter cake was washed with aq. HCl (pH=1), 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-chlor0pyridinyl)-1,3,5-triazine. The procedure is the same as Example 1 Step 3 described aboveLC-MS: m/z 260.9 .
Step 3 .' Preparation of 6-(6-chloropyridin-Z-yD-NZ,N4-bis((R)-1,1,1-triflu0r0pr0pan-2—yl)— 1,3,5-triazine-2,4-diamine. A mixture of 2,4-dichloro(6-chloro -pyridinyl)-1,3,5-triazine (0.27 g, 1.04 mol), (R)-1,1,1-trifluoropropanamine 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 product. 1H NMR (400 MHz, CDC13) 5 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 riate starting materials.
Compound 6-(6-Chlor0pyridinyl)—N2,N4-bis((S)—1,1,1-triflu0r0pr0panyl)—1,3,5- triazine-2,4-diamine F3C N \N N/\CF3 H H 1H NMR (400 MHz, CDC13)6 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)+. nd6-(6-Chlor0pyridinyl)-N2-((R)-1,1,1-triflu0r0propan-Z-yl)—N4-((S)-1,1,1- trifluoropropan-Z-yl)-1,3,5-triazine—2,4-diamine FsciNxNxNLCFsN| H H 1H NMR (400 MHz, CDC13) 5 8.41 — 8.23 (m, 1H), 7.83 (s, 1H), 7.51 (d, J: 6.2 Hz, 1H), 5.68 — .20 (m, 2H), 5.18 — 4.81 (m, 2H), 1.48 — 1.39 (m, 6H).LC-MS: m/z 415 (M+H)+.
C0mp0und6-(6-Chlor0pyridinyl)-N2,N4-bis(1,1,1-triflu0r0pr0panyl)—1,3,5-triazine- 2,4-diamine xNLCBN / N | H H 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, -MS: m/z 415 (M+H)+.
Compound6-(6-Chloropyridin-Z-yl)-N2,N4-bis(1,1,1-trifluorobutanyl)—1,3,5-triazine-2,4- diamine CF3 N/ N CF3 \ANAxNka/ H H 1H NMR (400 MHz, CDC13) 5 8.39 — 8.31 (m, 1H), 7.86 — 7.79 (m, 1H), 7.50 (d, J: 7.8 Hz, 1H), .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)+.
Comp0und6-(6-Chloropyridin-Z-yl)-N2,N4-bis((S)-1,1,1-triflu0r0butanyl)—1,3,5-triazine- 2,4-diamine CF3 N/ N 9:3 \/(§NJ\\NJ\N©\/I _ H H 1H NMR (400 MHz, CDC13) 5 8.30-8.35 (t, 1H), 7.78-7.82 (t, 1H), 7.47—7.52 (m, 1H), 5.49-5.63 (m, 2H), 4.72-4.89 (m, 2H), 1.95—1.99 (m, 2H), 1.59 (m, 2H), 1.02-1.08 (t, 6H).LC-MS: m/z 443 (M+H)+.
C0mpound6-(6-Chloropyridin-Z-yl)-N2,N4-bis((R)-1,1,1-trifluorobutanyl)-1,3,5-triazine- 2,4-diamine 9:3 N’ N CF3 WNkNANfig/I H H 1H NMR (400 MHz, CDC13) 5 8.31-8.35 (t, 1H), 7.78-7.82 (t, 1H), 7.47—7.49 (m, 1H), 5.16-5.71 (m, 2H), 4.72—4.74 (m, 2H), 1.94—2.01 (m, 2H), 1.62-1.64 (m, 2H), 1.02-1.08 (t, 6H).LC-MS: m/z 443 (M+H)+.
Compound6-(6-Chlor0pyridin-Z-yl)-N2-((R)-1,1,1-triflu0r0butan-Z-yl)—N4-((S)-1,1,1- trifluorobutan-Z-yl)-1 ,3,5-triazine-2,4-diamine CF3 N/ N CF3 \Jfimkamfvfi/I 1HNMR (400MHz, CDC13) 5830-835 (m, 1H), 7.81 (s, 1H), .49 (d, 1H), 5.35-5.66 (m, 2H), 4.91—5.13 (d, 1H), 4.72 (s, 1H), .23 (d, 3H), 1.31—1.42 (d, 1H), 1.03—1.07 (m, - MS: m/z 443 (M+H)+.
C0mp0und3,3'-((6-(6-Chlor0pyridinyl)—1 ,3,5-triazine-2,4- diyl)bis(azanediyl))dibutanenitrile /|C| NCJm/KNANk/CNIN H H 1H NMR (400 MHz, CDC13) 5 8.21 (s, 1H), 7.73 (t, J: 7.6 Hz, 1H), 7.41 (d, J: 7.8 Hz, 1H), .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 .
Comp0und6-(6-Chloropyridin-Z-yl)-N2,N4-bis(1-cyclopr0pylpr0pyl)-1 ,3,5-triazine-2,4- diamine 2848N/IN 1H NMR (400 MHz, CDC13) 5 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-Chlor0pyridinyl)—N2,N4-bis(dicyclopr0pylmethyl)—1,3,5-triazine-2,4- diamine WfiIN 1H NMR (400 MHz, CDC13) 5 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)+.
C0mp0und6-(6-Chlor0pyridinyl)-N2,N4-bis(4,4-diflu0r0cyclohexyl)—1,3,5-triazine-2,4- diamine /|C| F F Fill/EGFN\N N H H 1H NMR (400 MHz, CDC13) 5 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-Chlor0pyridinyl)-N2,N4-bis(3,3-difluorocyclopentyl)—1,3,5-triazine-2,4- diamine F>O\ N/ IN D Compound6-(6-Chlor0pyridinyl)-N2,N4-bis(2,2-difluorocyclopentyl)—1,3,5-triazine-2,4- $119164 1H NMR (400 MHz, CDC13) 5 8.48 — 8.26 (m, 1H), 7.82 (s, 1H), 7.49 (s, 1H), 5.63 (m, 2H), 4.70 (m, 2H), 2.41—2.08 (m, 6H), 1.83 (m, 4H), 1.66 (s, 2H). LCMS: m/z 431(M+H)+..
C0mp0und2,2'-((6-(6-Chlor0pyridinyl)—1 ,3,5-triazine-2,4- diyl)bis(azanediyl))dicyclopentanol cf"H H NAN/AN1 ‘1 H H 1H NMR (400 MHz, CDC13) 5 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)+.
C0mp0und6-(6-Chloropyridin-Z-yl)-N2,N4-bis(6,6-diflu0rospiro [3.3]heptanyl)—1,3,5- triazine-2,4-diamine /|C| Fflaffl F N\N N H H 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)+.
C0mp0und6-(4-Chloropyridin-Z-yl)-N2,N4-bis(4,4-diflu0r0cyclohexyl)—1,3,5-triazine-2,4- diamine F F PU "/fl UPNJ\\N N H H 1H NMR (400 MHz, CDC13) 5 8.68 (d, J = 8.0 Hz, 1H), 8.48 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), .28 (d, J: 8.0 Hz, 2H), .02 (m, 2H), 1.98-1.61 (m, 16H). LC-MS: m/z 459.1 (M+H)+.
Compound6-(5-Chlor0pyridinyl)-N2,N4-bis((R)cyclopr0pylethyl)—1,3,5-triazine-2,4- diamine VLMANAHWN : I E 1H NMR (400 MHz, CDC13) 5 9.36 (m, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.54 (t, J = 1.9 Hz, 1H), .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 9/0'\ MeO/©/\NH2 (E/NHPMB N N TFA,rr /N N N ; Pd2(dba)3,t-BuONa, NAN/*0 N N _ N N _ 100°C 44 4/4 H {W H N NW N N NW Step 1. ation of N2,N4-bis((R)cyclopr0pylethyl)—6—(6—((4-meth0xybenzyl) amino)pyridin-2—yl)—1,3,5-triazine—2,4—diamine. To a solution of 6-(6-chloropyridinyl)- bis((R)—l-cyclopropylethyl)—l,3,5-triazine-2,4-diamine (120 mg, 0.33 mmol), (4- methoxyphenyl)methanamine (69 mg, 0.51 mmol), BlNAP (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 ght then concentrated under reduced pressure to afford the desired product.
NHPMB WO 03640 2014/081957 LCMS: m/z 460 (M+H)+.
Step 2. Preparation of min0pyridin-2—yD-N2,N4-bis((R)cycl0pr0pyl ethyl)-1,3,5- triazine—2,4-diamine. N2,N4-bis((R)cyclopropylethyl)(6-(4-methoxybenzylamino) pyridin- 2-yl)-1,3,5-triazine-2,4-diamine (80 mg, 0.17 mmol) was dissolved in TFA (0.5 mL) under N2 atmosphere. The solution mixture was then stirred at r.t. overnight then concentrated under reduced pressure. The residue was purified by standard s to afford the desired product.
\ NH2 VLMAWWN \N : 1H NMR (400 MHz, CDC13) 5 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 OMe OH \ \ | | /N / N TMSCI/Nal 11? CHBCN, 80°C 11? Step 1. Preparation of 6-(4,6-bis((R)cyclopropylethylamin0)-1,3,5-triazinyDpyridin-Z-ol To a mixture of N2,N4-bis((R)cyclopropylethyl)(6-methoxypyridinyl)- 1,3,5-triazine- 2,4-diamine (50 mg, 0.14 mmol) and NaI (63 mg, 0.42 mmol) in anhydrous CH3CN (1 mL) at r.t. was added TMSCl (46 mg, 0.42 mmol) in one portion. The reaction mixture was d 80 °C for 6 hr then concentrated under reduced pressure. The residue was purified by standard methods to afford the desired product. 1H N1VIR (400 MHz, CDC13) 5 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 flB/O\B/\ \ 5 5 \ \ l \B/ I /N 2 / N NAN/VN \N s Pd(dppf)C|2 K2003 = dioxane/HZO H H VANJLNAN/VN \NH H Step 1. ation ofN2,N4-bis((R)cycl0pr0pylethyl)—6-(6-vinylpyridin-2—yl)— 1,3, 5-triazine— 2,4-diamine. To a suspension of 6-(6-chloropyridinyl)—N2,N4-bis ((R)cyclopropylethyl)— 1,3,5-triazine-2,4-diamine (200 mg, 0.56 mmol), 2,4,6-triVinyl-1,3,5,2,4,6-trioxatriborinane (135 mg, 0.84 mmol) and K2C03 (154 mg, 1.11 mmol) in dioxane (2 mL) and H20 (0.8 mL) under an atmosphere of N2 was added Pd(dppf)Clz (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 ted with EtOAc (20 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous Na2804, and concentrated under reduced pressure. The residue was ed by standard methods to afford the desired product. 1H N1VIR (400 MHz, CDC13) 5 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 nds of this Example are prepared by general Scheme 14, set forth below.
Scheme 14 I (1%ng \ F /N I 1)o3 DCM -78°C /N DAST DCM rt N \N V/LN E 2) Me 8 )L 2L 2 = - \N N NW ’HW V/LWN;' Step 1. Preparation of 6-(4,6-bis(((R)cyclopr0pylethyl)amin0)-1,3,5-triazin-2—yl) picolinaldehyde. Ozone was bubbled into a solution of N2, N4-bis((R)-l-cyclopropylethyl)(6- Vinylpyridinyl)-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, MeZS (0.2 mL) was added into the reaction mixture at 0 0C. The resulting mixture was concentrated and the residue was purified by standard methods to afford the d t. LCMS: m/z 353 (M+H)+.
Step 2. Preparation of N2,N4-bis((R)cyclopr0pylethyl)—6-(6-(diflu0r0methyl) pyridin-Z-yD- triazine—2,4—diamine. To a solution of 6-(4,6-bis((R)-l-cyclo propylethylamino)-l,3,5- triazinyl)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 NaZSO4, concentrated, and purified by standard s to afford the desired product. 1H NMR (400 MHz, CDClg) 5 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 e 14 was used to produce the following compounds using the appropriate starting als.
C0mp0undN2,N4-bis(4,4-diflu0r0cyclohexyl)—6-(6-(difluoromethyl)pyridinyl)—1,3,5- triazine-2,4-diamine 2014/081957 F F F0 fl GPN \N N H H 1H NMR (400 MHz, CDC13) 5 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)+.
C0mp0undN2,N4-bis(3,3-difluorocyclobutyl)—6-(6-(difluoromethyl)pyridinyl)-1 ,3,5- triazine-2,4-diamine |\ F F F F F N N N H H 1H NMR (400 MHz, CDC13) 5 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 \ / I \ O l \ OH /N /N I OAC)2 LiOH )NL \JN\ E N \N = = dppf/MeOH/60 c° l 3 N \N g / - H H H H M N MW \ CN | NH2 \ 1:oxaly| chloride POCls /N 2:NH3 N \ N g N\N = AA = JL/A Step 1: Preparation of methyl 6-(4,6-bis((R)cycl0pr0pylethylamin0)-1,3,5-triazin yl)picolinate. To a mixture of 6-(6-chloropyridinyl)-N2,N4-bis((R)cyclopropylethyl)-1,3,5- ne-2,4-diamine , 0.7mmol) in MeOH (1 OmL) were added dppf (80mg, 0.15mmol), Pd(OAc)2 (60mg, 0. 27 mmol) and Et3N (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 ated with EtOAc (100mL) and filtered. The filtrate was concentrated and purified by standard s to afford methyl 6-(4,6-bis((R)cyclopropylethylamino)-1,3,5- triazinyl)picolinate. 1H N1VIR (400 MHz, CDC13) 5 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 0f6—(4,6-bis(((R)cycl0pr0pylethyl)amin0)-1,3,5-triazinyl) picolinic acid. To a mixture of methyl 6-(4,6-bis((R)cyclopropylethylamino)-1,3,5-triazin 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 NaZSO4, and trated under d pressure to give the desired productLCMS: m/z 367 (M-H)'.
Step 3: Preparation of 6-(4,6-bis((R)cyclopr0pylethylamin0)-1,3,5-triazin-2—yl)picolinamide.
To an ice cold mixture of 6-(4,6-bis(((R)-l-cyclopropylethyl)amino)-l,3,5-triazinyl)picolinic acid , 0.32mmol) in dry DCM(5.0mL) and DMF(O.1mL) 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 e wasstirred for 10min at 00C, and then concentrated and purified by standard methods to give 6-(4,6-bis((R)—1-cyclopropylethylamino)- 1,3,5-triazin yl)picolinamide. 1H NMR (400 MHz, CDC13) 5 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)cyclopr0pylethylamin0)-1,3,5-triazin-2— pricolinonitrile. To a mixture of 6-(4,6-bis((R)-l-cyclopropylethylamino)-l,3,5-triazin yl)picolinamide(36mg, 0.1mmol) in dry pyridine(3.0mL) was added phosphorous trichloride (0.1mL). The reaction mixture was d at r.t. for 2 hr then concentrated under reduced re. The residue was purified by standard s to give 6-(4,6-bis((R) cyclopropylethylamino)-l,3,5-triazinyl)picolinonitrile. 1H Nl\/[R (400 MHz, CDCl3) 5 8.50- 8.48 (m, 1H), 8.24-8.22 (t, 1H), .71 (dd, 1H), 5.46-5.14 (m, 2H), 3.62-3.50 (m, 2H), 1.22- 1.18 (m, 6H), 0.89-0.84 (m, 2H), 0.46-0.20 . LCMS: m/z 350(M+H)+.
Example 16 The compounds of this Example are prepared by general Scheme 16, set forth below.
Scheme16 F F \ FNH2NH2 H Br2/CHCI3 F \ comm/«ob I |\ / ’NH2 I 6000 / 0 F N COMe F N F F N N F N Brdppf/MeOH/SO c 2 F F F F NH NH F | JL JK /N MeONa MeOH F131 M SF N N/ N H H Step 1: Preparation of 3,6-difluoro-Z-hydrazinyllwridine. 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 NaZSO4 and concentrated under reduced pressure to afford 3,6-difluorohydrazinylpyridine.LC-MS (m/z): 146 (M+H)+.
Step 2: Preparation of 2—br0m0-3,6-diflu0r0pyridine. To a stirred on of 3,6-difluoro hydrazinylpyridine(1.1 g, 7.0 mmol) in chloroform (20 mL) at r.t. was added dropwise bromine (1.8 g, 11.2 mmol). The on 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 and concentrated and purified by rd methods to afford 2-bromo-3,6-difluoropyridine. LC-MS: m/z 194 (M+H)+.
Step 3.°Preparati0n ofmethyl 3, 6-diflu0r0pic0linate. 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 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 e was triturated with EtOAc (150 mL) and filtered. The filtrate was concentrated and purified by rd s to afford methyl 3,6-difluoropicolinate.LC-MS: m/z 174 (M+H)+.
Step 4.°Preparati0n of N2,N4-bis(4,4-diflu0r0cycl0hexyl)—6-(3, 6-diflu0r0pyridinyl)-1,3,5- triazine-2,4-diamine. To a suspension of N1,NS-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 on mixture was stirred at r.t. overnight, then poured into water, and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2804, and concentrated under reduced re. The residue was purified by standard methods to afford N2, N4-bis (4,4-difluorocyclohexyl)(3,6-difluoropyridinyl)—1,3,5-triazine-2,4- diamine. 1H NMR (400 MHz, CDC13) 5 7.67-7.61 (m, 1H), 7.07—7.03 (m, 1H), 546-5. 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 |\ |\ N‘NH2 NH2 F F NH2—NH2 F F Raney Ni F F Ff) "P" fiFflFU "Pi 1NANAN NAN/ "P" If N NANAN H H H H H H Step 1: Preparation of N2,N4-bis(4,4-diflu0rocycl0hexyl)(3-fluorohydrazinylpyridin-2— yl)-1,3,5-triazine—2,4—diamine. To a on of N2,N4-bis(4,4-difluoro hexyl)(3,6- difluoropyridinyl)-l ,3,5-triazine-2,4-diamine (230 mg, 0.50 mmol) in THF(20 mL) was added hydrazine e(l50 mg, 3.0 mmol). The reaction e 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 NaZSO4, and concentrated under reduced pressure to give the desired product. LC-MS (m/z): 473.2 (M+H)+.
Step 2: Preparation of min0flu0r0pyridin-2—yl)-N2,N4-bis(4,4—diflu0rocycl0hexyl)- 1,3,5-triazine—2,4—diamine. To a solution of N2,N4-bis(4,4-difluoro -cyclohexyl)(3-fluoro hydrazinylpyridinyl)-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. 1H N1VIR (400 MHz, CDC13) 5 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 nds of this Example are prepared by general Scheme 18, set forth below.
Scheme 18 F \ F F HCI —’ FS©\ N \N F F{JIM/1N1}N \N F I G H H H H Step 1: Preparation of 6-(4,6-bis((4,4-diflu0r0cyclohexyl)amin0)—1,3,5-triazin- 5- fluoropyridin-Z-ol. A mixture of N2,N4-bis(4,4-difluorocyclohexyl)(3,6-difluoropyridin yl)-1,3,5-triazine-2,4-diamine (100 mg, 0.22 mmol) in conc. HCl (5.0 mL) was stirred at 100°C overnight. The resulting mixture was concentrated and purified by standard methods to afford the desired product. 1H N1VIR (400 MHz, CDC13) 5 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.
Scheme 19 NH2 —’ F F N N N 1600C H H H CH ONa \ [>—B(OH)2 \ CH30H I I N/ N F F a ,flN ,1er Pd(dPPf)Cl2 H H /\O /\ O 0 O toluene Step 1: Preparation of N1,N5-bis(3,3-difluorocyclopenWD-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 trated to afford the d product. LC-MS: m/z 310.2 (M+H)+.
Step 2: Preparation of ethyl 6-cycl0pr0pylpic0linate. To a mixture of ethyl 6-bromopicolinate (200 mg, 0.87 mmol) andcyclopropylboronic acid (149 mg, 1.74 mmol) in e (15 mL) were addedK3P04 (369 mg, 1.74 mmol) anddichloro(diphenylphosphinoferrocene)palladium (11 mg, 0.017 mmol). The ing e was stirred under N2 atmosphere at 1000C overnight, then cooled to r.t. and filteredThe filtrate was concentrated and purified by standard methodsto afford the desired product. LC-MS: m/z 192.1 (M+H)+.
Step 3: 6-(6—cycl0pr0pylpyridin-Z-yD-NZJW-bis(3,3-diflu0r0cycl0pen02l)—1,3,5-triazine—2,4— diamine. To a mixture of N1,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 on 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 ous NaZSO4,concentrated, and purified by standard methods to afford the desired product. 1H N1\/[R (400 MHz, CDC13) 58.43-833 (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), .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 ure set forth in Example 19 was used to produce the following compounds using the appropriate ng materials.
Compound 6-(6-Cyclopropylpyridin-Z-yl)—N2,N4-bis(4,4-difluorocyclohexyl)—1,3,5-triazine- 2,4-diamine F F F131 "P" GPNAN/AN H H 1H NMR (400 MHz, CDC13)5 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-methylpyridinyl)-1,3,5-triazine-2,4- diamine F0 1 1 OFN F N/ N H H 1H NMR z, 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 43 9(M+H)+.
Example 20 Preparation of Symmetric phatic Triazine Compounds of Formula M.
The compounds of this Example are prepared by general Scheme 20, set forth below.
Scheme 20 «HgF 0 _Z / F30 N\ CI co, dppf, TEA F30 N$0/ , EtONa, EtOH \[N/j/ MeOH,Pd(OAc)2, 70°C \[N/ HC(OMe)3, TFA HN o8110 NVFF R1 F R2 NH2 F iI F N R3 NI \ POCI3 EN J1]: R1 N \N R1 / RANANANXRsR2 | R2 CI N CI / H H FormulaM Step 1: Preparation of methyl 6-(trifluoromethpryrazine-Z-carboxylate. To a mixture of 2- chloro(trifluoromethy1)pyrazine (1 g,5.5 mol) in MeOH (5.5 mL) was added dppf (0.16 g, 0.29 mmol), )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 trated 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-Z-yl)-1,3,5-triazine-2,4(1H,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-(trifluoromethpryrazin-Z-yD-I,3,5—triazine. To a solution of 6-(6-(trifiuoromethyl)pyrazinyl)-1,3,5-triazine-2,4(1H,3H)-dione (2.8 g, 0.011 mol) in POC13 (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 e was concentrated and purified by standard methods to afford the desired product. LC-MS: m/z 296 (M+H)+.
Step 4: Preparation ofN2,N4-bis(4,4-difluorocyclohexyl)—6—(6-(trifluoromethyl) pyrazin-Z -yl)- 1,3,5-triazine-2,4-diamine.The procedure is the same as Example 1 Step 4. 1H NMR (400 MHz, CDC13) 5 9.73 (m, 1H), 9.07 (s, 1H), 5.49—5.15 (m, 2H), .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 ing compounds using the appropriate starting materials.
N2,N4-bis(3,3-diflu0rocyclopentyl)(6-(triflu0r0methyl)pyrazinyl)—1,3,5-triazine-2,4- diamine 1H NMR (400 MHz, CDC13) 5 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)+.
N2,N4-bis((R)-3,3-diflu0rocyclopentyl)(6-(triflu0r0methyl)pyrazin-Z-yl)—1,3,5-triazine- 2,4-diamine FAOQ?)F N \N NANANW| / "04FF H H 1H NMR (400 MHz, CDC13) 5 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), .13 (m, 6H).LC-MS: m/z 466 (M+H)+.
N2,N4-bis((S)—3,3-diflu01'0cyclopentyl)(6-(triflu0r0methyl)pyrazinyl)-1,3,5-triazine- 2,4-diamine F81 W INF 1,3) ANA F N N (S) H H 1H NMR (400 MHz, CDC13) 5 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)+.
Nz-((R)-3,3-difluorocyclopentyl)-N4-((S)-3,3-difluorocyclopentyl)—6-(6- (trifluoromethyl)pyrazinyl)—1,3,5-triazine-2,4—diamine F8: N \N (V (S) | F '""N J\N/)\N"‘?R)‘ F H H 1H NMR (400 MHz, CDC13) 5 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)+.
N2,N4-bis(3,3-diflu0rocyclobutyl)(6-(triflu0r0methyl)pyrazinyl)—1,3,5-triazine-2,4- diamine 1H NMR (400 MHz, CDC13) 5 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-(Triflu0r0methyl)pyrazin—2-yl)-N2,N4-bis((R)-1,1,1-triflu0r0pr0panyl)—1,3,5- ne-2,4-diamine 1L 1 ‘" F3C (R) NANANffi’}CF3 H H 1H NMR (400 MHz, CD30D) 6 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,N4-bis((S)-1,1,1-trifluorobutanyl)(6-(trifluoromethyl)pyrazinyl)-1,3,5-triazine- 2,4-diamine 'K/EN CF3 N/ N CF3 \/(~'9}N)\\NJ\N78)\/| H H 1HN1\/[R(4OOlVle,DMSO-d6) 969 (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 27'" ":ANTK co! dppf’ COOMe /CI C—MQ>MeM Br \ Pd(OAc)2 %\N NWD(Eh/IKE TEA/MeOH NW0 F ii i W6 "(K /N OCI3 DAST F>l\EN COOMe H2N N NH2 /N —> —H—> DCM \NJ/ H,90°C HN \N 100°C N \N OAfi/go CI IN/ CI R1 F Formula N Step 1: Preparation of 1-(6-chloropyrazin-Z—yDethanol. To a solution of methyl 6- formylpyrazine-Z-carboxy1ate (5 90 mg, 4.15 mmol) in anhydrous THF (5 mL) at -5°C was added dropwise CHgMgBr (2.1 mL, 6.2 mmol). The reaction mixture was stirred at r.t. for 1 hr, then quenched with satd. a.q. NH4Cl at 0°C and extracted with DCM (3 X 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaZSO4 and concentrated to afford the desired product.LC-MS: m/z 159.0 (M+H)+.
Step 2: Preparation of1-(6-chloropyrazin-Z-yl)ethanone. To a solution of 1-(6-chloropyrazin 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 d at r.t. for 3 hr then filtered. The filtrate was concentrated and purified by standard methods to afford the desired productlH N1V[R (400 MHz, CDC13) 5 9.12(s, 1H), 8.78(s, 1H), 2.72(s, 3H). LC-MS: m/z 157.1 (M+H)+.
Step 3: ation of methyl 6-acetylpyrazinecarboxylate. To a on of 1-(6- chloropyrazinyl)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 ed by standard methods to afford the desired product. LC-MS: m/z 181.0 (M+H)+.
Step 4: Preparation of methyl 6-(1,1-difluoroethyl)pyrazinecarboxylate. To a solution of methyl 6-acetylpyrazinecarboxylate(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 x1 0 mL). The combined organic layers were dried over anhydrous NaZSO4 and concentratedto afford the desired product. LC-MS: m/z 203.1 .
Step 5: ation of6—(6-(1,1-difluoroethpryrazin-Z-yD-I,3,5-triazine-2,4 (1H,3H)-dione.
The procedure is the same as Example 1 Step 2 described above.LC-MS: m/z 256.1 .
Step 6: Preparation of 2,4-dichloro-6—(6—(1,1-difluoroethyl)pyrazin-2—yl) -1,3,5-triazine. The ure is the same as Example 1 Step 3 described above. LC-MS: m/z 292.0 (M+H)+.
Step 7: Preparation osz,N4-bis(4,4—diflu0r0cyclohexyl)—6-(6-(1,1-diflu0r0ethyl) pyrazin-Z-yD- 1,3,5-triazine-2,4—diamine. The procedure is the same as Example 1 Step 4 described above. 1H NMR (400 MHz, CDClg) 5 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 e 21was used to produce the following compounds using the appropriate starting materials.
N2,N4-bis(3,3-diflu0r0cyclopentyl)(6-(1,1-diflu0roethyl)pyrazinyl)—1,3,5-triazine—2,4- diamine Rik/EN NAN"I ‘ N [yF F H H 1H NMR (400 MHz, CDC13) 6 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)+.
N2,N4-bis(3,3-diflu0r0cyclobutyl)—6-(6-(1,1-difluoroethyl)pyrazinyl)—1,3,5-triazine-2,4- diamine 2014/081957 1H NMR (400 MHz, CDC13) 5 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 0.
The compounds of this Example are ed by general Scheme 22, set forth below.
Scheme 22 mCPBA N N N N E l CICH2CH2CI E 1 SOCI2 i 1 NaBH4 i L / / / / OH N COOMe 50°C :51 COOMe CI N COOMe CI N N\ co,dppf, N _ N Dess Martln I l Pd(OAc)2 \ I DAST N/ l DCM CI CHO TEA / N DCM MeOO N MeOH Me02 F R1 F O O R2 NH2 )I\ )I\ VF NAfiF 3 NVF H2N \LI H N;|2 R POCI3 j EtONa/EtOH HN \N R2R 1 EN\ 1 A x N \N NI N R RAQXNAQXRE’R2 0 N O CIANACI FormulaO Step 1: Preparation of2—(methoxycarbonpryrazine 1-0xide. To a solution of methyl pyrazine- 2-carboxy1ate (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 ght. The resulting mixture was cooled to r.t. and filtered. The filtrate was dried over anhydrous K2C03and trated under reduced pressure. The residue was triturated with hexane and filtered and dried to afford hoxycarbony1)pyrazine l-oxideLC-MS: m/z 155.0 (M+H)+.
Step 2: Preparation of methyl 6-chloropyrazinecarboxylate. A mixture of 2- (methoxycarbonyl)pyrazine 1-oxide (4.8 g, 30 mmol) in SOClz (50 mL) was stirred at 85°C ght. The mixture was cooled to r.t. and concentrated under reduced pressureThe e was neutralized by satd.aq. NaHC03 and extracted with DCM (3 x 20 mL). The ed organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated and purified by standard methods to afford methyl 6-chloropyrazinecarboxylate.1H N1VIR (600 MHz, CDC13) 5 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 oropyrazin-Z-meethanol. To a solution of methyl 6- chloropyrazinecarboxylate (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 Na2SO4and concentrated and purified by standard methods to afford (6- chloropyrazinyl)methanol. LC-MS: m/z 145.0 (M+H)+.
Step4: Preparation of6-chloropyrazinecarbaldehyde. To a on of (6-chloropyrazin 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 d at r.t. for 3 hr, and then filtered. The filtrate was concentratedand purified by standard s to afford ropyrazine carbaldehyde.LC-MS: m/z 143.0 (M+H)+.
Step5: Preparation of methyl 6-formylpyrazine-Z-carboxylate. To a mixture of 6- chloropyrazinecarbaldehyde (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 ing mixture was cooled to r.t. and filtered. The filtrate was concentrated and purified by standard methods to afford methyl 6- formylpyrazinecarboxylate.LC-MS: m/z 167.0 (M+H)+.
Step6: ation ofmethyl 6-(difluoromethyl)pyrazinecarboxylate. To a mixture of methyl 6-formylpyrazinecarboxylate (4.1 g, 24.7 mmol) in ous 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 Na2804 and concentratedto afford the desired product. LC-MS: m/z 189.0 (M+H)+.
Step 7: Preparation of 6-(6-(difluoromethpryrazin-Z—yD-I,3,5-triazine-2,4(1H,3H)-dione. To a flame-dried three necked round bottom flask was added biuret (659 mg, 6.4 mmol) andmethyl 6- (difluoromethyl)pyrazinecarboxylate (1.0 g, 5.3 mmol), followed by addition of EtOH (12 mL). The mixture was ed and back-filled with Nzthree times. The mixture was stirred at °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 ature 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 re. The residue was treated with water (10 mL) and concentrated again to remove the remaining ethanol. The final residue was ded in water (30 mL), cooled to 10°C when the acidity was adjusted to pH=1 by slow addition of 6N HCl (solid precipitated out), and then stirred for 2hr. The mixture was filtered and the filter cake was washed withaq. HCl (pH=1). 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 chloro(6-(difluoromethpryrazin-Z-yD-I,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 ofNZ,N4-bis(4,4-difluorocyclohexyD(6-(difluoromethyl) pyrazin - 1,3,5-triazine-2,4-diamine. The procedure is the same as e 1 Step 4 described above. 1H NMR (400 MHz, CDC13) 5 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 nds using the appropriate starting materials.
N2,N4-bis(3,3-diflu01'0cyclopentyl)(6-(difluor0methyl)pyrazinyl)—1,3,5-triazine—2,4- diamine 1H NMR (400 MHz, CDC13) 5 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 N2,N4-bis(3,3-diflu0rocyclobutyl)(6-(difluor0methyl)pyrazinyl)—1,3,5-triazine-2,4- diamine F F Ffl N \" HF' A N N N H H 1H NMR (400 MHz, CDC13) 5 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,N4-bis(3,3-diflu0rocyclobutyl)(4-(difluor0methyl)pyrimidinyl)—1,3,5-triazine-2,4- diamine F I F F F H H 1H NMR (400 MHz, CDC13) 5 9.17 (d, J: 4.9 Hz, 1H), 7.77 (d, J: 4.9 Hz, 1H), 6.77 (m, 1H), .76 (m, 2H), 4.55 (m, 2H), 3.07 m, 4H), 2.61 (m, 4H).LC-MS: m/z420 (M+H)+.
N2,N4-bis(3,3-diflu0r0cyclopentyl)(4-(difluor0methyl)pyrimidinyl)—1,3,5-triazine-2,4- diamine 51| F N / N >CLNA ANDfiN F H H 1H NMR (400 MHz, DMSO-d6) 5 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)+. bis(4,4-diflu01'0cyclohexyl)(4-(diflu0r0methyl)pyrimidin-Z-yl)—1,3,5-triazine-2,4- diamine 2014/081957 N / N F I F0 JL A GPN F N \N N N H H 1H NMR (400 MHz, CDC13) 5(m, 1H),7.79-7.78 (m, 1H), 6.91-6.64 (m, 1H), 5.72—5.20 (m, 2H), 4.26-4.02 (m, 2H), 2.13—2.10 (m, 8H), 1.98-1.87 (m, 4H), 1.76-1.73 (m, 4H). LC-MS: m/z 476 (M+H)+.
Example 23 The nds of this Example are prepared by general Scheme 23, set forth below.
Scheme 23 F F N \ CI F0 NH NH OF |//\NrCI NIN NJLNJLN i F F /N Fr) w OF 0 (I) MeONa MeOH NANAN Step 1.°Preparati0n 0f6—(6—chloropyrazinyl)-N2,N4-bis (4,4-diflu0r0cyclohexyl)—1,3,5- triazine—2,4-diamine. To a mixture of methyl 6-chloropyrazinecarboxylate (300mg,l .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 The reaction mixture was d at r.t. overnight, and then partitioned between EtOAc (30 mL) and H20(3OmL). 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 N1V[R (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 — l.60(m, 16H).LCMS: rn/z 460(M+H)+.
The procedure set forth in Example 23 was used to produce the following nds using the appropriate starting materials. 6-(6-Chloropyrazin-Z-yl)—N2,N4-bis(3,3-difluorocyclopentyl)—1,3,5-triazine—2,4-diamine N/YCI FF>O\NJI\N/J\N N \N D Example 24 Preparation of SymmetricDi—aliphatic Triazine Compounds of Formula P. The compounds ofthis Example are prepared by general Scheme 24, set forth below.
Scheme 24 N CF3 N CF3 I NfixF CO/MeOH U /N POCI3 N\\H Step2: Preparation of 6-(2—(trifluoromethyl)pyrimidin-4—yl)—1,3,5-triazine-2,4(1H,3H)— dione.The 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—dichloro-6—(2—(trifluoromethpryrimidin-4—yl)—1,3,5-triazine. The procedure is the same as Example 1 Step 3 described above. LC-MS: m/z 296.0 (M+H)+.
Step 4: ation of N2,N4-bis(4,4-difluorocyclohexyl)-6—(2—(trifluoromethyl)pyri midin yl)—1,3,5-triazine-2,4-diamine. The procedure is the same as Example 1 Step 4 described above.
IN‘XFF F F Ff) 1’1 GPN \N N H H 1H NMR (400 MHz, CDC13) 5 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)F.
The procedure set forth in Example 24 was used to produce the following compounds using the appropriate starting materials.
N2,N4-bis(3,3-diflu0rocyclopentyl)(2-(triflu0r0methyl)pyrimidinyl)—1,3,5-triazine—2,4- | Vg ea "P" 1xF NANAN F H H 1H NMR (400 MHz, CDC13) 5 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), .87 (m, 2H). LC-MS: m/z 466.2 (M+H)F.
N2,N4-bis(3,3-diflu0r0cyclobutyl)(2-(triflu0romethyl)pyrimidinyl)—1,3,5-triazine—2,4- diamine \ F F F N \N F F JL A N N N H H 1H NMR (400 MHz, CDC13) 5 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-(Triflu0r0methyl)pyrimidinyl)—N2,N4-bis((R)-1,1,1-triflu0r0pr0panyl)-1,3,5- triazine-2,4-diamine | ‘WXF g3 N/ N CF3 /(R}NJ\\NJ\N7I'?)\| H H 1H NMR (400 MHz, CDC13) 5 9.11 (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,N4-bis((S)-1,1,1-triflu0r0butan-Z-yl)(2-(trifluor0methyl)pyrimidinyl)—1,3,5- triazine-2,4-diamine 1 N¢F CF3 N/ N g3 \éNkNANW| .
H H 1H NMR (400 MHz, CDC13) 5 9.11 (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 .
N2,N4-bis(4,4-diflu01'0cyclohexyl)—6-(4-(triflu0r0methyl)pyri midinyl)-1,3,5- triazine-2,4- diamine.
WO 03640 N /N F I Ff) I1 GN \N N H H 1H NNIR (400 MHZ, CDC13) 5 9.22 (d, J: 4.9 Hz,1H), 7.77 (d,J= 4.9 Hz,1H), 5.64 — 5.16 (m, 2H), 4.21 — 4.01 (m, 2H), 2.28 — 1.52 (m, 16H). LC-MS: m/z 494.2 (M+H)+.
N2,N4-bis(3,3-diflu0rocyclopentyl)(4-(triflu0r0methyl)pyrimidinyl)—1,3,5-triazine-2,4- diamine Ml:F in":1"1W3F lHNlVIR (400M1—IZ, CDC13) 5 9.22 (d, 1H), 7.77 (d, 1H), 5.87 (d, 2H), 4.58-4.53 (m, 2H), 2.69- 2.56 (m, 2H), 2.31-2.29 (m, 4H), .08 (m, 4H), 1.87-1.68 (m, 2H).LC-MSI m/z 466.2 (M+H)+.
N2,N4-bis(3,3-diflu0r0cyclobutyl)(4-(triflu0romethyl)pyrimidin-Z-yl)—1,3,5-triazine-2,4- diamine N /N F NIN F Ffl JL 4 D" N N N H H 1H NMR (400 MHz, DMSO-d6) 8 9.34 (m, 1H), 8.64 — 8.00 (m, 3H), 4.46 — 4.10 (m, 2H), 3.07 — 2.83 (m, 4H), 2.74 — 2.62 (m, 4H). LC-MS: m/z 438.1 (M+H)+.
N2,N4-bis((R)cyclopr0pylethyl)—6-(4-(trifluoromethyl)pyrimidinyl)—1,3,5-triazine-2,4- diamine VJRTN11N/ N(R) H H 1H NMR (400 MHz, CDC13) 5 9.19 (s, 0.6H), .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), .26(m, 8H). LCMS: rn/z 394(M+H)+.
N2,N4-bis(4,4-diflu0r0cyclohexyl)—6-(4-(2-meth0xyethyl)pyrimidin-Z-yl)-1,3,5-triazine-2,4- diamine N / N F I F NJ\\NJ\N| H H 1H NMR (400 MHz, CDC13) 68.83-8.82(rn, 1H),7.40—7.39 (m, 1H),5.60-5.58(m,2H), 4.26-4.01 (m, 2H), 3.81-3.77 (t, J:8Hz, 2H), 3.35 (s, 3H), 3.21-3.18 (m, J:8Hz,2 H), 2.11—2.05 (m, 8H), 1.94-1.86 (m, 4H), 1.74-1.69 (m, 4H). LC-MS: rn/z 484 (M+H)+.
Example 25 The compounds of this e are prepared by general Scheme 25, set forth below.
Scheme 25 O Lawesson's reagent F3CJJ\NH2 I THF, refux N EtOOC CF3 2 _ ' X? Br/YLOEt s N MeONa, MeOH F I F F F Ffl N/IN fiF F NaN (CN)2 NH NH F F NJ\\NJ\N NH —>2 Jk JL H H F HCI 160 0c N N N H H H Step 1: Preparation of ethyl 2—(triflu0r0methyl)thiazole—4-carb03qylate. To a solution of 2,2,2- trifluoroacetamide(1.42 g, 12.6 mmol) in dry THF(60 mL) was added Lawesson’s t (3.06 g,7.56 mmol). The reaction mixture was heated atreflux for 18 hr and then cooled, followed by addition ofethyl 3-bromooxopropanoate (1.6 mL, 12.6 mmol).The mixture was refluxed for another 18 hr and then cooled to r.t.. The resulting e was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous Na2SO4 and trated andpurif1ed by standard methods to afford ethyl 2-(trifluoromethyl)thiazolecarboxylate.1H N1\/[R(4001V1HZ,CDC13)88.42 (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: ation of N1,N5-bis (3,3-difluoracyclobuwD-biguanide. A mixture of 3,3- difluorocyclobutanamine hydrochloride(3.024 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 t.LC-MS: m/z 282 (M+H)+.
Step 3: Preparation of N2,N4-bis(3,3-diflu0r0cyclobug/l)(4—(triflu0r0methyl)thiazol-Z-yD— 1,3,5-triazine-2,4—diamine. To a mixture of N1,N5-bis(3,3-difluorocyclobutyl)-biguanide (60 mg, 0.22 mmol) in MeOH (5 mL) were added ethyl 2-(trifluoromethyl)thiazolecarboxylate (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 H20.The organic layer was ted, washed with brine, dried over anhydrous Na2SO4, and concentrated and purified by standard methods to afford the N2,N4-bis(3,3-difluorocyclobutyl)(4-(trifluoromethyl)thiazolyl)-l,3,5-triazine- 2,4-diamine. fliiifi H H 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), .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.
N2,N4-bis(4,4-diflu0r0cyclohexyl)—6-(4-(triflu0r0methyl)thiazolyl)-1,3,5-triazine-2,4- diamine F F S /N F F FU 11 GPN N/ N H H 1H NMR (400MHz, CDC13)6 7.84(s, 1H), 5.42 — 5.07 (m, 2H), 3.89 — 3.79 (m, 2H), 2.06 — l.79(m, 13H), 1.67 — 1.57 (m, 3H). LCMS: m/z 499(M+H)+. bis(3,3-diflu0rocyclopentyl)(4-(trifluoromethyl)thiazolyl)-1,3,5-triazine—2,4- diamine S /N FFfl QFN F H H 1H NMR (400MHz, CDC13)5 7.91(d,J=4Hz, 1H), 5.66 — 5.34 (m, 2H), 4.64 — 4.51 (m, 2H), 2.69 — 2.59 (m, 2H), 2.31 — 2.04 (m, 8H), 1.86 — 1.80 (m, 2H).LCMS: m/z H)+. 6-(4-(triflu0r0methyl)thiazolyl)-N2,N4-bis(1 ,1,1-triflu0r0pr0panyl)—1,3,5-triazine-2,4- diamine i N" L F3C "ANA" CF3 1H NMR (400MHz, CDC13)6 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,N4-bis(4,4-diflu0r0cyclohexyl)—6-(2-(triflu0r0methyl)thiazolyl)-1,3,5-triazine-2,4- diamine 1H NMR (400 MHz, CDC13) 5 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)+.
N2,N4-bis(3,3-diflu0rocyclobutyl)(2-(trifluoromethyl)thiazolyl)-1,3,5-triazine-2,4- diamine F F E"\ F F fl 414 HN \N F F H H 1H NMR (400 MHz, CDC13) 5 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-(triflu0r0methyl)thiaz01yl)-N2,N4-bis((R)-1 ,1 ,1-triflu0ropr0panyl)—1,3,5-triazine- 2,4-diamine F3C (R) NA JV"(R)CF3 1H NMR (400 MHz, CDC13) 5 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 H)+.
N2,N4-bis(4,4-diflu0r0cyclohexyl)—6-(2-methyloxazolyl)-1,3,5-triazine-2,4-diamine 1H NMR (400MHz, 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)+.
N2,N4-bis(3,3-diflu0r0cyclobutyl)(2-methyloxazolyl)-1 ,3,5-triazine-2,4-diamine O—\( FtF\N FflngiNfiF H H 1H NMR (400 MHz, CDC13) 5 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)+.
N2,N4-bis(4,4-diflu0r0cyclohexyl)—6-(5-methylis0xaz01—3-yl)-1 ,3,5-triazine-2,4-diamine 1H NMR (400MHz, 6 6.52 — 6.48 (m, 1H), 5.44— 5.09 (m, 2H), 4.15— 3.96 (m, 2H), 2.49(s, 3H), 2.11 — 189(m, 13H), 1.70 — 1.63 (m, 3H).LCMS: m/z 429(M+H)+.
N2,N4-bis(3,3-diflu0r0cyclobutyl)(5-methylisoxazolyl)-1 ,3,5-triazine-2,4-diamine //;\I F F FflngiNfiF H H 1H NMR (400 MHz, DMSO-d6) 5 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 nds of this Example are prepared by general Scheme 26, set forth below.
Scheme 26 o O o N Isoamy | nitrite N LIOH, THF, ' N HATU DIPEA H2N\Br~< i S / H: Dppf Et3N MeOH F F F Ffl JL xGNH NH2 F F / _ F F oHij H H s / N F I F ’ S Ff) li O" H N H Step 1: Preparation of ethyl 2—bromothiazolecarb0xylate. To a solution of ethyl 2- aminothiazolecarboxylate (15.0 g, 87.1 mmol) in MeCN (100 mL) was added isoamyl nitrite (24.5 g, 209 mmol) and CuBrz (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-bromothiazolecarboxylate. LC-MS: m/z 236 (M+H)+.
Step 2: Preparation of 2—br0m0thiazolecarb0xylic acid. To a on of ethyl 2- bromothiazolecarboxylate (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 e slayer 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-bromothiazolecarboxylic acid. LC-MS: m/z 206 (M—H)‘.
Step 3: Preparation ofZ-bromo-N-methoxy-N-methylthiazolecarb0xamide.To a solution of 2-bromothiazolecarboxylic acid (11.4 g, 55.0 mmol) in DCM (100 mL) were added N,O- dimethylhydroxylamine (6.9 g, 71.0 mmol), HATU (27.0 g, 71.0 mmol) and DIPEA (21.2 g, 164.0 mmol). The e 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 Na2SO4, and concentrated and purified by standard methods to afford 2-bromo-N-methoxy-N- methylthiazole- oxamide.LC-MS: m/z 251 (M+H)+.
Step 4: ation of1-(2-bromothiazolyl)ethanone. To a on of 2-bromo-N-methoxy- N—methylthiazolecarboxamide (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. NH4Cl (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 1-(2-bromothiazolyl)ethanone. LC-MS: m/z 206 (M+H)+.
Step 5.°Preparation of methyl 4-acetylthiazole-Z-carboxylate. To a solution of 1-(2- bromothiazolyl)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 trated and the residue ed by standard methods to afford methyl 4-acetylthiazolecarboxylate. LC-MS: m/z 186 (M+H)+.
Step 6: Preparation of methyl 4-(1,1-difluoroethyl)thiazole-Z-carboxylate. To a solution of 4- acetylthiazolecarboxylate (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 -difluoroethyl)thiazole carboxylate.LC-MS: m/z 208 (M+H)+.
Step 7: ation 4-bis(4,4-difluorocyclohexyD(4-(1,1-difluoroethyl) thiazol-Z-yl)- 1,3,5-triazine-2,4-diamine. To a mixture of N1,NS-bis(3,3-difluorocyclobutyl)-biguanide (60 mg, 2014/081957 0.22 mmol) in MeOH (5 mL) were added ethyl 4-(l,l-difluoroethyl)thiazolecarboxylate (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 H20.The organic layer was separated, washed with brine, dried over anhydrous , concentrated and purified by standard methods to afford N2,N4-bis(4,4-difluorocyclohexyl)(4-(l ,l-difluoroethyl)thiazolyl)-l,3,5-triazine-2,4- diamine. 1H NMR (400 MHz, CDC13) 5 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 e 26 was used to produce the following compounds using the appropriate starting materials.
N2,N4-bis(4,4-diflu0r0cyclohexyl)—6-(2-(1,1-difluoroethyl)thiazol—4-yl)—1,3,5-triazine—2,4- diamine FF if? MINDS/O; 1H NMR (400 MHz, DMSO-d6) 5 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)+.
N2,N4-bis(3,3-diflu0r0cyclopentyl)(2-(1,1-diflu0r0ethyl)thiazol—4-yl)—1,3,5-triazine—2,4- diamine 1H NMR (400 MHz, CDC13) 5 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, 11H), 1.82 — 1.75 (m, 2H) .LCMS: rn/z 467(M+H)+.
N2,N4-bis(3,3-diflu0r0cyclobutyl)—6-(2-(1,1-difluoroethyl)thiazolyl)-1,3,5-triazine-2,4- diamine F E" F N \N Ffl 4N4 EF 11 11 1H NMR (400 MHz, CDC13) 5 8.45 — 8.36 (m, 1H), 5.71 — 5.36 (m, 2H),4.47 — 4.35 (m, 2H), 3.05 (s, 4H), 3.6 1(s, 4H), 2.24 — 2.03 (m, 3H). LCMS: rn/z 439(M+H)+.- e 27 The compounds of this Example are prepared by general Scheme 27, set forth below.
Scheme 27 o H Pd(OAc)2 F dppf N /O\ [I] —’_ Br‘<’DIBALH N DAST Br‘ ‘0 s F131 11 UF/ H N H 2014/081957 Step 1: Preparation of2—bromothiazolecarbaldehyde. To a mixture of 2-bromo-N-methoxy- N—methylthiazolecarboxamide (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 EtOAc (80 mL) and H20 (60 mL). The organic layer was ted, washed with brine(40 mL), dried over anhydrous Na2804, concentrated and purified by standard methods to afford the desired product.LC-MS: m/z 192 (M+H)+.
Step 2: Preparation of2—bromo(difluoromethyDthiazole. To a mixture of othiazole 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 d 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 NaZSO4 and concentrated and purified by standard methods to afford the desired product. LC-MS: m/z 214 Step 3: Preparation ofmethyl 4-(difluoromethyl)thiazole-Z-carboxylate. A mixture of 2-bromo- 4-(difiuoromethyl)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 e was filtered, the e 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 Na2804, and concentrated and purified by standard methodsto afford the desired product.LC-MS: m/z 194 (M+H)+.
Step 4: Preparation of bis(4,4-difluorocyclohexyl)—6-(4-(difluoromethyDthiazol—Z-yD— 1,3,5-triazine-2,4-diamine.To a suspension of N1,NS-bis(3,3-difiuorocyclobutyl)-biguanide (45 mg, 13.3 mmol) and methyl 4-(difiuoromethyl)thiazolecarboxylate (40 mg, 20.7 mmol) in MeOH (10mL) was added NaOMe (20 mg, 37.0 mmol). The reaction mixture was stirred at r.t. ght, then poured into water and extracted with EtOAc.Combined organic layers were over anhydrous NaZSO4, concentrated and purified by standard s to afford the desired product. 1H NMR (400 MHz, CDC13) 5 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 ing compounds using the appropriate starting materials.
N2,N4-bis(3,3-diflu0rocyclobutyl)(4-(difluor0methyl)thiazolyl)-1,3,5-triazine—2,4- diamine F if F Ffl 1N; HF H H 1H NlVIR (400lVlHZ, CDC13)5 7.84 (d, J=8HZ, 1H), 7.02 - 6.74(m, 1H), 5.74 - , 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)+.
N2,N4-bis(3,3-diflu0r0cyclopentyl)(4-(difluor0methyl)thiazol—2-yl)—1,3,5-triazine—2,4- diamine Ffl NV" QFF N/ F H H 1H NMR (400MHz, CDC13)6 7.84(s, 1H), 7.04 — , 1H), 5.65 — 5.36 (m, 2H), 4.66 — 4.55 (m, 2H), 2.66 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 (Em/M42 \/0 CN 0 \g/ S’N\ (Z) C|\n/S\CI toluene s" \>(fl© DCE VojflZ’TN O refluxed O O O F NH NH F mph JK JK IN_ (2) N N N s N Step 1: ation of 5-phenyl-1,3,4-oxathiazol-Z-one. To a on of benzamide (200 mg, 1.65 mmol) in toluene (2 mL) under Nzatmospherewas 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 Na2804, concentrated and purified by standard methods to afford the desired tLC-MS: m/z 180 (M+H)+.
Step 2: Preparation of3-phenyl-1,2,4-thiadiazolecarboxylate. A mixture of 5-phenyl-1,3,4- oxathiazolone (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 s to afford the desired productLC-MS: m/z 235 (M+H)+.
Step 3: Preparation of N2,N4-bis(4,4—difluorocyclohexyl)—6—(3—phenyl—1,2,4-thiadiazol yl)- 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-thiadiazolecarboxylate (75 mg, 0.32 mmol) in MeOH (2 mL) was added NaOMe (43 mg, 0.8 mmol). The reaction e 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 Na2SO4and concentrated and purified by standard methods to afford the desired product. 1H NMR (400 MHz, CDC13) 5 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 e the following compounds using the appropriate starting materials. bis(4,4-difluor0cyclohexyl)—6-(3-methyl-1,2,4-thiadiazolyl)-1,3,5-triazine—2,4- diamine s /N F I F Fr) N/ 1 GP NJHNAN H H 1H NlVIR (400 MHz, CDCl3) 5 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 CI |>—\- 0' TN 2 ,\N A A N’ N NH2 HCI N/ N 1 IN E H g C|)\\NJ\CIl VA" : \ —> N N g DIPEA, CsF N NW NaH, THF V/LNkaH/V Step 1.Preparati0n of 6-chl0r0-N2,]\fl-bis((R)cycl0pr0pylethyl)—1,3,5-triazine—2,4— diamine.To a solution of 2,4,6-trichloro-1,3,5-triazine (2 g, 10.9 mmol) in acetone (35 mL) were added cyclopropylethanamine hydrochloride(2.7 mg, 22.8 mmol), DIPEA (3.5 mg, 27 mmol) and CsF (3.3 mg, 21.8 mmol). The mixture was stirred at 50°C overnight, and then filtered. The filtrate was concentrated and d by standard methods to give the desired product. LC-MS: m/z 282 .
Step B.Preparati0n of N2,N4-bis((R)cycl0pr0pylethyl)—6-(4-methyl-1H-pyrazol—I-yD-1,3,5- triazine—2,4-diamine. To an ice-cold solution of4-methyl-1H-pyrazole (207 mg, 1.07 mmol)in dry THF (5 mL) was slowly added NaH (34 mg, 1.42 mmol) over 30 min, ed by addition of a solution of 6-chloro-N2,N4-bis((R)cyclo -propylethyl)-1,3,5-triazine-2,4-diamine (200 mg, 0.71 mmol) in THF (3 mL). The reaction mixture was stirred at r.t. ght, and then concentrated and purified by standard methods to afford N2,N4-bis((R)cyclopropylethyl)(4- methyl-1H-pyrazolyl)-1,3 ,5 -triazine-2,4-diamine.
NAIN #03"th_ 1H NMR (400 MHz, CDC13) 5 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.
C0mp0undN2,N4-bis((R)cyclopropylethyl)(4-i0do-lH-pyrazolyl)—1,3,5-triazine-2,4- diamine Z/ }\N V/LM \N MW 1H NMR (400 MHz, CDC13) 5 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)+.
C0mp0und6-(4-Chlor0-1H—pyrazolyl)-N2,N4-bis(4,4-difluorocyclohexyl)—1,3,5-triazine- 2,4-diamine FF NiN UmaflFF H H 1H NMR (400MHz, CDC13)6 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 m,1.2H), 1.68 — 1.61 (m, 1.8H). LCMS: m/z 448 (M+H)+.
C0mp0undN2,N4-bis((R)cyclopr0pylethyl)(3-(triflu0r0methyl)-lH-pyrazolyl)-1,3,5- triazine-2,4-diamine 1H NMR (400 MHz, CDC13) 5 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)+. nd6-(3-(Trifluoromethyl)-1H—pyrazolyl)-N2,N4-bis(1,1,1-triflu0r0pr0panyl)— 1,3,5-triazine-2,4-diamine /’N\ CF3 N’ N CF3 ANkaNK H H 1H NMR (400 MHz, CDC13)6 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)-1,1,1-triflu0r0butan-Z-yl)—6-(3-(trifluoromethyl)-1H—pyrazolyl)- 1,3,5-triazine-2,4-diamine 1H N1V[R(4OOMHz, CDC13)6 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-difluor0cyclopentyl)—6-(3-(trifluoromethyl)—lH-pyrazolyl)-1 ,3,5- t riazine-2,4-diamine / )N iflMAN/imlfl 1H NMR (400MHz, 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 — 2.31(m, 8H), 1.81 — 1.86(m, 2H). LCMS: m/z 454(M+H)+.
C0mp0undN2,N4-bis(4,4-difluorocyclohexyl)(3-(trifluor0methyl)-1H-pyrazol—1-yl)—1,3,5- triazine-2,4-diamine / }N F j: F FfiNmNUF H H 1H NMR (400 MHz, DMSO-d6) 5 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)+.
C0mp0undN2,N4-bis(3,3-difluorocyclobutyl)(3-(trifluor0methyl)—1H—pyrazolyl)—1,3,5- triazine-2,4-diamine F F Fig "*1" DZNJ\\N/J\N H H 1H 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, MS: m/z 426(M+H)+.
Example 30 The compounds of this Example are prepared by general Scheme 30, set forth below.
Scheme30 F F / Ffi NH NH GF (2) / N / / NANJLN ,N N\ SOCI2 N\ F (E) 0" Q H H H F e e e a Ffifigf\ COOH COOMe H N H Step 1: Preparation yl 1-methyl-1H-pyrazole—3—carb03qylate. To a solution of yl- 1H—pyrazolecarboxylic acid (504 mg, 4 mmol) in MeOH (5 mL) was added SOClz (1.4 mL, 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. and concentrated to afford methyl 1-methyl-1H—pyrazolecarboxylate.LC-MS: m/z 141 (M+H)+.
Step 2: Preparation ofNZ,N4-bis(4,4-diflu0r0cycl0hexyl)—6—(1-methyl-1H-pyrazol—3—yl) -1,3,5- triazine—2,4-diamine. To a solution of N1,N5-bis(4,4-dif1uorocyclohexyl)-biguanide (120 mg, 0.36 mmol) and methyl 1-methyl-1H-pyrazole-3 -carboxylate (60 mg, 0.43 mmol) in MeOH (2 mL) was added NaOMe (28 mg, 1.07 mmol). The reaction mixture was stirred at r.t. overnight, then poured into water and extracted with EtOAc. Combined organic layers were dried over anhydrous NaZSO4,and concentrated and ed by rd methods to afford N2,N4-bis(4,4- difluorocyclohexyl)(1 -methyl-1H-pyrazol-3 -yl)-1,3 ,5-triazine-2,4-diamine.
F F 1H NMR (400 MHz, CDC13) 5 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)+.
WO 03640 2014/081957 The procedure set forth in Example 30was used to produce the following compounds using the appropriate starting materials. ndN2,N4-bis(4,4-difluorocyclohexyl)—6-(1H-pyrazol—3-yl)—1,3,5-triazine-2,4-diamine F F Ff) "/1 GPNAxNAN H H 1H NMR (400 MHz, CDC13) 5 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)+.
Comp0undN2,N4-bis(3,3-diflu0r0cyclopentyl)—6-(2-methyl-1H-imidazolyl)—1 ,3,5-triazine— 2,4-diamine HN—<\ 150E153\N 1H NMR (400 MHz, CDC13) 5 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)+.
C0mp0undN2,N4-bis(3,3-difluorocyclobutyl)(2-methyl—1H—imidazol—4-yl)—1,3,5-triazine— 2,4-diamine HN~\( F i" F Ffl JIN/Jx ELF H H 1H NlVIR (400 MHz, CDC13) 5 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)+. ndN2,N4-bis(4,4-diflu0rocyclohexyl)(2-methyl—1H—imidazol—4-yl)—1,3,5-triazine- 2,4-diamine HEWF HNMR (400 MHz, CDC13) 5 8.67-7.66 (m, 1H), 6.26-5.84 (m, 1H), 5.11-4.81 (m, 1H), 3.49— 3.ll(m, 7H), 2.48 (s, 2H), 2.10-1.66 (m, 12H). LC-MS: m/z 428.3 .
Example 31 The compounds of this Example are prepared by general Scheme 31, set forth below.
Scheme 31 £2: NIS AcOK DMF N —> /N 4 I Pd(dppf)C|2.DCM HN[\lli57B/O/ ‘o CF3 CF3 F F Ff) W UPNxNAN W H H / F c3 Y Pd(PPh3)4,K2CO3 F F PUM GP\N N N H H Step 1: Preparation of 4—i0d0(trifluoromethyD-IH-pyrazole. To a solution of 3- (trifluoromethyl)—lH—pyrazole (500 mg, 3.7 mmol) in 50% H2804 at O 0C was added NIS (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(trifluoromethyl)-1H—pyrazole.LC-MS: m/z 263 (M+H)+.
Step 2: Preparation of4-(4,4, 5,5-tetramethyl-1,3,2-di0xab0rolanyl)-3 -(triflu0r0methyl)—1H- pyrazole. To a mixture of 4-iodo(trifluoromethyl)-1H—pyrazole (100 mg, 0.38 mmol) and (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (397 mg, 0.57 mmol) in DMF (3 mL) were added 1,1'-bis enylphosphino)ferrocene-palladium(]I)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 EtZO. The combined organic layers were washed with brine, dried over anhydrous , and concentrated to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3 -(trifluoromethyl)-1H—pyrazole.LC-MS: m/z 263 (M+H)+.
Step 3: Preparation of N2,N4-bis(4,4-diflu0rocyclohexyl)(3-(triflu0r0methyl)—1H-pyrazol yl)—1,3,5-triazine-2,4-diamine. To a solution of 6-chloro-N2,N4-bis(4,4-difluorocyclohexyl)- 1,3,5-triazine-2,4-diamine (145 mg, 0.38 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 3-(trifluoromethyl)-1H—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 NaZSO4, and concentrated and purified by rd methods to afford N2,N4-bis(4,4-difluorocyclohexyl)(3- (trifluoromethyl)-1H—pyrazolyl)-1 ,3 ,5-triazine-2,4-diamine.
N—NH F3C / F F 1H NMR (400 MHz, 6) 5 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 ing compounds using the appropriate starting materials.
C0mp0undN2,N4-bis(4,4-diflu0rocyclohexyl)-N2-methyl(3-(trifluoromethyl)-1H-pyrazol- 4-yl)—1,3,5-triazine-2,4-diamine N-NH 1H NMR (400 MHz, CDC13) 5 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-(1-methyl—3-(trifluoromethyl)—1H—pyrazol—4- yl)—1,3,5-triazine-2,4-diamine F3C / F F 1H NMR (400 MHz, CDC13) 5 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)cyclopropylethyl)(5-(triflu0romethyl)pyridinyl)-1,3,5- triazine-2,4-diamine N \N 1H NMR (400 MHz, DMSO- d6) 5 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)cyclopropylethyl)(2-(triflu0romethyl)pyridinyl)-1,3,5- triazine-2,4-diamine VLMiN/AMWN \N E 1H NMR (400 MHz, CDC13) 5 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)+.
C0mp0undN2,N4-bis((R)cyclopropylethyl)(2,5-difluorophenyl)—1 ,3,5-triazine-2,4- diamine (R) NxNANfiW H H 1H NMR (400 MHz, CDC13) 5 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)+. ndN2,N4-bis((R)cyclopropylethyl)(3-(trifluor0meth0xy)phenyl)-1,3,5-triazine- 2,4-diamine OCF3 VLHiN/AH'WN \N 5 1H NMR (400MHz, CDC13): 5 8.25 — 8.18 (m, 2H), 7.46 — 7.42 (m, 1H), 7.32 — 7.26 (m, 1H), .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), O.28(s, 2H). LCMS: m/z 408(M+H)+.
C0mp0und3-(4,6-bis(((R)cyclopropylethyl)amin0)—1,3,5-triazinyl)benzonitrile ngANANN. \N : H H 1H NMR (400 MHz, CDC13) 5 8.63 — 8.55 (m, 2H), 7.75 (d, J: 8 Hz, 1H), 7.57 — 7.53 (m, 1H), .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 nds of Formula Q. The compounds ofthis Example are prepared by general Scheme 32, set forth Scheme 32 —» 1N1N1 —» GN1N1N1N: Step 1 .° Preparation of 4-chl0r0-N-(6-(1,1-diflu0r0ethyDpyridin-3—yl)—6-(6- (trifluaromethpryridin-Z-yD-I,3,5-triazin-2—amine. To a mixture of 2,4-dichloro(6- (trifluoromethyl)pyridinyl)—1,3,5-triazine (188 mg, 0.64 mmol) and 2-(1,1- difluoroethyl)pyridinamine (50 mg, 0.32 mmol) in 1, 4-dioxane (4 mL) were added tBuONa (61 mg, 0.64 mmol) and Pd(dppf)C12 (22 mg, 0.03 mmol) under an atmosphere of nitrogen. The reaction mixture was then d at 80°C overnight, and then filtered. The filtrate was concentrated and purified by standard methods to afford the desired product.
LC-MS: m/z 417.1 (M+H)+.
Step 2.°Preparati0n ofN2-(3,3-diflu0r0cycl0pen92l)—N4-(2-(1,1-diflu0r0ethyDpyridin-4—yl)—6-(6- (trifluoromethybpyridin-Z-yl)-1,3,5-triazine—2,4—diamine To a mixture of ro-N—(6-(1,1- difluoroethyl)pyridinyl)(6-(trifluoromethyl)pyridineyl)-1,3,5-triazinamine (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.
H NMR (400 MHz, CDC13) 5 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), 2.11 — 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 ing compounds using the appropriate starting materials.
(S)—N2-(3,3-difluorocyclopentyl)—N4-(2-(1,1-difluoroethyl)pyridinyl)(6- (trifluoromethyl)pyridinyl)—1,3,5-triazine—2,4-diamine N39N’0<(S) 1H NMR (400 MHz, CDC13) 8 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)+. -(3,3-diflu0r0cyclopentyl)—N4-(2-(1,1-difluoroethyl)pyridinyl)—6-(6- (trifluoromethyl)pyridinyl)—1,3,5-triazine—2,4-diamine %"N‘(R) 1H NMR (400 MHz, CDC13) 5 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-(1 ,1-difluoroethyl)pyridinyl)—6-(6- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine 1H NMR (400 MHz, CDC13) 5 8.69 — 8.43 (m, 3H), 8.07 (t, J: 7.8 Hz, 1H), 8.01 — 7.73 (m, 2H), 7.49 (m, 1H), 5.61 (m, 1H), 4.19 (m, 1H), 2.24 — 2.13 (m, 4H), 2.12 — 1.93 (m, 5H), 1.76 — 1.65 (m, -MS: m/z 516 (M+H)+.
N2-(3,3-difluorocyclobutyl)-N4-(2-(1 ,1-difluor0ethyl)pyridinyl)—6-(6- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine \| HANAMDLFI/ 1H NMR (400 MHz, CDC13) 5 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-(1,1-Diflu0r0ethyl)pyridinyl)amino)—6-(6-(trifluoromethyl)pyridinyl)-1,3,5- triazin-Z-yl)amino)propanenitrile 69*J\CN 1H NMR (400 MHz, DMSO-d6) 8 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-(1,1-Diflu0r0ethyl)pyridinyl)amino)—6-(6-(trifluoromethyl)pyridinyl)-1,3,5- triazin-Z-yl)amino)methylpr0panenitrile \ F FF l/N N/| N|\N \ NAN/k,"J N2-(3,3-difluorocyclopentyl)—6-(6-(triflu0r0methyl)pyridinyl)-N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine ' DLF \ NAxNAN H H 1H NMR (400 MHz, CDC13) 5 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-(triflu0r0methyl)pyridin-Z-yl)-N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4—diamine |\ F \ MXNAWEXP 1H NMR (400 MHz, CDC13)68.65-8.52 (m, 3H), 8.10-8.06 (m, 86—7.85 (m, 1H), 7.48-7.42 (m, 1H),6.00—5.86 (m, 1H), 4.81-4.60 (m 2.77-2.62 (m, 1H), 2.41—2.32 (m, 2H), 2.12—2.19 , 1H), (m, 2H), 1.93-1.86 (m, 1H). LCMS: m/z 506 (M+H)+.
(S)—N2-(3,3-diflu0r0cyclopentyl)—6-(6-(trifluor0methyl)pyridinyl)-N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine I 1% MkNAM(S) 1H NMR (400 MHz, CDC13) 5 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-difluor0cyclohexyl)—6-(6-(triflu0romethyl)pyridinyl)-N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine |\ F \ NAN/kl""P"GF H H 1H NMR (400 MHz, CDC13) 5857—862 (m, 3H), 7.85-8.17 (m, 3H), 7.37—7.72 (m, 1H), 5.45— .82 (m, 1H), 4.10-4.26 (m, 1H), .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)+.
Nz-(3,3-difluorocyclobutyl)(6-(trifluor0methyl)pyridinyl)-N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine |\ F "El F N'\N ELF \ NAN/AN H H 1H NMR (400 MHz, CDC13) 5 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-diflu0r0spir0 [3.3]heptanyl)(6-(triflu0r0methyl)pyridinyl)-N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine |\ F CF3 F "aufl\/ \ F N N/N H H 1H NMR (400 MHz, CDC13) 5855—870 (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 6-(6-(Trifluor0methyl)pyridinyl)-N2-(2-(trifluoromethyl)pyridinyl)—N4-(1,1,1- trifluoropropan-Z-yl)-1,3,5-triazine-2,4-diamine |\ F "@111\ N N/M CF3 1H NMR (400 MHz, CDC13) 5 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)+.
Nz-(2,2,2-triflu0r0ethyl)—6-(6-(triflu0r0methyl)pyridinyl)—N4-(2-(triflu0r0methyl)pyridin- 4-yl)—1,3,5-triazine-2,4-diamine 2014/081957 N\ N\N '/ )L/XA NNNCF3 H H 1H NMR (400MHz, DMSO-d6)6 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-diflu0rocyclobutyl)methyl)(6-(triflu0r0methyl)pyridinyl)-N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine |\ F "/I 11 \ / 1 N "m4 1H NMR (400 MHz, CDC13) 5 8.70 — 8.41 (m, 3H), 7.96 (m, 4H), 7.52 (m, 1H), 5.95 — 5.58 (m, 1H), 3.67 (m, 2H), 2.77 — 2.13 (m, 5H).LCMS: m/z 506 (M+H)+.
Nz-((2,2-diflu0r0cyclopr0pyl)methyl)(6-(trifluoromethyl)pyridinyl)-N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine |\ F N/ N \N \ MAN/AHA :F 1H NMR (400 MHz, DMSO-d6) 5 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, 1H), 7.96 — 7.86 (m, 1H), 3.61 — 3.43 (m, 2H), 2.17 — 2.09 (m, 1H), 1.67 — 1.32 (m, 2H). LCMS: m/z 492(M+H)+. 2014/081957 N2-(3,3-difluorocyclopentyl)—6-(6-(triflu0r0methyl)pyridinyl)-N4-(5- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine 1H NMR (400 MHz, CDC13) 5 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-MS2m/z 506 (M+H)+. 1-(4-((4-((3,3-Difluorocyclopentyl)amino)—6-(6-(triflu0r0methyl)pyridinyl)-1 ,3,5-triazin- 2-yl)amino)pyridinyl)cyclopropanecarbonitrile 1H NMR (600 MHz,HCDC13) 5 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)(4-((4-((3,3-diflu0rocyclopentyl)amin0)(6-(triflu0r0methyl)pyridinyl)-1,3,5- triazin-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile WO 03640 H NMR (400 MHz, DMSO-d6) 5 10.47 (s, 1H), 8.77 — 8.59 (m, 2H), 8.49 (s, 1H), 8.36 — 8.20 (m, 2H), 8.11 (d, J: 7.8 Hz, 1H), 7.55 (d, J: 4.6 Hz, 1H), 4.86 — 4.47 (m, 1H), 2.75 — 2.57 (m, 1H), 2.29 — 2.06 (m, 4H), 1.97 — 1.82 (m, 1H), 1.80 — 1.74 (m, 2H), 1.71 — 1.63 (m, 2H). LC-MS: m/z 503 (M+H)+.
(S)—1-(4-((4-((3,3-diflu0r0cyclopentyl)amin0)—6-(6-(triflu0r0methyl)pyridinyl)—1 ,3,5- triazin-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile N: 9*AN(3) 1H NMR (400 MHz, DMSO-d6) 5 10.47 (s, 1H), 8.79 — 8.60 (m, 2H), 8.49 (s, 1H), 8.38 — 8.19 (m, 2H), 8.11 (d, J: 7.7 Hz, 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)+. 1-(4-((4-((4,4-Diflu0r0cyclohexyl)amin0)—6-(6-(trifluoromethyl)pyridinyl)—1,3,5-triazin yl)amino)pyridinyl)cyclopropanecarbonitrile \ F NC F NI \ NI \N GP / NAN/AN H H 1H NMR (400 MHz, CDC13) 5 8.83 — 8.65 (m, 1H), 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,1H), 4.29 (s, 1H), 2.12 (m, 6H), 1.89-1.91 (m, 2H), 1.82 — 1.63 (m, 4H). LC-MS: m/z 517 (M+H)+. 1-(4-((4-((3,3-Diflu0r0cyclobutyl)amin0)(6-(triflu0r0methyl)pyridinyl)—1,3,5-triazin yl)amino)pyridinyl)cyclopropanecarbonitrile 339* 1H NMR (400 MHz, DMSO-d,) 5 10.48 (hrs, 1H), 8.89 (d, J: 6.5 Hz, 1H), 8.78 — 8.56 (m, 1H), 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, 1H), 3.13 — 2.97 (m, 2H), 2.71 — 2.56(m, 2H), 1.83 — 1.59 (m, 4H).LC-MS: m/z 489 . 1-(4-((4-((6,6-Diflu0r0spir0 [3.3]heptan-Z-yl)amin0)—6-(6-(trifluoromethyl)pyridinyl)— 1,35,-triazinyl)amin0)pyridinyl)cyclopropanecarbonitrile 939* 1HNMR (H400 MHz,HCDC13) 5 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). + 1-(4-((4-(((2,2-Diflu0rocyclopropyl)methyl)amin0)—6-(6-(trifluoromethyl)pyridinyl)- 1,3,5-triazinyl)amin0)pyridinyl)cyclopropanecarbonitrile 1259*FF HNMR (400 MHz, CDC13) 5 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)+. (4-((2,2,2-Trifluor0ethyl)amin0)—6-(6-(trifluor0methyl)pyridinyl)-1 ,3,5-triazin yl)amino)pyridinyl)cyclopropanecarbonitrile 339*CF3 H NMR (400 MHz, CDC13) 5 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, 1H), 6.34-6.03 (m, 1H), 4.36-4.29 (m, 2H), 1.74(s, 4H).
LC-MS: m/z 481.2 (M+H)+. 1-(4-((4-((2-Hydroxy-Z-methylpr0pyl)amino)—6-(6-(trifluoromethyl)pyridinyl)-1,3,5- triazin-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile |\ F 1H NMR (400 MHz, CDC13) 5 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)(4-((4-(6-(triflu0r0methyl)pyridinyl)((1,1,1-triflu0r0propanyl)amin0)—1,3,5- triazin-Z-yl)amin0)p|:7ridinyl)cyclopropanecarbonitrile AMWCB 1H NMR (400 MHz, CDC13) 5 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)—1-(4-((4-(6-(trifluoromethyl)pyridin-Z-yl)—6-((1 ,1 ,1-triflu0r0pr0panyl)amin0)—1,3,5- n-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile AMWCB H NMR (400 MHz, CDC13) 5 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-butylamin0)(6-(triflu0r0methyl)pyridinyl)-1,3,5-triazin yl)amin0)picolin0nitrile N.\ "Wk /NJ\\NJ\N H H 1H NMR (400 MHz, DMSO-d6) 5 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)amin0)—6-(6-(triflu0r0methyl)pyridinyl)-1 ,3,5-triazin yl)amin0)picolin0nitrile \ F \ Nx-NAN H H 1H NMR (400 MHz, DMSO-d6) 5 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-Difluor0cyclopentyl)amino)(6-(triflu0r0methyl)pyridinyl)—1,3,5-triazin yl)amin0)picolin0nitrile "6L I1 18F\ N \N N F H H 1H NMR (400 MHz, CDC13) 5 .66 (m, 4H), 7.86 (d, J = 8.0 Hz, 2H), 7.53-7.68 (m, 1H), .03 (m, 1H), 4.58-4.79 (m, 1H), 2.66-2.75 (m, 1H), 1.95-2.47 (m, 1H), 1.88-1.93(m, 1H).
LC-MS: m/z 463 (M+H)+. 4-((4-((4,4-Diflu0r0cyclohexyl)amin0)—6-(6-(triflu0r0methyl)pyridinyl)-1 riazin yl)amin0)picolin0nitrile "El 11 GP\ F N \N N H H 1HNMR (400 MHz, DMSO-d6) 5 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-Hydr0xymethylpr0pyl)amin0)—6-(6-(triflu0r0methyl)pyridinyl)—1,3,5-triazin- 2-yl)amin0)picolinonitrile N\ N/N I / NJ\\NJ\N H H/\KOH 1H NMR (400 MHz, CDC13) 8 8.57 - 8.50 (m, 2H), 8.43 - 8.36 (m, 1H), 8.22 - 8.02 (m, 2H), 7.85 (m,1H), 7.60 (s, 1H), 6.32 - 6.23 (m, 1H), 3.74 - 3.58 (m, 2H), 1.37 (s, 6H). LCMS: m/z 431 (M+H)+. 3-((4-((3,3-Difluor0cyclopentyl)amino)(6-(triflu0r0methyl)pyridinyl)—1,3,5-triazin yl)amin0)—5-flu0robenzonitrile |\ F "/1ng\ / F N N N N/ H H 1H NMR (400MHz, CDC13)5 8.64 — 8.55 (m, 1H), 8.16 — 7.74 (m, 5H), 7.08 — 7.02 (m, 1H),5.97 — .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-Diflu0r0cyclohexyl)amin0)—6-(6-(triflu0r0methyl)pyridinyl)-1 riazin yl)amin0)—5-flu0robenzonitrile |\ F IKUF\ 1H NMR (400MHz, : 5 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)amin0)—6-(6-(triflu0r0methyl)pyridinyl)-1 ,3,5-triazin yl)amin0)—5-flu0robenzonitrile |\ F KEEP\ N4 NNN 1H NMR (400MHz, DMSO-d6)6 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)amin0)(6-(triflu0r0methyl)pyridinyl)-1,3,5-triazin yl)amin0)—5-flu0robenzonitrile |\ F JL 4 N4 H N MAW 1H NMR (400MHz, CDC13)6 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-Fluor0((4-((2-hydr0xymethylpr0pyl)amin0)—6-(6-(trifluoromethyl)pyridinyl)- triazinyl)amin0)benz0nitrile N4 M" ufifim 1H NMR (400 MHz, DMSO-d6) 8 10.44 (s, 1H), 8.61 (m, 1H), 8.24 (m, 5H), 7.43 (t, J: 8.8 Hz, 1H), 4.61 (m, 1H), 3.45 (m, 2H), 1.18 (d, J: 4.4 Hz, 6H). LCMS: m/z 448 (M+H)+. 1-((4-((3-Chlor0phenyl)amin0)(6-(triflu0r0methyl)pyridinyl)-1 ,3,5-triazin yl)amino)—2-methylpr0panol \ F N’ N NAxNkN H H/W N2-(3,3-difluorocyclopentyl)—N4-(3,S-difluorophenyl)(6-(trifluor0methyl)pyridinyl)— 1,3,5-triazine-2,4-diamine \ F N \N FKlNANAN F H H 1H NMR (400 MHz, CDC13) 5 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-diflu0r0cyclohexyl)—N4-(3,5-difluor0phenyl)(6-(trifluor0methyl)pyridinyl)— triazine-2,4-diamine |\ F F N\N"MTN H H 1HNMR (400 MHz, CDC13) 5 8.50 (d, J: 10.5 Hz, 1H), 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 .
N2-(4,4-difluorocyclohexyl)-N4-(2-phenylpyridinyl)(6-(triflu0r0methyl)pyridinyl)- 1,3,5-triazine-2,4-diamine \ F N|\ N|\N OLF / HAN/AN 1H NMR (400 MHz, CDC13)58.59-8.58 (m, 2H), 8.30 (s,1H), 8.08-7.81 (m, 5H), 7.50—7.42 (m,4H), 5.87-5.85 (m, 1H),4.22-4.10 (m, 1H), 2.15-1.68 (m, 8H). LC-MS: m/z 528 (M+H)+.
N2-(3,3-diflu0r0cyclopentyl)-N4-(2-phenylpyridinyl)—6-(6-(triflu0romethyl)pyridinyl)— 1,3,5-triazine-2,4-diamine N’ N \N D ( R -N) 2 . . . . . 4 - 2-( phen31p} l‘ d n1 l 31) 6-( (tl‘ me hl t 30133 l‘ d n1 l 31)-N - (1 1 1 - a a trifluoropropan-Z-yl)-1,3,5-triazine-2,4-diamine |\ F N/l N‘N = 1H NMR (400 MHz, CDC13) 5 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-(6-(triflu0r0methyl)pyridinyl)((1,1,1-triflu0r0propanyl)amin0)—1,3,5- triazin-Z-yl)amino)pyridinyl)benz0nitrile |\ F N/ N\N : | I E \ HANAHQCB 1H NMR (400 MHz, CDC13) 5 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-flu0rophenyl)pyridinyl)(6-(triflu0romethyl)pyridin-Z-yl)—N4-(1,1,1- trifluoropropan-Z-yl)-1,3,5-triazine-2,4-diamine N: I 1 H N WEW3 1H NMR (400 MHz, CDC13) 5 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)pyridinyl)—6-(6-(trifluor0methyl)pyridinyl)-N4-(1,1,1- trifluoropropan-Z-yl)-1,3,5-triazine-2,4-diamine 1‘ F I N\Ng \ )L/ /\ H N Hm; CF3 1H NMR (400 MHz, CDC13) 5 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)+. 3-difluorocyclopentyl)—N4-(1H—indol—Z-yl)—6-(6-(triflu0r0methyl)pyridinyl)—1,3,5- triazine-2,4-diamine |\ F Q1 N'W J35 N NAN/AN F H H H 1H NMR (400 MHz, DMSO-d6) 5 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-(1-methyl-1H—indolyl)(6-(trifluor0methyl)pyridin yl)—1,3,5-triazine-2,4-diamine |\ F Q1013, N NANAN F / H H 1H NMR (400 MHz, CDC13) 5 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-(1,1-difluoroethyl)pyridin-Z-yl)-1 riazin- 2-yl)amino)pyridinyl)cyclopropanecarbonitrile 1H NMR (400 MHz, CDC13) 5 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, 1H), 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)+. 2014/081957 1-(4-((4-((3,3-Difluorocyclopentyl)amin0)—6-(6-(1,1-diflu0r0ethyl)pyridinyl)—1 ,3,5-triazin- 2-yl)amino)pyridinyl)cyclopropanecarbonitrile 1H NMR (400MHz, CDC13)6 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 H)+. 1-(4-((4-((3,3-Diflu0r0cyclobutyl)amin0)—6-(6-(1,1-diflu0roethyl)pyridinyl)—1,3,5-triazin- 2-yl)amino)pyridinyl)cyclopropanecarbonitrile //\lgF 1H 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)(4-((4-(6-(1,1-diflu0roethyl)pyridin-Z-yl)((1 ,1 ,1-triflu0r0pr0panyl)amino)—1,3,5- triazin-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile 199* J\N(R)CF3 1HNMR (400 MHz, CDC13) 5 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, 1H), 7.69 — 7.50 (m, 1H), 7.21 — 7.00 (m, 1H), 5.83 — .56 (m, 1H), 5.18 — 5.07 (m, 1H), 2.18 — 2.07 (m, 3H), 1.87 — 1.85 , 1.73 — 1.71 (m, 2H), 1.50 — 1.46 (m, 3H) .LCMS: m/z 491 (M+H)+.
(S)—1-(4-((4-(6-(1 ,1-diflu0r0ethyl)pyridinyl)—6-((1,1,1-triflu0r0propan-Z-yl)amin0)—1,3,5- triazin-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile 199*J\N(S) H NMR (400 MHz, CDC13) 8 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-S-flu0r0phenyl)amin0)—6-(6-(1,1-diflu0r0ethyl)pyridinyl)-1 ,3,5-triazin- 2-yl)amin0)—2-methylpropan-Z-ol 1H NMR (400 MHz, DMSO-d6) 5 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-(1,1-Diflu0r0ethyl)pyridinyl)—6-((2-hydroxy-Z-methylpropyl)amin0)—1,3,5- n-Z-yl)amino)flu0r0benzonitrile Q i/Jh:\ 1H NMR (400 MHz, CDC13) 5840—842 (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)+. 1-((4-(6-(1,1-Diflu0r0ethyl)pyridinyl)—6-((3-flu0ro-S-(trifluoromethyl)phenyl)amin0)— triazinyl)amino)—2-methylpr0panol Jill/i\ 1H NMR (400 MHz, CDC13) 5 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)+. 1-(4-((4-(6-Chlor0pyridinyl)—6-((3,3-diflu0r0cyclopentyl)amino)—1,3,5-triazin yl)amino)pyridinyl)cyclopropanecarbonitrile WO 03640 H NMR (400 MHz, CDC13) 5 8.68 (s, 1H), 8.53 = 4 Hz,1H), 7.86 — 8.43 (m, 1H), 8.30 (d, J — 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)(4-((4-(6-chloropyridinyl)((1-cyclopropylethyl)amin0)—1,3,5-triazin yl)amino)pyridinyl)cyclopropanecarbonitrile NN / (Eu/C - "(5’) H NMR (400 MHz, CDC13) 5 8.43 (s, 2H), 8.23 (d, J: 8 Hz, 1H), 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)+. 1-(4-((4-(6-Chlor0pyridinyl)((2,2,2-triflu0r0ethyl)amin0)—1 ,3,5-triazin yl)amino)pyridinyl)cyclopropanecarbonitrile NNINC/9:"/ ACF3 1H NMR (400 MHz,HCDC13) 5 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)+. 1-(4-((4-(6-Chlor0pyridinyl)((1,1,1-triflu0r0pr0panyl)amin0)—1 ,3,5-triazin yl)amino)pyridinyl)cyclopropanecarbonitrile NN|\ NC/ENK:J\J\CF3 H NMR (400 DC13) 5 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-Chlor0pyridinyl)—N2-(3,3-diflu0r0cyclopentyl)-N4-(2-(triflu0r0methyl)pyridinyl)- 1,3,5-triazine-2,4-diamine "a 1‘" ZN\ NANAN F H H 1H NMR (400 MHz, CDC13) 5 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-Chlor0pyridin-Z-yl)—N2-(cyclopropylmethyl)—N4-(2-(triflu0r0methyl)pyridinyl)— 1,3,5-triazine-2,4-diamine WO 03640 1H NMR (400MHz, CDC13)5 8.60 — 8.57 (m, 1H), 8.52 — , 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)+. 1-(4-((4-((3,3-Diflu0r0cyclobutyl)amin0)—6-(6-(triflu0r0methyl)pyrazinyl)-1,3,5-triazin yl)amino)pyridinyl)cyclopropanecarbonitrile "YFF £1 E F N/ N \N \l HAN/AMEF 1H NMR (400 MHZz, CDC13) 5 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)+. 1-(4-((4-((4,4-Diflu0r0cyclohexyl)amino)—6-(6-(triflu0r0methyl)pyrazinyl)-1,3,5-triazin yl)amino)pyridinyl)cyclopropanecarbonitrile NVFF NC F N/l N/IN GP \ NAxNAN H H 1H 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, 1H), 5.79 — 5.58 (m, 1H), 4.36 — 4.26(m, 1H), 2.20 — 2.13(m, 4H), 1.90 — 1.72 (m, 8H). LCMS: m/z 518(M+H)+. 1-(4-((4-((6,6-Diflu0rospir0 [3.3]heptan-Z-yl)amin0)—6-(6-(trifluoromethyl)pyrazinyl)— 1,3,5-triazinyl)amin0)pyridinyl)cyclopropanecarbonitrile WO 03640 NV (R)(4-((4-((3,3-difluorocyclopentyl)amin0)—6-(6-(trifluor0methyl)pyrazinyl)—1,3,5- triazin-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile NVFF ND "1‘" (y / NANANVR) F H H 1H N1V[R(4OOMHz,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)—1-(4-((4-((3,3-difluorocyclopentyl)amin0)—6-(6-(triflu0r0methyl)pyrazinyl)-1 ,3,5- triazin-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile 1H NMR z, CDC13)6 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)(4-((4-(6-(triflu0romethyl)pyrazinyl)—6-((1,1,1-triflu0r0pr0panyl)amino)—1 ,3,5- triazin-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile N/l "1‘" \ MANANQCB 1H 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), , 2H) 1.50 — 1.57 (m, 3H).LCMS: m/z 496(M+H)+.
(R)-N2-(3,3-difluorocyclopentyl)—6-(6-(triflu0r0methyl)pyrazinyl)-N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine CF3 "jib! 0 1‘1 EV\ NANAN‘VR) F H H 1HNMR (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-diflu0r0cyclopentyl)—6-(6-(trifluor0methyl)pyrazinyl)-N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine 0 "0" IN\ NAN/Aw) F 1H NMR (400 MHz, CDC13) 5 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, -MS: m/z 507 (M+H)+.
Nz-(3,3-diflu0r0cyclobutyl)(6-(trifluor0methyl)pyrazin-Z-yl)-N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4—diamine 1H NMR (400 MHz, CDC13) 5 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-difluor0cyclohexyl)—6-(6-(trifluor0methyl)pyrazin-Z-yl)—N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4—diamine 1H NMR (400 MHz, CDC13) 5 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-(cyclopr0pylmethyl)—6-(6-(triflu0r0methyl)pyrazinyl)-N4-(2-(triflu0romethyl)pyridin- 4-yl)—1,3,5-triazine-2,4-diamine NVFF \ 1 ‘1/ N N N H H/W 1H 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-diflu0r0spir0 [3.3]heptanyl)(6-(triflu0romethyl)pyrazin-Z-yl)—N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine | \ H H 1H NMR (400 MHz, CD30D) 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,S-difluorophenyl)—6-(6-(trifluoromethyl)pyrazin-Z- yl)—1,3,5-triazine-2,4-diamine WO 03640 F 5i"! F N N/ F N(S) H H 1H NMR (400 MHz, CDC13) 5 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-difluor0phenyl)(6-(triflu0r0methyl)pyrazin yl)—1,3,5-triazine-2,4-diamine F IK/EN FQNANANWN \NI O N2-(4,4-difluorocyclohexyl)—N4-(3,S-difluorophenyl)(6-(trifluor0methyl)pyrazinyl)— 1,3,5-triazine-2,4-diamine NVFF <1 F "/1 GP F N \NAN H H 1H NMR (400 MHz, CDC13) 5 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)+. 1-(4-((4-((4,4-Diflu0r0cyclohexyl)amin0)—6-(6-(difluor0methyl)pyrazinyl)—1,3,5-triazin yl)amino)pyridinyl)cyclopropanecarbonitrile NqAF No i F N/l N|\N GF \ NAN/AN H H 1H NMR (400 MHz, CDC13) 5 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)—1-(4-((4-(6-(diflu0r0methyl)pyrazinyl)—6-((1 ,1,1-triflu0r0pr0panyl)amin0)—1,3,5- n-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile m»,l N/ N \N | | \ NANA {EcaNH 1H NMR (400 MHz, CDC13) 5 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)(4-((4-(6-(difluor0methyl)pyrazin-Z-yl)—6-((1 ,1 ,1-triflu0r0pr0panyl)amino)—1,3,5- triazin-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile "/1 ND" \ HANkmfica 1H NMR (400 MHz, CDC13) 5 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-Chlor0pyrazinyl)—N2-(3,3-diflu0rocyclopentyl)-N4-(3,5-difluor0phenyl)-1 ,3,5- triazine-2,4-diamine NNCII i/N F FQNJLNANQFFN \N 1H NMR (400 MHz, CDC13) 5 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-Chlor0pyrazinyl)—N2-(3,3-diflu0rocyclobutyl)-N4-(3,5-diflu0r0phenyl)—1,3,5-triazine- 2,4-diamine 1H NMR (400MHz, 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, 1H), 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-(trifluor0methyl)pyridinyl)(2- (trifluoromethyl)pyrimidinyl)—1,3,5-triazine-2,4-diamine |N\W) (R)-N2-(3,3-difluorocyclopentyl)—N4-(2-(trifluoromethyl)pyridinyl)(2- (trifluoromethyl)pyrimidinyl)—1,3,5-triazine-2,4-diamine IN\%FF NW HIS N N/ N(R) H H 1H NMR (400 MHz, CDC13) 5 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)+. (4-((4-((3,3-diflu0r0cyclopentyl)amin0)—6-(2-(triflu0r0methyl)pyrimidinyl)—1,3,5- triazin-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile 1H NMR (400 MHz, CDC13) 5 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, 1H), 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)(4-((4-((3,3-diflu0rocyclopentyl)amino)—6-(2-(triflu0romethyl)pyrimidinyl)—1,3,5- triazin-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile NN / %" 'I=e) 1H NMR (400 MHz, CDC13) 5 9.14 (d, J: 5.1 Hz, 1H), 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, 1H), 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)+. 1-(4-((4-((3,3-Diflu0r0cyclopentyl)amino)—6-(4-(triflu0r0methyl)pyrimidinyl)—1,3,5- triazin-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile N /N NC I I NI \N Dd: \ NANA" F 1H NMR (400 MHz, CDC13) 5 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)(4-((4-((3,3-diflu0r0cyclopentyl)amin0)—6-(4-(triflu0r0methyl)pyrimidinyl)—1,3,5- triazin-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile 1H NMR (400 MHz, CDC13) 5 9.29 (d, J: 4.9 Hz, 1H), 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, 1H), 6.14 (d, J: 8.0 Hz, 1H), 4.94 (m, 1H), 2.89 — 2.69 (m, 1H), 2.51 (m, 1H), 2.34 — 2.07 (m, 3H), 1.94 — 1.72 (m, 5H). LCMS: m/z 504 (M+H)+.
(R)(4-((4-((3,3-diflu0rocyclopentyl)amino)—6-(4-(triflu0romethyl)pyrimidinyl)—1,3,5- triazin-Z-yl)amin0)pyridinyl)cyclopropanecarbonitrile N /N NC I | NI \N O Nz-(tert-butyl)-N4-(2-(1,l-difluoroethyl)pyridinyl)—6-(4-(triflu0r0methyl)pyrimidinyl)- 1,3,5-triazine-2,4-diamine F N/N N/ NIN \l kkk WO 03640 1H NMR (400 MHz, CDC13) 5 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)+.
Nz-(2-(1 ,1-difluor0ethyl)pyridinyl)-N4-is0propyl—6-(4-(triflu0r0methyl)pyrimidinyl)- 1,3,5-triazine-2,4-diamine Ml:\ F F I F N/N "i I 1 i k 1H NMR (400 MHz, CDC13) 5 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)(4-(triflu0r0methyl)pyrimidin-Z-yl)-1,3,5-triazinyl)amin0)—5- fluorobenzonitrile \ F Ii k\ / N N N N/ H H 1H NMR (400 MHz, DMSO-d6) 5 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+1)+. 1-((4-((3,S-Difluorophenyl)amin0)—6-(4-(triflu0r0methyl)pyrimidin-Z-yl)—1,3,5-triazin yl)amino)—2-methylpr0panol 1H NMR (400 MHz, DMSO-d6) 5 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 ed by general Scheme 33, set forth below.
Scheme 33 F F F NaN(CN)2, HCI 160°C F H 02 ,CN F NH2 F N N F N N N H H H H H 2 3 MeONa MeOH F F F F \ \ \ \ | NH2NH2 | Br2/CHCI3 | CO/Pd(OAc)2 | / ,NH2 / / F N F F N fl 60 0C F N Br dppf/MeOH/60 0c; F N COzMe 4 6 7 F F 191 GP F NAN/AN H H Step 1: Preparation of NI-(3,5-diflu0r0phenyl)—N3-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 t of water and conc. HCl (2M, 2 mL). The reaction mixture was then stirred at 90°C for 16 hours. The ing mixture was cooled to r.t. and quenched by satd. aq. NaHC03and 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)+.
WO 03640 Step 2: Preparation of NI-(3,5-diflu0r0phenyl)—N5-(4,4-diflu0r0cyclohexyl) -guanidine. A mixture of Nl-(3,5-difluorophenyl)-N°-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 1hr. The ing mixture was cooled to r.t. and then trituratedwith a mixed solvent of EtOAc and PE. The solid was ted by filtration and dried to afford the desired product. LC-MS: m/z 332 (M+H)+.
Step 3: Preparation of flu0r0-2—hydrazinylpyridine. To an ld 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 on 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 NaZSO4 and concentrated under reduced pressure to afford 3,6-difluorohydrazinylpyridine. LC-MS: m/z 146 (M+H)+.
Step 4.°Preparati0n 0f2—br0mo-3,6-diflu0r0pyridine. To a stirred solution of 3,6-difluoro hydrazinylpyridine(1.1 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 ing mixture was cooled to r.t.,then quenched with satd. aq. NaHC03, and extracted with dichloromethane (2 x 20 mL). The ed organic layers were dried over anhydrous Na2804, and concentrated and purified by standard methods to afford 2-bromo-3,6-difluoropyridine.
LC-MS: m/z 194 (M+H)+.
Step parati0n of methyl 3,6-diflu0r0picolinate. 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- difiuoropicolinate. LC-MS: m/z 174 (M+H)+.
Step 6: Preparation ofNZ-(4,4-dy‘luorocycl0hexyD-N4-(3,5-diflu0r0phenyl)—6—(3,6 - difluoropyridin-Z-yD-1,3,5-triazine—2,4—diamine. To a sion of Nl-(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. ed organic layers were dried over anhydrous NaZSO4, and concentrated and purified by standard methods to afford 4-difluorocyclohexyl)-N4-(3,5-difiuorophenyl)(3,6-difluoropyridin yl)-1,3 ,5-triazine-2,4-diamine.
F Fl/N QUITF F NAN/AN H H 1H NMR (400 MHz, CDC13) 5 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 nds using the appropriate starting materials.
Compound Nz-(3,3-difluorocyclopentyl)-N4-(3,5-difluorophenyl)(3,6-difluoropyridin-Z- yl)—1,3,5-triazine-2,4-diamine F F F<1le QFNJ\N/)\N F H H 1H NMR (400 MHz, CDC13) 5 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: rn/z 441 .
Comound Nz-(3,3-diflu0r0cyclobutyl)—N4-(3,S-difluorophenyl)(3,6-difluoropyridin-Z-yl)— 1,3,5-triazine-2,4-diamine F FI’N F(111%N NAN H H 1H NMR (400 MHz, CDC13) 5 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: rn/z 427 (M+H)+.
Example 34. The compounds of this Example are prepared by general Scheme 34, set forth below.
Scheme34 F N—NH2 I |\ /N /N F F F F F NHZ-NHZ F Raney NI_ 11 GF F NAN/AN F N11er—/N N H H H H \ NH2 F F <1M UF/ F F N N N H H Step 1: Preparation of N2-(4,4-diflu0rocyclohexyD-N4-(3,5-diflu0r0phenyl)—6-(3-flu0r0-6— hydrazinymyridin-Z-yD-I,3,5-triazine—2,4—diamine. To a on of NZ-(4,4- difluorocyclohexyl)-N4-(3 , 5 -difluorophenyl)—6-(3 ,6-difluoropyridinyl)-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 e 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 Na2804and concentrated under reduced pressure to give the desired product.
\ N—NH2 F F QUUPF F N N/ N H H LC-MS: m/z 467 .
Step 2: Preparation of 6-(6-amin0fluoropyridin-Z-yD-NZ-(4,4-diflu0r0cyclohexyl)—N4-(3,5- difluorophenyD-1,3,5-triazine—2,4-diamine. To a solution of N2-(4,4-difluorocyclohexyl)-N4- (3 ,5-difluorophenyl)—6-(3 -fluorohydrazinylpyridinyl)-l ,3 ,5-triazine-2,4-diamine(46 mg,O.l 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-aminofluoropyridinyl)-N2-(4,4- difluorocyclohexyl)-N4-(3 uorophenyl)-l ,3 ,5-triazine-2,4-diamine.
\ NH2 F F O F "0" GP F NkN/AN H H 1H NMR (400 MHz, CDC13) 5 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 ure set forth in Example 34was used to e the ing compounds using the appropriate starting materials.
Compound 6-(6-Aminofluoropyridin-Z-yl)-N2-(3,3-difluorocyclopentyl)-N4-(3,5- difluorophenyl)—1,3,5-triazine-2,4-diamine 1H NMR (400 MHz, CDC13) 5 .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), 2.3mm (m, 4H), 1.92-1.58 (m, 2H). LCMS: m/z 438 (M+H)+.
Example 35: Preparation of N4,N6-bis(4,4-difluorocyclohexyl)(6-(trifluoromethyl) pyrazin-Z-yl) pyrimidine-4, 6-diamine Scheme 35 CF3 N \ 1wCF3 CF3 1. NaOMe N/Y\ CF3 N \ NH4OH POCI3 "N IKfN KfN 2 NHI 4Cl EtOH EN COZMe j o NH2 CN HN NH2 I\f/\Nr\ CF3 N/YCF?’ i ’ | CH2(C02Et)2 I POCI3 /N DIPEA/CsF F F N/ N K2C03 N/ N DMSO F F / | solvent free M N N MVY1/ 1500C NMN HO OH | / 3 Step A: 6-(TrifluoromethyDpyrazine—Z-carboxamide.To a solution of methyl 6-(trifluoromethyl) pyrazine-Z-carboxylate (15 g, 72.8 mmol) in EtOH (20 mL) was added NH4OH (6 mL, 156 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- uoromethyl)pyrazinecarboxamide.LC-MS: m/z 192 (M+H)+.
Step B:6-(Trifluoromethpryrazine-Z-carbonitrile.A mixture of 6-(trifluoromethyl) pyrazine carboxamide (10 g, 52 mmol) in POC13 (80 mL) was stirred at 100°Covernight. The reaction mixture was cooled to r.t. and concentrated under d pressure. The residue was partitioned between DCM and ice water.The organic layer was separated, washed with brine, dried over anhydrous NaZSO4,concentrated, andpurified by standard methods to afford 6- (trifluoromethyl)pyrazinecarbonitrile.LC-MS: m/z 174 (M+H)+.
Step C: 6-(TrifluoromethyDpyrazinecarb0ximidamide hydrochlorideTo a solution of 6- (trifluoromethyl) pyrazinecarbonitrile (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 ofNH4Cl (1.5 g, 30 mmol). The mixture was stirred at 70°C for 3 hr, then cooled to r.t. and concentrated under reduced re. 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 trated under reduced pressure to afford 6-(trifluoromethyl) pyrazine carboximidamide hydrochloride. LC-MS: m/z 191 (M +H)+.
Step D: triflu0r0methyl)pyrazinyl)pyrimidine—4,6(1H,5H)-di0ne. To a mixture of 6- (trifluoromethyl) pyrazinecarboximidamide hydrochloride (1.6 g, 7.0 mmol) in l malonate (3.2 g, 21.2 mmol) was added potassium carbonate (3.0 g, 21.2 mmol). The reaction e 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 eum ether then treated with MeOH to form a suspension. The suspension was filtered and the filtrate was concentrated under d pressure to afford trifluoromethyl)pyrazinyl)pyrimidine-4,6-(1H,5H)— dione. LC-MS: m/z 259 (M+H)+.
Step E: 4, 6-Dichl0r0(6-(triflu0r0methyl) pyrazin-Z—pryrimidine. A mixture of 2-(6- (trifluoromethyl) pyrazinyl) pyrimidine-4, 6(1H, 5H)-dione (1.4 g, 5.4 mmol) in POC13 (10 mL) was stirred at 100°C overnight then cooled to r.t. and trated under reduced pressure.
The residue was purified by column chromatography (PE/EA = 20/1 to 10/1) to afford 4, 6- dichloro(6-(trifluoromethyl) pyrazinyl)pyrimidine.LC-MS: m/z 295 (M+H)+.
Step F: N', Nfi-bis (4,4-diflu0rocycl0hexyD(6-(trifluoromethyl) n-Z-yl) pyrimidine-4, 6-diamine. To a mixture of 4, 6-dichloro(6-(trifluoromethyl) pyrazinyl)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 on 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 ted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2804, and concentrated under reduced pressure. The residue was purified by standard methods to afford N4,N6-bis (4,4-difluorocyclohexyl)(6-(trif1uoromethyl) pyrazinyl) pyrimidine-4, 6-diamine.
N \CM" F F Ff) "/ .~ F H H 1H NMR (400 MHz, CDC13) 5 9.73 (s, 1H), 9.00 (s, 1H), 5.31 (s, 1H), 4.95 (m, 2H), 3.76 (m, 2H), 2.20—2.09 (m, 8H), 1.98-1.85 (m, 4H), 1.72-1.63 (m, 4H).LC-MS: m/z 493 (M+H)+.
Example 36. ation of Aromatic-aliphatic ne Compounds. The compounds of this Example are prepared by general Scheme 36, set forth below.
WO 03640 Sheme 36 PhYNH Br F I>—CN Br ph a Ph N \ \ | \ | CN \r/ | CN / N Ph LHMDSHHF 2(dba)3/Binap/dioxane / N ClYNYC' N /N Y H N N CI 2N Hm H2N CI THF/DIPEA \ Nc CN | \f Y l N\ N /N /N THF/N HCOa THF 3 Y F F No N; / \ NI \ N D N, / J\\J\ NC N FF N|\ W HNQX, OiF / NANA" Step 1: Preparation of 1-(4-bromopyridin-Z-yl)cyclopropanecarbonitrile. To a solution of 4- bromofluoropyridine (30 g, 170.47 mmol) and cyclopropane carbonitrile (22.9 g, 340.94 mmol) in THF (400 mL) below -100C was slowly added dropwise LiHMDS (1.2 , 284 mL). The reaction mixture was then stirred at r.t. for 12 hr. The resulting mixture was cooled to 00C, then ed with brine (200 mL). The mixture was concentrated under reduced pressure.
The e was extracted with EtOAc (3x200 mI.,).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 1-(4-(diphenylmethyleneamino)pyridin-2—yl)cyclopropanecarbonitrile.
To a solution of 1-(4-bromopyridinyl)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 tolOOOC for 1 hr under N2 atmosphere, then cooled andfiltered. The filtrate was concentrated to give the desired productLC-MS: m/z 324 (M+H)+.
Step 3: Preparation of 1-(4-aminopyridinyl)cyclopropanecarbonitrile. A mixture of 1-(4- (diphenylmethyleneamino)pyridinyl)cyclopropanecarbonitrile (42.1 g crude, 130 mmol) and THF/ aq. HCl (2N) (200 mL, 1) was stirred at r.t. for 1 hr and concentrated under reduced re. The aqueouslayer was extracted with PE (3x100 mL), then adjusted to pH 8-9 with satd. aq. Na2C03, and extracted with EtOAc (3x100 e combined organic layers were dried over anhydrous Na2S04, and concentrated concentrated and purified by standard methods to afford the desired productlHNlVIR (CDC13)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), .80 (m, 2H), 1.61-1.63 (m, 2H).LC-MS: m/z 160 (M+H)+.
Step 4: Preparation (4,6-dichloro-1,3,5-triazinylamino)pyridin-2—yl)cyclopropane carbonitrile.To a solution of minopyridinyl)cyclopropanecarbonitrile (2.5 g, 15.7 mmol), 2,4,6-trichloro-1,3,5-triazine (3.5 g, 18.8 mmol) in THF (40 mL) was added NaHC03 (2.64 g, 31.4 mmol). The reaction mixture was stirred at r.t. overnight thenfiltered. The e was concentrated and purified by standard methods to afford the desired product.LC-MS: m/z 307 (M+H)+.
Step 5: Preparation of 1-(4-(4-chloro(3,3-difluorocyclopentylamino)—1,3,5-triazinyl amino) n-Z-yl)cyclopropanecarbonitrile. To a solution of 1-(4-(4,6-dichloro-1,3,5-triazin- 2-ylamino)pyridinyl)cyclopropanecarbonitrile (0.75 g, 2.44mmol) and 3,3- difiuorocyclopentanamine hydrochloride (0.39 g, 2.44 mmol) in THF (10 mL) at 0 0C 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 s to afford the desired product.LC-MS: m/z 392 (M+H)+.
Step 6: Preparation ofl-(4-(4-(3,3-difluorocyclopentylamino)—6-(3-(trifluoromethyl)—1H- pyrazol-I-yD-1,3,5-triazinylamino)pyridinyl)cyclopropanecarbonitrile.To a solution of 1- WO 03640 (4-(4-chloro(3 ,3 -difluorocyclopentylamino)—l riazinylamino) pyridin 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 ght then concentrated under reduced pressureThe 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 Na2804, and concentrated and d by standard methods to afford the desired product. 1H NMR (400 MHz, CDC13) 5 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 .
The procedure set forth in Example 36was used to produce the following compounds using the appropriate starting materials.
Compound (S)—1-(4-(4-(3,3-Difluorocyclopentylamino)—6-(3-(trifluoromethyl)-1H—pyrazol— 1-yl)-1,3,S-triazin-Z-ylamino)pyridinyl)cyclopropanecarbonitrile.
{—(MF\/N’N ND fl IN N \N N(S) F H H 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)(4-(4-(3,3-Difluorocyclopentylamino)(3-(trifluoromethyl)-1H—pyrazol— 1-yl)-1,3,S-triazin-Z-ylamino)pyridinyl)cyclopropanecarbonitrile.
WO 03640 F F /N’N\ "0 f1 w N \N N"‘FR) F H H 1H NMR (400 MHz, CDC13) 8 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 1-(4-((4-((4,4-Difluorocyclohexyl)amino)—6-(3-(trifluoromethyl)-lH-pyrazol-l- yl)—1,3,S-triazin-Z-yl)amino)pyridinyl)cyclopropanecarbonitrile 1H NMR (400 MHz, CDC13) 5 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 1-(4-((4-((3,3-Difluorocyclobutyl)amino)(3-(trifluoromethyl)—1H—pyrazol-l- yl)—1,3,S-triazin-Z-yl)amino)pyridinyl)cyclopropanecarbonitrile F F 6%/N)N N/l NIJ§N \ NANANBil: H H 1H NMR (400 MHz, CDC13) 5: 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 (4-(3-(Trifluoromethyl)-1H—pyrazolyl)((1,1,1-trifluoropropan yl)amino)—1,3,5-triazinyl)amino)pyridinyl)cyclopropanecarbonitrile 6%/N)N N/I NIJ§N \ NANANJ\CF3 H H 1H NMR (400 MHz, CDC13) 5 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)(4-((4-(3-(trifluoromethyl)-1H—pyrazol—1-yl)—6-((1,1,1-trifluoropropan yl)amino)—1,3,5-triazinyl)amino)pyridinyl)cyclopropanecarbonitrile (4MP\/N’N \ 1*1 N N/ "@CB 1H NMR (400 MHz, CDC13) 5 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)—1-(4-((4-(3-(trifluoromethyl)—lH-pyrazolyl)—6-((1,1,l-trifluoropropan-Z- yl)amino)—1,3,5-triazinyl)amino)pyridinyl)cyclopropanecarbonitrile F F /N’N\ \ 1&1 L N N/ "(90% 1H NMR (400 MHz, CDC13) 5 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 .
Compound Nz-(3,3-difluorocyclopentyl)(3-(trifluoromethyl)—1H—pyrazol-l-yl)-N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine F F (—(MF/ )N F3 N I NIJ§N Dd: \ NANAN F H H 1H NMR (400 MHz, CDC13) 5 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)pyridinyl)—1,3,5-triazine-2,4-diamine 1H NMR (400MHz, CDC13)5 8.64 — 8.55 (m, 2H), 8.48 — 8.11 (m, 1H), 7.75 — 7.41 (m, 2H), 6.77 — 6.75 (m, 1H), 5.97 — 5.73 (m, 1H), 4.71 — 4.61(m, 1H), 2.74 — 2.61 (m, 1H), 2.42 — 2.36 (m, 2H), 2.30 — 2.16 (m, 2H), 1.93 — 1.86 (m, MS: m/z 495(M+H)+.
Compound N2-(3,3-difluorocyclobutyl)(3-(trifluoromethyl)-1H-pyrazolyl)-N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine F F 6%/ )N CF3 N "CL "1*" MP\ NANAN H H 1H NMR (400MHz, CD30D)5 8.69 — 8.62 (m, 1H), 8.51 — 7.67 (m, 3H), 6.84 — 6.834(m, 1H), 4.51 — 4.29 (m, 1H), 3.09 — 3.02 (m, 2H), 2.68 — 2.64 (m, 2H).LCMS: m/z 481(M+H)+.
Compound N2-(cyclopropylmethyl)(3-(trifluoromethyl)-1H-pyrazolyl)-N4-(2- (trifluoromethyl)pyridinyl)—1,3,5-triazine-2,4-diamine F F 0%/ TN CF3 JN\ "/1 "1‘" \ NANAN H H 1H NMR (400 MHz, CDC13) 5 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 Trifluoromethyl)—1H—pyrazolyl)-N2-(2-(trifluoromethyl)pyridinyl)- N4-(1,1,1-trifluoropropanyl)—1,3,5-triazine-2,4-diamine | NI \N i \ NANAN CF3 H H 1H NMR (400 MHz, CDC13) 5 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)(3-(trifluoromethyl)-1H—pyrazol-l-yl)-N2-(2-(trifluoromethyl)pyridin yl)-N4-(1,1,1-trifluoropropanyl)—1 ,3,5-triazine-2,4-diamine /,N\ F3 1 "I 11 N N/ "flog 1H NMR (400 MHz, CDC13) 5 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, -MS: m/z 487 (M+H)+.
Compound (S)—6-(3-(trifluoromethyl)-1H-pyrazolyl)-N2-(2-(trifluoromethyl)pyridin yl)-N4-(1,1,1-trifluoropropanyl)—1 ,3,5-triazine-2,4-diamine F3 N NJ§N \ AA 1H 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)(3-(trifluoromethyl)-1H—pyrazol—1-yl)— 1,3,5-triazinyl)amino)fluorobenzonitrile F F (C/}N CN O )N\ "P" EFF F N)\N/)\N H H 1H NMR (400 MHz, CDC13) 5 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-S-((4-(3-(trifluoromethyl)-1H—pyrazolyl)—6-((1,1,l-trifluoropropan- 2-yl)amino)—1,3,S-triazinyl)amino)benzonitrile F F CN /JN\’N F(11:11N N N CF3 H H 1H NMR (400 MHz, CDC13) 5 8.60 — 8.53 (m, 1H), 7.99 — 7.62 (m, 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)(3-(trifluoromethyl)—1H—pyrazolyl)- 1,3,5-triazinyl)amino)fluorobenzonitrile 1H NMR (400 MHz, CDC13) 5 8.63 — 8.55 (m, 1H), 7.83 — 7.66 (m, 3H), 7.12 — 7.08 (m, 1H), 6.77 = 4 Hz, 1H),6.21 — 6.75 (m, 1H), 6.68 (d, J — 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 .
Compound 4-((4-((3,3-Difluorocyclopentyl)amino)—6-(3-(trifluoromethyl)—1H—pyrazolyl)- 1,3,5-triazinyl)amino)picolinonitrile (—(MF/\N CN N, "d M [N\ N \N N F H H 1H NMR (400 MHz, CDC13) 5 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 yl)-1,3,5-triazinyl)amino)picolinonitrile 1H NMR (400 MHz, DMSO- d6) 5 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)(3-(trifluoromethyl)-1H—pyrazol—1-yl)— 1,3,5-triazinyl)amino)picolinonitrile F F 6%/\N CN N, 0 "1*" m;\ NANAN H H 1H NMR (400 MHz, CDC13) 5 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-(3-(trifluoromethyl)-lH-pyrazol-l-yl)((1,1,1-trifluoropropan yl)amino)—1,3,5-triazinyl)amino)picolinonitrile F F (—(MF/\N CN N, 0~01 \ NJ\N/J\N7>CF3 H H 1H NMR (400 MHz, CDC13) 5 8.64 (d, J: 8 Hz, 1H), 8.61 — 8.57 (m, 1H), 8.45 — 8.32 (m, 1H), 8.14 — , 1H), 7.78 — 7.48 (m, 1H), 6.78 — 6.68 (m, 1H), 6.05 — 5.96 (m, 1H), 5.26 — 4.70 (m, 57 — 1.51 (m, 3H).LCMS: m/z 444 (M+H)+.
Compound Nz-(3,3-difluorocyclopentyl)-N4-(3,S-difluorophenyl)(3-(trifluoromethyl)-1H- pyrazol-l-yl)-1 ,3,5-triazine-2,4-diamine F F ((MF\/ ,N F N FQNANANN \N F ' D Compound 3-diflu0r0cyclobutyl)-N4-(3,S-difluorophenyl)—6-(3-(trifluoromethyl)-1H- pyrazol-l-yl)-1 ,3,5-triazine-2,4-diamine F F (—(MF/ )N FONxNxm/DLi F N/ N 1H NMR (400 MHz, CDC13) 5 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-diflu0r0phenyl)(3-(triflu0r0methyl)—1H—pyraz01—1-yl)—N4-(1,1,1- trifluoropropan-Z-yl)-1,3,5-triazine-2,4-diamine F F / )N F N K) "1*" 1 F NANAN CF3 H H 1H NMR (400 MHz, CDC13) 8 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 ((3,S-Difluorophenyl)amino)—6-(3-(trifluoromethyl)-1H-pyrazolyl)- 1,3,5-triazinyl)amino)methylpropanol F F 6%/)N F N F<1 1*1N N/ NASH 1H NMR (400 MHz, CDC13) 5 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 ofthis Example are prepared by general Scheme 37, set forth below.
Scheme 37 CI N CI TI T Y/ CF3 CI CF3 CI H2" \ CF3 CI 6NH§N THF/DIPEA | N|\ MAIN Dip /N THF/NaHCOs / NJ\N/)\C| / NANAN H H H CF3 3 CHZNISF3 NaCN F NaHS/M CI —, N/ l NI \N ELF —MFg>2 N/ N \N ELFF MeCN/DMSO \ HXNAH \ I" I NAN F3C_Jl\/> [fik/DLFF TrIphosgene/TEA / N MeCN B5\HN:EJJ\)LJ/A cog—2:1 \/I>l|sjilNuflLN/ Step 1: Preparation of 4, 6-dichl0r0-N-(2—(triflu0r0methyl)pyridinyI)-1,3,5-triazin-2—amine.
To a solution of 2-(trifiuoromethyl)pyridinamine (3 g, 18.7 mmol) and 2,4,6-trichloro-1,3,5- triazine (3.6 g, 19.5 mmol) in THF (40 mL) was added NaHC03(3.1 g,37.5 mmol). The reaction mixture was stirred at r.t. for 16 hr and filtered. The filtrate was trated concentratedand purified by standard sto affordthe desired product.LC-MS: m/z 310 (M+H)+.
Step 2.°Preparati0n of r0-N2-(3,3-diflu0r0cycl0buljyl)—N4-(2-(triflu0r0methyl)pyridin-4— yl)-1,3,5-triazine—2,4-diamine. To a solution of 4,6-dichloro-N-(2-(trifiuoromethyl)pyridinyl)- 1,3,5-triazinamine (4 g, 12.9 mmol) and 3,3-difiuorocyclobutanamine hydrochloride (1.9 g, 13.5 mmol) in THF (40 mL) was added DIPEA (4.8 g, 37.2 mmol). The reaction mixture was d at r.t. for 15 hr then concentrated under reduced pressureThe 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 ,concentratedand purified by standard sto affordthe desired product.
LC-MS: m/z 3 81 (M+H)+. 2014/081957 Step 3.°Preparation of 4-(3,3-difluorocyclobutylamino)(2—(trifluoromethyl)pyridin-4— ylamino)-1,3,5-triazinecarbonitrile. To a solution of 6-chloro-N2-(3,3-difluorocyclobutyl)— N4-(2-(trifluoromethyl)pyridinyl)-1,3,5-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 e organic layer was separated, washed with brine, dried over anhydrous NaZSO4, 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 ylamino)-1,3,5-triazinecarbothioamide. To a solution of 4-(3,3 -difluorocyclobutylamino) (2-(trifluoromethyl)pyridinylamino)—1,3,5-triazinecarbonitrile (0.7 g, 1.88 mmol) in DMF (15 mL) were added NaHS (0.5 g, 9.0 mmol) and MgClz (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 ted, washed with brine, dried over anhydrous Na2804, and concentratedand purified by standard methodsto affordthe desired t.LC-MS: m/z 406 (M+H)+.
Step 5: ation of 3,3-difluorocyclobutylamino)(2-(trifluoromethpryridin-4— ylamino)-1, 3, 5-triazinyl)(trifluoromethyl)—4,5-dihydrothiazoloL A mixture of - difiuorocyclobutylamino)(2-(trifiuoromethyl)pyridinylamino)-1,3,5-triazine carbothioamide (350 mg, 0.86 mmol) and 3-bromo-1,1,1-trifluoropropanone (180 mg, 0.95 mmol) in MeCN (10 mL) was stirred at 60°C for 2 hr then ioned between EtOAc (20 mL) and H20 (10 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2804, and concentratedand purified by standard methodsto affordthe desired product. 1H NMR (400 MHz, DMSO-d6) 5 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-difluorocyclobutyD-N4-(2-(trifluoromethpryridin-4—yl)—6-(4- (trifluoromethyl)thiazol-Z-yl)-1,3,5-triazine-2,4-diamine. To a solution of 2-(4-(3,3- difluorocyclobutylamino)(2-(trifluoromethyl)pyridinylamino)-l ,3 ,5 -triazinyl) (trifluoromethyl)-4,5-dihydrothiazolol (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 , and concentratedand purified by standard methodsto affordthe desired productlH NMR (400 MHz, DMSO-d6) 5 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 .
The procedure set forth above in Example 37 used to produce the following compounds using the riate starting materials.
Compound N2-(cyclopropylmethyl)—N4-(2-(trifluoromethyl)pyridinyl)—6-(4- uoromethyl)thiazol—2-yl)—1,3,5-triazine—2,4-diamine fQLF s N CF3 I \ NAN/NWH H 1H NMR (400 MHz, CDC13) 8 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 Nz-(3,3-difluorocyclopentyl)-N4-(2-(trifluoromethyl)pyridinyl)(4- (trifluoromethyl)thiazol—2-yl)—1,3,5-triazine—2,4-diamine F F S ’ N Q 1:1 [V 1H NMR (400 MHz, DMSO-d6) 5 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 Nz-(3,3-difluorocyclopentyl)-N4-(3,5—difluorophenyl)—6-(4- (trifluoromethyl)thiazol—2-yl)—1,3,5-triazine-2,4-diamine F F S N FQNKNANIN \N F H H 1H N1VIR (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)+. nd N2-(3,3-difluorocyclobutyl)—N4-(3,5-difluorophenyl)—6-(4- (trifluoromethyl)thiazol—2-yl)—1,3,5-triazine-2,4-diamine OHMF F NJ\\N N H H 1H 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)(4-(trifluoromethyl)thiazolyl)—1,3,5- triazin-Z-yl)amino)fluorobenzonitrile SFfiq/N ElMJNLNMI F ANDL 1H NMR (400MHz, CDC13)6 , 1H), 7.87 — 7.797(m, 2H), 7.66 Hz, 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)(4-(trifluoromethyl)thiazolyl)-1,3,5- triazin-Z-yl)amino)fluorobenzonitrile Ji 1 I N \N I J3< NC NANAN F H H 1H NMR (400MHz, 6 8.00(s, 1H), 7.28 - 7.02 (m, 3H), 6.61(s, 1H), 6.01 — 5.76 (m, 1H), 4.51 — 4.44 (m, 1H), , 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 ofthis Example are prepared by general Scheme 32, set forth below.
Scheme 32 CI CI N OMa e I NaOMe, \ N MeOH \N \N NH4C| \N MeOH | | I / NH —’ / NH —> / N/ N 0\ NH2 CI CI CI / / \ IN I I \ N \ N POCI3 CsF,D|PEA CsF DIPEA —> —> ’—> N/ N R1 N/ N R1 N/ N R4 M 2X MI R2>l\ M XR5 H H H Step 1: Preparation of methyl 6-chlor0picolinimidate. 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-chlor0pic0linimidamide. 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 ed. The filtrate was trated under reduced pressure to give thedesired productLC-MS: m/z 156 (M+H)+.
Step 3: Preparation of 2—(6-chloropyridinyl)pyrimidine—4,6-di0L To a solution of sodium metal (0.9 g, ) 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 re. The residue was triturated with EtOAc (30 mL) and filtered. The solid was collected and dried under high vacuum to give the desired tLC-MS: m/z 224 (M+H)+.
Step 4: Preparation of 4,6-dichloro-Z-(6-chl0r0pyridinyDpyrimidine. A mixture of 2-(6- chloropyridinyl)pyrimidine-4,6-diol (2 g, 9 mmol) in POC13 (20 mL) was d at 90 °C ght 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 Na2SO4and concentrated under reduced pressure. The residue was purified by rd methods to give the desired product.LC-MS: m/z 260 (M+H)+.
Step 5: Preparation of (R)chl0r0(6-chl0r0pyridinyl)-N-(1,1,1-triflu0r0pr0pan-2— pryrimidin-4—amine. A mixture of 4,6-dichloro(6-chloropyridinyl)pyrimidine ( 200 mg, 0.77 mmol ), 1,1,1-trifluoropropanamine 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 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was d bystandard s to give the desired productlH N1VIR (400 MHz, 6) 5 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—chl0r0pyridin-2—yl)—N4-(4,4-diflu0rocycl0he3qu-N6-(1,1,1- triflu0r0pr0pan-Z-pryrimidine—4,6-diamine. A mixture of (R)chloro(6-chloropyridin yl)-N-(1,1,1-trifluoropropanyl)pyrimidinamine (100 mg, 0.3 mmol ) , 4,4- difluorocyclohexanamine hloride ( 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 ovemightThe 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.
/|CI L "1" UP\ N N H H 1H NMR (400 1Vle, DMSO-d6) 5 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)Inhibit0rs The following describes the experimental procedures that can be used to obtain data on s 2 and 4 of Table 4 and column 2 of Table 5.
In the primary reaction, the ion of 01-KG acid to 2-HG is accompanied by a concomitant oxidation ofNADPH to NADP. The amount ofNADPH remaining at the end ofthe reaction time is ed 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 resorufln. Uninhibited reactions exhibit a low fluorescence at the end of the assay, while reactions in which the consumption H by R132H IDH1 has been inhibited by a small molecule show a high fluorescence.
The primary reaction is performed in a volume of 50 uL 1X Buffer (150 mM NaCl, 20 mM Tris 7.5, 10 mM MgC12, 0.05% (w/v) bovine serum albumin), contained 0.25 ug/mL (2.7 n1\/I) IDH1 wt/ IDH1 R132H heterodimer, 0.3 mM alpha-ketoglutarate, 4 uM NADPH, and either 300 uM NADP (saturated) or 30 uM NADP (without saturation), and 1 uL of 50X compound in DMSO. The mixture of compound, enzyme, and cofactor is pre-incubated at room temperature for 1 hr prior to the addition ofa1pha-ketog1utarate. To perform the ary reaction, 10 uL of 1X buffer containing 36 ug/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 nd dilutions are ed in 100% DMSO concentration and diluted 1:50 into the final reaction. IDH1 wt / IDH1 R132C is assayed under similar conditions except that 1X Buffer is 50 mM KZHP04, pH 6.5; 10 mM MgC12; 10% glycerol; 0.03% (w/v) bovine serum albumin and final concentrations are 0.4 ug/mL (4.3 nM) IDHl wt / IDHl R132C heterodimer, 0.02 mM alpha-ketoglutarate, 4 uM NADPH, and either 300 uM NADP ated) or 30 uM NADP (without saturation). 1C5 0s are ined.
IDHl or IDH2 wildtype (wt) and mutant heterodimers are expressed and purified by methods known in the art. For example, IDlet/Rl32m heterodimer is expressed and purified as follows. Co-expression of IDlet-his and IDHlRl32C-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 er (Microfluidics) set to 500 psi, and then fuged at 22,000 rcf for 20min at 4°C. The supernatant is harvested and loaded at lScm/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 bration buffer followed by equilibration buffer containing 20mM imidazole and 60mM imidazole to baseline. IDlet-his homodimer and IDHl wt-his / IDHlRl 32C-flag are eluted by equilibration buffer containing 250mM imidazole. Fractions eluted by 250mM imidazole are pooled together and loaded at lScm/h onto a column pre-packed with 10ml ANTI-FLAG® M2 Affinity Gel ), the column is equilibrated with 50mM Tris, 500mM NaCl, pH7.4. After washing with equilibration buffer, IDlet-his/IDHlRl 32C-flag heterodimer is eluted by equilibration buffer containing flag e (0.2mg/ml). Aliquots of IDlet-his/IDHlRl32C-flag are flash frozen in liquid N2 and stored at -80°C.Same conditions are used for the purification of IDHl wt- H1R132H-flag.
In Vitro Assays for IDHlm (R132H or R132C) Inhibitors The following bes the mental 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 ul reaction mixture. IDH enzyme activity converting alpha- utarate to 2-hydroxyglutaric acid is ed using a NADPH depletion assay. In the assay the remaining cofactor is ed 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 ofNADPH remaining. IDHl -R132 homodimer enzyme is diluted to 0.125 ug/ml in 40 ul of Assay Buffer(150 mM NaCl, 20 mM Tris-Cl pH 7.5, 10 mM MgC12, 0.05% BSA, 2 mM b- mercaptoethanol); 1 ul 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 ul of Substrate Mix (20 ul NADPH, 5 mM alpha-ketoglutarate, in Assay Buffer) and the mixture is incubated for 90 minutes at room ature. The on is terminated with the addition of 25 ul of Detection Buffer (36 ug/ml diaphorase, 30 mM resazurin, in 1X Assay Buffer), and is incubated for 1 minute before reading on a SpectraMax platereader at Ex544/Em590.
Compounds are assayed for their activity against IDHl R132C following the same assay as ith the following modifications: Assay Buffer is (50 mM potassium phosphate, pH 6.5; 40 mM sodium carbonate, 5 mM MgC12, 10% glycerol, 2 mM b-mercaptoethanol, and0.03% BSA). The concentration ofNADPH and alpha-ketoglutarate in the Substrate Buffer is 20 uM and 1 mM, respectively.
In Vitro Assays for IDHlm (R132H or R132C) Inhibitors WO 03640 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 d to 50X final concentration in DMSO, for a 50 ul reaction mixture. IDH enzyme activity converting alpha- ketoglutarate to 2-hydroxyglutaric acid is measured using a NADPH depletion assay. In the assay the ing 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 tion to the amount H ing. IDHl -Rl32H homodimer enzyme is diluted to 0.125 ug/ml in 40 ul of Assay Buffer(l 50 mM NaCl, 20 mM Tris-Cl pH 7.5, 10 mM MgC12, 0.05% BSA, 2 mM b- mercaptoethanol) containing 5 uM NADPH and 37.5 uM NADP; 1 ul 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 ul of Substrate Mix (20 ul 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 ul of Detection Buffer (36 ug/ml diaphorase, mM resazurin, in 1X Assay Buffer), and is incubated for 1 minute before reading on a SpectraMax platereader at Ex544/Em590.
Compounds are assayed for their activity against IDHl R132C following the same assay as abovewith the ing modifications: IDHl -Rl32C homodimer enzyme is diluted to 0.1875 ug/ml in 40 ul of Assay Buffer (50 mM potassium phosphate, pH 6.5; 40 mM sodium carbonate, mM MgC12, 10% ol, 2 mM b-mercaptoethanol, and0.03% BSA) containing 5 uM NADPH and 28.75 uM NADP. The tration 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 Rl40Qinhibitory activity through a cofactor depletion assay. Compounds are preincubated with enzyme, then the reaction is started by the addition of NADPH and d-KG, and allowed to proceed for 60 minutes under conditions previously demonstrated to be linear with t 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 resoruf1n with the concomitant oxidation ofNADPH 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 h quantitative production of an easily detected fluorophore.
Specifically, into each of 12 wells of a 384-well plate, 1 ul of 100x compound dilution series is placed, followed by the addition of 40 ul of buffer (50 mM potassium phosphate (K2HP04), pH 7.5; 150 mM NaCl; 10 mM MgC12, 10% glycerol, 0.05% bovine serum n, 2 mM beta-mercaptoethanol) containing 0.25 ug/ml IDH2 R140Q protein. The test compound is then incubated for one hour at room temperature with the enzyme; before ng the IDH2 reaction with the on of 10 ul of ate mix containing 4 uM NADPH and 1.6 mM d-KG in the buffer described above. After a further 16hours of incubation at room temperature, the reaction is halted and the remaining NADPH ed h conversion of resazurin to resorufin by the addition of 25 ul Stop Mix (36 ug/ml diaphorase enzyme and 60 uM resazurin; in ). After one minute of incubation the plate is read on a plate reader at Ex544/Em590.
For determination of the inhibitory potency of nds 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 ug/ml IDH2 R140Q protein, 4 uM NADPH and 1.6 mM d-KG.
For ination of the inhibitory potency of compounds t IDH2 R140Q in a high throughput screening format, a similar procedure is performed, except that 0.25 ug/ml IDH2 R140Q protein is utilized in the preincubation step, and the reaction is started with the addition of 4 uM NADPH and 8 uM d-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 or, then the reaction is started by the addition ofd-KG, and allowed to proceed for 60 minutes under conditions previously demonstrated to be . The on is terminated by the addition of a second enzyme, diaphorase, and a corresponding substrate, resazurin. Diaphorase s rin to the highly fluorescent resoruf1n with the concomitant oxidation ofNADPH to NADP, both halting the IDH2 reaction by depleting the available cofactor pool and facilitating quantitation of the amount of cofactor ing after a specific time period h quantitative production of an easily detected hore.
Specifically, into each of 12 wells of a 384-well plate, 1 ul of 50x compound on series is placed, followed by the addition of 40 ul of buffer (50 mM potassium phosphate (K2HP04), pH 7.5; 150 mM NaCl; 10 mM MgC12, 10% glycerol, 0.05% bovine serum albumin, 2 mM beta-mercaptoethanol) containing 0.39 ug/ml 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 ul of substrate mix containing 8 mM d-KG (final concentration 1.6 m1\/I) in the buffer described above. After a r 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 ul Stop Mix (36 ug/ml diaphorase enzyme and 60 uM 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, 1x penicillin/streptomycin and 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 100ul are added to each cell well. The final concentration ofDMSO 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, 100ul of media isremoved from each well and ed 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 ofPromega Cell Titer Glo reagent is thawed and mixed. The cell plate is removed from the incubator and d to equilibrate to roomtemperature. Then 100ul ofPromega 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 scence 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, 1x penicillin/streptomycin and 500ug/uL G418. HT1080 cells ntained in RPMI containing % FBS, 1x 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 % 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 uL of the compound dilutions are added to each well. After 48 hours of incubation with compound at 37°C, 100 uL 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 nd effects on growth inhibition .
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 ) are grown at 37C in 5% C02 in Stem Cell Technologies NeuroCultTM NS-A media supplemented with 1% Primocin, 1% Normocin, 0.0002% Heparin, 20ng/mL EGF and 10ng/mL bFGF. Cells are harvested, pelleted and resuspended in Accumax for cell dissociation and ng. Cells are d and then resuspended in NeuroCult media with 2x heparin, EGF and bFGF at 4 million cells/l OmL media. lOOul of cell on are plated in each well of a 96 well with the exception of columns 1 and 12. Columns 1 and 12 contain 200uL PBS. Compound dose responses are set up at a 2X concentration in Neurocult media t heparin, EGF and bFGF. The final concentration ofDMSO 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, 100 pl 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 ofPromega Cell Titer Glo reagent is thawed and mixed. The cell plate is removed from the incubator and allowed to equilibrate to room temperature. 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 ature 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, Rl 32Cenzymatic assay, Rl 4OQ tic assay, R132C ased assay, and R1 4OQ ased assay as described above or r 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 uM; values indicated as "D" represent an IC50 of greater than or equal to 1 uM; 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/Rl32H IDHl NADPH/ IDHl wt/Rl32C IDHl IDH2 "I???" NADP R132H NADPH/ HchlggO R132C R140Q mfg/5G IC50 IC50 NADP not IC50 WO 03640 4>4> LII-b 4>4> \]O\ —LII N LIIJ>UJ WO 03640 AAAACC A BA A A 56789 AAAAAAAAAnAnAAAAAAA" A C A D u2 n m A A n2 A AAAA —5 — A A 1 27 nn WO 03640 "nun" nB n A A " B7 A A u—u———n—n———u——nn—BBMMMMMMMMMMUUUUUU A A A A C A C A B A B n51 n— """AAAAAAAAAAAAAAAAAAA —U n— A "AAA —mm n A n— WO 03640 uNW n— fl n6 A A C A —N n n mn— n mn n mn n mn n mn— n mn— n"nflnflnAAACAAAAAAA u001 n— A A C A —w n A C n un— n"AAAA —91 n un— n n91 n —w n— n uw n n —w n— n u02 n n u2 n n"CAAAAAA —0022 n A CA a— WO 03640 WO 03640 WO 03640 U.) [\3 L114; I:- WO 03640 WO 03640 4 CAAA 7 AC O O Table 5. Inhibitory Activities of Representative Compounds of formula I IIDHl IDH R132C IDH2 R140Q wt/R132H IDglfilgfIZ/H phere NADPH/ 16hr Compound NADPH / 1c5 0 NADP NADPH / NADP No. NADP IC50 IC50 NADP 1C5 0 saturated IC50 100 _— 102 A A 104 _— 106 —— A 108 _— ——— A _—— A A A _—— A 120 _— 122 _— 124 _— 128 BAA BB A BBBBBBBBMMMMMMMMMMU ABABA AAAAAAAB 151 AAAAAAAAAAAAAAAAAAAAAA BBMMMM AAAAAAABABAAB AAAAAAAAAA 164 B 165 B AAA WO 03640 1111111111111111111111111111111112222222 666777777777780080000008008899999999990000000I AAACBAAABCBBAAACC AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA B CCCCBCBAC CD CBBCA A WO 03640 209 C 210 B 2222222222222222222 1111111122222222223 CCBCBCB BCCCC 231 CC AAAAAAAAAAAAAAAAAAAAAA 2222222222222222 33333333444444441 C CCCC AAA CC A WO 03640 242 —-:—2- 255 —— B 251 C A 255 —— 254 B 255 —— 257 —— 255 —— 252 —— 255 —— 251 —-:—3- 252 —-:— c 255 —— c 254 —— 255 —-:— c 255 —— c 257 —_ B 255 —— B 252 —— 275 —_ 271 —— c 272 —-:— 275 —_ B 274 —-:— c 275 —-:— 275 —-:— 277 —— 275 —— 272 —-:— 255 —-:— c 251 —— 254 —— 257 —-:— 255 —— "—n— B WO 03640 290 —— 291 —— 294 —— 297 —-:— 299 —-:— 19 299 —— 900 —— 901 —-:— 902 —_ 909 —— 904 —— 909 —— 900 —— 907 —— 909 —— 909 —-:— ——-:— ——-:— ——-:— ———:- ——-:— 920 —— 921 —-:— 922 —— 929 —— 19 929 —-:— 929 —— 2014/081957 2—4mgnA5 _3 67890—444455333333 AAAAAnA A AAAAAAA 368 A 370 ——AAAAAAA "——AA A WO 03640 u7733 nn nu70033 "n__ 333 888 C AAA 333333 88000088 B AAAAAA 41 1 2014/081957 Having thus described several aspects of l 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 (27)

Claims
1. A compound having a (Ia) or a pharmaceutically acceptable salt or hydrate thereof, wherein: R4 N N R1 R5 R2 R6 N N N R3 R7 R8 (Ia), ring A is selected from phenyl, pyrazolyl, yl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, wherein ring A is optionally substituted with up to two substituents independently selected from halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(O)2-(C1-C4 , -S(O)2NH(C1-C4 alkyl), -(C1-C4 alkyl), C1-C4 alkoxy, -NH(C1-C4 alkyl), -OH, -OCF3, -CN, -NH2, -C(O)NH2, -C(O)NH(C1-C4 alkyl), N(C1-C4 alkyl)2, 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, - C4 alkyl), or -N(C1-C4 alkyl)2; R2 and R5 are each independently selected from: -(C1-C6 alkyl), 6 alkyl)-C(O)- NH2, -(C1-C6 alkyl)-CO2H, -(C2-C6 alkenyl or alkynyl), -(C1-C6 ne)-O-(C1-C6 alkyl), -(C0-C6 alkylene)-C(O)N(R6)-(C1-C6 alkyl), and-(C0-C6 alkylene)-C(O)-(C1-C6 alkyl), wherein: any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, C4 , -CO2H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN, or CO2H; R7 and R8 are each independently selected from hydrogen and C1-C6 alkyl; and R1 and R2 are optionally taken together to form a carbocyclyl or heterocyclyl either of which is optionally substituted with up to 3 substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, =O, -OH, aryl, heteroaryl, -SO2C1-C4 alkyl, -CO2C1-C4 alkyl, -C(O)aryl, and -C(O)C1-C4 alkyl; or R4 and R5 are optionally taken together to form a substituted carbocyclyl, or a substituted cyclyl either of which is optionally substituted with up to 3 substituents independently ed from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, =O, -OH, aryl, heteroaryl, -C4 alkyl, -CO2C1-C4 alkyl, -C(O)aryl, and -C(O)C1-C4 alkyl; wherein: (i) when A is pyridyl ally substituted as described above, then (A) N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHCH2CH2OH or lohexyl, and (B) when N(R7)C(R4)(R5)(R6) is NHC(CH3)3, then N(R8)C(R1)(R2)(R3) is not NHCH2CH3 (ii) when A is a heteroaryl selected from pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl substituted as described above then N(R7)C(R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both N(CH2CH3)2, NHCH2CH2-i-propyl or NHCH2CH(CH3)2; (iii) when A is 1-pyrazolyl ally substituted as bed above, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is NHisopropyl, NHCH2CH3 or N(CH2CH3)2, (iv) when A is substituted 1-pyrazolyl, then (R4)(R5)(R6) and N(R8)C(R1)(R2)(R3) are not both NHC(CH3)3, (v) when A is phenyl optionally substituted as described above, then N(R7)C(R4)(R5)(R6) is not the same as N(R8)C(R1)(R2)(R3), and (vi) the compound is not N2-isopropylphenyl-N4-(tetrahydro-2H-pyranyl)-1,3,5-triazine-2,4-diamine.
2. A compound having Formula (B) or pharmaceutically acceptable salt or hydrate thereof, wherein: Xa R9 Xa N R4 N N R1 R5 R2 R6 N X N R3 R7 R8 (B), X is N, CH or C-halo; Xa is N or C-R9a, provided that when one Xa is N, then the other two Xa are both CR9a R9 is halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(O)2-(C1-C4 alkyl), -S(O)2NH(C1-C4 alkyl), -S(O)2-(C1-C4 alkyl), C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)- N(C1-C4 alkyl)2, -(C1-C6 alkylene)-O-(C1-C6 alkyl), aryl, or cyclopropyl optionally substituted with OH; each R9a is independently selected from hydrogen, halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(O)2-(C1-C4 alkyl), -S(O)2NH(C1-C4 alkyl), -S(O)2-(C1-C4 alkyl), C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OH, -OCF3, -CN, -NH2, -C(O)NH2, -C(O)NH(C1-C4 alkyl), N(C1-C4 alkyl)2, -(C1-C6 alkylene)-O-(C1-C6 alkyl), aryl, and cyclopropyl optionally substituted with 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 ally substituted with -OH, -NH2, -CN, -O-C1-C4 alkyl, - NH(C1-C4 alkyl), or C4 alkyl)2; R2 and R5 are each ndently selected from: -(C1-C6 alkyl), -(C1-C6 alkyl)-C(O)- NH2, -(C1-C6 alkyl)-CO2H, -(C2-C6 alkenyl or alkynyl), -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C0-C6 ne)-C(O)N(R6)-(C1-C6 alkyl), -(C0-C6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-C6 , and 6 alkylene)-C(O)-(C0-C6 alkylene)-Q, wherein: any alkyl or alkylene moiety t in R2 and R5 is optionally substituted with one or more -OH, -O(C1-C4 alkyl), -CO2H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with , CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN, or CO2H; R7 and R8 are each independently ed from hydrogen and C1-C6 alkyl; and Q is ed from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is ally substituted with up to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, =O, -C(O)-C1-C4 alkyl, -CN, and halo; wherein R1 and R2 are optionally taken together to form a carbocyclyl or a heterocyclyl either of which is optionally substituted with up to 3 substituents independently ed from halo, e.g., fluoro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, =O, -OH, and -C(O)C1-C4 alkyl; or R4 and R5 are optionally taken together to form a carbocyclyl or a 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, =O, -OH, and -C(O)C1-C4 alkyl; wherein the compound is not selected from the group: (1) 4,6-Pyrimidinediamine, ethylpyridinyl)-N4,N6-dipropyl-; (2) 4,6-Pyrimidinediamine, yl(6-methylpyridinyl)-N6-propyl-; and (3) 4,6-Pyrimidinediamine, diethyl(6-methylpyridinyl)-N6-propyl-.
3. The compound of claim 2 or a pharmaceutically acceptable salt or hydrate thereof, wherein R4 and R5 are ally taken together to form an optionally substituted 3- to 6-member carbocyclyl or an optionally substituted 3- to 6-member 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, =O, -OH, and 1-C4 alkyl.
4. A nd having Formula (C) or pharmaceutically acceptable salt or hydrate thereof, wherein: Xb Xb R4 N N R1 R5 R2 R6 N X N R3 R7 R8 (C), 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 Xc is N, and when one Xb is N-R9b, O, or S, then Xc is C; R9b is en or -C1-C4 alkyl; R9c is halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(O)2-(C1-C4 alkyl), -S(O)2NH(C1-C4 alkyl), -CN, -S(O)2-(C1-C4 alkyl), C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -OH, -OCF3, -NH2, -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)-N(C1-C4 alkyl)2, -(C1-C6 alkylene)-O-(C1-C6 alkyl), aryl, or cyclopropyl optionally substituted with 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, C4 alkyl, - NH(C1-C4 alkyl), or -N(C1-C4 alkyl)2; R2 and R5 are each independently selected from: -(C1-C6 alkyl), -(C1-C6 alkyl)-C(O)- NH2, -(C1-C6 alkyl)-CO2H, 6 alkylene)-Q, -(C0-C6 alkylene)-C(O)-(C1-C6 alkyl) and -(C0-C6 alkylene)-C(O)-(C0-C6 ne)-Q, wherein: any alkyl or alkylene moiety present in R2 and R5 is optionally substituted with one or more -OH, -O(C1-C4 , -CO2H, or halo; any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN, or CO2H; R7 and R8 are each independently ed from hydrogen and C1-C6 alkyl; and Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, any of which is ally substituted with up to 3 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, =O, -C(O)-C1-C4 alkyl, -CN, and halo; wherein R1 and R3 are optionally taken together with the carbon atom to which they are attached to form C(=O); or R4 and R6 are optionally taken together with the carbon atom to which they are attached to form C(=O); or R1 and R2 are optionally taken er to form a yclyl or a cyclyl, either of which is ally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, =O, -OH, and -C(O)C1-C4 alkyl; or R4 and R5 are optionally taken together to form a carbocyclyl or a 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, =O, -OH, and -C(O)C1-C4 alkyl; wherein: Xb Xb (i) when X is CH and is optionally substituted 1-pyrazolyl, then neither N(R7)C(R4)(R5)(R6) nor N(R8)C(R1)(R2)(R3) is 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 or N(CH2CH3)2.
5. The compound of claim 4 or a pharmaceutically acceptable salt or hydrate thereof, wherein: R9c is halo, -OH, CN, -NH2, -O-C1-C4 alkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C1-C4 alkyl, -C1-C4 kyl, and -(C1-C6 alkylene)-O-(C1-C6 alkyl); R1 and R4 are 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 -(C1-C6 alkyl), wherein: the alkyl moiety present in R2 and R5 is optionally substituted with one or more -OH, -O(C1-C4 , -CO2H, or halo; and any terminal methyl moiety present in R2 and R5 is optionally replaced with -CH2OH, CF3, -CH2F, -CH2Cl, C(O)CH3, C(O)CF3, CN, or CO2H.
6. The compound of claim 4 or a pharmaceutically acceptable salt or e thereof, wherein R1 and R4 are each independently selected from C1-C4 alkyl and C1-C4 haloalkyl, and R2 and R5 are each -(C1-C6 alkyl).
7. The nd of claim 1, 2 or 4 or a pharmaceutically acceptable salt or e thereof, n R3 and R6 are both hydrogen, R1 and R4 are each independently selected from C1-C4 alkyl and C1-C4 haloalkyl, and R2 and R5 are each 6 alkyl).
8. A compound of Formula (Ig) or a pharmaceutically acceptable salt or hydrate thereof, wherein: R4 N N R1 R5 R2 R6 N N N R3 H H (Ig), ring A is a 5-6 member monocyclic aryl or monocyclic heteroaryl substituted with 0-2 instances of halo, -C1-C4 alkyl, -C1-C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(O)2(C1-C4 alkyl), -S(O)2NH(C1-C4 alkyl), S(O)2-(C1-C4 alkyl), C1-C4 alkoxy, -NH-(C1-C4 alkyl), - OH, OCF3, CN, -NH2, -C(O)NH2, H-(C1-C4 alkyl), (C1-C4 alkyl)2, azetidinyl, phenyl and cyclopropyl tuted with 0-1 instances of OH; R3 and R6 are both hydrogen; R1 and R4 are each independently selected from C1-C4 alkyl and C1-C4 haloalkyl; and R2 and R5 are each -(C1-C6 alkyl); or R1 and R2 are optionally taken together to form a monocyclic carbocyclyl substituted with 0-3 substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, =O, -OH and –C(O)C1-C4 alkyl; or R4 and R5 are optionally taken together to form a monocyclic carbocyclyl substituted with 0-3 substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, =O, -OH and –C(O)C1-C4 alkyl; wherein: (i) ring A is not an optionally tuted triazolyl, 3,5-dimethyl-1H-pyrazolyl, (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 ed from the group: (1) imidazolyl)-N2,N4-bis(1-methylethyl)-1,3,5-Triazine-2,4-diamine, or (2) N2,N4-bis(1-methylpropyl)phenyl-1,3,5-Triazine-2,4-diamine.
9. The compound of claim 8 or a pharmaceutically able salt or hydrate thereof, wherein ring A is pyridinyl tuted with 0-2 instances of halo, -C1-C4 alkyl, -C1- C4 haloalkyl, -C1-C4 hydroxyalkyl, -NH-S(O)2(C1-C4 alkyl), -S(O)2NH(C1-C4 alkyl), S(O)2-(C1-C4 alkyl), C1-C4 alkoxy, -NH-(C1-C4 , -OH, OCF3, CN, -NH2, -C(O)NH2, -C(O)NH-(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2 , azetidinyl, phenyl and cyclopropyl substituted with 0-1 instances of OH.
10. A compound or a pharmaceutically able salt or hydrate thereof, wherein the compound is selected from N O Chiral 1 CH N N 8 F N N N H H CH N N CH 3 3 R N N N R F Chiral F H H 2 F CH N N CH 3 3 F R N N N R H H N F N N F H N N N N H CH N N 3 F Chiral H F H C N N N 3 F 3 H N 3 10 N N F H C F 3 CH N N N 3 F R H H OH CH N N H C 3 OH Chiral 3 H CH H C N N N 3 3 H CH 3 11 F Chiral CH N N CH 3 3 F R N N N R H H 5 F N N F 3 NH F N N N 2 R N H H O 12 N N 3 CH N N N 3 R H H Chiral OH F F 6 F CH N N CH 3 3 N R N N N R 13 H H CH N N 3 CH H C 3 3 N N N H H CH CH 3 3 F H C F 3 7 N N N N N H H F H H F N N N F F F N N N F 14 N N 31 N N N 3 F HO H H OH F CH F H H F Chiral F CN N N N CH H C CH N 3 3N N CH 15 32 CH N N F R N N N 3 H H CH O O Chiral 3 Chiral 16 CH N N CH CH N N CH 3 3 3 3 N N N R N N N S S R H H H H CH CF 3 Chiral 3 Chiral 3 H N H C S N 17 3 H 34 N N CH CH N N CH 3 3 3 S N N N F N H C CH S R 3 3 H H H H CN N N N CH 3 Chiral H C CH H C 3 3N N CH 35 3 3 H H C R N F 18 3 H N N CH R OH F N H C CH 3 3 F CF F 3 F Chiral N N N N N 19 H H CH N N CH 3 3 CF 3 Chiral R N N N R H H N CH N N CH 3 CN3 R N N N CH H H 3 CH N N 44 3 O CH N N CH 3 3 R N N N O H H R N N N CH H H 3 F Cl Chiral 39 N CH N N CH 3 3 45 3 N N CH R N N N CH H H 3 R N N N R H H H H H C N N N 3 Cl Chiral CN N N CHR 40 3 N N 46 CH N N 3 R N N N CH H 3 41 F F CF Chiral F N N F 3 N N N H H 47 CH N N CH 3 3 R N N N R H H 3 Chiral 3 Chiral CH N N 42 3 N R N N NH H 48 OH CH N N CH CH 3 3 3 S N S R N N N R CH H H 3 H H Chiral 3 Chiral N N N F N N CHR 50 3 43 CH N N 3 N R N N NH CF H 3 Chiral Chiral 51 57 CH N N CH 3 3 CH N N CH 3 3 R N N N R N N H H R N R H H F CF 3 Chiral N F 52 58 F CH N N F N N O R N N N F H H N N N H H F F F N 53 59 F N N O N N N F N Boc F N N N N N N O H H H H F Chiral F F N F 54 N F 60 N N NH CH N N F 3 N N N N N N H H R H H Chiral 55 N 61 CH N N CH 3 3 F N N O F N R N N N R H H N N N CH H H 3 3 Chiral F 63 CH N N R N N NH N H 56 O O H C CH 3 3 N O F N N S O F N N N H H CH Cl Chiral N 64 73 N N CH N N CH 3 3 N N N R N N N R H H H H Cl Chiral N N N CH N N CH 3 3 N N N H H R N N N R H H Chiral N Cl 75 66 O N N CH N N CH 3 3 N N N R N N N R H H H H N Chiral N 67 N N CH N N CH 3 3 R N N N R N N N H H H H HN F 69 N N N N O HN N N N H H OCH3 N F 72 O N N O N N N N N N N N H H H H CF3 Cl N N 79 N N 88 N N N N N N N N H H OH H OH N 80 89 N N N N N N N N N N H H H H N N 81 90 F N N O N N F N N N N O N N N H H H H OH CF3 82 91 N N F N N F NH N N N N N N H H H H OH N 86 92 N N N N N N N N N N N H H H H 87 93 N N N N N N N N N N N H H H H Cl N 94 103 N N CF3 N N CF3 N N N N N N H H H H N Cl 95 104 N N CF3 N N CF3 N N N N N N H H H H 96 F F F N N 105 F F F N N N N N N H H N N N H H Cl Cl N N 100 110 CF3 N N N N F3C N N N CF3 N N N H H H H 101 111 CF3 N N CF3 F N N F N N N F N N N F H H H H CF3 Cl N N 102 113 F N N F F N N F F N N N F F N N N F H H H H N N 114 130 N N CF3 N N CF3 F F N N N N N N F H H F H H F F N N 118 131 F N N F N N F N N N F H H N N N H H CF3 CF3 121 135 N N N N N N N N N N H H H H F F N N 126 F F 136 CF3 N N CF3 N N F F N N N N N N H H H H F F N F N F F N 138 F S N N 128 F F N N N N N F F H H N N N H H CF3 N 141 N CF3 N N CF3 129 N N N F N N F H H F N N N F H H Cl F F S N 142 148 CF3 N N CF3 F N N F N N N F H H N N N F H H 143 F F F F 149 N N F N N F F N N N N N N H H H H N CF3 F F 144 N N 150 F F N F F N N N N F N N N H H H H 145 F F F N N F N N F F N N N H H N N N H H CF3 S N 155 146 F N N F F F F N N F N N N F N N N F H H H H Cl N N 156 147 F F CF3 N N CF3 F N N F N N N N N N H H H H Cl Cl N N 157 180 N N CF3 N N CF3 N N N N N N F F H H F F H H CF3 CF3 160 F F 182 N N Cl F N N F F N N N N N N H H H H CF3 F F N S 161 F F N N 183 F F F F F N N F N N N H H N N N H H 166 F F N N OMe 184 N N N N N N N N H H H H F3C F N N F 170 N F F 186 N N F F F F F N N F N N N H H N N N H H CF3 F F N N 176 F F F N N F 187 F F F N N F N N N H H N N N H H CF3 F N F 188 199 F F N N F N N F N N N N F N N N H H H H F CF3 F N 191 F 203 F N N F N N F N N N N N N CF3 H H H H CF3 F N S 193 205 N N F F F N N F N N N H H N N N H H N CF3 F N F F F N 194 F F 208 N N F N N N N N F N N N H H H H Cl F N S 196 209 CF3 N N CF3 F F F N N F N N N H H N N N H H N N 198 212 F F F N N F N N N N N H H N N N H H CF3 F N F 214 N N 224 F F F N N F N N N H H N N N H H F F N F 216 N N 225 F N N N N N N N N H H H H F F F F F F N 227 F N N 218 F F F N N N N N F N N F H H N N N H H CF3 F N N F 228 219 F F F N N N N F N N N N N N H H H H F F F F F N N 230 F F N N F N N N N F N N N F N N N H H H H S N 223 F F N N F N N F N N N O H H N N N H H OCF3 F F 234 N N 252 F F N N N N N H H N N N H H CF3 CF3 N N N F F 237 255 N F N N F N O F N N N N N N H H H H N N N N 256 F F F N N F N N N H H N N N H H 241 N N N 258 F F O F F N N N N N H H N N N H H 249 F F N F N N F N N N N N H H N N N H CN N H N F 251 F F N N N F F N N N F N N O H H N F N N N H H F Cl 264 N N F N N HO NC CN N N N F N N N H H H H F N 272 F F F N N 265 F F N N N N N H H N N N H H CF3 N N 273 O F N N N 266 F S F N N N N N N H H N N N H H N N 274 F F N N N O N N N N N H H N N N H H N 275 F F F N N F N N N N N H H N N N H H N CF3 N F F N 276 F N N F 270 F F F N N F N N N H H N N N H H OCF3 277 F F 284 F N N F N N N N N H H N N N H H Cl NH2 278 285 N N N N N N N N N N H H H H I CF3 N N 279 286 N N O N N N N N O N N N H H H H F F F F N N 281 287 F F N N N N OH N N N N N N H H H H F 290 OH HO 282 F N N F N N F N N N N N N H H H H S F N 292 283 F F N N F N N F N N N N N N H H H H F O F N N N 293 F F 301 F F F N N F F N N F N N N N N N H H H H OMe Cl N N 294 F F N N F N N F N N N N N N H H H H 295 N N 303 O N N O N N N O H H N N N NH2 H H OCF3 N N 296 F F 304 F F F N N F F N N F N N N N N N H H H H N NH 297 F F F N N F 305 F F F N N N N N F H H N N N H H N CF3 300 306 N N N N O N N N N N N H H H H CONH2 N N 307 314 F F N N F N N F N N N N N N H H H H F O F N N N N 308 F F F F 315 F N N F F N N F N N N N N N H H H H OH HN 309 F F 317 F F F N N F F N N F N N N N N N H H H H COOMe 310 318 F F N N F N N F N N N N N N H H H H F F F F F N N 319 F F F N N N N N H H N N N H H 312 320 N N N N N N N N N N H H H H O N N S N 321 F F 328 F F F N N F F N N F N N N N N N H H H H O F F O F N 322 329 F F N N F N N F N N N N N N H H H H F3C N 323 330 F F N N F N N F N N N N N N H H H H N N 324 F F 331 F N N F N N N N N N N N H H H H N N 326 332 F F N N F N N F F N F N N N N N N H H H H N N S N 327 333 N N F F F N N F N N N H H N N N H H N NH F F N 334 F N N F 354 N N N N N F F H F N N N F H H F F F N S N 335 357 F F CF3 N N CF3 F N N F N N N N N N H H H H F CF3 N F N N N 339 363 CF3 N N CF3 CF3 N N CF3 N N N N N N H H H H F F N N 344 366 F F N N CF3 N N CF3 F F N N N N N N H H H H F F N F 345 N 370 F F CF3 N N CF3 F F N N N N N H H N N N F H H F F N N 346 N 374 F F CF3 N N CF3 F N N F N N N N N N H H H H N CF3 N N 386 406 CF3 N N CF3 F N N F F N N N F N N N H H H H N F N N 395 F 408 F F F N N F F F N N N F N N H H N N N H H N F F N N F 409 F F F N N N F F N N F H H N N N H H N S 402 N F F F F F N N N 410 F N N F N N N F F H H N N N F H H F F N S F N N 403 F F F N N F 411 F F F N N F N N N H H N N N H H F F S N 404 N N CF3 N N CF3 F N N F F N F N N N N N H H H H F F F F F F N N 414 419 N N N N N N N N H H H H F CF3 F N 415 420 N N N N N N N N H H H H CF3 CF3 N N 421 F F 416 F N N F N N N N H H N N H H 417 N N N N F3C N N CF3 N N H H H H . Cl HN N N F F F 423 F N N F 418 N N F N N N F3C N N H H and HN N F F 424 F N N F N N N H H .
11. The compound of claim 10 or a pharmaceutically acceptable salt or e thereof, having the structure: O CH C CH N N CH 3 3 R N N N R H H
12. The compound of claim 10 or a pharmaceutically acceptable salt or hydrate thereof, having the structure: N N N N N H H
13. The compound of claim 10 or a pharmaceutically acceptable salt or hydrate thereof, having the structure: F N N O F N N N N O H H
14. The compound of claim 10 or a ceutically acceptable salt or hydrate thereof, having the structure: CF3 N N CF3 N N N H H .
15. The compound of claim 10 or a pharmaceutically acceptable salt or hydrate thereof, having the structure: F N N F F F N N N H H .
16. The compound of claim 10 or a pharmaceutically acceptable salt or hydrate thereof, having the structure: CF3 N N CF3 N N N H H .
17. The compound of claim 10 or a pharmaceutically acceptable salt or hydrate thereof, having the structure: N S F F F F N N N N N H H .
18. The nd of claim 10 or a pharmaceutically acceptable salt or e thereof, having the structure: N F F F F N N F N N N H H .
19. The compound of claim 10 or a pharmaceutically acceptable salt or hydrate thereof, having the structure: N F F N N F F F N N N H H .
20. The compound of claim 10 or a pharmaceutically acceptable salt or e thereof, having the structure: HN N F F F N N F N N N H H .
21. A pharmaceutical composition comprising a compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.
22. The pharmaceutical ition of claim 21, further comprising a second therapeutic agent useful in the treatment of cancer.
23. A compound of any one of claims 1-20 or a composition of claim 21 or 22 for use in the manufacturing of a medicament for treating a cancer characterized by the presence of an IDH1 mutation, wherein the IDH1 on results in a new y of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)hydroxyglutarate in a patient.
24. The compound or composition for use of claim 23, n the IDH1 mutation is an IDH1 R132H or R132C mutation.
25. The compound or ition for use of claim 23 or 24, wherein the cancer is selected from glioma (glioblastoma), acute myelogenous leukemia, sarcoma, ma, nonsmall cell lung cancer (NSCLC), cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer, and angio- immunoblastic non-Hodgkin’s lymphoma (NHL) in a patient.
26. The compound or composition for use of claim 25 wherein the cancer is
27. A compound for use in the manufacturing of a medicament for the treatment of glioma characterized by the presence of an IDH1 mutation, wherein the compound is CF3 N N CF3 N N N H H or a pharmaceutically acceptable salt thereof.
NZ715717A 2013-07-11 2014-07-10 Therapeutically active compounds and their methods of use NZ715717B2 (en)

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CNPCT/CN2013/079200 2013-07-11
PCT/CN2013/079200 WO2015003360A2 (en) 2013-07-11 2013-07-11 Therapeutically active compounds and their methods of use
PCT/CN2014/081957 WO2015003640A1 (en) 2013-07-11 2014-07-10 Therapeutically active compounds and their methods of use

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NZ715717B2 true NZ715717B2 (en) 2021-05-27

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