WO2012149528A1 - Inhibitors of inducible form of 6-phosphofructose-2-kinase - Google Patents

Inhibitors of inducible form of 6-phosphofructose-2-kinase Download PDF

Info

Publication number
WO2012149528A1
WO2012149528A1 PCT/US2012/035794 US2012035794W WO2012149528A1 WO 2012149528 A1 WO2012149528 A1 WO 2012149528A1 US 2012035794 W US2012035794 W US 2012035794W WO 2012149528 A1 WO2012149528 A1 WO 2012149528A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
ethyl
phenyl
pyrimidin
amine
Prior art date
Application number
PCT/US2012/035794
Other languages
French (fr)
Inventor
Amy Lew Tsuhako
Charles K. Marlowe
Christiana A. ZAHARIA
Lori Kabigting
William Bajjalieh
Zerom Tesfai
Ping Huang
Kim Moon
Naing Aay
Arlyn TAMBO-ONG
John M. Nuss
Wei Xu
Patrick Kearney
Original Assignee
Exelixis, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Exelixis, Inc. filed Critical Exelixis, Inc.
Priority to EP12725560.2A priority Critical patent/EP2702043A1/en
Publication of WO2012149528A1 publication Critical patent/WO2012149528A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D417/02—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

Definitions

  • Glycolysis is a metabolic pathway in which sugars are degraded to generate energy (ATP).
  • ATP energy
  • the rate o f glycolysis is regulated by the enzymes hexokinase.
  • phosphofructokinase, and pyruvate kinase These enzymes catalyze irreversible reactions, and each is controlled to meet metabolic needs.
  • Phosphofructokinase is the most important control point in glycolysis, and the rate limiting enzyme 6-phosphofructo- l -kinase (PF - 1 ) normally controls the rate of glycolysis.
  • PFKFB 6- phosphofructo-2-kinase/fructose-2,6-bisphosphatase
  • PFKFB3 Unlike normal healthy cells, cancer cells maintain a high glycolic rate for ATP production, even under aerobic conditions. The glycolic rate can be up to 200 times greater in malignant, rapidly-growing tumor cells. This is known as the Warburg effect.
  • One of the four PFKFB isozymes, PFKFB3 is responsible for encoding an inducible form of 6- phosphofructose-2-kinase, iPFK-2.
  • PFK.FB3 is expressed at high levels in tumor cell lines. Treatment with specific antisense oligonucleotides reverses this high expression of PFKFB3 in tumor cells, shrinking the tumors in vivo.
  • PFKFB3 is also essential for Ras-mediated transformation, as shown in vitro by soft agar colony formation and in vivo by
  • iPFK-2 which is encoded by PFKFB3. is a potent allosteric activator of PFK- 1 , the rate-limiting enzyme in glycolysis. iPFK-2 thus functions as an activator of anaerobic glycolysis within the hypoxic microenvironmenl of growing tumors. Blocking the activity of iPFK-2 can decrease tumor growth by reducing the extremely high rate of glycosis in cancer cells. Inhibition of i PFK-2 is thus useful for the treatment of a wide variety of cancers.
  • Regulation of the rate of glycolysis by inhibiting iPFK-2 can also be useful in the treatment of a range of other disorders, including, but not limited to, metabolic disorders, autoimmune disorders, Alzheimer's disease, muscular dystrophy, and osteoarthritis.
  • W is a branched or straight C M? aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Qt) 2 -, -C(Q 2 ) 2 -, -CHQi-, -CHQ 2 -, -CO-, -CS-, -CONR' ⁇ -CONR A R A -.
  • each R A is independently hydrogen, Cj.s aliphatic; cycloaliphatic,
  • heterocycloaliphatic, aryl, or heteroaryl optionally substituted with 1 -3 of Qi, Q 2 , or Q3;
  • . X 2, and X3 are each independently absent or are a cycloaliphatic
  • Y is absent or is a branched or straight C 1.12 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q
  • each R Lt is independently hydrogen, C
  • heterocycloaliphatic, aryl, or heteroaryl optionally substituted with 1 -3 of Qi, Q 2 , or Q3 ;
  • Z is independently hydrogen, C
  • L is absent or is NH, N(C
  • Ring A is a monocyclic, bicyclic, or tricyclic cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, any of which may be optionally substituted with 1 -3 of halo, -OH, oxo, -CF 3 , -OCF 3 , cyano, or a C
  • each Q 2 is independently hydrogen, aliphatic, alkoxy, cycloaliphatic. aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally including 1-3 substituents independently- selected from Q ;
  • each Q 3 is halo, oxo, CN, N0 2 , NH 2 , CF 3 , OCF 3 , OH, -COOH or Ci-C alkyl optionally substituted with 1 -3 of halo, oxo, -CN. -N0 2 , -CF 3 , -OCF 3 , -OH, -SH, -S(0) 3 H, - NH 2 , or -COOH;
  • the invention is directed to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable earner, excipient, or diluent.
  • the invention is directed to a method of treating a disease or disorder mediated by IPFK-2. comprising administering to a subject in need of such treatment a compound of formula I or a pharmaceutical composition comprising a compound of formula I.
  • the symbol "-" indicates a single bond, indicates a double bond, indicates a triple bond, and " " indicates a single or double bond.
  • the symbol : vvw " refers to a group on a double bond as occupying either position on the terminus of a double bond to which the symbol is attached; that is. the geometry, E- or Z-, of the double bond is ambiguous. When a group is depicted as removed from its parent formula, the symbol will be used at the end of the bond which was theoretically cleaved in order to separate the group from its parent structural formula.
  • the "R” group may reside on either the 5-membered or the 6-membered ring of the fused or bridged ring system.
  • administration and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, and chemotherapy, etc.)
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the Compound or prodrug thereof and other agents.
  • “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • aliphatic encompasses the terms alkyl, alkenyl, and alkynyl.
  • cycloaliphatic means a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic hydrocarbon ring that has a single point of attachment to the rest of the molecule.
  • Cycloaliphatic rings are 3- to 8-membered monocyclic rings (e.g., 3- to 6-membered rings).
  • Cycloaliphatic rings also include 8- to 12-membered bicyclic hydrocarbon rings, (e.g., 10-membered bicyclic hydrocarbon rings).
  • a cycloaliphatic group encompasses both "cycloalkyl” groups and "cycloalkenyF' groups.
  • heterocycloaliphatic and “heterocyclic” encompass heterocycloalkyl groups and heterocycloalkenyl groups.
  • heterocycloalkyl refers to a 3- to 10-membered mono cyclic or bicyclic (including fused and bridged) (e.g., 5- to 10-membered monocyclic or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g.. N, O, S, or combinations thereof).
  • heterocycloalkyl groups include, but are not limited to, optionally substituted piperidyl, piperazyl, telrahydropyranyl,
  • a monocyclic heterocycloalkyl group may be fused with a phenyl moiety, such as tetrahydroisoquinoline.
  • Heterocycloalkyl ring structures can be optionally substituted at any chemically viable position on the ring or rings.
  • heterocycloalkenyl refers to a monocyclic or bicylic (e.g., 5- to 10-membered monocyclic or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof)-
  • heterocycloalkenyls include, but are not limited to, 2- pyrrolyl, 3-pyrrolyl, 2-imidazolyl, and 2-pyrazolyl.
  • Monocyclic heteroaliphatics, including both heterocycloakyls and heterocycloalkenyls are numbered according to standard chemical nomenclature. For instance:
  • a heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents. including, but not limited to, alkyl (e.g. carboxyalkyl, hydroxyalkyl, and haloalkyl, such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl (e.g., benzimidazolidinyl), (hetei ocycloalkyl)alkyl, aryl, heteroaryl, alkoxy (wherein two alkoxy groups on the same atom or adjacent atoms may form a ring together with the atom(s) to which they are bound), cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralky!oxy. aroyl, heteroaroyl, amino, nitro, carboxy, alkoxy
  • heterocycloalkyl alkylcarbonylamino, heteroarylcarbonylamino,
  • heteroaralkylcarbonylamino cyano. halo, hydroxyl, acyh mercapto, sulfonyl (e.g..
  • alkylsulfonyl or aryl sulfonyl sulfinyl (e.g., alkylsulfinyl).
  • sulfanyl e.g., alkylsulfanyl
  • sulfoxy urea, thiourea, sulfamoyl, sulfamide, oxo, and carbamoyl.
  • substituted heterocycloaliphatics include, but are not limited to, alkoxycarbonylheterocycloalkyl (e.g., ethoxycarbonyltropane),
  • alkoxycarbonylheterocycloalkyl e.g., ethoxycarbonylpiperidyl
  • alkoxycarbonylheterocycloalkyl e.g., ethoxycarbonylpiperidyl
  • a “heteroaryl” group refers to a monocyclic, bicyclic, or tricyclic ring structure having 4 to 1 5 ring atoms, wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof), and wherein one or more rings of the bicyclic or tricyclic ring structure is aromatic.
  • Heteroaryl groups include benzofused ring systems having 2 to 3 rings. Examples of benzofused groups include, but are not limited to, phenyl fused with one or two C .s heterocyclic moieties (e.g., indolizyl.
  • indolyl isoindolyl, 3 H-indolyl, indolinyl. benzo[Z)] furyl, benzo[7>]thiophenyl : quinolinyl. or isoquinolinyl).
  • heteroaryls include, but are not limited to azetidinyl, pyridyl, 1 H- indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene. thioxanthene.
  • phenothiazine dihydroindole, benzo[l ,3]dioxole, benzo[Z>]furyl, benzo[Z>]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl.cinnolyl. phthalazyl, quinazolyi, quinoxalyL isoquinolyl, 4H-quinolizyl, benzo- l ,2,5-thiadiazolyl, and 1 ,8-naphthyridyl.
  • Monocyclic heteroaryls include, but are not limited to, fury I, thiophenyl, 2H- pyrrolyl, pyrrolyl, oxazolyl, thazolyl. imidazolyl, pyrazolyl, isoxazolyl. isothiazolyl, 1 ,3,4- thiadiazolyl, 2H-pyranyl. 4-H-pranyl, pyridyl, pyridazyl. pyrimidyl, pyrazolyl, pyrazyl, and 1 ,3.5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature. For example:
  • Bicyclic heteroaryls include, but are not limited to, indolizyl. indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[6]furyl, benzo[0]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indazolyl. benzimidazyl. benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl. cinnolyl, phthalazyl. quinazolyi, quinoxalyl, 1 ,8-naphthyridyl. and pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature. For example:
  • Heteroaryls are optionally substituted with one or more substituents, including, but not limited to, aliphatic groups, including alkyl (e.g., alkoxyalkyl, carboxyalkyl.
  • cyanoalkvl aminoaikyl, oxoalkyl. alkoxycarbonylalkyl. (cycloalkyl)alkyl heterocycloalkyl, (heterocycloalkyl)alkyl aralkyl, or haloalkyl. such as trinuoromethyl), alkenyl, and alkynyl; cycloaliphatic. including cycloalkyl (e.g., cyclopropyl.
  • heterocycloaliphatic including heterocylcoalkyl (e.g., thiomorpholyl, piperazinyl, 1 ,3,5-trithianyl, morpholinyl, pyrrol l, 1 ,3-dioxolanyl, pyrazolidyl, or piperidinyl): aryl; heteroaryl (e.g., quinolyl, indolyl, 3H-indolyl, isoindolyl, benzo[Z>]-4H- pyranyl, cinnolyl, quinoxylyl.
  • heterocylcoalkyl e.g., thiomorpholyl, piperazinyl, 1 ,3,5-trithianyl, morpholinyl, pyrrol l, 1 ,3-dioxolanyl, pyrazolidyl, or piperidinyl
  • aryl e.g., quinolyl, ind
  • benzimidazyl benzo- l ,2,5-tliiadiazolyl, benzo- 1 ,2,5- oxadiazolyl, or benzthiophenyl
  • alkoxy cycloalkyloxy; heterocycloalkyloxy; aryloxy; heleroaryloxy; aralkyloxy; heteroaralkyloxy; aroyl; heferoaroyl
  • amino e.g., carbonylamino, alkylcarbonylamino, alkylsul fonylamino, arylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, (lieterocycloalkyl)carbonylamino,
  • cycloalkylalkylcarbonylamino sul fanylamino, or (heterocycloalkyl)alkylcarbonylamino); nitro; carboxy; carbonyl (e.g., alkylcarbonyl, alkoxycarbonyl, aminocarbonyl,
  • aminoalkylaminocarbonyl alkylcarbonyloxy; cyano; halo; hydroxyl; acyl; mercapto; sulfonyl (e.g., aminosulfonyl, alkylsul lbnyl, moipholinesLilfonyl, or arylsulfonyl); sulfinyl (e.g., alkylsulfinyl); sulfanyl (e.g., alkylsulfanyl); sulfoxy; urea; thiourea; sulfamoyl;
  • substituted heteroaryls include, but are not limited to, haloheteroaryl, alkoxycarbonylheteroaryl, alkylaminoalkylaminocarbonylheteroaryl, dihalpheteroaryl, cyanoheteroaryl, aminoheteroaryl, alkylcaibonylaininoheteroaryl, cyanoalkylheteroaryl, alkoxyheteroaryl, aminosulfonylheteroaryl, alkylsulfonylheteroaryl, aminoheteroaryl, aminoheteroaryl, aminoheteroaryl, hydroxyalkylheteroaryl, alkoxyalkylheteroaryl, hydroxyheteroaryl, carboxyalkylheteroaryl, dialkylaminoalkylheteroaryl, heterocycloaliphaticheteroaryl, heteroarylaminocarbonylheteroaryl, nitroalkylhe
  • alkylsulfonylaminoalkylheteroaryl heterocycloaliphaticcarbonylheteroaryl, alkylsulfonyla!kylheteroaryl, cyanoalkylheteroaryl, heterocycloaliphaticcarbonylheleroaryl, alkylcarbonylaminoheteroaryl.
  • an "aryl” group used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl,” refers to monocyclic (e.g., phenyl), bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, or tetrahydroindenyl), tricyclic (e.g., fluorenyl, telrahydrofluorenyl, anthracenyl, or tetrahydroanthracenyl), or benzofused group with 3 rings.
  • monocyclic e.g., phenyl
  • bicyclic e.g., indenyl, naphthalenyl, tetrahydronaphthyl, or tetrahydroindenyl
  • tricyclic e.g., fluorenyl, telrahydrofluorenyl,
  • benzofused groups include, but are not limited to, phenyl fused with two or more C4. carbocyclic moieties.
  • An aryl is optionally substituted with one or more substituents, including, but not limited to, aliphatic (e.g., alkyl, alkenyl, or alkynyl);
  • cycloalkyl (cycloalkyl)alkyl; heterocycloalkyl; (heterocycloalkyl)alkyl; aryl; heteroaryl; alkoxy; cycloalkyloxy; heterocycloalkyloxy; aryloxy; heteroaryloxy; aralkyloxy;
  • heteroaralkyloxy aroyl; heteroaroyl; amino; aniinoalkyl; nitro; carboxy; carbonyl (e.g., alkoxycarbonyl, alkylcarbonyl, aniinocarbonyl, (alkylamino)alkylarninocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, or sulfonylcarbonyl); aryalkylcarbonyloxy; sulfonyl (e.g., alkylsulfonyl or aminosulfonyl); sulfinyl (e.g., alkylsulfinyl); sulfanyl (e.g., alkylsulfanyl); cyano; halo; hydroxyl; acyl; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; oxo; or carbamo
  • substituted aryls include, but are not limited to, haloaryl,
  • alkoxycarbonylaryl alkylaminoalkylaminocarbonylaryl, ,w-dihaloaryl, p-amino- '- alkoxycarbonylaryl, M-amino-w-cyanoaryl, aminoaryl, alkylcarbonylaminoaryl,
  • cyanoalkylaryl alkoxyaryl, aniinosulfonylaryl, alkylsulfonylaryl, aminoaryl, p- a ⁇ o-m- aminoaryl.
  • alkylsulfonylalkylaryl cyanoalkylaryl, heterocycloaliphaticcarbonylaryl,
  • alkylcarbonylaminoaryl hydroxyalkylaryl. alkylcarbonylaryl. aminocarbonylaryl, alkylsulibnylaminoaryl, dialkylaminoaryl, alkylaryl, and trihaloalkylaryl.
  • halogen or halo group refers to fluorine, chlorine, bromine, or iodine.
  • an "alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1 to 8 (e.g., 1 to 6 or 1 to 4) carbon atoms.
  • An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, and 2-ethylhexyl.
  • An alkyl group can be optionally substituted with one or more substituents, including, but not limited to, halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, nitro, cyano, amino, acyl, sulfonyl, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl, cycloalkyloxy,
  • heterocycloalkyloxy aryloxy, heteroaryloxy, aralkyloxy. heteroarylalkoxy, and hydroxyl.
  • substituted alkyls include, but are not limited to, alkylcarbonylalkyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, carbonylalkyl, carboxyalkyl, hydroxyalkyl, oxoalkyl, aralkyl, alkoxyaralkyl, (alkylsulfonylamino)alkyl,
  • (sulfonylamino)alkyl carbonylaminoalkyl, aminocarbonylalkyl, cycloaliphaticalkyl, cyanoalkyl, aniinoalkyl, oxoalkyl, alkoxycarbonylalkyl. (alkoxycarbonylheterocycloalkyl)alkyl. (cycloalkyl)alklyl, (cycloalkenyl)alkyl,
  • heterocycloalkyl alkyl
  • haloalkyl alkyl
  • an "alkoxy” group refers to an alkyl-O- group, wherein ; 'alkyl" has been defined previously. Moreover, an alkoxy group includes structures comprising two alkoxy groups on the same atom or adjacent atoms that form a ring together with the atom(s) to which they are bound.
  • yield for each of the reactions described herein is expressed as a percentage of the theoretical yield.
  • Certain compounds of Formula I have two or more asymmetric centers and therefore can exist in a number of stereoisomers configurations. Consequently, the compounds of the present invention can occur as mixtures of enantiomers and as individual (pure) enantiomers, as well as diastereomers and mixtures of different diastereomers.
  • the present invention includes al l such enantiomers and diastereomers and mixtures thereof in all ratios.
  • compounds of Formula I include a cycloalkyl group about which geometric cis/trans isomers are possible.
  • the scope of the present invention includes all stereoisomers, as well as all geometric isomers and tautomeric forms ("tautomers") of the compounds of formula 1, and all mixtures thereof in any ratio. It will be appreciated by one skilled in the art that a single compound may exhibit more than one type of isomerism.
  • Compounds of the present invention may be resolved into the pure enantiomers by methods known to those skilled in the art. for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterificalion; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support with a bound chiral ligand or in the presence of a chiral solvent.
  • the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form.
  • the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation or inversion.
  • intermediates in the course of the synthesis may exist as racemic mixtures and be subjected to resolution by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enanliomer-specific reagent, for example enzymatic esterification; or gas- liquid or liquid chromatography in a chiral environment, for example on a chiral support with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation or inversion.
  • a compound of the invention contains an alkenyl or alkenylene group
  • geometric cis/trans (or Z/E) isomers are possible.
  • the compounds of the invention exist as cis and trans configurations and as mixtures thereof.
  • Cis/lrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
  • tautomeric isomerism ( ' tautomerism ' ) can occur.
  • This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto. or oxime group, or so- called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. All such tautomeric forms are included within the scope of the present invention.
  • Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the present compounds.
  • compositions and methods of treatment that employ or contain compounds of formula I, either by themselves or in combination with additional agents, similarly encompass all stereoisomers, geometric isomers and tautomeric forms of the compounds, and mixtures thereof in any ratio.
  • the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. It should be understood that pharmaceutically acceptable solvents includes isotopically substituted solvents such as D 2 0, dc-DMSO and the like.
  • the term 'solvate' is used herein to describe a complex comprising the compound of the invention and one or more
  • the present invention also includes all pharmaceutically acceptable isolopically- labelled compounds, which are identical to those described by Formula I but wherein one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, chlorine, fluorine, iodine, nitrogen, oxygen, and sulfur, such as 2 H, 3 H, "C, l C, 1 C, 36 C1, I S F, l 23 I, .' 2: ⁇ , 13 N, N, "O, l 7 0, 1!i O and 35 S, respectively.
  • compounds of the present invention prodrugs thereof, and pharmaceutical acceptable salts of the compounds or of the prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the invention.
  • Certain isotopically labeled compounds of the present invention such as, for example, those incorporating a radioactive isotope such as 3 H and > 4 C, are useful in drug and/or substrate tissue distribution studies. Tritium, i.e. 'T-I.. and carbon- 14, i.e. 1 C, are particularly preferred due their ease of preparation and detection.
  • isotopically labeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds of the invention may be isolated and used per se or in the form of their pharmaceutically acceptable salts or solvates.
  • Pharmaceutically acceptable salts as used herein in relation to the compounds of the present invention, include pharmacologically acceptable inorganic and organic salts of said compound. These salts can be prepared in situ during the final isolation and/or purification of a compound (or prodrug), or by separately reacting the compound (or prodrug) with a suitable organic or inorganic acid and isolating the salt thus formed.
  • a pharmaceutically acceptable salt of a compound of formula I may be readily prepared by mixing together solutions of the compound of Formula I and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • the compounds of the invention may be isolated and used per se or in the form of their pharmaceutically acceptable salts or solvates.
  • Pharmaceutically acceptable salts as used herein in relation to the compounds of the present invention, include pharmacologically acceptable inorganic and organic salts of said compound. These salts can be prepared in situ during the final isolation and/or purification of a compound (or prodrug), or by separately reacting the compound (or prodrug) with a suitable organic or inorganic acid and isolating the salt thus formed.
  • a pharmaceutically acceptable salt of a compound of Formula I may be readily prepared by mixing together solutions of the compound of Formula I and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate. hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonale, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate. nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen
  • phosphate/dihydrogen phosphate saccharate, stearate. succinate, tartrate, tosylate.
  • salts include alkali or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.
  • the invention further includes mixtures of salt forms.
  • a "patient" for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. The methods are thus applicable to both human therapy and veterinary applications.
  • the patient is a mammal, and in a more specific embodiment, the patient is human.
  • a " pharmaceutically acceptable salt” of a compound means a salt that is phannaceutically acceptable and that it possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are nontoxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 17 1 ' 1 ed., Mack Publishing Company, Easton, PA, 1985, or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66: 1 -1 9, both of which are incorporated herein by reference.
  • Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like) and those formed with organic acids (e.g., acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4- hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2- ethanedisulfonic acid, 2-hydi xyethanesulfonic acid, benzenesulfonic
  • Examples of a pharmaceutically acceptable base addition salt includes those formed when an acidic proton present in the parent compound is replaced by a metal ion, including, but not limited to. sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Specific salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins.
  • organic bases include, but are not limited to, isopropylamine, Irimethylamine, diethylamine. triethylamine, tripropylamine, ethanolamine, 2-dirnethylaminoelhanoL 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine. choline, betaine. ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N- ethylpiperidine, tromethamine, /V-methylglucamine, polyamine resins, and the like.
  • organic bases are isopropylamine, diethylamine. ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • a “therapeutically effective amount” is an amount of a compound of the invention that, when administered to a patient, ameliorates a symptom of the disease.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like.
  • the therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
  • preventing or “prevention” of a disease, disorder, or syndrome includes, but is not limited to, inhibiting the disease from occurring in a human, i.e.. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome.
  • treating includes, but is not limited to, (i) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (ii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
  • adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction, and the severity of the condition may be necessary and will be ascertainable with routine experimentation by one of ordinary skill in the art.
  • the invention provides a compound of formula I.
  • L is absent.
  • L is NH
  • W is a absent
  • W is a branched or straight C i-n aliphatic chain. [00611 In another embodiment, W is -CH(CH 3 )-.
  • Ring A is heteroaryl or aryl.
  • W when W is a branched or straight C 1.12 aliphatic chain.
  • W is -CI- CH3)-, L is absent, and Ring A is aryl or heteroaryl.
  • X is a fused bicyclic cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl and X 2 and X3 are absent. More particularly, in one embodiment, Xi is naphthalenyl, chromanyl, isochromanyl, thiocromanyl, isothiocromanyl,
  • tetrahydroquinolinyl tetrahydroisoquinolinyl, tetraliydronaphthyl, indanyl, or indenyl, each of which is optionally and independently substituted with 1 -3 of halo, nitro, cyano, hydroxy, amino, C
  • is a monocyclic cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl.
  • is cyclohexyl, phenyl, pyridyl, pyrimidinyl, piperidinyl, or pyrrolidinyl.
  • X t is phenyl, pyridyl, or pyrimidinyl.
  • X3 is absent or both X 2 and X 3 are absent.
  • is phenyl or pyridyl. In another embodiment, when X
  • Xi is phenyl or pyridyl and X 2 is present.
  • X 2 is aryl or heteroaryl. More particularly, X 2 is pyridyl, pyrimidinyl, tetrazolyl, triazolyl, imidazolyl, or pyrazolyl.
  • X 2 is attached to Xi at a position that is meta relative to the attachment point of W.
  • is phenyl or pyridyl
  • X 2 is pyridyl, pyrimidinyl, tetrazolyl, triazolyl, imidazolyl, or pyrazolyl
  • W is -CH(CH3)-
  • L is absent
  • Ring A is aryl or heteroaryl.
  • Xi is phenyl or pyridyl
  • X 2 is pyridyl, pyrimidinyl, tetrazolyl, triazolyl, imidazolyl, or pyrazolyl
  • X 3 is cycloaliphatic or heterocycloaliphatic. More particularly, X 3 is piperizinyl, piperidinyl. or morpholinyl.
  • is phenyl or pyridyl and X 2 is pyridyl
  • X 3 is piperizinyl, piperidinyl, or morpholinyl.
  • Y is absent or is a branched or straight C M 2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Qi) 2 -, -C(Q 2 ) 2 - : -CHQi-, -CHQr, -CO-, -CS-, -CONR R -, -CONR B NR B -, -C0 2 -, -OCO-, -NR 13 -.
  • Y is a branched or straight C
  • Z is H. In another embodiment, Z is C
  • the compound of formula I is a compound of formula IA,
  • the compound of formula I is a compound of formula IA-1 , IB-1 , or IC- 1 .
  • is chosen from chromanyl, isochiomanyl, thiocromanyi, isothiocromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl. tetrahydronaphthyl, indanyl, or indenyl. each of which is optionally and independently substituted with 1-3 of halo, nitro. cyano. hydroxy, amino, C
  • .6 alkoxy Ci.6 alkyl, Ci-6 alkylcarbonyl, Cj.r, alkoxycarbonyl, C
  • is optionally substituted phenyl or pyridyl.
  • Xi is optionally substituted phenyl or pyridyl and X2.
  • X3. and Z have any of the meaning provided herein.
  • the compound of formula 1 is a compound of formula IB-2 or IC-2
  • and A 3 are N, and A 2 is CH or C-halo or A2 is N. and A
  • R.2 is H, alkyl, alkoxy, haloalkoxy. or halo.
  • the compound of formula I is a compound of formula ⁇ -3, IB-4, IC-3, or IC-4
  • X2 is a six-membered ring.
  • X2 is pyridyl or pyrimidinyl.
  • X 3 is
  • Another embodiment of a compound of formula I is a compound of formula IE
  • Ring D is optionally substituted cyclohexyl, phenyl, pyt idyl, or pyrimidinyl.
  • Another embodiment of a compound of formula IE and thus of formula I is a compound of formula I E- 1
  • Ring D is phenyl or pyridyl optionally substituted with R which is H. alkyl, haloalkyl. alkoxy, haloalkoxy, halo. -OH, CN. N0 2 ; and Ring E is a aryl or heteroaryl
  • Ring E is phenyl, or G/
  • R 9 is selected from H, alkyl. haloalkyl, alkoxy, haloalkoxy. halo, -OH, CN, N0 2 , and NH; and R,o is selected from H,-CHOHCH 3! -CHOH(CH 3 ) 2 COMe, C0 2 Et, NHMe, NHEt,
  • NMe 2 Nl3 ⁇ 4.
  • NHCHMe 2 CH 2 OH, -CH 2 CO Et ; CH 2 C0 2 H. -CONH 2 , -NHCH 2 CH 2 CH 2 OH, ⁇
  • the compound of formula IE-2 is a compound of formula IE-3
  • Ring E, R , R9.. and R]o are as previously defined.
  • Ring A is an optionally substituted monocyclic or bicyclic aryl or heteroaryl.
  • Ring A is an optionally substituted phenyl.
  • Ring A is wherein at least one of A, B, and C are N, NH, N(alkyl), S, SO,
  • ol ' A, B, and C are CH, CM, or C(alkyl); and R 5 is H or alkyl.
  • one ol ' A and C is N, S ; or 0.
  • one of A and C is N and the other of A and C is S or O.
  • Ring A is selectexd from the group consisting of phenyl substituted one, two. or three groups selected from halo, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, -CONH 2 , -CONHMe, -NH-CH 2 -CN ; -CN, -C0 2 alkyl, NH-CH 2 - CONHMe, CH2CONH-CH 2 CH 2 OH, 1 ,3-benzodioxol-5-yl, 2,2-difluoiO-l,3-benzodioxoI-5- yl, benzo[cJthiazol-5-yl.
  • l,3-benzothiazol-6-yl 1-alkyl-l H-indol-6-yl, l-[2- (methyloxy)ethyl]-lH-indol-6-yl, 1 H-indol-4-yl , 1 -methyl- 1 H-indol-4-yl , lH-indol-5-yl , lH-indol-6-yl, l-methyl-2,3-dihydro-lH-indol-6-yl. lH-indol-7-yl.
  • Ring A is N
  • Het is a heteroaryl ring which is optionally substituted with 1 -3 ot " Q 3 ;
  • R-3 is Q_;
  • R 3 on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a 5-6 membered cycloaliphatic or heteroaliphatic, saturated or unsaturated ring, which is optionally substituted with 1-3 of Q 2 .
  • two instances of R 3 on adjacent carbon atoms are taken together with the carbon atoms to which they are attached form a benzo-fused furanyl or thiophenyl ring, which is optionally substituted with 1 -3 of Q 2 .
  • W is a branched or straight C
  • R, t is X
  • A, B, and C are N, NH, N(alkyl), S, SO, S0 2 , or O and the others of ABC are CH, CH, or C(alkyl): and
  • R 5 is 0, 1 , 2. or 3 groups independently selected from halo, -OH, oxo, -CF 3 , -OCF 3 , cyano, or a Ci_ s branched or straight aliphatic, wherein 1 -3 methylene groups of the aliphatic are optionally and independently replaced with -C(O)-, -0-, -NH-, -C(0)NH- or -C(0)0-, and wherein the aliphatic is optionally further substituted with 1 -3 of halo, cyano, OH, or Ci- 3 aliphatic.
  • one of A and C is N, S, or O.
  • one of A and C is and the other of A and C is S.
  • the compound of formula 111 is a compound of formula IIIA, II I-
  • the compound of formula HI is a compound of formula III- DJII-E, or 111-F.
  • the compound of formula III is a compound of formul G. III-H, or III- J, wherein the variables have any of the definitions provided herein.
  • the compound of formula I is a compound of formula IV, wherein the variables have any of the defintions provided herein.
  • the compound of formula I is a compound of formula IV-A, wherein the variables have any of the defintions provided herein.
  • the compound of fonnula IV-A is a compound of formula IV-B, wherein the variables have any of the definitions provided herein.
  • the compound of formula I is a compound of formula V
  • Ring A is as previously defined for a compound of formula I and R.6 is
  • cycloaliphatic heterocycloaliphatic, aryl, or heteroaryl, each or which are optionally and independently substituted with 1 -3 of Qi, Q 2 , or Q 2 .
  • each Q 2 is independently hydrogen, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally including 1 -3 substituents independently selected from Q 3 ;
  • each Q 3 is halo, oxo, CN, N0 2: H , CF 3 , OCF 3 , OH, -COOH or C1-C4 alkyl optionally substituted with 1 -3 of halo, oxo, -CN. -N0 2 , -CF 3 , -OCF3, -OH, -SH, -S(0) 3 H, - NH 2 , or -COOH.
  • R 6 is selected from the group consisting of 2.3-dihydro-l H-inden-l -yl ,1 ,2,3,4-tetrahydronaphthalen-l -yl, naphthalen- l -yl, 6-nitro-3,4-dihydro-2H-chromen-4-yl), 3,4-dihydro-2H-chromen-6-yl, 3,4-dihydro-2H- chromen-4-yl, 3,4-dihydro-2H-l -benzothiopyran-4-yl, furanyl, wherein each of the groups may be optionally substituted with one, two, or three groups selected from halo, nito, -NH- CO- e, -NH-CO-Et, alkyl, and alkoxy.
  • the compound of formula V is a compound of formula VA.
  • Ring A is as previously defined, X v C, N, or 0, and R )2 is one or two groups independently selected from alkyl, -NHCO e, -NHCOEt.
  • the compound of formula V is a compound of formula VB.
  • Ring A is as previously defined.
  • the compound of formula I is one of the compounds listed in table 1 .
  • the invention provides a pharmaceutical composition which comprises: ( 1 ) a compound, as a single stereoisomer or mixture of isomers thereof, according to any one of formula compounds of formula I. or according to any one of the above embodiments or a compound in Table 1 , optionally as a pharmaceutically acceptable salt thereof, and (2) a pharmaceutically acceptable carrier, excipient, and/or diluent thereof.
  • the invention provides a method of treating disease, disorder, or syndrome where the disease is associated with uncontrolled, abnormal, and/or unwanted cellular activities effected directly or indirectly by iPF -2 which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of any of the formulas described herein, a compound of any one of the above embodiments, or a compound from Table 1 , optionally as a pharmaceutically acceptable salt or
  • the disease is cancer.
  • the disease is cancer and the compound is a compound of formula I or a compound from Table 1 .
  • the invention provides a method of treating a disease, disorder, or syndrome which method comprises administering to a patient a therapeutically effective amount of a compound of any of formula I, a compound of any one of the above
  • the disease is cancer
  • the Compound is the compound of formula 1 or a compound from Table I .
  • the invention provides pharmaceutical compositions comprising an inhibitor of iPFK-2 according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
  • administration is by the oral route.
  • Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, speci fically in unit dosage forms suitable for simple administration of precise dosages.
  • compositions wi ll include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include carriers and adjuvants, etc.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as. for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as. for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.

Abstract

The invention is directed to inhibitors of inducible form of 6-phosphofructose-2-kinase of formula I, as well as to pharmaceutically acceptable salts of formula I, and pharmaceutical compositions comprising a compound of formula I. The compounds can be used to treat cancer.

Description

Inhibitors of Inducible Form of 6-Phosphofructose-2-Kinasc
Cross-Refcrcncc to Related Applications
[00011 This application claims the benefit of priority of U.S. Provisional Application No. 61 /481.035. the entire contents of which are incorporated herein by reference.
Background of the Invention
[0002] Glycolysis is a metabolic pathway in which sugars are degraded to generate energy (ATP). In a normal healthy cell, the rate o f glycolysis is regulated by the enzymes hexokinase. phosphofructokinase, and pyruvate kinase. These enzymes catalyze irreversible reactions, and each is controlled to meet metabolic needs. Phosphofructokinase is the most important control point in glycolysis, and the rate limiting enzyme 6-phosphofructo- l -kinase (PF - 1 ) normally controls the rate of glycolysis. However, the four bifunctional 6- phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) isozymes regulate the steady- state concentration of 6-phosphofructo-2-kinase (PFK-2), one of the most potent activators of PFK- 1 , and this concentration is what ultimately controls the rate of glycolysis.
[0003] Unlike normal healthy cells, cancer cells maintain a high glycolic rate for ATP production, even under aerobic conditions. The glycolic rate can be up to 200 times greater in malignant, rapidly-growing tumor cells. This is known as the Warburg effect. One of the four PFKFB isozymes, PFKFB3, is responsible for encoding an inducible form of 6- phosphofructose-2-kinase, iPFK-2. PFK.FB3 is expressed at high levels in tumor cell lines. Treatment with specific antisense oligonucleotides reverses this high expression of PFKFB3 in tumor cells, shrinking the tumors in vivo. PFKFB3 is also essential for Ras-mediated transformation, as shown in vitro by soft agar colony formation and in vivo by
tumorigenensis.
[0004] iPFK-2, which is encoded by PFKFB3. is a potent allosteric activator of PFK- 1 , the rate-limiting enzyme in glycolysis. iPFK-2 thus functions as an activator of anaerobic glycolysis within the hypoxic microenvironmenl of growing tumors. Blocking the activity of iPFK-2 can decrease tumor growth by reducing the extremely high rate of glycosis in cancer cells. Inhibition of i PFK-2 is thus useful for the treatment of a wide variety of cancers.
[0005] Regulation of the rate of glycolysis by inhibiting iPFK-2 can also be useful in the treatment of a range of other disorders, including, but not limited to, metabolic disorders, autoimmune disorders, Alzheimer's disease, muscular dystrophy, and osteoarthritis.
[0006] Thus, a need remains for the treatment of a wide range of diseases by the inhibition of iPFK-2. [0006] Thus, a need remains for the treatment of a wide range of diseases by the inhibition of iPFK-2.
Summary of the Invention
[0007] These and other needs are met by the present invention, which in one aspect is directed to a compound of formula 1
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein:
W is a branched or straight C M? aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Qt)2-, -C(Q2)2-, -CHQi-, -CHQ2-, -CO-, -CS-, -CONR'\ -CONRA RA-. -C02-, -OCO-, -NRA-, -NRAC02-, -0-, -NRACONRA-, -OCONRA- , -NRANRA-, -NRACO-, -S-, -SO-, -S02-s -S02NRA-, -NRAS02-, or -NRAS02NRA;
each RA is independently hydrogen, Cj.s aliphatic; cycloaliphatic,
heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1 -3 of Qi, Q2, or Q3;
X| . X2, and X3 are each independently absent or are a cycloaliphatic,
heterocycloaliphatic, aryl. or heteroaryl. each or which are optionally and independently substituted with 1 -3 of Oj or Q2, and wherein at least one of X|, X2, and X3 is presentt;
Y is absent or is a branched or straight C 1.12 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q|)2-, -C(Q2)2-, -CTIQ 1 -, -CHQ2-, -CO- , -CS-, -CONRB-, -C(=NRB)NRB-, -C(=NORB)NRB-, -NRBC(=NRB)NRB-, -CONRBNRB-, - CO2-, -OCO-, -NRB-, -NRBC02-, -0-, -NR CONRB-, -OCONRB-, -NRBNRB-, -NRBCO-, -S-, -SO-, -SO2-, -S02NRB-, -NRBS02-, or -NRBS02NRB;
each RLt is independently hydrogen, C|.g aliphatic, cycloaliphatic,
heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1 -3 of Qi, Q2, or Q3 ;
Z is independently hydrogen, C|.s aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1 -3 of Oj, Q2, or Q3 ; or
L is absent or is NH, N(C|_s aliphatic), or is a branched or straight Cm aliphatic chain wherein up to two carbon units of L are optionally and independently replaced by -C(Qi)2-, -C(Q2)2-; -CO-, -CS-, -CONRc-, -CONRcNRc-, -C02-, -OCO-, -NRC-, -NRcC02-, -0-, -NRcCONRc-, -OCONRc-, -NRC RC-, -NRcCO-, -S-, -SO-, -S02-: -S02 Rc-, -NRcS02-, or -NRcS02NRc; each Rc is independently hydrogen, C|.s aliphatic, cycloaliphalic, heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1 -3 of Qj. Q2. or Q3;
Ring A is a monocyclic, bicyclic, or tricyclic cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, any of which may be optionally substituted with 1 -3 of halo, -OH, oxo, -CF3, -OCF3, cyano, or a C|.« branched or straight aliphatic, wherein 1 -3 methylene groups of the aliphatic are optionally and independently replaced with -C(O)-, -0-, -NH-, -C(0)NH-, or -C(0)0-, and wherein the aliphatic is optionally further substituted with 1 -3 of halo, cyano, OH, or C|. aliphatic;
each Qi is independently halo, oxo, -CN, -N02, -N=0, -NHOQ2, =NQ2, =N0Q2, -0Q2, -SOQ2, -S02Q2, -SON(Q2)2, -S02N(Q2)2, -N(Q2)2, -C(0)OQ2, -C(0)-Q2, -C(0)N(Q2)2, -C(=NQ2)NQ2-, -NQ2C(=NQ2)NQ2-, -C(0)N(Q2)(0Q2), -N(Q2)C(0)-Q2, -N(Q2)C(0)N(Q2)2, -N(Q2)C(0)0-Q2; -N(Q2)S02-Q2 - ( h)SO-Q2. or aliphatic optionally including 1 -3 substituents independently selected from Q2 or Q3.
each Q2 is independently hydrogen, aliphatic, alkoxy, cycloaliphatic. aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally including 1-3 substituents independently- selected from Q ;
each Q3 is halo, oxo, CN, N02, NH2, CF3, OCF3, OH, -COOH or Ci-C alkyl optionally substituted with 1 -3 of halo, oxo, -CN. -N02, -CF3, -OCF3, -OH, -SH, -S(0)3H, - NH2, or -COOH;
provided that the compound of formula 1 is not
Figure imgf000004_0001
[0008] In another aspect, the invention is directed to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable earner, excipient, or diluent. [0009] In another aspect, the invention is directed to a method of treating a disease or disorder mediated by IPFK-2. comprising administering to a subject in need of such treatment a compound of formula I or a pharmaceutical composition comprising a compound of formula I.
Detailed Description of the Invention
[0010] The following abbreviations and terms have the indicated meanings throughout:
Figure imgf000005_0001
Abbreviation Meaning
Ms Mesyl (methanesul fonyl)
N Normal or normality
nM Nanomolar
NMR Nuclear magnetic resonance spectroscopy
q Quartet
quant Quantitative
rt Room temperature
s Singlet
t or tr Triplet
THF Telrahydrofuran
Ts Tosyl (/ toluenesulfonyl)
[0011] The symbol "-" indicates a single bond, indicates a double bond, indicates a triple bond, and " " indicates a single or double bond. The symbol :vvw " refers to a group on a double bond as occupying either position on the terminus of a double bond to which the symbol is attached; that is. the geometry, E- or Z-, of the double bond is ambiguous. When a group is depicted as removed from its parent formula, the symbol will be used at the end of the bond which was theoretically cleaved in order to separate the group from its parent structural formula.
[0012] When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons are assumed to have hydrogen substitution to conform to a valence of four. For example, in the structure on the left in the schematic below, there are nine hydrogen atoms implied. The nine hydrogen atoms are depicted on the right in the schematic below. Sometimes a particular atom in a structure is described in the textual formula as having a hydrogen or multiply hydrogen atoms as siibstituents (expressly defined hydrogen); for example. -CH2CH2-. U is understood by one of ordinary skill in the art that the aforementioned descriptive techniques are common in the chemical arts to provide brevity and simplicity to description of otherwise complex structures.
Figure imgf000006_0001
[0013] If a group "R" is depicted as "floating" on a ring system, such as in the formula:
Figure imgf000006_0002
then, unless othenvise defined, a substituent " " may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
[001 ] If a group "R" is depicted as floating on a fused or bridged ring system, such as in the formulae:
Figure imgf000007_0001
then, unless otherwise defined, a substituent "R" may reside on any atom of the fused or bridged ring system, assuming replacement of a depicted hydrogen (e.g., the -NH- in the formulae above), implied hydrogen (e.g., where, in the formulae above, the hydrogen atoms are not shown but are understood to be present), or expressly defined hydrogen (e.g., where, in the formula above, "Z" equals =CH-) from one of the ring atoms, so long as a stable structure is formed. In the examples depicted, the "R" group may reside on either the 5-membered or the 6-membered ring of the fused or bridged ring system.
[0015] When a group "R" is depicted as existing on a ring system containing saturated carbons, such as in the formula:
Figure imgf000007_0002
and where "y" can be more than one, assuming each "R" replaces a currently depicted, implied, or expressly defined hydrogen on the ring; then, unless othenvise defined, where the resulting structure is stable, two "R's" may reside on the same carbon. In another example, two "R's" on the same carbon, including that carbon, may form a ring, thus creating a spirocyclic ring structure with the depi as in the formula:
Figure imgf000007_0003
[0016] As used herein, "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, and chemotherapy, etc.), "administration" and its variants are each understood to include concurrent and sequential introduction of the Compound or prodrug thereof and other agents. [0017] As used herein, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. One of ordinary skill in the art would understand that, with respect to any molecule described as containing one or more optional substituents, only sterically practical and/or synthetically feasible compounds are meant to be included. "Optionally substituted" refers to all subsequent modifiers in a term, unless staled otherwise.
[0018] As used herein, the term "aliphatic" encompasses the terms alkyl, alkenyl, and alkynyl.
[0019] As used herein, the term "cycloaliphatic" means a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic hydrocarbon ring that has a single point of attachment to the rest of the molecule. Cycloaliphatic rings are 3- to 8-membered monocyclic rings (e.g., 3- to 6-membered rings). Cycloaliphatic rings also include 8- to 12-membered bicyclic hydrocarbon rings, (e.g., 10-membered bicyclic hydrocarbon rings). A cycloaliphatic group encompasses both "cycloalkyl" groups and "cycloalkenyF' groups.
[0020] As used herein, the terms "heterocycloaliphatic" and "heterocyclic" encompass heterocycloalkyl groups and heterocycloalkenyl groups.
[00211 As used herein, a "heterocycloalkyl" group refers to a 3- to 10-membered mono cyclic or bicyclic (including fused and bridged) (e.g., 5- to 10-membered monocyclic or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g.. N, O, S, or combinations thereof). Examples of heterocycloalkyl groups include, but are not limited to, optionally substituted piperidyl, piperazyl, telrahydropyranyl,
tetrahydrofuryl, 1 ,4-dioxolanyl, 1 ,4-dithianyl, 1 ,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydro-benzofuryl, octahydro-chromenyl, octahydro- thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl, octahydro- benzo[/>]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, l -aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1 ]octanyl, 2,6-dioxa-tricyclo[3.3.1 .0]nonyl, and tropane. A monocyclic heterocycloalkyl group may be fused with a phenyl moiety, such as tetrahydroisoquinoline. Heterocycloalkyl ring structures can be optionally substituted at any chemically viable position on the ring or rings.
[00221 As used herein, a "heterocycloalkenyl" group refers to a monocyclic or bicylic (e.g., 5- to 10-membered monocyclic or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof)- Examples of heterocycloalkenyls include, but are not limited to, 2- pyrrolyl, 3-pyrrolyl, 2-imidazolyl, and 2-pyrazolyl. Monocyclic heteroaliphatics, including both heterocycloakyls and heterocycloalkenyls, are numbered according to standard chemical nomenclature. For instance:
Figure imgf000009_0001
e
[0023] A heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents. including, but not limited to, alkyl (e.g. carboxyalkyl, hydroxyalkyl, and haloalkyl, such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl (e.g., benzimidazolidinyl), (hetei ocycloalkyl)alkyl, aryl, heteroaryl, alkoxy (wherein two alkoxy groups on the same atom or adjacent atoms may form a ring together with the atom(s) to which they are bound), cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralky!oxy. aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy. aminocarbonyl, alkylcarbonylamino,
cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino, cyano. halo, hydroxyl, acyh mercapto, sulfonyl (e.g..
alkylsulfonyl or aryl sulfonyl), sulfinyl (e.g., alkylsulfinyl). sulfanyl (e.g., alkylsulfanyl), sulfoxy. urea, thiourea, sulfamoyl, sulfamide, oxo, and carbamoyl.
[0024] Examples of substituted heterocycloaliphatics include, but are not limited to, alkoxycarbonylheterocycloalkyl (e.g., ethoxycarbonyltropane),
alkoxycarbonylheterocycloalkyl (e.g., ethoxycarbonylpiperidyl), and the like.
[0025] As used herein, a "heteroaryl" group refers to a monocyclic, bicyclic, or tricyclic ring structure having 4 to 1 5 ring atoms, wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof), and wherein one or more rings of the bicyclic or tricyclic ring structure is aromatic. Heteroaryl groups include benzofused ring systems having 2 to 3 rings. Examples of benzofused groups include, but are not limited to, phenyl fused with one or two C .s heterocyclic moieties (e.g., indolizyl. indolyl, isoindolyl, 3 H-indolyl, indolinyl. benzo[Z)] furyl, benzo[7>]thiophenyl: quinolinyl. or isoquinolinyl).
Some examples of heteroaryls include, but are not limited to azetidinyl, pyridyl, 1 H- indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene. thioxanthene. phenothiazine, dihydroindole, benzo[l ,3]dioxole, benzo[Z>]furyl, benzo[Z>]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl.cinnolyl. phthalazyl, quinazolyi, quinoxalyL isoquinolyl, 4H-quinolizyl, benzo- l ,2,5-thiadiazolyl, and 1 ,8-naphthyridyl.
[0026] Monocyclic heteroaryls include, but are not limited to, fury I, thiophenyl, 2H- pyrrolyl, pyrrolyl, oxazolyl, thazolyl. imidazolyl, pyrazolyl, isoxazolyl. isothiazolyl, 1 ,3,4- thiadiazolyl, 2H-pyranyl. 4-H-pranyl, pyridyl, pyridazyl. pyrimidyl, pyrazolyl, pyrazyl, and 1 ,3.5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature. For example:
Figure imgf000010_0001
Furan Thiazole Pyrimidine
[0027] Bicyclic heteroaryls include, but are not limited to, indolizyl. indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[6]furyl, benzo[0]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indazolyl. benzimidazyl. benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl. cinnolyl, phthalazyl. quinazolyi, quinoxalyl, 1 ,8-naphthyridyl. and pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature. For example:
Figure imgf000010_0002
Cinnoline 3,1 -Benzoxazine Indolizine
Figure imgf000010_0003
Quinoxaline
[0028] Heteroaryls are optionally substituted with one or more substituents, including, but not limited to, aliphatic groups, including alkyl (e.g., alkoxyalkyl, carboxyalkyl.
hydroxyalkyl, oxoalkyl, aralkyl, (alkylsulfonylamino)alkyl, (sulfonylamino)alkyl.
cyanoalkvl, aminoaikyl, oxoalkyl. alkoxycarbonylalkyl. (cycloalkyl)alkyl heterocycloalkyl, (heterocycloalkyl)alkyl aralkyl, or haloalkyl. such as trinuoromethyl), alkenyl, and alkynyl; cycloaliphatic. including cycloalkyl (e.g., cyclopropyl. cyclobutyl, cyclopentyl, or cyclohexyl); heterocycloaliphatic, including heterocylcoalkyl (e.g., thiomorpholyl, piperazinyl, 1 ,3,5-trithianyl, morpholinyl, pyrrol l, 1 ,3-dioxolanyl, pyrazolidyl, or piperidinyl): aryl; heteroaryl (e.g., quinolyl, indolyl, 3H-indolyl, isoindolyl, benzo[Z>]-4H- pyranyl, cinnolyl, quinoxylyl. benzimidazyl, benzo- l ,2,5-tliiadiazolyl, benzo- 1 ,2,5- oxadiazolyl, or benzthiophenyl); alkoxy; cycloalkyloxy; heterocycloalkyloxy; aryloxy; heleroaryloxy; aralkyloxy; heteroaralkyloxy; aroyl; heferoaroyl; amino (e.g., carbonylamino, alkylcarbonylamino, alkylsul fonylamino, arylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, (lieterocycloalkyl)carbonylamino,
(cycloalkyl)alkylcarbonylamino, sul fanylamino, or (heterocycloalkyl)alkylcarbonylamino); nitro; carboxy; carbonyl (e.g., alkylcarbonyl, alkoxycarbonyl, aminocarbonyl,
arylaminocarbonyl, thiazoleaminocarbonyl, thiomorpholinecarbonyl,
aminoalkylaminocarbonyl); alkylcarbonyloxy; cyano; halo; hydroxyl; acyl; mercapto; sulfonyl (e.g., aminosulfonyl, alkylsul lbnyl, moipholinesLilfonyl, or arylsulfonyl); sulfinyl (e.g., alkylsulfinyl); sulfanyl (e.g., alkylsulfanyl); sulfoxy; urea; thiourea; sulfamoyl;
sulfamide; oxo; or carbamoyl.
[0029] Examples of substituted heteroaryls include, but are not limited to, haloheteroaryl, alkoxycarbonylheteroaryl, alkylaminoalkylaminocarbonylheteroaryl, dihalpheteroaryl, cyanoheteroaryl, aminoheteroaryl, alkylcaibonylaininoheteroaryl, cyanoalkylheteroaryl, alkoxyheteroaryl, aminosulfonylheteroaryl, alkylsulfonylheteroaryl, aminoheteroaryl, aminoheteroaryl, hydroxyalkylheteroaryl, alkoxyalkylheteroaryl, hydroxyheteroaryl, carboxyalkylheteroaryl, dialkylaminoalkylheteroaryl, heterocycloaliphaticheteroaryl, heteroarylaminocarbonylheteroaryl, nitroalkylheteroaryl. alkylsulfonylaminoalkylheteroaryl, heterocycloaliphaticcarbonylheteroaryl, alkylsulfonyla!kylheteroaryl, cyanoalkylheteroaryl, heterocycloaliphaticcarbonylheleroaryl, alkylcarbonylaminoheteroaryl.
hydroxyalkylheteroaryl, alkylcarbonylheteroaryl, aminocarbonylheteroaryl,
alkyls lfonylaminoheteroaryl, dialkylaminoheteroaryl, alkylheteroaryl, and
trihaloalkylheteroaryl.
[0030] As used herein, an "aryl" group, used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl," refers to monocyclic (e.g., phenyl), bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, or tetrahydroindenyl), tricyclic (e.g., fluorenyl, telrahydrofluorenyl, anthracenyl, or tetrahydroanthracenyl), or benzofused group with 3 rings. Examples of benzofused groups include, but are not limited to, phenyl fused with two or more C4. carbocyclic moieties. An aryl is optionally substituted with one or more substituents, including, but not limited to, aliphatic (e.g., alkyl, alkenyl, or alkynyl);
cycloalkyl; (cycloalkyl)alkyl; heterocycloalkyl; (heterocycloalkyl)alkyl; aryl; heteroaryl; alkoxy; cycloalkyloxy; heterocycloalkyloxy; aryloxy; heteroaryloxy; aralkyloxy;
heteroaralkyloxy; aroyl; heteroaroyl; amino; aniinoalkyl; nitro; carboxy; carbonyl (e.g., alkoxycarbonyl, alkylcarbonyl, aniinocarbonyl, (alkylamino)alkylarninocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, or sulfonylcarbonyl); aryalkylcarbonyloxy; sulfonyl (e.g., alkylsulfonyl or aminosulfonyl); sulfinyl (e.g., alkylsulfinyl); sulfanyl (e.g., alkylsulfanyl); cyano; halo; hydroxyl; acyl; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; oxo; or carbamoyl. Alternatively, an aryl may be unsubstituted.
[0031 ] Examples of substituted aryls include, but are not limited to, haloaryl,
alkoxycarbonylaryl, alkylaminoalkylaminocarbonylaryl, ,w-dihaloaryl, p-amino- '- alkoxycarbonylaryl, M-amino-w-cyanoaryl, aminoaryl, alkylcarbonylaminoaryl,
cyanoalkylaryl, alkoxyaryl, aniinosulfonylaryl, alkylsulfonylaryl, aminoaryl, p- a\o-m- aminoaryl. cyanoaryl, hydroxyalkylaryl, alkoxyalkylaryl, hydroxyaryl, carboxyalkylaryl, dialkylaminoalkylaryl, w-heterocycloaliphatic-o-alkylaryl, heteroarylaminocarbonylaryl, nitroalkylaryl, alkylsulfonylaminoalkylaryl, heterocycloaliphaticcarbonylaryl,
alkylsulfonylalkylaryl, cyanoalkylaryl, heterocycloaliphaticcarbonylaryl,
alkylcarbonylaminoaryl, hydroxyalkylaryl. alkylcarbonylaryl. aminocarbonylaryl, alkylsulibnylaminoaryl, dialkylaminoaryl, alkylaryl, and trihaloalkylaryl.
[0032] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine, or iodine.
[0033] As used herein, an :ioxo" refers to =0.
|0034] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1 to 8 (e.g., 1 to 6 or 1 to 4) carbon atoms. An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, and 2-ethylhexyl. An alkyl group can be optionally substituted with one or more substituents, including, but not limited to, halo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, nitro, cyano, amino, acyl, sulfonyl, sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carbamoyl, cycloalkyloxy,
heterocycloalkyloxy. aryloxy, heteroaryloxy, aralkyloxy. heteroarylalkoxy, and hydroxyl. Examples of substituted alkyls include, but are not limited to, alkylcarbonylalkyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, carbonylalkyl, carboxyalkyl, hydroxyalkyl, oxoalkyl, aralkyl, alkoxyaralkyl, (alkylsulfonylamino)alkyl,
(sulfonylamino)alkyl. carbonylaminoalkyl, aminocarbonylalkyl, cycloaliphaticalkyl, cyanoalkyl, aniinoalkyl, oxoalkyl, alkoxycarbonylalkyl. (alkoxycarbonylheterocycloalkyl)alkyl. (cycloalkyl)alklyl, (cycloalkenyl)alkyl,
(heterocycloalkyl)alkyl, and haloalkyl.
|0035J As used herein, an "alkoxy" group refers to an alkyl-O- group, wherein ;'alkyl" has been defined previously. Moreover, an alkoxy group includes structures comprising two alkoxy groups on the same atom or adjacent atoms that form a ring together with the atom(s) to which they are bound.
[0036] As used herein, "yield" for each of the reactions described herein is expressed as a percentage of the theoretical yield.
[0037] Certain compounds of Formula I have two or more asymmetric centers and therefore can exist in a number of stereoisomers configurations. Consequently, the compounds of the present invention can occur as mixtures of enantiomers and as individual (pure) enantiomers, as well as diastereomers and mixtures of different diastereomers. The present invention includes al l such enantiomers and diastereomers and mixtures thereof in all ratios. In addition, compounds of Formula I include a cycloalkyl group about which geometric cis/trans isomers are possible. The scope of the present invention includes all stereoisomers, as well as all geometric isomers and tautomeric forms ("tautomers") of the compounds of formula 1, and all mixtures thereof in any ratio. It will be appreciated by one skilled in the art that a single compound may exhibit more than one type of isomerism.
[0038] Compounds of the present invention may be resolved into the pure enantiomers by methods known to those skilled in the art. for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterificalion; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation or inversion.
[0039] When compounds of the present invention contain one or more additional stereogenic centers, those skilled in the art will appreciate that all diastereoisomers and diastereoisomeric mixtures of the compounds illustrated and discussed herein are within the scope of the present invention. These diastereoisomers may be isolated by methods known to those skilled in the art. for example, by crystallization, gas-liquid or liquid chromatography. Alternatively, intermediates in the course of the synthesis may exist as racemic mixtures and be subjected to resolution by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enanliomer-specific reagent, for example enzymatic esterification; or gas- liquid or liquid chromatography in a chiral environment, for example on a chiral support with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation or inversion.
|0040| Where a compound of the invention contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof. Cis/lrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
[0041 ] Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto. or oxime group, or so- called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. All such tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the present compounds.
[0042] It should be understood that pharmaceutical compositions and methods of treatment that employ or contain compounds of formula I, either by themselves or in combination with additional agents, similarly encompass all stereoisomers, geometric isomers and tautomeric forms of the compounds, and mixtures thereof in any ratio. [0043] The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. It should be understood that pharmaceutically acceptable solvents includes isotopically substituted solvents such as D20, dc-DMSO and the like. The term 'solvate' is used herein to describe a complex comprising the compound of the invention and one or more
pharmaceutically acceptable solvent molecules. It is intended that the present invention embrace unsolvated forms, solvated forms and mixtures of solvated forms.
[0044) The present invention also includes all pharmaceutically acceptable isolopically- labelled compounds, which are identical to those described by Formula I but wherein one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, chlorine, fluorine, iodine, nitrogen, oxygen, and sulfur, such as 2H, 3H, "C, l C, 1 C, 36C1, I SF, l 23I, .'2:Ί, 13N, N, "O, l 70, 1!iO and 35S, respectively. It should be understood that compounds of the present invention, prodrugs thereof, and pharmaceutical acceptable salts of the compounds or of the prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the invention. Certain isotopically labeled compounds of the present invention such as, for example, those incorporating a radioactive isotope such as 3H and > 4C, are useful in drug and/or substrate tissue distribution studies. Tritium, i.e. 'T-I.. and carbon- 14, i.e. 1 C, are particularly preferred due their ease of preparation and detection. Further, substitution with heavier isotopes such as deuterium, 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Isotopically labeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
[0045| The compounds of the invention may be isolated and used per se or in the form of their pharmaceutically acceptable salts or solvates. Pharmaceutically acceptable salts, as used herein in relation to the compounds of the present invention, include pharmacologically acceptable inorganic and organic salts of said compound. These salts can be prepared in situ during the final isolation and/or purification of a compound (or prodrug), or by separately reacting the compound (or prodrug) with a suitable organic or inorganic acid and isolating the salt thus formed. A pharmaceutically acceptable salt of a compound of formula I may be readily prepared by mixing together solutions of the compound of Formula I and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.
[0046] The compounds of the invention may be isolated and used per se or in the form of their pharmaceutically acceptable salts or solvates. Pharmaceutically acceptable salts, as used herein in relation to the compounds of the present invention, include pharmacologically acceptable inorganic and organic salts of said compound. These salts can be prepared in situ during the final isolation and/or purification of a compound (or prodrug), or by separately reacting the compound (or prodrug) with a suitable organic or inorganic acid and isolating the salt thus formed. A pharmaceutically acceptable salt of a compound of Formula I may be readily prepared by mixing together solutions of the compound of Formula I and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.
[0047] Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate. hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonale, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate. nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, saccharate, stearate. succinate, tartrate, tosylate.
trifluoroacetate and the like. Other examples of representative salts include alkali or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like. The invention further includes mixtures of salt forms.
[0048] In accordance with the present invention, compounds with multiple basic nitrogen atoms can form salts with a varying number of equivalents of acid. A practitioner of ordinary skill will readily appreciate that all such salts are within the scope of the invention.
[0049] As used herein, a "patient" for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. The methods are thus applicable to both human therapy and veterinary applications. In a specific embodiment, the patient is a mammal, and in a more specific embodiment, the patient is human.
[0050] As used herein, a "pharmaceutically acceptable salt" of a compound means a salt that is phannaceutically acceptable and that it possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are nontoxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 171'1 ed., Mack Publishing Company, Easton, PA, 1985, or S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66: 1 -1 9, both of which are incorporated herein by reference.
[0051 ) Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like) and those formed with organic acids (e.g., acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4- hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2- ethanedisulfonic acid, 2-hydi xyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesiilfonic acid, 4-toluenesulfonic acid,
camphorsulfonic acid, glucoheptonic acid, 4,4:-methylenebis-(3-hydroxy-2-ene- l -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesullbnic acid, salicylic acid, or the like).
[0052] Examples of a pharmaceutically acceptable base addition salt includes those formed when an acidic proton present in the parent compound is replaced by a metal ion, including, but not limited to. sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Specific salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples of organic bases include, but are not limited to, isopropylamine, Irimethylamine, diethylamine. triethylamine, tripropylamine, ethanolamine, 2-dirnethylaminoelhanoL 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine. choline, betaine. ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N- ethylpiperidine, tromethamine, /V-methylglucamine, polyamine resins, and the like.
Exemplary organic bases are isopropylamine, diethylamine. ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
[0053| As used herein, a "therapeutically effective amount" is an amount of a compound of the invention that, when administered to a patient, ameliorates a symptom of the disease. The amount of a compound of the invention which constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
[0054] As used herein, "preventing" or "prevention" of a disease, disorder, or syndrome includes, but is not limited to, inhibiting the disease from occurring in a human, i.e.. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome.
[0055] As used herein, "treating" or "treatment" of a disease, disorder, or syndrome, includes, but is not limited to, (i) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (ii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction, and the severity of the condition may be necessary and will be ascertainable with routine experimentation by one of ordinary skill in the art.
Embodiments of the Compound of Formula I
[0056] As indicated previously, in one aspect, the invention provides a compound of formula I.
Figure imgf000018_0001
I
[0057] In one embodiment of the compound of formula I, L is absent.
[0058] in another embodiment, L is NH.
[0059] In another embodiment, W is a absent,
[0060] In another embodiment, W is a branched or straight C i-n aliphatic chain. [00611 In another embodiment, W is -CH(CH3)-.
[0062] In another embodiment, when L is absent. Ring A is heteroaryl or aryl.
[0063] In another embodiment, when W is absent, L is absent.
[0064] In another embodiment, when W is a branched or straight C 1.12 aliphatic chain. In another embodiment, W is -CI- CH3)-, L is absent, and Ring A is aryl or heteroaryl.
[0065] In one embodiment, X | is a fused bicyclic cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl and X2 and X3 are absent. More particularly, in one embodiment, Xi is naphthalenyl, chromanyl, isochromanyl, thiocromanyl, isothiocromanyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetraliydronaphthyl, indanyl, or indenyl, each of which is optionally and independently substituted with 1 -3 of halo, nitro, cyano, hydroxy, amino, C|-6 alkyl, C |.6 alkoxy, C |.e alkyl, d.(, alkylcarbonyl, Ci-6 alkoxycarbonyl, C i-6 alkylaminocarbonyl, C |.() alkylcarbonylamino, or Ci-o alkylcarbonyloxy.
[0066] In another embodiment, X| is a monocyclic cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl. In a particular embodiment. X| is cyclohexyl, phenyl, pyridyl, pyrimidinyl, piperidinyl, or pyrrolidinyl. In a more particular embodiment, Xt is phenyl, pyridyl, or pyrimidinyl. In this embodiment of Xi , X3 is absent or both X2 and X3 are absent. |0067] When present, X? is heterocycloaliphatic, aryl, or heteroaryl. More particularly, X2 is pyridyl, pyrimidinyl, tetrazolyl, triazolyl, imidazolyl. or pyrazolyl.
[0068] In another embodiment, when X| is a fused bicyclic ring as provided above, W is absent, L is absent, and Ring A is aryl or heteroaryl.
[0069] In another embodiment. X| is phenyl or pyridyl. In another embodiment, when X| is phenyl or pyridyl. W is -CH(CH3)-, L is absent, and Ring A is aryl or heteroaryl.
[0070] In another embodiment, Xi is phenyl or pyridyl and X2 is present. In this embodiment, X2 is aryl or heteroaryl. More particularly, X2 is pyridyl, pyrimidinyl, tetrazolyl, triazolyl, imidazolyl, or pyrazolyl. In this and other embodiment, X2 is attached to Xi at a position that is meta relative to the attachment point of W.
[0071 ] In another embodiment, when X| is phenyl or pyridyl, X2 is pyridyl, pyrimidinyl, tetrazolyl, triazolyl, imidazolyl, or pyrazolyl, W is -CH(CH3)-, L is absent, and Ring A is aryl or heteroaryl.
[0072] In another embodiment, Xi is phenyl or pyridyl, X2 is pyridyl, pyrimidinyl, tetrazolyl, triazolyl, imidazolyl, or pyrazolyl and X3 is cycloaliphatic or heterocycloaliphatic. More particularly, X3 is piperizinyl, piperidinyl. or morpholinyl. [0073] In another embodiment, when X| is phenyl or pyridyl and X2 is pyridyl,
pyrimidinyl, tetrazolyl. triazolyl, imidazolyl, or pyrazolyl, X3 is piperizinyl, piperidinyl, or morpholinyl.
[0074J In another embodiment, when X| is phenyl or pyridyl and X2 is pyridyl, pyrimidinyl. tetrazolyl, triazolyl, imidazolyl, or pyrazolyl, and X of X|-X2-X3, W is -CH(CH3)-, L is absent, and Ring A is aryl or heteroaryl.
[0075] In another embodiment, Y is absent or is a branched or straight C M2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Qi)2-, -C(Q2)2-: -CHQi-, -CHQr, -CO-, -CS-, -CONRR-, -CONRBNRB-, -C02-, -OCO-, -NR13-. - NRIJC02-, -0-, -NRBCONRL}-, -OCONRB-, -NRBCO-, -S-, -SO-, -S02-; -S02NRB-, or -NRBS02NR" ; and Z is hydrogen, C).s aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1 -3 of Qi or Q2.
[0076] In another embodiment, Y is a branched or straight C|.|2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Qi)2-. -C(Q2)2-, -CHQi-, -CHQr, -CO-, -CS-, -CONR15-.. -CONR NRB-, -C02-, -OCO-, -NR13-, -NRBC02-, -0-, -NR"CONRB-, -OCONR"-, -NRBCO-, -S-, -SO-, -S02-, or -S02NRB-; and Z is hydrogen or Ci-s aliphatic.
[0077] In one embodiment, Z is H. In another embodiment, Z is C|.s aliphatic.
[0078] In another embodiment, the compound of formula I is a compound of formula IA,
IB, or IC.
Figure imgf000020_0001
[0079] In another embodiment, the compound of formula I is a compound of formula IA-1 , IB-1 , or IC- 1 .
Figure imgf000021_0001
[0080] In one embodiment of the compound of formula IA-1. IB-1, or IC-1, X| is chosen from chromanyl, isochiomanyl, thiocromanyi, isothiocromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl. tetrahydronaphthyl, indanyl, or indenyl. each of which is optionally and independently substituted with 1-3 of halo, nitro. cyano. hydroxy, amino, C|.e alkyl. C|.6 alkoxy, Ci.6 alkyl, Ci-6 alkylcarbonyl, Cj.r, alkoxycarbonyl, C|_6 alkylaminocarbonyl,
Figure imgf000021_0002
alkylcarbonylamino, or C|_6 alkylcarbonyloxy.
[0081] In one embodiment of the compound of formula IA-1, IB-1, or IC-1. X| is optionally substituted phenyl or pyridyl.
[0082] In another embodiment of the compound of formula IA-1, IB-1, or IC-1. Xi is optionally substituted phenyl or pyridyl and X2. X3. and Z have any of the meaning provided herein.
[0083] In another embodiment, the compound of formula 1 is a compound of formula IB-2 or IC-2
Figure imgf000021_0003
wherein: A| and A3 are N, and A 2 is CH or C-halo or A2 is N. and A| and A3 are CH or C-halo; and
R.2 is H, alkyl, alkoxy, haloalkoxy. or halo.
[0084] In another embodiment, the compound of formula I is a compound of formula ΓΒ-3, IB-4, IC-3, or IC-4
Figure imgf000022_0001
Figure imgf000022_0002
[0085] In one embodiment of the compound of formula IC, X2 is a six-membered ring. In one embodiment, X2 is pyridyl or pyrimidinyl. When X2 is phenyl or pyrimidinyl, X3 is
R2
A1 ¾* A3
attached to 2 at a the 4-position, so that X3 is effectively para to M2 . This embodiment is depicted by the compound of formula ID, wherein
Figure imgf000022_0003
is pyridyl or pyrimidinyl.
Figure imgf000023_0001
Figure imgf000024_0001

Figure imgf000025_0001

Figure imgf000026_0001

Figure imgf000027_0001
Figure imgf000028_0001

Figure imgf000029_0001
28
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
|0087] Another embodiment of a compound of formula I is a compound of formula IE
Figure imgf000035_0002
I E
wherein Ring D is optionally substituted cyclohexyl, phenyl, pyt idyl, or pyrimidinyl.
[0088| Another embodiment of a compound of formula IE and thus of formula I is a compound of formula I E- 1
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
[0089J Another embodiment of a compound of formula IE and thus of formula 1 is a compound of formula 1E-
Figure imgf000038_0002
IE-2
wherein ring D is phenyl or pyridyl optionally substituted with R which is H. alkyl, haloalkyl. alkoxy, haloalkoxy, halo. -OH, CN. N02; and Ring E is a aryl or heteroaryl
Figure imgf000038_0003
¾ ¾ Λ More particularly, Ring E is phenyl, or G/
R9 is selected from H, alkyl. haloalkyl, alkoxy, haloalkoxy. halo, -OH, CN, N02, and NH; and R,o is selected from H,-CHOHCH3! -CHOH(CH3)2 COMe, C02Et, NHMe, NHEt,
NMe2: Nl¾. NHCHMe2 CH2OH, -CH2CO:Et; CH2C02H. -CONH2, -NHCH2CH2CH2OH,■
NHCH,C02H,-NHCH2C02Me, -NHCH2CH2OH, -N HCH2C02H. -NHCH2CHOHCH2OH,
Figure imgf000039_0001
-NHCH2CH2NH2: NHCH2CH2N e2, -
Figure imgf000039_0002
[0090] In another embodiment, the compound of formula IE-2 is a compound of formula IE-3
Figure imgf000039_0003
wherein Ring E, R , R9.. and R]o are as previously defined.
[0091 ] In one embodiment of any of the compounds of formula I depicted above, Ring A is an optionally substituted monocyclic or bicyclic aryl or heteroaryl.
[0092] In another embodiment of any of the compounds of formula I depicted above, Ring A is an optionally substituted phenyl.
[0093] I bodiment of any of the compounds of formula I depicted above.
Ring A is
Figure imgf000039_0004
wherein at least one of A, B, and C are N, NH, N(alkyl), S, SO,
S02. or O and the others ol' A, B, and C are CH, CM, or C(alkyl); and R5 is H or alkyl. In a further embodiment, one ol'A and C is N, S; or 0. In a further embodiment, one of A and C is N and the other of A and C is S or O.
|0094] In another embodiment of any of the compounds of formula I depicted above Ring A is selectexd from the group consisting of phenyl substituted one, two. or three groups selected from halo, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, -CONH2, -CONHMe, -NH-CH2-CN; -CN, -C02alkyl, NH-CH2- CONHMe, CH2CONH-CH2CH2OH, 1 ,3-benzodioxol-5-yl, 2,2-difluoiO-l,3-benzodioxoI-5- yl, benzo[cJthiazol-5-yl. l,3-benzothiazol-6-yl, 1-alkyl-l H-indol-6-yl, l-[2- (methyloxy)ethyl]-lH-indol-6-yl, 1 H-indol-4-yl , 1 -methyl- 1 H-indol-4-yl , lH-indol-5-yl , lH-indol-6-yl, l-methyl-2,3-dihydro-lH-indol-6-yl. lH-indol-7-yl. l,3-benzodioxol-5-yl, 1- benzofuran-5-yl , 3-methyl-l-benzofuran-5-yI, 7-fluoro-3-methyl-l-benzofuran-5-yl.1- benzothien-5-yl, 1 ,3-benzoxazol-6-yl, 2,3-dihydro- 1 ,4-benzodioxin-6-yl, 1 H-benzimidazol-6- yl, 1 -methyl- lH-benzimidazol-6-yl, lH-indazol-5-yl, 1 -alkyl- lH-indazol-6-yl, 4-acety 1-3,4- dihydro-2H-l,4-benzoxazin-6-yl, 1,2,3,4-tetrahydronaphthalen-l-yl , 6-naphthalen-2-yl, and 1 -methyl- 1 H-pyrroloj 3 ,2-b]pyridin-6-yl.
[0095] In another embodiment, Ring A is
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000041_0001
Figure imgf000042_0001
41 wherein:
Het is a heteroaryl ring which is optionally substituted with 1 -3 ot" Q3; and
R-3 is Q_; or
two instances of R3 on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a 5-6 membered cycloaliphatic or heteroaliphatic, saturated or unsaturated ring, which is optionally substituted with 1-3 of Q2.
[0097] In a further embodiment, two instances of R3 on adjacent carbon atoms are taken together with the carbon atoms to which they are attached form a benzo-fused furanyl or thiophenyl ring, which is optionally substituted with 1 -3 of Q2.
[0098] In another embodiment is a compound of formula 111
Figure imgf000043_0001
III
wherein:
W is a branched or straight C|.|2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Qi)2-; -C(Q2)2-, -CHQr, -CHQ2-, -CO-, -CS-, -CO RA-, -CONRANRA-, -C02-: -OCO-, -NRA-, -NRAC02-, -0-, -NRACONRA-, -OCONRA- , - RANRA-, -NRACO-, -S-, -SO-, -S02-, -S02NRA-: -NRAS02-, or -NRAS02NRA;
R,t is X|-X2-X3-Y-Z, wherein X|, X2, X3, Y, and Z are as previously defined;
at least one of A, B, and C are N, NH, N(alkyl), S, SO, S02, or O and the others of ABC are CH, CH, or C(alkyl): and
R5 is 0, 1 , 2. or 3 groups independently selected from halo, -OH, oxo, -CF3, -OCF3, cyano, or a Ci_s branched or straight aliphatic, wherein 1 -3 methylene groups of the aliphatic are optionally and independently replaced with -C(O)-, -0-, -NH-, -C(0)NH- or -C(0)0-, and wherein the aliphatic is optionally further substituted with 1 -3 of halo, cyano, OH, or Ci-3 aliphatic.
[0099] More particularly in this embodiment, one of A and C is N, S, or O. Alternatively, one of A and C is and the other of A and C is S.
[00100] More particularly, the compound of formula 111 is a compound of formula IIIA, II I-
B, or II1-C.
Figure imgf000044_0001
[00101 ] In another embodiment, the compound of formula HI is a compound of formula III- DJII-E, or 111-F.
Figure imgf000044_0002
[00102] In another embodiment, the compound of formula III is a compound of formul G. III-H, or III- J, wherein the variables have any of the definitions provided herein.
Figure imgf000045_0001
|00103j In another embodiment, the compound of formula I is a compound of formula IV, wherein the variables have any of the defintions provided herein.
Figure imgf000045_0002
IV
[00104] In another embodiment, the compound of formula I is a compound of formula IV-A, wherein the variables have any of the defintions provided herein.
Figure imgf000045_0003
IV-A
[00105] In another embodiment, the compound of fonnula IV-A is a compound of formula IV-B, wherein the variables have any of the definitions provided herein.
Figure imgf000046_0001
IV-B
[00106] In another embodiment, the compound of formula I is a compound of formula V
Figure imgf000046_0002
wherein Ring A is as previously defined for a compound of formula I and R.6 is
cycloaliphatic. heterocycloaliphatic, aryl, or heteroaryl, each or which are optionally and independently substituted with 1 -3 of Qi, Q2, or Q2. wherein:
each Qi is independently halo, oxo, -CN, -N02: -N=0, -NHOQ2, =NQ2, =NOQ2, -OQ2, -SOQ2, -S02Q2, -SON(Q2)2, -S02N(Q2)2 -N(Q2)2; -C(0)OQ2: -C(0)-Q2, -C(0)N(Q2)2; -C(=NQ2)NQ2-, -NQ2C(=NQ2)NQ2-, -C(0)N(Q2)(OQ2), -N(Q2)C(0)-Q2, -N(Q2)C(0)N(Q2)2, -N(Q2)C(0)0-Q2, -N(Q2)S02-Q2 -N(Q2)SO-Q2. or aliphatic optionally including 1 -3 substituents independently selected from Q2 or Q3.
each Q2 is independently hydrogen, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally including 1 -3 substituents independently selected from Q3;
each Q3 is halo, oxo, CN, N02: H , CF3, OCF3, OH, -COOH or C1-C4 alkyl optionally substituted with 1 -3 of halo, oxo, -CN. -N02, -CF3, -OCF3, -OH, -SH, -S(0)3H, - NH2, or -COOH.
[00107] In one embodiment of the compound of formula V, R6 is selected from the group consisting of 2.3-dihydro-l H-inden-l -yl ,1 ,2,3,4-tetrahydronaphthalen-l -yl, naphthalen- l -yl, 6-nitro-3,4-dihydro-2H-chromen-4-yl), 3,4-dihydro-2H-chromen-6-yl, 3,4-dihydro-2H- chromen-4-yl, 3,4-dihydro-2H-l -benzothiopyran-4-yl, furanyl, wherein each of the groups may be optionally substituted with one, two, or three groups selected from halo, nito, -NH- CO- e, -NH-CO-Et, alkyl, and alkoxy.
100108] In another embodiment, the compound of formula V is a compound of formula VA.
Figure imgf000047_0001
VA
wherein Ring A is as previously defined, Xv C, N, or 0, and R)2 is one or two groups independently selected from alkyl, -NHCO e, -NHCOEt.
[00109] In another embodiment, the compound of formula V is a compound of formula VB.
Figure imgf000047_0002
wherein Ring A is as previously defined.
(001 10] In another embodiment, the compound of formula I is one of the compounds listed in table 1 .
Table 1
Conip Chemical IUPAC Name
N-(2,3-dihydro-lH-inden-l - yl)-6-(3-fluorophenyl)-2- methylpyrimidin-4-amine
6-(Benzo[c ]thiazol-5-yl)-2- methyl-N-(2- methylbutyl)pyrimidin-4- amine
(5)-6-(Benzo[£ ]thiazol-5-yl)- Nr( 1 -cyclohexylethyl)-2- methylpyrimidin-4-amine
2-methyl-6-[3-
(methyloxy)phenyl]-N-[(l R)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl]pyrimidin-4-amine
Figure imgf000047_0003
Corap Structure Chemical I UP AC Name
Figure imgf000048_0001
Comp Structure Chemical IUPAC Name
Figure imgf000049_0001
Comp Structure Chemical IUPAC Name
Figure imgf000050_0001
utanoae Comp Structure Chemical IUPAC Name
Figure imgf000051_0001
Comp Structure Chemical IUPAC Name
Figure imgf000052_0001
Comp Chemical IUPAC Name -methyl- 1 -
Figure imgf000053_0001
62
63
3- [l -({2-methyl-6-[3-
64 (melhyIoxy)pheny!]pyrimidin-
4- yl }amino)ethyl]phenol
Figure imgf000053_0002
Figure imgf000053_0003
yl]pyrimidin-4-amine Comp Structure Chemical IUPAC Name
Figure imgf000054_0001
Comp Structure Chemical IUPAC Name
Figure imgf000055_0001
Comp Structure Chemical IUPAC Name
Figure imgf000056_0001
Comp Structure Chemical IUPAC Name
Figure imgf000057_0001
y pyrm n- -amne Comp Structure Chemical IUPAC Name
Figure imgf000058_0001
Comp Structure Chemical IUPAC Name
Figure imgf000059_0001
Comp Structure Chemical IUPAC Name
Figure imgf000060_0001
Figure imgf000061_0001
Comp Structure Chemical IUPAC Name
Figure imgf000062_0001
Comp Structure Chemical IUPAC Name
Figure imgf000063_0001
Comp Structure Chemical IUPAC Name
Figure imgf000064_0001
Comp Structure Chemical IUPAC Name
Figure imgf000065_0001
Comp Structure Chemical IUPAC Name
Figure imgf000066_0001
Comp Structure Chemical IUPAC Name
Figure imgf000067_0001
-
Figure imgf000068_0001
Comp Structure Chemical IUPAC Name
Figure imgf000069_0001
Comp Structure Chemical IUPAC Name
Figure imgf000070_0001
Comp Structure Chemical IUPAC Name
Figure imgf000071_0001
o nip Structure Chemical IUPAC Name
Figure imgf000072_0001
amne Comp Structure Chemical IUPAC Name
Figure imgf000073_0001
Comp Structure Chemical IUPAC Name
Figure imgf000074_0001
Comp Structure Chemical IUPAC Name -
Figure imgf000075_0001
Comp Chemical IUPAC Name
264
265
266
267
268
269
Figure imgf000076_0001
Comp Chemical IUPAC Name
2-methyl-6-[4-
(methyloxy)phenyl]-N-{ 1 -[3-
270 (1 -methyl- 1 ti-pyrazol-4- yl)phenyl] ethyl } pyrimidin-4- amine
6-(2,4-dichlorophenyl)-2- methyl-N-{l-[3-(l-methyl-
271 I H-pyrazoI-4- yl)phenyl]ethyl}pyTimidin-4- amine
2-methyl-6-(2-methylphenyl)-
N-{l-[3-(l-methyl-lH-
272 pyrazol-4- yl)phenyl]ethyl}pyrimidin-4- amine
6-(3-chloro-4-fluorophenyl)- 2-methyl-N-{ l-[3-(l-methyl-
273 1 H-pyrazol-4- yl)phenyl]ethyl } pyrimidin-4- amine
N-{2-[3-({[6-(!,3- benzothiazol-6-yl)-2-
274 methylpyiimidin-4- yl]amino}methyl)piperidin-l- yl]-2-oxoethyl}-N- methylbenzamide
Figure imgf000077_0001
Chemical IUPAC Name
2-methyl-N- { -[3-( 1 -methyl- l H-pyrazol-4- yl)phenyl]ethyl }-6- naphthalen-2-ylpyrimidin-4- amine
6-(l ,3-benzothiazol-6-yl)-2- methyl-N-[(2R)-2- phenylpropyl]pyrimidin-4- amine
6-(l ,3-benzothiazol-6-y])-2- methyl-N-(2-pyridin-3- ylethyl)pyrimidin-4-amine
6-( 1 ,3-benzothiazol-6-yl)-N-
(2-ethyIhexyl)-2- methylpyrimidin-4-amine
6-(l ,3-benzothiazol-6-yl)-2- methyl-N-( 1 -pyridin-3- ylethyl)pyrimidin-4-amine
Figure imgf000078_0001
Comp Chemical l UPAC Name
6-(l .3-benzothiazol-6-yl)-N-
280 (2,3-dihydro- 1 H-inden-2-yl)- 2-methylpyrimidin-4-amine
6-(l ,3-benzothiazol-6-yl)-N-
281 ( 1.4-dimethylpentyl)-2- melhylpyrimidin-4-arnine
6-( 1 ,3-benzolhiazol-6-yl)-N-
282 [2-(l H-imidazol-4-yl)ethyl]- 2-methylpyrimidin-4-amine
6-( 1 ,3-benzoihiazol-6-yl)-2-
283 melhyl-N-[(2S)-2- phenylpropyl]pyrimidin-4- amine
5-{ [6-(l ,3-benzothiazol-6-yl)- 2-methylpyrimidin-4- yl]amino}-2,2- dimethylpentan-1 -ol
Figure imgf000079_0001
Chemical IUPAC Name
6-(l ,3-benzothiazol-6-yl)-2- methy 1-N- { [3-( 1 H-pyrrol- 1 - yl)phenyl]methyl}pyrimidin- 4-amine
U -dimethylethyl 3-({ [6-(l ,3- benzothiazol-6-yI)-2- methylpyrimidin-4- yl]amino}methyl)piperidine-
1 -carboxylate
Figure imgf000080_0001
6-( 1.3-benzothiazol-6-yI)-2-
287 methyl-N-(2-pyridin-4- ylethyl)pyrimidin-4-amine
6-(l ,3-benzothiazol-6-yl)-2-
288 methyl-N-[(3-phenylisoxazol
5-yl)methyl]pyrimidin-4- amine
Figure imgf000080_0002
Chemical I UPAC Name
N'-[6-(l .3-benzothiazol-6-\ 2-methylpyrimidin-4-yl]-N methyl-N-phenylpropane- 1 diamine
2-methyl-6-(3-methyl- 1 - benzofuran-5-yl)-N-{ 1 -[3- (l H-tetrazol-1 - yl)phenyl]ethyl } pyrimidin-4- amine
2-methyl-6-(3-methyl- 1 - benzofuran-5-yl)-N-{ l -[3-
(4H- l ,2,4-triazol-4- yl)phenyl]ethyl}pyrimidin-4- amine
2-methyl-6-(3-methyI-l - benzo uran-5-yl)-N-[l -(3- nitrophenyl)ethyl]pyrimidin- 4-amine
2-methy]-6-[4-methyl-3- (melhyloxy)phenyl]-N-[(lR)- 1 ,2.3,4-tetrahydronaphthalen- 1 -y l]pyrimidin-4-amine
6-(l ,3-benzothiazol-6-yl)-2- methyl-N-{ l-[3-(l H-1 ,2,3- triazol- 1 - yl)phenyl]ethyl}pyrimidin-4- amine
N-[3-(l -{[2-methyl-6-(3- methyl-1 -benzofuran-5- yl)pyrimidin-4- yl]amino}ethyl)phenyl]prop- 2-enamide
2-methyl-6-(l -methyl- 1 H- indol-6-yl)-N-{ l -[3-( l - melhyl- 1 H-pyrazol-4- yl)pheny l]ethyl } py rimidin-4-
Figure imgf000081_0001
amine Comp Structure Chemical IUPAC Name
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Comp Structure Chemical IUPAC Name
Figure imgf000085_0001
Com Structure Chemical IUPAC Name
Figure imgf000086_0001
Comp Structure Chemical IUPAC Name
Figure imgf000087_0001
Comp Structure Chemical IUPAC Name
Figure imgf000088_0001
Comp Structure Chemical IUPAC Name
Figure imgf000089_0001
Figure imgf000090_0001
Comp Structure Chemical I UPAC Name
1 , 1 -dimethylethyl 3-({ [3-(l - {[6-(l ,3-benzothiazol-6-yl)-2- methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}m ethyl)piperidine- 1 -carboxylate
1 , 1 -dimethylethyl 4-({ [3-(l -
{ [6-( 1 ,3-benzothiazol-6-yl)-2- methylpyrimidin-4- yl]amino}ethyl)phenyI]oxy}m ethyl)piperidine- 1 -carboxylate
6-( 1 ,3-benzothiazol-6-yl)-2- methyl-N-(l -{3-[6-
(methyloxy)pyridin-3- yl]phenyl}ethyl)pyrimidin-4- amine
N,N-diethyl-2-{[3-(l -{[2- methyl-6-(4-methyl-3,4- dihydro-2H- 1 ,4-benzoxazin-
6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}a cetamide
2-methyl-N-{( l S)-l -[3- (methyl oxy)pheny l]ethy 1 } -6- (1 -methyl- 1 H-pyrrolo[3 ,2- b]pyridin-6-yl)pyrimidin-4- amine
6-(l ,3-benzothiazol-6-yl)-N- [(5-bromo-2- fluorophenyl)methyl]-2- methylpyrimidin-4-amine
2-methyl-6-(3-methyl- 1 - benzoiuran-5-yl)-N-[l -(2- methylphenyl)ethyl]pyrimidin -4-amine
6-(l ,3-benzothiazol-6-yl)-N- {[2-fluoro-5-
(methyloxy)phenyl]methyl }- 2-methylpyrimidin-4-amine
6-(L3-benzothiazol-6-yl)-N-
[(5-{ [( l ,3-dimethyl- l H- pyrazol-5-yl)methyl]oxy}-2- fluorophenyl)methyl]-2-
Figure imgf000091_0001
methylpyrimidin-4-amine Conip Structure Chemical IUPAC Name
Figure imgf000092_0001
Comp Structure Chemical IUPAC Name
Figure imgf000093_0001
amne Comp Structure Chemical IUPAC Name
Figure imgf000094_0001
Comp Structure Chemical IUPAC Name
Figure imgf000095_0001
Comp Structure Chemical IUPAC Name
Figure imgf000096_0001
m n- -amne Co nip Structure Chemical IUPAC Name
Figure imgf000097_0001
Comp Chemical IUPAC Name yl)-N-
440 thy l]-2- ine
441
l]oxy}et
Figure imgf000098_0001
442
443
444
445
446
447
448
449
Figure imgf000098_0002
Comp Structure Chemical IUPAC Name
-
r
Figure imgf000099_0001
N,N-diethyl-2-t(3-{ l -[(2- methyl-6-naphthalen-2- ylpyrimidin-4- yl)amino]ethyl}phenyl)oxy]ac
Figure imgf000099_0002
etamide
- -
Figure imgf000099_0003
Comp Structure Chemical IUPAC Name
Figure imgf000100_0001
Comp Structure Chemical IUPAC Name
Figure imgf000101_0001
cetam e Comp Structure Chemical IUPAC Name
Figure imgf000102_0001
Comp
485
486
487
488
489
Figure imgf000103_0001
Structure Chemical IUPAC Name
6-[3-(dimethylamino)phenyl]- 2-methyl-N-{ l -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl }pyrirnidin-4- amine
6-( 1 ,3-benzothiazol-6-yl)-2- methyl-N-(l - methylbutyl)pyrimidin-4- amine
6-( l ,3-benzothiazol-6-yl)-2- methyl-N-(3- methylbutyl)pyrimidin-4- amine
6-(l ,3-benzothiazol-6-yl)-N- (2-cyclohex- 1 -en- 1 -y lethyl)- 2-methylpyrimidin-4-amine
4-(2-{ [6-(l ,3-benzothiazol-6- yl)-2-methylpyrimidin-4- y]]amino}ethyl)phenol
6-(l ,3-benzothiazol-6-yl)-2- methyl-N-pentylpyrimidin-4- amine
Figure imgf000104_0001
Comp Chemical IUPAC Name
Figure imgf000105_0001
.
Figure imgf000106_0001
Comp Structure Chemical IUPAC Name
Figure imgf000107_0001
Comp Structure Chemical IUPAC Name
Figure imgf000108_0001
Co nip Structure Chemical IUPAC Name
Figure imgf000109_0001
Comp Structure Chemical IUPAC Name
Figure imgf000110_0001
Co nip Structure Chemical IUPAC Name
N-{(lR)-l-[4-fluoro-3-(l- methyl-1 l-I-pyrazol-4- yl)phenyl]ethyl}-2-methyl-6- (3-methyl- 1 -benzofuran-5- yI)pyrimidin-4-amine
N-{(lS)-l-[4-fluoro-3-(l- methyl-1 H-pyrazol-4- yI)phenyi]ethyl}-2-methyI-6- (3-methyl- 1 -benzofuran-5- yl)pyrimidin-4-amine
5- [3-( 1 - { [6-(l ,3-benzothiazol-
6- yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]pyridi ne-3-carboxamide
6-( 1 ,3-benzothiazol-6-yl)-2- methyl-N-[(lS)-l-{3-[2-(4- methylpiperazin-1- yl)pyrimidin-5- yl]phenyr}ethyl]pyrimidin-4- amine
6-( 1 ,3-benzothiazol-6-yl)-2- methyl-N-(l-{3-[5-
(tri II uoromethy 1 )pyridin-3 - yljphenyl } ethyl)pyrimidin-4- amine
2- methyl-6-(3-methyl-l- benzofuran-5-y l)-N-[( 1 S)- 1 - {3-[2-(4-methylpiperazin-l - yI)pyrimidin-5- yl]phenyl}ethyl]pyrimidin-4- amine
3- [(5-{3-[(lS)-l-{[2-methyl- 6-(3-methyl-l-benzo uran-5- yl)pyrimiclin-4- yl]amino}ethyl]phenyl}pyrimi din-2-yl)amino]propan- 1 -ol methyl N-(5-{3-[(lS)-l -{[2- methyl-6-(3-methyl- 1 - benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimi
Figure imgf000111_0001
din-2-yl)glycinate Comp Structure Chemical IUPAC Name
Figure imgf000112_0001
Figure imgf000113_0001
amne Comp Structure Chemical IUPAC Name
Figure imgf000114_0001
amne Corap Structure Chemical IUPAC Name
Figure imgf000115_0001
amine Comp Structure Chemical lUPACNamc
Figure imgf000116_0001
Comp Structure Chemical IUPAC Name
Figure imgf000117_0001
Comp Structure Chemical IUPAC Name
604
605
606
607
608
609
610
61 1
612
Figure imgf000118_0001
o ni Structure Chemical I UPAC Name
Figure imgf000119_0001
din-2-yl)amino]ethano Comp Structure Chemical IUPAC Name
622
623
624
625
626
627
628
629
630
Figure imgf000120_0001
19 Comp Structure Chemical IUPAC Name
Figure imgf000121_0001
amine Comp Structure Chemical IUPAC Name
Figure imgf000122_0001
Comp Structure Chemical IUPAC Name
2- methyI-N-{ 1 -[3-(l -methyl- l H-pyrazol-4- yl)phenyl]ethyl}-6-(3,4,5- trifluorophenyl)pyrimidin-4- amine
N-{( l S)- l -[3-(5-amino-6- chloropyridin-3- yl)phenyl]ethyl }-6-(7-fluoro-
3- methyl- 1 -benzofuran-5-yl)- 2-methy 1 py ri m idi n-4-ami ne
5-{3-[( l S)- l - {[6-(3,4- difluoiophenyl)-2- methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimi din-2-amine
5- {3-[(l S)-l -{[6-(4-chloro- 3,5-difluorophenyl)-2- methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimi din-2-amine
1 -(5- { 3- [( 1 S)- 1 - { [2-methy I -6-
(3-methyl-l-benzof ran-5- yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridi n-3-yl)ethanone
6- (7-fluoro-3 -methyl- 1 - benzofuran-5-yl)-2-methyl-N- { l -[5-(l H-pyrazol-4- yl)pyridin-3- yl]ethyl}pyrimidin-4-amine
N-{ l -[5-( 1-ethy 1- 1 H-pyrazol-
4- yl)pyridin-3-yl]ethyl}-6-(7- fluoro-3-methyl-l- benzofuran-5-yl)-2- methylpyrimidin-4-amine
6-(7-fluoro-3-methyl-l - benzofuran-5-yl)-N-{( 1 S)- 1 - [3-(6-fluoropyridin-3- yl)phenyljethyl}-2- methylpyrimidin-4-amine
Figure imgf000123_0001
Comp Structure Chemical IUPAG Name
Figure imgf000124_0001
Comp Structure Chemical IUPAC Name
663
664
665
666
667
668
669
670
671
Figure imgf000125_0001
Comp Structure Chemical IUPAC Name
Figure imgf000126_0001
amne Comp Structure Chemical IUPAC Name
Figure imgf000127_0001
Comp Structure Chemical IUPAC Name
i i
Figure imgf000128_0001
Comp Structure Chemical IUPAC Name
Figure imgf000129_0001
Comp Structure Chemical IUPAC Name
6-(4-chloro-3-fluorophenyl)- N-{(lS)-l-[3-(l-ethyl-lH- pyrazol-4-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine
5-{3-[(lS)-l-{[2-methyl-6-(3- methyl-l-benzofuran-5- yl)pyrimidin-4- yl]amino}ethyl]phenyI}pyridi ne-3-carboxamide
3-[2-methyl-6-({l-[3-(l- methyl-1 H-pyrazol-4- yl)phenyl]ethyl}amino)pyrimi din-4-yl]phenol
6-(2,3-dihydro-l-benzofuran- 5-yl)-2-methyl-N-{l-[3-(l- methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4- amine
6-[2-fluoro-3-
(methyloxy)phenyl]-2-methyl
N-{l-[3-(l-methyl-lH- pyrazoi-4- yl)phenyl]ethyl}pyrimidin-4- amine
6-(l,3-benzothiazol-6-yl)-2- methyl-N-(l-{3-[5-
(methyloxy)pyridin-3- yl]phenyl}ethyl)pyrimidin-4- amine
6-(l ,3-benzothiazol-6-yl)-N- { 1 -[3-(2-fluoropyi"imidin-5- yl)phenyl]ethyl}-2- methylpyrimidin-4-amine
Figure imgf000130_0001
Comp Structure Chemical IUPAC Name
Figure imgf000131_0001
Comp Structure Chemical IUPAC Name
Figure imgf000132_0001
Comp Structure Chemical IUPAC Name
732
734
735
736
Figure imgf000133_0001
[00111 ] In another embodiment, the compound of formula I is:
(uS 6-(Benzo[i/]thiazol-5-yl)-N-(l-cyclohexylethyl)-2-methylpyrimidin-4-amine;
2-methyl-6-[3-(methyloxy)phenyl]-N-{(l R)- 1 -[3- (methyloxy)phenyl]ethyl } pyrimidin-4-amine;
2-methyl-6-[3-(methyloxy)phenyl]-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-
4-amine;
2- methyl-6-[3-(methyloxy)phenyl]-N-{(lS)-l-[4-(methyloxy)phenyl]ethyl}pyrimidin- 4-amine;
N,N-diethyl-2-{ [3-(l -{ [2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
N,N-dimethyl-2-{ [3-(l -{ [2-methyl-6-( 1 -methyl- 1 H-indol-6-y l)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
3- (l -{[2-methyl-6-(l -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)benzenesullbnamide; N-ethyl-2-{[3-(]-{[2-methyl-6-(l-methyl-lH-indoI-6-yl)pyrii-nidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
N-(cyanomethyl)-3-(l-{[2-methyl-6-(l-metliyi-lH-indol-6-yl)pyriiTiidin-4- yl]amino}ethyl)benzenesullOnamide;
2-methyI-6-(]-melhy]-lH-indol-6-yl)-N-(l-{3-[(2-morpholin-4-yl-2- oxoethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
4-{[3-(l-{[2-methyl-6-(l-methyl-lH-indol-6-y])pyrimidin-4- yl]amino}ethyl)phenyl]oxy}butanoic acid;
2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)-N-{( 1 S)- 1 -[3- (methyloxy)phenyl]ethyI}pyrimidin-4-amine;
2- methy 1-6-0 -methyl- 1 H-indol-6-yl)-N-[(l S)-l -phenylethyl]pyrimidin-4-amine; 6-[2-chloro-3-(methyloxy)phenyl]-2-methyl-N-{(lS)-l-[3-
(methyloxy)phenyljethyl } pyrimidin-4-amiiie;
6-(l,3-benzodioxol-5-yl)-2-methyl-N-i(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin- 4-amine;
3- (l-{[2-methyl-6-(l -methyl- lH-inclol-6-yl)pyrimidin-4-yl]amino}ethyl)phenol: 6-(lH-indol-5-yl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
ethyl N-({ [3-( 1 - { [2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetyl)glycinate;;
N-[( IS)- l-(4-fluorophenyl)ethyl]-2-methyI-6-(l -methyl- lH-indol-6-yl)pyrimidin-4- amine;
2-methyl-6-(l-methyl-lH-indol-6-yl)-N-[(lS)-l-(4-methylphenyl)ethyl]pyrimidin-4- amine;
ethyl 4-{[3-(l-{[2-methyt-6-(l -methyl- lH-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}butanoate;
6-(3-nuoi phenyl)-2-methyl-N-{(lS)-l-[3-(melhyloxy)phenyl]ethyl}pyrimidin-4- amine;
2-({3-[l-({6-[2-chloro-3-(methyloxy)phenyl]-2-methylpyrimidin-4- yl}amino)ethyl]phenyl}oxy)-N-methylacetamide;
2-{[3-(l-{[6-(l,3-benzodioxol-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-methylacetamide;
N-(cyanomethyl)-3- l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]benzenesulf namide; ({3-[l-({2-rnethyl-6- 3-(methyIoxy)phenyl]pyrimidin-4- yI}amino)ethyl]phenyl}oxy)acetonilriIe;
3-[l-({6-[2-chloro-3-(methyloxy)phenyl]-2-methyIpyrimidin-4- yl}amino)ethyl]benzenesulfonamide;
6-[2-nuoiO-3-(methyloxy)phenyrj-2-methyl-N-{(lS)-l-[3- (mefhyloxy)phenyl]ethyl}pyrimidin-4-amine;
N-methyl-2-({3-[l-({2-methyl-6-[3-(methyIoxy)phenyl]pyrimidin-4- yl }amino)etliyl]phenyl } oxy)acetamide;
N-[l-(3-bromophenyl)ethyl]-6-[2-cliloi -3-(methyloxy)phenyl]-2-methylpyrimidin-4- amine;
methyl ({3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl] phenyl }oxy)acetate;
methyl N-{3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenyl}glycinate;:
N-[( 1 S)- 1 -(4-chlorophenyl)ethyl]-2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- amine;
3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]benzenesulfonamide;
6-(l-ethyl-lH-indol-6-yl)-2-methyl-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
methyl N-({3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenyl}sulfonyl)glycinale;;
2- methyl-6-( 1 -methyl- 1 H-indol-5-yl)-N-{( 1 S)- 1 -[3- (methyloxy)phenyl]ethyl } pyrimidin-4-amine;
3- [l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4-yl}amino)ethyl]phenol;
1,1-dimethylethyl (cyanomethyl)({3-[l-({2-methyl-6-[3-
(methyloxy)phenyl]pyrimidiiv4-yl}amino)ethyl]phenyl}sulfonyl)carbamate;
2-methyl-6-[3-(methyloxy)pheayl]- -((lS)-l-[3- (trifluoromethyl)phenyl]ethyl}pyrimidin-4-amine;
2-melhyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-6-{3- [(trifluoromethyl)oxy]phenyl}pyrimidin-4-amine;
2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-6-[3!4..5- tris(methyloxy)phenyl]pyrimidin-4-amine; methyl N-{[(l,l-dimethyiethyl)oxy]carbonyl}-N-({3-[l-({2-methyl-6-[3- (methyloxy)phenyl]pyiMmidin-4-yl}amiiio)ethyl]phenyl}sulfbnyl)glycinate;;
6-[2-chloro-5-(methyIoxy)phenyl]-2-methyl-N-{(lS)-l-[3- (methyloxy)phenyI]ethyl}pyrimidin-4-amine;
6-( 1 H-indol-6-y l)-2-methyl-N- {( 1 S)- 1 -[3-(methyloxy)phenyl]ethyl } pyrimidin-4- amine;
N-{3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- y 1 } amino)ethy 1] phenyl } glyci ne
N-({3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenyl}sulfonyl)glycine;
N-methyl-2-{ [3-( 1 -{ [2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N- { ( 1 S)- 1 -[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
6-(l-benzofuran-5-yl)-2-n thyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
6-( 1 -benzothien-5-yl)-2-methyl-N- { ( 1 S)- 1 -[3-(methyloxy)phenyl]ethyl } pyrimidin-4- amine;
2-methyl-N-{( 1 S)- 1 -[3-(methyloxy)phenyI]ethyl } -6-(4-methylphenyl)pyriniidin-4- amine;
6-(4-chlorophenyl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin^ amine;
6-(3-chloiOphenyl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pynmidin-4- amine;
6-(2-fluorophenyl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
6-(4-fluorophenyl)-2-methyl- -{( 1 SH ^
amine;
2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-6-(2-methylphenyl)pyrimidi]> amine;
6-(l;3-benzoxazol-6-yl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin- 4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-{(l R)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine: 6-(lH-indol-4-yl)-2-metliyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrirnidin-4- amine;
6-(lH-indol-7-yl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
6-(2-chlorop enyl)-2-melhyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
2-methyl-6-(l-methyl-lH-benzimidazol-6-yl)-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
6-[3-(dimethylamino)phenyl]-2-methyl-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine:
6-(lH-indazol-5-yl)-2-met yl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
6-[4-(dimethylamino)phenyl]-2-methyl-N-{(1S)-l-[3- (methyloxy)phenyjethyl}pyrimidin-4-amiiie;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
2-met yl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-6-phenylpyri.midin-4-amine;
6-(3-ethylpheny])-2-methyl-N-{(lS)-l-[3.-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-6-(3-methylphenyl)pyrimidin-4- amine;
2-methyl-6-pyridin-4-yl-N-[(l )-l,2.3,4-tetrahydronaphthalen-l-yl]pyrimidin-4- amine;
2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-6-pyridin-3-ylpyrimidin-4-amine;
2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-6-pyridin-4-ylpyrimidin-4-amine;
N-[l-(3-bromophenyl)etliyl]-2-methyI-6-[3-(methyloxy)phenyl]pyrimidin-4-amine:
N-[l-(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)methyl]oxy}phenyl)ethyl]-2-methyl-6-(l- methyl-lH-indol-6-yl)pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-[(lS)-l-(3-{[(l,3-dimethyl-lH-pyrazol-5- yl)methyl]oxy}phenyl)ethyl]-2-methylpyrimidin-4-amine;
2-fluoro-5-(l-{[2-methyl-6-(3-met yl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)phenol
-{l-[4-fluoro-3-(l -methyl- lH-pyrazol-4-yI)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine: 6-[2-c loro-3-(methyloxy)phenyl]-N-[l-(3-{[(l!3-dimethyl-lH-pyrazol-5- yl)methyl]oxy}phenyl)elhyl]-2-metliylpyrimidin-4-amine;
2- methyl-6-[4-methyl-3-(metliyloxy)phenyl]-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
3- [(lS)-l-{[6-(l -beiizotln^zol-6-yl)-2-methyIpyrimidin-4-yI]amino}ediyl]phenol N-[l-(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)methyl]oxy}phenyl)ethyl]-2-methyl-6-[4- methyl-3-(methyloxy)phenyl]pyrimidin-4-amine;
6-(l,3-benzolhiazol-6-yl)-2-methyl-N-(l-{3-[(lH-pyrazol-3- ylmethyl)oxy]plienyl}ethyl)pyrimidin-4-amine;
3-(l-{[6-(l,3-benzothiazol-6-yl')-2-methylpyrimidin-4-yl]amino}ethyl)-N- (cyanomediyl)benzenesulfonamide;
6-( 1 ,3-benzothiazol-6-yl)-N-( 1 -{ 3-[(isoxazol-3-ylmethyl)oxy]phenyl } ethyl)-2- methylpyrimidin-4-amine;
3-(l-{[6-(1.3-benzotlnazol-6-yl)-2-rnethylpyrimidin-4-yl]amino}ethyl)-N-but-2-yn-l- ylbenzenesulfonamide;
2-methyl-6-[4-methyl-3-(mediyloxy)plienyl]-N-[l-(3-{[(l-methyl-lH-pyrazol-3- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
6-(l ,3-benzothiazol-6-yl)-N-[ 1 -(3-{ [(1 ,3-dimethyl-l H-pyrazol-5-yl)methyl]oxy}-4- fluorophenyl)ethyl]-2-methylpyrimidin-4-amine;
2- ({3-[l-({2-methyl-6-[4-melhyl-3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenyl}oxy)acetamide;
3- (l-{[6-(l53-benzothiazol-6-yl)-2-met ylpyrimidin-4-yl]amino}ethyl)-N-prop-2-yn- .1 -ylbenzenesulfbnamide;
6 1 -benzothiazol-6-yl)-N-{l-[4-fluoro-3-(l-methyl-lH-pyrazol-4-yl)phenyl]ethy }- 2-methylpyrimidin-4-amine;
{ [3-( 1 -{ [6-( 1 ^-benzothiazol-G-y ^-methylpyrimidin^- yl]amino}ethyl)phenyl]oxy}acetonitrile
N-(l-{3-[(2-azepan-l-yl-2-oxoethyl)oxy]phenyl}ethyl)-6-(l,3-benzothiazol-6-yl)-2- methylpyrimidin-4-amine;
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-( 1 -methylethyl)acetamide;
6-(2!3-dihydro-l-benzofuian-5-yl)-2-methyl-N-{(lS)-l-[3- (met yloxy)phenyI]ethyl}pyrimidin-4-amine; 6-(l,3-benzothiazol-6-yl)-2-methyl-N-[l-(3-{[2-(2-methylaziridin-l-yl)-2- oxoethyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
2- {[3-(l-{[6-(l,3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)p enyI]oxy}-N.N-dimethylacetamide;
3- (l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino }ethyl)benzenesul fonamide;
6-(l ,3-benzolhiazo]-6-yl)-2-methyl-N-[ 1 -(3- { [(5-methylisoxazol-3- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
{ [3-( 1 - { [2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)py rimidin-4- yl]amino}ethyl)phenyl]oxy}acetonitrile;
6-(l ,3-benzolhiazol-6-yl)-2-methyl-N-{ 1 -[3-(prop-2-yn- 1 - yloxy)phenyl]ethyl} pyrimidin-4-amine;
N-{l-[2-l]uo!O-3-(methyloxy)phenyl]ethyl}-2-methyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-amine;
2- chloro-5-(l-{[2-methyl-6-(3-methyI-l-benzofuran-5-yl)pyrimidin-4- yl]amino } ethyl)phenol;
3- [l-({2-methyl-6-[4-methyl-3-(methyIoxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenol
6-(1.3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(2-oxo-2-piperidin-l- ylethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
N-(l-{3-[(2-azetidin-l-yl-2-oxoethyl)oxy]phenyl}ethyl)-6-(l,3-benzothiazol-6-yl)-2- methylpyrimidin-4-amine;
2- {[3-(l-{[6-(L3-benzothiazol-6-yl)-2-methylpyrimidin-4- yI]amino}ethyl)phenyl]oxy}-N-(2-hydroxypropyl)acetamide;
3- (l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)-N-(2- hydroxyethyl)benzenesulibnamide;
6-(l,3-benzothiazol-6-yl)-N-[l-(5-{[(1 -dimethyl-lH-pyrazol-5-yl)methyl]oxy}-2- fluorophenyl)ethyl]-2-methy]pyrimidin-4-aiTiine:
3-(l-{[6-(1.3-benzothiazol-6-yl)-2-methylpyrimiciin-4-yl]amino}ethyl)-N-[2- (methyloxy)ethyl]benzenesiilfonamide;
3-[(lR)-l-{[6-(1 -benzothiazol-6-yl)-2-melhylpyrimidin-4-yl]amino}ethyl]phenol
0-(1..3-benzotliiazol-6-yl)-2-methyl-N-(l-{3-[(2-morpholin-4-yl-2- oxoethyl)oxy]phenyl}ethyl)pyrimidin-4-amine; 3-( 1 - { [6-( 1 ,3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]araino}ethyl)-4- fluorophenol
3-[l-({6-[2-fluora-3-(inethyloxy)phenyl]-2-methylpyrimidin-4-yl}amino)ethyI]phenol
N,N-dicthyl-2-({3-[l-({6-[2-lluoro-3-(methyloxy)p eny j-2-methylpyrimidin-4- yl } amino)ethyl]phenyl } oxy)acetamide;
6-(l;3-benzothiazol-6-yl)-N-[(lR)-l-(3-{[(L3-dimethyl-lH-pyrazol-5- yl)niethyl]oxy}phenyl)ethyl]-2-methy pyrimidin-4-amine;
6-(l,3-benzolhiazol-6-yl)-2-metliyl-N-(l-{3-[(2-oxo-2-pyrrolidin-l- yIethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)-N-[l -(3- { [2-oxo-2-(4-pyridin-2-ylpiperazin- 1 - yl)ethyl]oxy}phenyl)ethyI]pyrimidin-4-amine;
methyl ]-({[3-(l-{[2-methyl-6-(l -methyl- 1 H-indol-6-yI)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acety])piperidine-4-carboxylate;
2- { [3-( 1 -{ [6-( 1.3-benzothiazol-6-y l)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-methylacetamide;
2- {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-ethylacetamide;
3- (l-{[6-(] ,3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)phenol { [3-(l - { [2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acelic acid;
4- {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-melhylpyrimidin-4- yiJamino}etliyl)phenyl]oxy}butanoic acid;
ethyl 4-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}butanoale;
1,1-dimethylethyl (3S)-3-({|6-(l,3-benzothiazol-6-yl)-2-melhylpyrimidin-4- yl]amino}melhyl)piperidine-l-carboxylate:
2-{[3-(l-{[6-(l,3-benzothiazol-6-y)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N,N-diethylacetamide:
6-(4-chloiOphenyl)-2-methyl-N-{l-[3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3-fluorophenyl)-2-methyl-N-{l-[3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-[3-(methyloxy)phenyl]-N-{ 1 -[3-(l -methyl-1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine; 6-(l H-indol-5-yl)-2-methyl-N-{ 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methylphenyl)-N-{l-[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(l;3-benzothiazol-6-yl)-N-[(2-chloiO-6-lluoiOphenyl)niethyl]-2-methylpyrimidin-4- amine;
2-methyl-N- { 1 -[3-( 1 -methyl- lH-pyrazol-4-yl)phenyl]ethyl }-6-phenylpyrimidin-4- amine;
2-methyl-6-[4-(methyloxy)phenyl]- -{ 1 -|3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(2!4-dichlorophenyl)-2-methyl-N-{ 1 -[3-( 1 -methyl- 1 H-pyrazol-4- y l)phenyl]ethyl } pyrimidin-4-amine;
2-methyl-6-(2-methylphenyl)-N-{l-[3-(l -methyl- lH-pyrazol-4- yl)phenyrjethyl}pyrimidin-4-amine;
6-(3-chloro-4-fluorophenyl)-2-methyl-N-{ 1 -[3-(l-methyl-l H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
N-{2-[3-({[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}methyl)piperidin-l-yl]-2-oxoethyl}-N-methylbenzamide;
2-methyl-N-{l-[3-(l-methyl-lH-pyrazol-4-yl)phenyl]ethyl}-6-naphthalen-2- ylpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-pyridin-3-ylethyl)pyrirnidin-4-aniine;
2-methyl-6-(3-methyl- 1 -benzoruran-5-yl)-N-{ 1 -[3-( 1 H-tetrazol- 1 - yl)phenyjethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-{ 1 -[3-(4H-l ,2,4-triazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzoruran-5-yl)-N-[l-(3-nitrophenyl)ethyl]pyrimidin-4- amine;
• 6-(L3-benzothiazol-6-yl)-2-methy -N-{ 1 -[3-(l H-l ,2,3-triazol-l - yl)phenyl]ethyl}pyrimidin-4-amine;
N-[3-( 1 -{ [2-methyl-6-(3-methy 1- 1 -benzofuran-5-yl)pyrimidih-4- yl]amino}ethyl)phenyl]prop-2-enamide;
2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)-N-{ 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine; N-[l-(3-aminophenyl)ethj'l]-2-methyl-6-(3-met yl-l-benzofuran-5-yl)pyrimidin-4- amine;
6-(l :3-benzothiazol-6-yl)-2-methyl-N-{ 1 -[3-(5-methyl- 1 H-tetrazol- 1 - yI)phenyl]ethyl}pyrimidin-4-amine;
6-(L3-benzolhiazol-6-yl)-2-methyl-N-{ l-[3-(l H-tetrazol- 1- yl)phenyl]et yl}pyrimidin-4-amine;
6-(l ,3-benzothiazol-6-y1)-2-methyl- -{ 1 -[3-(4H- 1 ;2,4-triazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
3-(l-{[6-(l,3-benzotliiazol-6-yl)-2Mnetliylpyrimidin-4-yl]arnino}etliyl)benzonitrile
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-melhylpyrimidin-4- yl]amino}et yl)phenyl]oxy}-N,N-diethylpropanamide;
2- { [3-( 1 -{ [6-( 1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- yI]amino}ethyl)phenyl]oxy}-2-methyIpropanamide:
6-(l,3-benzothiazol-6-yI)-2-rnethyl-N-{ l-[3-(5-methyl-l,2,4-oxadiazol-3- yl)phenyl]ethyl}pyrimidin-4-amine;
2- {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-mcthylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}propanamide;
3- (l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}elhyl)benzenecarboximidamide:
N-[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)phenyl]- 1 H-pyrazole-5-carboxamide;
N-[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)phenyl]-l- methyl-lH-pyrazole-3-carboxamide;
N-[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]dicarbonimidic diamide;
N-[3-(l-{[6-(l ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]formamide;
l-[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]urea;
N-[3-(l-{[6-(l,3-benzothiazol-6-y -2-methylpyrimidin-4-yl]amino}ethyl)phenyl]-l- methyl-lH-imidazole-4-sulfonamide;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-{l-[3-(2H-letrazoI-5- yl)phenyl]ethyl}pyrimidin-4-amine; 1,1-dimethylethyl (2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]amino}.-2-o.\oethyl)methylcarbamate;
3-(l-{[6-(l,3-benzolhiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)-Tsl'- hydroxybenzenecarboximidamide;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-[(l S)-l-(3-pyrimidin-5- ylphenyl)ethyl|pyrimidin-4-amine;
5- {3-[(lS)-l-{[2-melhyl-6-(3-melhyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
-{(lS)-l-[3-(6-aminopyridin-3-yl)plienyI]etliyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
ethyl (4-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yi]amino}ethyl jphenyl }- 1 H-pyrazol- 1 -yl)acetate;
2-methyl-l-{[3-(l-{|2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}propan-2-ol;
1- {[3-(l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yI]amino}ethyl)phenyl]oxy}propan-2-one;
6- (3 -ethyl- 1 -benzofuran-5-yl)-2-methyl-N-[( 1 R)- 1.2,3,4-tetrahydronaphthalen- 1 - yl]pynmidin-4-amine;
(4-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino} ethyljphenyl } - 1 H-pyrazol- 1 -y l)acetic acid;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-[(lS)-l-(3-pyrimidin-5- ylphenyl)elhyl]pyrimidin-4-amine;
2- methyl-6-(3-methyl-l-benzofuran-5-yl)-N-[l-(3-{[(5-methyl-l,2,4-oxadiazol-3- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
5- [3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]pyrimidin-2 -amine;
ethyl (4-{3-[(lS)-l-{[6-(l,3-benzothiazol-6-yr)-2-methylpyrimidin-4- y ljamino} ethyljphenyl } - 1 H-pyrazol- 1 -yl)acetate:
6- (7-fluoro-1 -benzofuran-5-yl)-2-methyl-N-{( 1 S)- 1 -[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine:
2-methyl-6-(3-methyl-l-benzoftirai>
amine;
6-(l,3-benzothiazol-6-yl)-N-[l-(3-{[(l-ethylpiperidin-3-yl)methyl]oxy}phenyl)ethyl]- 2-methylpyrimidin-4-amine; N-{l-[3-(6-aminopyridin-3-yl)phenyl]ethyl}-6-(l,3-benzothiazol-6-yl)-2- methylpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-[l-(3-{[(l-methylpiperidin-3- yl)niethyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
N-[l -(3-{ [(1 ,3-dimethyl- 1 H-pyrazol-5-yl)methyl]oxy}phenyl)ethyl]-2-methyl-6-(l- methyl- 1 H-indol-2-yl)pyrimiclin-4-amine;
2-methyl-6-(3-methyl-l -benzofuran-5-yl)- -[(l S)- 1 -(4- metliylphenyl)elhyl]pyrimidin-4-amine;
N-[l-(3-{[(1 -dimethyl-U^-pyrazol-5-yl)methyl]oxy}phenyl)ethyl]-6-(3-ethyl-l- benzofuran-5-yl)-2-methylpyvimidin-4-amine;
6-(1.3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(piperidin-3- ylmethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
1 -{ [3-( 1 - { [6-( 1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- yI]amino}ethyl)phenylJoxy}piOpan-2-one;
6-(l,3-benzolhiazol-6-yl)-2-methyl-N-{l-[3-(2-methyl-l,3-thiazol-4- yl)phenyr]ethyl}pyrimidin-4-amine;
6-(l ,3-benzothiazol-6-y l)-N-[ 1 -(5-{ [( 1 ,3-dimethyl- 1 H-pyrazol-5- yl)methyrjoxy}pyridin-3-yl)ethyl]-2-methylpyrimidiii-4-amine;
6-(3-ethyl- 1 -benzof ran-5-yl)-2-methyl-N- {( 1 S)- 1 -[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
2- methyl-6-(3-methyl- 1 -benzoiuran-5-yl)-N-{(l R)- 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
1 -{ [3-( 1 -{ [6-( 1 ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}propan-2-ol;
1- {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yrjamino}ethyl)phenyl]oxy}-2-methylpropan-2-ol;
-[l-(2-lluorophenyr)ethyl]-2-metliyl-6-(3Hiiethyl-l-benzo uran-5-yl)pynmidi amine;
3- (l-{[6-(3-ethyl-l-benzofuran-5-yr)-2-methylpyrinn'din-4-yl]amino}ethyl)phenol;
2- methyl-6-(l-methyl-lH-iiidol-2-yl)-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pynmidin-4-amine;
6-( 1 ,3-benzoiliiazol-6-yl)-N-[ 1 -(2-chloropyridin-4-yl)ethyl]-2-methy lpyrimidin-4- amine; 6-(l53-benzothiazol-6-yl)-2-methyl-N-[l-(3-{[(5-methyI-l,2,4-oxadiazol-3- yl)methyl]oxy}phenyl)etliyl]pyrimidin-4-amine;
N-[l-(3-{[(l-acetyIpiperidin -yl)methyl|oxy}phenyl)ethyl]-6-(K3-benzothiazol-6- yl)-2-methylpyrimidin-4-amine;
2-{[3-(l-{[2-methyl-6-(l -methyl- 1 H-indol-2-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetamidc;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(pipendin-4- ylmethy )oxy]phenyl}ethyl)pyrimidin-4-amine;
2-mcthyl-6-(4-niethyl-3!4-dihvdro-2H-l,4-benzoxazin-6-yl)-N-{l-[3-(l-methyl-lH- pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine;
N-[l-(3-{[2-(4-acetylpipeiOzin-l-yl)e(hyl]oxy}phenyl)ethyl]-6-(l!3-benzothiazol-6- yl)-2-methylpyriniidin-4-amine;
{4-[3-(l-{[6-(l ,3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ediyl)phenyl]- 1 H-pyrazol-l-yl} acetic acid;
6-(3-ethyl-l-benzofuran-5-yl)-2-methyl-N-{l-[3-(l -methyl- lH-pyrazol-4- yl)phenyl]elhyl}pyrimidin-4-amine;
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-[2-(methyloxy)ethyl]acetamide;
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-l-cyclopropylelhanone;
2- { [3-( 1 - { [6-( 1 ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}elhyl)phenyl]oxy}-N-phenylacetamide;
6-(l -benzofuran-2-yl)-2-methy 1- - { ( 1 S)- 1 -[3-(methyloxy)phenyl]ethyl } pyrimidin-4- amine;
1,1-dimethylethyl 3-({[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-melhylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}methyl)piperidine-l-carboxylale;
1,1-dimethylethyl 4-({[3-(l-{[6-(L3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}methyl)piperidine-l-caiboxylale;
6-(l!3-benzothiazol-6-> )-2-methyl-N-(l-{3-[6-(methyloxy)pyridin-3- yl)phenyl}ethyl)pyrimidin-4-amine;
N,N-diethyl-2-{[3-(l-{[2-methyl-6-(4-methyl-3,4-dihydiO-2I-I-L4-benzoxazin-6- yl)pyrimidin-4-yl]amino}ethyl)phenyl]oxy}acetamide;
2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-6-(l-methyl-lH-pyrrolo[3,2- b]pyndin-6-yl)pyrimidin-4-amiiie; 2-methyl-6-(3-melhyI-l-benzofiii^-5-yI)-N-[l-(2-methylphenyl)ethyl]pyrimidin-4- amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-{(]R)-l-[3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
(lS)-3-{[3-(l-{[6-(l?3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-l-phenylpropan-l-ol;
N,N-diethyl-2-{ [3-( 1 - { [2-melhyl-6-(3-methyl- 1 -benzofuran-5-yI)pyrimidin-4- yl]aniino}ethyl)phenyl]oxy}acetamide;
N-[l-(3-{[2-(]H-imidazol-l vl)ethyl]oxy}pbenyl)ethyl]-2-methyl-6-(3-niethyl-]- benzomran-5-yl)pyrimidtn-4-amine;
N-{(lS)-l-[3-(l-ethyl-lM-pyrazol-4-yl)phenyl]ethyl}-2-methyl-6-(3-melhyl-l- benzoi\iran-5-yl)pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-(l-{3-[(piperidin-3- ylmethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
2-methyl-6-(3-methyl- 1 -benzoi uran-5-yl)-N- {( 1 S)- 1 -[3-( 1 -methyl- 1 H-pyrazol-5- yl)phenyl]ethyl } pyrimidin-4-amine;
2- { [3-( 1 - { [2-methyl-6-( 3-methyl- 1 -benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}ethanol;
2-methyl-6-(3-methyl-l-benzofiiran-5-yl)-N-[(lS)-l-{3-[(2-n^holin-4-yl-2- oxoethyl)oxy]phenyl}ethyl]pyrimidin-4-amine;
N-[l-(3-{[3-(dimethylamino)piOpyl]oxy}phenyl)ethyl]-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
2-metliyl-6-(3-meth> -l-benzo(uran-5-yl)-N-[l-(3-{[(l-methyl-lH-pyrazol-3- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
3_(l_{[2-niethyl-6-(3-methyl-l-benzotin^n-5-yl)pyrimidin-4-yl]amino}ethyl)phenol N-[(lS)-l-(3-biOmophenyr)ethyl]-2-methyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-amine;
2- methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
3- [(]S)-l-{[2-methyl-6-(3-methyl-l-benzoliiran-5-yl)pynmidin-4- yl]amino}elhyljphenol
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-{(l S)-l -|3-(1 -methyl- 1 H-pyrrol-2- yl)phenyl]ethyl}pyvimidin-4-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-[( 1 S)- 1 -phenylethyl]pyrimidin-4-amine; 6 l,3-benzoth_iazol-6-yl)-2-methyl-N-[l-(3-pyridin-3-ylphenyl)ethyl]pyritnidin-4- amine;
6-(l,3-benzofhiazol-6-yl)-2-methyl-N-{l-[3-(l -methyl- lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
N-[(lS)-l-(4 1uorophenyl)ethyl]-2 iiethyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin- 4-amine;
6-(l -benzofuran-5-yl)-N-[l -(3-{[(l ,3-dimethyl-l H-pyrazol-5- yl)methyl]oxy}phenyl)ethyl]-2-methylpyrimidin-4-amine;
6-(13-benzothiazol-6-yl)-2-methyl-N-{(lS)-l-[3-(l-methyl-rH-pyrazol-5- yl)phenyl]ethyl}pyrimidin-4-amine;
N-[l-(3-fluorophenyl)ethyl]-2-methyl-6 3-methyl-l-benzofuran-5-yl)pyrimidin-4- amine:
6-(l,3-benzothiazol-6-yl)-N-{(lS)-l-[3-(l-ethyl-lH-pyrazol-4-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(lH-pyrazol-5- yl)phenyl]ethyl}pyrimidin-4-amine;
2- methyl-6-(3-methyl-l-benzofuran-5-yl)-N-[(lR)-l-{3-[(2-moipholin-4-yl-2- oxoethyl)oxy]phenyl}ethyl]pyrimidin-4-amine;
3- [( 1 R)- 1 - { [2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenol
6-( 1 ,3-benzothiazol-6-yl)-2-methyl- - { ( 1 S)- 1 -[3-( 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yr)-2-methyl-N-[l-(3- {[(methylsullbny methylJoxyJpheny ethyllpyrimidin^-an-iine;
[(2-1luoro-5-{2-methyl-6-[(lR)-l!2:3^tetrahydronaplnhalen-l-ylamino]pyrimi yl}phenyl)amino]acetonitrile;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-((lR)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine:
2-(methyloxy)-4- {2-methyl-6-f( l R)- 1 ,2,3,4-tetrahydronaphthalen- 1 - ylamino]pyrimidin-4-yl}benzamide;
6-(l;3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(2-morpholin-4- ylethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
6-(K3-benzothiazol-6-yl)-2-methyl-N-{(lS)-l-[3-(l-methyl-lH-pyrrol-2- yl)phenyl]ethyl}pyrimidin-4-amine; 6-(l:3-benzothiazol-6-yl)-2-methyl-N-[l-(3-{[2-(2-methyl-lH-imidazol-]- yl)ethyl]oxy}phenyl)ethyl]pyrim idin-4-amine;
6-( 1 -benzofuran-5-yl)-2-methyl-N-[ 1 -(3- { [( 1 -methyl- 1 H-pyrazol-3- yl)methyI]oxy}phenyl)ethyl]pyrimidin-4-amine;
N-[(lS)-l-biphenyl-3-yIeihyl]-2-methyl-6-(3-methyl-l-benzol'uran-5-y])pyriniidin-4- amine;
4-{[3-(l-{[6-(l,3-benzothiazoI-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}butan-l-oI;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-[l-(3-morpholin-4-ylphenyl)ethyl]pyrimidin-4- amine;
3-{[3-(l-{[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}p!Opane- 1 ,2-diol;
6-(1.3-benzothiazol-6-yl)-N-[(lS)-l-biplienyl-3-ylethyl]-2-methylpyrimidin-4-arnine;
2- {[3-(l-{[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}ethanol;
1- {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-3-fluoropropan-2-ol;
6-(l ,3-benzothiazol-6-yl)-N-[ 1 -(3-biOmophenyl)ethyl]-2-methylpynmidin-4-amine;
3- {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}propan-l-ol;
4- {[3-(l-{[6-( 3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N:N-dimetliylbutanamide;
6-(l,3-benzothiazol-6-yl)- -[l-(3-{[3-(diethylamino)propyl]oxy}phenyl)ethyl]-2- methylpyriniidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-[l-(3-{[2-(lH-pyrrol-l- yl)ethyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(3-morpholin-4- ylpropyl)oxy]phenyl}ethyl)pynmidin-4-amine;
2- {[3-(l-{[6-(l:3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino} ethyl)phenyl]oxy } -N-(2-hydroxyethyl)acetamide;
2-{[3-(l-{[6-(L3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-cyc!opropylacetamide;
6-(1 -benzoUiiazol-6-yl)-2-methyl-N-{l-[3-(lH-pyiTol-2-yl)phenyrjethyl)pyrimidin-
4-amine; 6-0 ,3-benzothiazol-6-yl)-2-methy]-N-[ 1 -(3- { [2-( 1 H-pyrazol- 1 - y!)ethyl]oxy}phenyl)ethyl]pyrimidin-4-ainine;
N,N-diethyl-2-[(3-{l-[(2-methyl-6-naphthalen-2-ylpyrimidin-4- yI)amino]ethyl}pheny!)oxy]acetamide:
6-( 1 ,3-benzothiazoi-6-yl)-2-methyl-N-( 1 -{3-[(3-pyrrolidin- 1 - ylpropyl)oxy]phenyI}ethyl)pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-[l-(3-{[3 dimelhylamino)propyl]oxy}phenyl)ethyl]-2- melliylpyrimidin-4-amine;
6-(l!3-benzothiazol-6-yl)-2-methyI-N-{l-[2-(methyloxy)pyridin-4- yl]ethyl}pyrimidin-4-amine;
Ll-dimethylethyl 3-({[3-(l-{[2-metiiyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyr)phenyl]oxy}methyl)pipeHdine-l-carboxylate;
2-{[3-(l-{[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyI)phenyl]oxy}-N-cyclohexylacetamide;
6-(l,3-benzothiazol-6-yl)-N-[l-(3'-nuorobiphenyl-3-yl)ethyl]-2-methylpynmidin-4- amine;
methyl {[3-(l-{[6-(l .3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy} acetate;
6-(l:3-benzothiazol-6-\i)-2-methyl-N-[l-(3-{[2- (methylsulfonyl)ethyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
6-(3-amino-4-methylphenyl)-2-methyl-N-{(lS)-l-[3-
(methyloxy)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-N-{(IS)-l-[3-(methyloxy)phenyl]ethyl}-6-quinolin-6-ylpyrimidin-4-amine;
{[3-(l-{[6-(l:3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy } acetic acid;
2-methyl-6-(3-melhyl- 1 -benzofuran-5-yl)-N-{ ( 1 S)- 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(l,3-benzothiazol-6-y )-2-methyl-N-{(lS)-l-[3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
N,N-dimethyl-2-({3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzoluran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}oxy)acetamide;
N-[l-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)ethyl]-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine; N..N-dimethy]-2-({3-[(lR)-l-{[2-metliyl-6-(3-methyl-l-benzol\iran-5-yl)pyrimidin-4- yl]amino}ethyI]phenyl}oxy)acetamide;
6-(l,3-benzothiazol-6-yl)-N-[l-(3-{[2-(dimethylamino)ethyl]oxy}plienyl)ethyl]-2- methylpyrimidin-4-amine;
6-(2,5-dimethylphenyl)-2-methyI-N-{ l-[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3.4-dichlorophenyl)-2-methyl-N-{ l-[3-(l -methyl- lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(4-ethylphenyl)-2-methyl-N-{ 1 -[3-( 1 -methyl- 1 H-pyrazol-4- y)phenyl]ethyl}pyrimidin-4-amine;
6-(4-fluoro-3-methy phenyl)-2-methyl-N-{ 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-[4-( 1 -melhylethyl)pheny ]-N- { 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phcnyl]ethyl}pyrimidin-4-amine;
6-[2- luoro-4-(methyloxy)phenyl]-2-methyl-N- {l-[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-[3-(dimethylamino)phenyl]-2-methyl-N-{ 1 -[3-(l -methyl- 1 H-pyrazol-4- y)phenyl]ethyl}pyrimidin-4-amine;
6-( K3-benzothiazol-6-yl)-N-[( 1 S)-l -(3-bromophenyl)ethyl]-2-methylpyrimidin-4- amine;
6-(L3-benzothiazol-6-yl)-2-methyl-N-{(lS)-l-[3-(lH-pyrazol-5- yl)phenyl]ethy 1 } py rimidin-4-amine;
(2E)-3-{3-[(lS)-l-{[6-(l;3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}-N-ethylprop-2-enamide;
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-melhy pyrimidin-4- yl]amino}ethyl)phenyl]oxyj- -[2-(dimethylamino)ethyl]acetamide;
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}- -propylacetamide;
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-ethyl-N-methylacetamide;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-| l-(3-nitiOphenyl)ethyl]pyrimidin-4-amine;
(2E)-3-{3-[(lS)-l-{[6-(l!3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}-N-(l,l-dimethylethyl)prop-2-enamide;
N-[l-(3-aminophenyl)ethyl]-6-(l ,3-benzothiazol-6-yl)-2-methylpyrimidin-4-amine; 2-({[3-(l-{[6-(l33-benzothiazol-6-yl)-2-niethylpyriinidin-4- yl]amino}ethyl)phenyl]oxy}methyl)-1.3-oxazole-4-carboxylic acid;
methyl 2-({[3-(l-{[6-(l,3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yI]amino}ethyl)phenyl|oxy}methyl)-l,3-oxazoIe-4-carboxylate;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-[(lS)-l-phenylethyl]pyrimidin-4-amine;
2-methyl-6-(3-methyI-l-benzofliran-5-yl)-N-{(lS)-l-[4- (methyloxy)pheny!jethyl}pyrimidin-4-amine;
6-( 1 ,3-benzothiazo!-6-yl)-N-[ 1 -(3- { [( 1 ,3-dimethyl- 1 H-pyrazol-5- yl)methyl]oxy}phenyl)ethyl]-2-inethylpyrimidin-4-amiiie;
N-[]-(3-(uran-3-ylphenyl)ethyl]-2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin- 4-amine;
6-(1..3-benzothiazol-6-yl)-2-methyl-N-(l-{3- [(phenylmethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{ l-[3-(3-thienyl)phenyl]ethyl}pyrimidin- 4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(pyridin-3- ylmethyl)oxy]phenyl}ethyl)pyrimidin-4-aminc;
6-(l,3-benzolhiazol-6-yl)-2-methyl-l\'-| l-(3-{[(3-methylisoxazol-5- yl)methyl]oxy}phenyl)elhyl|pyrimidin-4-amine;
6-( "1 ,3-benzolhiazol-6-yl)-2-methyl- -[ 1 -(3-{ [(2-methyl- 1 ,3-thiazol-4- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
6-( 1.3-benzothiazol-6-yl)-2-methyl- - { 1 -[3-(propy loxy)phenyl]ethyl } pyrimidin-4- amine;
6-(l,3-benzothiazol-6-yI)-N-{l-[3-(3,5-dimethylisoxazol-4-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
6-{2-methyl-6-[(lR)-L2;3,4 etrahydiOnaplnhalen-l-ylamino]pyrimidin-4-yl}-4H- cliromen-4-one;
6-( 1 ;3-benzolhiazol-6-yl)-2-methyl-N-[l -(3-{ [(4- methylphenyl)methyl]oxy}phenyl)ethy |pyrimidin-4-amine;
6-(1 -benzothiazol-6-yl)-N-[l-(3-i iran -ylphenyl)ethyl]-2-methylpyrimidin-4- amine;
6-( 1 ,3-benzolhiazol-6-yl)-2-methyl-N-[ ! -(3-{ [(3-{ [(4-methylplienyl)oxy]methyl}- 1.2.4-oxadiazol-5-yl)methyl|oxy}phenyl)eihyl]pyrimidin-4-amine; 6-(l,3-benzothiazol-6-yl)-2-methyl-N-{ l-[3-(3-l ienyl)phenyl]ethyl}pynmidin-4- amine;
6-(1 -benzothiazol-6-yl)-N-[l-(3-{[2-(lH-imidazol-l-yl)ethyl]oxy}phenyl)ethyl]-2- methylpyrimidin-4-aniine;
2-{[3-(l-{[2-methyl-6 3-met yl-l-benzofiiran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyI]oxy}acetamide;
N-[l-(3-{[(l,3-dimethyl-lH^yrazol-5-yl)methyl]oxy}phenyl)ethyl]-2-methyl-6-(3- methyl- 1 -benzofuran-5-yl)pyrimidin-4-amine;
2-{[3-(l-{[6-(l,3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-(l-{3-[(2-morpholin-4-yl-2- oxoethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
N.N-dimethy 1-2- { [3-( 1 - { [2-methy l-6-(3-methyl- 1 -benzo furan-5-yl)pyr imidin-4- yl]amino}etliy])phenyl]oxy}acetamide:
6-( 1 !3-benzothiazol-6-yl)-2-methyl-N-[ 1 -(3-{ [( 1 -methyl- 1 H-pyrazol-3- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-N-( 1 - { 3-[(2-fluoroethyl)oxy]phenyl }ethyl)-2- methylpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(2,2,2- trifluoroethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
N-[ 1 -(3-bromo-4-fluorophenyl)ethyl ]-2-methyl-6-(3-methyl- 1 -benzofuran-5- yl)pyrimidin-4-amine;
5-[2-(luoiO-5-(l-{[2-nielhyl-6-(3-methyl-l-benzofuraii-5-yl)pyrimidin-4- yl]amino}ethyl)phenyl]pyrimidin-2-amine;
N-{(lR)-l-[4-f]uoro-3-(l-niethyl-lH-pyrazol-4-yl)phenyl]ethyl}-2-methyl-6-(3- methyl-l-benzoiuran-5-yl)pyrimidin-4-aniine;
N-{(1S)-l-[4-fluoro-3-(l-methyl-lH-pyrazol-4-yl)phenyl]ethyl}-2-methYl-6-(3- metliyl-l-benzofuran-5-yl)pyrimidin-4-amine;
5- [3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]pyridine-3-carboxamide;
6- (l!3-benzothiazol-6-yl)-2-methyl-N-[(lS)-l-{3-[2-(4-methylpiperazin-l- yl)pynmidin-5-yl]phenyl}ethyl]pyrimidin-4-amine;
6-(1.3-benzolhiazol-6-yl)-2-metliyl-N-(l-{3-[5-(tri{liioromethyl)pyridin-3- yl]phenyl}ethyl)pyrimidin-4-amine; 2- methyl-6-(3-met-hyl-l-benzofuran-5-yl)-N-[(lS)-l-{3-[2-(4-methylpiperazin-l- yl)pyrimidin-5-yl]phenyl}ethyl]pyrimidin-4-amine;
3- [(5-{3-[(lS)-l-{[2-niethyl-6-(3-methyl-l-benzofurari-5-yl)pyrimidin-4- yl]amino}elhyl]p enyl}pyrimidin-2-yl)amino]propan-l-ol;
methyl N-(5-{3-[(l S)-I-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)glycinate;
2MnelhyI-6-(3-methyi-l-benzofuian-5-yl)-N-[(lS)-l-{3-[6-(4-methylpiperazin-l- yl)pyridin-3-yl]phenyl}elliyrjpyrimidin-4-amine;
2,2<limethyl-3-[(5-{3-[(lS)-l-{[2-metl^
4-yl]amino}ethyl]phenyl}pyrimidin-2-yl)aminoJpropan-l-ol;
N-(5-{3-f(lS)-l-{[2-methyl-6-(3-metliyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)glycine;
3-[(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pynmidin-2-yl)amino]propane-l,2-diol;
N-[(lS)-l-(5'-nuoro-3:3'-bipyndin-5-yi)ethyl]-2 nethyl-6-(3-methyl-l-benzofura^ yl)pyrimidin-4-amine;
N-[(lS)-l-(6'-nuoro-3,3'-bipyndin-5-yl)ethyl]-2-methyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-amine;
N-{(lS)^-[5-(l-ethyl-lH^yrazol -yl)pyridin-3-yl]ethyl}-2-methyl-6-(3-meth^^ benzofuran-5-yl)pyrimidin-4-amine;
6-chloro-5'-[(lS)-l-{[2-methyl-6-(3-melhyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]-3.3'-bipyndin-5-amine;
5-{5-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yrjamino}ethyl]pyridin-3-yl}pyrimidin-2-aniine;
N-[ 1 -(3-biOmo-5-fluoiOphenyl)ethyl ]-2-methyl-6-(3-methyl- 1 -benzofiiran-5- yl)pyrimidin-4-arnine;
5-[3-fluoi -5-(l - {[2-methyl-6-(3-melhyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyl]pyrimidin-2-amine;
N-{l-[3-fluoro-5-(l-methyl-lH-pyrazol-4-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
l-(5-{5-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzol iran-5-yl)pyrimidin-4- yl]amino}ethyl]pyndin-3-yl}pyi'imidin-2-yl)piperidin-4-ol
N-{l-[3-(5-amino-6-chloropyridin-3-yl)-5-fliiorophenyl]ethyr}-2-methyl-6-(3-methyl- l-benzofuran-5-yl)pyrimidin-4-amine; N-[l-(3-biOmo-4-methylplienyl)etliyl]-2-methyI-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-amine;
5-[2-methyl-5-(l-{[2-methyl-6-(3-methyl-]-benzofuran-5-y])pyrimidin-4- yl]amino}ethyl)phenyjpyrimidin-2 -amine:
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{ l-[4-methyl-3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyI]etliyl}pyrimidin-4-amine:
5- {3-[(lS)-l-{[2-methyl-6-(l-methyl-l H-indoI-6-yl)pyrimidin-4- yI]amino}ethyl]phenyl}pyrimidin-2-amine;
2-methyl-6-(3-methy I- 1 -benzofuran-5-yl)-N-{( 1 S)- 1 -[5-( 1 -methyl- 1 H-pyrazol-5- yl)pyridin-3-yl]ethyl}pyrimidin-4-amine:
2-methyI-6-(3-methyl- 1 -benzol uran-5-yl)-N-{ ( 1 S)- 1 -[5-( 1 H-pyrazol-4-yl)pyridin-3- yl]ethyl}pynmidin-4-amine;
(2S)-3-[(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzoi\iran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pynmidin-2-yl)amino]propane-l .2-diol
2-methyl-N-{l-[3-(l -methyl- lH-pyrazol-4-yl)phenyl]ethyl}-6-[4- (trifluoromethyl)phenyl]pyrimidin-4-amine;
6- (2..3-dihydro- 1 ,4-benzodioxin-6-yl)-2-methyl-N- { 1 -[3-( 1 -methyl-l H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-y )-N-{(lS)-l-[3-(lH-pyrazol-l- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(2H-l,2;3-triazol-2- yl)phenyl]ethyl}pyrimidin-4-amine;
6-( 1 -benzothien-5-yl)-2-methyl-N-{ 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
N'-{5-[3-(l-{[6-(l ,3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yl]annno}ethyl)phenyl]pyrimidin-2-yl}-N.N-dimethylethane-1.2-diamine:
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(l S)-l-[3-(l H-tetrazol-1- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l -benzoi'uran-5-yl)-N-{(l R)-l -[3-(l H-tetrazol-1- yl)phenyl]ethyl}pyrimidin-4-amine:
N-{(] S)-l-[3-(2-{4-[2-(dimethylamino)ethyl|pipeiazin-l-yl}pyrimidin-5- yl)phenyr]ethyl}-2-methyl-6-(3-methyl-l-benzofuran-5-yl)pynmidin-4-amine;
2-[4-(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzoluran-5-yl)pyrimidin-4- yrjamino}ethyl]phenyl}pyrimidin-2-yl)piperazin-l-yl]ethanol 2-methyl-6-(3-methyl- 1 -benzoI'uran-5-y])-N-{(l S)-l -[3-(2-{4-[(l -methyl- 1 H- imidazol-2-yl)methyl]piperazin-l-yl}pyriniidin-5-yl)phenyl]ethyl}pyrimidi
2-methyl-6-(3-melhyl- 1
Figure imgf000155_0001
S)- 1 -[3-(2-{4-[2- (methyloxy)ethyl]piperazin-l-yl}pyrim^
2-({2-[4-(5-{3-[(lS)-l-{[2-metliyl-6-(3-methyl-l-benzoliran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperazin-l-yl]ethyl}oxy)ethanol
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-[(lS)-l-(3-{2-[4-(2-moi holin-4- ylethyl)piperazin-l-yl]pyrimidin-5-yl}phenyl)ethyl]pynmidin-4-amine;
N-[(lS)-l-(3-bromoplienyl)ethyl]-2-methyl-6-(3-niethyl-l-benzothien-5-yl)pyrimidin- 4-amine;
2-methyl-6-(3-methy 1- 1 -benzothien-5-yl)-N- {(1 S)- 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
N-{(lS)-l-[3-(5-aminopyndin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzothien-5-yl)pyrimidin-4-amine;
N-{(lS)-l-[3-(6-nuoropyndin-3-yl)phenyl]ethyl}-2-methy!-6-(3-methyl-l- benzothien-5-yl)pyrimidin-4-amine;
N-{(lS)-l-[3-(5-nuoropyridin-3-yl)phenyl]ethyr}-2-methyl-6-(3-methyl-l- benzothien-5-yl)pyrirnidin-4-amine;
5- {3-[(l S)-l-{[6-(3-chloro-l-benzoruran-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
ethyl 5-[3-(l-{[6-(l .3-benzothiazoI-6-yl)-2-methylpyrimidin-4- yl]amino}elhyl)phenyiJpyridine-3-carbox late;
6- (1.3-benzothiazol-6-yl)-N-(l-{3-[6-(dimethylaniino)pyridin-3-yl]phenyl}ethyl)-2- methylpyrimidin-4-amine;
N-[(lS)-l-(3-biOmophenyl)ethyl]-6-(3-ethyl-l-benzofuran-5-yl)-2-methylpyrimidin- 4-ainine;
5- {3-[(lS)-l-{[6-(l,3-benzothiazol-6-yl)-2-melhylpynmidin-4- yl]amino}ethyljphenyl } pyrimidin-2-amine;
6- (l,3-benzothiazol-6-yl)-N-{(lS)-l-[3-(5-jUioi pyridin-3-y])phenyl]ethyl}-2- methylpyrimidin-4-amine;
6-(l ,3-benzothiazol-6-yl)-2-methyl-N-{(l S)- 1 -[3-(6-methylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
5-{3-[(lS)-l-{[6-(3-ethyl-l-benzof ian-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine; 6-(l,3-benzothiazol-6-yl)-2-melhyl-N-{(lS)-l-[3-(5-melhylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-N- {( 1 S)- 1 -[ 3-(6-iluoro-5-methylpyridin-3- yl)phenyl]ethyl}-2-metIiylpyrimidin-4-amine;
6-(l!3-benzolhiazol-6-yl)-N-{(lS)-l-[3-(6-fluoropyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
N-{(lS)-l-[3-(5-fluoropyridin-3-yI)phenyl]ethyl}-2-melhyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
6-(7-fluoro- 1 -benzoiuran-5-yl)-2-methyl-N- { 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl } pyrimidin-4-amine;
N-{(lS)-l-[3-(2-chloropynmidin-5-yl)phenyl]ethyl}-2-melhyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
6 L3-benzothiazol-6-yl)-N-{(lS)-1 .3-(2-chloropyrimidin-5-yl)phenyl]ethyl}-2 methylpyrimidin-4-amine;
N-{(lS)-l-[3-(6-fluoropyridin-3-yl)pheiiyl]elhyl}-2-methyl-6-(3-methyI-l- benzofuran-5-yl)pyrimidin-4-amine;
5-{3-[(lS)-l-([6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}-N-niethylpyrimidin-2-amine:
N-methyl-5-{3-[(l S)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
5-{3-[(lS)-l-{[6-(7-fluoro-l-benzofuran-5-yl)-2-methylpynmidin-4- yl]amino}ethyjphenyl}pyrimidin-2-amine;
5-{3-[( 1 S)- 1 -{[6-(l ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}-N,N-dimethylpyrimidin-2-amine;
N^N-dimethyl-5-{3-[(lS)-l-{[2-melhyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
N-ethyl-5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyI]phenyl}pyrimidin-2-amine;
5-{3-[(lS)-l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}-N-ethylpyrimidin-2-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(2-morpholin-4-ylpyrirnidin- 5-yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(2-pipeiazin-l-ylpyrimidin-5- yl)phenyl]elhyl}pyrimidin-4-amine; N-{(lS)-l-[3-(5-aniinopyridin-3-yl)p enyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
2-[(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzoftiran-5-y!)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)amino]ethanoI
N,N-diethyl-5-{3-[(lS)-l-{[2-methyl-6-(3^^
yl]amino}ethyl]phenyl}pyrimiclin-2-amine;
N-{(lS)-l-[3-(5-chloropyridin-3-yl)pheny]]ethyl}-2-methyl-6-(3-methy]-l- benzofuran-5-yl)pyrimidin-4-amine;
6-(13-benzothiazol-6-yl)-N-{(lS)-l-[3-(5-chloropyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
5- {3-[(lS)-l-{[6-(L3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethy ]phenyl}-N.N-dielhylpyrimidin-2-amine;
6- (l .3-benzothiazol-6-yl)-N-| ( 1 S)- 1 -{3-[2-(4-etliy]piperazin-l -yl)pyrimidin-5- yl]phenyl}ethyl]-2-methylpyrimidin-4-amine;
1 -(5- {3-[( 1 S)- 1 - { [6-( 1 :3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperidin-4-ol
N-[(lS)-l-{3-[2-(4-ethylpipei in-l-yl)pyrinn'dm
methyl- l-benzofuran-5-yl)pyrimidin-4-amine;
l-(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzo(:uran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperidin-4-ol;
1 -(5-{3-[( 1 S)- 1 - { [2-methyl-6-(3-methyl- 1 -benzof ran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)pyrrolidin-3-ol;
N-(l-methylethyl)-5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-yl]amino}ethyl]phenyl}pyrimidin-2-amine;
[l 5-{3-[(lS)-l-{[2 nethyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperidin-4-yl]methanol;
N-[(lS)-l-{3-[2 4-lliioropipe! din-l-yl)pyrimidin-5-yrjphenyl}ethyrj-2-methyl-6-(3- methyl- 1 -benzofuran-5-yl)py rimidin-4-amine;
N-(furan-2-ylmethyl)-5- { 3-[( 1 S)- 1 -{ [2-methyl-6-(3-methyl- 1 -benzofuran-5- yl)pyrimidin-4-yl]amino}ethyl]phenyl}pyrimidin-2-amine;
N-(furan-3-ylmethyl)-5-{3-[(lS)-l-{[2 iiethyl-6-(3-mcthyl-l-benzofuran-5- yl)pyrimidin-4-yl]amino}ethyl]phenyl}pyrimidin-2-amine;
6-(7-nuoro-3-methyl- 1 -benzoluran-5-yl)-2-methyl-N-{ 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine; (5-{3-[(lS)-l-{[6-(l,3-benzothiazol-6-yl)-2-me(hylpynmidin-4- yl]amino}ethyl]pheny!}pyridin-2-yl)methanol
2-methyl-6-(3-melhyl-l-benzofuran-5-y])-N-{(IS)-l-[3-(4-methyl-3J4-dihydro-2H- pyndo[3.2-b][1.4]oxazin-7-yl)pheny!]ediyl}pynmidin-4-amine;
(5-{3-[(lS)-l-{[6-(1)3-benzotliiazol-6-yl)-2-methyIpyiimidin-4- yl]amino}elhyl]plienyl}pyridin-3-yl)melhanol
N-{(lS)-l-[3-(5-an^'no-6-chloropyndin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
6-(7-nuoro-3-methyl-l-benzoft>ran-5-yl)-2-methyl-N-{(lS)-l-[3-(l-methyl-lH- pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3,4-difluorophenyl)-2-methyl-N-{ 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzoruian-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridin-3-yl)methanol;
N-{(lS)-l-[3-(5-aminopyridin-3-yl)phenyl]ethyl}-6-(7-fluoro-3-methyl-l- benzoiuran-5-yl)-2-methylpyrimidin-4-amine;
6-(7-fluoi -3-methyl-l-benzoiu'an-5-yl)- -{(lS)-l-[3-(5-fluoropyridin-3- yl)phenyl]ethyl}-2-methylpyrimidin-4-amine;
6-(4-chloro-3.5-diiluoiOphenyl)-2-methy - -{ 1 -[3-(l -methyl-1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-N-{l-[3-(l -methyl- lH-pyrazol^-y phenyl'JethylJ-e-CS^^- trifluorophenyl)pyrimidin-4-amine;
-{(lS)-l-[3-(5-amino-6-chloropyridin-3-yl)phenyl]ethyl}-6-(7-fluoro-3-methyl-l- benzoturan-5-yl)-2-methylpyrimidin-4-amine;
5-{3-[(lS)-l-{[6-(3;4-difluorophenyl)-2-methylpyriniidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amiiie;
5- {3-[(lS)-l-{[6-(4-chloiO-3,5-dinuorophenyl)-2-melhylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
1 -(5-{ 3-[( 1 S)- 1 -{ [2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridin-3-yl)ethanone;
6- (7-fluoro-3-methyl-l-benzofuran-5-yl)-2-metliyl-N-{l-[5-(lH-pyrazol-4-yl)pyridin- 3-yl]etliyl}pyrimidin-4-amine;
N-{l-[5-(l-etliyl-lI-l-pyrazol-4-yl)pyridin-3-yl]ethyl}-6-(7-nuoi -3-methyl-l- benzofuran-5-yl)-2-methylpyrimidin-4-amine; 6-(7-fluoro-3-mefhyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(6-nuoropyridin-3- yl)phenyl]ethyl}-2-methylpyrimidin-4-amine;
ethyl 5-{3-[(l S)-l -{[2-methyl-6-(3-methyl-l -benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridine-3-carboxylate;
3-[(5-{3-[(lS)-l-{[6-(7-fluoro-3-methyl-l-benzofuran-5-yl)-2-methylpyrimidin-4- ylJamino}ethyl]phenyl}pyrimidin-2-yl)amino]propane-l:2-diol
1- (5-{3-[(lS)-l-{[6-(7-fluoro-3-methyl-l-benzofuran-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperidin-4-ol;
1 -(5- { 3-[( 1 S)- 1 - { [2-melhyl-6-(3-methyl- 1 -benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridin-3-yl)ethanol;
2- (5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridin-3-yl)propan-2-ol;
6-(7-iluoro-3-methyl-l-benzofuran-5-yl)-2-methyl-N-{l-[5-(l-methy -lH-pyrazol-4- yl)pyridin-3-yl]ethyl}pyrimidin-4-amine;
5-[5-( 1 - { [ 6-(7-fluoro-3-methyl- 1 -benzoi iran-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl)pyridin-3-yl]pyrimidin-2-amine;
5- {3-[(lS)-l-{[6-(7-i1uoro-3-methyl-l-benzofuran-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
2-methyl-6-(3-methyl-l-benzoiuran-5-yl)-N-[(lS)-l-(3-pyridin-3- ylphenyl)ethyl]pyrimidin-4-amine;
6- (l,3-benzothiazol-6-yl)-N-{l-[3-(2-fluoropyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
6-(l ,3-benzothiazol-6-yl)-2-methyl-N-{ 1 -[3-(2-methylpyridin-4- yl)phenyl]ethyl}pyrimidin-4-amine;
N-[(lS)-l-{3-[6-(dimethylamino)pyridin-3-yl]phenyl}ethyl]-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidiii-4-amine;
6-(l ,3-benzothiazol-6-yl)-2-methyl-N-{ 1 -[3-(6-piperazin- 1 -ylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyI-l -benzofuran-5-yl)-N-{l -[5-(l -methyl- 1 H-pyrazol-4- yl)pyridin-3-yl]elhyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-1-benzofuran-5-yl)-N-{(lS)-l-[3-(6-methylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine:
2-methyl-6-(3-met1iyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(6-piperazin-l-ylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine; 2-methyl-6-(3-melhyl-l-benzofiiran-5-yl)-N-{(lS)-l-[3-(5-methylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
N-{(lS)-l-[3-(6 1uoro-5-methylpyridin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-N-{( 1 S)- 1 -[3-(2-fluoropyridin-4-yl)phenyl]ethyl } -2- methylpyrimidin-4-amine;
5- [4-(]-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)pyridin-2-yl]pyrimidin-2-amine;
N-{(lS)-1 '3-(6-chloropyridin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzoiuran-5-yl)pyrimidin-4-amine;
2-methyl-N-[( IS)- 1 -{3-[6-(methylamino)pyridin-3-yl]phenyl } ethyI]-6-(3-methyl- 1 - benzofuran-5-yl)pyrimidin-4-amine;
2-methyl-6-(3-methyl-l -benzoΓυran-5-yl)-N-{(lS)-l-[3-(6-mo holin-4-ylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
' 2-[(5-{3-[(lS)-l-{[2-methyl-6-(3-met yl-1 )enzoiiiran-5-yl)pyrimidin-4- yl]amino}ethylJphenyl}pyridin-2-yl)amino]ethanoI
6- (l,3-benzothiazoI-6-yl)-N-{(lS)-l-[3-(6-chloropyridin-3-yl)phenyl]ethyI}-2- methylpyrimidin-4-amine;
6-(l -benzol iran-5-yl)-2-methyl-N-{ 1 -| 3-( 1 -methyl-1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)- - {( 1 R)- 1 -[2-( 1 -methyl- 1 H-pyrazol-4- yl)pyridin-4-yl]ethyl}pyrimidin-4-amine;
2-niethyl-6-(3-methyl-l-benzoruran-5-yl)-N-{(lS)-l-[2-(l-methyl-lH-pyrazol-4- yl)pyridin-4-yl]ethyl}pyrimidin-4-amine;
N-[(lS)-l-{3-[6-(ethylamino)pyridin-3-yl]pheiiyl}ethyl]-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
N-[(lS)-l-{3-[6-(4-ethylpiperazin-l-yl)pyridin-3-yl]phenyl}ethyl]-2-methyl-6-(3- methyl-l-benzoi\iran-5-y])pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-N-[( 1 S)- 1 - {3-[6-(4-ethylpiperazin-l -yl)pyridin-3- yl]phenyl}ethyl]-2-methylpyrimidin-4-amine;
5- [5-(l-{[2-methyl-6-(3-niethyl-1 ienzol iran-5-yl)pyrit'nidin-4- yl]amino}etliyl)pyridin-3-yl]pyrimidin-2-aniine;
6- (l ,3-benzothiazol-6-yl)-2-methyl-N-.{(l S)-l -[3-(6-moi holin-4-ylpyridin-3- yl)phenyl]ethyl } pyrimidin-4-amine; 2-methyl-6-(3-methyl-l-benzofiiran-5-yl)-N-{(l )-l-[5-(l-methyl-lH-pyrazol-4- yl)pyridin-3-yl]ethyl}pyrimidin-4-amine;
l-(5-{3-[(lS)-l-{[2-niethyl-6-(3-methyl-l-benzofuran-5-yl)pynniidin-4- yl]amino}ethyl]phenyl}pyridin-2-yl)piperidin-4-ol
6-(l,3-benzothiazol-6-yl)-N-{(lS)-l-[3-(6-chloro-5-methylpyridin-3- yl)phenyl]ethyl}-2-methyIpyrimidin-4-amine;
N-{(lS)-l-[3-(6-chloro-5-methylpyridii 3-y!)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
N-[l-(5-bromopyndiiv3-yl)ethyl]-2-n thyl-6-(3-methyl-]-benzof'uran-5- yl)pyrimidin-4-amine;
5'-(l-{[2-methyl-6-(3^nethyl-l-benzofuran-5-yl)pyrimidin-4-yl]amino}ethyl)-3.3'- bipyridin-5-amine;
6-(4-chloro-3-fluorophenyl)-2-methyl-N- { 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3-fluorophenyl)-2-methyl-N-{(lS)-l-[3-(l -methyl-1 H-pyrazol-4- yl)phenyl]elhyl}pyrimidin-4-amine;
5-{3-[(l S)-l-{[6-(4-chIorophenyl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
5-{3-[(lS)-l-{[6-(4-chloi -3-fluorophenyl)-2-niethylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
N-{(lS)-l-[3-(5-aminopyridin-3-yl)phenyl]ethyl}-6-(4-chloro-3-lluoiOphenyl)-2- methylpyiimidin-4-amine;
5- [5-(l-{[6-(4-chloro-3-fluorophenyl)-2-methylpyrimidin-4-yl]amino}ethyl)pyridin-
3-yl]pyrimidin-2-amine;
6- (4-chloro-3-fluorophenyl)-2-methyl-N-{ 1 -[5-(l -methyl-1 H-pyrazol-4-yl)pyridin-3- yl]ethyl}pyrimidin-4-amine;
6-(4-chloro-3-nuorophenyl )-N- { 1 -[5-( 1 -ethyl- 1 H-pyrazol-4-yl)pyridin-3-yl]ethyl } -2- methylpyrimidin-4-amine;
6-(4-chloro-3-fluoiOpheny l)-2-methyl-N- { ( 1 S)- 1 -[3-(6-piperazin- 1 -y lpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(4-chIoro-3-fluorophenyl)-2-methyl-N-{(lS)-l-[3-(l-melhyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3-fluorophenyl)-2-methy l-N-{( 1 R)- 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl } pyrimidin-4-amine; 3-[(5-{3-[(l S)-l -{ [6-(4-chloro-3-fluorop eny l)-2-melhyipynmidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)amino]propane-l,2-dioI
1 -(5-{3-[(l S)-l -{[6-(4-chloiO-3-fluorop enyl)-2-methylpynmidin-4- yl]amino}ethyl]phcnyl}pyrimidin-2-yl)piperidin-4-ol
N-{(lS)-l-[3-(4-chloropyridin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuraii-5-yl)pyrimidin-4-amine;
6-(4-chloro-3-nuorophenyl)-N-{(lS)-l-[3-(l-ethyl-n-I-pyrazol-4-yl)phenyl]ethy]}-2- methylpynmidin-4-aniine;
5- {3-[(lS)-l-{[2-melhyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridine-3-carboxamide;
3- [2-methyl-6-({ 1 -[3-( 1 -methyl- 1 H-pyrazol-4-yl)phenyl]ethyl } amino)pyriinidin-4- yljphcnol
6- (2,3-dihydro- 1 -benzofuran-5-yl)-2-methyl-N-{ I -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-[2-fluoro-3-(methyloxy)phenyl]-2-methyl-N-{ 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yI)-2-methyl-N-(l-i3-[5-(methyloxy)pyridin-3- yl]phenyl}ethyl)pyrimidin-4-amiie;
6-(l,3-benzothiazol-6-yl)-N-{ l-[3-(2-nuoiopynmidin-5-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
5- [3-(l-{[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyr)phenyl]pyrimidine-2-carbonitrile;
6- (13-benzothiazol-6-yl)-N-{l-[3-(6-nuo!O-2-methylpyndin-3-yl)phenyl]ethyl}-2- mcthylpyi'imidin-4-amine;
5- [3-(l-{[6-(1.3-benzolliiazol-6-yl)-2-methylpyiimidin-4- yljamino}ethyl)phenyl]pyridine-3-carbonitrile;
6- (l,3-benzothiazol-6-yl)-N-{l-[3-(4-chloropyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-{l-[3-(2;6-dimethylpyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
4- [3-(l-{[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]pyrimidin-2-aniine;
6-( 1 s3-benzothiazol-6-yl)-2-methyI-N- {(1 S)- 1 -[3-(2-piperidin- 1 -ylpyrimidin-5- yl)phenyl]ethyl}pyrimidin-4-amine; N'-(5-{3-[(lS)-l-{[6-(l:3-benzolhiazoI-6-yl)-2-melhylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)-N,N-dimethylpropane-l,3-diamine;
N-[(lS)-l-{3-[2-(4-acetylpiperazin-l-y])pyrimidin-5-yl]phenyl}ethyl]-2-rnethyl-6-(3- methyl-l-benzofuran-5-yl)pyrimidin-4-amine;
5- {3-[( 1 S)- 1 - {[2-methyl-6-(3-methyl- 1 -benzo uran-5-yl)pyrimidin-4- yl]amino}etliyl]phenyl}-N-(telrahydrofuran-2-yImethyl)pyrirnidin-2-ainiiie;
6- (3-amino-4-chIorophenyl)-2-methyI-N-{ l-[3-(l -methyl- lH-pyrazol-4- yl)phenyi]ethyI}pyrimidin-4-amine;
6-(4-chloi -3-methylplienyl)-2-methyl-N-{l-[3-(l-methyl-lI-l-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-fluoro-4-[2-methyl-6-({l-[3-(l -methyl- 1 H-pyrazol-4- yI)phenyl]ethyl}amino)pyrimidin-4-yl]benzamide;
6-(l :3-benzothiazol-5-yl)-2-methyl-N-{ 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
-[(lS)-l-{3-[2-(4-acetylpiperazin-l-yl)pyrimidin-5-yl]phenyl}ethyl]-2-methyl-6-(3- methyl- 1 -benzothien-5-yl)pyrimidin-4-amine;
N-{(lS)-l-[3-(2-{4-[2-(dimethylamino)ethyl]piperazin-l-yl}pyrimidin-5- yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l-benzothien-5-yl)pyrimidin-4-amine;
5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzoi\iian-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridine-3-carbonitrile;
2-methyl-6-(3-methyl-l-benzo†uran-5-yl)-N-[(lS)-l-(6'-methyl-3!3'-bipyridin-5- yl)ethyl]pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lS)-l-[5-(l-methyl-lH-pyrazol-4- yl)pyridin-3-yl]ethyl}pyrimidin-4-amine;
5-{3-[( 1 S)- 1 - { [2-methyl-6-(3-methyl- 1 -benzothien-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
-{(lS)-l-[3-(5-aminopyridin-3-yl)phenyl]ethyl}-6-(l!3-benzothiazol-6-yl)-2- methylpyrimidin-4-amine;
5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-bcnzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-ol;
(S)-5-(3-(l-(6-(7-fluoro-3-methylbenzofuran-5-yl)-2-methylpyrimidin-4- ylamino)ethyl)phenyl)pyrimidin-2-amine;
(S)-2-methyl-N-( 1 -(5-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-3-yl)ethyl)-6-(3- methylbenzoiuran-5-yl)pyrimidin-4-amine; (S)-N-( l -(3-(5-aminopyridin-3-yl)phenyl)ethyl)-6-(4-chloi -3-iluorophenyl)-2- methylpyrimidin-4-amine;
(S)-5-(3-( l -(2-methy]-6-(3-methylbenzofuran-5-yl)pyrimidin-4- ylamino)ethyl)phenyl)pyrimidin-2-amine;
N-( l -(5-( l -ethyl- l H-pyrazol-4-yl)pyridin-3-yl)ethyl)-6-(7-fluoro-3- methylbenzofuran-5-yl)-2-methylpyrimidin-4-amine;
5-(3-nuoro-5-( l -(2^iiethyl-6-(3-melhylbenzofuraii-5-yl)pyrimidin-4- yIamino)ethyl)phenyl)pyrimidin-2-amine;
(S)-5-(3-(l -(2-methyl-6-(3-methylbenzo[b]thiophen-5-yl)pyrimidin-4- ylamino)ethyl)phenyl)pyrimidin-2-amine; or
(S)-N-(l -(3-(5-aminopyridin-3-yl)phenyI)ethyl)-2-melhyl-6-(3- methylbenzo[b]thiophen-5-yl)pyrimidin-4-amine.
[00112] In another aspect, the invention provides a pharmaceutical composition which comprises: ( 1 ) a compound, as a single stereoisomer or mixture of isomers thereof, according to any one of formula compounds of formula I. or according to any one of the above embodiments or a compound in Table 1 , optionally as a pharmaceutically acceptable salt thereof, and (2) a pharmaceutically acceptable carrier, excipient, and/or diluent thereof.
[00113] In another aspect, the invention provides a method of treating disease, disorder, or syndrome where the disease is associated with uncontrolled, abnormal, and/or unwanted cellular activities effected directly or indirectly by iPF -2 which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of any of the formulas described herein, a compound of any one of the above embodiments, or a compound from Table 1 , optionally as a pharmaceutically acceptable salt or
pharmaceutical composition thereof. In another embodiment, the disease is cancer. In another embodiment, the disease is cancer and the compound is a compound of formula I or a compound from Table 1 .
[00114] In another aspect, the invention provides a method of treating a disease, disorder, or syndrome which method comprises administering to a patient a therapeutically effective amount of a compound of any of formula I, a compound of any one of the above
embodiments, or a compound from Table 1 , optionally as a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, a compound of any one of the above embodiments, or a compound from Table 1 , and a pharmaceutically acceptable carrier, excipient, or diluent. [00115j In another embodiment, the disease is cancer, and the Compound is the compound of formula 1 or a compound from Table I .
General Administration
[00116] In one aspect, the invention provides pharmaceutical compositions comprising an inhibitor of iPFK-2 according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent. In certain other specific embodiments, administration is by the oral route. Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, speci fically in unit dosage forms suitable for simple administration of precise dosages.
[001 17] The compositions wi ll include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include carriers and adjuvants, etc.
[001 18] Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
[00119] If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as. for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.
|00120] The choice of formulation depends on various factors such as the mode of drug administration (e.g.. for oral administration, formulations in the form of tablets, pills or capsules) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4, 1 07,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 mil in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5, 145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailabi lity.
|00121 ] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
[00122] One specific route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
[00123] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders (e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid), (b) binders (e.g., cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia), (c) humectants (e.g., glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate), (c) solution retarders (e.g., paraffin), (0 absorption accelerators (e.g., quaternary ammonium compounds), (g) wetting agents (e.g., cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, as for example, kaolin and bentonite), and (i) lubricants, (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof). In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. [00124] Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coalings and others well known in the art. They may contain paci fying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. |00125] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a
pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like;
solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol,
1.3-butyleneglycol, dimethylforrnamide; oils, in particular, cottonseed oil, groundnut oil. corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.
[00126] Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, benlonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
[00127] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non- irritating excipients or carriers such as cocoa butler, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore melt while in a suitable body cavity and release the active component therein.
[00128] Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
[00129] Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. [00130] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1 % to about 99% by weight of a compound(s) of the invention, or a pharmaceutical ly acceptable salt thereof, and 99% to 1 % by weight of a suitable phannaceiitical excipient. In one example, the composition will be between about 5% and about 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
|00131] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 1 8th Ed., (Mack Publishing Company, Easton. Pa., 1 990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-slate in accordance with the teachings of this invention.
[00132] The compounds of the invention, or their pharmaceutically acceptable salts or solvates, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1 .000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per clay is an example. The speci fic dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity ot the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
100133] If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
Utility
[00134] Compounds of the Invention have activity for iPFK-2. Compounds of this invention have been tested using the assays described in the Biological Examples and have been determined to be inhibitors of iPF -2. Suitable in vitro assays for measuring iPF -2 activity and the inhibition thereof by compounds are known in the art . For further details of an in vitro assay for measuring iPFK-2, see the Biological Examples herein. Cell-based assays for measurement of in vitro efficacy in treatment of cancer are known in the art. In addition, assays are described in the Biological Examples provided herein. Suitable in vivo models for cancer are known to those of ordinary skill in the art. Following the examples disclosed herein, as well as that disclosed in the art, a person of ordinary skil l in the art can determine the activity of a compound of this invention.
(001351 Compounds of formula I are useful for treating diseases, including autoimmune disorders, inflammatory diseases, and cancers, including: cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel
(adenocarcinoma, lymphoma, carcinoid tumors, arposi's sarcoma, leiomyoma,
hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney
(adenocarcinoma, Wilm's tumor [neph roblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma,
teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma. Evving's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors: Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis). brain
(astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, SertoliLeydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,
adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma,
myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis: and Adrenal glands: neuroblastoma.
Synthetic Examples
[00136] Described below are specific examples relating to the synthesis of the compounds of the invention, and procedures for determining the activity of the compounds. The examples are provided so the invention may be more fully understood and are not meant to limit the scope of the invention in any way.
[00137) In some of the reaction schemes and examples below, certain compounds can be prepared using protecting groups, which prevent undesirable chemical reaction at otherwise reactive sites. Protecting groups may also be used to enhance solubility or otherwise modify physical properties of a compound. For a discussion of protecting group strategies, a description of materials and methods for installing and removing protecting groups, and a compilation of useful protecting groups for common functional groups, including amines, caiboxylic acids, alcohols, ketones, aldehydes, and the like, see T. W. Greene and P. G. Wuts, Protecting Groups in Organic Chemistry ( 1999) and P. Kocienski, Protective Groups (2000), which are herein incorporated by reference in their entirety for all purposes.
[00138] In addition, some of the schemes and examples below may omit details of common reactions, including oxidations, reductions, and so on, which are known to persons of ordinary skill in the art of organic chemistry. The details of such reactions can be found in a number of treatises, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi-volume series edited by Michael B. Smith and others, Compendium of Organic Synthetic Methods ( 1 974-2003). Generally, starting materials and reagents may be obtained from commercial sources or may be prepared from literature sources.
General Scheme 1
[00139J Compound of general formula AA can be synthesized according to Scheme 1 .
Scheme 1 : General Synthesis of Compounds of formula AA
Figure imgf000171_0001
[00140] Compoundss of formula AA. wherein R| | . R|2, and R 13 are non-reactive substituents such as hydrogen, alkyl, or alkoxy. can be produced by the coupling of a compound of formula a with a compound of formula b. Typical coupling conditions used to complete this transformation include a catalyst, such as a palladium catalyst, i.e. Pd(dppf)Cl2 or Pd(Ph3)4, in a solvent such as DME. in the presence of a base, such as Na2C03- In some instances, the coupling is performed at elevated an temperature, such as 90 °C. The intermediate compound of formula c can then be reacted with an amine of formula d under substitution conditions to form the compound of formula AA. The substitution can be accomplished by reacting c and d in the presence of a base, such as DIEA or NaHC03, and a solvent, such as DMA or N- Methyl-pyrollidinone, under elevated temperature. Alternatively, the substitution may be performed first, as shown in Scheme 1 , to produce a compound of formula e, followed by coupling to produce a compound of formula AA.
[00141 ] Example 1 : Synthesis of 3-] l-( {6-|2-chloro-3-(methyloxy)phenyl]-2- mcthylpynmidin-4-yl}amino)ethyl] bcnzcncsulfonaniide (Compound 49)
Figure imgf000172_0001
Step 1
[00142] A pressure vessel was charged witli 4,6-dichloro-2-methyl-pyrimidine (1 .0g, 6.0 mmol. 1 .0 eq.), 2-(2-chloro-3-methoxyphenyl)-4.4.5,5-tetramethyl-[l ,3,2]dioxaborolane ( 1.6 g, 6.0 mmol, 1 .0 eq.), 1 ,2 DME ( 15 mL), and I Na2COj (2.0 mL). The reaction was purged with nitrogen before adding Pd(dppf)2Cl2CH2Cl2 (400 mg, 0.49 mmol, 0.08 eq.), then sealed and heated to 90 °C for 15 hours. The reaction was then cooled to it and partitioned between water and EtOAc. The organic layer was dried with Na2S04 and concentrated under vacuum to give the crude product as a brown oil. The product was purified by Si02 flash
chromatography (80:20 hexanes/ethyl acetate) to afford 4-chloro-6-(2-chloro-3- methoxyphenyl)-2-methylpyrimidine as a white solid (878 mg, 55% yield). Ή NMR (400
MHz, dfi-DMSO): 7.78 (s, 1 H), 7.46 (t, 1 H), 7.33 (d, 1H), 7.19 (d, 1 H), 3.88 (s, 3 H), 2.64 (s, 3H); MS (EI) for C |2H ioCl2N20: 433.1 (MI-f).
Step 2
[00143] A pressure vessel was charged with 4-chloro-6-(2-chloro-3-methoxyphenyl)-2- methylpyrimidine (50.0 mg, 0.19 mmol, 1 .0 eq.), DMA (2.0 mL),
3-aminoethyl)benzenesulfonamide (74.0 mg. 0.373 mmol, 2.0 eq.), and DIEA (0.040 mL, 0.23 mmol, 1.2 eq.). The reaction vessel was sealed and heated to 120 °C for 15 hours: The reaction was then cooled to rt and partitioned between water and EtOAc. The organic layer was dried with Na2S0 and concentrated under vacuum to give the crude sulfonamide product as a brown oil. Purification by preparative HPLC (reverse-phase, acetonitrile/water with 25 niM ammonium acetate), followed by concentration at reduced pressure and lyophilization, afforded 3-[ l -({6-[2-chloro-3-(methyloxy)phenyl]-2-methylpyrimidin-4- yl}amino)ethyl]benzenesulfonamide (Compound 49, 27 mg, 34%) as a white solid. Ή NMR
(400 MHz, df,-DMSO): 8.10 (br s, 1 H), 7.78 (s, Hi), 7.75 (d, 1 H), 7.61 (d, 1 H), 7.55 (t, 1 H), 7.40 (m, 1 H), 7.20 (m, 1 H), 7.02 (m, 1 H), 6.56 (m, 1 H), 5.36 (br s, 0.5H), 2.38 (br s, 3H), 1.90 (s, 2H), 1.23 (d, 3H); MS (El) for C18H16C1N303S: 433.1 (MH+).
|00144] The following compounds were prepared by a manner analogous to Example 1 :
[00145] Compound 1 N-(2,3-dihydro-lH-inden-l-yl)-6-(3-fluorophcnyl)-2- methylpyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.72 (br m, 3H), 7.32 (m, IH), 7.18 (m, 4H), 6.80 (s, IH), 5.71 (s, IH), 2.94 (m, 2H), 2.81 (m, 2H), 2.46 (s, 3H); MS (EI) for C20H18FN3: 320.2 (MH*).
100146] Compound 26-(Bcnzo[rf|thiazol-5-yl)-2-methyl-N-(2-methyIburj'I)pyrimidin-4- amine. Ή NMR (400 Hz. CDClj): 9.06 (s, IH), 8.70 (s, IH), 8.15 (d, IH), 8.05 (d, IH), 6.64 (s, 1I ), 3.25 (m, IH), 3.12 (m, IH), 2.57 (s, 3H), 2.11 (s, 2H), 1.74 (dt, 11-1), 1.53 (m, IH), 1.26 (m, IH), 1.01 (d, 3H), 0.96 (t, 3H); MS (El) for C7H20N4S: 313 (MH+).
[001471 Compound 3 (5 -6-(Benzo[i/|thiazol-5-yI)-N-(l-cyclohexylcthyl)-2- methylpyrimidin-4-amine. Ή NMR (400 MHz, CDC ): 9.07 (s, IH), 8.68 (s, IH), 8.16 (d, IH), 8.05 (d, IH), 6.62 (s, IH), 3.59 (br, IH), 2.56 (s, 3H), 2.11 (s, 2Ή), 1.76-1.79 (m, 4H), 1.48 (m, IH), 1.24 (m, 6H), 1.09 (m, 3H); MS (EI) for C-20H24N4S: 353 (MH*).
[00148] Compound 42-mcthyl-6-[3-(mcthyloxy)phenyl]-N-[(lR)-l,2,3,4- tctrahydronaphthaIen-l-yI]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.68 (m, 1 H), 7.50 (br s, 2H), 7.39 (t, 1 H), 7.15 (m, 4H), 7.05 (d, 1 H), 6.78 (br s, 1 H), 5.41 (br , 1 H), 3.81 (s, 3H), 2.79 (m, 2H), 2.45 (s, 3H), 1.88-2.02 (m, 3H), 1.68 (m, 2H); MS (EI) for C22H23N3O: 346.2 (MH+).
[00149] Compound 52-methyl-6-[3-(methyloxy)phenyI]-N-{(lR)-l-[3- (methyIoxy)phenyl|cthyl}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.78 (br s, IH), 7.52 (m, 2H), 7.36 (t, IH), 7.22 (t, IH), 7.00 (m, 3H), 6.78 (br d, IH), 5.31 (br , IH), 3.78 (s, 3H), 3.70 (s, 3H), 2.36 (s, 3H), 1.42 (d, 3H); MS (EI) for C21H23 3O2: 350.2 (MH*).
[001501 Compound 62-methyl-6-[3-(methyloxy)phcnyl]-N-{(lS)-l-[3- (methyloxy)phenyl]cthyl}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO):7.78 (br s, IH), 7.52 (m: 2H), 7.36 (t, IH), 7.22 (t, IH), 7.00 (m, 3H), 6.78 (brd, IH), 5.31 (br , IH), 3.78 (s, 3H), 3.70 (s, 3H), 2.36 (s, 3H), 1.42 (d, 3H); MS (EI) for C21H23N3O2: 350.2 (MH*).
[00151] Compound 72-methyl-6-[3-(methyloxy)phenyi]-N-{(lS)-l-[4- (methyloxy)phenyI)cthyl}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.70 (br m, IH), 7.49 (m, 2H), 7.39 (m, 3H), 7.01 (dd, IH), 6.88 (d, 2H), 5.21 (br s, 0.6 H), 3.80 (s, 3H), 3.72 (s, 3H), 2.38 (s, 3H); MS (EI) for C21H23N3O2: 350.2 (MH*).
[00152] Compound 8 (/?)-6-(Bcnzo[rf]thiazol-5-yl)-2-methyl-N-(l,2,3,4- tetrahydronaphthaIcn-l-yl)pyrimidin-4-aminc. Ή NMR (400 MHz, CDC13): 9.06 (s, IH), 8.52 (d, I H), 8.41 (d, I H), 7.73 (d; 1 H), 7.54 (m, 3H), 6.70 (br s, I H), 5.27 (br, I H), 3.21 (m, 2H), 2.99 (s, 3H), 2.86 (m, 1 H), 1 .88-2.02 (m, 3H), 1 .68 (br s, 1 H); MS (EI) for C22H20 4S : 353 (ΜΙ-Γ).
[00153] Compound 66 2-methyl-6-[3-(mcthyloxy)phcnyl]-N-{(l S)-l-[3- (trifluoromethyl)phenyljcthyl}pyi-imidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.90 (br s, I H), 7.79 (br m, 2H), 7.61 (m, 2H), 7.49 (m, 2H), 7.38 (t, 114), 7.00 (dd, 1 H), 6.78 (br s, I H), 5.38 (br, I H), 3.78 (s, 3H), 2.35, s 3H), 1.42 (d, 31 1): MS (EI) for C-21 H20F3N3O: 387.9 (MH").
[00154] Compound 69 2-methyI-N-{(l S)-l-[3-(niethyloxy)p enyl]ethyl}-6-[3,4,5- tris(methyloxy)phenyl|pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.80 (d, I H), 7.23 (t, I H), 7.20 (br s, 2H), 7.00 (br s, 2H), 6.80 (dd, 1 M), 5.30 (br, 1 H), 3.83 (s, 6H), 3.74 (s, 3H), 3.70 (s, 3H), 2.39 (s 314), 1.42 (d, 3H); MS (EI) for C-23H27N3O4: 410.2 (MH*).
[00155] Compound 43 6-(3-fluorophenyl)-2-methyl-N-{(lS)-l-[3- (methyIoxy)phenyl]erhyI}pyrimidin-4-amine. Ή NMR (400 MHz, dfi-DMSO): 7.80 (m, 2H), 7.58 (q, I H), 7.35 (dt, I H), 7.28 (t, I H), 7.00 (br s, 2H), 6.80 (d, 2 H), 5.25 (br, I H),
3.73 (s, 3H), 2.38 (s 3H), 1.44 (d, 3H); MS (EI) for C20H20FN3O: 338.2 (MH+).
100156] Compound 34 6-[2-chloro-3-(mcthyloxy)phenyl]-2-methyl-N-{(lS)-l-[3- (mcthyloxy)phcnyl|ethyl}pyrimidin-4-amine. Ή NMR (400 MHz, dfl-DMSO): 7.90 (br m, I H), 7.39 (t, I H), 7.22 (t, I H), 7.20 (d, I H), 7.05 (br s, I H), 6.95 (s, 2H), 6.80 (d, 2 H), 6.58 (br s, I H), 5.25 (br, I H), 3.88 (s, 3H), 3.73 (s, 3H), 2.35 (s 3H), 1.44 (d, 3H); MS (EI) for C21 H22CIN3O2: 384.2 (Μ1- ).
[00157] Compound 50 6-[2-fluoro-3-(methyloxy)phenyI|-2-mcthyl-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.93 (br s, I H), 7.40 (br s, I H), 7.23 (m, 4H), 6.95 (m, 2H), 6.79 (d, 2H), 5.28 (br s, I H), 3.86 (s, 3H),
3.74 (s, 3H), 2.36 (s 3H), 1.43 (d, 3H); MS (EI) for C21 H22FN3O2: 368.2 (MH+).
[00158] Compound 67 2-methyl-N-{(l S)-l -[3-(mcthyloxy)phcnyl]cthyI}-6-{3- [(trifluoromethyl)oxy]phcnyl}pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.98 (m, 3H), 7.60 (t, I H), 7.50 (d, I H), 7.23 ( I H), 7.00 (br s, 2H), 6.80 (br m, 2H), 5.41 (br s, I H), 3.73 (s, 314), 2.39 (s 3H), 1 .44 (d, 3H); MS (EI) for C21 H20F3N3O2: 404.2 (MH+).
[00159] Compound 51 6-[2-chloro-3-(mcthyloxy)phenyl]-N-(2,3-dihydro-l H-indcn-l- yl)-2-methylpyrimidin-4-aminc. Ή NMR (400 MHz, d<j-DMSO): 7.80 (br s, I H), 7.40 (m, I H), 7.28-7.18 (m, 514), 6.49 (br s, I H), 5.70 (br s, I H), 3.89 (s, 314), 3.03-2.80 (m, 214), 2.41 (s, 314), 1.90 (m, 114); MS (EI) for C21 H20CIN3O: 366.2 (MH*). |00160| Compound 35 6-(l ,3-bcnzodio.\oI-5-y!)-2-methyI-N-{(lS)-l -[3- (mcthylo.\y)phcnyl]ethyl}pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.71 (br s, 1 H), 7.53 (m, 2H), 7.23 (t, 1 H), 7.00 (d, 3H), 6.76 (d, 1 H), 6.68 (br s, 1 H), 6.08 (s, 2H), 5.22 (br, I H), 3.73 (s, 3H), 2.35 (s, 3H), 1 .89 (s, I H), 1.46 (d, 3H); MS (EI) for C21 H21N3O3 : 459.3 ( H+).
100161 ] Compound 38 6-(l H-indol-5-yl)-2-nicthyl-N-{(lS)-l-[3- (mcthyloxy)phcnyl]ethyl}pynmidin-4-amine. Ή NMR (400 MHz, d -DMSO): 8.20 (s, I H), 7.52 (d, I H), 7.51 (mf I H), 7.45 (m, 2H), 7.25 (t, I H), 7.00 (br s, 2H), 6.25(d, I H), 6.50 (s, I H), 3.74 (s, 3H), 2.37 (s, 3 H), 1.89 (s, I H), 1 .44 (d, 3H); MS (EI) for C22H21N4O: 359.2 (ΜΙ-Γ).
[00162] Compound 126 Ethyl 3-({2-methyl-6-[3-(methyloxy)phcnyI|pyrimidin-4- yI}amino)-3-[3 (mcthyloxy)phenyl|propanoatc. Ή NMR (400 MHz, d6-DMSO): 7.42 (m, 2H), 7.26 (m, 2H), 6.95 (m, 3H), 6.80 (dd, I H), 6.45 (s, I H), 5.83 (br s, 1 H), 4.1 1 (q, 2H),
3.85 (s, 3H), 3.70 (s, 3H), 2.90 (m, 2H), 2.56 (s, 3H), 1 .19 (t, 31 ); MS (EI) for C24H27N3O4: 422.2 (MH÷).
[00163] Compound 21 2-mcthyl-6-(l-methyl-l H-indoI-6-yl)-N-[(l R)-l,2,3,4- tctrahydronaphthaIen-l -yl]pyrimidin-4-aminc. Ή NMR (400 MHz, d5-DMSO): 8.04 (s, 1 H), 7.71 (d, I H), 7.54 (m, 2H), 7.20 (m, 4H), 6.95 (s, I H), 6.51 (s, 1 H), 5.50 (br s, I H), 3.88 (s, 3H), 2.80 (m, 2H), 2.63 (s, 3H), 2.05- 1.75 (m, 4H); MS (EI) for C2 H2 4: 369.3 (MH+).
[00164] Compound 22 N-[(4R)-3,4-dihydro-2H-chromen-4-yI]-2-mcthyl-6-(l-mcthyN l H-indol-6-yl)pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.04 (s, 1 H), 7.61 (m, 3H), 7.43 (s, I H), 7.1 7 (m, 2H), 6.89 (m, 2H), 6.46 (s, 1 H), 5.40 (br s, 1 H), 4.26 (br s, 2H),
3.86 (s, 3H), 2.10 (m, I H), 2.05 (m, I H), 1.90 (s, IH-acetate peak); MS (EI) for C-23H22N4 O: 371.2 (ΜΙ- ).
[00165] Compound 25 3-(l-{[2-methyI-6-(l -mcthyl-l H-indol-6-yl)pyrimidin-4- yl]amino}cthyl)bcnzencsulfonamidc. Ή NMR (400 MHz, d6-DMSO): 8.04 (s, 1 H), 7.90 (s, I H), 7.78 (m, 2H), 7.71 (m, 2H), 7.42 (m, 2H), 7.00 (s, 1 H), 6.80 (s, I H), 5.45 (br s, I H), 3.95 (s, 3H), 2.61 (s, 3H), 1.60 (d, 3H); MS (EI) for C22H23NSO2S: 422.2 (ΜΙ- ).
[00166] Compound 30 6-(l,3-bcnzodioxol-5-yl)-2-mcthyI-N-[(l R)-l , 2,3,4- tetrahydronaphthalcn-l -y!]pyrimidin-4-aminc. Ή NMR (400 MHz. d6-DMSO): 7.65- 7.40 (m, 3 H); 7.19 (m, 4H), 7.00 (m, 1 H), 7.71 (m, 2H), 6.70 (br s, I H), 6.14 (m, 2 H), 5.41 (br s, 1 H), 3.95 (s, 3H), 2.80 (m, 2H), 2.40 (s, 3H), 1.98 (m, 3H), 1 .80 (br s, 2H); MS (EI) for C22H21N3O2: 360.2 (ΜΙ- ). [00167J Compound 312-mct yi-6-(l-nicthy]-lH-indol-6-yl)-N-{(lS)-l-|3- (mcthyloxy)phenyI]cthyl}pyrimidin-4-aminc. Ή NJ R (400 MHz, d6-DMSO): 8.04 (s, 1 H), 7.65 (br s, IH), 7.60 (q, 2H), 7.41 (s, IH), 7.22 (t, IH), 7.00 (br s, 2 H); 6.80 (br d, 2H), 6.42 (d, 1 H), 5.30 (br s, 1 H), 3.85 (s, 3H), 3.73 (s, 3H), 2.40 (s, 3H), 1.90 (s, 1 H-acetate peak), 1.45 (d, 3H); MS (EI) for C23H2l|R,0: 373.2 (Ml-f).
[00168] Compound 322-methyl-6-(l-methyI-lH-indol-6-yl)-N-[(lS)-l- phenylethyI]pyrirnidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 13.79 (br s, IH), 9.80 (br s, IH), 8.04 (s, 1 H), 7.80 (m, IH), 7.60 (s, IH), 7.45 (m, 5H), 7.30 (t, IH), 7.00 (m, 1 H), 6.60 (s, IH), 5.50 (q, 1 II ), 3.98 (s, 3H), 2.65 (s, 3H), 2.58 (s, 3H), 1.45 (d, 3H); MS (EI) for
Figure imgf000176_0001
[00169] Compound 336-(lH-indol-6-yl)-2-mcthyl-N-[(lR)-l, 2,3,4- tctrahydronaphthalen-l-yl]pynmidin-4-amiiic. Ή NMR (400 MHz, d6-DMSO): 11.45 (s, IH), 7.98 (s, 1 H), 7.80 (d; IH), 7.60 (s, IH), 7.43 (d, IH), 7.21 (m,4H), 6.82 (s, 1 H), 6.60 (s, IH), 5.50 (t, IH), 2.85 (m, 2H), 2.20-1.80 (m, 4H): MS (EI) for C23H22 4: 355.2 (MPf).
[00170] Compound 376-(lH-indo]-5-yl)-2-mcthy!-N-|(lR)-l,2,3,4- tctrahydronaphthaIen-l-yl]pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 11.20 (s, IH), 8.25 (br s, 1 H), 7.75 (br s, IH), 7.50 (m, 3H), 7.22 (m, 4H), 6.80 (br s, IH), 6.52 (s, 1 H), 5.49 (br s, IH), 2.80 (m, 2H), 2.48 (s, 3H), 2.05-1.90 (m, 4H); MS (EI) for C23H22N4: 355.2 (Mf-f).
[00171] Compound 40 N-[(lS)-l-(4-fluorophcnyl)cthyl]-2-mcthyl-6-(l-methyl-lH-indol- 6-yl)pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 9.58 (brs, IH), 8.01 (s, 1 H), 7.75 (brd, IH), 7.60 (d, IH), 7.50 (m, 311), 7.25 (t, 2H), 6.89 (brs, IH), 6.52 (s, 1 H), 5.49 (brm, IH), 3.89 (s, 3H), 2.53 (s, 3 H), 1.52 (d, 3H); MS (EI) for C22H2i FN4: 361.2 (MH+).
[00172] Compound 412-methyl-6-(l-methy -lH-indol-6-yl)-N-[(lS)-l-(4- mcthylphcnyl)cthyl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.13 (m, IH), 7.74 (m, 1 H), 7.58 (s, IH), 7.42 (d, IH), 7.32 (m, 2H), 7.15 (d, 2H), 7.02 (s, IH), 6.54 (s, 1 H), 5.42 (q, IH), 3.89 (s, 3H), 2.62 (s, 3H), 2.26 (m, 3H), 1.51 (d, 3H); MS (EI) for
C.2 l½N : 357.0 (MH+).
[00173] Compound 446-[2-cliloro-3-(methyloxy)phenyl]-2-methyl-N-[(l R)-l,2,3,4- tetrahydronaphthalen-l-yl]pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.80 (d, IH), 7.39 (t, 1 H), 7.20 (m, 4H), 7.19 (d, 1 H), 6.44 (s, 1 H), 5.42 (br s, 1 H), 3.90 (s, 3H), 2.80(m, 2 H), 2.41 (s, 3M), 2.10-1.75 (m, 4H); MS (EI) for C22H22N3CIO: 380.2 (ΜΙ-Γ).
[00174] Compound 53 N-[l-(3-bromophcnyl)cthyl)-6-[2-cliloro-3-(methyloxy)phenyl]- 2-methylpyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.98 (s, IH), 7.80 (s, 1 H), 7.38 (m, 4H), 7.20 (d, 1 H), 7.03 (m, 1 H), 6.52 (br s, 1 H), 5.25 (br s, 1 H), 3.92 (s: 3 H), 2.39 (s, 3H), 1.42 (d, 3H); MS (El) for C20H ,yN3ClBrO: 431.8:433.8 (Bromine isotope).
[00175] Compound 55 6-|2-fIuoro-3-(mcthyloxy)phenyl]-2-mcthyl-N-|(l R)-l ,2,3,4- tetrahydronaphthaIen-l-yl|pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.82 (d, IH), 7.45 (br t, 1 H), 7.20 (m, 6H), 6.78 (s, 1 H), 5.41 (br s, 1 H), 3.89 (s, 3H), 2.80(m. 2 H), 2.41 (s, 3H), 2.05- 1 .75 (m, 4H); MS (EI) for C22H22N3FO: 364.0 (MH÷).
[00176] Compound 58 N-|(l S)-l-(4-chIorophcnyl)cthyl]-2-methyl-6-(l-methyI-lH- indoI-6-yl)pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 8.1 1 (s, I H), 7.83 (d, I H), 7.63 (d, 1 H), 7.60 (m, 5H), 7.00 (br s, I H), 6.62 (d, I H), 5.50 (br m, 1 H), 3.99 (s, 3H), 3.22 (s, 2H), 2.50 (s, 3H), 1 .60 (d, 3H); MS (El) for C22H21N4CI: 377.2 (MH+).
|00177] Compound 59 3-| l -({2-mcthyl-6-[3-(mcthyIoxy)phenyl]pyrimidin-4- yl}amino)ethyl]benzcnesuIfonamide. Ή NMR (400 MHz, d6-DMSO): 7.92 (br s, I H), 7.70 (m, 2H), 7.42 (m, 6H), 7.15 (br s, I H), 6.80 (br s, I H), 5.41 (br s, I H), 3.83 (m, 3H), 2.96 (t, 2H), 2.81 (t, 2H), 2.43 (br s, 3H), 1 .99 (m, 2H), 1 .50 (m, 3H); MS (El) for C20H22N4O3S: 399.0 (MH÷).
[00178] Compound 61 6-[2-chIoro-5-(nicthyloxy)phcnyll-2-mcthyl-N-[(lR)-l,2,3,4- tctrahydronaphthaIcn-l -yI]pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.60 (d. I H), 7.30 (m, 7H), 6.70 (s, I H), 5.50 (q, I H), 3.80 (s, 3H), 2.82 (m, 2H), 2.05-1 .75 (m, 4H); MS (EI) for C22H22N3OCI : 380.2 (Μ1-Γ).
[00179] Compound 63 2-mcthyI-6-(l-mcthyI-l H-indol-5-yl)-N-{(lS)-l-[3- (methyloxy)phcnyI]cthyl}pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.20 (s, I H), 7.80 (d, I H), 7.62 (br s, I H), 7.45 (d, I H), 7.39 (d, I H), 7.24 (t, I H), 7.00 (br s, 2H), 6.80 (d, 2H), 6.51 (d, I H), 5.30 (br s, 1 H), 3.82 (s, 3H), 3.78 (s, 3H), 2.40 (s, 3H), 1 .43 (d, 3H); MS (El) for C23H24N4O: 373.2 (MH+).
[00180] Compound 64 3-[ l-({2-mcthyl-6-[3-(mcthyloxy)phcnyl)pyrimidin-4- ) }amino)ethyl]phcnol. 3-[l -({2-methyl-6-[3-(met yloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenol was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. 1 H NMR (400 MHz, d6- DMSO+D20): 7.40 (m, 3 H), 2.1 8 (t, I H), 7.05 (d, I H), 6.80 (m, 3H), 6.62 (dd, I H), 5.21 (br s, 1 H), 3.80 (s, 3 H), 2.40 (s, 3H), 1.90 (s, acetate peak), 1 .42 (d, 3H); MS (EI) for
C20H21 N3O2: 336.2 (MH+).
[00181] Compound 68 2-mcthyl-6-{3-[(methyloxy)mcthyl]phcnyl}-N-[(lR)-l,2,3,4- tctrahydronaphthaIen-l-yl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.90 (br s, 2H), 7.72 (m, I H), 7.42 (t, I H), 7.40 (d, I H), 7.20 (m, 4H), 6.80 (br s, I H), 5.41 (br s, I H), 4.84 (s, 2H), 3.18 (s, 3H), 2.80 (m, 2H), 2.45 (s, 3H), 2.10- 1 .75 (m, 4H); MS (El) for C23H25N3O: 360.2 (iVlI-f).
100182] Compound 71 6-[2-chloro-5-(methyloxy)phcnyI|-2-mcthyl-N-{(lS)-l-[3- (methyloxy)phcnyl]ethyI}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.51 (m, I H), 7.25 (m, 3H), 7.00 (m, 2H), 6.88 (m, 2H), 5.42 (br s, I H), 3.80 (s, 3 H), 3.75 (s, 3H), 1 .50 (d, 3H); MS (EI) for C21 H22N3O2CI: 384.2 (MH+).
[00183] Compound 72 2-methyl-6-|3-(methyloxy)phenyl]-lN-(5,6,7,8- tetrahydronaphthaIen-l-yl)pyrimidin-4-aininc. Ή NMR (400 MHz, d6-DMSO): 8.76 (s, 1 H): 7.46 (m, 3 H), 7.30 (d, 1 H), 7.18 (t, 1 H): 7.05 (d, I H), 6.99 (d, I H), 6.80 (s, I H), 3.78 (s, 3H), 2.73 (br s, 2H), 2.59 (br s, 2H), 2.41 (s, 3H), 1 .69 (br s, 4H); MS (EI) for C22H23N3O: 346.2 (ΜΗ ' ).
[00184] Compound 73 6-(l H-indol-6-yl)-2-mcthyI-N-{(lS)-l -[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 1 1 .15 (s, I H), 8.09 (s, I H), 7.84 (br s, I H), 7.60 (s, 2H), 7.43 (m, I H), 7.25 (t, I H), 7.00 (br s, 2H), 6.80 (d, 2H), 6.45 (s, I H), 5.13 (br s, I H), 3.78 (s, 3H), 2.40 (s, 3H), 1 .90 (s, 3H-acetate peak), 1 .43 (d, 3H); MS (EI) lor C22H22N4O: 359.0 (MH+).
[00185] Compound 74 2-methyl-6-[3-(methyloxy)phenyI|-N-naphthalen-l-yIpyrimidin- 4-amine. Ή NMR (400 MHz, d6-DMSO):8.05 (m, 3H), 7.71 (d, I H), 7.62 (m, 3H), 7.43 (m 3H), 7.21 (br d, I H), 3.85 (s, 3H), 2.62 (br s, 3H); MS (EI) for C22H 19N3O: 342.2 (MH1).
[00186] Compound 75 2-methyl-6-|3-(methyloxy)phenyl[-N-[(lS)-l,2,3,4- tetrahydronapht alen-l -yl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO):7.62 (m, I H), 7.50 (br s, 2H), 7.38 (t, I H), 7.18 (m, 4H), 7.00 (d, I H), 6.78 (br s, 1 H), 5.40 (br s, I H), 3.80 (s; 3H), 2.78 (m 2H), 2.48 (s, 3H), 2.10- 1.75 (m, 4H); MS (EI) for C22H23N3O: 346.2 (MH.+).
[00187] Compound 76 2-mcthyl-N-[(l R)-l,2,3,4-tctrahydronaphthaIcn-l -yl]-6-{3- [(trifluoromethyl)oxy]pheny }pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO):7.98 (m, 2H), 7.80 (m, I H), 7.63 (t, I H), 7.50 (dd, I H), 7.20 (m, 4H), 6.82 (s, I H), 5.42 (br s, I H), 2.80 (m, 2H), 2.47 (s, 3H), 2.10-1.75 (m, 4H); MS (El) for C22H20F3N3O: 400.2 (MH+).
[001881 Compound 82 6-(l ,3-bcnzothiazol-6-yl)-2-mcthyl-iN-(6-nitro-3,4-dihydro-2H- chromcn-4-yl)pyrimidin-4-aminc. 6-( l ,3-benzolhiazol-6-yl)-2-methyl-N-(6-nitro-3.4- dihydro-2H-chromen-4-yl)pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, d3-MeCN): 9.14 (s, I H), 9.05 (d, I H), 8.80 (d, I H), 8.72 (d, I H), 8.24 (m, 3H), 8.06 (m, I H), 7.65 (s, I H), 6.95 (d, I H), 6.71 (s, I H), 5.42 (br s, I H), 4.45 (m, 2H). [00189] Compound 81 2-methyl-6-[3-(methyloxy)phcnyI]-N-{l-|3- (nicthyIoxy)phenyl|propyI}pyrimidin-4-aminc. 2-methyl-6-[3-(methyloxy)phenyl]-N-{ 1 - [3-(methyloxy)phenyl]propyl }pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz; d3-MeCN): 7.45 (br t, 2H); 7.34 (br s, 2H), 7.29 (t, 1 H), 7.13 (dd, 1 H), 7.0 (s, 2H), 6.85 (dd , 1 H), 3.84 (s, 3 H), 3.78 (s, 3H), 2.56 (s, 3H): 1 .9 (m, 1 H); MS (EI) for C22 H25 N3 02: 364.14 (ΜΙ-Γ').
[00190] Compound 83 N-(4-{|6-(l ,3-bcnzothiazoI-6-yl)-2-methylpyrimidin-4-yl]amino}- 3,4-dihydi o-2H-chromen-6-yI)acetamidc. N-(4-{ [6-(l ,3-benzothiazol-6-yl)-2- methylpyrimidin-4-yl]aniino) -3.4-dihydro-2H-chromen-6-yl)acetamide was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, d3-MeCN) 9.18 (s, 1 H), 8.78 (s, 1 HO, 8.20 (br s, 1 H), 8.18 (d, 1 H), 7.44 (d: 1 H), 7.33 (dd, 1 H), 6.84 (br s, 1 H), 6.76 (d, 1 H), 6.19 (d, 1 H), 4.25 (m, 3H), 2.51 (s, 3H), 2.38 (m, 2H), 2.12 (m, 2H), 1 .92 (s, 3H); MS (El) for C23 H2i N5 02 S: 432.14 (Ml- ).
[00191 ] Compound 87 6-(l ,3-benzothiazol-6-yl)-2-mcthyl-N-[(lR)-l,2,3,4- tetrahydronaphthalen-l -yl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 9.47 (s, 11-1), 8.79 (br s, 1 H), 8.16 (m, 1 H), 8.08 (m, 1 H), 7.77 (m, l H), 7.24-6.87 (m, 4H), 6.87 (br s; I H), 5.42 (br s, 1 H), 2.81 (m, 2H), 2.47 (s, 3H), 1.98 (m, 2H), 1 .89 (s, 1 H), 1.80 (m, 2H). MS (EI) for C22H20N4S: 373.2 (ΜΙ-Γ).
[00192] Compound 99 6-(l ,3-bcnzothiazol-6-yl)-2-mcthyI-N-(2-mcthylbutyl)pyrimidin- 4-amine. Ή NMR (400 MHz, d6-DMSO): 9.60 (s, 1 H), 8.70 (s, 1 H), 8.32 (m, 1 H), 7.93 (d, 1 H), 6.96 (s, 1 H), 3.47 (d, 2H, overlapped), 2.60 (s, 3H), 1 .70 (m, I H), 1 .43 (m, 1 H), 1.18 (m, 1H), 0.891 (d, 3H, overlapped), 0.891 (t, 3H, overlapped); MS (EI) for C17H20N4S: 313.2 (MH+).
[00193] Compound 105 6-(2-nuoroplienyl)-2-nicthyl-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.70 (m, 211), 7.47 (m, 2H), 7.28 (t, 1 H), 7.00 (m, 2H), 6.94 (s, 1 H), 6.84 (m, 1 H), 5.41 (m, I H), 3.76 (s, 3H), 2.56 (s, 3H), 1.53 (d, 3H); MS (El) for C20H20FN3O: 338.2 (Ml-f).
[00194] Compound 106 6-(l H-iiidol-4-yl)-2-methyl-N-](l R)-l , 2,3,4- tctrahydronaphthalen-l -yl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 1 1.3 (s, I H), 7.64 (m, I H), 7.57 (d, I H), 7.48 (d, I H), 7.44 (s, I H), 7.26 (d, I H), 7.19-7.10 (m, 4H), 6.9 (br s, I H), 5.40 (br s, I H), 2.75 (m, 2H), 2.47 (s, 3H), 1.96 (m, 2H), 1.80 (m, 2H); MS (El) for C23H22N4: 355.2 (ΜΙ- ). [00195] Compound 1116-(lH-indazol-5-yl)-2-mcthyl-N-[(lR)-l, 2,3,4- tetrahydronaphtha!en-l-yl]pyriniidin-4-aniine. 6-(l H-indazol-5-yl)-2-methyl-N-[(lR)- l,2,3,4-tetrahydronaphthalen-l-yl]pyrimidin-4-amine was synthesized in a manner analogous to Example 1 and and the boronic ester was synthesized from the corresponding bromide in a manner analogous to Example 7a. Ή NMR (400 MHz, d6-DMSO): 13.2 (s, 1 H), 8.42 (br s, lH),8.19(s, 1H),7.95 (br s 1 H), 7.61 (fn, 2H); 7.24-7.10 (m, 3H), 6.81 (br s, 1H), 5.41 (brs, 1H), 2.78 (m, 2H), 2.46 (s, 3H), 1.97 (m, 2H), 1.90 (s, 3H)S 1.80 (m, 2H); MS (El) for C22H21N5: 356.2 (MH+).
[00196] Compound 1156-(lH-indol-7-yI)-2-nicthyl-N-[(lR)-l,2,3,4- tetrahydronaphthalen-l-yl]pyrimidin-4-aniinc. Ή NMR (400 MHz, df)-DMSO): 11.5 (s, 1 H), 7.67 (m, 2H), 7.55 (br s, 1 H), 7.45 (t, 1 H), 7.26-7.10 (m: 4H), 6.92 (br s, 1 H), 6.51 (m, 1H), 5.40 (br s, 1H), 2.79 (m, 2H), 2.58 (s, 3H), 1.98 (m, 2H), 1.89 (s, 3H), 1.82 (m, 2H); MS (El) for C23H22N4: 355.3 (MH+).
[00197] Compound 1196-(lH-indoI-4-yl)-2-mcthyl-N-{(lS)-l-[3- (methyloxy)phenyl]ethyI}pyrimidin-4-amine. Ή NMR (400 MHz, d(l-DMSO): 11.28 (s, 1H), 7.75 (m, 1H), 7.52-7.38 (m, 3H), 7.26 (t, 1H), 7.16 (m, 1H), 6.99 (m, 2H), 6.81 (dd, 1H), 3.74 (s, 3H), 2.40 (s, 3H), 1.46 (d, 3H); MS (EI) for C22H22N4O: 359.2 (MH÷).
[00198] Compound 1206-(lH-indol-7-yl)-2-methyl-N-{(lS)-l-[3- (methyloxy)phcnyl]ethyl}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.81 (m, 1H), 7.51 (s, 1H), 7.33-7.20 (m, 3H), 7.01 (m, 2H), 6.86 (m, 2H)t 6.63 (br s, 1H), 5.40 (br s, 1 H), 3.76 (s, 3H), 2.56 (s, 3H), 1.53 (s, 3H); MS (EI) for C22H22N4O: 359.2 (MH+).
[001991 Compound 1216-(2-chIorophcnyl)-2-methyl-N-{(lS)-l-[3- (mcthyloxy)phenyl]cthyl}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.64 (m, 4H), 7.26 (m, 1H), 7.03 (m, 2H), 6.83 (d, 1H): 6.74 (br s, 1H), 5.40 (br s, 1H), 3.75 (s, 3H), 2.48 (s, 3H): 1.48 (d, 3H); MS (EI) for C20H20CIN3O: 354.2 (MH+).
[00200] Compound 1286-(lH-indazol-5-yl)-2-mcthyl-N-{(JS)-l-|3- (mcthyIoxy)phenyl]cthyl}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 13.2 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H),'7.94 (d, 1H),7:73 (m, 1H),7.60 (d, 1H), 7.26-7.22 (m, 1H), 7.01 (m, lH), 6.86 (m, 1H), 6.75 (m, 1H), 5.40 (br s, 1H), 3.73 (s, 3H), 2.39 (s, 3H), 1.45 (d, 3H); MS (EI) for C2|H2|N50: 360.2 (ΜΙ- ).
[00201] Compound 1316-(l,3-bcnzothiazol-6-yl)-2-methyl-N-{(lS)-l-[3- (methyioxy)phenyIJcthyl}pyrimidin-4-amine. 6-(l,3-benzothiazol-6-yl)-2-methyl-N- {(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 1 and and the boronic ester was synthesized from the corresponding bromide in a manner analogous to Example 7a. Ή N R (400 MHz, d6-DMSO): 9.47 (s, lH),8.79(s, 1H), 8.16-8.11 (m, 2H), 7.86 (br s, 1 H), 7.24 (t, 1H), 7.01 (br s, 1H), 6.87 (brs, 1H), 6.78 (m, 1H), 5.40 (br s, 1H), 3.74 (s, 3H), 2.41 (s, 3H), 2.07 (s, 1H), 1.46 (d, 3H); MS (EI) for C21H20N4OS: 377.1(MH+).
[00202J Compound 1666-(l,3-bcnzothiazol-6-yl)-N-[(4R)-3,4-dihydro-2H-chromcn-4- yIj-2-mcthylpyrimidin-4-aminc. 6-(l,3-benzothiazol-6-yl)-N-[(4R)-3,4-dihydro-2H- chromen-4-yl]-2-methylpyrimidin-4-amine made according to Example 1 where the non- commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, d6-DMSO): 9.5 (s, 1 H), 8.8 (br s, 1 H), 8.2 (d, 1 H), 8.1 (br s, 1 H), 7.9 (br s, 1 H), 7.25 (d, 1H), 7.2 (L 2H), 6.9 (s; 2H), 6.8 (d, 1H), 4.25 (br m, 2H), 2.7 (s; 1H), 2.15 (br m, 1H), 2.05 (br m, 1 H); MS (EI) for C2lH,gN4OS: 375.0 (ΜΙ- ).
[00203] Compound 1676-(I,3-benzothiazol-6-y])-N-[(4S)-3,4-dihydiO-2H-chromen-4- yl]-2-mcthylpyrimidin-4-aminc. 6-(1.3-benzothiazol-6-yl)-N-[(4S)-3,4-dihydro-2H- chromen-4-yl]-2-methylpyrimidin-4-amine made according to Example 1 where the non- commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, de-DMSO): 9.5 (s, 1H), 8.8 (brs, 1H),8.2 (d, 1H), 8.1 (brs, 1H), 7.9 (brs, 1H),7.25 (d, 1H), 7.2 (t, 2H), 6.9 (s, 2H), 6.8 (d.1 H), 4.25 (br m, 2H), 2.7 (s, lH), 2.15 (br m, IH), 2.05 (br m, 1H); MS (EI) for C2|H,8N4OS: 375.1 (MI-f).
[00204] Compound 1686-(l,3-benzothiazol-6-yI)-N-(3,4-dihydro-2H-chromcn-4-yl)-2- mcthylpyrimidin-4-amine. 6-(l,3-benzothiazol-6-yl)-N-(3,4-dihydro-2H-chromen-4-yl)-2- methylpyrimidin-4-amine made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, d6-DMSO): 9.5 (s, 1 H), 8.8 (br s, 1 H), 8.2 (d, 1 H), 8.1 (br s, 1 H), 7.9 (br s, 1 H), 7.25 (d, 1 H), 7.2 (t, 2H), 6.9 (s, 2H), 6.8 (d, IH), 4.25 (br m, 2H), 2.7 (s, IH), 2.15 (br m, lH), 2.05 (br m, 1H); MS (EI) for C21H18N4OS: 375.0 (MH+).
[00205] Compound 1696-(l,3-bcnzothiazol-6-yl)-N-(3,4-dihydro-2H-l-bcnzothiopyran- 4-yl)-2-mcthylpyrimidin-4-aminc. 6-(l,3-benzothiazol-6-yl)-N-(3,4-dihydro-2H-l- benzothiopyran-4-yl)-2-methylpyrimidin-4-amine made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, d6-DMSO):9.5 (s, 1H), 8.8 (brs, 1H),8.2 (d, 1H),8.1 (brs, 1H),7.9 (brs, 1H),7.25 (d, 1H), 7.15 (t, 2H), 7.05 (t, 1H), 6.9 (s, 1I-L), 5.5 (brs, 1H), 3.15 (t, 1H), 3.05 (brs, 1H), 2.3 (brs, 1H),2.1 (brs, 1H); MS (EI) for C2,H,8N4S2: 391.0 (MH+).
[00206] Compound 1706-(l,3-benzothiazol-6-yl)-N-(3,4-dihydro-lH-2-benzothiopyran- 4-yI)-2-methyIpyrimidin-4-amine. 6-(l,3-benzothiazol-6-yl)-N-(3,4-dihydro-lH-2- benzothiopyran-4-yl)-2-methylpyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz. d6-DMSO): 9.5 (s, 1H), 8.8 (brs, 111), 8.2 (d, 1H), 8.1 (brs, 1H), 7.9 (brs, 1H), 7.35 (brm, 1H), 7.25 (br m, 3H), 7.05 (brs, IH), 5.5 (brs, IH), 3.85 (br s, 2H),3.15(d, IH),
3.1 (d, IH), 2.90 (br s, IH); MS (EI) for C2|HI8 4S2: 391.0 (MH+).
[00207] Compound 171 N-(5-{[6-(l,3-bcnzothiazol-6-yl)-2-methyIpyrimidin-4- yl]amino}-5,6,7,8-tctrahydronaphthaIcn-2-yl)acctamide. N-(5-{[6-(l,3-benzothiazol-6- yl)-2-inethylpyrimidin-4-yl]amino}-5.6,7,8-tetrahydronaphthalen-2-yl)acetamide was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, d6-DMSO): 9.85 (s, IH), 9.5 (s, IH), 8.8 (br s, IH),
8.2 (d, IH), 8.1 (br s, IH), 7.7 (br s, IH), 7.4 (s, IH), 7.3 (d, ΓΗ), 7.15 (d, IH), 6.9 (br s, IH), 5.5 (br s, IH), 2.75 (br m, 2H), 2.7 (br m, IH), 2.35 (br m IH), 2.0 (s, 3H), 1.9 (s, IH), 1.8 (br m, 2H); MS (EI) for C24H23N5OS: 430.1 (MH+).
[00208] Compound 175 N-l-[6 l,3-benzothiazoI-6-yl)-2-methylpyrimidin-4-yl]-l,2,3,4- tetrahydronaplithalcne-l,6-diaminc. lM-l-[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]-1.2,3,4-tetrahydronaphthalene-l,6-diamine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, de-DMSO): 9.5 (s, 1 H), 8.8 (s, IH), 8.75 (br s, IH), 8.15 (d, 2H), 7.6 (br s, IH), 6.9 (br s, IH), 6.4 (d,2H)s 6.3 (t, 2H), 5.3 (br s, IH), 4.9 (s, 2H), 4.4 (b s, 1H);MS (EI) for
C22H21N5S: 388.1 (ΜΙ- ).
[00209] Compound 1786-(l,3-benzothiazol-6-yl)-2-methyl-N-[6-(methyloxy)-l, 2,3,4- tctrahydronaphthalen-l-yl]pyrimidin-4-aminc. 6-(l,3-benzothiazol-6-yl)-2-methyl-N-[6- (methyloxy)-l,2,3,4-tetrahydronaphthalen-l-yl]pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, d6-DMSO): 9.5 (s, 1 H), 8.8 (s, IH), 8.2 (d, IH), 8.1 (br s, IH), 7.7 (brs, lH),7.15(d, 1H),6.95 (d, IH), 6.85 (brs, IH), 6.7 (m, 2H), 5.4 (br s, IH), 3.75 (s, 3H), 3.7 (s, 3H), 2.7 (t, 2H), 2.2 (m, 2H), 1.8 (m, 2H); MS (EI) for C23H22N4OS: 403.0 (MH+).
[00210] Compound 1796-(l,3-benzothiazol-6-yI)-2-methyI-N-[5-(methyloxy)-l,2,3,4- tctrahydronaphthalen-l-yl|pyrimidin-4-amine. 6-(l,3-benzothiazol-6-yl)-2-methyl-N-[5- (methyloxy)-l,2,3,4-tetrahydronaphthalen-l-yl]pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, d6-DMSO): 9.5 (s, lH),8.8(s, IH), 8.2 (d, IH), 8.1 (brs, 1 H), 7.7 (br s: 1 H), 7.15 (d, 1 H), 6.85 (br d: 2H), 6.7 (m, 2H), 5.4 (br s, 1 H), 3.8 (s, 3H), 1 .9 (br s, 2H), 1 .8 (m, 2H); MS (El) for C^H^OS: 403.1 (MH+).
[00211] Compound 180 6-(l,3-benzothiazol-6-yl)-2-methyl-N-(6-methyl-3,4-dihydro- 2H-chromen-4-yl)pyrimidin-4-aminc. 6-( l ,3-benzothiazol-6-yl)-2-methyl-N-(6-methyl- 3,4-dihydro-2H-chromen-4-yl)pyrimidin-4-amine made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, d6-D SO): 9.5 (s, 1 H), 8.8 (s, lH), 8.2 (d, 1 H), 8. 1 (br s, 1 H), 7.9 (br s, 1 1-1), 7.05 (s, 2H), 7.0 (d, 2H), 6.9 (br s, 1 H), 6.7 (d, 1 H), 5.4 (br s, 1 H), 4.2 (m, 2H), 2.2 (s, 3H), 2.1 (m, 1 H), 2.0 (m, 1 H); MS (EI) for C22H2oN4OS: 389.1 (MH+).
[00212] Compound 183 6-(l ,3-bcnzothiazoI-6-yl)-2-methyl-N-|7-(methyloxy)-l ,2,3,4- tetrahydronaphthalen-l -yl]pynmklin-4-aminc. 6-(1.3-benzothiazol-6-yl)-2-methyl-N-[7- (methyloxy)-l ,2,3,4-tetrahydronaphthalen- l -yl]pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 M Hz, d6-DMSO): 9.5 (s8 1 H), 8.8 (br s, 1 H), 8.2 (d, ΓΗ), 8.1 (br s, 1 H), 7.7 (br s, l H), 7.05 (d, 1 H), 6.9 (br s, 1 H), 6.8 (d, 2H), 5.4 (br s, 1 H), 3.65 (s, 3H), 2.7 (m, 2H), 1.9 (br d, 2H), 1 .8 (m, 2H); MS (EI) for C23H22N4OS: 403.0 (MH+).
[00213] Compound 191 6-(2,3-dihydro-l-bcnzofuran-5-yl)-2-methyl-N-[(JR)-l,2,3,4- tetrahydiOnaphthalen-l-yl]pyrimidin-4-amine. 6-(2,3-dihydro- l -benzofuran-5-yl)-2- methyl-N-[(l R)- l ,2,3.4-tetrahydronaphthalen- l -yl]pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made accordin to General Scheme 5. Ή NMR (400 Hz, DMSO-D,,): 13.40 (br s, 1 H), 9.62 (br s, 1 H), 7.75 (s, 2H), 7.62 (d, 2H), 7.21 (m, 4H), 7.05 (d, 1 H), 6.81 (s, 1 H): 5.52 (br m, 1 H), 4.72 (t, 2H), 3.16 (t, 2H), 2.82 (m, 2H), 2.62 (s, 3H)f 1 .82-2.21 (m: 4H); MS (EI) for C23H23N3O: 358.1 (MH+). 100214] Compound 1 2 2-mcthyI-6-[(E)-2-phenylethenyl]-N-[(l R)-l , 2,3,4- tetrahydronaphthalen-l-yI]pyrimidin-4-aminc. 2-methyl-6-[(E)-2-phenylethenyl]-N- [(l R)- l ,2,3,4-tetrahydiOnaphthalen-l -yl]pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, DMSO-Dc): 7.72 (m, 2H), 7.41 -7.38 (m, 3H), 7.31 -7.02 (m, 5H), 6.30 (br s, 1H), 5.40 (br s, 1H), 2.82 (m, 2 H), 2.41 (s, 3H), 1.92-1.72 (m, 4H); MS (EI) for C23H23N3: 342.1 (Ml-f).
[002151 Compound 193 6-(l ,3-benzothiazol-6-yI)-N-(6-fluoro-3,4-dihydro-2H-chromcn- 4-yl)-2-methylpyrimidin-4-aminc. 6-( l ,3-benzothiazol-6-yl)-N-(6-fluoro-3,4-dihydro-2H- chromen-4-yl)-2-methylpyrimidin-4-amine was made according to Example 1 where the non- commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, DMSO-De): 9.51 (s, I H), 9.82 (br s, 1 H), 8.20 (d, 2H), 7.91 (br s, I H), 7.02 (t, 2H), 6.82 (m, 2H), 5.41 (br m, I H), 4.30 (m, 2H), 3.38 (s, 3H), 2.20 (m, 2H), 2.01 (m, 2H); MS (EI) for C2iH|7F 4OS: 393.1 (ΜΗ ' ).
[00216J Compound 194 (4-{2-methyl-6-[(lR)-l ,2,3,4-tetrahydronaphthalen-l- ylamino]pynmidin-4-yl}phenyl)rnethanoI. (4-{2-methyl-6-[(l R)- l ,2,3,4- tetraliydronapluhaIen-l -ylamino]pyrimidin-4-yl}phenyl)methanol was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, DMSO-D6): 7.92 (br m, 2H), 7.64 (br m, 1 H), 7.45 (d, 2H), 7.26-7.12 (m, 3H), 6.78 (br s, 1 H), 5.42 (br s, 1 H), 5.23 (t, 1 H), 4.52 (d, 2H), 2.81 (m, 2H), 2. 1 (s, 3H), 1.98- 1 .82 (m, 4H); MS (EI) for C22H23N3O: 346.1 (ΜΙ-Γ).
[002171 Compound 195 2-mcthyl-6-phcnyl-N-[(lR)-l,2,3,4-tctrahydronaphthalcn-l- yl]pyrimidin-4-aminc. 2-methyl-6-phenyl-N-[(l R)-l ;2.3.4-tetrahydronaphthalen-l - yl]pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, DMSO-D6): 8.81 (br s, l H), 7.86 ( dd, 2H), 7.65 (m, 3H), 7.22 (m, 4H), 6.81 (s, I H), 5.53 (m, I H), 2.83 (m, 2H), 2.62 (s, 3H), 2.15- 1 .82 (m, 4H); MS (EI) for C2iH2|N3: 316.1 (MH÷).
[00218] Compound 196 4-{2-methyl-6-[(l R)-l ,2,3,4-tctrahydronaphthalen-l- ylamino]pyrimidin-4-yI}phcnoi. 4-{2-melhyl-6-[(l R)- l ,2,3,4-tetrahydronaphthalen- l - ylamino]pyrimidin-4-yl } phenol was made according to Example 1 where the non- commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, DMSO-D6): 10.63 (s, I H), 7.73 (m, 3H), 7.23 (m, 4H), 7.02 (d, 2H), 6.81 (s, I H), 5.51 (m, I H), 2.83 (m, 2H), 2.64 (s, 3H), 2.08-1.72 (m, 4H); MS (EI) for C2| H2iN30: 332.1 (ΜΗ',').
100219] Compound 197 6-(l,3-bcnzothiazoI-6-yl)-2-methyl-N-(2-methyl-l, 2,3,4- tctrahydronaphthalen-l-yI)pyrimidin-4-aminc. 6-(l ,3-benzothiazol-6-yl)-2-methyl-N-(2- methyl-l ,2,3,4-tetrahydronaphthalen-l -yl)pyrimidin-4-amine was made according to
Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, DMSO-Dfi): 9.62 (s, I H), 8.74 (s,l H), 8.32 (m, I H), 8.02 (m, I H), 7.31 -6.91 (m, 5H), 5.30 (m, I H), 5.10 (m, I H), 2.90-2.50 (m, 5H), 2.12-1 .82 (m, I H), 1 .62-1 .52 (m, I H), 1.42- 1 .21 (m, I H), 1.02-0.84 (m, 3H); MS (EI) for C23H2 N4S: 387.1 (MH÷).
[00220] Compound 198 6-(l-bcnzof'uran-2-yl)-2-mcthyI-N-|(l R)-l,2,3,4- tetrahydronaphthalcn-l-yl]pyrimidin-4-aminc. 6-(l -benzofuran-2-yl)-2-methyl-N-[(l R)- l ,2,3,4-tetrahydronaphthalen- l -yl]pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. H NMR (400 MHz, DMSO-Dr,): 7.92 (d, 1 H), 7.74 (d, IH), 7.65 (d, 2H), 7.53 (br S, IH), 7.42 (t, IH), 7.32 (t, IH), 7.10-7.28 (m, 3H), 6.86 (br s, IH), 5.42 (br s, IH), 2.82 (m, 2H), 2.51 (s, 3H), 2.08-1.73 (m, 4H): MS (EI) for C23H21N3O: 356.1 (MH+).
100221] Compound 1996-[3,4-bis(methyloxy)phenylJ-2-methyl-N-[(lR)-l, 2,3,4- tctrahydronaphthalen-l-yl|pyrimidin-4-aminc. 6-[3,4-bis(methyloxy)phenyl]-2-melhyl- N-[(lR)-l,2,3,4-tetrahydronaphthalen-l-yl]pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, DMSO-D6): 7.45 (m, 2H), 7.21 (m, 5H), 6.88 (s, IH), 5.10 (m, IH), 3.80 (s, 3H), 3.75 (s,3H), 2.80 (m, 2H), 2.70 (s, 3H), 2.10-1.72 (m, 4H); MS (EI) for C23H2S 3O2: 376.1 (MM").
100222) Compound 2002-methyl-6-naphthalen-2-yl-N-|(lR)-l, 2,3,4- tetrahydronaphthaIen-l-yl]pyrimidin-4-aminc. 2-methyl-6-naphthalen-2-yl-N-[(lR)- 1.2,3!4-tetrahydronaphthalen-l-yl]pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, DMSO-D6): 8.78 (br s, IH), 8.01 (m, 4H), 7.72 (m, IH), 7.58 (m: 2H), 7.23 (d, 1 H), 7.15 (m, 3 H), 6.90 (br s, 1 H), 5.49 (br s, 1 H , 2.80 (m, 2H), 2.51 (s, 3H), 2.10- 1.62 (m, 4H); MS (EI) for C25H23N3: 366.1 (Ml-f ).
[002231 Compound 2013-{2-mcthyl-6-[(l )-l,2,3,4-tctrahydronaphthaIcn-l- ylamino]pyrimidin-4-yI}phenol. 3-{2-methyl-6-[(lR)-l,2,3.4-tetrahydronaphthalen-l- ylamino]pyrimidin-4-yl}phenol was made according to Example I where the non- commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, di-MeOH): 10.10 (s, IH), 7.41 (t, IH), 7.23 (m, 6H), 6.83 (s, IH), 5.52 (m, IH), 2.81 (m, 2H), 2.62 (s, 3H):2.10-1.79 (m, 4H): MS (EI) for C21H21N3O: 333.1 (MH+).
|00224| Compound 202 N-(l-(3-bromophcnyl)cthyl]-2-methyl-6-|3- (mcthyloxy)phenyl)pyrimidin-4-aminc. N-[l-(3-bromophenyl)elhyl]-2-methyl-6-[3- (methyloxy)phenyl]pyrimidin-4-amine was made according to Example 1 where the non- commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz. DMSO-D6): 7.59 (br s, IH), 7.55 (t, IH), 7.42 (m, 2H), 7.35 (m, 3H), 7.22 (dd, 2H), 6.82 (s, IH), 5.51 (m, IH), 3.82 (m, 2H), 2.63 (s, 3H), 1.64 (d, 3H); MS (EI) for
C2oH20BrN30: 400.1 (ΜΙ-Γ).
100225] Compound 2033-{2-mcthyl-6-|(l )-l,2,3,4-tetrahydronaphthalcn-l- ylamino]pyrimidin-4-yl}bcnzaldchyde. 3-{2-melhyl-6-[(l R)- 1 ,2,3,4-tetrahydronaphthalen- l-ylamino]pyrimidin-4-yl}benzaldehyde was made according to Example 1 where the non- commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, DMSO-D6): 10.15 (s, I H), 8.38 (s, I H), 8.21 (t, 2H), 7.87 (t, I H), 7.21 (m, 4H), 6.91 (s, I H), 5.58 (m, I H), 2.82 (m, 2H), 2.71 (s, 3H),2. 1 5-1 .75 (m, 4H); MS (EI) for C22H21N3O: 343.1 (ΜΙ-Γ).
[00226] Compound 204 6-|2-fluoro-5-(methyloxy)phenylJ-2-mcthyl-N-f(l R)-l , 2,3,4- tetrahydronaphthaIcn-l-yIjpyrimidin-4-amine. 6-[2-fluoro-5-(methyloxy)phenyl]-2- methyl-N-[(l R)- l ,2,3,4-tetrahydronaphthalen-l -yl]pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, DMSO-D6): 7.46 (ts I H), 7.36 (br m, I H), 7.26-7.18 (m, 5H), 6.82 (s, I H), 5.51 (m, I H), 3.82 (s, 3H), 2.83 (m, 2H), 2.64 (s, 3H),2.16-1.81 (m, 4H); MS (EI.) for C22H22FN3O: 364.1 (MI-F).
[00227] Compound 205 6-(l ,3-benzothiazol-6-yl)-N-(5,7-dimethyI-l , 2,3,4- tetrahydronaphthaIcn-l -yI)-2-methyIpyrimidin-4-amine. 6-(l ,3-benzothiazol-6-yl)-N- (5,7-dimethyl- l ,2,3,4-tetrahydronaphthalen-l -yl)-2-methylpyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, DMSO-D6): 9.48 (s, 1 H), 8.82 (s, I H), 8.20 (d, I H), 8.10 (br s, I H), 7.75 (br s, I H), 6.91 (s, 2H), 5.51 (m, I H), 3.82 (s, 3H), 2.83 (m, 2H), 2.64 (s, 3H), 2.16- 1 .81 (m, 4H); MS (EI) for C24H24N4S: 401.1 (MH+).
[00228] Compound 206 l-(3-{2-mcthyl-6-l(lR)-l ,2,3,4-tctrahydronaphthalen-l- yIamino]pyrimidin-4-yl}phcnyl)cthanonc. l -(3-{2-methyl-6-[(l R)- l ,2.3,4- tetrahydronaphthalen- l -ylamino]pyrimidin-4-yl}phenyl)ethanone was made according to Example 1 where the non-commercially available amine was made according to General Scheme s. Ή NMR (400 MHz, DMSO-D6): 9.82 (br s, 1 H), 8.41 (s, I H), 8.23 (d, 1 H), 8.08 (d, I H), 7.82 (t, IH), 7.21 (m, 4H), 6.92 (s, I H), 5.58 (m, I H), 2.82 (s, 2H), 2.72 (s, 6H), 2.64 (s, 3H),2.10-1.80 (m, 4H); MS (EI) for C23H23N3O: 358.1 (MH+).
[00229] Compound 207 (3-{2-mcthyI-6-[(l R)-l ,2,3,4-tetrahydronaphthalen-l- ylamino[pyrimidin-4-yI}phcnyl)mcthanol. (3-{2-methyl-6-[( l R)- 1.2,3,4- tetrahydronaphthalen- l -ylamino]pyrimidin-4-yl}phenyl)melhanol was made according' to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, DMSO-D6): 9.84 (br s, I H), 7.78 (br s, I H), 7.21 (br s, I H), 7.62 (br d, 2H), 7.21 (m, 4H), 6.92 (s, I H), 5.06 (m, I H), 4.63 (s, 2H), 2.81 (m, 2H), 2.68 (s, 3H), 2.10- 1 .82 (m, 4H); MS (EI) for C22H23N3O: 346.1 (MH+).
[00230] Compound 208 6-|3-(cthyloxy)phcnyl]-2-inethyI-N-[(lR)-l,2,3,4- tetrahydronaphthaIcn-l-yl]pyrimidin-4-aminc. 6-| 3-(ethyloxy)phenyl]-2-methyl-N-[(l R)- l ,2,3,4-tetrahydronaphthalen- l -yl]pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, DMSO-D6): 9.82 (br s, 1Ή), 7.52 (d, I H), 7.41 (br s, I H), 7.35 (d, I H), 7.23 (m, 5H), 6.82 (s, I H), 5.60 (m, I H), 4.15 (q, 2H), 2.82 (m, 2H), 2.71 (s, 3H), 1.81 -2. 10 (m, 4H), 1.38 (t, 31-1); MS (El) for C23H25N3O: 360.1 (MH+).
[00231 ] Compound 209 2-mcthyl-6-(4-methyl-3,4-dihydro-2H-l,4-benzoxazin-7-yl)-N- [(l R)-l ,2,3,4-tetrahydronaphthalen-l-yl]pyrimidin-4-amine. 2-methyl-6-(4-methyl-3,4- dihydro-2H-l ,4-benzoxazin-7-yl)-N-[(l R)-l ,2,3,4-telrahydronaphthalen-l -yl]pyrimidin-4- amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, DMSO-D6): 13.21 (br s, I H), 9.52 (br s, 1 H), 7.38 (d, I H), 7.42-7.21 (m, 5H), 6.85 (d, I H), 6.78 (s, 1 H), 5.50 (m, 1 H), 4.25 (m, 2H), 2.90 (s, 3H), 2.82 (m, 2H), 2.61 (s, 2H), 2.51 (s, 3H), 2.08- 1 .80 (m, 4H); MS (EI) for C24H26N4O: 387. 1 (MH+).
[00232] Compound 212 2-fluon>-5-(l-{[2-methyl-6-(3-methyl-l-bcnzofuran-5- yl)pyrimidin-4-yl|amino}ethyl)phenol. 2-.fluoro-5-( 1 -{ [2-melhyl-6-(3-methyl- 1 - benzofuran-5-yl)pyrimidin-4-yl]amino}ethyl)phenol was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5. Ή NMR (400 MHz, d6-DMSO): 8.2 (s, I H), 7.92 (d, I H), 7.81 (s, I H), 7.72 (br s, I H), 7.60 (d, I H), 7.10 (dd, l H), 7.00 (br d, I H), 6.85 (br s, 2H), 2.41 (s, 3H), 2.30 (s, 3H), 1.89 (s, 2H- Oac peak), 1.45 (d, 3H); MS (EI) for C22H20N3O2F: 378.2 (MJ-f).
[00233] Compound 213 N-{l-|4-fluoro-3-(l-mcthyl-lH-pyrazol-4-yl)phcnyI|cthyl}-2- mcthyl-6-(3-methyl-l -benzofuran-5-yl)pyrimidin-4-amine. N-{ l -[4-t1uoro-3-(l -methyl- l H-pyrazol-4-yl)phenyl]ethyr}-2-methyl-6-(3-methyl-l -benzofuran-5-yl)pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 7. Ή NMR (400 MHz, d6-DMSO): 8.18 (s, 1 H), 8.1 1 (s, 1 H), 7.93 (m, 2H), 7.80 (m, 2H), 7.60 (d, 1 H), 7.28 (br s, 1 H), 7.20 (m, 1 H), 6.85 (br s, 1 H), 5.35 (br s, I H), 3.89 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 1.83 (s, 3H), 1 .43 (d, 3H): MS (EI) for C26H2.iNjOF: 442.2 (ΜΗ ').
[00234] Compound 215 2-mcthyl-6-[4-mcthyl-3-(mcthyloxy)phcnyI|-N-{(l S)-l-[3- (methyloxy)phenyl|cthyl}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.78 (s, I H). 7.45 (m, I H), 7.21 (m, 2H), 7.00 (s, 2H), 6.80 (d. I H), 5.21 (br s, 1 H), 3.84 (s, 3H), 3.72 (s, 3H), 2.37 (s, 3H), 2.17 (s, 3H), 1 .45 (d, 3H); MS (EI) for C22H25N3O2: 364.2 (MH+).
[002351 Compound 216 3-[(lS)-l-{|6-(l ,3-benzothiazol-6-yI)-2-methyIpyriniidin-4- yl]amino}ethyl]phcnol. Ή NMR (400 MHz, d6-DMSO): 9.50 (s, IH), 9.45 (s, I H), 8.80 (s, 1H), 8.19 (d, 1H), 8.15 (d, III), 7.79 (brs, 1H), 7.12 (t, 1 H), 6.90 (m, 3H), 6.61 (d, 1H), 5.21 (br s, 1H), 2.40 (s, 3H), 1.45 (d, 3H); MS (EI) for C2oHixN4OS: 363.1 (MH+).
[002361 Compound 2236-(l,3-benzothiazoI-6-yI)-iN-[l-(3-{|(l,3-dimethy!-lH-pyrazol-5- yl)mcthylloxy}-4-fluorophcnyl)ethyl|-2-methylpyrimidin-4-aminc. 6-(L3-benzothiazol- 6-yl)-N-[l-(3-{[(l,3-dimethyl-lI-I-pyrazoI-5-yl)methyl]oxy}-4-fluorophenyl)ethyl]-2- melhylpyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 5, and then alkylated with the pyrazole according to Scheme 3. MS (EI) for C26H.5 6OSF: 489.2 (Ml-f ).
[00237] Compound 2266-(l,3-bcnzothiazol-6-yl)-N-{l-[4-nuoro-3-(l-methyl-lH- pyrazol-4-yl)phcnyI]ethyl}-2-mcthylpyrimidin-4-aminc. 6-(l,3-benzolhiazol-6-yl)-N-{l- [4-fluoro-3-(l -methyl- 1 H-pyrazol-4-yl)phenyl]ethyl}-2-methylpyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 7. MS (EI) for C2<iH2iN6SF: 445.2 (MH+).
[002381 Compound 2306-(2,3-dihydro-l-benzofuran-5-yl)-2-mcthyI-N-{(lS)-l-[3- (methyIoxy)phcnyI]ethy!}pyrimidin-4-amine. MS (EI) for C22H23 3O2: 362.2 (MIT).
[00239] Compound 2333-(I-{[6-(l,3-bcnzothiazoI-6-yl)-2-methylpyrimidin-4- yI]amino}ethyl)benzenesulf'onamidc. MS (EI) for C20H19 5O2S2: 426.1 (ΜΙ- ).
[00240] Compound 237 N-{l-l2-fluoro-3-(methyloxy)phenyl]ethyl}-2-methyl-6-(3- methyl-l-benzofuran-5-yl)pyrimidin-4-amine. N-{l-[2-fl oro-3- (methyloxy)phenyl]ethyl}-2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 7. MS (El) for C23H22N3O2F: 392.2 (MI ).
[00241] Compound 2382-chIoro-5-(l-{[2-mcthyI-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-yl|amino}ethyI)phcnol. 2-chloro-5-(l-{[2-melhyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-yl]ammo}ethyl)phenol was made according to Example 1 where the non-commercially available amine was made according to General Scheme 8. MS (EI) for C22H20N3O2CI: 394.3 (MlT).
[00242] Compound 2393-[l-({2-methy -6-[4-mcthyl-3-(mcthyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phcnol. MS (El) for C21H23N3O2: 350.2 (Μ1- ).
100243] Compound 2446-(l,3-benzothiazoI-6-yl)-N-[l-(5-{[(l,3-dimcthyl-lH-pyrazol-5- yI)methyl]oxy}-2-fluorophcnyl)cthyl]-2-methyIpyrimidin-4-aminc. 6-(l,3-benzothiazoI- 6-yl)-N-[l-(5-{[(l,3-dimethyl-lH-pyrazol-5-yl)methyl]oxy}-2-nuorophenyl)ethyl]-2- methylpyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 8, and then alkylated with the pyrazole according to Scheme 3. MS (EI) for C26H25N6OSF: 489.2 (MH+).
100244] Compound 2463-[( 1 R)-l -{[6-(l ,3-bcnzothiazol-6-yI)-2-mcthylpyrimidin-4- yl]amino}erhyl]phenol. MS (EI) for C2oH|8N„OS: 363.1 (ΜΙ- ).
100245] Compound 2483-(l-{[6-(l,3-benzothiazol-6-yl)-2-mcthylpyrimidin-4- yl]amino}ethyl)-4-fluorophenol. 3-(l-{[6-(l!3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)-4-fluorophenol was made according to Example 1 where the non- commercially available amine was made according to General Scheme 8. MS (EI) for
C20H17N4OSF: 381.1 (MH+).
[00246] Compound 2493-[l-({6-|2-fIuoro-3-(methyIoxy)phenyIJ-2-mcthylpyrimidin-4- yl}amino)ethyl]phcnoI. MS (EI) for C2nH2„ 302F: 354.2 (MH+).
[00247] Compound 2573-(l-{[6-(l,3-bcnzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyI)phenol. MS (El) for C2oH18N4OS: 363.1 (Ml-f).
100248] Compound 2611,1-dimcthylcthyl (3S)-3-({[6-(l,3-benzothiazoI-6-yl)-2- mcthylpyrimidin-4-yl]amino}methyI)pipcridinc-l-carboxylate. MS (EI) for
C23H29N5O2S: 440.2 (MH+).
100249] Compound 2686-(l,3-bcnzothiazol-6-yl)-N-[(2-chloro-6-fIuorophenyl)methyI]- 2-methylpyrimidin-4-aminc. 'HNMR (400MHz. d6-DMSO): 9.45 (s, IH), 8.78 (s: IH), 8.16 (d, IH), 8.09 (m, IH), 7.67 (t, IH), 7.47-7.35 (m, 2H), 7.28-7.23 (m, IH), 6.91 (s, IH), 4.66 (d, 2H), 2.46 (s, 3H); MS (EI) for C19H14CIFN4S: 385.9 (MH+).
[00250] Compound 274 N-{2-|3-({|6-(l,3-bcnzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}methyl)piperidin-l-yI]-2-oxocthyl}-N-mcthylbenzamide. MS (EI) for
C28H30N6O2S: 515.7 (MH+).
[002511 Compound 2766-(l,3-bcnzothiazoI-6-yl)-2-mcthyl-N-[(2R)-2- phcnylpropyl]pyrimidin-4-aminc. MS (EI) for C21H20N4S: 361.5 (MH+).
[00252] Compound 2776-(l,3-bcnzothiazoI-6-yl)-2-methyl-N-(2-pyridin-3- ylcthyl)pyrimidin-4-amine. MS (EI) for C19H17N5S: 348.4 (MH+).
[00253] Compound 2786-(l,3-benzothiazol-6-yl)-N-(2-cthylhcxyl)-2-methylpyrimidin- 4-amine. MS (EI) for C2oH26N4S: 355.5 (MH+).
[00254] Compound 2796-(l,3-benzothiazol-6-yI)-2-methyI- -(l-pyridin-3- ylethyl)pyrimidin-4-amine. MS (El) for C|9H|7N5S: 348.4 (MH+).
[00255] Compound 2806-(l,3-benzothiazol-6-yl)-N-(2,3-dihydiO-lH-inden-2-yl)-2- mcthylpyrimidin-4-aminc. MS (EI) for C2|HigN4S: 359.5 (MH+). 100256] Compound 2816-(l,3-benzothiazoN6-yl)-N-(l,4-dimethyIpcntyI)-2- mcthylpyrimidin-4-amine. MS (El) for C|9H2<)NjS: 341.5 (MH+).
[002571 Compound 2826-(l,3-benzothiazol-6-yl)-N-[2-(l H-imidazol-4-yl)ethyI|-2- mcthylpyrimidin-4-amine. MS (EI) for C|7Hi6N6S: 337.4 (MH+).
[002581 Compound 2836-(l,3-bcnzothia/.ol-6-yI)-2-methyl-N-[(2S)-2- phcnyIpropyl]pyrimidin-4-aminc. MS (EI) for C21H20N4S: 361.5 (MH+).
[0025 | Compound 2845-{[6-(l,3-bcnzothiazol-6-yl)-2-methylpyrimidin-4-yI[amino}-
2,2-dimethyIpenran-I-ol. MS (EI) for C19H24N4OS: 357.5 (MH+).
[00260J Compound 2856-(l,3-benzothiazol-6-yI)-2-mcthyI-N-{[3-(lFi-pyrrol-l- yI)phcnyl[mcthyI}pyrimidin-4-aminc. MS (El) for C23H|9 SS: 398.5 (MH+).
[00261] Compound 286 l,l-dimcthylcthyl3-({[6-(l,3-bcnzothiazol-6-yl)-2- methylpyrintidin-4-yI]amino}me(hyl)pipcridinc-l-carboxylate. MS (EI) for
C23H29N5O2S: 440.6 (MH+).
[00262] Compound 2876-(l,3-bcnzothiazol-6-yl)-2-mcthyl-N-(2-pyridin-4- yIcthyl)pyrimidin-4-aminc. MS (EI) for C|9H|7N5S: 348.4 (MH+).
[00263] Compound 2886-(l,3-bcnzothiazol-6-yl)-2-mcthyI-N-|(3-phcnylisoxazoI-5- yl)methy!]pyrimidin-4-aminc. MS (EI) for C22H17N5OS: 400.5 (MH+).
[00264] Compound 289 N'-[6-(l,3-bcnzothiazol-6-yI)-2-mcthylpyrimidin-4-yl]-N- merhyl-N-phcnytpropane-l,3-diaminc. S (EI) for C22H23N5S: 390.5 (MIR).
[00265] Compound 2986-(l,3-bcnzothiazol-6-yl)-2-mcthyI- -{l-[3-(5-methyl-lH- tetrazol-l-yI)phenyl]cthyl}pyrimidin-4-amine. 6-(l,3-benzothiazol-6-yl)-2-melhyl-N-{l- [3-(5-methyl-lH-tetrazol-l-yl)phenyl]elhyl}pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to Example 6f. 1 H NMR (400 MHz, d3-ACN): 9.15 (s, 1 ), 8.68 (s, 1), 8.1 (q, 2): 7.67 (d, 1 ), 7.6 (dd, 2), 7.42 (d, 1), 6.72 (brs, 1), 6.38 (br s, 1), 5.25 (br s, 1).2.60 (s, 3), 2.47 (s, 3), 1.60 (d, 3); MS (EI) for C22 H20 N8 S: 429.09 (MH+).
[00266] Compound 2986-(l,3-benzolhiazoI-6-yl)-2-mcthyl-N-{l-[3-(5-mcthyl-lH- tetrazol-l-yl)phenyI]cthyl}pyrimidin-4-aniine. 6-(l,3-benzothiazol-6-yl)-2-methyl-N-{l- [3-(5-methyl-lH-tetrazol-l-yl)phenyl]ethyl}pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to General Scheme 9. Ή NMR (400 MHz, d3-ACN): 9.34 (s, 1), 9.16 (s, 1), 8.70 (s, 1), 8.12 (s , 2), 7.90 (s, 1), 8.63 (m, 3), 6.77 (brs, 1), 6.33 (d, 1), 5.29 (brs, 1), 2.43 (s, 3), 1.61 (d, 3). MS (EI) for C22 H20N8 S: 415.07 (ΜΙ-Γ). [00267] Compound 301 6-(l ,3-bcn/otliiazol-6-yl)-2-mcthyl-N-{l-[3-(4H-l,2,4-triazoI-4- yl)phenyl]erhyI}pyrimidin-4-aminc. 6-( 1 ,3-benzothiazol-6-yl)-2-methyl-N-{ 1 -[3-(4H- l ,2,4-triazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was made according to Example 1 where the non-commercially available amine was made according to Example 6f. MS (EI) for C22 Wig N7 S: 427.0 (MH+).
[00268] Compound 307 3-(l-{]6-(l,3-bcnzothiazol-6-yl)-2-methylpyrimidin-4- yl|amino}ethyl)benzenccarboximidamidc. MS (El) for C2|H20N6S: 389.06 (MH+).
[00269] Compound 317 3-(l-{|6-(l ,3-bcnzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)-N'-hydroxybcnzcnccarboximidamide. MS (EI) for C2|H2oN6OS: 405.00 (MH+).
[00270] Compound 318 N-|6-(l ,3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]-l , 2,3,4- tctrahydroquinolin-4-amine. Ή NMR (400 MHz, d3-ACN): 9.09 (s, 1 ), 8.78 (s, 1 ), 7.1 1 (d, 1 ), 7.0 (t, 1), 6.88 (t, 2), 6.55 (i, 2), 6.50 (t, 1 ), 6.43 (d, 1), 6.0 (d, 1 ), 5.28 (br s, 1), 4.67 (br s, 1 ), 3.30 (m, 2), 3.22 (t, 2), 2.68 (t, 1 ), 2.50 (s, 3), 2.08 (m, 2), 1.85 (m, 2); MS (EI) for
C21 H 19N5S : 324.14 (ΜΙ-Π).
[00271] Compound 319 N-[6-(l ,3-bcnzothiazoI-6-yl)-2-methylpyrimidin-4-yl]-l-mcthyl- l ,2,3,4-tetrahydroquino!in-4-amine. Ή NMR (400 MHz, d3-ACN): 9.14 (s, 1), 8.73 (s, 1), 8.13 (s, 1 ), 7.53 (s, 1 ), 7.35 (m, 2), 6.78 (br s, 1 ), 6.67 (d, 1 ), 6.62 (t, 1 ), 5.88 (d, 1), 5.25 (br s, 1 ), 3.28 (t, 2), 2.92 (s, 3), 2.53 (s, 3), 2.17 (q, 2); MS (El) for C22H2iN5S: 388.16 (MH*).
[00272] Compound 327 6-(l-bcnzothien-5-yl)-N-[(4R)-3,4-dihydro-2H-chromen-4-yl]-2- mcthylpyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO):6 8.54 (br s, I H), 8.10 (d, I H), 7.93 (br s, I H), 7.82 (d, I H), 7.82 (br s, IH, overlapped), 7.59 (d, I H), 7.23 (br d, I H), 7.15 (m, I H), 6.89 (t, I H), 6.81 (d, I H), 5.40 (br s, I H), 4.27 (m, 2H), 2.49 (s, 3H, overlapped), 2.15 (m, I H), 2.04 (m, 1Ή), 1 .91 (s, 3H, acetate peak). MS (EI) for C22Hi9N3OS: 374.2 (MH+).
1002731 Compound 337 2-mcthyl-6-(3-methyl-l -bcnzofuran-5-yl)-N-[l-(3- methylphenyl)ethyl]pyrimidin-4-aminc. 2-methyl-6-(3-methyl- l -benzofuran-5-yl)-N-[l - (3-methylphenyl)ethyl]pyrimidin-4-amine was synthesized in a manner analogous to Example 1 and the amine was synthesized in a manner analogous to Example 6a. Ή NMR (400 MHz, d6-D SO):5 8.16 (s, I H), 7.90 (dd, I H), 7.82 (d, I H), 7.774 (br s, 1 H), 7.61 (d, I H), 7.27-7.19 (m, 3H), 7.03 (m, I H), 2.39 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H), 1 .44 (d, 3H). MS (EI) for C23H23N3O: 358.1 (ΜΙ-Γ).
[00274] Compound 342 2-mcthyI-6-(3-mcthyl-l-bcnzofuran-5-yl)-N-[(l S)-l-(4- methylphenyl)ethyl]pyrimidin-4-aminc. Ή NMR (400 MHz, dfi-DMSO):5 8.1 1 (s, I H), 7.96 (s, I H), 7.83-7.71 (m, 2H), 7.37-7.29 (m, 2H), 7.17 (m, 2H), 6.90 (br s, I H), 5.41 (br s, Hi), 2.58 (s, 3H), 2.28 (s, 6H, overlapped), 1 .52 (d, 3H). MS (EI) for C23H23N3O: 358.1 (MH+).
100275] Compound 347 6-(l ,3-bcnzothiazol-6-yl)-N-| l-(5-{[(l ,3-dimethyl-lH-pyrazol-5- yI)methyl|oxy}pyridin-3-yI)cthyl|-2-methyIpyriniidin-4-aminc. 6-(L3-benzothiazol-6-yl)- N-[l -(5-{[(l ,3-dimethyl-l H-pyrazol-5-y])methyl]oxy}pyridin-3--yl)'ethyl]-2- methylpyrimidin-4-amine was synthesized in a manner analogous to Examples 1 and 3, while the amine was synthesized in a manner analogous to Example 6a. Ή NMR (400 MHz, d6- DMSO):8 9.60 (s, 1 H), 8.71 (br s, 1 H), 8.33 (m, 3H), 7.97 (br s, I H), 7.57 (m, 1 H), 6.93 (m, I H), 6.17 (m, I H), 5.48 (br s, I H), 5.23 (s, 2H), 3.74 (s, 3H), 2.56 (s, 3H), 2.07 (s, 3H), 1.58 (d, 3H). MS (EI) for C25H25N7OS: 472.1 (MH+).
100276] Compound 348 6-(3-cthyI-l-benzofuran-5-yl)-2-methyl-N-{(lS)-l -]3- (me(hyloxy)phenyI]ethyl } pyrimidin-4-amine. 6-(3-ethyl-l -benzofuran-5-yl)-2-methyl-N- {(l S)-l -[3-(methyloxy)phenyl]ethyl }pyrimidin-4-amine was synthesized in a manner analogous to Example 1 and the boronic ester was synthesized in a manner analogous to Example 7a. Ή NMR (400 MHz, d6-DMSO):5 8.16 (s, I H), 7.97 (s, I H), 7.83 (m, I H), 7.75 (m, I H), 7.28 (ms I H), 7.01 -6.99 (m, 2H), 6.97 (s, I H), 6.86 (d, I H), 5.43 (m, I H), 3.73 (s, 3H), 2.73 (q, 2H), 2.62 (s, 3H), 1 .53 (d, 3H), 1.3 1 (t, 3H). MS (EI) for C24H25N3O2:
388.1 (MH+).
[00277] Compound 351 2-mcthyl-6-(3-mcthyI-l-benzofuran-5-yl)-N-{[3- (methyloxy)phenyl]methj }pyrimidin-4-amine. Ή NMR (400 MHz, d<-,-DMSO):5 8.15 (m, I H), 7.97 (s, I H), 7.84-7.69 (m, 2H), 7.30 (t, I H), 7.01 -6 92 (m, 3H), 6.88 (m, IH), 4.72 (br s, 2H), 3.76 (s, 3H), 2.63 (s, 3H), 2.29 (s, 3H). MS (EI) for C22H21N3O2: 360.1 (MH÷).
[00278] Compound 354 -[l -(2-fluorophcnyl)ethyI]-2-methyl-6-(3-mcthyl-l- benzofuran-5-yl)pyrimidin-4-amine. MS (EI) for C22H20FN3O: 362.1 (MH^).
[00279] Compound 355 3-(l -{[6-(3-ethyl-l -bcnzofuran-5-yl)-2-methylpyrimidin-4- yl|amino}cthyl)phcnol. MS (El) for C23H23N3O2: 374.2 (MH+).
[00280] Compound 357 6-(l ,3-benzothiazol-6-yl)-N-[l-(2-chloropyridin-4-yl)cthyI]-2- methylpyrimidin-4-amine. MS (EI) for C|9H,6C1N5S: 382.1 (MH÷).
[00281 ] Compound 365 6-(l ,3-benzothiazol-6-yI)-N-{[2-bromo-5- (methyloxy)phenyl|mcthyl}-2-mcthylpyriinidin-4-amine. MS (EI) for C2oH i7BrN40S: 442.0 (MH+).
[00282] Compound 371 3-({[6-(l,3-bcnzothiazol-6-yl)-2-mcthylpyrimidin-4- yI|amino}methyl)-4-fluorophcnoI. MS (El) for Ci9Hl sFN4OS: 367.2 (MH+). |002831 Compound 3826-(l,3-ben othiazol-6- l)-N-[(5-bromo-2-fluorophenyl)methylJ- 2-methylpyrimidin-4-aminc. MS (El) for Ci9H,4BrFN S: 429.1 (Ml-f).
100284] Compound 3832-methy!-6-(3-mcthyl-l-benzofuran-5-yl)-N-|l-(2- nicthylphenyl)ethyl]pyrimidin-4-aminc. MS (EI) for C23H23N3O: 358.1 (MH+).
[002851 Compound 3846-(l,3-benzorhiazol-6-yl)-N-{[2-fluoro-5- (methyloxy)phcnyl]nicthyl}-2-methylpyrimidin-4-aniinc. MS (El) for C2oHl7FN4OS: 381.2 (ΜΙ-Γ).
[00286] Compound 396 N-[(4R)-3,4-dihydro-2H-chronicn-4-yI|-2-methyl-6-(3-methyl- t-benzofuran-5-yl)pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO):88.21 (br s, 1 H), 7.92 (brs: 11-0,7.84 (s: IH), 7.80 (br s, IH), 7.63 (d, IH), 7.23-7.15 (m, 2H), 6.87 (t, IH), 6.81 (d, IH), 5.40 (br s, IH), 4.26 (m, 2H), 2.26 (s, 3H), 2.15 (m, IH), 2.02 (m, IH), 1.90 (s, 2H, acetate peak). MS (EI) for C23H21N3O2: 372.2 (MH+).
[00287] Compound 4016-(4-chloro-3-mcthylphenyl)-N-[(4R)-3,4-dihydiO-2H-chromcn- 4-yl]-2-mcthylpyrimidin-4-amine. Ή NMR (400 MHz. dfl-DMSO): 7.95 (m, IH), 7.79 (m, 2H), 7. 1 (d, IH), 7.19 (m, IH), 7.17 (m, IH), 6.87 (t, IH), 6.80 (m, 2H), 5.38 (br s, IH), 4.24 (m, 2H), 2.46 (s, 3H), 2.41 (s, 3H), 2.13 (m, IH), 2.02 (m, IH); MS (EI) for C21H20CIN3O: 366.1 (MH*).
[00288] Compound 4083-(l-{[2-mcthyl-6-(3-mcthyl-l-bcnzofuran-5-yl)pyrimidin-4- yI]amino}ethyl)phenoi. Ή NMR (400 MHz, CDCI3): 7.96 (s, IH), 7.66 (d, IH), 7.41 (m, 2H), 7.23 (t, IH), 6.91 (d, IH), 6.82 (s, IH), 6.76 (dd, IH), 6.37 (s, IH), 5.43 (br s, IH), 4.76 (br s, IH), 2.54 (s, 3H), 2.22 (s, 3H), 1.53 (d, 3H); MS (EI) for C22H21N3O2: 3.60.2 (MH÷).
[00289] Compound 409 N-[(lS)-l-(3-bromophenyl)cthyI]-2-ntcthyI-6-(3-methyl-l- bcnzofuran-5-yl)pynmidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.20 (s, IH), 7.92 (dd, IH), 7.83 (m, 2H), 7.62 (111, 2H), 7.43 (m, 2H), 7.30 (t, 1 H), 6.85 (br s, IH), 5.28 (br s, IH), 2.40 (s, 3H), 2.26 (s, 3H), 1.45 (d, 3H); MS (EI) for C22H2oBrN30: 422.1 (MH+).
[002901 Compound 4113-[(lS)-l-{[2-mcthyl-6-(3-mcthyl-l-bcnzofuran-5-yl)pyrimidin- 4-yl]amino}erhyl]phenol. Ή NMR (400 MHz, d6-DMSO): 9.32 (s, IH), 8.14 (s, IH), 7.88 (dd, IH), 7.80 (s, IH), 7.68 (m, IH), 7.57 (d, IH), 7.09 (t, IH), 6.78 (m, 3H), 6.58 (d, IH), 5.23 (br s, IH), 2.38 (s, 3H), 2.24 (s, 3H), 1.40 (d, 3H); MS (EI) for C22H21N3O2: 360.2 (MH+).
[00291] Compound 413 N-[(4R)-3,4-dihydro-2H-chromcn-4-yl|-2-methyl-6-(4-methyl- 3,4-dihydro-2H-l,4-bcnzoxazin-6-yl)pyrimidin-4-amine. N-[(4R)-3,4-dihydro-2H- chromen-4-yl]-2-methyl-6-(4-methyl-3,4-diliydiO-2H-l,4-benzoxazin-6-yl)pyrinn^in-4- amine was made in a manner analogous to Example 1 , while t e boron ester was synthesized in a manner analogous to Example 7a. Ή NMR (400 MHz, d6-DMSO): 7.64 (m, 11-1), 7.30 (m, IH), 7.18 (m, 3H), 6.87 (t, IH), 6.79 (d, IH), 6.73 (m, 2H), 5.35 (m, IH), 4.27 (m, 4H), 3.26 (m, 2H), 2.89 (s, 3H), 2.44 (s, 3H), 2.13 (m, IH), 2.00 (m, IH); MS (EI) for
C23H2 N4O2: 389.2 (ΜΙ- ).
100292] Compound 4142-niethyl-6-(3-mcthyl-l-bcnzofuran-5-yl)-N-[(lS)-l- phcnylethyl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.17 (s, I H), 7.91 (d, IH), 7.82 (s, IH), 7.78 (m, IH), 7.59 (d, IH), 7.43 (m, 2H), 7.33 (m, 2H), 7.22 (t: IH), 6.83 (m, IH), 5.31 (br s, IH), 2.40 (s, 3H), 2.26 (ss 3H), 1.48 (d, 3H); MS (EL) for C22H21N3O: 344.2 (ΜΙ- ).
[00293] Compound 417 N-[(lS)-l-(4-fluorophcnyl)ethyl]-2-mcthyl-6-(3-mcthyl-l- bcnzofuran-5-yl)pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.18 (s, IH), 7.90 (dd, IH), 7.83 (s, IH), 7.78 (m, IH), 7.60 (d, IH), 7.47 (m, 2H), 7.15 (t, 2H), 6.83 (m, IH), 5.28 (br s, 1 H), 2.40 (s, 3H), 2.26 (s, 3H), 1.45 (d, 3H); MS (EI) for C22H20FN3O: 362.2 (MH+).
100294] Compound 420 N-[l-(3-fluoropheny!)cthyI]-2-mcthyl-6-(3-methyl-l- bcnzofuran-5-yI)pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.18 (s, IH), 8.05 (m, IH), 7.91 (d, IH), 7.85 (s, IH), 7.65 (cl, IH), 7.37 (m, IH), 7.28 (m, 2H): 7.05 (t, IH), 6.86 (m, IH), 5.32 (s, IH), 2.42 (s, 3H), 2.26 (s, 3H), 1.47 (d, 3H); MS (EI) for C22H20FN3O: 362.2 (MH+).
[00295] Compound 4263-|(lR)-l-{]2-mcthyI-6-(3-methyI-l-benzofuran-5-yI)pyrimidin- 4-yl]amino}ethyl]phenol. Ή NMR (400 MHz, d6-DMSO): 9.32 (s, IH), 8.14 (s, IH), 7.88 (dd, IH), 7.80 (s, IH), 7.68 (m, IH), 7.57 (d, IH), 7.09 (t, IH), 6.78 (m, 3H), 6.58 (d, IH), 5.23 (br s, 1 H), 2.38 (s, 3H), 2.24 (s, 3H), 1.40 (d, 3H); MS (EI) for C22H21 3O2: 360.2 (MH+).
[00296] Compound 4302-methyl-6-(3-metliyl-l-bcnzofuran-5-yl)-N-{(lR)-l-[3- (niethyloxy)phcnyl]ethyl}pyrimidin-4-amine. 2-methyl-6-(3-methyl-l-benzofuran-5-yl)- N-{(lR)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4-amine was made in a manner analogous to Example 1 , while the boron ester was synthesized in a manner analogous to Example 7a. Ή NMR (400 MHz, d6-DMSO): 8.19 (s, IH), 7.92 (dd, lH),7.82(s, IH), 7.76 (m,lH), 7.60 (d, IH), 7.25 (t, IH), 7.02 (m, 2H), 6.87 (m, I IT), 6.80 (d, IH), 5.31 (br s, IH), 3.74 (s, 3H), 2.41 (s, 3H), 2.26 (s, 3H), 1.46 (d, 3H); MS (EI) for C23H23N3O2: 374.2 (MH+).
[002971 Compound 4386-(1 ,3-henzothiazo!-6-yl)-2-mcthyI-N-[l-(3-morpholin-4- yIphenyl)ethyl]pyrimidin-4-amine. 6-( 1 ,3-benzothiazol-6-yl)-2-methyl-N-[ 1 -(3-morpholin- 4-ylphenyl)ethyl]pyrimidin-4-amine was made in a manner analogous to Example 1, while the amine was synthesized in a manner analogous to Example 6j. Ή NMR (400 MHz, άβ- DMSO): 9.47 (s, 1 H), 8.79 (s, I H), 8.15 (m, 2H), 7.82 (m, I H), 7.17 (t, 1 H), 7.04 (m, 1 H), 6.88 (m, 2H), 6.77 (m, I H), 5.31 (br s, I H). 3.74 (t, 41-1), 3.10 (m, 4H), 2.41 (s, 3H), 1.47 (d, 3H); MS (El) for C24H25N5OS: 432.2 ( H+).
100298] Compound 443 6-(l ,3-bcn othiazol-6-yl)-N-ll-(3-bromophenyl)cthyl]-2- mcthyIpyrimidin-4-aminc. MS (EI) for C2oH | 7BrN4S: 425.1 (MH+).
[00299] Compound 456 6-(l ,3-benzothiazol-6-yl)-2-methyl-N-{l -[2-(mcthyIoxy)pyridin-
4-y!]cthyI}pyrimidin-4-aminc. MS (EI) for C2oH|9N5OS: 378.1 (MH+).
[00300] Compound 461 6-(l ,3-benzothiazol-6-yl)-N-[(2-nuorophenyI)methyl]-2- methyIpyrimidin-4-amine. MS (EI) for C|9H |$FK,S: 351 .1 (MH*).
[00301 J Compound 468 6-(l,3-bcnzothiazol-6-yI)-2-mcthyI-N-(piperidin-3- yIincthyl)pyrimidin-4-aminc. MS (EI) for C|S[-I2| N5S: 340.2 (MH ").
[00302] Compound 470 6-(l,3-bcnzothiazoI-6-yl)-N-|(2-chlorophenyl)mcthyl]-2- mcthyIpyrimidin-4-aminc. MS (EI) for C 19H 15CIN4S: 367.1 (MH+).
[003031 Compound 471 6-(l,3-bcnzothiazol-6-y])- -[(2-chloro-6-fluoro-3- mcthylphenyl)methyl]-2-mcthylpyrimidin-4-aminc. MS (EI) for C2oHi6ClFN4S: 399.1
(Ml-f).
[00304] Compound 472 6-(l,3-bcnzothiazol-6-yl)-N-{[2-chIoro-6-fluoro-3- (mcthyloxy)phenyI]mcthyl}-2-methyIpyrimidin-4-aminc. MS (EI) for C20H 16CIFN4OS: 415.1 (MH" ).
[00305] Compound 479 6-(l ,3-bcnzothiazoI-6-yl)-2-mcthyI-N-{[l-(l H-pyrrol-2- ylcarbonyl)pipcridin-3-yl]methyl}pyrimidin-4-amine. MS (EI) for C23l I2i 60S: 433.5 (ΜΙ-Γ).
[00306] Compound 484 6-(l,3-bcnzothiazoI-6-yl)-2-methyl-N-({l -](l- methyIcyclopropyl)carbonyl]piperidin-3-yI}mcthyI)pyrimidin-4-amine. MS (EI) for C23H27N5OS: 422.6 (ΜΙ-Γ).
100307] Compound 485 6-(l ,3-bcnzotliiazoI-6-yI)-N-{[ l-(cyclopcnrj lcarbonyl)piperidin- 3-yI]methyl}-2-methylpyrimidin-4-amine. MS (EI) for C24H29N5OS: 436.6 (MH÷).
100308] Compound 487 6-(l,3-bcnzothiazoI-6-yl)-N-{[ l-(cyclobutyIcarbonyl)piperidin- 3-yI]methyl}-2-methylpyrimidin-4-aminc. MS (EI) for C23H27N5OS: 422.6 (MH+).
100309] Compound 489 6-(l,3-bcnzothiazol-6-yl)-N-{] l-(cyclohcxylcarbonyl)piperidin- 3-yI]methyI}-2-methylpyrimidin-4-aminc. MS (EI) for C25I-l3iN5OS: 450.6 (ΜΙ- ).
[00310] Compound 491 6-(l,3-benzothiazol-6-yl)-2-methy!-N-(l- methylbut 'l)pyrjmidin-4-aminc. MS (EI) for C17H20N4S: 313.4 (MH*). [003111 Compound 492 6-(l ,3-benzothiazol-6-yl)-2-methyl-N-(3- mcthylbutyl)pyrimidin-4-aminc. MS (EI) for C17H20N4S: 313.4 (MH+).
[00312] Compound 493 6-(l ,3-benzothiazol-6-yl)-N-(2-cycIohcx-l -cn-l-ylethyl)-2- mcthylpyrimidin-4-aminc. MS (EI) for C20H22N4S: 351 .5 (ΜΙ-Γ").
[00313] Compound 494 4-(2-{[6-(l ,3-bcnzothiazol-6-yl)-2-methylpyrimidin-4- yl[amino}cthyl)phenol. MS (EI) for CSoH m ^OS: 363.5 (MH+).
[003141 Compound 495 6-(l ,3-bcnzothiazol-6-yl)-2-mcthyl- -pcntylpyrimidin-4-amine.
MS (EI) for C 17H20N4S: 313.4 (ΜΙ-Γ).
[00315] Compound 496 6-(l ,3-benzorhiazol-6-yl)-2-merhyl-N-(l- methylpropyl)pyrimidin-4-amine. MS (EI) for Ci6H |8R,S: 299.4 (MH+).
[003161 Compound 497 6-(l ,3-bcnzorhiazoI-6-yl)-2-mcthyl-N-(l- mcthyIhcxyl)pyrimidin-4-amine. MS (EI) for C|9H2jN4S: 341.5 ((MI-f).
[00317] Compound 498 6-(l ,3-bcnzothiazo!-6-yl)-2-methyI-N-|(lS)-l,2,2- trimethylpropyl]pyrimidin-4-aminc. MS (EI) for C 18H22N4S: 327.5 (MH+).
[00318] Compound 499 6-(l ,3-bcnzothiazol-6-yl)-2-methyl-N-(2-pyridin-2- ylethyl)pyrimidin-4-aminc. MS (EI) for C 19H17N5S: 348.4 (MH+).
[00319] Compound 500 6-(l,3-bcnzothiazol-6-yl)-2-mcthyI-N-[ l-methyl-2-
(methyloxy)ethyI]pyrintidin-4-aminc. MS (EI) for Ci6r¼N OS: 31 .4 (MH÷).
[003201 Compound 501 6-(l,3-benzothiazol-6-yl)-N-|(l S)-l-(3-bromophenyl)cthyl]-2- methylpyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 9.42 (s, 1 H), 8.72 (d, 1 H), 8.12
(m, 2H), 7.85 (m, 1 H), 7.61 (m, 1 H), 7.42 (m, 2H), 7.28 (t, 1 H), 6.85 (br s, l H), 5.32 (m, 1 H),
2.45 (s, 3H), 1.48 (d, 3H); MS (EI) for C.oH nBrN.S: 427.0 (MH+).
[003211 Compound 503 (2E)-3-{3-[(l S)-l -{[6-(l,3-bcnzothiazoI-6-yl)-2- methylpyrimidin-4-yl]amino}cthyl]phcnyl}- -ethylprop-2-cnamidc. MS (EI) for
C25H25N5OS: 444.1 (ΜΙ-Γ).
[00322] Compound 507 6-(l ,3-bcnzothiazol-6-yl)-2-mcthyl-N-[l-(3- nitrophenyI)ethyI]pyrimidin-4-aminc. MS (EI) for C20H 17N5O2S: 392.1 (ΜΙ- ).
[00323] Compound 508 (2E)-3-{3-[(l S)-l-{[6-(l,3-bcnzothiazoI-6-yl)-2- methylpyrimidin-4-yl]amino}cthyl]phcnyl}-N-(l ,l-dimethylethyl)prop-2-enamidc. MS
(EI) for C27H29N5OS: 472.2 (MH÷).
[00324] Compound 509 N-[l -(3-aminoplienyl)cthyl]-6-(l ,3-bcnzothiazol-6-yl)-2- methylpyrimidin-4-amine. MS (EI) for C20H 19N5S: 362.1 (ΜΗ ').
[00325] Compound 512 6-(l,3-bcnzothiazol-6-yI)-2-methyl-N-[(lS)-l - phcnylcthyl]pyrimidin-4-aminc: MS (EI) for C20H 18 4S: 347.1 (ΜΙ- ). 100326] Compound 513 6-(l ,3-bcnzothiazol-6-yl)-N-(2,2-dimethyI-3,4-dihydro-2H- chromcn-4-yl)-2-mcthylpyrimidin-4-aminc. MS (EI) for C23H22N4OS: 403.1 (MH+). 100327] Compound 516 2-mcthyl-6-(3-mcthyI-l-bcnzofuran-5-yl)-N-{(lS)-l-]4- (methyloxy)phenyl]cthyl}pyrimidin-4-amine. Ή NMR (400 MHz, d4-MeOH): 8.05 (br s, I H), 7.71 (br d, 3H), 7.38 (d, 2H), 6.95 (d, 2H), 6.75 (s, IH), 5.50 (m, I H), 3.75(s, 3H), 2.63 (s, 3H), 2.34 (d, 3H), 1 .62 (s, 3H); MS (EI) for C23H23N3O2: 374.1 (ΜΙ-Γ).
100328] Compound 524 6-(l ,3-ben/.othiazol-6-yl)-2-mcthyI-N-{l-[3- (propyIoxy)phenyl]cthyl}pyriniidin-4-amine. MS (EI) for
Figure imgf000197_0001
405.1 (Mi l "). 100329] Compound 533 N-(5-{|6-(l,3-bcnzothiazol-6-yl)-2-methyIpyrimidin-4- yl]amino}-5,6,7,8-tetrahydronaphthalen-2-yI)piOpanamide. (EI) for C25H25N5OS: 444.2 (MH+).
100330] Compound 582 2-mcthyl-6-(3-methyl-l-bcnzofuran-5-yI)-N-{(lS)-l-]3-(lH- tetrazoI-l-yl)phenyl]ethyl}pyriinidin-4-aminc. 2-methyl-6-(3-methyl-l -benzonjran-5-yl)- N-{(l S)- l -[3-(l H-tetrazol- l -yl)phenyl]elhyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 1 while the amine was synthesized in a manner analogous to Example 6f. Ή NMR (400 MHz. CD3CN) δ 9.33 (s, 1 H), 8.17 (s, 1 H), 7.94 - 7.85 (m, 2H), 7.67 - 7.62 (m, I H), 7.61 (t, ./ = 1.5 Hz, I H), 7.59 (d, ./ = 7.5 Hz, 1 H), 7.56 - 7.54 (m, I H), 7.50 (d, ./ = 8.6 Hz, I H), 6.71 (s, I H), 6.28 (d, ./ = 7.2 Hz, I H), 5.26 (s, I H), 2.43 (s, 3H), 2.27 (dd, J = 4.4, 1.4 Hz, 3H), 1.60 (d, ./ = 7.0 Hz, 3H); MS (EI) for C23H21N7O: 412.01 (MH+).
[00331 ] Compound 583 2-mcthyl-6-(3-mcthyl-l-bcnzofuran-5-yI)-N-{(lR)-l-[3-(lH- tcirazol-l-yl)phcnyl]cthyl}pyrimidin-4-aniinc. 2-methyl-6-(3-methyl- l -benzofuran-5-yl)- N-{(l R)-l -[3-(l H-tetrazol-l -yl)phenyl |ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 1 while the amine was synthesized in a manner analogous to Example 6f. MS (EI) for C23H21 N7O: 412.01 (MH+).
[00332] Compound 692 N-[l-(5-bromopyr idin-3-yI)cthyl]-2-methyl-6-(3-methyI-l- benzofuran-5-yI)pyrimidin-4-amine. N-[l -(5-bromopyridin-3-yl)ethyl]-2-methyl-6-(3- methyl-l -benzofuran-5-yl)pyrimidin-4-amine was synthesized in a manner analogous to Example 1 while the amine was synthesized in a manner analogous to Example 6a. Ή NMR (400 MHz, d6-DMSO: 8.66 (s, 1 H), 8.58 (d, I H), 8.21 (s, 1 1-1), 8.10 (s, I H), 7.95 (d, I H), 7.86 (d, I H), 7.83 (d, 1 H), 7.62 (d, I H), 6.88 (s, I H), 5.28 (s, I H), 2.38 (d, 3H), 2.27 (d, 3H), 1.51 (d, 3H); MS (EI) for C2| Hi9BrN40: 422.9 (ΜΙ- ).
|00333] Compound 674 5-|4-(l -{[2-methyl-6-(3-mcthyl-l-benzofuran-5-yl)pyrimidin-4- yI]amino}cthyl)pyridin-2-yl]pyrimidin-2-amine. 5-[4-( l -{ [2-methyl-6-(3-methyl-l - benzofuran-5-yl)pyrimidin-4-yl]amino }ethyl)pyHdin-2-yl]pyrimidin-2-amine was synthesized in a manner analogous to Example 1 while the amine was synthesized in a manner analogous to Example 6d. Ή NMR (400 MHz, d6-DMSO: 8.92 (s, 2H), 8.52 (d, 1 H), 8.19 (s, 1 H), 7.94 (d, 2H), 7.82 (s, 2H), 7.60 (ds 1 H), 7.30 (s, 1 H), 7.00 (s, 2H), 6.95 - 6.86 (m, 1 H), 5.42 - 5.21 (m, 1 H), 2.39 (s, 3H), 2.25 (s, 3H), 1 .52 (d, 3H); MS (EI) for C25H23N7O: 438.2 (MH+).
100334) Compound 681 2-mcthyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(l R)-l-[2-(l - mcthyl-l H-pyrazol-4-yI)pyridin-4-yI]ethyl}pyrimidin-4-arnine. 2-melhyI-6-(3-methyl- l - benzofuran-5-yl)-N-{( l )-l -[2-(l -methyl- l H-pyrazol-4-yl)pyridin-4-yl]ethyl}pyrimidin-4- amine was synthesized in a manner analogous to Example 1 while the amine was synthesized in a manner analogous to Example 6d. MS (EI) for CjjHwNcO: 425.1 (MH+).
[00335] Compound 682 2-mcthyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(l S)-l-|2-(l- methyl-lH-pyrazol-4-yI)pyridin-4-yl]cthyl}pyrimidin-4-aminc. 2-methyl-6-(3-methyl-l - benzofuran-5-yl)-N-{(l S)-l-[2-( l -methyl- l H-pyrazol-4-yl)pyridin-4-yl']ethyl}pyrimidin-4- amine was synthesized in a manner analogous to Example 1 while the amine was synthesized in a manner analogous to Example 6d. Ή NMR (400 MHz, d6-DMSO: 8.54 - 8.52 (d, 1 H), 8.40 (s, 1 H), 8.15 (s, 1 H), 8.12 (s, 1 H); 7.97 (s, 1 H), 7.88 - 7.75 (m, 3H), 7.39 - 7.29 (m, I I I), 7.03 (s, 1 H), 5.49 - 5.45 (1 , H), 5.34 - 5.26 (m, 1 H), 3.91 (s, 3H), 2.58 (sf 3H), 2.28 (s: 3H), 1 .61 - 1 .59 (d, 3H); MS (El) for C25H2.iNf,0: 425.1 (MH+).
[003361 Compound 545 N-| 1-(3-bromo-4-fIuorophcnyl)ethyl|-2-methyl-6-(3-methyI-l- benzofuran-5-yl)pyrimidin-4-aminc. N-[l -(3-bromo-4-fluorophenyl)ethyl]-2-methyl-6-(3- methyl-l -benzofuran-5-yl)pyrimidin-4-amine was synthesized in a manner analogous to Example 1 while the amine was synthesized in a manner analogous to Example 6e. Ή NMR (400 MHz, dmso) δ 8.24 - 8.09 (m, 1 H), 7.95 (d, 1 H), 7.80 (d, 2H), 7.61 (dt, 1 H), 7.56 - 7.45 (m, 1 H), 7.43 - 7.24 (m, 2H), 7.02 (d, 1 H), 5.39 (dd, 1 H), 4.70 (q, 1 H), 2.71 - 2.55 (m, 4H), 2.31 - 2.22 (m, 3H), 1 .26 (t, 3H); MS (El) for C22H ,9BrFN30: 440:442 (M+ Bromine isotope).
[00337] Compound 564 N-| l-(3-brom()-5-fluorophenyl)ethy!]-2-inethyl-6-(3-mcthyl-l- benzofuran-5-yl)pyrimidin-4-amine. N-[ 1 -(3-bromo-5-fluorophenyl)ethyl]-2-methyl-6-(3- methyl-l -benzofuran-5-yl)pyrimidin-4-amine was synthesized in a manner analogous to Example 1 the amine was synthesized in a manner analogous to Example 6e. MS (EI) for C22H |9BrFN30: 439.8: 441 .8 (M+ Bromine isotope).
[00338] Compound 569 N-Il-(3-bromo-4-mcthylphcnyl)cthyl]-2-mcthyl-6-(3-methyl-l- benzofuran-5-yI)pyrimidin-4-aminc. N-[ l -(3-bromo-4-methylphenyl)ethyl]-2-methyl-6-(3- methyl-l -benzofuran-5-yl)pyrimidin-4-amine was synthesized in a manner analogous to Example 1 while the amine was synthesized in a manner analogous to Example 6e. MS (EI) for C23H22BrN30: 436.1 :438.1 (M+ Bromine isotope).
100339] Compound 598 N-[(lS)-l-(3-brotnophcnyl)ethyl|-6-(3-ethyl-l-benzofuran-5-yl)- 2-mcthyIpyrimidin-4-aminc. N^(l S)-l 3-bromophenyl)ethyl]-6-(3-ethyl- l -benzoruran-5- yl)-2-methylpyrimidin-4-amine was synthesized in a manner analogous to Example 1 while the boronic ester was synthesized in a manner analogous to Example 7a. MS (EI) for C23H22BrN30: 436.0, 439.0 (Ml-!*).
[00340] Compound 590 N-[(l S)-l-(3-bromophenyl)cthyl]-2-methyl-6-(3-niethyl-l- bcnzothicn-5-yl)pyrimidin-4-amine. N-[( l S)-l -(3-bromophenyl)ethyl]-2-methyl-6-(3- methyl-l -benzolhien-5-yl)pyrimidin-4-amine was synthesized in a manner analogous to Example 1 while the boronic ester was synthesized in a manner analogous to Example 7f. Ή NMR (400 MHz, CD3CN) δ 8.23 - 8.07 (m, 1 H), 7.97 (dd, J = 32.2, 12.8 Hz, 1 H), 7.69 - 7.57 (m, 2H), 7.57 - 7.39 (m, 2H), 7.3 1 (dd, ./ = 16.4, 8.4 Hz, 2H), 6.90 (s, 1 H), 5.41 (d, ./ = 6.7 Hz, lH), 3.25 (d, ./ = 15.7 Hz, 1 H), 2.58 - 2.49 (m: 3H), 2.48 (s, 3H), 2.42 (s, 1 H), 1.58 (d, J= 6.9 Hz, 3H); MS (EI) for C22H20BrN3S: 437.95, 439.81 (MH+)
Example 2: Synthesis of 6-(4-chlorophcnyl)-2-methyI-N-[(l R)-l , 2,3,4- tetrahydronaphthalen-l-yl]pyrimidin-4-amine (Compound 138).
Figure imgf000199_0001
Figure imgf000199_0002
Step 1 :
[00341 ] A pressure vessel was charged with 4,6-dichloro-2-methylpyrimidine (3.87 g, 23.7 mmol, 1.5 eq), (R)-l ,2,3.4-tetrahydronaphthalen-l -amine (2.33 niL, 15.8 mmoL 1.0 eq), DMA (25.0 mL). and D1EA (5.51 mL, 31.7 mmol, 2.0 eq). The reaction vessel was sealed and stirred at room temperature for 18 hours. The reaction was then partitioned between water and EtOAc, and the aqueous layer was extracted 3 times with EtOAc. The organic layers were combined, dried over Na2S04. and concentrated under vacuum to give the crude product. The product was purified by Si02 flash chromatography (80:20 to 75:25 hexanes/ethyl acetate) to afford (R)-6-chloro-2-methyl-N-( l ,23,4-telrahydronaphthalen- l - yl)pyrimidin-4-amine as a yellow solid (3.82 g, 88% yield). Ή NMR (400 MHz. d6-DMSO): 7.97 (d, 1 H), 7.15 (m, 3H), 6.34 (s: l H), 5.31 (br d, 1 H), 2.76 (m, 2H), 2.36 (s, 3H), 1 .93 (m, 2H), 1.86 (m, 1 H), 1.76 (m, 2H); MS (EI) for C, 5H 16CIN3: 274.1 (ΜΙΤ' ).
Step 2:
[00342| A pressure vessel was charged with (R)-6-chloro-2-methyl-N-(l ,2,3,4- tetrahydronaphlhalen-l -yl)pyrimidin-4-amine (1 18.0 mg, 0.431 mmol, 1.0 eq), 4- chlorophenylboronic acid (74.0 mg, 0.474 mmol, 1.1 eq), 1 ,2-DME (1 .5 mL), and 2M
NaiCO.1 (0.43 1 mL, 0.862 mmol, 2.0 eq). The reaction was purged with nitrogen before adding Pd(dppf)Cl2 (18 mg, 0.022 mmol, 0.05 eq), sealed, and heated to 100 °C for 18 hours. The reaction was then cooled to rt and filtered through a pad of Celite. The reaction was partitioned between water and EtOAc, and the aqueous layer was extracted 3 times with EtOAc. The organic layers were combined, dried over Na2SCX|, and concentrated under vacuum to give the crude product as a brown oil. Purification by preparative HPLC (reverse- phase, acetonitrile/water with 25 mM ammonium acetate), followed by concentration at reduced pressure and lyophilization. afforded 6-(4-chlorophenyl)-2-methyl-N-[(l R)-l .2,3,4- tetrahydronaphthalen-l -yl]pyrimidin-4-amine (Compound 138, 19 mg. 13%) as a white solid. Ή NMR (400 MHz, d6-DMSO): 7.94 (d, 2H), 7.72 (m, 1 H), 7.52 (d, 2H), 7.18 (t, 1 H), 7.1 1 (m, 2H), 6.76 (s, 1 H), 5.38 (br s, 1 H), 2.76 (m, 2H), 2.42 (s, 3H), 1.95 (m, 2H), 1 .87 (m, 1 H), 1.77 (m, 2H); MS (EI) for C2iH2oClN3: 350.2 (MH+).
[00343| The following compounds were prepared by a manner analogous to example 2:
[00344] Compound 84 2-mcthyl-6-(3-mcthyl-l-bcnzofiiran-5-yl)-N-|(l )-l,2,3,4- tetrahydronaphthalcn-l-yl]pyriniidin-4-amine. 2-methyl-6-(3-methyl- l -benzofuran-5-yl)- N-[( l R)- L2,3,4-tetrahydronaphthalen- l -yl]pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the boronic esler was synthesized in a manner analogous to Example 7a. Ή NMR (400 MHz, d6-DMSO): 8.20 (br s, 1 H), 7.91 (m, 1 H), 7.82 (s, 1 H), 7.61 (m, 2H), 7.24 (m, 1 H), 7.22-7.1 1 (m, 3H), 6.86 (br s, 1 H), 5.43 (br s, 1 H), 2.79 (m, 2H), 2.46 (s, 3H), 2.27 (s, 3H), 1 .99 (m, 2H), 1.89 (s, 2H), 1 .83 (m, 2H); MS (EI) for C24H23N3O: 370.3 (MH+).
[00345] Compound 85 6-(l -bcnzofuran-5-yl)-2-mcthyl-N-|(l R)-l,2,3,4- tctrahydronaphthaIen-l-yl]pyrimidin-4-amine. Ή NMR (400 Hz. d6-DMSO): 8.29 (br s. IH), 8.05 (s, IH), 7.90 (m, 1 H), 7.67 (m, 2H), 7.25-7.06 (m, 5H), 6.81 (br s, IH), 5.42 (br s, IH), 2.39 (m, 2H), 2.46 (s, 3H), 1.94 (m, 2H), 1.79 (m, 2H); MS (EI) for C23H21N3O: 356.2 (ΜΙ- ).
100346] Compound 866-(l-benzothicn-5-yl)-2-methyI-N-[(lR)-l,2,3,4- tctrahydronaphthalen-l-yljpyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 8.52 (br s, IH), 8.09 (d, IH), 7.91 (m, IH), 7.82 (d, IH), 7.70 (m, IH), 7.58 (m, IH), 7.24-7.13 (m, 4H), 6.86 (br s, IH), 5.42 (br s, IH), 2.79 (m, 2H): 2.47 (s, 3H), 1.97 (m, 2H), 1.89 (s, IH), 1.79 (m, 2H); MS (EI) for C23H2,N3S: 372.1 (ΜΙ- ).
[00347] Compound 882-mcthyl-6-(4-methyl-3,4-dihydro-2H-l,4-bcnzoxazin-6-yl)-N- |(lR)-l,2,3,4-tctrahydronaphthalcn-l-yl|pyrimidin-4-aminc. 2-methyl-6-(4-methyl-3,4- di ydro-2H-l,4-benzoxazin-6-yl)-N-[(l )-l,2.3,4-tetrahydronaphthalen-l-yl]pyri amine was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized in a manner analogous to Example 7b. Ή NMR (400 MHz, d6-DMSO): 7.51 (m, IH), 7.30 (s, IH), 7.22 (m, 2H), 7.14-7.12 (m, 3H), 6.74 (d, IH), 6.71 (br s, IH), 5.39 (br s, IH), 4.28 (t, 2H), 3.25 (t, 2H), 2.81 (s, 3H), 2.77 (m.2H), 2.42 (s, 3H), 1.97 (m, 2H), 1.89 (3H), 1.78 (m, 2H); MS (EI) for C24H26 4O: 387.3 (MH+).
[00348] Compound 892-methy!-6-(3-mcthyI-l-bcnzofuran-5-yI)-N-{(lS)-l-[3- (methyloxy)phcnyl|crhyl}pyrimidin-4-aminc.2-methyl-6-(3-methyl-l-benzofuran-5-yl)- N-{(1 S)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and and the boronic ester was synthesized from the corresponding bromide in a manner a nalogous to Example 7a. Ή NMR (400 MHz, d6-DMSO): 8.16 (m, IH), 7.97 (s, IH), 7.81 (m, IH), 7.75 (m, IH), 7.30 (m, IH), 7.02 (m, 3H), 6.85 (m, IH), 5.42 (br s, IH), 3.76 (s, 3H), 2.62 (s, 3H), 2.28 (s, 3H), 1.53 (d, 3H); MS (EI) for C23H23N302: 374.2 (MH÷).
[00349] Compound 902-methyl-6-(l-methyI-2,3-dihydro-lH-inclol-6-yl)-N-](l R)- l,2,3,4-tetrahydronaphthalen-l-yl]pyrimidin-4-amine. 2-methyl-6-(l-methyl-2,3- dihydro-lH-indoI-6-yl)-N-[(lR)-l,2,3,4-tetrahydronaphthalen-l-yl]pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and and the boronic ester was synthesized in a manner analogous to Example 7c. Ή NMR (400 MHz, d6-DMSO): 7.56 (m, IH), 7.20- 7.10 (m, 6H), 7.04 (111 IH), 6.73 (m, IH), 5.40 (m, IH), 3.29 (t, 2H), 2.90 (t, 2H), 2.78 (m, 2H), 2.74 (s, 3H), 2.43 (s, 3H), 1.95 (m, 2H), 1.90 (s, 2H), 1.78 (m, 2H); MS (EI) for C24H26N4: 371.3 (MH+).
[00350] Compound 916-(l,3-bcnzoxazoI-6-y])-2-methyl-N-|(lR)-l,2,3,4- tctrahydronaphthalcn-l-yl]pyrimidin-4-amine. 6-(l,3-benzoxazol-6-yl)-2-methyl-N-
200
I [(l )-l,2,3,4-tetrahydronaphthalen-l-yl]pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized from the corresponding bromide in a manner analogous to Example 7a. Ή NMR (400 MHz, d6-DMSO): 8.84 (s, IH), 8.31 (b s: lH),8.0(brs, IH), 7.S8 (ms IH), 7.75 (br s, IH), 7.23-7.13 (m, 4H), 6.86 (br s: IH), 5.45 (br s, 1 H), 2.78 (m, 2H), 2.47 (s, 3H), 1.98 (m, 2H), 1.90 (s, 2H), 1.81 (m, 2H); MS (El) for C22H20N4O: 357.2 (ΜΙ- ).
[003511 Compound 926-(l-bcnzofuran-5-yl)-2-methyl-N-{(lS)-l-[3- (mcthyIoxy)phcnyl]cthyl}pyrimidin-4-amine. Ή NMR (400 MHz, drt-DMSO): 8.20 (s, IH), 8.15 (s, IH), 7.88 (d, IH), 7.75 (m, IH), 7.30 (m, IH), 7.17 (s, IH), 7.02 (m, 2H), 6.90 (m, 2H), 5.48 (m, IH), 3.75 (s, 3H), 2.59 (s, 3H), 1.53 (d, 3H); MS (El) for C22H21N3O2: 360.1 (MH+).
[00352] Compound 936-(2,3-dihydro-l,4-bcnzodioxin-6-yl)-2-mcthyI-N-[(l R)-l, 2,3,4- tetrahydronaphthalen-l-yljpynmidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.52 (s, IH), 7.48 (dd, IH), 7.32 (dd, IH), 7.19-7.13 (m, 4H), 6.91 (d, IH), 6.47 (br s, IH), 5.15 (br s, IH), 4.27 (m, 4H, overlapped), 2.82 (m, 2H), 2.56 (s, 3H), 2.09 (m, 2H), 1.92 (m, 2H); MS (El) for C23H23N3O2: 374.2 (MH+).
[00353] Compound 942-methyl-6-(l-mcthyl-lH-benzimidazol-6-yl)-N-['(lR)-l, 2,3,4- tctrahydronaphthalen-l-yl]pyrimidin-4-amine. Ή NMR (400 MHz. d6-DMSO): 8.24 (s, IH), 8.18 (m, IH), 7.80 (m, IH), 7.68 (m, IH), 7.62 (m, IH), 7.22-7.10 (m, 4H), 6.85 (br s, IH), 5.42 (br s, IH), 3.89 (s, 3H), 2.77 (m, 2H), 2.48 (s, 3H), 1.94 (m, 2H), 1.90 (s, 3H), 1.78 (in, 2H); MS (EI) for C23H23N5: 370.1 (MH+).
[00354] Compound 956-(l-bcnzothicn-5-yl)-2-mcthyl-N-{(lS)-l-[3- (methyloxy)phenyl]cthyl}pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.52 (s, IH), 8.08 (d, IH), 7.92 (d, IH), 7.82 (m, 2H).7.57 (m, IH), 7.24 (t, IH), 7.01 (m, 2H), 6.79 (m, IH), 5.31 (brs, 1 H), 3.74 (s,3H),2.41 (s, 3H), 1.46 (d, 3H); MS (EI) for C22H21N3OS: 376.1 (ΜΙ-Γ).
[00355] Compound 966-(3-amino-4-methylphenyl)-2-mcthyI-N-[(lR)-l, 2,3,4- tetrahydronaphthalcn-l-yl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.58 (m, 1 H), 7.30 (m, 1 H), 7.23-7.10 (m, 4H), 6.98 (m, 2H), 6.67 (br s, 1 H), 5.40 (br s, 1 H), 4.98 (br s, 2H), 2.77 (m, 2H), 2.41 (s, 3H), 2.08 (s, 3H), 1.95 (m, 2H), 1.89 (s, 3H), 1.78 (m, 2H); MS (EI) for C22H24K1: 345.3 (ΜΙ- ).
[00356] Compound 972-met yI-N-{(lS)-l-[3-(mcthyloxy)phcnyl]ethyl}-6-(4- rnetliylphenyl)pyrimidin-4-amine. Ή NMR (400 MHz, dft-DMSO): 7.73 (m, 2H), 7.42 (m, 2H), 7.27 (t, 1 H), 7.00 (m, 2H), 6.87 (m, 2H): 5.40 (br s, 1 H), 3.75 (s, 3H), 2.55 (s, 3H), 2.40 (s, 3I-I), 1.51 (d, 3H); MS (EI) for C21 H23N3O: 334.2 (MH÷).
[00357] Compound 98 6-(4-chlorophcnyl)-2-methyl-N-{(l S)-l-[3- (mcthyloxy)phenyI]cthyl}pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.85 (m, 2H), 7.72 (m, 2H), 7.28 (t, 1 H), 7.0 (m, 2H), 6.85 (m, 2H), 5.40 (br s, 1 H), 3.75 (s, 3H), 2.56 (s, 3H), 1.52 (d, 3H); MS (EI) for C20H20CIN3O: 354.1 (MH+).
[00358] Compound 101 6-(3-ch!orophenyl)-2-methyl-N-{(lS)-l-[3- (mcthyIoxy)phcnyl]cthyl}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.92 (s, 1 H), 7.70 (m, 1 H), 7.63 (m, 1 H), 7.27 (t, 1 H), 6.98 (m, 3H), 6.84 (m, 1 H), 5.41 (br s, 1H), 3.74 (s, 3H), 2.57 (s, 3H), 1 .51 (d, 3H); MS (EI) for C20H20CIN3O: 354.2 (MH+).
[00359) Compound 102 6-(l ,3-bcnzothiazoI-6-yl)-2-methyI-N-|(l S)-l , 2,3,4- tetrahydronaphthalen-l-yl]pyrimidin-4-amine. Ή NMR (400 MHz, CDC13): 9.06 (s, l H), 8.69 (s, l H), 8.19 (d, 1 H), 8.07 (s, 1 H), 7.34 (d, 1 H), 7.21 -7.16 (m, 3H), 6.67 (br s, l H), 2.85 (in, 2H), 2.61 (s, 3H), 2.14 (m, 2H); 2.05 (s, 1 H), 1 .95 (m, 2H); MS (EI) for C22H2oN4S: 373.2 (ΜΙ-Γ).
[00360] Compound 103 6-(3,4-dihydro-2H-l,4-benzoxazin-6-yl)-2-mcthyl-N-[(l R)- l ,2,3,4-tctrahydronaphthalen-l-yl|pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.1 5-7.08 (m, 6H), 6.70 (d, 1 H), 5.98 (br s, 1 H), 5.40 (br s, 1 H), 4.15 (t, 2H), 3.30 (m, 2H), 2.76 (m, 2H), 2.40 (s, 3H), 1.95 (m, 2H), 1 .90 (s, 3H), 1 .78 (m, 2H): MS (EI) for C23H24N4O:. 373.2 (MH+).
[00361 ] Compound 107 6-(2,3-dihydro-l H-indol-6-yl)-2-mcthyI-N-|(l R)-l , 2,3,4- terrahydronaphthalen-l-yl]pyrimidin-4-amine. 6-(2,3-dihydro- l H-indol-6-yl)-2-methyl- N-[(l R)- l ,2,3.4-tetrahydronaphthalen- l -yl]pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized in a manner analogous to Example 7c. Ή NMR (400 MHz, d6-DMSO): 7.56 (br s, 1 H), 7.22 -7.07 (m, 6H), 6.68 (br s, 1 H), 5.64 (br s, 1 H), 5.40 (br s, 1 H), 3.44 (t, 2H), 2.93 (t. 2H), 2.51 (in. 2H), 2.41 (s, 3H), 1.97 (m, 2H), 1 .90 (ss 2H)S 1.79 (ms 2H); MS (El) for C23H24N4: 357.3 (MH+).
[00362] Compound 108 6-(2,2-dilluoro-l ,3-bcnzodioxoI-5-yl)-2-mcthyl-N-[(lR)-l, 2,3,4- tetrahydronaphthalcn-l -ylJpyrimidin-4-aminc. 6-(2.2-difluoro- l ,3-benzodioxol-5-yl)-2- methyl-N-[(l R)-l !2,3.4-tetrahydronaphthalen-l -yl]pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized from the
corresponding bromide in a manner analogous to Example 7a. Ή NMR (400 MHz, CDCI3): 7.73 (s, 1 H), 7.71 (d, IH), 7.32 (d, l H), 7.23-7.10 (m, 4H), 6.48 (br s, 1 H), 5.20 (br s, 1H), 2.81 (m, 2H), 2.57 (s, 3H), 2. 12 (m, 2H), 1.90 (m, 2H); MS (EI) for C22H19F2 3O2: 396.2 (ΜΙ-Γ).
[00363] Compound 109 6-(4-fluorophenyl)-2-niethyI-N-{(l S)-l-[3- (methyIoxy)phcnyl|ethyl}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.88 (m, 21-1), 7.50 (t, 21-1), 7.28 (m, I H), 7.1 -6.91 (m, 3H), 6.85 (m, I H), 5.41 (m, I H), 3.74 (s, 3H), 2.58 (s, 3H), 1 .52 (d, 3H); MS (EI) for C2oH2oFN30: 338.2 (MH+).
[003641 Compound 110 2-mcthyl-N-{(lS)-l-[3-(mcthyloxy)phcnyl]cthyl}-6-(2- mcthylphenyl)pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.50 (m, I H), 7.45- 7.37 (m, 3H), 7.30 (m, ΓΗ), 7.02-7.00 (m, 2H), 6.87 (m, I H), 6.74 (br s, 1 H), 5.40 (m, I H), 3.76 (s, 3H), 2.53 (s, 3H), 2.32 (s, 3H), 1 .52 (d, 3H); MS (EI) for C21 H23N3O: 334.2 (MH÷).
[00365] Compound 1 13 6-(l,3-benzoxazol-6-yl)-2-methyI-N-{(lS)-l-[3- (methyloxy)phcnyl|cthyl}pyrimidin-4-amine. 6-( l ,3-benzoxazol-6-yI)-2-methyl-N-{(l S)- l -[ 3-(methyloxy)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized from the corresponding bromide in a manner analogous to Example 7a. Ή NMR (400 MHz, d6-DMSO): 8.84 (s, IH), 8.34 (br s, I H), 8.03 (m, I H), 7.89 (m, 2H), 7.24 (t, I H), 7.07-6.88 (m, 2H), 6.79 (m, IH), 5.28 (br s, I H), 3.73 (s, 3H), 2.41 (s, 3H), 1 .90 (s, 2H), 1 .46 (d, 3H); MS (EI) for C2 i H20N O2: 361.1 (ΜΙ-Γ).
[00366] Compound 1 14 4-{[6-(l,3-bcnzothiazol-6-yl)-2-mcthylpyrimidin-4-yl]amino}-4- [3-(methyloxy)phenyI]butanenitriIe. 4-{[6-(l ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}-4-[3-(methyloxy)phenyl]butanenitrile was synthesized in a manner analogous to Example 2 and the amine was synthesized in a manner analogous to Example 6c. Ή NMR (400 MHz, d6-DMSO): 9.45 (s, I H), 8.81 (I H), 8.15 -7.90 (m, 3H), 7.26 (t, IH), 6.99 (br s, I H), 6.91 (br s, I H), 6.82 (m, IH), 5.27 (br s, I H), 3.76 (s, 3H), 2.56 (m, 2H), 2.52-2.45 (m, 2H, overlapped), 2.41 (s, 3 H), 2.2-2.01 (m, 4H); MS (EI) for C-23H21N5OS: 416.2 (MH÷).
[00367] Compound 116 6-(l H-indazoI-6-yI)-2-methyl-N-[(l R)-l,2,3,4- tetrahydronaphthalcn-l -yl]pyrimidin-4-aniinc. Ή NMR (400 MHz, d6-DMSO): 13.2 (s, I H), 8.18 (br s, I H), 8.09 (s, I H), 7.81 (d, 1 H), 7.67 (m, ΓΗ), 7.24-7.1 1 (m, 4H), 6.85 (br s, I H), 5.4 (br s, I H), 2.76 (m, 2H), 2.46 (s, 3H), 1.93 (m, 2H), 1 .78 (m, 2H); MS (EI) for C22H21N5: 356.2 (MH+).
[00368] Compound 117 6-(l H-bcnzimida o!-6-yl)-2-mcthyl-N-[(lR)-l,2,3,4- tctrahydronaphthalen-l-yl]pyrimidin-4-aminc. 6-(l H-benzimidazol-6-yl)-2-methyl-N- [(l R)-l ,2,3,4-tetrahydronaphthalen- l -yl]pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized from the corresponding bromide in a manner analogous to Example 7a. Ή NMR (400 MHz, dfi-DMSO): 12.59 (s, I H), 8.28 (d, I H), 8.21 (m, I H), 7.71 -7.60 (m, 2H), 7.24-7.12 (m, 414), 6.83 (br s, 1 H), 5.42 (br s, I H), 2.79 (m, 2H), 2.45 (s, 3H), 1.99 (m, 2H), 1.81 (m, 2H); MS (EI) for C22H21 5 : 356.2 (MH+).
[00369] Compound 118 6-(l,3-bciizothiazol-6-yI)-2-methyl-N-{(lR)-l-f3- (methyloxy)phenyl]ethyl}pyrimidin-4-aniine. 6-(l ,3-benzothiazol-6-yl)-2-methyl-N- {(l R)- l -[3-(methylo.xy)phenyljethyl }pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized from the corresponding bromide in a manner analogous to Example 7a. Ή NMR (400 MHz, CDC13): 9.04 (s, I H), 8.55 (s, I H), 8.13 (d, I H), 7.86 (dd, I H), 7.29 (t, I H), 6.98 (d, I H), 6.93 (s, I H), 6.89 (dd, I H), 6.43 (s, I H), 4.78 (br s, I H), 3.80 (s, 3H), 2.57 (s, 3H), 1.61 (d, 3H); MS (El) for C21 H20N4OS: 377.2 (MH+). '
100370] Compound 122 2-methyl-6-(l -methyl-l H-benzimidazol-6-yl)- -{(lS)-l-[3- (methyloxy)phenyl]cthyl}pyrimidin-4-aminc. Ή NMR (400 MHz, CDC13): 8.24 (s, 1 H), 8.16 (s, I H), 7.80-7.68 (m, 3H), 7.22 (t, 1 H), 6.99 (m, 2H), 6.78 (dd, I H), 5.40 (br s, IH), 3.88 (s, 3H), 3.71 (s, 3H), 2.39 (s, 3H), 1.89 (I H), 1 .43 (d, 3H); MS (EI) for C22H23N5O: 374.1 (Μ1- ).
1003711 Compound 125 6-(4-acetj'l-3,4-dihydro-2H-l ,4-bcnzoxazin-6-yl)-2-methyl-N- [(l R)-l,2,3,4-tetrahydronaphthalen-l-yl|pyrimidin-4-amine. 6-(4-acetyI-3.4-dihydro-2H- 1 ,4-benzoxazin-6-yl)-2-methyl-N-[( 1 R)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl]pyrimidin-4- amine was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized from the corresponding bromide in a manner analogous to Example 7b. Ή NMR (400 MHz, de-DMSO): 7.64 (m, 2H), 7.22-7.12 (m, 4H), 7.10 (d, I H), 6.69 (br s, I H), 5.40 (br s, 1 H), 4.30 (m, 2H), 3.88 (m, 2H), 2.77 (m, 2H), 2.42 (s, 3H), 2.27 (s, 3H), 1 .94 (m, 2H), 1 8 (m, 2H); MS (EI) for C25 H2 N4O2: 415.1 (MH÷).
(003721 Compound 127 6-[3-(dimcthylamino)phcnyIl-2-mcthyl-N-{(l S)-l -[3- (niethyloxy)phenyl]ethyl}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.41 (m, I H), 7.29 (m, I H), 7.04-6.97 (m, 5H), 6.93 (s, I H), 6.84 (m, I H), 5.40 (m, I H), 3.76 (s, 3H), 2.98 (s, 6H), 2.59 (s, 3H), 1 .52 (d, 3H); MS (EI) for C22H26N4O: 363.3 (Ml-f ).
1003731 Compound 130 6-[4-(dimcthyIainino)phcnyl]-2-methyl-N-{(l S)-l-[3- (methyloxy)phenyl]cthyl}pyrimidin-4-aminc. Ή NMR (400 MHz, d -DMSO): 7.80 (d, 2H), 7.57 (m, I H), 7.21 (t, I H), 6.98 (m, 2H), 6.75-6.63 (m, 3H), 5.40 (br s, I H), 3.73 (s, 3H), 2.96 (s, 6H), 2.34 (s, 3H), 1 .42 (d, 31 1); MS (EI) for 022Η26 Ο: 363.2 (MH+). |00374| Compound 1336-(4-chloro-3-methylphcnyl)-2-mcthyI-N-[(lR)-l,2,3,4- tcrrahydronaphthalen-1-yl]pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.94 (s, IH), 7.75 (dd, IH), 7.50 (d, IH), 7.20 (t, IH), 7.13 (m, 3H), 6.77 (s, IH), 5.41 (brs, IH), 2.77 (in, 2H), 2.44 (s, 3H), 2.40 (ss 3H).1.98 (m, 2H), 1.90 (m, 1 H), 1.79 (m, 2H); MS (EI) for C22H22CIN3: 364.2 (MH+).
100375] Compound 1342-fluoro-4-{2-methyl-6-|(lR)-l,2^,4-tetrahydronaphthalen-l- ylamino]pyrimidin-4-yl)benzamide. Ή NMR (400 MHz, d6-DMSO): 7.77 (m, 4H), 7.69 (s, IH), 7.18 (t, IH), 7.11 (m, 3H), 6.81 (s, IH), 5.40 (brs, IH), 2.76 (m, 2H), 2.44 (s, 3H),
1.96 (m, 2H), 1.88 (m, 1 H), 1.78 (m, 2H); MS (EI) for C22H21F 4O: 377.2 (ΜΙ- ).
[00376] Compound 1362-mcthyl-6-(4-mcthylphcnyl)-N-[(lR)-l,2,3,4- tctrahydronaphfhalen-l-yIJpyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.85 (s, 2H), 7.62 (s, IH), 7.27 (d, 2H), 7.20 (d, IH), 7.13 (m, 2H), 6.75 (s, IH), 5.41 (brs, IH), 2.78 (m, 2H), 2.43 (s, 3H), 2.35 (s, 3H), 1.96 (m, 2H), 1.91 (m, IH), 1.79 (m, 2H); MS (EI) for C22H23N3: 330.2 (MH+).
(003771 Compound 1406-(3,4-dichlorophenyl)-2-methyl-N-|(lR)-l,2,3,4- tetrahydronaphthalen-l-yl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.17 (s, IH), 7.88 (d, IH), 7.77 (d, 2H), 7.18 (m, 3H), 6.81 (s, IH), 5.42 (br s, IH), 2.78 (m, 2H), 2.46 (s, 3H), 1.97 (m, 2H), 1.91 (m, IH), 1.80 (m, 2H); MS (El) for C2|H,9Cl2N3: 384.1 (Ml-f).
[00378] Compound 1426-(4-chloro-3-fluorophcnyl)-2-mcthyl-N-|(lR)-l,2 ,4- terrahydronaphthalen-l-yl]pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.94 (d, IH), 7.78 (m, IH), 7.71 (t, IH), 7.20 (t, IH), 7.13 (m, 3H), 6.80 (s, IH), 5.42 (br s, IH), 2.78 (m, 2H), 2.45 (s, 3H), 1.96 (m, 2H), 1.90 (m, IH), 1.80 (m, 2H); MS (EI) for C-21H19CIF 3: 368.1 (MH+).
[003791 Compound 1432-chloro-5-{2-methyl-6-|(lR)-l,2,3,4-tetrahydronaphthalcn-l- ylaminolpyrimidin-4-yl}benzonitrile. Ή NMR (400 MHz, dfl-DMSO): 8.78 (s, IH), 8.45 (d,lH), 7.86 (d, 2H), 7.18 (m, 3H), 6.84 (s, IH), 5.43 (brs, IH), 2.78 (m, 2H), 2.46 (s, 3H),
1.97 (m, 3H), 1.80 (m, 2H); MS (El) for C22H19CIN4: 375.1 (MH+).
[00380] Compound 1442-methyl-N-[(lR)-l,2,3,4-tetrahydronaphthaIcn-l-yl]-6-[4- (trifluoromethyl)phenyl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.15 (d, 2H), 7.85 (d, 3H), 7.22 (t,lH), 7.14 (m, 2H), 6.86 (s, IH), 5.43 (br s, IH), 2.78 (m, 2H), 2.47 (s.3H), 1.98 (m, 2H), 1.92 (m, IH), 1.81 (m, 2H); MS (EI) for C22H20F3 ;,: 384.2 (Ml-f).
[00381] Compound 1456-(3-fluorophcnyl)-2-mcthyl-N-[(lR)-l,2,3,4- tctrahydronaphthalen-l-yl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.74 (br s, 2H), 7.52 (m, IH), 7.30 (m, 1 H), 7.21 (t, IH), 7.15 (m, 3H), 6.79 (s, IH), 5.41 (br s, IH), 2.78 (m, 2H), 2.45 (s, 3H), 1.97 (m, 2H), 1.91 (m, 1 H), 1.80 (m, 2H); MS (EI) for C21H20FN3: 334.2 (MH+).
100382] Compound 1466-|3-(dimethylamino)pIienyl]-2-mcthyl-N-[(lR)-l,2,3,4- tctrahydronaphthaIen-l-yl|pyrimidin-4-amine. Ή N R (400 MHz, d6-DMSO): 7.59 (d, IH), 7.21 (m, 6H), 6.82 (dd, IH), 6.77 (s, IH), 5.41 (brs, IH), 2.95 (s, 6H), 2.77 (rn.2H): 2.44 (s, 3H), 1.93 (m, 3H), 1.80 (m, 2H); MS (EI) for C23H26 4: 359.3 (MH+).
[00383] Compound 1472-methyl-6-(2-mcthylphenyl)-N-[(lR)-l,2,3,4- tetrahydronaphthalen-l-yl]pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.64 (d, 1 H), 7.32 (m, 2H), 7.26 (m, 3H), 7.15 (m, 3H), 6.37 (br s, 1 H), 2.77 (m, 2H), 2.41 (s, 3H), 2.32 (s, 3H), 1.97 (m, 2H), 1.89 (m, IH), ' -80 (m, 2H); MS (EI) for C22H23N3: 330.2 (MH+). 100384] Compound 1483-{2-mcthyl-6-[(lR)-l,213,4-(ctrahydronaphthalcn-l- ylamino]pyrimidin-4-yl}benzonitrile. Ή NMR (400 MHz, d6-DMSO): 8.33 (m, IH), 8.23 (m, IH), 7.95 (d, IH), 7.81 (m. IH), 7.71 (t, IH), 7.20 (m, IH), 7.14 (m, 2H), 6.83 (s, IH), 5.43 (br s, IH), 2.79 (m, 2H), 2.46 (s, 3H), 1.98 (m, 2H), 1.88 (m, IH), 1.80 (m, 2H); MS (EI) for C22H20N4: 341.2 (ΜΙ-Γ).
[00385] Compound 1496-(3-chlorophcnyl)-2-mcthyl-N-|(lR)-l, 2,3,4- tctrahydronaphthaIen-l-yI|pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.98 (s, IH), 7.86 (s, IH), 7.74 (s, IH), 7.53 (m, 2H), 7.21 (m, IH), 7.13 (m, 2H), 6.80 (s, IH), 5.42 (br s, 1 H), 2.78 (m, 2H), 2.45 (s, 3H), 1.98 (m, 2H), 1.89 (m, 1 H), 1.80 (m, 2H); MS (EI) for C21H20CIN3: 350.2 (MH+).
[00386] Compound 1502-met yl-6-|4-(mcthylamino)phcnyl]-N-[(l R)-l, 2,3,4- tctrahydronaphthaIen-l-yllpyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.76 (br s,2H), 7.40 (brs, IH), 7.20 (d, IH), 7.12 (m, 3H), 6.51 (m, 2H), 6.09 (q, IH), 5.38 (br s, IH), 2.77 (m, 2H), 2.71 (d, 3H), 2.39 (s, 3H), 1.95 (m, 2H), 1.90 (m, IH), 1.77 (m, 2H); MS (EI) forC22HMN : 345.3 (MH+).
[003871 Compound 1516-(4-fluorophcnyl)-2-mcthyl-N-[(lR)-l, 2,3,4- tctrahydronaphthalen-l-yl|pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.98 (br s, 2H), 7.68 (m, IH), 7.29 (t, 2H), 7.19 (m, IH), 7.12 (m, 2H), 6.73 (s, IH), 5.39 (br s, IH), 2.76 (m, 2H), 2.42 (s, 3H), 1.96 (m, 2H), 1.88 (m, IH), 1.78 (m, 2H); MS (EI) for C2|H2oFN3: 334.2 (MH+).
[00388] Compound 152 methyl 2-chloro-5-{2-mcthyl-6-|(l R)-l, 2,3,4- tctrahydronaphthalcn-l-ylamino]pynmidin-4-yl}benzoatc. Ή NMR (400 MHz, de- DMSO): 8.40 (s, IH), 8.09 (d, IH), 7.78 (d, IH), 7.70 (d, IH), 7.21 (m, IH), 7.14 (m, 2H), 6.84 (s, 1 H), 5.41 (br s, I H), 3.90 (s, 3H), 2.78 (m, 2H), 2.46 (m, 31-1), 1 .97 (m, 3H), 1.80 (m, 2H); MS (EI) for C23H22CIN3O2: 408.1 (ΜΙ- ).
100389] Compound 153 '6-(4-aminophenyl)-2-methyl-N-|(l R)-l ,2,3,4- tetrahydronaphthaIcn-l-yl]pyrimidin-4-amine. Ή NMR (400 Hz, d6-DMSO): 7.69 (br s, 2H)S 7.40 (m, I'H), 7.21 (m, I H), 7.12 (m, 2H), 6.59 (d, 3H), 5.51 (s, 2H), 5.39 (br s, I H), 2.67 (m, 2H), 2.38 (s, 3H), 1.88 (m, 3H), 1 .77 (m, 2H); MS (El) for C21H22N : 331.2 (Μ1- ). |00390| Compound 154 6-(2-fluorophcnyI)-2-mcthyI-N-[(lR)-1 , 2,3,4- tetrahydronaphthalen-l-yl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.01 (t, I H), 7.82 (d, I H), 7.49 (m, I H), 7.31 (m, 2H), 7.21 (m, I H), 7.13 (m, 2H), 6.79 (s, I H), 5.42 (br s, I H), 2.77 (m, 2H), 2.44 (s, 3H), 1.96 (m, 2H), 1 .91 (m, I H), 1.79 (m, 2H): MS (El) for C21 H20FN3: 334.2 (MH+).
[00391 ] Compound 155 '6-(2-chlorophenyl)-2-mcthyl-N-[(l R)-l,2,3,4- tctrahydronaphthalcn-l-yl|pyrimicliri-4-aniinc. Ή NMR (400 MHz, d6-DMSO): 7.78 (d, I H), 7.54 (m, 2H), 7.42 (m, 2H), 7.22 (m, I H), 7.14 (m, 2H), 6.55 (s, I H), 5.41 (br s, I H),
2.76 (m, 2H), 2.42 (s, 3H), 1 .96 (m, 2H), 1.89 (m, I H), 1.80 (m, 2H); MS (El) for
C21 H20CIN3 : 350.2 (MI-f).
[00392] Compound 156 '4-{2-methyI-6-[(l )-l,2,3,4-tetrahydronaphthaIen-l- yIamino]pyrimidin-4-yl}benzonitrile. Ή NMR (400 MHz. d6-DMSO): 8.12 (d, 2H), 7.90 (d, 2H), 7.85 (s, I H), 7.21 (m, I H), 7.14 (m, 2H), 6.85 (s, I H), 5.42 (br s, I H), 2.78 (m, 2H), 2.47 (s, 3H), 1.98 (m, 3H), 1.80 (m, 2H); MS (EI) for C22H20N4: 341.2 (ΜΙ- ).
[00393] Compound 157 6-(3-aminoplienyl)-2-methyI-N-[(lR)-l , 2,3,4- tctrahydronaphthalcn-l-yl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.61 (m, 111), 7.22 (m, 2H), 7.10 (m, 4H), 6.67 (s, I H), 6.61 (m, I H), 5.39 (br s, I H), 5.22 (s, 2H),
2.77 (m, 2H), 2.42 (s, 3H), 1 .96 (m, 3H), 1 .79 (m, 2H); MS (EI) for C21H22 : 331.2 (MH+).
[003941 Compound 159 6-|4-(dimctliylamino)phenyl]-2-methyl-N-[(l )-l,2,3,4- tctrahydronaphtha]cn-l-yl]pyriinidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 7.82 (br s, 2H), 7.43 (s, I H), 7.22 (m, 1 H), 7.12 (m, 2H), 6.75 (d, 2H), 6.65 (s, I H), 5.39 (br s, I H), 2.97 (s, 6H), 2.77 (m, 2H), 2.40 (s, 3H), 1 .96 (m, 3H), 1 .78 (m, 2H); MS (El) for C23H26N4 : 359.3 (MH+).
[003951 Compound 160 2-chloro-N-mcthyl-5-{2-mcthyl-6-|(lR)-l , 2,3,4- tctrahydronaphthalcn-l-ylamino ]pyrimidin-4-yl}bcnzamidc. Ή NMR (400 MHz, d6- DMSO): 8.49 (d, I H), 7.98 (s, I H), 7.74 (d, I H), 7.61 (d, I H), 7.20 (m, I H), 7.13 (m, 3H), 6.83 (s, 1 H), 5.42 (br s, 1 H), 2.81 (m, 2H), 2.78 (d, 3H), 2.45 (s, 3H), 1 .97 (m, 2H), 1 .91 (m, I H), 1.80 (m, 2H); MS (EI) for C23H23CIN4O: 407.2 (MH+). [00396] Compound 161 '2-methyl-N-|(l R)-l,2,3,4-tetrahydronaphthalcn-l-yl]-6-{4- |(trinuoromethyl)oxy]phcnyl}pyrimidin-4-aminc. Ή N R (400 MHz, d6-DMSO): 8.06 (d, 2H), 7.77 (d} IH), 7.49 (d, 2H), 7.21 (t, IH), 7.13 (m, 2H), 6.79 (s, IH), 5.42 (br s, IH),
2.78 (m, 2H), 2.45 (s, 3H), 1.98 (m, 2H), 1.92 (m, 1 H), 1.80 (m, 2H); MS (EI) for C22H20F3NJO: 400.2 (MH").
[00397] Compound 1623-{2-mcthyl-6-|(lR)-l,2,3,4-tctrahydronaphtha!en-l- ylamino[pyrimidin-4-yl}bcnzamidc. Ή NMR (400 MHz, d6-DMSO): 8.45 (s, IH), 8.11 (s, IH), 7.93 (d, IH), 7.72 (d, IH), 7.56 (t, IH), 7.46 (s, IH), 7.22 (m, IH), 7.15 (m, 3H), 6.84 (s, IH), 5.43 (br s, IH), 2.78 (m, 2H), 2.47 (s, 3H), 1.99 (m, 2H), 1.93 (m, 1Ή), 1.80 (m, 2H); MS (El) for C22H22N4O: 359.2 ( Ι-Γ).
[003981 Compound 1636-(3-amino-4-chIorophenyl)-2-mcthyl-N-|(lR)-l, 2,3,4- tctrahydronaphtlialcn-l-yl|pynmidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.35 (in, 21-1), 7.20 (m, 3H), 7.16 (m, 3H), 6.99 (m, 1 H), 6.68 (s, 111), 5.44 (br s, IH), 2.78 (m, 2H), 2.45 (s, 3H), 2.01 (m, 2H), 1.91 (m, IH), 1.81 (m, 2H): MS (EI) for C21H21CIN4: 365.2 (ΜΙ-Γ).
[00399] Compound 164 ,4-{2-mcthyl-6-[(lR)-l,2,3,4-tetrahydronaphthalcn-l- ylamino]pyrimidin-4-yl}benzamide. Ή NMR (400 MHz. d6-DMSO): 8.06 (m, IH), 7.97 (m, 2H), 7.74 (m, IH), 7.45 (s, IH), 7.21 (m, IH), 7.13 (m, 4H), 6.83 (s, ΊΗ), 5.43 (br s, IH),
2.79 (m, 2H), 2.46 (s, 3H), 1.96 (m, 2H), 1.91 (m, IH), 1.79 (m, 2H); MS (EI) for C22H22N4O: 359.2 (MH4).
(00400] Compound 1726-furan-3-yl-2-methyI-N-[(lR)-l,2,3,4-tctrahydronaphthalen-l- yl|pyrimidin-4-aininc. Ή NMR (400 MHz, d3-ACN): 8.45 (d, IH), 7.9 (d. IH), 7.7 (s, IH), 7.25 (br m, 4H), 6.9 (d, 1 H), 6.7 (s, 1 H), 5.6 (q, 1 H), 2.85 (br m, 3H), 2.65 (s, 3H), 2.5 (s, IH), 2.1 (br m, IH), 1.9 (br m, 2H); MS (EI) for C19H19N3O: 306.1 (MH+).
[00401] Compound 1732-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-6- phcnyIpyrimidin-4-aminc. Ή NMR (400 MHz. d6-DMSO): 7.85 (br s, 2H), 7.65 (br s, 3H), 7.25 (t, 1.H), 7.0 (br s, 2H), 6.8 (s, IH), 6.7 (d, IH), 5.4 (br s, IH), 3.75 (s, 3H), 2.55 (s, 3H), 1.5 (d, 3H); MS (EI) for C20H21N3O: 320.1 (MH*).
100402] Compound 1746-(3-cthylphenyl)-2-methyl-N-{(lS)-l-[3- (methyIoxy)phcnyl]cthyl}pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 9.5 (br s, 1 I I), 7.7 (s, 1 H), 7.65 (br s, 1 H), 7.5 (q, 2H), 7.25 (I, 1 H), 7.0 (br s, 2H), 6.95 (br s, 1 H), 6.85 (d, 2H), 5.4 (br s, IH), 3.8 (s, 3H), 2.7 (q, 2H), 2.55 (s, 3H), 1.5 (d, 3H), 1.25 (t, 3H); MS (EI) for C22H25N3O: 348.1 (MH+). [00403] Compound 1762-mcthyl-6-(3-methylphcn l)-N-[(lR)-l,2,3,4- tetrahydronaphthaIcn-l-yl]pyrimidin-4-aminc. Ή NMR (400 MHz, df)-DMSO): 9.70 (d, IH), 7.65 (s, IH), 7.60 (d, IH), 7.5 (br m, 2H), 7.2 (m, 4H), 6.8 (s, IH), 5.5 (q, IH), 2.85 (br m, 3H), 2.65 (s, 3H), 2.55 (s, 1 H), 2.4 (s, 3H), 2.05 (m, 1 H), 1.9 (br m, 2H); MS (El) for
Figure imgf000210_0001
[00404] Compound 1772-mcthy!-N-{(lS)-l-|3-(methyloxy)phenyl]cthyl}-6-(3- methylp cnyl)pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 9.5 (br s, 1 H), 7.7 (s, IH), 7.65 (brs, IH), 7.45 (m, 2H), 7.25(1. lH);7.0(brs: 2H , 6.95 (brs, IH), 6.85 (d, IH), 5.4 (br s, 1 H), 3.8 (s, 3H), 2.55 (s, 3H), 2.4 (s, 3H), 1.5 (d, 3H); MS (El) for C21H23N3O: 334.1 (ΜΙ- ).
100405] Compound 1816-(3-cthylphcnyl)-2-mcthyl-N-[(lR)-l,2,3,4- tetrahydronaphthalen-l-yl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 9.70 (d, IH), 7.60 (m, 4H), 7.2 (m, 4H), 6.8 (s, IH), 5.5 (d, IH), 2.8 (m, IH), 2.75 (q, 2H), 2.65 (s, 3H), 2.55 (s, IH), 2.05 (m, IH), 1.9 (br m, 3H), 1.25 (t, 3H); MS (EI) for C23H25N3: 344.1 (MH+).
[00406] Compound 1822-mcthyl-6-(2-mcthylpyridin-4-yl)-N-[(lR)-l, 2,3,4- tctrahydronaph.halen-l-yl|pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.55 (d, IH), 7.85 (d, IH), 7.75 (s, 111), 7.65 (brs, III), 7.25 (t, 1H): 7.15 (m, 3H), 6.85 (s, IH), 5.4 (brs, IH), 2.8 (m, 2H), 1.9 (br m, 2H), 1.8 (t, 2H); MS (EI) for C21H22N,,: 331,1 (MH÷).
[00407] Compound 1842-mcthyl-6-pyridin-4-yl-N-[(lR)-l,2,3,4-tctrahydronaphthalen- l-yl]pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 8.70 (d, 2H), 7.85 (br s, 2H), 7.25 (d, IH), 7.15 (m, 3H), 7.1 (dd, IH), 6.85 (s, IH), 5.4 (br s, IH), 2.8 (m, 2H), 2.45 (s, 3H), 1.9 (m, 2H), 1.8 (t, 2H): MS (EI) for C20H20 4: 317.1 (ΜΙ- ).
[00408] Compound 1852-mcthyl-N-{(lS)-l-|3-(methyloxy)phenyI]ethyl}-6-(2- methylpyridin-4-yl)pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.7 (d, IH), 7.9 (br d, 2H), 7.3 (t, IH), 7.05 (s, 2H), 7.0 (br s, IH), 6.8 (d, IH), 5.4 (br s, IH), 3.8 (s, 3H), 2.65 (s, 3H), 1.5 (d, 3H); MS (EI) for C2oH22N40: 335.1 (MH+).
100409] Compound 1862-mcthyl-6-(lH-pyrazol-4-yl)-N-[(lR)-l,2,3,4- tctrahydronaphthalen-l-yl]pyrimidin-4-aminc. Ή NMR (400 MHz, dft-DMSO): 8.1 (br s, IH), 7.5 (s, IH), 7.15 (m, 4H).6.5 (br s, 1 H), 5.4 (br s, IH), 2.75 (br m, 2H), 2.35 (s, 3H), 1.75 (br m, 2H); MS (EI) for C|8HmN5: 306.1 (ΜΗ').
[00410] Compound 1872-mcthyl-6-pyridin-3-yl-N-|(lR)-l,2,3,4-tetrahydronaphthalen- l-yl]pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 9.1 (s, IH), 8.65 (d, IH), 8.3 (br d, 1 H), 7.8 (br d, 1 H), 7.5 (q, 1 H), 7.15 (m, 4H), 6.85 (s, 1 H), 5.4 (br s, 1 H), 2.8 (m, 2H), 2.45 (s, 3H), 1.9 (m, 2H), 1.8 (t, 2H); MS (EI) for C20H20N4: 317.1 (MH+).
|00411] Compound 1882-methyI-N-[(lR)-l,2,3,4-tctrahydronaphthalcn-l-yl]-4,5'- bipyrimidin-6-amine. Ή NMR (400 MHz, d6-DMSO): 9.3 (s, 1H), 9.25 (br s, 1H), 7.9 (d, 1H), 7.15 (m, 5H), 6.85 (s, 1H), 5.4 (brs, IH), 2.8 (m, 2H), 2.45 (s, 3H), 1.95 (m, 2H), 1.8 (t, 2H); MS (El) for C19H19N5: 318.1 (Mi-f).
[00412] Compoiind 1892-niethyl-N-{(lS)-l-|3-(mcthyloxy)phcnyl]cthyl}-6-pyridin-3- ylpynmidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 9.0 (br s, IH), 8.8 (d, IH), 8.3 (br s, IH), 7.6 (t, 1H): 7.3 (t, IH), 7.05 (brs,2H),7.0 (s, lH),6.85(d, IH), 5.4 (brs, IH).3.8 (s, 3H), 2.55 (s, 3H), 1.5 (d, 3H); MS (El) for C19H20N4O: 321.1 (MH+).
[00413] Compound 1902-niethyl-N-{(lS)-l-|3-(methyloxy)phenylJcthyl}-6-pyridin-4- ylpyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 8.8 (d, 2H), 7.9 (br s, 2H), 7.3 (t, IH), 7.0 (brs, 3H), 6.85 (d, 2H), 5.4 (brs, IH), 3.8 (s, 3H), 2.5 (s, 3H), 1.5 (d, 3H); MS (El) forC|9H2oN40: 321.1 (Ml-f).
[004141 Compound 2636-(4-chlorophenyl)-2-methyl-N-{l-|3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-aminc. 6-(4-chlorophenyl)-2-methyl-N-{ l-[3-(l -methyl- 1H- pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the non-commercially available amine was synthesized in a manner analogous to Example 6d. Ή NMR (400 MHz, d6-DMSO): 8.08 (s, 1 H), 7.96 (d, 2H), 7.82 (s, 2H), 7.51 (m, 2H), 7.38 (m, 2H), 7.28 (t: IH), 7.21 (m, IH), 3.84 (s, 3H), 2.36 (s, 3H); 1.47 (d, 3H); MS (EI) for C23H22CIN5: 404.9 ( H+).
[00415] Compound 2646-(3-fluorophcnyl)-2-methyl-N-{l-[3-(l-mcthyI-lH-pyrazol-4- yl)phenyl|ethyl}pynmidin-4-amine. 6-(3-fluorophenyl)-2-methyl-N-{ l-[3-(l -methyl- 1H- pyrazol-4-yl)phcnyl]ethyl}pyrimidin-4-aminc was synthesized in a manner analogous to Example 2 and the non-commercially available amine was synthesized in a manner analogous to Example 6d. Ή NMR (400 MHz, d6-DMSO): 8.09 (s, IH), 7.82 (s, IH), 7.74 (m, 2 H), 7.60 (m, IH), 7.48 (m, IH), 7.38 (m, IH), 7.27 (t, 2H), 7.22 (m, IH), 6.79 (s, IH), 3.84 (s, 3H), 2.37 (s, 3H), 1.48 (d, 3H); MS (El) for C23II22FN5: 388.5 (MH+).
[00416] Compound 2652-methyl-6-[3-(mcthyIoxy)phcny!]-N-{l-[3-(l-niethyI-lH- pyrazoI-4-yI)phcnyI]ethyI}pyrimidin-4-arnine. 2-methyl-6-[3-(methyloxy)phenyl]-N-{ 1- [3-(l-methyl-lH-pyrazol-4-yl)phenyr]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the non-commercially available amine was synthesized in a manner analogous to Example 6d. Ή NMR (400 MHz, d6-DMSO): 8.09 (s, IH), 7.82 (s, IH), 7.76 (m, 1 H), 7.61 (m, IH), 7.47 (m, 2H), 7.36 (m, 2H), 7.28 (m, IH), 7.22 (m, IH), 7.00 fm, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 2.36 (s, 3H), 1.47 (d, 3H); MS (EI) for
Figure imgf000212_0001
400.5( H+).
100417] Compound 2666-(lH-indol-5-yl)-2-methyl-N-{l-[3-(l-mcthyl-lH-pyrazol-4- y])phcnyl|cthyl}pyrimidin-4-aminc. 6-(lH-indol-5-yl)-2-methyl-N-{ l-[3-(l -methyl- 1H- pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the non-commercially available amine was synthesized in a manner analogous to Example 6d. MS (EI) for C25H24N(,: 409.5 (MH+).
100418] Compound 2672-mcthyI-6-(3-nicthylphenyI)-N-{l-[3-(l-mcthyl-lH-pyrazol-4- yl)phcnyl]cthyl}pyrimidin-4-amine. 2-methyl-6-(3-methylphenyl)-N-{l-[3-(l -methyl-1 H- pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the non-commercially available amine was synthesized in a manner analogous to Example 6d. Ή NMR (400MHz, d6-DMSO): 8.09 (s, 1H), 7.82 (sf 1H), 7.73 (m, 2H), 7.69 (d, 1H), 7.38 (d, 1H), 7.33-7.20 (m, 4H), 6.77 (m, 1 H), 3.84 (s, 3H), 2.36 (s, 3H), 2.33 (s, 3H), 1.47 (d, 3H); MS (EI) for C24H25 5: 384.5 (MH+).
[00419] Compound 2692-mcthyl-N-{l-|3-(l-methyl-lH-pyrazol-4-yl)phcnyI]ethyl}-6- phenylpyrimidin-4-amine. 2-methyl- -{ l-[3-(l -methyl-1 H-pyrazol-4-yl)phenyl]ethyl} -6- phenylpyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the non- commercially available amine was synthesized in a manner analogous to Example 6d. MS (EI) for C23H23N5: 370.5 (MH+).
[00420] Compound 2702-methyI-6-[4-(mcthyloxy)phenyl[-N-{l-[3-(l-methyl-lH- pyrazol-4-yl)phenyl|cthyI}pyrimidin-4-amine. 2-methyl-6-[4-(methyloxy)phenyl]-N-{l- [3-( 1 -methyl- lH-pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the non-commercially available amine was synthesized in a manner analogous to Example 6d. MS (EI) for C24H25N5O: 400.5 (MH+).
[00421] Compound 2716-(2,4-dichlorophcnyl)-2-methyl-N-{l-[3-(l-methyl-lH-pyrazol- 4-yl)phenyl|cthyl}pyrimidin-4-aminc. 6-(2,4-dichlorophenyl)-2-methyl-N-{ 1 -[3-(l - methyl- lH-pyrazol-4-yl)phenyl]ethyl jpyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the non-commercially available amine was synthesized in a manner analogous to Example 6d. MS (EI) for C23H21CI2N5: 439.4 (MH+).
[00422] Compound 2722-methyl-6-(2-methylphenyl)-N-{l-[3-(l-nicthyl-lH-pyrazol-4- yl)phcnyI]erhyl}pyrimidin-4-aminc. 2-methyl-6-(2-methylphenyl)-N-{ 1 -[3-(l -methyl- 1H- pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the non-commercially available amine was synthesized in a manner analogous to Example 6d. MS (EI) for C-24H25N5: 384.5 (MH+). 100423] Compound 273 6-(3-chl()ro-4-fluorophenyl)-2-methyl-N-{l-[3-(l-methyl-lH- pyrazol-4-yl)phenyl|cthyl}pyrimidin-4-amine. 6-(3-chloro-4-fluorophenyl)-2-methyl-N- { l -[3-(l -methyl- 1 H-pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the non-commercially available amine was synthesized in a manner analogous to Example 6d. MS (El) for C23H21CIFN5: 422.9 (MH+).
[00424] Compound 275 2-mcthyI-N-{l -|3-(l -methyl-lH-pyrazol-4-yl)phenyl]cthyl}-6- naphthalen-2-ylpyriniidin-4-amine. 2-mcthyl-N-{ l -[3-( l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}-6-naphthalen-2-ylpyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the non-commercially available amine was synthesized in a manner analogous to Example 6d. MS (EI) for C27H25N5; 420.5 (MH+).
(00425]. Compound 293 2-mcthyl-6-[4-mcthyl-3-(methyloxy)phcnyl]-N-[(l R)-l,2,3,4- tctrahydronaphtha!cn-l-yl] pynmidin-4-aniinc. Ή NMR (400 MHz: d3-MeOD): 7.39 (d, 1 ), 7.32 (d, 1 ), 7.24 (d, 1 ), 7.22 (d 1 ): 7.13 (m, 3), 6.64 (br s, 1 ), 5.98 (br s, 1 ), 3.90 (s, 3), 3.85 (m, 2), 2.52 (s, 3), 2.08 (m, 2), 1.92 (m, 4); MS (El) for C23H25N3O: 360.26 (MH+). 100426] Compound 296 2-methyI-6-(l-methyl-lH-indo]-6-yI)-N-{l -I3-(l-methyl-lH- pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-aminc. Ή NMR (400 MHz, dj-ACN): 8.00 (s, 1 ), 7.81 (s, 1), 7.6 (m, 3), 7.38 (dt, 1 ), 7.33 (t, 1 ), 7.26 (dt, 1 ), 7.24 (d, 1 ), 6.67 (br s, 1 ), 6.45 (br s, 1 ), 6.12 (d, 1 ), 3.87 (s, 3), 3.8 (s, 3), 2.45 (s, 3), 1.57 (d, 3); MS (El) for C26 H26 N6: 423.04 (MH+).
(00427] Compound 310 2-methyl-5-{2-methyl-6-f(l R)-l ,2,3,4-tctrahydronaphthaIcn-l- ylamino]pyrimidin-4-yl}phenoI. MS (EI) for C22H23N3O: 346.20 (MH+).
(00428] Compound 326 6-(3-ethyl-l-bcnzofuran-5-yl)-2-methyl-N-[(l R)-l ,2,3,4- tetrahydronaphthalcn-l-yl]pyrimidin-4-aminc. 6-(3-ethyl-l -benzofuran-5-yl)-2-methyl- N-[(l R)-1.2.3,4-tetrahydronaphthalen-l -yl]pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized in a manner analogous to Example 7a. Ή NMR (400 MHz, d6-DMSO): 8.21 (br s, 1 H), 7.91 (br s, 1 H), 7.83 (s: 1 H), 7.62 (d, 1 H), 7.23 (m, 1H), 7.1 7-7.10 (m, 3H), 6.85 (br s, 1 H), 5.42 (br s, 1 H), 2.84-2.71 (m, 2H, overlapped), 2.72 (q, 2H), 2.47 (s, 3H), 2.02-1 .92 (m, 1 H), 1 .90 (s, 2H, acetate peak), 1.85- 1.76 (m, 1 H), 1.29 (t, 3H). MS (EI) for C25H25N30: 384.1 (MH+).
100429] Compound 330 2-mcthyI-6-(l-mcthyI-l H-indol-2-y!)-N-[(l R)-l ,2,3,4- teti ahydronaphthalen-l -yI]pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO):6 7.75 (br d, 1 H), 7.59 (d, 1 H), 7.51 (d, 1 H), 7.27-7. 19 (m, 2H), 7.18-7.1 1 (m, 2H), 7.07 (t, 1 H), 6.84 (br s, 1 H), 6.71 (b s, 1 H), 5.43 (br s, 1 H), 4.03 (s, 3H), 2.78 (m, 2H), 2.47 (s, 3H), 2.03-1.87 (m, 1 H), 1.84-1.77 (m, 1 H). MS (EI) for Ci^I-b^: 369.2 (ΜΙ- ). [00430] Compound 333 2-inethyI-6-(l -mcthyI-lH-pyrrolo|3,2-b]pyridin-6-yl)-N-[(lR)- l,2,3,4-tctrahydronaphtlialcn-l-yl|pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO):5 8.89 (br s, 1 H), 8.40 (br s, 1 H), 7.72 (d, 1 H), 7.67 (br s, 1 H), 7.24 (m, 1 H); 7.18-7.09 (m, 2H), 6.90 (br s, I H), 6.58 (dd, 1 H), 5.42 (br s, 1 H), 3.89 (s, 3H), 2.83-2.72 (m, 2H), 2.48 (s, 3H), 2.00- 1.91 (m, 2H), 1 .88 (s, 3H, acetate peak), 1.88- 1 .74 (m, 2H). MS (El) for C23H23N5 : 370.2 (MH+).
[00431 ] Compound 335 6-(7-fluoro-l -benzofuran-5-yI)-2-mcrhyl- -{(l S)-l-[3- (methyIoxy)phenyl]ethyl}pyrimidin-4-amine. 6-(7-fluoro-l -benzot\iran-5-yl)-2-methyl-N- {( l S)-l -[3-(methyloxy)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized in a manner analogous to Example 7d. Ή NMR (400 MHz, d6-DMSO):8 8.29 (s, I H), 8.06 (s, IH), 7.85-7.73 (m, I H), 7.29 (m, 2H), 7.09-6.98 (m, 2H), 6.92-6.82 (m, 2H), 5.41 (br s, I H), 3/75 (s, 3H), 2.57 (s, 3H), 1 .53 (d, 3H). MS (El) for C22H20FN3O2: 378.1 (MH+).
[00432] Compound 336 6-(4-ethyl-3,4-dihydro-2H-l,4-benzoxazin-6-yl)-2-mcthyl-N- [(l R)-l,2,3,4-teirahydronaphthalcn-l-yl|pyrimidin-4-aminc. 6-(4-ethyl-3,4-dihydro-2H- l ,4-benzoxazin-6-yl)-2-methyl-N-[( l R)- l ,2,3,4-tetrahydronaphthalen-l -yl]pyrimidin-4- amine was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized in a manner analogous to Example 7b. Ή NMR (400 MHz, d6-DMSO):5 7.28- 7.13 (m, 4H), 7.07 (s, I H), 6.99 (dd, I H), 6.89 (d, I H), 6.74(s, I H), 5.50 (m, I H), 4.26 (m, 2H), 3.42 (q, 2H), 3.45-3.35 (m, 2H, overlapped), 2.85-2.74 (m, 2H), 2.64 (s, 3H), 2.07-1 .99 (m, I H), 1 .90- 1.77 (m, 3 H), 1 .10 (t, 3H). MS (EI) for C25H2SN4O: 401.2 (MH+).
[00433] Compound 356 2-mcthyl-6-(l-methyl-l H-indol-2-yl)-N-{(l S)-l -[3- (mcthyloxy)phenyI|ethyI}pyrimidin-4-amine. MS (EI) for C23H24 40: 373.2 (MH÷).
[00434] Compound 361 methyl {|(2-chloro-5-{2-mcthyl-6-|(l R)-l,2,3,4- tetrahydronaphthalen-l -ylamino]pyrimidin-4-yl}phcnyl)methyl|oxy}acctate. MS (EI) for C25H26CI 3O3: 452.2 (Ml-f ).
[00435] Compound 367 6-(l-bcnzothien-2-yl)-2-methyl-N-[(l R)-l ,2,3,4- tetrahydronaphthalen-l -yl|pyrimidin-4-amine. MS (EI) for C23H21N3S: 372.1 (MH+).
[00436] Compound 372 6-(lH-indo!-2-yl)-2-methyl-N-[(l R)-l,2,3,4- tctrahydronaphthalen-l-yl]pyrimidin-4-amine. MS (EI) for C2 H22 4: 355.2 (MH*).
[00437] Compound 375 6-(l-bcnzofuran-2-yl)-2-mcthyI-N-{(lS)-l-[3- (methy]oxy)phenyl]ethyl}pyrimidin-4-amine. MS (EI) for C22H21N3O2: 360.2 (MH+). 100438] Compound 381 2-mcthyl-N-{(l S)-l -[3-(methyloxy)phcnyl|cthyl}-6-(l-methyl- lH-pyrrolo]3,2-b]pyridin-6-yl)pyrimidin-4-amine. MS (EI) for C22H23N5O: 374.2 (MH*). [004391 Compound 389 (2-chloro-5-{2-tncthyI-6-[(lR)-l,2,3,4-tctrahydronaphthalcn-l- ylamino]pyrimidin-4-yl}phenyl)mcthanol. Ή NMR (400 MHz, d6-DMSO):58.18 (br s, 1H), 7.83 (bid, 1H), 7.72 (bi d, 1H), 7.50 (d, 1 H), 7.23-7.11 (m, 3H), 6.83 (brs, 1H), 5.41 (brs, 1H), 4.61 (s, 2H), 2.84-2.71 (m, 2H), 2.45 (s, 3H), 2.02-1.91 (m, 2H), 1.90 (s, 3H, acetate peak), 1.83-1.74 (ms 2H). MS (EI) for C22H22CIN3O: 380.2 (MH+).
[00440] Compound 3906-(3-chloro-4-mcthyIphenyl)-2-mcthyl-N-[(l )-l, 2,3,4- tctrahydronaphthaIen-l-yl|pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO):67.99 (br s, 1H), 7.78 (brs, 1H), 7.63 (brs, 1H), 7.46 (d, 1H), 7.23-7.10 (m, 3H), 6.79 (brs, 1H), 5.41 (brs, 1H), 2.80-2.74 (m, 2H), 2.44 (s, 3H), 2.38 (s, 3H), 1.99-1.92 (m, 2H), 1.90 (s, 3H, acetate peak), 1.86-1.75 (m, 2H). MS (El) lor C22H22CIN3: 364.2 (MH+).
[00441] Compound 391 N-(2-hyd!Oxycthyl)-2-(5-{2-mcthyl-6-](lR)-l ,2,3,4- tctrahydronaphthalen-l-ylamino]pyrimidin-4-yl}-l-benzofuran-3-yl)acctamidc. N-(2- hydroxyethyl)-2-(5-{2-methyl-6-[(lR)-l,2,3.4-tetrahydronaphthalen-l-ylamino]pyrimidin-4- yl}-l-benzofuran-3-yl)acetamide was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized in a manner analogous to Example 7a. MS (EI) for C27H28 O3: 457.3 (MH+).
[00442] Compound 3922-(6-{2-met yl-6-[(l R)-l,2,3,4-tetrahydronaphthalen-l- ylamino]pyrimidin-4-yl}-2,3-dihydro-4H-l,4-bcnzoxazin-4-yl)cthanol. 2-(6-{2-methyl-6- [(lR)-l,2,3,4 etrahydronaphthalen-l-ylamino]pyrimidin-4-yl}-2,3-dihydro-4H-l,4- benzoxazin-4-yl)ethanol was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized in a manner analogous to Example 7b. MS (EI) for C25H28 O2: 417.3 (ΜΙ-Γ).
[00443] Compound 3932-(6-{2-mcthy]-6-[(lR)-l,2,3,4-tetrahydronaphthalen-l- ylamino[pyriniidin-4-yl}-2,3-dihydro-lH-indol-l-yl)ethanol. 2-(6-{2-methyl-6-[(l R)- l,2,3.4 etrahydronaphthalen-l-ylamino]pyrimidin-4-yl}-2,3-dihydro-lH-indol-l-yl)ethanol was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized in a manner analogous to Example 7c. MS (EI) for C25H28N4O: 401.2 (MH+).
[00444] Compound 394 Ethyl (5-{2-mcthyI-6-[(lR)-l,2,3,4-tetrahydronaphthalen-l- yIamino|pyrimidin-4-yl}-l-benzofuran-3-yI)acetate. Ethyl (5-{2-methyl-6-[(lR)-l, 2,3,4- tetrahydronaphthalen-l-ylamino]pyrimidin-4-yl}-l-benzofuran-3-yl)acetate was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized in a manner analogous to Example 7a. MS (EI) for C27H27N3O3: 442.3 (MH+).
[00445] Compound 395 Methyl (6-{2-methyl-6-[(lR)-l,2,3,4-tetrahydronaphthaIcn-l- ylamino]pyrimidin-4-yI}-2,3-dihydro-lH-indoI-l-yl)acetatc. Methyl (6-{2-methyl-6- [(lR)-l,2.3,4-tetrahydronaphthalen^
yljacetate was synthesized in a manner analogous to Example 2 and the boronic ester was synthesized in a manner analogous to Example 7c. MS (El) for C26H28N4O2: 429.3 (MH ). 100446] Compound 4312-(mcthyloxy)-4-{2-mcthyl-6-[(l R)-l,2,3,4- tetrahydronaphthaIen-l-ylamino]pynmidin-4-yl}bcnzamidc. Ή NMR (400 MHz, d(,- DMSO): 7.88 (d, 1H), 7.70 (m, 3H), 7.61 (s, 111), 7.56 (m, 1H), 7.21 (m, IH), 7.13 (m, 3H), 6.85 (s, IH), 5.43 (m, IH), 3.97 (s, 3H), 2.78 (m, 2H), 2.47 (s, 3H), 1.94 (m, 2H), 1.80 (m, 2H); MS (EI) for C23H24N4O2: 389.2 (Μ1-Γ).
100447] Compound 4602-methyl-6-quinolin-6-yI-N-[(l )-l, 2,3,4- tetrahydronaphthalen-l-yl]pyrimidin-4-aminc. MS (EI) for C24H22N : 367.2 (MH+).
[00448] Compound 4622-mcthyl-6-quinoxalin-6-yl-N-[(lR)-l,2,3,4- tctrahydronaphthalcn-l-yI]pyrimidin-4-aminc. MS (EI) for C23H21N5: 368.2 (ΜΙ- ).
[00449] Compound 4656-(3-amino-4-mcthylp cnyl)-2-mcthyl-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-aminc. MS (EI) for C21H24 4O: 349.2 (MH+).
[00450] Compound 4662-methyI-N-{(lS)-l-[3-(methyloxy)phenyl]ethyI}-6-quinolin-6- ylpyrimidin-4-aminc. MS (El) for C23H22N4O: 371.2 (MH*).
[00451] Compound 4696-(3-amino-4-chlorophenyI)-N-|(4R)-3,4-dihydro-2H-chronien- 4-yI]-2-methylpyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.81 (s, IH), 7.49 (s, IH), 7.28 (d, IH), 7.20 (m, IH), 7.17 (m, IH), 7.06 (m, IH), 6,87 (t, IH), 6.80 (d, IH), 6.69 (m, IH), 5.53 (s, 2H), 5.37 (m, IH), 4.24 (111, 2H)f 2.44 (s, 3H), 2.13 (m, IH), 2.02 (m, IH); MS (EI) forC2oH19Cl 40: 367.1 (MH*).
[004521 Compound 4806-(2,5-dinicthyIphenyl)-2-methyI-N-{l-[3-(l-mcthyI-lH- pyrazol-4-yl)phenyl|ethyl}pyrimidin-4-amine. 6-(2.5-dimethylphenyl)-2-methyl-N-{l-[3- (l-methyl-lH-pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the amine was synthesized in a manner analogous to Example 6d. Ή NMR (400 MHz, d6-DMSO): 8.43 (s, 1H): 8.09 (s, IH), 7.81 (s, IH), 7.59 (s, IH), 7.39 (d, IH), 7.28 (t, IH), 7.19 (d, 1 H), 2.35 (br s, 2H), 6.81 (s, 1H),3.84 (s, 3H), 2.46 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H), 1.45 (d, 3H); MS (EI) for C25H27N5: 398.5 (MH+).
100453] Compound 4816-(3,4-dichlorophenyI)-2-meihyI-N-{l-[3-(l-mcthyI-lH-pyrazol- 4-yl)phcnyl|cthyI}pyrimidin-4-amine. 6-(3,4-dichlorophenyl)-2-methyl-N-{ l-[3-(l - methyl- 1 H-pyrazol-4-yl)plienyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the amine was synthesized in a manner analogous to Example 6d. Ή NMR (400 MHz, de-DMSO): 8.16 (s, lH),8.08(s, lH),7.87(s, lH),7.82(s, IH), 7.71 (d, 1 II), 7.59 (brs, IH), 7.38 (d..1H),7.28 (t, IH), 7.22 (s br, IH), 6.83 (s, lH),3.84(s, 3H), 2.33 (s, 3H).1.47 (d, 3H); MS (EI) for C23H21G2N5: 439.4 (MH+).
100454] Compound 4826-(4-ethyIphenyl)-2-mcthyl-N-{l-[3-(l-methyI-l H-pyrazol-4- yl)phenyl|cthyl}pyrimidin-4-amine. 6-(4-ethylphenyl)-2-methyl-N-{l-[3-(l-methyl-lH- pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the amine was synthesized in a manner analogous to Example 6d. Ή NMR (400 MHz, d6-DMSO): 8.29 (s, IH), 8.09 (s, IH), 7.84 (s, IH), 7.82 (s, IH), 7.81 (s, IH),
7.72 (br s, IH), 7.61 (br s, IH), 7.38 (d, IH), 7.27 (t, 2H), 7.21 (d, IH), 3.84 (s, 3H), 2.63 (m, 2H), 2.35 (s, 3H), 1.46 (d, 3H), 1.17 (t, 3H); MS (EI) for C2sH27N5: 398.5 (MH+).
[004551 Compound 4836-(4-fIuoro-3-methyIphcny!)-2-mcthyI-N-{l-[3-(l-niethyl-lH- pyrazoI-4-yl)phenylJuthyl}pyrimidin-4-aniine. 6-(4-fIuoro-3-methylphenyl)-2-methyl-N- {l-[3-(l-methyl-lH-pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the amine was synthesized in a manner analogous to Example 6d. MS (EI) for C24H24FN5: 402.5 (MH+).
100456] Compound 4862-meihy-6-[4-(l-methylethyI)phenyl]-N-{l-]3-(l-methyl-lH- pyrazol-4-yI)phcnyl]ethyl}pyrimidin-4-amine. 2-methyl-6-[4-(l-methylethyl)phenyl]-N- {l-[3-(l-methyl-lH-pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the amine was synthesized in a manner analogous to Example 6d. MS (EI) for C2f)H29N5: 412.6 (MH+).
(00457] Compound 4886-[2-fluoro-4-(methyloxy)phenyl|-2-mcihyl-N-{l-[3-(l-methyl- lH-pyrazol-4-yI)phcnyl|ethyI}pyrimidin-4-amine. 6-[2-fiuoro-4-(methyloxy)phenyl]-2- methyl-N-{ l-[3-(l -methyl- 1 H-pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 and the amine was synthesized in a manner analogous to Example 6d. MS (EI) for C24H24FN30: 418.5 (ΜΙ-Γ).
[00458] Compound 4906-[3-(dimcthylamino)phcnyl|-2-methyI-N-{l-|3-(l-mcthyl-lH- pyrazol-4-yl)phcnyI]cthyl}pyrimidin-4-aminc. 6-[3-(dimelhylamino)phenyl]-2-methyl-N- {l-[3-(l-methyl-lH-pyrazol-4-yl)phenyl]ethyl}pynmidin-4-amine was synthesized in a manner analogous to Example 2 and the amine was synthesized in a manner analogous to Example 6d. MS (EI) for C2JH28N6: 413.5 ((ΜΙ-Γ).
[004591 Compound 5402-methyl-6-quinolin-3-yl-N-|(lR)-l, 2,3,4- tetraliydronaphthalcn-l-yI]pyrimidin-4-amine. MS (EI) for C24H2->N4: 367.2 (MH+).
[00460] Compound 5266-{2-mcthyl-6-|(lR)-l,2,3,4-tctrahydronaphthalen-l- yIamino|pyrimidin-4-yI}-4H-chromcn-4-one. MS (EI) for C24H2|N302: 384.2 (MH+). 1004611 Compound 531 6-(2,l ,3-bcnzoxadiazol-5-yl)-2-mcthyl-N-|(l R)-l,2,3,4- tetrahydronaphthalcn-l-yl]pyrimidin-4-aminc. MS (EI) for C2iH,yN50: 358.1 (MET). 100462] Compound 534 2-mctliyl-6-(l-mcthyl-l H-indol-5-yl)-N-|(l R)-l ,2,3,4- tetrahydronaphthalcn-l -yl]pyriniidin-4-amine. MS (El) for C^l^ ^ 369.2 (MH+). 100463] Compound 576 2-mct yl-N-{ l-[3-(l -methyl-l H-pyrazol-4-yl)phenyl]cthyl}-6- |4-(trifluoromethyl)phcnyl|pyrimidin-4-aminc. 2-methyl-N-{ l -[3-( l -methyl-l H-pyrazol- 4-yl)phenyl]ethyl}-6-[4-(trifluoiOmcthyl)pheiiyl]pyrimidin-4-aniine was synthesized in a manner analogous to Example 2 while the amine was synthesized in a manner analogous to Example 6d. MS (EI) for C24 H22F3N5 : 438.5 (MM4).
[004641 Compound 577 6-(2,3-dihydro-l,4-bcnzodioxin-6-yI)-2-methyI-N-{l-[3-(l- methyI-l H-pyrazoI-4-yI)phcnyl]ethyl}pyrimidin-4-amine. 6-(2.3-dihydro-l ,4- benzodioxin-6-yl)-2-methyl-N-{ l -[3-( l -methyl-l H-pyrazol-4-yl)phenyl]ethyl}pyrimidin-4- amine was synthesized in a manner analogous to Example 2 while the amine was synthesized in a manner analogous to Example 6d. MS (EI) for C25H2 5O2: 428.5 (MH+).
[00465] Compound 710 3-[2-methyl-6-({l-|3-(l-methyl-l H-pyrazoI-4- yl)phcnyI]ethyl}amino)pyrimidin-4-yl| phenol. 3-[2-methyl-6-({ l -[3-( l -methyl- 1 H- pyrazol-4-yl)phenyl]ethyl}amino)pyrimidin-4-yl]phenol was synthesized in a manner analogous to Example 2 while the amine was synthesized in a manner analogous to Example 6d. MS (EI) for C23H23N5O: 386.5 (Ml f).
[00466] Compound 711 6-(2,3-dihydiO-l -bcnzofuran-5-yl)-2-mcthyl-N-{l-|3-(l-methyl- l H-pyrazol-4-yl)phenyl]cthyl}pyrimidin-4-amine. 6-(2,3-dihydro-l
Figure imgf000218_0001
methyl-N-{ l -[3-(l -methyl- l H-pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 while the amine was synthesized in a manner analogous to Example 6d. MS (EI) for C25H25 5O: 412.5 (MH÷).
[00467] Compound 712 6-|2-nuoro-3-(methyIoxy)phcnyl]-2-methyl-N-{l-[3-(l-methyl- l H-pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine. 6-[2-fluoro-3-(methyloxy)phenyl]-2- melhyl-N-{ l -[3-( ] -methyl-l H-pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 2 while the amine was synthesized in a manner analogous to Example 6d. MS (EI) for C24H2.|FN50: 418.5 (MH+).
General Scheme 2
[00468) Compounds of formula BB can be produced according to the general synthesis described in Scheme 2. Scheme 2: General Synthesis of Compounds of formula BB
Figure imgf000219_0001
[00469] Compounds of formula 1". wherein RM, R]2, R|3, and Ru are non-reactive groups, such as hydrogen, alkyl, and alkoxy, and X is a nucleophilic group, such as amino, hydroxy, or mercapto, can be converted to compounds of formula BB under nucleophilic substitution conditions. These conditions may include a solvent, such as DMF or acetone, and base, such as DIEA or Na2C03.
Example 3: Synthesis of N,N-dimethyl-2-{|3-(l-{[2-mcthyl-6-(l-methyl-lH-indol-6-
Figure imgf000219_0002
[00470] A round bottom flask was charged with 3 -(l -(2-methyl-6-( 1 -methyl- l H-indol-6- yl)pyrimidin-4-ylamino)ethyl)phenol (60 mg, 0.17 mmol, 1.0 eq.), 2-Chloro-N,N-dimethyl- acetamide (41 mg, 0.33 mmol, 2.0 eq.), DMF (2.0 mL), and Cs2C03 (235 mg, 0.67 mmol, 4.0 eq.). The reaction was heated to 90 °C for 15 hours, then cooled to rt. and partitioned between water and EtOAc. The aqueous layer was extracted 2 times with EtOAc. The combined organic layers were dried with Na2SC>4, and concentrated under vacuum to give the crude product as an oil. Purification by preparative HPLC (reverse-phase, acetonitrile/water with 25 mM ammonium acetate), followed by concentration at reduced pressure and lyophilization, afforded ,N-dimethyl-2-{ [3-(l -{ [2-methyl-6-(l -methyl- l H-indol-6- yl)pyrimidin-4-yl]amino}ethyl)phenyl]oxy}acetamide as a solid ( 1 1.0 mg, 24 % yield). Ή NMR (400 MHz, d6-DMSO): 8.05 (s, I H), 7.73-7.57 (m, 3H), 7.42 (d, I H), 7.21 (t, I H), 7.00 (br m, 2 H), 6.75 (br d, 2H), 6.45 (d, I H), 4.79 (s, I H), 3.88 (s, 2H), 2.98 (s, 3H), 2.80 (s, 3H), 2.4 (s, 3H), 1 .87 (s, 3H), 1 .44 (d, 3H) ; MS (EI) for C26H29N502: 444.2 (MH+).
[00471 ] The following compounds were prepared by a manner analogous to Example 3 : [004721 Compound 20 N,N-dicth l-2-{|3-(l-{[2-meth l-6-(l-mcthyl-lH-indol-6- yl)pyrimidiii-4-yI]amino}ethyl)phenyl|oxy}acctamide. Ή NMR (400 MHz. d6-DMSO): 8.05 (s, IH), 7.73-7.57 (m, 3H), 7.42 (d, 1 H), 7.21 (t, IH), 7.00 (br m, 2 H), 6.75 (br d, 2H), 6.45 (s, 1 H), 5.30 (br s, IH), 4.75 (s, 2H), 3.88 (s, 3H), 3.50-3.40 (hurried quartets, 4H), 2.40 (s, 3H), 1.48 (d, 3H), 1.1.0 (t, 3H), 1.00 (t, 3H); MS (EI) for C28H33N5O2: 472.3 (ΜΙ- ).
[00473] Compound 26 N-cthyl-2-{[3-(I-{|2-nicthyl-6-(l-mcthyl-lH-indol-6- yl)pyrimidin-4-yl|amino}ethyl)phcnyl]oxy}acctamitlc. Ή NMR (400 MHz, d6-DMSO): 8.05 (m, 2 H), 7.73-7.57 (m, 3H), 7.42 (d, IH), 7.21 (t, IH), 7.00 (br m, 2 H), 6.75 (br d, 2H), 6.45 (s, IH), 5.30 (br s, IH), 4.48 (s, 2H), 3.89 (s, 3H), 3.20 (q,2H), 2.40 (s, 3H), 1.89 (s, 1H- acetate peak), 1.49 (d, 3H), 1.00 ( 3H); MS (EI) for C26H29 5O1: 444.2 (MH+).
[004741 Compound 282-mcthyI-6-(l-mcthyl-l H-indoI-6-yl)-N-(l-{3-[(2-morpholin-4-yl- 2-oxocthyl)oxyJphenyl}cthyl)pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.04 (s, 1 H), 7.65-7.58 (m, 3H), 7.41 (s, 1 H), 7.21 (t, IH), 7.00 (br s, 2 H), 6.75 (br d, 2H), 6.43 (s, IH), 5.12 (br s, IH), 4.77 (s, 2H), 3.83 (s, 3H), 3.55 (m, 8H), 2.38 (s, 3H), 1.87 (s, 3H-acetate peak), 1.44 (d, 3H); MS (EI) for C28H31N5O3: 486.3 (MH+).
[00475] Compound 294-{[3-(l-{[2-methyl-6-(l-nicthyl-lH-indoI-6-yl)pyrimidin-4- yl]amino}ethyl)phcnyl]oxy}butanoic acid. Ή NMR (400 MHz, d6-DMSO): 12.15 (br s, IH), 8.04 (s, 1 H), 7.65-7.58 (m, 2H), 7.41 (s, IH), 7.21 (t, IH), 7.00 (br s, 2 H), 6.75 (br d, 2H),6.43 (s, IH), 5.40 (br s, 1H),3.98 (t, 2H), 3.81 (s, 3H), 2.38 (s, 3H), 2.37 (m, 2H), 1.88 (m, 2H), 1.87 (s, H-acetate peak), 1.45 (d, 3H): MS (EI) for
Figure imgf000220_0001
445.2 (ΜΙ- ). (004761 Compound 39 Ethyl N-({[3-(l-{[2-methyl-6-(l-methyl-lH-indol-6-yI)pyrimidin- 4-yI]amino}ethyI)phenyI]oxy}acetyl)gIycinate. Ή NMR (400 MHz, d6-DMSO): 8.58 (br m, IH), 8.04 (s, 1 H), 7.75-7.58 (m, 3H), 7.41 (s, IH), 7.23 (t, IH), 7.05 (br s, 2 H), 6.75 (br d, 2H), 6.43 (s, IH), 5.30 (br s, IH), 4.52 (s, 2H), 4.10 (q, 2H), 3.84 (s, 2H), 2.37 (s, 3H), 1.42 (d, 3H), 1.19 (t, 3H); MS (El) for C28H31N5O4: 502.2 (MH+).
[00477] Compound 42 Ethyl 4-{[3-(l-{[2-methyl-6-(l-methyI-lH-indol-6-yI)pyrimidin- 4-yl]amino}ethyl)phcnyl|oxy}butanoate. Ή NMR (400 MHz, d6-DMSO): 8.04 (s, 1 H), 7.71-7.55 (m,4H), 7.41 (d, IH), 7.21 (t, IH), 7.00 (br s, 3 H), 6.75 (br d, 2H), 6.43 (s, IH), 5.25 (br s, IH), 4.05 (q, 2H), 3.98 (t, 2H), 3.85 (s, 3H), 2.38 (s, 3H), 1.98 (m, IH), 1.45 (d , 3H), 1.15 (t, 3H); MS (EI) for C28H32N4O3: 473.3 (MH+).
[00478] Compound 452-({3-[l-({6-[2-chloro-3-(methyIo.\y)pIicnyI]-2-mcthylpyrimidin- 4-yl}amino)ethylJphcnyl}oxy)-N-methylacctamide. Ή NMR (400 MHz, d6-DMSO + D20): 7.56 (t, 1 H), 7.40 (d, 2H), 7.30 (m, 1 H), 7.19 (d, 1 H), 7.00 (m, 2 H), 6.85 (d, IH), 6.65 (s, IH), 5.40 (q, I H), 4.40 (s, 2H), 3.90 (s, 3H), 2.60 (s, 3H), 1.54 (d, 3H); MS (El) for
C23H25N4O3CI : 441.2 (MH+).
[00479] Compound 46 2-{[3-(l-{[6-(l ,3-bcnzodioxol-5-yl)-2-mcthyIpyrimidin-4- yI|amino}ethyI)phenyl]oxy}-N-methylacetamide. Ή NMR (400 MHz, d6-DMSO + D20): 7.46 (m, 3 H), 7.20 (1, I H), 7.09 (m, 2H), 6.84 (t, I H), 6.80 (s, 1 H), 6.20 (s, 2H), 5.42 (q, I H), 4.42 (s, 2H), 2.52 (s, 3H), 2.51 (s, 3H), 1 .50 (d, 3H); MS (EI) for C23H24N4O4: 421 .2 (MH+).
[00480] Compound 48 ({3-[ l-({2-mcthyl-6-|3-(mcthyloxy)pheny]]pyrimidin-4- yl}amino)cthyl]pheny!}oxy)acetonitrile. Ή NMR (400 MHz, d6-DMSO): 7.80 (br s, 1 H), 7.50 (m, 2H), 7.40 (m, 2H), 7.22 (m, 2H), 7.00 (dd, 1 H), 6.82 (dd, IH), 5.30 (br s, I H), 5.22 (ss 2H)f 3.80 (s, 3H), 2.47 (s, 3H), 1.50 (d, 3H); MS (El) for C22H22 4O2: 375.2 (MH1).
[00481] Compound 52 N-methyI-2-({3-[l-({2-mcthyI-6-[3-
(mcthyloxy)phenyl|pyrimidin-4-yl}amino)cthyI]phenyl}oxy)acetamidc. Ή NMR (400 MHz, d6-DMSO): 8.10 (m, 1 H), 7.80 (m, I H), 7.42 (m, 2H), 7.22 (l, I H), 7.15 (t, 1 H), 7.05 (m, 3H), 6.80 (d; I H), 5.25 (br s, IH), 4.41 (s, 2H), 3.81 (s, 3H), 2.63 (d, 3H), 2.37 (s, 3H), 1.50 (d, 3H): MS (El) for C23H26N4O3: 407.3 (MH*).
[00482] Compound 56 Methyl ({3-|l -({2-mcthyl-6-|3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenyl}oxy)acetate. Ή NMR (400 MHz, d6-DMSO): 10.00 (m, I H), 7.59 (m, I H), 7.43 (m, 2H), 7.30 (m, 2H), 7.00 (m, 3H), 6.80 (m, 1 H): 5.48 (t, I H), 4.80 (s, 2H), 3.86 (s, 3H), 3.69 (s, 3H), 2.60 (s, 3H), 1 .51 (d, 3H); MS (EI) for C23H25N3O4: 408.2 (Mlf).
[00483] Compound 57 Methyl N-{3-[ l-({2-methyl-6-[3-(methyIoxy)phcnyl]pyrimidin-4- yl}amino)ethyl]phenyI}glycinate. Ή NMR (400 MHz, d6-DMSO): 7.65 (br s, 1 H), 7.50 (m, 2H), 7.40 (t, I H), 7.02 (m, 2H), 6.82 (m, 3H), 6.40 (ds I H), 6.01 (t, I H), 5.21 (br s, I H), 3.92 (d, 2H), 3.81 (s, 3H), 3.60 (s, 3H), 2.40 (s, 3H), 1.90 (s, acetate peak), 1 .42 (d, 3H); MS (EI) for C23H26N4O3: 407.0 (MH ").
[00484] Compound 77 N-{3-[l-({2-mcthyl-6-[3-(methyloxy)phenyl]pyriniidin-4- yl}amino)ethyl]phenyl}glycine. Ή NMR (400 MHz, d6-DMSO): 7.42 (m, 3H), 7.05 (t, 2H), 6.80 (m, I H), 6.60 (m, 2H), 6.40 (d, I H), 5.23 (br s, I H), 2.40 (s, 3H), 1 .45 (d, 3H); MS (El) for C22H24N4O3: 393.2 (MH" ).
[00485] Compound 79 Methyl N-{3-[({2-mcthyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)methyl]phenyl}glycinate. Ή NMR (400 MHz, df)-DMSO+D20): 7.59 (m, I H), 7.40 (m, 2H), 7.20 (d, I H), 7.10 (t, I H), 6.90 (s, I H), 6.60 (m, 2H), 6.44 (m, I H), 4.60 (m, 2H), 3.88 (s, 2H), 3.83 (s, 3H), 3.59 (s, 3H), 2.61 (s, 3H); MS (El) for C22H24N4O3: 393.2 (MH÷). 100486] Compound 80 N-meth -2-{[3-(l -{[2-mcthyl-6-(l-mcthyI-l H-indol-6- yl)pyrimidin-4-yl]amino}cthyl)phcnyl|oxy}acctamide. Ή NMR (400 MHz. d6-DMSO+ D20): 8.04 (s, 1 H), 7.80 (m, I H), 7.60 (s, I H), 7.50 (m, I H), 7.32 (t, 1 H), 7.05 (m, 2H), 6.90 (m, 2H), 6.60 (s, 1 H), 5.41 (m, 1 H), 4.42 (s, 2H), 3.91 (s, 3H), 2.60 (d, 6H), 1 .45 (d , 3H); MS (EI) for C25H27NSO2: 430.3 (MH+).
[00487] Compound 210 N-[ l-(3-(|(l ,3-dimcthyl-l H-pyrazol-5- yl)methyl]oxy}phenyl)cthyl]-2-methyl-6-(l-mcthyI-l H-indol-6-yl)pyrimidin-4-aminc. Ή
NMR (400 MHz, d6-DMSO): 8.04 (s, 1 H), 7.80 (m, I H), 7.63 (s, IH), 7.48 (dd, I H), 7.31 (t,
1 H), 7.19-6.9 (br m, 4H), 6.59 (d, I H), 6.15 (m, I H), 5.45 (m, I H), 5.10 (m, 2H), 3.95 (s, 3H), 3.72 (d, 3H), 2.60 (s , 3H), 2.10 (m, 3H), 1 .45 (d, 3H); MS (El) for C^oNeO: 467.2 (MH+).
[00488] Compound 21 1 6-(l ,3-benzothiazol-6-yI)-N-|(lS)-l-(3-{[(l,3-dimethyl-l H- pyrazol-5-yl)mcthyl]oxy}phcnyl)ethyl]-2-mcthylpyrimidin-4-amine. Ή NMR (400 MHz, de-DMSO): 9.42 (s, 1 H), 8.81 (s, 1 H), 8.08 (m, 2H), 7.95 (br s, 1 H), 7.21 (t, 1 H), 7.05 (br m:
2 H), 6.85 (br d, 2H), 6.10 (s, I H), 5.05 (m, 2H), 4.40 (d, 2H), 3.68 (s, 3H), 3.65 (s, 3H), 2.39 (s, 3H), 2.04 (m , 6H-Oac peak), 1.45 (d, 3H); MS (EI) for C26H26 6OS: 471 .2 (ΜΙ- ).
[00489] Compound 214 6-[2-c loro-3-(methyloxy)phenyl|-N-[l -(3-{|(l ,3-dimethyI-l H- pyrazol-5-yl)methyl]oxy}phenyI)cthyI]-2-mcthyIpyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 7.39 (m, IH), 7.25 (m, 2 H), 7.05 (s, I H), 7.00 (d, I H), 6.90 (m, IH), 6.14 (s, I H), 5.30 (br s, IH), 5.1 1 (m, 2H), 3.90 (s, 3H), 3.71 (s, 3H), 2,36 (s, 3H), 2.09 (d, 3H), 1.45 (dd, 3H); MS (EI) for
Figure imgf000222_0001
478.2 (MH+).
[00490] Compound 217 N-[ l-(3-{[(l ,3-dimcthyl-l H-pyrazol-5- yl)methyl|oxy}phenyl)ethyl]-2-nicthyl-6-[4-methyl-3-(mcthyloxy)phcnyl]pyrimidin-4- amine. Ή NMR (400 MHz, d6-DMSO): 7.70 (s, 211), 7.48 (s, 1 H), 7.40 (d, I H), 7.00 (d, 2H), 6.82 (d, 1 1-I), 6.1 1 (s, 1 H), 5.01 (s, 2H), 3.82 (s, 3H), 3.65 (s, 3H), 2.39 (s, 3H), 2.20 (s, 3 H), 2.03 (s, 3H-OAc peak), 1 .43 (d, 3H); MS (EI) for C27H31 5O2: 458.2 (MH+).
[00491 ] Compound 218 6-(l ,3-bcnzothiazol-6-yl)-2-methyl-N-(l-{3-|(l H-pyrazol-3- yImcthyl)oxylphcnyl}cthyl)pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 9.43 (s, I H), 8.80 (s, 1 H), 8.18 (m, I H), 7.21 (t, I H), 7.05 (m, 2H), 6.82 (m, 2H), 6.32 (s, I H), 5.01 (s, I H), 2.40 (s, 3H), 1 .90 (s, 3H-OAc peak), 1.43 (d, 3H); MS (El) for C2*H22N6OS: 443.2 (MH+).
[00492] Compound 220 6-( l ,3-bcnzothiazol-6-yl)-N-(l-{3-|(isoxazol-3- ylmethyl)oxy|phenyl}cthyI)-2-mcthylpyrimidin-4-aminc. MS (EI) for C^I^INJCHS: 444.1 (ΜΙ- ). 100493] Compound 222 2-methyl-6-]4-nicthyl-3-(methyIoxy)phenyl]-N-[l-(3-{[(l- methyl-lH-pyrazol-3-yI)mfthyl]oxy}phcnyI)ctliyl]pyrimidin-4-aniinc. MS (EI) For C26H29N5O2: 444.3 (MH+).
100494] Compound 224 2-({3-| l -({2-methyl-6-|4-methyI-3-
(methyloxy)plienyl]pyriniidin-4-yl}amino)cthyl]phcnyI}oxy)acetamide. MS (EI) for C23HMK,03: 407.2 (MH*).
100495] Compound 227 {13-(l-{|6-(l,3-bcnzothiazol-6-yl)-2-mcthylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetonirrile. MS (EI) for C22H19N5OS: 402.1 (MH+).
100496] Compound 228 N-(l -{3-[(2-azepan-l-yl-2-oxocthyl)oxy]phcnyl}cthyI)-6-(l ,3- benzothiazoI-6-yl)-2-methyIpyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 9.43 (s, 1 H), 8.80 (s, 1 H), 8.1 8 (ms 2H), 7.85 (s, 1 H), 7.22 (t, 1 H), 7.00 (m, 3H): 6.72 (d, l H), 4.39 (s, 2H), 2.40 (s, 3H), 1.88 (s, 1 H-OAc peak), 1.62 (m, 8H), 1.43 (d, 3H); MS (EI) for C28H31 5O2S: 502.2 (MH+).
[00497] Compound 229 2-{|3-(l-{|6-(l,3-bcnzothiazol-6-yI)-2-methyIpyrimidin-4- yI|amino}ethyl)phcnyl|oxy}-N-(l-methylcthyl)acctamide. Ή NMR (400 MHz, d6- DMSO): 9.43 (s, I H), 8.80 (s, 1 H), 8.18 (dd, 2H), 7.85 (d, 2H), 7.25 (t, I H), 7.02 (s, 2H), 6.80 (d, 2H), 5.35 (br s, 1 H), 4.40 (s, 2H), 3.90 (sextet, 1 H), 2.40 (s, 3H), 1.90 (s, l H-OAc peak), 1.42 (d, 3H), 1 .08 (d, 6H); MS (EI) for C2SH27N5O2S: 462.2 (MH").
100498] Compound 231 6-(l ,3-benzothiazoI-6-yl)-2-mcthyl-N-[ l-(3-{[2-(2- mcthy azindin-l-yl)-2-oxocthyI|oxy}phcnyl)ethyl|pyrimidin-4-aminc. Ή NMR (400 MHz, dG-DMSO+D20): 9.42 (s, I H), 8.80 (s, 1 H). 8.18 (m, 2H), 7.80 (s, 1 H), 7.29 (t, 1 H), 7.02 (br s, 2H), 6.80 (m, 2H), 5.32 (br s, I H), 4.72 (s, 2H), 4.39 (m, I H), 4.05 (m, H ), 3.80 (m, I H), 2.40 (s, 3H), 1.43 (d,3H), 1 .1 1 (d, 3H); MS (EI) for C25H25N5O2S: 460.2 (MH+). 100499] Compound 232 2-{[3-(l -{|6-(l ,3-benzothiazoI-6-yI)-2-methylpyrimidin-4- yI]amino}ethyl)phcnyl|oxy}-N,N-dimethylacetamide. MS (EI) for C24H25N5O2S: 440.2 (MH+).
[00500] Compound 234 6-(l ,3-benzothiazoI-6-yl)-2-methyl-N-[l-(3-{|(5-nicthyIisoxazoI- 3-yl)mcthyl]oxy}phcnyl)cthyl]pyrimidin-4-amine. MS (EI) for C25H23N502S: 458.2 (MH+).
[00501 ] Compound 235 {|3-(l -{[2-methy]-6-(l-mcthyl-l H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phcnyl]oxy}acctonitrile. MS (EI) for C2.1H23N5O: 398.2 (MH+).
[00502] Compound 236 6-(l ,3-benzothiazoI-6-yl)-2-mcthyl-N-{l-[3-(prop-2-yn-l- yIoxy)phenyl]cthyl}pyrimidin-4-aminc. MS (EI) for C23H20N4OS : 401.2 (MH÷). [00503] Compound 240 6-(l ,3-benzothiazoI-6-yl)-2-methyl-N-(l-{3-|(2-oxo-2-piperidin-
1- ylethyl)oxy]phcnyl}ethyI)pyrimidin-4-aminc. MS (EI) for C27H29N5O2S: 488.2 (MH+).
[00504] Compound 241 N-( l -{3-[(2-azctidin-l -yl-2-oxocthyl)oxy]phcnyl}ethyl)-6-(l,3- bcnzothiazol-6-yl)-2-methylpyrimidin-4-aminc. MS (El) for C25H25N5O2S: 460.2 (MH÷).
[00505] Compound 242 2-{[3-(l-{[6-(l ,3-bcnzothiazol-6-yl)-2-mcthylpyrimidin-4- yl]amino}ethy )phenyl]oxy}-N-(2-hydroxypropyl)acetamidc. MS (EI) for C25H27N5O3S: 478.2 (MH+).
[00506] Compound 247 6-( l ,3-bcnzothiazol-6-yl)-2-methyl-N-(l-{3-|(2-morpholin-4-yI-
2- oxoethyI)oxy)phenyI}ethyl)pyrimidin-4-amine. MS (EI) for C26H27N5O3S: 490.2 (Ml-f).
[00507] Compound 250 N,N-dicthyl-2-({3-[l-({6-[2-fluoro-3-(methyIoxy)phcnyll-2- methylpyrimidin-4-yI}amino)ctliy]]phcnyl}oxy)acctamidc. MS (EI) for C26H31 N4O F: 467.2 (MH+).
100508] Compound 251 6-(l ,3-benzotbiazol-6-yl)-N-[(lR)-l-(3-{[(l,3-dimcthyI-l H- pyrazoI-5-yl)mcthyl|oxy}phcnyl)ethyl|-2-methylpyrimidin-4-aminc. MS (EI) for CjeHjeNeOS: 471.2 (Ml-f).
[00509] Compound 252 6-(l ,3-benzotliiazol-6-yl)-2-methyl-N-(l-{3-[(2-oxo-2- pyrrolidin-l-ylethyI)oxylphcnyl}ethyl)pyrimidin-4-amine. MS (EI) for C26H27N5O S: 474.2 (MI-f ).
100510] Compound 253 2-niethyI-6-(l-methyl-lH-indol-6-yl)-N-[l-(3-{[2-oxo-2-(4- pyridin-2-ylpiperazin-l-yl)cthyl]oxy}phenyl)cthyl]pyrimidin-4-aminc. Ή NMR (400 MHz. dd-DMSO): 8.10 (d, I H), 8.00 (s, 1 H), 7.65 (m, I H), 7.60 (t, I H), 7.50 (m, I H), 7.40 (s, I H), 7.20 (t, I H), 7.00 (br s5 2H); 6.80 (m, 2H), 6.68 (dd, I H), 6.21 (s, I H), 4.80 (s, 2H), 3.80 (s, 3H), 3.58 (m, 8H), 2.40 (s, 3H), 1.86 (s, l H-OAc peak), 1 .42 (d, 3H); MS (EI) for C33H3JN7O2: 562.3 (MH+).
[00511] Compound 254 methyl l-({[3-(l -{[2-mcthyl-6-(l-methyl-lH-indol-6- yl)pyrimidin-4-yI]amino}cthyl)phenyl|oxy}acetyl)piperidinc-4-carboxylate. Ή NMR
(400 MHz, d6-DMSO+D20): 8.05 (s, I H), 7.60 (m, 2 H), 7.40 (d, I H), 7.21 (t, I H), 7.00 (m, 2H), 6.80 (dd, I H), 6.51 (d, I H), 5.12 (br s, I H), 4.80 (q, 2H), 3.85 (s, 3H), 3.80 (br d, I H), 2.40 (s, 3H), 2.39 (s, 2H), 1 .91 (s, lH-OAc peak), 1 .80 (m, 2H), 1 .45 (d, 3IT), 1.35 (m, 2H); MS (EI) for C31H35NSO : 542.3 (MH+).
[005121 Compound 255 2-{[3-(l -{|6-(l ,3-bcnzothiazol-6-yl)-2-methylpyrimidin-4- yl|amino}cthyl)phcnyl]oxy}-N-mcthy acctamidc. MS (EI) for C23H23N5O2S: 434.2 (MH+). [00513J Compound 256 2-{|3-(l-{|6-(l ,3-bcnzothiazol-6-yl)-2-metliylpyrimidin-4- yl]amino}cthyl)phenyl)oxy}-N-ethylacctamidc. MS (El) for C34H25N5O2S: 448.2 (MH+).
[00514] Compound 258 {|3-(l-{[2-methyl-6-(l-methyl-l H-indol-6-yl)pyrimidin-4- yl|amino}ethyl)phcnyI]oxy}acetic acid. MS (El) for C24H24N4O3: 542.3 (MH+).
[00515] Compound 259 4-{|3-(l-{[6-(l ,3-bcnzothiazol-6-yI)-2-mcthylpyrimidin-4- yI|amino}cthyl)phcnyl]oxy}butanoic acid. MS (El) for C24H24N4O3S: 9.2 (MH÷).
[00516] Compound 260 ethyl 4-{|3-(l -{[6-(l ,3-bcnzothiazol-6-yl)-2-mcthyIpyrimidin-4- yI]amino}cthyl)phcnyl]oxy}butanoate. MS (El) for C26H28N4O3S: 477.2 (MH*).
[00517] Compound 262 2-{[3-(l-{[6-(l ,3-bcnzotliiazol-6-yl)-2-mcthylpyrimidin-4- yl|amino}ethyI)phenyl|oxy}-N,N-dicthylacctamide. Ή NMR (400 MHz, d6-DMSO): 9.42 (s, I H), 8.80 (s, 1 H), 8.18 (m, 2H), 7.85 (br s, I H), 7.21 (t, I H), 7.00 (m, 3H), 6.75 (d, I H), 5.22 (br s, 1 H), 4.78 (s: 2H), 2.40 (s, 3H), 1.90 (s, 1 H-OAc peak), 1 .43 (d, 3H), 1.18 (t, 3H), 1 .01 (t, 3H); MS (EI) for C^^N^S: 476.2 (MH+).
[00518] Compound 295 N-[3-(l-{[2-methyl-6-(3-methyl-l-bcnzofuran-5-yl)pyrimidin-4- yl[amino}ethyl)phenyl]prop-2-enamide. Ή NMR (400 MHz, d3-ACN): 8.46 (s, 1 ), 8.14 (s, 1), 7.87 (d, 1 ), 7.78 (s, 1 ), 7.55 (d, 1), 7.47 (d, 1 ), 7.30 (t, 1 ), 7. 17 (d, 1), 6.63 (br s, 1 ), 6.33 (d, 1), 6.12 (d, 1 ), 3.87 (s, 3), 3.8 (s, 3), 2.45 (s, 3), 1.57 (d, 1 ); MS (EI) for C25 H24 N 02: 413.05 (MH").
[00519] Compound 303 2-{[3-(l-{|6-(l ,3-bcnzothiazoI-6-yI)-2-methylpyrimidin-4- yl]amino}cthyl)phenyl| oxy}- N,N-diethylpropanamidc. Ή NMR (400 MHz, d3-ACN): 9.17 (s, 1 ), 8.67 (s, 1 ), 8.1 (I, 2), 7.24 (t, 2), 7.02 (t, 1 ), 6.87 (dt, 1 ), 6.69 (dt, 2), 6.25 (d, 1 ), 5.03 (dq, 1 ), 3.37 (q, 2), 3.23 (m, 2), 2.43 (s, 3), 1 .52 (d, 3), 1 .45 (dd, 1 ), 1 .1 (q, 3), 0.95 (dt, 3); MS (EI) for C27 H3, N5 02 S: 490.28 (MH+).
[00520] Compound 304 2-{[3-(l -{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}cthyl)phenyl]oxy}-2-methylpropanamide . MS (EI) for C24 H2s 5 02 S:
448.20 (MH+).
[00521 ] Compound 306 2-{|3-(l-{|6-(l,3-benzothiazol-6-yl)-2-mcthylpyrimidin-4- yl]amino}cthyl)phcnyl]oxy}propanamide. MS (EI) for C23H23N5O2S: 434.41 (ΜΙ- ).
[00522] Compound 308 N-|3-(l -{[6-(l ,3-bcnzothiazol-6-yl)-2-mcthyIpyrimidin-4- yl)amino}cthyl)phenyl]-l H-pyrazole-5-carboxamidc. MS (EI) for C24H21N7OS: 456.05 (ΜΙ-Γ).
[005231 Compound 309 N-[3-(l -{|6-(l ,3-benzothiazol-6-yl)-2-mcthylpyrimidin-4- yl]amino}cthyl)phcnyl]-l-mcthyl-lH-pyrazolc-3-carboxamidc. MS (EI) for C25 H23 N7 O S: 470.13 (MH+). [00524] Compound 311 N-[3-(l-{[6-(l ,3-bcnzothiazol-6-yl)-2-mcthylpyrimidin-4- yl|amino}erhyl)phcnyl[dicarbonimidic diamide. MS (El) for C22H21 7O2S: 448.12 (MH+).
[00525] Compound 312 N-|3-(l -{|6-(l,3-benzothiazoI-6-yl)-2-mcthylpyrimidin-4- yl|amino}ethyl)phcnyl]formamidc. MS (EI) for C21H,9N5OS: 390.03 (MH+).
100526] Compound 313 l-[3-(l -{[6-(l,3-bcnzothiazoI-6-yl)-2-mcthyIpyrimidin-4- yl|amino}ethyl)phcnyl]urca. MS (EI) for C2| H2oN6OS: 405.13 (ΜΙ- ).
[00527] Compound 314 -[3-(l-{[6-(l,3-benzothiazol-6-yI)-2-mcthylpyrimidin-4- yl]amino}ctliyl)phcnyl]-l-methyI-l H-imidazole-4-sulfonamide. MS (EI) for
C24H23N7O2S2: 506.10 (ΜΙ-Γ).
[00528] Compound 316 1,1-dimcthylcthyI (2-{|3-(l-{[6-(I ,3-benzothiazol-6-yl)-2- mcthylpyrimidin-4-yl|amino}ethyl)phenyl)amino}-2-oxocthyl)mcthylcarbamatc. MS
Figure imgf000226_0001
100529] Compound 324 2-mcthyI-l -{[3-(l -{[2-mcthyl-6-(3-methyl-l-benzofuran-5- yI)pyrimidin-4-yl]amino}ethyl)phenyl]oxy}propan-2-ol. Ή NMR (400 MHz, d - DMSO):6 8.18 (s, 1 H), 7.92 (d, 1 H), 7.82 (s, 1 H), 7.75 (br s, 1 H), 7.59 (br d, 1 H), 7.22 (t, 1 H), 7.00 (br s, 2H), 6.77 (dd, 1 H), 5.3 1 (br s, 1 H), 4.63 (s, 1 H), 3.60 (s, 2H), 2.40 (s, 3H),
2.25 (s, 3H), 1.45 (d, 3H), 1.1 (s, 6H). MS (EI) for C26H29N3O3: 432.1 (MH*).
[00530] Compound 325 l -{|3-(l -{|2-methyl-6-(3-methyI-l -benzofuran-5-yl)pyrimidin- 4-yl]amino}cthyl)phenyI|oxy}propan-2-one. Ή NMR (400 MHz. d6-DMSO):6 8.18 (s, I H), 7.90 (d, 1 H), 7.82 (s, I H), 7.75 (br s, I H), 7.60 (d, 1 H), 7.22 (t, I H), 7.01 (m, 1 H), 6.72 (dd, IH), 5.30 (br s, I H), 4.77 (s, 2H), 2.40 (s, 3H), 2,26 (s, 3H), 2.14 (s, 3H), 1.44 (d, 3H). MS (EI) for C25H25N3O3: 416.1 (MH+).
[00531 ] Compound 331 2-metliyI-6-(3-incthyl-l -benzofuran-5-yl)-N-|l-(3-{[(5-mcthyI- l ,2,4-oxadiazoI-3-yl)mcthyl]oxy}phcnyl)ethyI|pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO):5 8.18 (s, 1 H), 7.92 (s, 1 H), 7.82 (s, 1 H), 7.75 (br s, 1 H), 7.60 (br d, 1 H), 7.27 (t, I H), 7.12-7.02 (m, 2H), 6.90 (d, I H), 5.32 (br s, I H), 5.21 (s, 2H), 2.58 (s, 3H), 2.40 (s, 3H),
2.26 (s, 3H), 1.90 (s, 2H, acetate peak), 1 .45 (d, 3H). MS (El) for C26H25N5O3: 456.1 (MH+).
[00532] Compound 338 6-(l,3-benzothiazol-6-yl)-N-[l -(3-{[(l-ethylpiperidin-3- yI)methyl]oxy}phenyI)ethyI]-2-mcthylpyrimidin-4-aminc. Ή NMR (400 MHz, df,- DMSO):8 9.47 (s, I H), 8.80 (s, I H), 8.16-8.10 (m, 2H), 7.84 (br s, I H), 7.23 (t, I H), 6.99 (br s, I H), 6.87 (br s, I H), 6.77 (dd, 1 H), 5.40 (br s, 1 H), 3.82 (m, 2H), 3.35 (s, 2H, overlapped), 2.87-2.84 (m, I H), 2.71 -2.68 (m, I H), 2.30 (s, 3H), 2.30-2.25 (m, 2H), 1.93- 1.84 (m, I H), 1 .90 (s, 3H, overlapped, acetate peak), 1.78- 1.67 (m, 2H), 1 .63- 1.58 (m, I H), 1.46 (d, 3H), 1 .09- 1.01 (m, I H), 0.96 (t, 3H). MS (EI) for C2XH33N5OS: 488.2 (ΜΙ- ). 100533} Compound 3406-(l,3-bcnzothiazoI-6-yI)-2-methyl-N-|l-(3-{|(l- methyIpiperidin-3-yl)mcthyl]o.\y}phenyl)cihyI]pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO):59.47 (s, 1 H), 8.80 (s, 1 H), 8.18-8.06 (m, 2H), 7.85 (br s, 1 H), 7.22 (t, 1 H), 7.0 (br s, IH), 6.88 (brs, IH), 6.77 (dd, 1H),5.40 (brs, 1 H), 3.86-3.76 (m, 2H), 3.36 (s, 2H, overlapped), 2.76 (m, IH), 2.59 (m, IH), 2.41 (s, 3H), 2.11 (s, 3H), 1.99-1.86 (m, IH), 1.90 (s, 3H, acetate peak), 1.87-1.80 (m, IH), 1.78-1.64 (m, 3H), 1.46 (d, 3H), 1.09-0.93 (m, IH). MS (EI) for C27H31N5OS: 474.1 (MH+).
[00534] Compound 341 N-Il-(3-{|(l,3-dimethyI-lII-pyrazol-5- yl)methyI]oxy}phenyl)cthyl]-2-mcthyl-6-(l-mcthyl-ni-indol-2-yl)pyrimidin-4-amine. Ή
NMR (400 MHz, d6-DMSO):57.84 (br s, 1 H), 7.55 (dd, IH), 7.30-7.18 (m, 2H), 7.14-6.98 (m, 3H), 6.94-6.85 (m, 2H), 6.13 (s, IH), 5.32 (br s, IH), 5.09 (s, 2H), 3.98 (s, 3H), 3.73 (s, 3H), 2.41 (s, 3H), 2.07 (s, 3H), 1.99 (s, IH, acetate peak), 1.46 (d, 3H). MS (EI) for
C2gH3oN60: 467.2 (MH+).
[00535] Compound 343 N-[l-(3-{|(l,3-dimethyl-lH-pyrazol-5- yl)methyl]oxy}phcnyl)ethyl]-6-(3-ethyl-l-benzofuran-5-yl)-2-methylpyrimidin-4-aminc.
Ή NMR (400 MHz, d6-DMSO):58.18 (s, IH), 7.93 (dd, IH), 7.83 (s, IH), 7.74 (br s, IH), 7.60 (d, 1 H), 7.25 (t, 1 H).7.10 (br s, 1 H), 7.04 (br s, 1 H), 6.88 (dd, 1 H), 6.10 (s, 1 H), 5.32 (br s, IH), 5.07 (s, 2H), 3.71 (s, 3H), 2.71 (q, 2H), 2.40 (s, 3H), 2.06 (s, 3H), 1.45 (d, 3H), 1.29 (t, 3H). MS (EI) for C29H31N5O2: 482.2 (ΜΙ-Γ').
[00536] Compound 3446-(l,3-benzothiazol-6-yI)-2-methyl-N-(l-{3-[(piperidin-3- ylmcthyl)oxy]phenyl}et yl)pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO):69.45 (s, IH), 8.78 (s, 1 H), 8.18 -8.06 (m, 2H), 7.83 (br s, IH), 7.2 (t, IH), 7.1-6.89 (m, IH), 6.85 (br s, 1 H), 6.75 (dd, 1 H), 5.30 (br s, 1 H), 3.76 (m, 2H), 2.98 (dd, 1 H), 2.88 (dd, 1 H), 2.47-2.34 (m, IH, overlapped), 2.40 (s, 3H), 2.31-2.23 (m, IH), 1.84-, 1.70 (m, 2H), 1.57-1.47 (m, IH), 1.44 (d, 3H), 1.38-1.25 (m, IH), 1.20-1.08 (m, IH). MS (EI) for C-26H29N5OS: 460.1 (MH+).
[00537] Compound 345 l-{[3-(l-{[6-(l,3-benzotliiazol-6-yI)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl|oxy}propan-2-one. Ή NMR (400 MHz, d6-DMSO):59.47 (s, IH), 8.80 (s, IH), 8.17-8.11 (m, 2H), 7.85 (brs, IH), 7.22 (t, IH), 7.06-6.93 (m, IH), 6.87 (brs, 1 H), 6.72 (dd, 1 H), 5.30 (br s, 1 H), 4.77 (s, 2H), 2.41 (s, 3H), 2.14 (s, 3H), 1.89 (s, 2H, acetate peak), 1.45 (d, 3H). MS (El) for C23H22N4O2S: 419.1 (MH+).
[00538) Compound 3502-{[3-({|6-(l,3-benzothiazo!-6-yl)-2-methylpyrimidin-4- yl]amino}mcthyl)-4-fluoiOphcnyl]oxy}-N,N-diethylacetamidc. Ή NMR (400 MHz, d6- DMSO):59.48 (s, IH), 8.83 (s, IH), 8.18-8.07 (m, IH), 7.85 (br s, IH), 7.12 (t, IH), 6.94 (s, IH), 6.89 (br s, IH), 6.82-6.79 (m, IH), 4.70 (s, 2H), 4.59 (ni 2H), 3.34-3.18 (m, 4H), 2.45 (s, 31-1), 1 .89 (s, 1 H, acetate peak), 1.05 (t, 3H), 0.95 (t, 3H). MS (EI) for C23H22N4O2S: 419.1 (Mt-f).
100539] Compound 352 l -{|3-(l-{[6-(l ,3-benzothiazol-6-yI)-2-methyIpyrimidin-4- yl]amino}cthyl)phcnyl]ox }propan-2-ol. MS (EI) for C23H24 4O2S: 421 .1 (MH+).
|00540| Compound 353 l-{[3-(l-{[6-(l ,3-hcnzothiazoI-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-2-methylpropan-2-oI. MS (EI) for C24H26 4O1S: 435.1 (MH+).
[00541 ] Compound 358 6-( l ,3-benzotliiazoI-6-yl)-2-methyI-N-[l-(3-{|(5-methyl-l,2,4- oxadiazoI-3-yl)methyI]oxy}phcnyI)ethyI|pyrimidin-4-amine. MS (EI) for C2 H22 6O2S: 459.2 (MH+).
[00542] Compound 359 N-[ l -(3-{[( l-acet) lpipcridin-3-yl)mcthyl]oxy}phcnyl)cthyl]-6- (l,3-bcnzothiazol-6-yl)-2-methyIpyrimidin-4-aminc. MS (EI) for C2SH31N5O2S: 502.1 (MH+).
[00543] Compound 360 2-{[3-(l-{[2-incthyI-6-(l -mcthyl-l H-indol-2-yl)pyrimidin-4- yl]amino}cthyl)phcnyl]oxy}acctamide. Ή NMR (400 MHz, d6-DMSO):5 7.85 (br s, 1 H), 7.60 (dd, 1 H), 7.54-7.47 (m, 1 H), 7.40 (s, 1 H), 7.3 1 -7.19 (m, 2H), 7.1 1 -6.98 (m, 2H), 6.84 (s, 1 H), 6.80 (dd, 1 H), 5.40 (br s, 1 H), 4.41 (s, 2H), 3.98 (s, 3H), 2.40 (s, 3H), 1 .89 (s, 1 H, acetate peak), 1.45 (d, 3H). MS (El) for C24H25N5O2: 416.1 (Ml-f ).
[00544] Compound 362 6-(l ,3-bcnzothiazoI-6-yl)-2-methyl-N-(l-{3-[(piperidin-4- ylmethyl)oxy]phenyl}ethyl)pyrimidin-4-amine. MS (EI) for C26H29N5OS : 460.1 (MIT").
[00545] Compound 364 N-[ l -(3-{[2-(4-acctylpipcrazin-l-yI)ethyI]oxy}phenyI)ethyI]-6- (l ,3-bcnzothiazol-6-yl)-2-mcthylpyrimidin-4-aminc. MS (EI) for
Figure imgf000228_0001
517.1 1 (MH+).
[00546] Compound 366 2-{[3-({[6-(l ,3-benzothiazol-6-yl)-2-incthylpyrimidin-4- yl|amino}methyI)-4-fluorophcnyl]oxy}-N,N-dimcthylacctamide. MS (El) for
C23H22FN5O2S: 452.1 (MH+).
[00547] Compound 370 2-{[3-(l-{[6-(l ,3-bcnzotI»iazoI-6-yl)-2-methyIpyrimidin-4- yI|amino}cthyl)phcnyI]oxy}-N-[2-(methyloxy)ethyl]acctamide. MS (El) for C25H27N5O3S: 478.2 (ΜΗ ').
[00548] Compound 373 2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}cthyI)phcnyl]oxy}-l -cycIopropylcthanonc. MS (EI) for C25H24N4O2S : 445.1 (MH+).
[00549] Compound 374 2-{[3-(l-{[6-(l ,3-benzothiazol-6-yl)-2-methyIpyrimidin-4- yl]amino}cthyl)phcnyl]oxy}-N-phenylacctamide. MS (EI) for C28H25N5O2S: 496.2 (MH+). [00550] Compound 376 6-(l,3-benzothiazol-6-yl)-N-({2-fluoro-5-I(2-morpholin-4-yI-2- oxocthyl)oxy]phenyI}mctliyl)-2-mcthy]pyrimidin-4-aminc. MS (El) for C25I-I24FN5O3S: 494.2 (MKT).
[00551 ] Compound 377 1 ,1-dimcthyIethyl 3-({|3-(l -{]6-(l ,3-bcnzothiazol-6-yI)-2- methylpyrimidin-4-yl|amino}cthyl)phcnyl]oxy}mcthyl)piperidinc-l-carboxylate. MS
(EI) for C31 H37N5O3S : 560.2 (ΜΙ- ).
[00552] Compound 378 1 ,1-dimcthylethyI 4-({]3-(l-{[6-(l ,3-benzothiazol-6-yl)-2- mctliylpyriniidin-4-yl|amino}cthyl)phcnyl]oxy}mcthyl)pipcridinc-l-carboxylatc. MS
(EI) l r C3iH37 503S: 560.2 (MH+).
[005531 Compound 380 iN,N-dicthyI-2-{|3-(l -{[2-mcthyl-6-(4-mctliyl-3,4-dihydro-2H- l,4-bcnzoxazin-6-yl)pyrimidin-4-y]|amino}cthyl)pIicnyl]oxy}acetamide. MS (EI) for C28H35 5O3 : 490.3 (ΜΙ- ).
[00554] Compound 385 6-(l ,3-bcnzothiazol-6-yI)-N-[(5-{[(l ,3-dimethyl-lH-pyrazoI-5- yl)methyl[oxy}-2-fluorophcnyl)incthyl|-2-niethyIpyrimidin-4-aminc. MS (EI) for C25H23FN6OS: 475.1 (MH+).
[00555] Compound 386 Methyl {[3-({[6-(l ,3-benzothiazol-6-yl)-2-mcthylpyrimidin-4- yI]aniino}mcthyl)-4-fluorophenyl|oxy}acctate. MS (EI) for C22H19FN O3S: 439.1 (MH÷).
[00556] Compound 388 (lS)-3-{[3-(l-{[6-(l,3-bcnzothiazol-6-yI)-2-mcthylpyrimidin-4- yl]amino}ethyl)phenyl|oxy}-l-phenylpropan-l-ol. MS (EI) for C29H28N4O2S:
497.1 (MH÷).
[00557] Compound 397 N,N-dicthyI-2-[[3-(l-{[2-mcthyl-6-(3-methyl-l-benzofuran-5- yI)pyrimidin-4-j ]amino}cthyl)phcnyl]oxy}acetamide. Ή NMR (400 MHz, d6-DMSO):8 8.18 (s, IH), 7.91 (dd, I H), 7.82 (s, I H), 7.74 (br s, I H), 7.60 (d, 1 H): 7.23 (t, I H), 7.04-6.88 (m, 2H), 6.73 (dd, I H), 5.30 (br s, I H), 4.73 (s, 2H), 3.34-3.19 (m, 4H), 2.39 (s, 3H), 2.25 (s, 3H), 1.44 (d, 3H), 1.1 1 (l, 3H), 0.99 (t, 3H). MS (El) for C28H32 4O3: 473.3 (MH+).
1005581 Compound 399 N-[ l -(3-{[2-(l H-imidazol-l -y!)cthyI]oxy}phenyl)ethyl]-2- methyl-6-(3-mcthyI-l-bcnzofuran-5-yl)pyrimidin-4-aminc. Ή NMR (400 MHz, d6- DMSO): 8.1 (s, I H), 7.90 (d, I H), 7.83 (s, I H), 7.74 (br s, I H), 7.68 (s, I H), 7.60 (d, I H), 7.23 (m, 2H), 7.01 (m, 2H), 6.87 (s, I H), 6.78 (d, I H), 5.28 (br s, I H), 4.35 (t, 2H), 4.22 (t, 2H), 2.40 (s, 31-1), 2.26 (s, 3H), 1 .43 (d, 3H); MS (EI) for C27H27 JO2: 454.2 (MH+).
[00559] Compound 402 2-methyI-6-(3-mcthyl-l-bcnzofuran-5-yl)-N-(l-{3-[(piperidin-3- yImcthyl)oxy)phenyI}ethyl)pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 8.18 (s, 1 H), 7.92 (dd, 1 H), 7.82 (s, 1 H), 7.75 (br s, 1 H), 7.60 (d, 1 H), 7.22 (t, 1 H), 7.00 (m, 2H), 6.86 (m, 1 H), 6.76 (m, 1 H), 5.31 (br s, 1 H), 4.90 (br s, 1 H). 3.79 (d, 2H), 3.02 (m, 1 H), 2.83 (m, IH), 2.44 (m, IH), 2.40 (s, 3H), 2.32 (m, IH), 2.26 (s, 3H), 1.79 (m, 2H), 1.54 (m, IH), 1.44 (d, 3H), 1.35 (m, IH), 1.16 (m, IH); MS (EI) for C^slb.N^C : 457.3 (MH+).
[00560] Compound 4042-{[3-(l-{|2-methyl-6-(3-mcthyI-l-benzofuran-5-yI)pyrimidjn- 4-yl]amino}ethyl)phenyl|oxy}ethanol. Ή NMR (400 MHz, d6-DMSO): 8.18 (s, I H), 7.92 (dd, ΓΗ), 7.82 (s, IH), 7.75 (br s, IH), 7.62 (d, IH), 7.23 (t, IH), 7.00 (m, 2H), 6.87 (m, IH), 6.77 (d, IH), 5.30 (br s, IH), 4.88 (br s, 1 H), 3.96 (t, 2H), 3.70 (t, 2H), 2.40 (s, 3H), 2.26 (s, 3H), 1.45 (d, 3H); MS (EI) for C24H25N3O3: 404.2 (MH+).
[00561] Compound 4052-methyl-6-(3-mcthyl-l-bcnzofuran-5-yl)-N-f(lS)-l-{3-[(2- morpholin-4-yl-2-oxocthyl)oxy]phcnyI}cthyI]pyrimidin-4-aminc. Ή NMR (400 MHz, d&- DMSO): 8.16 (s, IH), 7.89 (dd, IH), 7.80 (s, IH), 7.72 (br s, IH), 7.59 (d, IH), 7.21 (t, IH), 6.99 (m,2H), 6.85 (br s, IH), 6.74 (d, IH), 5.29 (brs, 1H),4.77 (s, 2H), 3.55 (m, 4H), 3.41 (m, 4H), 2.38 (s, 3H), 2.24 (s, 3H), 1.43 (d, 3H); MS (El) for C28H30N4O4: 487.2 (MH+).
[00562] Compound 406 N-[l-(3-{[3-(dimcthyIamino)propyl]oxy}phcnyl)ethyI]-2- mcthyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4-aminc. Ή NMR (400 MHz, d6- DMSO): 8.18 (s, IH), 7.92 (dd, IH), 7.82 (s, IH), 7.75 (s, IH), 7.59 (d, IH), 7.22 (t, IH), 7.00 (m, 1 H), 6.86 (br s, 1 H), 6.75 (d, 1 H), 5.28 (br s, 1 H), 3.96 (t, 2H), 2.40 (s, 3H), 2.32 (t, 2H), 2.26 (s, 3H), 2.11 (s, 6H), 1.82 (m, 2H), 1.44 (d, 3H); MS (EI) for C27H32N4O2: 445.3 (ΜΙ-Γ).
[00563] Compound 4072-mcthyl-6-(3-mcthyI-l-bcnzofuran-5-yI)-N-[l-(3-{[(l-methyl- lH-pyrazoI-3-yl)mcthyl]oxy}phcnyl)cthyl]pyrimidin-4-amine. Ή NMR (400 MHz, d6- DMSO): 8.18 (s, IH), 7.91 (dd, IH), 7.83 (s, IH), 7.74 (br s, IH), 7.62 (m, 2H), 7.24 (t, IH), 7.08 (m, IH), 7.01 (m, IH), 6.86 (d, 1H),6.28 (s, 1 H), 5.31 (brs, IH), 4.97 (s, 2H), 3.81 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H), 1.45 (d, 3H); MS (EI) for C27H27N5O2: 454.2 (MH+).
[00564] Compound 4186-(l-benzofuran-5-yI)-N-[l-(3-{|(l,3-dimethyl-lH-pyrazoI-5- yl)mcthyl|oxy}phenyI)cthyl]-2-mcthylpyrimidin-4-aminc. Ή NMR (400 MHz, d6- DMSO): 8.30 (s, IH), 8.05 (d. IH), 7.93 (d, IH), 7.78 (m, IH), 7.68 (d, IH), 7.26 (t, IH), 7.08 (m, 3H), 6.88 (d, IH), 6.82 (br s, IH), 5.32 (br s. IH), 5.08 (s, 2H), 3.72 (s, 3H), 2.40 (s, 3H), 2.07 (s, 3H), 1.45 (d, 3H); MS (EI) for C-27H27N5O2: 454.2 (MH+).
[00565] Compound 4242-mcthyl-6-(3-methyl-l-benzofuran-5-yl)-N-I(lR)-l-{3-j(2- morphoIin-4-yI-2-oxocthyl)oxy]phenyI}ethyl]pyrimidin-4-amine. Ή NMR (400 MHz, d6- DMSO): 8.16 (s, IH), 7.89 (dd, IH), 7.80 (s, IH), 7.72 (brs, IH), 7.59 (d, IH), 7.21 (I, 11-1), 6.99 (m,2H), 6.85 (brs, IH), 6.74 (d, IH), 5.29 (brs, lH),4.77(s, 2H), 3.55 (m, 4H), 3.41 (m, 4H), 2.38 (s, 3H), 2.24 (s.3H), 1.43 (d, 3H); MS (El) for C28H30 4O4: 487.2 (Mhf). [005661 Compound 4286-(l,3-benzorhiazol-6-yl)-2-mcthyl-N-[l-(3- {[(mcthyIsulfonyI)mcthyl]o.\y}phcnyl)ethyl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6- DMSO): 9.44 (s, 1H), 8.77 (s, IH), 8.12 (ms IH), 7.85 (m, 1H), 7.27 (t, IH), 7.14 (m, 2H, 6.97 (d, 2H), 6.84 (m, 1 H), 5.28 (s, 2H), 4.89 (br s, 1 H), 3.02 (s, 3H), 2.39 (s, 3H), 1.44 (d, 3H); MS (EI) for C22H22N4O3S2: 455.1 ( H*).
[00567] Compound 4326-(l,3-bcnzothiazoI-6-yl)-2-mcthyl-N-(l-{3-[(2-morpholin-4- ylethyI)oxy]phcnyI}ethyl)pyrimidin-4-aminc. Ή NMR (400 MHz. d6-DMSO): 9.47 (s, IH), 8.80 (s, IH), 8.15 (m, IH), 8.12 (m, IH), 7.86 (m, IH), 7.23 (t, IH), 7.01 (m, 2H), 6.89 (m, IH), 6.78 (d, IH), 5.32 (br s, IH), 4.06 (t, 2H), 3.55 (t, 4H), 2.66 (t, 2H), 2.44 (m, 4H), 2.41 (s, 3H), 1.46 (d, 3H); MS (EI) for C26H29NS02S: 476.2 (MH*).
[005681 Compound 4346-(l,3-benzothiazoI-6-yI)-2-methyl-N-|l-(3-{[2-(2-methyl-lH- imidazol-l-yl)ethyI]oxy}phcnyI)cthyI]pyrimidin-4-amine. Ή NMR (400 MHz. d6- DMSO): 9.48 (s, IH), 8.80 (s, IH), 8.16 (d, IH), 8.10 (m, IH), 7.86 (m, IH), 7.47 (s, IH), 7.25 (t, IH), 7.01 (m, 2H), 6.83 (m, 2H), 5.30 (br s, IH), 4.42 (t, 2H), 4.27 (t, 2H), 3.40 (s, 3H), 2.41 (s, 3H), 1.44 (d, 3H); MS (EI) for C2i,H26N6OS: 471.2 (ΜΙ-Γ).
[00569] Compound 4356-(l-benzofuran-5-yl)-2-mcthyl-N-[l-(3-{[(l-mcthyl-lH- pyrazol-3-yl)mcthylIoxy}phcnyI)cthy]]pyrimidin-4-aminc. MS (EI) for C-26H25 5O2: 440.2 (MH+).
[00570] Compound 4374-{[3-(l-{|6-(I,3-bcnzothiazo!-6-yI)-2-mcthylpyrimidin-4- yl]amino}ethyl)phcnyl|oxy}butan-l-ol. MS (EI) for C2 H26N4O2S: 435.2 (MH*).
[00571] Compound 4393-{[3-(l-{|6-(l,3-bcnzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}propanc-1,2-dio]. Ή NMR (400 MHz, d6-DMSO): 9.47 (s, IH), 8.80 (s, IH), 8.15 (d, IH), 8.11 (m, IH), 7.86 (m, IH), 7.23 (t, IH), 7.00 (m, 2H), 6.88 (m, IH), 6.77 (d, IH), 5.31 (br s, IH), 4.94 (br s, 1H), 4.69 (br s, IH), 3.96 (m, IH), 3.80 (m, 2H), 3.44 (d, 2H), 2.41 (s, 3H), 1.46 (d, 3H); MS (EI) for C23H24N4O3S: 437.1 (MH+).
[00572] Compound 4412-{[3-(l-{[6-(l,3-bcnzothiazol-6-yl)-2-mcthylpyrimidin-4- yl|amino}ethyl)phcnyr[oxy}cthanol. MS (EI) for C26H22N4S: 423.2 (MH+).
1005731 Compund 442 l-{[3-(l-{l6-(l,3-bcnzothiazol-6-yl)-2-mcthylpyrimidin-4- yl|amino}cthyl)phcnyI[oxy}-3-fluoropropan-2-ol. MS (EI) for C23H23FN4O2S: 439.2 (MH").
[00574] Compound 4443-{[3-(l-{|6-(l,3-bcnzothiazol-6-yl)-2-mcthylpyi imidin-4- yl|amino}ethyI)phenyl]oxy}propan-l-ol. MS (EI) for C23H24N4O2S: 421.2 (MH+). [00575] Compound 445 4-{[3-(l-{[6-(l ,3-bcnzothiazol-6-yl)-2-methyIpyrimidin-4- yI]amino}cthyl)phciiyl]oxy}-N,N-dimcthylbutanamidc. MS (EI) for C26H29N5Q2S: 470.2 (MH*).
[00576] Compound 446 6-(l,3-benzothiazol-6-yl)-N-[ l -(3-{[3- (dicthyIamino)propyl]oxy}phcnyl)cthyl]-2-niethylpyriniidin-4-aminc. MS (EI) for C27H33N5OS: 476.2 (MH*).
[00577] Compound 447 6-(l,3-benzothiazoI-6-yl)-2-mcthyI-N-[l -(3-{[2-(l H-pyrrol-l- yl)cthyl]oxy}phenyI)ethyI]pyrimidin-4-amine. MS (EI) for C26H25 5OS: 456.2 (MH.*).
[00578] Compound 448 6-(I ,3-bcnzothiazoI-6-yI)-2-methyl-N-(l -{3-|(3-morpholin-4- ylpropyl)oxy]phenyI}ethyl)pyrimidin-4-aminc. MS (EI) for C27H31N5O2S: 490.2 (MH+).
[00579] Compound 449 2-{[3-(l -{]6-(1 ,3-benzothiazol-6-yI)-2-methylpyrimidin-4- yI]amino}cthyl)phcnyI]oxy}-N-(2-hydroxyclhyl)acctamidc. MS (EI) for C24H25N5O3S: 464.2 (MH+).
100580] Compound 450 2-{[3-(l -{[6-(l ,3-bcnzothiazoI-6-yl)-2-methylpyrimidin-4- yl]amino}cthyI)phcnyl]oxy}-N-cycIopropyIacetaniide. Ή NMR (400 MHz, d6-DMSO): 9.47 (s, IH), 8.79 (s, 1 H), 8.12 (m, 3H)S 7.86 (br s, I H), 7.25 (t, 1 H), 7.03 (br s, 2H), 6.87 (m, I H), 6.76 (d, I H), 5.31 (br s, I H), 4.41 (s, 2H), 2.67 (m, IH), 2.41 (s, 3H), 1.46 (d, 3H), 0.60 (m, 2H), 0.46 (m, 2H); MS (EI) for C25H25N5O2S: 460.1 (MH+).
[00581] Compound 452 6-(l ,3-benzothiazoI-6-yl)-2-mcthyl-N-Il-(3-{[2-(l H-pyrazol-l - yl)ethyI]oxy}phcnyl)cthyl]pyrimidin-4-aminc. MS (EI) for C25H24N6OS: 457.2 (Ml ).
[00582] Compound 453 N,N-dicthyl-2-[(3-{l-[(2-methyl-6-naphthalcn-2-ylpynmidin-4- yl)amino]ethyI}phenyl)oxy]acciamidc. Ή NMR (400 MHz, d6-DMSO): 8.55 (s, I H), 8.05 (m, 2H), 7.97 (m, 2H), 7.83 (br s, 1 H), 7.58 (m, 3H), 7.24 (t, I H), 7.00 (m, 2H), 6.74 (d, I H), 5.33 (br s, I H), 4.74 (s, 2H), 3.24 (m, 4H), 2.43 (s, 3H), 1.46 (d, 3H), 1.1 1 (t, 3H), 1.00 (t, 3H); MS (EI) for C29H32N4O2: 469.2 (MH+).
[00583] Compound 454 6-(l ,3-bcnzothiazoI-6-yI)-2-methyl-N-(l-{3-[(3-pyrrolidin-l- ylpropyl)oxy|phcnyl}cthyl)pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 9.47 (s, 1 H), 8.80 (s, 1 H), 8.15 (m, 2H), 7.86 (m, 1 H), 7.22 (t, 1 H), 7.00 (m, 2H), 6.89 (m, 1 H), 6.76 (d: 1 H), 5.32 (br s, 1 H), 3.98 (t, 2H), 2.52 (m, 2H), 2.41 (m, 7H), 1 .86 (m, 2H), 1.65 (4H), 1.46 (d, 3H); MS (EI) for C27H31N5OS: 474.2 (MH*).
100584] Compound 455 6-(l,3-bcnzothiazol-6-yl)-N-|l-(3-{|3-
(dimctliylamino)propyI]oxy}phcnyl)cthyl]-2-methylpyrimidin-4-amine. MS (EI) for C25H29N5OS: 448.2 (MH*). [00585] Compound 4571,1-dimcthylcthyl 3-({[3-(l-{[2-mcthyl-6-(3-methyl-l- bcnzofuran-5-yI)pyrimidin-4-yllamino}cthyl)phcnylIoxy}mcthyl)pipcridinc-l- carboxylatc. MS (EI) for C33H 0N4O4: 557.3 (MH+).
[00586] Compound 4582-{|3-(l-{|6-(l,3-bcnzothiazol-6-yl)-2-mcthylpyrimidin-4- yI]amino}ethyl)phenyl|oxy}-N-cycIohexylaccramide. MS (EI) for C2SH31N5O2S: 502.2 (MH+).
[00587] Compound 463 methyl {|3-(l-{|6-(l,3-benzothiazol-6-yl)-2-mcthylpyrimidin-4- yl]amino}ethyl)phenyI]oxy}acetate. MS (EI) for C23H22N4O3S: 435.2 (MH+).
[00588] Compound 4646-(l,3-bcnzothiazol-6-yl)-2-niethyl-N-]l-(3-{[2- (mcthylsulfonyl)ethyl[oxy}phenyl)ethyl|pyrimidin-4-aminc. MS (EI) for C23H 4 4O3S1: 469.1 (MH÷).
[00589] Compound 467 {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpynmidin-4- yI]amino}cthyl)phenyl]oxy}acetic acid. MS (EI) for C22H20N4O3S: 421.1 (ΜΙ-Γ).
[005901 Compound 475 N,N-dimcthyl-2-({3-[(lS)-l-{[2-methyI-6-(3-mcthyl-l- benzofuran-5-yl)pyrimidin-4-yI]amino}ethyl]phenyI}oxy)acetamide. Ή NMR (400 MHz, de-DMSO): 8.18 (s, IH), 7.90 (dd, IH), 7.82 (s, IH), 7.74 (br s, IH), 7.59 (d, IH), 7.22 (t, IH), 7.00 (m, 2H), 6.85 (m, IH), 6.74 (d, IH), 5.27 (br s, IH), 4.7.6 (s, 2H), 2.97 (s, 3H), 2.81 (s, 3H), 2.40 (s, 3H), 2.26 (s 3H), 1.46 (d, 3H); MS (EI) for C26H28 O3: 445.2 (MH+).
[00591] Compound 476 -|l-(3-{[2-(dimethylamino)cthyI]oxy}phcnyl)ethyl]-2-methyl- 6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 8.18 (s, IH), 7.92 (dd, 1H); 7.83 (s, IH), 7.74 (br s, IH), 7.60 (d, IH), 7.22 (t, 1H)47.00 (m, 2H), 6.87 (m, IH), 6.78 (d, 1 H), 5.29 (br s, IH), 4.02 (t, 2H), 2.59 (t, 2H), 2.40 (s, 3H), 2.26 (s, 3H), 2.18 (s, 6H), 1.44 (d, 3H); MS (EI) for C26H30N4O2: 431.2 (MI-P).
[00592] Compound 477 N,N-dimethyl-2-({3-|(lR)-l-{[2-methyl-6-(3-mcthyI-l- benzofuran-5-yl)pyrimidin-4-yllamino}cthyl|phenyl}oxy)acetamide. Ή NMR (400 MHz, d6-DMSO): 8.18 (s, III), 7.90 (dd, IH), 7.82 (s, IH), 7.74 (br s, IH), 7.59 (d, IH), 7.22 (t, IH), 7.00 (m, 2H), 6.85 (m, IH), 6.74 (d, IH), 5.27 (br s, IH), 4.76 (s, 2H), 2.97 (s, 3H), 2.81 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H), 1.46 (d, 3H); MS (EI) for C26H28N4O3: 445.2 (MH+).
[00593] Compound 4786-(l,3-benzothiazol-6-yl)-N-[l-(3-{[2-
(dimcthyIamino)cthyl|oxy}phenyl)ethyl]-2-mcthylpyrimidin-4-amine. Ή NMR (400 MHz, d6-DMSO): 9.47 (s, 1 H), 8.80 (s, IH), 8.15 (m, 2H), 7.85 (br s, IH), 7.23 (t, IH), 7.01 (m, 2H), 6.89 (m, I H), 6.77 (d, I H), 5.30 (br s, I H), 4.02 (t, 2H), 2.59 (t, 2H), 2.41 (s, 3H), 2.1 8 (s, 6H), 1 .46 (d, 3H); MS (El) for C24H27N5OS: 434.2 (Μ1- ).
[005941 Compound 504 2-{|3-(l-{[6-(l ,3-ben/.othiazol-6-yl)-2-mcthylpyrimidin-4- yI]amino}ethyl)phcnylloxy}-N-[2-(dimcthylamino)ethyl|acetamide. MS (EI) for C:6H3oNr,02S: 491.2 (MH+).
[00595] Compound 505 2-{[3-(l-{[6-(l ,3-benzothiazol-6-yl)-2-mcthylpyrimidin-4- yI]amino}ethyl)phcnyl]oxy}-N-propylacctamidc. Ή NMR (400 MHz, d6-DMSO): 9.44 (s, I H), 8.81 (br s, I H), 8.05 - 8.20 (m, 3H), 7.84 (br s, I H), 7.25 (t s, I H), 7.06 (br s, 2H), 6.85 (br d, l H), 5.45 (m, 1 H), 4.43 (s, 2H), 3.06 (m, 2H'), 2.42 (s, 3H), 1.48 (d, 3H), 1 .41 (m, 2H), 0.74 (t, 3H); MS (EI) for C25H27NSO2S: 462.1 (MH+).
[00596] Compound 506 2-{[3-(l -{[6-(l,3-bcnzothiazol-6-yl)-2-mcthyIpyrimidin-4- yllaniino}cthyl)phcnyl|oxy}-N-ethyl-N-mcthylacctamide. MS (EI) for C25H27N5O2S: 462.1 (MH÷).
[00597] Compound 510 2-({[3-(l -{|6-(l ,3-bcnzothiazol-6-yl)-2-methylpyrimidin-4- yI]amino}ethyl)phenyl]oxy}methyI)-l,3-oxazolc-4-carboxyIic acid. MS (EI) for C25H21N5O4S: 488.1 (MH+).
[00598] Compound 51 1 methyl 2-({[3-(l-{[6-(l ,3-bcnzothiaz0l-6-yl)-2- methylpyrimidin-4-yl]amino}ethyl)phcnyl|oxy}niethyl)-l,3-oxazoIe-4-carboxylatc. MS
(EI) for C26H23 504S: 502.1 (ΜΙ- ).
[00599] Compound 517 6-(l ,3-bcnzothiazol-6-yI)-N-[1 -(3-{[(l ,3-dimcthyI-l H-pyrazol-5- yl)mcthyl]oxy}phenyl)ethyl]-2-mcthylpyrimidin-4-amine. Ή NMR (400 MHz. d6- DMSO): 9.62 (s, I H), 8.71 (br s, I H), 8.35 (d, I H), 7.82 (dd, I H), 6.92-7.32 (m, 5H), 6.17 (s, I H), 5.45 (m, I H), 5.08 (s, 2H), 3.61 (s, 3H), 2.61 (s, 3H), 2.06 (s, 3H), 1.58 (d, 3H); MS (EI) for C26H26N6OS: 471 .0 (ΜΙ- ).
100600] Compound 519 6-(l,3-bcnzothiazol-6-yl)-2-mcthyl-N-(l-{3- |(phenylmethyl)oxy]phenyl}cthyl)pyrimidin-4-aniine. MS (EI) for C27H24N.1OS: 453.1 (MH+).
100601 ] Compound 521 6-(l ,3-bcnzothiazol-6-yl)-2-mcthyl-N-(l-{3-[(pyridin-3- ylmethyl)oxy]phenyl}ethyl)pyrimidin-4-amine. MS (EI) for C26H23N5OS: 454.2 (ΜΙ- ).
[00602] Compound 522 6-(l ,3-bcnzothiazoI-6-yl)-2-mcthyl-N-[l-(3-{[(3-mcthyIisoxazol- 5-yI)mcthyl]oxy}phenyl)ethyl|pyrimidin-4-amine. MS (EI) for C25H23N5O2S: 458.1 (MH+). 100603] Compound 5236-(l,3-bcnzothiazol-6-yI)-2-mcthyl- -ll-(3-{[(2-mcthyl-l,3- tliiazol-4-yl)mcthyI]oxy}phcnyl)cthyl]pynmidin-4-amine. MS (EI) for C25H23 3OS2:
474.1 (MH+).
[00604] Compound 5276-(l,3-bcnzothiazol-6-yl)-2-mcthyI-N-[l-(3-{[(4- mcthyIphenyI)methyl|oxy}phcnyI)ethyl]pyrimidin-4-amine. MS (EI) for C2gH26N40S:
467.2 (ΜΙ-Γ).
100605] Compound 5296-(l,3-bcnzothiazol-6-yl)-2-mcthyI-N-Il-(3-{|(3-{[(4- methylphcnyI)oxy]methy }-l,2,4-oxadiazoI-5-yl)mctliyI]oxy}phcnyI)cthyl]pyrimidin-4- aminc. MS (El) for C3iH28N603S: 565.2 (ΜΙ- ).
100606] Compound 5362-{|3-(l-{[2-methyl-6-(3-mcthyl-l-bcnzofuran-5-yI)pyrimidin- 4-yI]amino}ethyl)phcnyI]oxy}acetamidc. Ή NMR (400 MHz, d6-DMSO): 8.18 (s, IH), 7.92 (dd, 1 H), 7.82 (s, 1 H), 7.76 (br s, 1 H), 7.62 (d, 1 H), 7.54 (s, 1 H), 7.40 (s, 1 H), 7.26 (t, IH), 7.05 (m,2H), 6.86 (m, IH), 6.80 (d, 1 H).5.30 (br s, ΓΗ), 4.41 (s, 2H), 2.41 (s, 3H), 2.26 (s, 3H), 1.45 (d, 3H); MS (EI) for C24H24 4O3: 417.2 (MH+).
[00607] Compound 5356-(l,3-bcnzothiazol-6-yl)-N-[l-(3-{[2-(lH-imidazol-l- yI)ethyI]oxy}phcnyl)ethyl]-2-mcthylpyrimidin-4-amine. Ή NMR (400 MHz. d6-DMSO):5 9.47 (s, IH), 8.80 (s, IH), 8.19-8.07 (m, 2H), 7.85 (br s, IH), 7.67 (s, IH), 7.26-7.21 (m, 2H), 7.08-6.95 (m, 2H), 6.86 (s, IH), 6.78 (dd, IH), 5.30 (br s, IH), 4.34 (m, 2H), 4.21 (m, 2H), 2.40 (s, 3H), 1.44 (d, 3H). MS (EI) for C2sH24N6OS: 457.2 (MH+).
[00608] Compound 537 N-(l-(3-{|(l,3-dimcthyl-lH-pyrazoI-5- yI)methyl]oxy}phenyl)ethyl]-2-methyI-6-(3-methyI-l-bcnzofuran-5-yl)pyrimidin-4- aminc. Ή NMR (400 MHz, d,,-DMSO): 8.19 (s, lH),7.92(dd, lH),7.83(s, IH), 7.75 (br s, IH), 7.60 (d, IH), 7.25 (t, IH), 7.11 (m, IH), 7.03 (m, 2H), 6.88 (d, IH), 6.11 (s, IH), 5.30 (brs, IH), 5.08 (s, 2H), 3.71 (s, 3H), 2.40 (s, 3H), 2.25 (s, 3H), 2.07 (s, 3H), 1.45 (d, 3H); MS (EI) for C28H29N5O2: 468.2 (Ml- ).
[00609] Compound 5382-{|3-(l-{[6-(l,3-bcnzothiazol-6-yI)-2-mcthylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}acctamide. Ή NMR (400 MHz, df)-DMSO): 9.47(s, IH), 8.79 (s, IH), 8.15 (m, 2H), 7.92 (br s, IH), 7.53 (s, IH), 7.39 (s, IH), 7.25 (t, IH), 7.04 (br s, 2H), 6.80(m, IH), 5.25 (brs, IH), 4.40 (s, 2H), 2.41 (s, 3H), 1.45 (d, 3H); MS (EI) for
C2:H2|N502S: 420.1 (MH+).
|00610| Compound 5392-mcthyl-6-(3-mcthyI-l-bcnzofuran-5-yl)-N-(l-{3-|(2- morphoIin-4-yI-2-oxoethyI)oxy|phcnyl}ethyl)pyrimidin-4-aminc. Ή NMR (400 MHz, dg- DMSO): 8.18 (s, IH), 7.90 (dd, IH), 7.82 (s, IH), 7.76 (brs, IH), 7.60 (d, IH), 7.24 (t, IH), 7.00 (m, 2H), 6.86 (m, 1 H), 6.76 (d, 1 H), 5.29 (br s, 1 H), 4.79 (s, 2H), 3.55 (m, 4H), 3.44 (m, 4H), 2.40 (s, 3H), 2.26 (s, 3H), 1.45 (d, 3H); MS (EI) for C28H30N4O4: 487.2 (MH+).
10061 1 ] Compound 541 N,N-dimethyI-2-{|3-(l-{(2-methyI-6-(3-mcthyI-l-benzofuran-5- yl)pyrimidin-4-yl|amino}cthyI)phcnyI|oxy}acctamidc. Ή NMR (400 MHz, d6-DMSO): 8.18 (s, l H), 7.90 (dd, 1 H), 7.83 (m, 2H)f 7.60 (d, 1 H), 7.22 (t, 1 H), 7.00 (m, 2H), 6.87 (m, 1 H), 6.74 (d, 1 H), 5.31 (br s, 1 H), 4.76 (s, 2H), 2.98 (s, 3H), 2. 1 (s, 3H), 2.41 (s, 3H), 2.26 (s, 3H), 1.45 (d, 3H); MS (EI) for C26H2SN4O3: 445.2 ( H+).
[00612] Compound 542 6-(l,3-benzothiazoI-6-yl)-2-mcthyI-N-[l-(3-{[(l-mcthyl-l H- pyrazol-3-yI)mcthyl]oxy}phenyl)cthyl]pyrimidin-4-amine. MS (El) for C25H24 6OS: 457.1 (MH+).
[00613] Compound 543 6-(l ,3-benzo(liiazol-6-yl)-l\-(l-{3-|(2- fluorocthyI)oxy]phenyl}ethyl)-2-mcthyIpyrimidin-4-aminc. Ή NMR (400 MHz, dmso) 5 9.47 (s, 1 H), 8.80 (s, 1 H), 8.1 5 (t, 2H), 7.86 (s, 1 H), 7.26 (t, 1 H), 7.04 (s, 2H), 6.84 (t, 2H), 5.32 (s, 1 IT), 4.90 - 4.73 (m, 1 H), 4.67 (dd, 1 H), 4.35 - 4.09 (m, 2H), 2.41 (s, 3H), 1 .47 (d, 3H); MS (EI) for C22H21 FN4OS : 409.1 (MH÷).
[00614] Compound 544 6-(l ,3-bcnzothiazoI-6-yI)-2-mcthyl-N-(l-{3-[(2,2,2- trifluorocthyl)oxy]phcnyI}cthyI)pyrimidin-4-amine. Ή NMR (400 MHz, dmso) δ 9.47 (d, 1 H), 8.80 (s, 1 H), 8.14 (t, 2H), 7.85 (s, 1 H), 7.30 (t, 1H), 7.12 (s, 2H), 6.91 (d, 2H), 5.32 (s, 1 H), 4.74 (q: 2H), 2.41 (s, 3H), 1.47 (d, 3 H); MS (EI) for C22H19F3 OS: 445.1 (MH+).
[00615] Compounds of a general formula CC can be synthesized according to general scheme 3.
General Scheme 3
Scheme 3: General Synthesis of Compounds of formula CC
Figure imgf000236_0001
CC
[00616] Sulfonamide compounds of formula g, wherein Ri3 and R12 are non-reactive substituents such as hydrogen, alkyl, and alkoxide. can be alkylated by first protecting, and then alkylating, the sulfonamide nitrogen. Typical protecting groups useful for this transformation are carbamate protecting groups, such as a Boc or CBz group. The sulfonamide nitrogen can be protected by contacting the sulfonamide with an activated group, such as BocjO, in the presence of a base, such as triethylamine, and a solvent, such as THF. The reaction conditions optionally include a catalyst, such as DMAP. The protected nitrogen is alkylated as shown in Scheme 3, wherein Ru is an alkyl group and Lg is a Leaving Group, to produce a compound of formula h. The reaction conditions for alkylation can include a base such as 2CO3 in a solvent, such as water or D!vlF. The protecting group is then removed from the compound of formula h to produce a compound of formula CC. The deprotection conditions are specific to the protecting group used and can include anhydrous acidic conditions (such as TFA/CH2CI2 lo remove a Boc group) or hydrogenation conditions (such as Pd/C and H2 (g) to remove a CBz group), among others commonly used by those skilled in the art.
Example 4a: Synthesis of Tert-b tyl cyanomethyl(3-(l-(6-(3-methoxyphcnyl)-2- mcihylpyrimidin-4-ylamino)ethyl)phenylsulf'onyl)carbamate (Compound 65).
Figure imgf000237_0001
[00617] A round bottom flask was charged with 3-(l -(6-(3-methoxyphenyl)-2- methylpyrimidin-4-ylamino)ethyl)benzenesulfonamide (130 mg, 0.33 mmol, 1.0 eq.), DMAP (19.9 mg, 0.16 mmol, 0.5 eq.), THF (2.0 niL), di-lerl-butyldicarbonate (213 mg, 0.98 mmol, 3.0 eq). and triethyl amine (0.05 mL, 0.39 mmol, 1 .2 eq.). The reaction was stirred at rt for 3 hours, before adding K.2C03 (90 mg, 0.64 mmol, 2.0 eq.) and bromoacetonitrile (57 ul, 0.81 mmol, 2.5 eq.). The reaction was stirred overnight at rt before quenching with saturated aqueous NaHC03. The aqueous layer was extracted 2 times with EtOAc. The combined organic layers were dried with Na2S04 and concentrated under vacuum to give the crude product. The product was purified by Si02 flash chromatography (70:30 hexanes/ethyl acetate) to afford tert-bulyl cyanomethyl(3-(l -(6-(3-methoxyphenyl)-2-methylpyrimidin-4- ylamino)ethyl)phenylsulfonyl)carbamate as clear oil (169 mg, 96% yield). Ή NMR (400 MHz, d6-DMSO+D20): 8.05 (s, 1 H), 7.88 (d, 2H), 7.75 (t, 1 H), 7.55 (br t, 1 H), 7.40 (m, 2 H), 7.22 (dd, 1 H), 6.91 (s, I H), 5.50 (br q, 1 H), 4.90 (s, 2H), 3.82 (s, 3H), 1.60 (d, 3H), 1 .20 (s, 9H) ; MS (EI) for C27H31N5O5S: 538.2 (ΜΙ-Γ). Example 4b: Synthesis of N-(cyanoinethyl)-3-[ l-({2-methyl-6-[3- (methyloxy)phcnyl]pyrimidin-4-yl}amino)ethyl|benzcnesulfonamide (Compound 47).
Figure imgf000238_0001
[00618] A round bottom flask was charged with terl-butyl cyanomethyl(3-( l -(6-(3- methoxyphenyl)-2-methylpyrimidin-4-ylamino)ethyl)phenylsulfonyl)carbamate (30 mg, 0.055 mmol, 1 .0 eq.), dichloromelhane ( 1 mL), and TFA (1.0 mL). The reaction was stirred for 4 hours at rt before concentrating via rotary evaporation. Methanol was added to the residue and concentrated via rotary evaporation. This was repeated 3 times to remove residual TFA. Purification by preparative HPLC (reverse-phase, acetonitrileAvater with 0.01 % TFA), followed by concentration at reduced pressure and lyophilization, afforded 'N,N-dimethyl-2-{ [3-( 1 - { [2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino} ethyl)phenyl]oxy}acelamide as a solid (1 1 .0 mg, 24% yield). The product was purified by SiCb flash chromatography (70:30 hexanes/ethyl acetate) to provide N- (cyanomethyl)-3-[l -({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl }amino)ethyl]benzenesul fonamide (Compound 47) as a solid ( 15 mg, 68% yield). ' H NMR (400 MHz, d6-DMSO+D20): 7.90 (s, 1 H), 7.80 (m, 2IT), 7.62 (t, 1 H): 7.55 (br t, 1 H), 7.38 (m, 2 H), 7.22 (dd, 1 H), 6.85 (s, ΓΗ). 5.50 (br q, 1 H), 4.1 5 (br s, 2H), 3.85 (s, 3H), 1 .60 (d, 3H); MS (EI) for C22H23 503S: 437.9 (ΜΙ-Γ).
|00619] The following compounds were prepared by a manner analogous to examples 4a and/or 4b:
[00620] Compound 27 N-(cyanomcthyl)-3-( l -{[2-methyl-6-(l-methyl-l H-indol-6- yl)pynmidin-4-yI]amino}ethyl)benzenesulfonamide. Ή NMR (400 MHz, d6-DMSO): 7.92 (br s, 1 H), 7.82 (br s, 1 H), 7.70 (m, 2H), 7.60 (t, 1 H), 7.42 (m, 2 H), 6.82 (br s, 1 H), 6.51 (s, 1 H), 5.40 (br s, 1 H ), 3.80 (s, 3 H), 3. 1 5 (s, 1 1-1), 1 .24 (d, 3 H); MS (EI) for
C2 H2 N602S: 461 .1 (Ml-f).
[00621J Compound 62 Methyl N-({3-| l -({2-methyI-6-[3-(methyloxy)phcnyl]pyrimidin- 4-yl}amino)cthyl)phcnyI}suIfonyl)glycinate. Ή NMR (400 MHz, d6-DMSO): 7.80 (br d, 2H), 7.63 (m, 1 H), 7.51 (m, 3H), 7.39 (br t, 1 H), 7.01 (dd, 1 H), 6.82 (br s, 1 H), 5.45 (br s, 1 H), 3.80 (s, 3H), 3.67 (s, 2H), 3.46 (s, 3H), 2.36 (s, 3H), 1 .49 (d, 3 H); MS (EI) for C23H26N4O5S : 471 .2 (ΜΙ-Γ).
[00622] Compound 70 Methyl N-{[(l ,l-dimcthylcthyl)oxy]carbonyl}-N-({3-|l-({2- methyl-6-|3-(nicthyloxy)phenyl]pyrimidin-4-yl}amino)cthyI]phenyl}sulfonyl)gIycinatc.
Ή NMR (400 MHz, d6-DMSO): 8.00 (m, 2H), 7.89 (d, 1 H), 7.80 (m, 1 H), 7.62 (t, 1 H), 7.51 (m, 2H), 7.40 (br t, 1 H), 7.01 (dd, 1 H), 6.82 (br s, 1 H), 5.40 (br s, 1 H), 4.60 (s, 2H), 3.80 (s, 3H), 3.70 (s, 3H), 2.39 (s, 3H), 1 .49 (d, 3 H), 1.10 (br s, 9H); MS (EI) for C28H34 4O7S: 570.9 (MH+).
[00623] Compound 78 N-({3-[l -({2-mcthyI-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl|phcnyl}sulfonyl)glycinc. Ή NMR (400 MHz, d6-DMSO+ D20): 7.85 (br s, 1 H). 7.70 (m, 2H), 7.55 (m, 3H), 7.40 (br t, I ), 7.02 (dd, 1 H), 6.80 (br s, 1 H), 5.33 (br s, l H), 3.80 (s, 3H), 3.53 (s, ZH), 2.39 (s, 3H), 1.49 (d, 3 H); MS (EI) for C22H24N4O5S: 457.2 (MH+).
[00624] Compound 219 3-(l-{[6-(l ,3-bcnzothiazol-6-yl)-2-mcthylpyrimidin-4- yl]amino}cthyl)-N-(cyanomethyl)benzenesuIfonamide. MS (EI) for C22H20N6O2S2: 465.1 (MH+).
[00625] Compound 221 3-(l-{|6-(l ,3-benzothiazoI-6-yl)-2-mcthylpyrimidin-4- yI]amino}cthy])-N-but-2-yn-l-ylbenzcncsulfonamidc. MS (EI) for C24H23N5O2S2: 478.1 (MH+).
[00626] Compound 225 3-(l-{|6-(l,3-bcnzothiazol-6-yl)-2-mcthylpyrimidin-4- yl|amino}ethyI)-N-prop-2-yn-l-yIbenzcnesulfonamide. MS (EI) for C23H21N5O2S2: 464.1 (MH+).
[00627] Compound 243 3-(l-{[6-(l ,3-benzothiazoI-6-yl)-2-mcthylpyrimidin-4- yl]amino}cthyI)-N-(2-hydroxycthyl)bcnzenesuIfonamidc. MS (EI) for C22H23N5O3S2: 470.1 (MH+).
[00628] Compound 245 3-(l-{[6-(l ,3-bcnzothiazol-6-yI)-2-mcthylpyrimidin-4- yl]amino}cthyl)-N-[2-(methyIoxy)cthyl|benzcnesuIfonamide. MS (EI) for C23H25 5O3S2: 484.1 (ΜΙ- ).
General Scheme 4
Scheme 4: Synthesis of Compounds of formula DD
Figure imgf000240_0001
[00629] Scheme 4 shows the process for producing a compound of formula DD. starting with a compound of formula a. The coupling of a compound of formula i to a compound of formula a, wherein PG is a suitable protecting group and X and Y are each independently a carbon or nitrogen atom, can be accomplished using a palladium catalyst analogously to the process shown in Scheme 1 . The resulting intermediate, j, is then deprotected using known methods and can be further alkylated to produce a compound of formula k according to Scheme 4 (also analogous to the process shown in Scheme 3), wherein RM is an alkyl group and Lg is a Leaving Group. Nucleophilic displacement of the chloride of the compound of formula k by the amine compound of formula 1 is accomplished analogously to the process shown in Scheme 1 to produce the compound of formula DD.
Example 5: Synthesis of '6-(l-cthyl-l H-indol-6-yl)-2-methyl-N-[(l R)-l,2,3,4- tctrahydronaphthalen-1 -yl|pyrimidin-4-aminc (Compound 24).
Figure imgf000241_0001
Figure imgf000241_0002
Step 1
[00630] Synth esis of l -(tcrt-butyldimcthy!silyl)-6-(6-chloro-2-methyIpyrimidin-4-yl)- l H-indole
[00631] A pressure vessel was charged with 4.6-dichIoro-2-niethyl-pyriniidine (l .Og, 6.0 mmol, 1.0 eq.), l -TBDMS-indole-6-boronic acid ( 1.6 g, 6.0 mmol, 1 .0 eq.), 1 ,2 DME (10 niL). and 1 M a2C03 (2.0 niL). The reaction was purged with nitrogen before adding
Pd(dppf)2Cl2CH2Cl2 (249 mg, 0.3 mmol, 0.05 eq.), sealed, and heated to 90 °C for 15 hours. The reaction was then cooled to rt, and partitioned between water and EtOAc. The organic layer was washed with brine, dried with a2SO |. and concentrated under vacuum to give crude product. The crude product was purified by SiO? flash chromatography (95:5 hexanes/ethyl acetate) to afford l -(tert-buiyldimethylsilyl)-6-(6-chloro-2-methylpyrimidin-4- yl)- l H-indole as a clear oil ( 1 .25 g, 58% yield). Ή N R (400 MHz, d6-DMSO): 8.45 (s, 1 H), 8.05 (s, 1 H), 7.94 (d, 1 H), 7.70 (d, 1 H), 7.57 (d, l H), 6.72 (s, 1 H), 2.69 (s, 3H), 0.95 (s, 9H), 0.65 (s, 6H); MS (El) for C19H24CIN3S1 : 358.2 (MH+).
Step 2
1006321 Synthesis of 6-(6-chloro-2-methylpyrimidin-4-yl)-lH-indole
[00633] A round bottom flask was charged with l -(tert-butyldimethylsilyl)-6-(6-chloro-2- methylpyrimidin-4-yl)- l H-indole (200 mg: 0.56 mmol, 1 .0 eq.), dio anes (3 mL), and 4N HCI in dioxanes (1.5 niL). The reaction was stirred at rt overnight. EtOAc was added to precipitate out the product, which was collected via vacuum filtration to give the product as an orange solid. The precipitate was rinsed 2 times with EtOAc to give pure 6-(6-chloro-2- methylpyrimidin-4-yl)-l H-indole (116 mg, 58% yield). Retention time: 1.79 min., MS (EI) forC|3H2oClN3: 244.0 (ΜΙ- ).
Step 3
(006341 Synthesis of 6-(6-chloro-2-methyIpyriniidin-4-yl)-l-cthyl-l H-indole
[00635] A round bottom flask was charged with 6-(6-chloro-2-methylpyrimidin-4-yl)-lH- indole (119 mg, 0.43 mmol, 1.0 eq.); potassium t-butoxide (105 mg, 0.94 mmol, 2.2 eq.). and acetone (5.0 mL). The mixture was stirred at rt until all the reagents were in solution. Then the mixture was cooled to 0 °C before iodoethane (43 ul, 0.52 mmol, 1.2 eq) was added. After complete addition, the reaction was warmed slowly to rt and allowed to stir for 2 hours before concentrating via rotary evaporation. The residue was dissolved in EtOAc and partitioned between water. The organic layer was washed with brine, dried with Na2S0. and concentrated under vacuum to give crude product 6-(6-chloro-2-methylpyrimidin-4-yl)-l- ethyl-1 H-indole, as an orange oil, which crystallized overtime (150 mg, quantitative yield). Ή NMR (400 MHz, d6-DMSO): 8.41 (s, IH), 8.20 (s, 1H), 7.99 (d, 1H), 7.82 (d, 1H), 7.80 (s, IH), 6.50 (s, IH), 4.15 (q, IH), 2.62 (s, 3H), 1.40 (t, 3H). MS (EI) for C|5H,4C1N3: 272.1 (MH+).
Step 4
100636] Synthesis of 6-(l-ethyl-lH-indol-6-yl)-2-mcthyl-N-((lR)-l,2,3,4- tetrahydronaphthalcn-l-yl|pyrimidin-4-arnine (24)
|00637] A microwave vessel was charged with 6-(6-chloro-2-methylpyrimidin-4-yl)-l- ethyl-1 H-indole (50 mg, 0.18 mmol, 1.0 eq.), R-l-Aminotetraline (54 ul, 0.37 mmol, 2.0 eq.), DIEA (68 ul, 0.37 mmol, 2.0 eq.), and DMF (1.0 mL). The vessel was capped and microwaved in a CEM microwave reactor at 120°C. power 150 watts, for 3hours. The reaction was then cooled to rt and partitioned between water and EtOAc. The organic layer was washed with brine, dried with Na2S04, and concentrated under vacuum to give crude product. Purification by preparative H LC (reverse-phase, acetonitrile/water with 25 mM ammonium acetate), followed by concentration at reduced pressure and lyophilization afforded 6-(l-ethyl-lH-indol-6-yl)-2-methyl-N-[(lR)-l,2,3!4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine as a solid (22.0 mg, 31 % yield). ). Ή NMR (400 MHz. d6-DMSO): 9.60 (br s, 1H), 8.05 (s, 1H), 7.72 (d, 1 H), 7.70 (m, 1H), 7.41 (d,l H), 7.22 (m, 4H), 6.89 (s, IH)f 6.60 (d, 1H), 5.58 (br q, 1 H), 4.19 (q, 2H), 2.82 (m, 2H), 2.68 (s, 3 H), 2.10-1.80 (m, 4H), 1.43 (t, 3H); MS (El) for C25H26N4: 383.5 (MH÷).
[00638| The following compounds were made in a manner analogous to Example 5:
100639] (Compound 54) 2-mcthyI-6-{1-|2-(mcthyloxy)cthyI|-lH-indol-6-yl}-N-l(lR)- l,2,3,4-tcfrahydronaphthaIen-l-yl]pyrimidin-4-aminc. Ή NMR (400 MHz, d6-DMSO): 8.05 (s, 1H): 7.61 (m, 3H), 7.40 (m, 1H): 7.20 (m,4 H), 6.82 (br s, 1H), 6.43 (s, 1H)S 5.40 (br s, 1 H), 4.20 (m, 2H), 3.85 (m, 21-1), 3.23 (s, 3 H), 2.80 (m, 2H), 2.50 (s, 3H), 2.00-1.78 (m, 4H); MS (EI) for C26H28N4O: 413.2 (ΜΙ- ).
[00640] (Compound 60) 6-(l-ethyl-lH-indol-6-yl)-2-mcthyl-N-{(lS)-l-[3- (mcthyloxy)phcnyl]ethyl}pyrimidin-4-amine. Ή NMR (400 MHz. d6-DMSO): 8.05 (s, ll-I), 7.62 (m, 3H); 7.23 (t, 1H), 7.05 (br s, 2 H), 6.80 (brd, 2H), 6.46 (d, 1H), 5.24 (brs, 1H), 4.27 (q, 2H), 3.73 (s, 3H), 2.39 (s, 3 H), 1.46 (d, 3H), 1.38 (t, 3H); MS (EI) for C24H26 4O: 387.2 (ΜΙ-Γ).
[00641] (Compound 100) 2-methyl-6-(l-methyl-lH-indazol-6-yl)-N-[(lR)-l,2,3,4- tetrahydronaphthalcn-l-yl]pyrimidm-4-aminc. 2-methyl-6-( 1 -methyl- 1 H-indazol-6-yl)- -[(lR)-1.2,3,4-tetrahydronaphthalen-l-yl]pyrimidin-4-amine was synthesized in a manner analogous to Example 5. Ή NMR (400 MHz, CDCI3): 8.15 (s, 1H), 8.0 (s, 1H), 7.78 (d, lH), 7.63 (d, 1H), 7.35 (d, 1H), 7.26-7.15 (m, 3H), 6.67 (brs, 1H), 5.40 (brs, 1H), 4.16 (s, 3H), 2.86 (m, 2H), 2.60 (s, 3H), 2.13 (m, 2H), 1.95 (m, 2H); MS (El) for C23H23 5: 370.2 ( H*).
[00642] (Compound 104) 2-methyl-6-(l-mcthyl-lH-indol-4-yl)-N-|(lR)-l,2,3,4- tctrahydronaphthaIen-l-yI]pyrimidin-4-aminc. 2-methyl-6-(l -methyl- 1 H-indol-4-yl)-N- [(lR)-1.2,3,4-tetrahydronaphthalen-l-yr]pyrimidin-4-amine was synthesized in a manner analogous to Example 5. Ή NMR (400 MHz, d6-DMSO): 7.63 (m, 2H), 7.52 (d, 1H), 7.43 s, 1H), 7.26 (m, 2H), 7.16-7.14 (m; 3H), 6.90 (br s, 1H), 5.40 (br s, 1H), 3.83 (s, 3H), 2.78 (m, 2H), 2.47 (s, 3H), 1.96 (m, 2H), 1.81 (m, 2H); MS (EI) for C24H24N4: 369.3 (MH+).
[00643] (Compound 112) 6-(l-ethyl-l H-indazol-6-yl)-2-methyl-N-[(l R)-l, 2,3,4- tctrahydronaphthaIen-l-yI]pyriniidin-4-aminc. 6-(l -ethyl- 1 H-indazol-6-yl)-2-methyl-N- [(lR)-l,2,3,4-tetrahydronaphthalen-l-yrjpyrimidin-4-amine amine was synthesized in a manner analogous to Example 5. Ή NMR. (400 MHz, CDC13): 8.15 (s, 1H), 8.01 (s, 1H), 7.77 (d, 1H), 7.62 (d, 1H), 7.35 (d, 1H), 7.21-7.15 (m, 3H), 6.65 (brs, 1 H), 5.20 (brs, 1H), 4.52 (q, 2H), 2.85 (m, 2H), 2.64 (s, 3H), 2.13 (m, 1 H), 1.94 (m, 3H), 1.56 (t, 3H); MS (EI) for C24H25N5: 384.3 (ΜΙ-Γ). General Scheme 5
Scheme 5: Synthesis of an Intermediate Compound of Formula EE
Figure imgf000244_0001
|00644] Compounds of formula EE can be synthesized via 2 different synthetic pathways starting from a compound of formula m. wherein R|5 and Rifi are non-reactive substituents, such as hydrogen, alkyl, and alkoxide; n is 0. 1 , or 2; and X is C, N, O, or S. In the first pathway, intermediate EE is produced in one reductive amination step from a compound of formula m, using ammonia or a suitable ammonium salt, according to Scheme 5. In the second pathway, reduction of the carbonyl moiety produces a compound of formula n, which can then be activated to a mesylate group using a standard reagent such as methansulfonyl chloride. The mesylate group can then be displaced by a nitrogen containing nucleophile, such as azide. to produce a compound of formula p. The compound of fomiula p can then be reduced to a compound of formula EE using a reducing agent such as Tin chloride.
Example 6a: Synthesis of 6-nitrochroman-4-amine.
Figure imgf000244_0002
|00645] To a solution of 386 mg (2.0 mmol) of 6-nitrochromanone was added 2.7 g (10 mmol) of ammonium acetate and 628 mg (10 mmol) of NaCNBI-^ dissolved in 8 niL of methanol. After warming to 60 °C and stirring for 18 hours, the solvent was removed at reduced pressure. 10 mL of water was added, followed by addition of 8 mL of 6N HC1. The acidic solution was extracted once with ether, and the aqueous layer was basified with 5 mL of I ON NaOH. The basic aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were dried over 2CO3 and concentrated at reduced pressure to afford 250 mg (64%) of 6-nitrochroman-4-amine as an oil.
Figure imgf000245_0001
Step 1
[00647] 6-FIuorochroman-4-ol
[00648] To a slurry of sodium borohydride (0.24 g, 6.39 mmol) in methanol (6 mL) at 0 °C was added a solution of 6-l1uorochi man-4-one (0.53 g, 3.20 mmol ) in methanol (2 mL). The reaction was slowly warmed to room temperature and stirred until the reaction was completed as monitored by thin layer chromatography (4 hours). The reaction mixture was carefully quenched with 1 .0 N aqueous hydrochloric acid at 0 °C until a clear solution was obtained, then diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate and saturated aqueous brine, and dried over anhydrous magnesium sulfate.
Filtration and concentration gave crude 4-fluorochroman-4-ol (0.48 g, 89%), which was used in the next step without further purification. MS (El) for CyH9F02: 1 51 (M-H20+).
Step 2
[00649] 4-azido-6-Fluorochroman
[00650] To a solution of 6-iluorochroman-4-ol (0.48 g, 2.86 mmol) in tetrahydrofuran (6 mL) was added diphenylphosphoryl azide (1.06 g, 3.84 mmol) at 0 °C. The reaction was stirred for 5 minutes prior to the addition of l ,8-diazabicyclo{5.4.0]undec-7-ene (DBU, 0.58 g. 3.84 mmol). The reaction was further stirred for 15 minutes at 0 °C before the reaction was allowed to warm to room temperature. The reaction was stopped after l hour when the reaction was completed as monitored by thin layer chromatography. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water and saturated aqueous brine, and dried over anhydrous magnesium sulfate. Filtration, concentration, and column chromatography on silica (9: 1 hexanes/ethyl acetate) gave 4-azido-6-fliiorochroman (0.44 g, 79%) as an oil. Ή N R (400 MHz, DMSO-D6) 7.21 (dd, I H), 7.10 (m, I H), 6.91 (m, 1 H), 5.91 (m, 1 H), 4.32 (m, ΓΗ), 4.10 (m, I H), 2.16 (m, 1 H), 1.9 (m, 1 H).
Step 3
[00651] 6-FIuorochroman-4-aminc
[00652] To a solution of 4-azido-6-fluorochroman (0.24 g, 0.99 mmol) in methanol (2 mL) was added solid tin chloride dihydrate (0.45 g, 1.99 mmol) at rt under nitrogen. The reaction was stirred at rt overnight. The crude reaction mixture was poured into a separatory funnel and diluted with ethyl acetate (200 ml). The organic layer was washed with 2N aqueous sodium hydroxide (50 ml) and saturated aqueous sodium chloride (brine) and dried over anhydrous magnesium sulfate. Filtration, concentration, and column chromatography on silica (9: 1 dichloromethane/methanol) afforded the amine product which was further treated with 4N HCl/dioxane solution to give 6-iluorochroman-4-amine (0.215 g, 51%) as the hydrochloric acid salt: Ή NMR (400 MHz, ^DMSO) 8.92 (br s, 3H), 7.52 (dd, l'H), 7.18 (m, I H), 6.91 (m, 1 H), 4.51 (m, 1 H), 4.30 (m, I H), 4.21 (m, 111), 2:20 (m, 1 H), 2.18 (m, 1 H); MS (El) for C9H 10FO: 151 (Μ-ΝΗ3 ').
General Scheme 6
Scheme 6: Synthesis of an Intermediate Compound of formula FF
Figure imgf000246_0001
Figure imgf000246_0002
|00653] Compounds of formula FF can be synthesized startin from a compound of formula q, wherein R|5 and R|6 are non-reactive substituents such as hydrogen, alkyl, and alkoxide, and n is 0, 1 , or 2. Protection of the amine moiety of the compound of formula q can be accomplished with a common protecting group, such as Boc. Reduction of the ester moiety of the compound of formula r can be accomplished using a reducing agent, such as Lithium Aluminum Hydride to produce alcohol s. Activation of the hydroxide moiety of compound s with a mesylating agent such as methanesulfonyl chloride, provides a compound of formula t, which can then be converted into a cyano compound of f ormula u by contacting with a cyanide containing reagent such as KCN, in the presence of a solvent and a base. Treatment of a compound of formula u with an anhydrous acid such as HCl in dioxane provides the HCl salt compound of formula.FF.
Example 6c: Synthesis of 4-amino-4-(3-methoxyphcnyl)butanenitrile hydrochloride
Figure imgf000247_0001
Step 1
|00654] Ethyl 3-(/e/,/'-butoxycarbonylamino)-3-(3-mcthoxyphenyl)propanoate
[00655J To a solution of ethyl 3-amino-3-(3-methoxyphenyl)propanoate (921 mg, 4.13 mmol) in THF (10 mL) was added Boc20 (1.17 g. 5.37 mmol). The reaction mixture was stirred at room temperature for 5 hours, quenched with water (20 mL), and extracted with ethyl acetate ( 2 x 50 mL). The combined organic layers were dried over Na2S04 and concentrated at reduced pressure to give the crude product. The product was purified by Si02 flash chromatography (70:30 hexanes/ethyl acetate) to afford Ethyl 3-(tert- butoxycarbonylamino)-3-(3-methoxyphenyl)propanoate (611 mg, 46% yield). Ή NM (400 MHz, CDCb): 7.24 (m, 1 H), 6.84 (m, 3H), 5.46 (br s, 1 H), 5.07 (br s, 1 H), 4.07 (q, 2H), 3.81 (s, 3H), 2.79 (m, 1 H), 1.5 1 (s, 9H), 1.48 (t, 3H).
Step 2
[00656| tert-butyl 3-hydroxy-l-(3-mcthoxyphcnyI)propylcarbamate |00657] To a solution of ethyl 3-(tert-butoxycarbonylamino)-3-(3- methoxypheny propanoate (1.84 mg, 5.71 mmol) in THF (20 mL) was added LiAlH (6.2 mL, 1.0 M solution in THF) over 10 minutes. The reaction was warmed up to room temperature and stirred for 16 hours. The excess LiAlH4 was quenched carefully with water at 0 °C. Solid Na2S04 was added, and the reaction mixture was stirred at room temperature for 10 minutes. The solids were filtered off, and the resulting solution was partitioned between water and ethyl acetate. The reaction was extracted with ethyl acetate (2x 100 mL), and combined organic layers were dried over Na_SO,i, filtered, and concentrated at reduced pressure. The product was purified by Si02 flash chromatography (hexanes:ethyl acetate = 50: 50) to afford 1 .308 g of tert-butyl 3-hydroxy-l -(3-methoxyphenyl)pi pylcarbamate (81% yield). Ή N R (400 MHz, CDC13): 7.26 (m, 1 H), 6.89-6.83 (m, 3H), 4.99 (m, 1 H), 4.87 (m, 1 H), 3.81 (s, 3H), 3.70 (m, 2H), 2.08 (m, 1 H), 1 .79 (m, 1 H), 1.44 (s, 9H).
Step 3
[00658] 3-(toY-butoxycarbonylamino)-3-(3-riiethoxyphenyl)propyl methancsulfonate
[00659] To a solution of tert-butyl 3-hydroxy- l -(3-methoxyphenyl)propylcarbamate (1.308 g, 4.65 mmol) in CH2CI2 (15 mL) were added methanesulfonyl chloride ( 983 g. 8.55 mmol) and Et3 (1.15 g. 1 1 .41 mmol). The reaction mixture was stirred at room temperature for 12 hours, quenched with water (20 mL), and extracted with ethyl acetate ( 2 x 50 mL). The combined organic layers were dried over Na2SO.i and concentrated at reduced pressure to give the crude product (1 .48 g, 74% yield). Ή NMR (400 MHz, CDC13): 7.26 (m, 1 H , 6.86- 6.81 (m, 3H), 4.84 (m, 2H), 4.35 (m, 2H), 3.82 (s, 3H): 3.01 (s, 3H), 2.21 (m, 2H), 1.38 (s, 3H).
Step 4
[00660] tert-butyl 3-cyano-1 -(3-mcthoxyphcnyl)propylcarbamate
[006611 To a solution of 3-(/e/V-butoxycarbonylamino)-3-(3-methoxyphenyl)propyl methanesulfonate ( 1 .47 g: 4.1 1 mmol) in DMF (15 mL) was added KCN (294 mg, 4.52 mmol). The reaction mixture was heated to 70 °C for 2 hours, quenched with water (20 mL), and extracted with ethyl acetate ( 2 x 50 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated at reduced pressure to give the crude product (612 mg, 50% yield). Ή NM R (400 MHz, CDCI3): 7.26 (m, 1 H), 6.86 (m, 3H), 4.85 (m, 1 H), 4.65 (m, 1 H), 3.80 (s, 3 H), 2.35 (m, 2H), 2.1 8 (m, 1 H), 2.07(m: 1 H), 1.39 (s, 3H). Step 5
(006621 4-amino-4-(3-methoxyphenyl)butanenitrile hydrochloride
[00663] To a solution of tert-butyl 3-cyano-l -(3-niethoxyphenyl)propylcarbamate (163 mg, 0.565 mmol) in methanol (5 mL) was added HC1 (4N in dioxane. lmL) and stirred at room temperature for 10 hours. The reaction was concentrated at reduced pressure and used as the amine in Scheme 2. MS (EI) for CnH|.,N20: 191 (MH+), t = 0.384 min.
General Scheme 7
Scheme 7: Synthesis of a compound of formula GG
Figure imgf000249_0001
x GG
[00664] Compounds of formula GG, wherein 1½ is a non-reactive substituent such as hydrogen, alkyl or alkoxide, and W, X, Y and Z are each independently C, O or N, can be synthesized according to Scheme 7. Coupling of a compound of formula v with an aryl compound can be accomplished with a boron containing reagent, such as the boronic acid pinacole ester of formula w, in the presence of a catalyst, such as a palladium catalyst, such as Pd(dppf)2Cl2. The resulting compound of formula x can then be converted to the amine of formula GG via, for example, reductive amination using, for example, an ammonia containing compound, such as ammonium acetate, in the presence of a reducing agent such as sodium cyanoborohydride.
Example 6d: Synthesis of l-(4-fluoro-3-(l -mcthyl-l H-pyrazol-4-yl)phenyl)ethanaminc.
Figure imgf000249_0002
Pd(dppf)2CI2
Step 1
[00665| l-(4-fluoro-3-(l-mcthyl-l H-pyrazol-4-yl)phcnyI)cihanonc
[006661 To a pressure vessel was added 3'-Bromo-4'-fluoroacetophenone (1.Og, 4.6 mmol), 1 ,2-DME (15 mL), 1 -Methyl- l H-Pyrazolc-4-boronic acid pinacole ester (1 .05 g, 5.1 mmol) and 1 M Na2C03 aq. (1.5 mL). The vessel was purged with nitrogen before adding
Pd(dppfhCl2CH2Cl2 (187 mg, 0.23 mmol) and heated overnight at 80 °C. The reaction was then cooled to rt and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc 2 times. The combined organic layers were dried over Na2S04, Filtered, and concentrated at reduced pressure. The product was purified by Si02 flash chromatography (hexanes:ethyl acetate = 1 : 1 ) to afford 900 mg (90% yield) of l -(4-fluoro-3-( 1 -methyl- 1 H- pyrazol-4-yl)phenyl)ethanone as a tan solid. Ή N R (400 MHz, d6-DMSO): 8.26 (m, 2H), 8.00 (s: 1 H), 7.83 (m, 1 H), 7.40 (dd, 1 H), 3.92 (s, 3H), 2.62 (s, 3H); MS (El) for
C|2H| |N2FO: 219.1 (ΜΙ- ).
Step 2
[00667] l -(4-fluoro-3-(l-nicthyl-l H-pyrazol-4-yl)phcnyl)ethanaminc
[00668] To a round bottom flask was added l -(4-iluoro-3-( l -methyl-l H-pyrazol-4- yl)phenyl)ethanone (500 mg, 2.29 mmol), MeOH (30 mL), ammonium acetaic (441 mg, 5.73 mmol), and sodium cyanoborohydride (359 mg. 5.73 mmol). The mixture was heated to reflux overnight, cooled to rt. and concentrated to remove MeOH. The residue was taken up in EtOAc and extracted with water, then brine. The EtOAc layer was dried over Na2S04, filtered, concentrated at reduced pressure, and used crude in subsequent reactions. MS (El) for C,2HMN3F: 220.1 (ΜΙ-Γ)
General Scheme 8
Figure imgf000250_0001
[00669] Compounds of formula HH. wherein R]« and m are non-reactive substituents such as hydrogen, alkyl and alkoxy, can be synthesized from carboxylic acids of formula y according to Scheme 8. Conversion of the carboxylic acid of formula y to the Weinreb amide of formula z using, for example, the conditions shown in Scheme 8, followed by nucleophilic substitution using, for example, a methyl nucleophile such as the Grignard reagent methylmagnesium chloride, provides a compound of formula AA. The compound of formula HH can then be prepared from the compound of formula AA using, for example, reductive animation as described above.
Example 6e: Synthesis of 5-(l-aminoethyI)-2-cliIorophenol
Figure imgf000251_0001
Step 1
[00670] Synthesis of 4-chIoro-3-hydroxy-N-methoxy-N-methylbenzamide
[00671] To a round bottom llask was added 4-Chloro-3-hydroxy benzoic acid (3.0 g, 17.4 mmol), CH2CI7 (90 mL), Et3N (8.8 mL, 69.6 mmol), EDC1 (5.02 g, 26.2 mmol), HOBt (705 mg. 5.2 mmol). and N.O-Dimethyi hydroxyl amine HCI (3.56 g. 36.54 mmol). The reaction was refluxed overnight, cooled to rt, and quenched with water. The mixture was extracted with CH2C12, dried over Na2S04, filtered, and and concentrated at reduced pressure. The product was purified by S1O2 Hash chromatography (hexanes:ethyl acetate 80:20) to afford 2.0g (53% yield) of 4-chloro-3-hydroxy-N-methoxy-N-methylbenzamide as an orange solid. MS (EI) for C9H 10NCIO3: 21 .1 ( H+)
Step 2
|00672] Synthesis of l -(4-chloro-3-hydroxyphenyl)cthanone
[00673] To a round bottom flask was added 4-Chloro-3-hydroxy-N-methoxy-N- methylbenzamide (1 .0 g, 4.65 mmol) and THF (30 mL). The reaction was cooled to 0 °C before adding 3M methyl magnesium chloride in THF (7.7 mL, 23.2 mmol) dropvvise. Upon complete addition, the reaction was warmed to rt and allowed to stir for l hour before pouring onto ice. The mixture was neutralized to pH2 with IN HCI and extracted with EtOAc, dried over a2S04, filtered, and concentrated at reduced pressure. The residual solid was sonicated in 3 mL EtOAc. and filtered to remove the impurities. The residual supernatant was concentrated to give l -(4-chloro-3-hydroxyphenyl)ethanone (591 mg, 74 % yield). Ή NMR (400 MHz, d6-DMSO): 10.61 (s, I H), 7.51 (m, 2H), 7.43 (m, I H), 2.53 (s, 3H); MS (EI) for
Figure imgf000252_0001
Step 3
[00674] Synthesis of 5-(l -aminocthyl)-2-chlorophcnol
|00675] To a round bottom flask was added 1 l -(4-chloro-3-hydroxyphenyl)ethanone (591 mg, 3.48 mmol), MeOH (50 mL), ammonium acetate (669 mg, 8.69 mmol), and sodium cyanoborohydride (546 mg, 8.69 mmol). The mixture vvas heated to reflux overnight, cooled to rt, and concentrated to remove MeOH. The residue was taken up in EtOAc and extracted with water, then brine. The EtOAc layer was dried over N 2S04, filtered, concentrated at reduced pressure, and used crude in subsequent reactions. MS (EI) for C12H14N3F: 172.1 ( H+)
General Scheme 9
Scheme 9: Synthesis of Compounds of formula JJ and KK
Figure imgf000252_0002
100676] Compounds of formula .1.1 and KK, wherein W, X, and Y are C, N, or O, and R2o is a non-reactive group, such as hydrogen, alkyl. or alkoxy, can be synthesized from 3- nitroacetophenone according to Scheme 9. Reductive animation, as described above, provides 1 -amino- l -(3-nilrophenyl)ethane from 3-nitroacetophenone, and subsequent nucleophilic substitution of the chloride of a compound of formula BB provides a compound of formula CC. Reduction of the nitro group of a compound of formula CC using known methods, such as SnCh with an acid catalyst, provides an amine of formula dd. which can then be converted to a compound of formula JJ by converting the amino group to a tetrazole, or to a compound of K by converting the amino group to a 1 ,2,4 triazole. Interconversion to the tetrazole can be accomplished by contacting the amine with a formic acid derivative such as HC(OEt)3 in the presence of azide. Interconversion to the triazole can be accomplished by contacting the amine with a formamide reagent such as CH(0)-NH-NH- CH(O).
Example 6f: Synthesis of 2-methyl-6-(3-mcthyl-l -benzofuran-5-yl)-N-{l-I3-(4H-l ,2,4- triazol-4-yl)phenyl]cthyI}pyrimidin-4-amine and 2-mcthyl-6-(3-methyl-l -bcnzofuran-5- -N-{l -[3-(l H-tetrazol-l -yl)phenyI| ethyl} pyi imidin-4-aminc.
Figure imgf000253_0001
Step 1
(00677] Synthesis of l-(3-nitrophenyl)cthanaminc
|00678] To a solution of 2.64 g ( 1 6 mmol) of l -(3-nitrophenyl)ethanone in 48 mL of anh. methanol is added 12g of ammonium acetate, 700 mg of NaCNBF , and 8g of 3 A molecular sieves. The reaction mixture is stirred for 1 -2 days. The reaction mixture is concentrated at reduced pressure, diluted with 30 mL of water, and carefully acidified with 5 eq of 6N HC1 (13 mL). The solution is extract once with ether, and the aqueous layer is basified with 14 eq of 1 0N NaOH (appox. 45 mL). This solution is then extracted 3 times with EtOAc, washed 1 time with brine, dried over K2C03, and concentrated at reduced pressure to afford 790 mg (30%) as a oil. ' H NMR (400 MHz, CDC13): 8.35 (s, l H), 8.09 (dd, 1 H), 7.72 (d, I H), 7.50 (t, I H), 4.30 (q, 1 H), 1.64 (d, 3H);MS (EI) for C8H 10N2O2: 150.07 (MH-17+).
Step 2
[00679] Synthesis of 2-mcthyl-6-(3-mcthylbenzofuran-S-yl)-N-(l -(3- nitrophenyl)ethyl)pyrimidin-4-amine (Compound 292)
[00680] A DMA solution (5mL) of 600mg (2.3 rnmol) of 4-chloro-2-methyl-6-(3- methylbeirzofuran-5-yl)pyrirnidine, 661 mg (4.0 mmol) of l -(3-nitrophenyl)ethanamine, and 800 uL of DIEA is heated at 1 10°C for 18 hours. The mixture is cooled and load directly onto a 40 g silica gel column and eluted with a stepwise gradient of 10%->66% EtOAc/hexane. The product is concentrated at reduced pressure to give 434 mg (49%) of a slightly orange oil. Ή NMR (400 MHz, d3-ACN): 8.29 (s, I H), 8.18 (s, ΓΗ), 8.09 (dd, I H), 7.92 (d, IH), 7.83 (d, I H), 7.58 (t, I H), 7.50 (d, I H), 6.73 (br s, I H), 6.38 (d, I H), 5.28 (br s, I H), 2.41 (3, 3H), 2.25 (s, 3H), 1.56 (d, 3H); MS (Ei) for C22H20N4O3: 389.02 (MH+).
Step 3
[00681] Synthesis of N-(l-(3-aminophenyl)ethyl)-2-mcthyl-6-(3-methylbenzofuran-5- yl)pyrimidin-4-amine (Compound 297)
[00682] To a solution of 410 mg (1.06 mmol) 2-methyl-6-(3-methylbenzofuran-5-yl)-N-(l - (3-nitrophenyl)ethyl)pyrimidin-4-amine and 510 mg (2.26 mmol) of tin dichloride dehydrate in 2.5 mL of EtOH is added 437 uL (5 equiv.) of cone. HC1. The mixture is heated at 100°C for 2hours. The reaction is cooled, 10 eq. of 2M NaiCCb is added and stirred. The white precipitate is removed by filtration and washed 3 times with EtOAc. The combined organic layers are washed with brine, dried over MgSCu, and concentrated at reduced pressure to give an orangish oil: 456 mg (94%). Ή NMR (400 MHz, CDC13): 8.03 (s, I H), 7.71 (dd, I H), 7.44 (d, I H), 7.42 (s, I H), 7.16 (t, I H), 6.77 (d, I H), 6.72 (s, I H), 6.59 (dd, I H), 6.40 (s, IH), 5.35 (br s, 1 H), 4.74 (br s, 1 H), 3.68 (brs , 2H), 2.59 (s, 3H), 2.27 (s, 3H), 1.57 (d, 3H); MS (EI) for C22H22N O: 359.03 (MH+).
Step 4a
[006831 Synthesis of 2-methyl-6-(3-metIiyl-l-benzofuran-5-yl)-N-{l-[3-(l H-tetrazol-l- yl)phcnyl| ethyl} pyrimidin-4-aminc (Compound 290)
[00684] A solution of 107 mg (0.30 mmol) of N-( 1 -(3-aminophenyl)ethyl)-2-methyl-6-(3- methylbenzofuran-5-yl)pyrimidin-4-amine, 44 mg (2.25 eq.) of sodium azide, 162 uL (3.2 eq.) of trimethylorthoformate, and 300 uL of glacial AcOH is heated to 85°C for 1 hours. The reaction mixture is purified by RP-HPLC eluting with a gradient of 25mM NHjOAc/ACN, and the appropriate fractions are pooled and lyophilized to give 18 mg (15% yield) of a white powder. Ή NMR (400 Hz. d3-ACN): 9.32 (s, HI), 8.1 8 (s, 1 H), 7.90 (m, 2H), 7.65 (tt, 1H), 7.62 (s, 1 H), 7.58 (d, 1 H), 7.55 (d, 1 H), 7.50 (d, 1 H), 6.72 (br s, 1 H), 6.28 (s, 1 H), 5.26 (br s, 1 H), 2.43 (s, 1 H), 2.27 (d, 3H), 1.59 (d, 3H); MS (El) for C23H21N70: 41 1.47 (ΜΉ+).
Step 4b
[00685] Synthesis of 2-methyl-6-(3-methyl-l-bcnzofuran-5-yI)-N-{l-(3-(4H-l ,2,4- triazol-4-yl)phenyI]ethyl}pyrimidin-4-amine (Compound 291)
[00686] A solution of 50 mg (0.14 mmol) of N-( l -(3-aminophenyl)ethyl)-2-methyl-6-(3- methylbenzofuran-5-yl)pyrimidin-4-amine, 22 mg (2.5 eq.) of sym-diformylhydrazine, 45 mg (2 eq.) of p-toluenesulfonic Acid Monohydrate, and 1 .2 mL uL of a 1 : 10 solution of DMF: toluene is heated to 1 10 °C for 2hours. The reaction mixture is purified by RP-HPLC eluting with a gradient of 0.025 M I-LOAc/ACN, and the appropriate fractions are pooled and lyophilized to give 9 mg (1 6% yield) of a white powder. Ή NMR (400 MHz, d3-ACN): 8.65 (s, 2H), 8.17 (s, 1 H), 7.90 (dd, 1 H), 7.63 (s, 1 H), 7.17 (d, ΓΗ), 7.53 (t, 1H), 7.51 (s, 1 H), 7.40 (m, 1 H), 6.70 (br s, 1 H), 6.27 (d, 1 H), 5.23 (br s, 1 H), 2.44 (s, 3H), 2.27 (s, 3H), 1.58 (d, 3H); MS (EI) for C24H22 6O: 41 1 .03 (ΜΉ+).
General Scheme 10
heme 10: Synthesis of Compounds of Form
Figure imgf000255_0001
Figure imgf000255_0002
[00687] Compounds of formula LL, wherein W, X, and Y are C, N, or O, can be synthesized according to Scheme 10. The amino group of 3-aminoacetophenone can be converted to azide group using known methods, such as conversion to the diazonium salt using NaN02, followed by nucleophilic substitution with azide using an azide source, such as sodium azide. Triazole formation of the azide functional group using an alkynyl compound such as trimethylsilylethyne, followed by reductive animation as described above, may provide a mixture of amino compounds. Subsequent nucleophilic substitution with a compound of formula ee using anhydrous and basic conditions, optionally at elevated temperatures provides a compound of formula LL.
Example 6g: Synthesis of 6-(l,3-bcnzothiazol-6-yl)-2-methyl-N-{l-[3-(l H-l ,2,3-triazoI-l - yl)- phenyl]ethyl}pyrimidin-4-amine (Compound 294)
Figure imgf000256_0001
Step 1
[00688] Synthesis of l-(3-azidophenyl)ethanonc
[00689] To a 5°C solution of 1 .62 g (12 mmol) of 1 -(3-aminophenyl)ethanone in 5 mL AcOH, 2mL cone HC1. and 3 mL of water is added a solution of 900 mg of sodium nitrite in 3 mL of water. After 10 minutes, a solution of 855 mg of sodium azide dissolved in 3 mL of water is added dropvvise. After stirring al 23°C for 18 hour, the reaction misture was extrated 2 times with EtOAc, the combined organic layers were washed with 5% NaHCC>3, and dried over a2SC>4. and concentrated under reduced pressure to afford 2.3 g of the azido compound as an oil. This material was used directly in the next step.
Step 2
[00690] Synthesis of l-(3-(l H-l ,2,3-triazol-l -yl)phcnyl)ethanone
[00691 ] A 500 mg sample (3.1 mmol) of l -(3-azidophenyl)ethanone is placed in a sealed tube and 2 mL of triinethylsilylethine is added. After stirring for 1 8h, the reaction is heated to 60°C for 2h. The reaction mixture is concentrated under reduced pressure to afford the target molecule in 98% yield as a 10: 1 mixture of the TMS containing material . Ή NMR (400 MHz. CDCI3): 7.32 (t, 1H , 7.28 (d, ΓΗ), 7.13 (dd, 1 H), 7.19 (s, IH), 6.95 (dt, 1H), 1.37 (d, 31-1), 0.6 (s, 9H); MS (EI) C13H17N30Si: 260-10 (MH+).
Step 3
[00692] Synthesis of l-(3-(4-(tnmethylsilyl)-lH-l,2,3-triazol-l-yI)phenyl)ethanamine 100693] To a solution of 780 mg (3.1 mmol) of l-(3-(lH-l,2,3-triazol-l-yl)phenyl)ethanone in 12 niL of methanol is added 4.2 g (78 mmol) NH.,OAc, 970 mg (5 eq) of NaCNBH3. The reaction mixture is healed to 601>C for 18h, cooled to 23"C, concentrated, dissolved in 25 mL of water, quenched with 5 eq 6N HCl, extracted with ether 1 time. The aqueous layer is then basified with ~10 eq of 1 ON NaOH, and extracted 3 times with ElOAc. The combined organic layers are washed 1 time with brine, dried over 2CO3 and concentrated to afford 132 mg (23%) of a brownish oil. Ή NMR (400 MHz, CDCI3): 7.32 (7,1H) 7.28 (d, 1 H), 7.13 (dd, 1H), 7.19 (s, 1H), 6.95 (dt, IH), 4.13 (q, IH), 1.37 (d, 3H).
Step 4
[00694] Synthesis of 6-(l,3-benzothiazol-6-yl)-2-methyl-N-{l-[3-(lH-l,2,3-triazol-l-yl)- phenyl]ethyl}pyrimidin-4-amine (Compound 294)
[00695] A solution of 132 mg (0.70 mmol) of l-(3-(4-(trimethylsilyl)-lH-1.2!3-triazol-l- yl)phenyl)ethanamine and 183 mg (0.70 mmol) of l-(3-(4-(tnmethylsilyl)-lH-l,2.3-triazol- l-yl)phenyl)ethanamine in 1.4 mL ofNMP with 176 mg (3 eq) of NaHC03 is heated to 120°C for lh. The reaction mixture is purified by RP-HPLC eluting with a gradient of O.025 M NH4OAc/ACN, the appropriate fractions are pooled and lyophilized to give 49 mg (17% yield) of a white powder.1 H NMR (400 MHz, d3-ACN): 8.98 (s, IH), 8.50 (s, 1 H), 7.85 (d, lH),7.75(d, 1H),7.60 (s, 1H),7.50 (m, 1H),7.40 (d, 2H), 7.26 (s, IH), 6.46 (br s, IH), 6.10 (br s, IH), 5.05 (br s, IH), 2.54 (s, 3H), 2.05 (s, 3H), 1.64 (s, 3H); MS (EI) for C22H19N7S: 413.99 (MH+).
General Scheme 1 1
Scheme 1 1 : Synthesis of compounds of formula MM
Figure imgf000258_0001
[00696] Compounds of formula MM, wherein W. X, and Y are each independently C, O, or N, can be synthesized according to Scheme 1 1 . Reductive animation as described above converts 3-cyanoacetophenone to the corresponding amine, and subsequent nucleophilic substitution, as described above, of 4,6-dichloi -2-inethylpyrimidine provides 3-( l -(6-chloro- 2-methylpyrimidin-4-ylamino)ethyl)benzonitrile. This intermediate can then be coupled with a boronic ester of formula ff (described above) to provide a compound of formula gg.
Conversion of the cyano functional group to the corresponding tetrazole by treatment with azide provides a compound of formula MM.
Example 6h: Synthesis of 6-(l ,3-benzothiazol-6-yl)-2-methyl- -{l -[3-(2H-tetrazol-5- yl)phenyl]ethyl}pyrimidin-4-aminc (Compound 31 )
Figure imgf000258_0002
Step 1
[00697] Synthesis of l-(3-cyanophenyl)cthanaminc
|00698] To a solution of 1 .23 g (8.5 mmol) of l -(3-cyanophenyl)ethanone in 32 mL of anh. methanol is added 1 l g of ammonium acetate, 2.66 g of NaCNBT . The reaction mixture is .
heated to 85°C for l hour, concentrated under reduced pressure, diluted with 30 mL of water, and carefully acidified with 5 eq of 6N HCl (7 mL). The solution is extract once with ether, and the aqueous layer is basified with 14 eq of I ON NaOH (approx. 20 mL). This solution is then extracted 3 times with EtOAc, washed 1 time with brine, dried over 2CO3, and
concentrated under reduced pressure to afford l . l (44% based on 50% purity) as a oil. Ή NMR (400 M Hz, CDCB): 7-63 (s, 1 H), 7.55 (m, 2H), 7.42 (t, 1 H), 3.93 (q, 1 H), 1 .32 (d, 3H).
Step 2
(00699] Synthesis of 3-( l -(6-chloro-2-methylpyrimidin-4-ylamino)ethyl)benzonitrile
[00700] A mixture of 1 . 1 g (-7.4 mol) l -(3-cyanophenyl)ethanamine, 1 .6 g (7.4 mmol) of 4,6 dichloropyrimidine, and 2.6 mL (2 eq) of D1EA in 5 mL of DMA is heated to 60"C for 3hours. The reaction mixture is diluted with EtOAc and extracted 2 times with IN HCl, 1 time with brine, dried with MgSO-i, and concentrated under reduced pressure and lyophilized to give 540 mg (59%) of the desired compound. Ή NMR (400 MHz, d0-DMSO): 7.63 (s, 1 H), 7.58 (m: 2H), 7.48 (t, 1 H), 6.0 (br s, 1 H), 2.47 (s, 3H), 1 .57 (d, 3H); MS (EI) for
C MHUCINJ: 273.08 (MH+).
Step 3 :
[00701 ] Synthesis of 3-( l-(6-(benzo|d]thiazol-6-yl)-2-rnethyIpyrimidin-4- ylamino)cthyl)benzonitnlc Compound 302
|00702] To a solution of 540 mg (2 mmol) of 3-( 1 -(6-chloro-2-methylpyrimidin-4- ylamino)ethyl)benzonitri le, 620 mg 1 .2 eq) of 6-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2- yl)benzo[d]thiazole with 4.5 mL of 2M Na2C03 and 8 mL of DME is added 200 mg of
Pd(dppf)2CL ( 10 mol %). Nitrogen is bubbled through the mixture for 5 min and heated to 1 10°C for 4hours. Dilution with EtOAc followed by extraction with I N HCl and brine, drying over MgS04, and concentration under reduced pressure affords the desired product in 88% yield. Ή NMR (400 MHz. CDC13): 9.07 (s, 1 H), 8.57 (s, 1 H), 8.16 (d, 1 H), 7.86 (d, 1 H), 7.70 (s, 1 H), 7.67 (d, 1 I I ), 7.57 (d, 1 H), 7.49 (t, 1 H), 7.27 (s, 1 H), 6.36 (s, 1 H), 4.85 (br s, 1 H), 2.57 (s, 3 H), 2. 1 3 (s; 3 H), 1 .63 (d, 3H). MS (EI) for C2i H |7NsS: 372.00 (MH+).
Step 4
[00703] Synthesis of 6-(l ,3-benzothiazol-6-yI)-2-methyl-N-{l -[3-(2H-tctrazol-5- yl)phenyl]cthyl}pyrimidin-4-aminc Compound 315
100704] A mixture of 50 mg (0.13 mmol) of 3-( l -(6-(benzo[d]thiazol-6-yl)-2- methylpyrimidin-4-ylamino)ethyl) benzonilrile. 36 mg (4 eq) of sodium azide, 29 mg of ammonium chloride in 540 uL of DMF is healed to 1 10°C of 3hours. The reaction mixture is purified by RP-HPLC eluting with a gradient of 0.025 M NR|OAc/ACN: the appropriate fractions are pooled and lyophilized to give 25 mg (47% yield) of the desired product as a white powder. Ή NMR (400 MHz, d3-ACN): 9.1 (s, 1 H), 8.57 (s, 1 H), 8.32 (s, 1 H), 8.00 (m, 3H), 7.55 (t, 1 H), 7.50 (t, 1 H), 6.72 (br s: 1 H), 5.30 (br s, 1 H), 2.48 (s, 3 I ), 1 .58 (d, 3H). MS (El) for C2|H|8N8S: 415.07 (Ml-f).
General Scheme 12
Scheme 12: Synthesis of compounds of formula NN
Figure imgf000260_0001
|00705] Compounds of formula NN, wherein !½, R24, and R25 are non-reactive groups such as hydrogen, alkyl. and alkoxy, can be synthesized according to Scheme 12. Coupling or nucleophilic substitution of a compound of formula ii by an amine of formula hh can be accomplished in coupling conditions including, for example, a palladium catalyst, such as Pd(OAc)?, to provide a compound of formula j j. Reductive amination, as described above, of a compound of formula jj provides the corresponding compound of formula NN.
Example 6i: Synthesis of l -(3-morpholinophcnyl)ethanamine
Figure imgf000260_0002
Step 1
[00706| Synthesis of l-(3-MorpholinophenyI)cthanone [00707| A pressure vessel was charged with morpholine (3.51 mL, 40.4 mmol, 3.0 eq), l -(3- bromophenyl)ethanone ( 1 .80 mL, 1 3.5 mmol. 1 .0 eq), 2-Dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (321 mg, 0.68 mmol, 0.05 eq), palladium acetate (225 mg, 0.34 mmol, 0.025 eq), sodium tert-butoxide ( 1 .81 g, 1 8.9 mmol, 1 .4 eq), and DME (45 mL). The reaction vessel was sealed and stirred at 1 00 C for 1 8 h. The reaction was then cooled to rt and preadsorbed onto silica gel. The product was purified by Si02 flash chromatography (80:20 to 50:50 hexanes/ethyl acetate) to afford l -(3-morpholinophenyl)ethanone as a yellow oil (534 mg, 19%). MS (EI) for Ci2H l sNOi: 206.2 ( Ι- ).
Step 2
[00708] Synthesis of l -(3-morpholinophenyl)ethanamine
[00709 j A round bottomed flask was charged with l -(3-morpholinophenyl)ethanone (250 mg, 0.97 mmol. 1 .0 eq), ammonium acetate ( 1 88 mg, 2.4 mmol, 2.5 eq), sodium
cyanoborohydride ( 1 53 mg, 2.4 mmol, 2.5 eq), and MeOH (3.5 mL). The reaction mixture was refluxed for 18 hours, then cooled to rt and concentrated. The mixture was then partitioned between saturated aqueous NaHC03 and ElOAc, and the aqueous layer was extracted 3 times with EtOAc. The organic layers were combined, dried over Na2S04, and concentrated under vacuum to give the crude product. The product was purified by Si02 flash chromatography ( 1 00:0: to 80:20 ethyl acetate/melhanol) to afford l -(3- morpholinophenyl)ethanamine as a brown oil (39 mg, 19%). MS (EI) for C 12H 18N2O: 207.2 (MH+).
Example
Figure imgf000261_0001
Step 1
[007101 Synthesis of (R)-l-(5-bromopyridin-3-yl)ethanol
|00711 ) Spiroborane catalyst, (S)-3'.3'-diphenyltetrahydro-3'H-spiiO[[l ,3.2]dioxaborolane- 2, l '-pyrrolo[ 1.2-c][l ,3,2]oxazaborol]- l '-uide, was synthesized according to Ortiz-Marciales, Margarita et al. Tetrahedron: Asymmetry 18 (2007) 2738-2745.
[00712] To a solution of the spiroborane catalyst ( 1.65 g, 5 mmol) in THF ( 120 mL) was added BH3 DMS (8.5 mL, 0.085 mol) over 10 minutes and stirred at rt for 30 minutes. A solution of l -(5-bromopyridin-3-yl)ethanone (10 g, 0.05 mol) in THF (48 mL) was added via a syringe pump for 6 hours and 30 minutes at a rate of 6.4 ml/h. After stirring for 1 hour, the reaction was cooled to 0 °C. quenched with MeOH ( 175 mL) and stirred at room temperature for 14 hours. After concentrating under reduced pressure, the residue was dissolved in EtOAc (250 mL) and washed several times with saturated aqueous NaCl (100 mL). The combined organic layers were dried over Na2SO;|, filtered, and concentrated under reduced pressure. The product was purified by SiC Hash chromatography (hexanes:ethyl acetate = 50:50 to 20:80) to afford 8.92 g of (j?)- l -(5-bromopyridin-3-yl)ethanol (85% yield). Ή NMR (400 MHz, CDCl3):6 8.55 (d, I H), 8.47 (d, 1 H), 7.98 - 7.83 (m, 1 H), 4.95 (ddd, 1 H), 1.53 (d, 3H). Chiralpak AD-column: EtOH/MeOH, 0.8 ml/min, 20 min run, 5.32 min, 99% ee.
Step 2
[00713| Synthesis of (S)-2-(l -(5-bromopyriclin-3-yl)ethyl)isoindoline-l,3-dionc
[00714| A round-bottomed flask was charged with (R)- l -(5-bromopyridin-3-yl)ethanol (1.43 g. 7.08 mmol, 1 .00 eq), isoindoline-l ,3-dione (1 .30 g. 8.85 mmol, 1.25 eq),
triphenylphosphine (3.34 g, 12.7 mmol, 1.80 eq), and THF (23 mL). Diisopropyl azodicarboxylate (2.00 mL, 12.7 mmol, 1 .80 eq) was then added dropwise, and the reaction was stirred at room temperature for 16 hours. The reaction was concentrated, the mixture was partitioned between H20 and EtOAc, and the aqueous layer was extracted 3 times with EtOAc. The organic layers were combined, dried over aiSCXi, and concentrated under vacuum to give the crude product. The product was purified by Si02 flash chromatography (85: 15: to 80:20 hexanes/ethyl acetate) to afford (S)-2-(l -(5-bromopyridin-3- yl)ethyl)isoindoline- l ,3-dione as a pale yellow solid (2.38 g, > 100%). MS (EI) for
C 15H 1 1 B1 2O2 : 33 1.9 (Ml-f). Step 3
[00715] Synthesis of (S)-l -(5-bromopyridin-3-yl)cthanaminc
[00716] A round-bottomed flask was charged with (S)-2-( l -(5-bromopyridin-3- yl)ethyl)isoindoline-l ,3-dione (2.38 g, 7.19 mmol, 1 .00 eq), hydrazine hydrate ( 1.05 niL, 21.6 mmol, 3.00 eq), and I MF (24 mL). The reaction was re fluxed for 1 8 hours, then cooled to rt and concentrated. The crude mixture was redissolved in CHiCl?, and the solid was filtered away and washed with Cl-bCk The filtrate was then concentrated to give crude product, which was purified by S1O2 Hash chromatography ( 100:0 to 90: 10 ethyl
acelate/methanol) to afford (S)-l -(5-biOmopyridin-3-yl)elhanamine as a yellow oil (1.00 g, 70%). Ή NMR (400 MHz, CDCI3) 8.56 (d, 1 H), 8.50 (d, 1 H), 7.92 - 7.87 (m, 1 H), 4.26 - 4.12 (m, l H), 1.46 - 1 .36 (m, 3H); MS (El) for C7H9BrN2: 201 .2 (MH+).
Example 6k: Synthesis of 2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(l S)-l-[3-(lH- pyrazoI-l-yl)phenyl]ethyl}pyrimidin-4-amine and 2-methyl-6-(3-mcthy'l-l-benzofuran-5- -N-{(l S)-l-[3-(2H-l ,2,3-triazol-2-yl)phcnyl|ethyl}pyrimidin-4-amine.
Figure imgf000263_0001
[007171 Preparation of 2-methyI-6-(3-mcthyI-l-benzofuran-5-yl)-N-{(l S)-l-[3-(lH- pyrazol-l-yl)phenyl]ethyl}pyrimidin-4-aminc Compound 578:
[007181 To a solution of 50 mg (0.1 18 mmol) of (S)-N-(l -(3-bromophenyl)ethyl)-2-methyl- 6-(3-methylbenzofuran-5-yl)pyrimidin-4-amine in 153 uL of NMP, is added 16 mg (0.236 mmol) of imidazole, 33 mg of K2C03 and 4 mg of CuF. The solution was place in a microwave apparatus and heated to 180°C for 2hours and 1 0°C for 2hours. The reaction mixture is purified by preparative RP-HPLC CI 8 eluting wit a gradient of NHOAc & MeOH. Fractions were pooled and lyophilized to give 29 mg of the named product as a white solid in 60% yield. Ή NMR (400 MHz. CD3C ) δ 8.23 - 8.07 (m, 1H)S 7.94 - 7.83 (m, 1H), 7.69 (d,./= l.7Hz, 1 H), 7.61 (ddd, J= 8.0, 2.2, 1.0 Hz, lH), 7.55 (d,J= 1.3 Hz, 1H),7.49 (d, J= 8.7 Hz, 1 H), 7.45 (t, = 7.8 Hz, 1 H), 7.37 (d, ./ = 7.7 Hz, 1 H), 6.69 (s, 1 H), 6.56 - 6.43 (m, 11-1), 6.28 (d,./= 7.1 Hz, 1H), 5.18 (s, 1H), 2.43 (s, 2H), 2.25 (d,./= 1.0 Hz, 2H), 1.97 - 1.96 (m, 1H), 1.58 (d, J= 6.9 Hz, 2H); MS (EI) for C25H23N5O: 357.2 (ΜΙ- )
[00719] 2-mcth>1-6-(3-mcthyl-l-benzoluran-5-yl)-N-{(lS)-l-(3-(2H-l,2,3-triazol-2- yl)phenyI]ethyl}pyrimidin-4-aminc (Compound 579 - prepared according to the preparation of Compound 578): Ή NMR (400 MHz, CD3CN) S 8.23 - 8.10 (m, 2H), 7.95 - 7.83 (m, 2H), 7.69 (d,J= 1.7 Hz, 1H), 7.61 (ddd,./ =8.0, 2.2, 1.0 Hz, 1H),7.55 (d, J = 1.3 Hz, 1 H), 7.52 - 7.47 (m, 1 H), 7.45 (t, J= 7.8 Hz, 1 H), 7.37 (d J = 7.7 Hz, 1H), 6.60 (d, J = 78.3 Hz, 1H), 6.50-6.46 (m, 1H), 6.28 '(d, J = 7.1 Hz, 1H), 5.18 (s, 1H), 2τ43 (s, 3H), 2.25 (d,./= 1.0 Hz, 3IT), 1.98 - 1.96 (m, IH), 1.56 (dd,./= 19.7, 6.9 Hz, 3H); MS (EI) for C26H23 60: 411.06 (ΜΗ ' )
General Scheme 13
Scheme 13: Synthesis of Compounds of Formula OO
Figure imgf000264_0001
kk 11 OO
100720] Compounds of formula OO, wherein R26 and R27 are non-reactive compounds, such as hyrogen, alkyl, and alkoxy, can be synthesized according to Scheme 13. The
transformation of a compound of formula kk to a compound of formula 11 can be accomplished using know methods, such as the method described in Yoo, Sung-eun; Lee, Seung-Heui; Kim, Soo-Kyung; Lee, Sung-Hou. The conformation and activity relationship of benzofuran derivatives as angiotensin II receptor antagonists. Bioorganic & Medicinal Chemistry (1997), 5(2), 445-459. Coupling of bispinacolato(diboron) vvith a compound of formula 11 provides a compound of formula OO.
Example 7a: Synthesis of 4,4,5,5-tctramethyl-2-(3-methylbenzofuran-5-yl)-l,3,2- dioxaborolane
Figure imgf000265_0001
Step 1
|0072I ] Synthesis of 5-bromo-3-mcthyIbenzofuran
(00722| 5-bromo-3-methylbenzofuran was synthesized starting from l -(5-bromo-2- hydroxyphenyl)ethanone according to the following reference: Yoo, Sung-eun; Lee, Seung- Heui; Kim, Soo-Kyung; Lee, Sung-Hou. The conformation and activity relationship of benzofuran derivatives as angiotensin II receptor antagonists. Bioorganic & Medicinal Chemistry (1997), 5(2), 445-459 (ref. l). Ή NMR (400 MHz, dr>-DMSO): 7.83 (s, I H), 7.82 (s: I H, overlapped), 7.53 (d, I H), 7.45 (dd, I H), 2. 19 (s, 3H); MS (EI) for C9H7BrO: 210.1 (Ml-f)
Step 2
[00723] Synthesis of 4,4,5,5-tetraniethyl-2-(3-niethylbenzofuran-5-yl)-l ,3,2- dioxaborolanc
[00724] A 25 niL pressure vessel was purged with nitrogen and charged with 5-bromo-3- methylbenzofuran (424 mg, 2.03 mmol), bispinacolato(diboron) (567 mg, 2.23 mmol), and potassium acetate (397 mg, 4.06 mmol) in DMSO (5 mL). Pd(dppf)ClvCH2Cl2 (83 mg, 0.10 mmol, 5 mol%) was added, and nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was heated to 80 °C for 12 hours, cooled to rt, and filtered through a pad of Celite and Si02. After partitioning between water and ethyl acetate, the reaction mixture was extracted with EtOAc ( 2 X 50 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure. The product was purified by Si02 Hash chromatography (hexanes:ethyl acetate = 80:20) to afford 237 mg of 4,4,5,5-tetramethyl-2-(3-methylbenzofuran-5-yr)-l ,3,2-dioxaborolane (45% yield). 'H MR (400 MHz, d6-DMSO): 7.91 (s, I H), 7.78 (s, 1 H): 7.62 (dd, I H), 7.53 (dd, I H), 2.23 (s, 3H), 1 .32 (s, 12H); MS (EI) for C 15H 19B03 : 259 (MH+). General Scheme 14
Scheme 14: Synthesis of Compounds of Formula PP
Figure imgf000266_0001
nn QQ
[00725| A compound of formula QQ, wherein R > is a non-reactive substituent, such as hydrogen, alkyl, or alkoxy. can be synthesized according to Scheme 14. The cyclization of 2- amino-4-bromophenol to 6-bromo-2H-benzo[b][ l ,4]oxazin-3(4H)-one can be accomplished with a "capping" reagent such as chloroacetyl chloride, or an equivalent thereof. Subsequent alkylation with a compound of formula mm, wherein Lg is a Leaving Group, provides a compound of nn, which can be converted to the boronate compound QQ as described above.
Example 7b: Synthesis of 4-mcthyl-6-(4,4,5,5-teti amcthyl-l ,3)2-dioxaborolan-2-yl)-3,4-
Figure imgf000266_0002
Step 1
[00726] 6-bromo-2H-benzo[b] [ l ,4]oxaziii-3(4H)-one.
[00727] To a solution of 2-amino-4-bromophenol (5.0 g, 0.022 mmol) in acetonitrile (50 mL) were added K2C03 (15.3 g, 0.1 1 1 mol) and chloroacetyl chloride (4.0 g, 0.0356 mmol).
The reaction mixture was heated to reflux for 12 hours, cooled to rt, and quenched with water
( 100 mL). The dark brown mixture was extracted with ethyl acetate ( 2 x 200 mL) and washed with saturated aqueous NaCI (100 mL). The combined organic layers were dried over a2S04, filtered, and concentrated under reduced pressure. The product was purified by Si02 flash chromatography (hexanes:ethyl acetate = 50:50 to ethyl acetate) to afford 2.93 g of 6- bromo-2H-benzo[b][l ,4]oxazin-3(4H)-one (58% yield). Ή NMR (400 MHz. d6-DMSO): 10.8 (s, 1 H), 7.07 (dd, 1 H), 7.01 (d, 1 H), 6.9 l (d, l H), 4.6 (s, 2H) ; MS (EI) for C8H6BrN02: 228.1 (MH+)
Step 2
[007281 6-bromo-3,4-dihydro-2H-benzo|b]| l ,4|oxazine.
[00729] To a 0 °C solution of 6-bromo-2H-benzo[b][ l,4]oxazin-3(4H)-one ( 721 mg, 3.17 mmol) in THF (1 5 mL) was added L1AIH4 (4.8 mL, 1 .0 M solution in THF) over 10 minutes. The reaction was warmed up to room temperature and stirred for 16 hours. The excess L1AIH4 was quenched carefully with water at 0 °C, and Na2S04 was added, and the reaction mixture was stirred for 10 minutes. The solids were filtered off, and the resulting solution was partitioned between water and ethyl acetate. The reaction was extracted with ethyl acetate (2x 50 mL) and combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure. The product was purified by Si02 flash
chromatography (hexanes:ethyl acetate = 80: 20) to afford 507 g of 6-bromo-3.4-dihydro-2H- benzo[b][l ,4]oxazine (74% yield). Ή NMR (400 MHz, d6-DMSO): 6.69 (d, 1 H), 6.55 (m, 2H), 6.07 (br s, 1 H), 4.08 (t, 2H), 3.26 (m, 2H) ; MS (EI) for C8H8BrNO: 214.1 (MH+)
Step 3
[00730] 6-bromo-4-methyI-3,4-dihy(lro-2H-benzo[b][l ,4]oxazine.
[00731] To a suspension of NaH (60%, 52 mg, 1.30 mmol) in DMF (5 mL) at 0 °C was added a solution of 6-bromo-3,4-dihydro-2H-benzo[b][ 1.4]oxazine (217 mg, 1.00 mmol) in DMF (3 mL). After 15 minutes, Mel (568 mg, 4.0 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure. The product was purified by Si02 flash chromatography (hexanes:ethyl acetate = 80: 20) to afford 181 mg of 6-bromo-4- methyl-3,4-dihydro-2H-benzo[b][ l ,4]oxazine (80% yield). MS (EI) for C9H i0BrNO:
228.1 (MH ') 230.1 (M+2H). t = 1 .855 min Step 4
[00732] 4-mcthyl-6-(4,4,5,5-tctramethyl-l ,3,2-clioxaborolan-2-yl)-3,4-dihydro-2H- benzo[b]|l ,4|oxazine.
[00733] A 25 mL pressure vessel was purged with nitrogen and charged with 6-bromo-4- ineth}'l-3,4-dihydro-2I-l-benzo[b] 1.4]oxazine ( 181 mg, 0.797 mmol), bispinacolato(diboron) (263 mg, 1.04 mmol), potassium acetate (156 mg, 1.6 mmol) in DMSO (5 mL).
Pd(dppf)Cl2 CH2Cl2 (33 mg. 0.039 mmol, 5 mol%) was added, and nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was heated to 80 °C for 12 hours, cooled to rt, and filtered through a pad of Celite and Si02. After partitioning between water and ethyl acetate, the reaction mixture was extracted with EtOAc (2 X 50 mL). The combined organic layers were dried over a2SC>4. filtered, and concentrated under reduced pressure. The product was purified by Si02 Hash chromatography (hexanes:ethyl acetate = 80:20) to afford 202 mg of 4-methyl-6-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)-3,4- dihydro-2H-benzo[b][l ,4]oxazine (92% yield). MS (EI) for C 15H22BNO3: 276.2 (MH+), t = 1.903 min
General Scheme 15
Scheme 15: Synthesis of compounds of fortnul
Figure imgf000268_0001
RR
|00734] A compound of formula RR, wherein R2g and Lg are described above, can be synthsized accdording to Scheme 15. 6-bromoindole can be reduced to the corresponding 6- bromoindoline using a reducing agent, such as sodium cyanoborohydride. Subsequent alkylation provides a compound of formula 00. which can be converted to a boronic ester of formula RR as described above.
Example 7c: Synthesis of l-methyI-6-(4,4,5,5-tctramcthyl-l ,3,2-dioxaborolan-2-
Figure imgf000268_0002
Slep 1
[00735| 6-bromoindolinc
(00736) To a solution of 6-bromoindole (1 .08 g. 5.51 mmol) in acetic acid (10 mL) was added NaCNBH3 ( 1.04 g, 16.53 mmol). The reaction mixture was stirred for 12 hours at room temperature and slowly quenched with saturated aqueous NaHC03. The reaction was extracted with ethyl acetate (2 x 100 mL) and washed with water (2 x 100 mL). The combined organic layers were dried over
Figure imgf000269_0001
filtered, and concentrated under reduced pressure. The product was purified by Si02 flash chromatography (hexanes:ethyl acetate = 80:20) to afford 431 mg of 6-bromoindoline (40% yield). Ή NMR (400 MHz, d6-DMSO): 6.92 (d, 1 H), 6.62 (d, 1 H), 6.57 (s, 1 H), 5.77 (br s, 1 IT), 3.44 (t, 2H), 2.85 (t, 2H). MS (EI) for CsHgBrN: 198.1 (MH+)
Step 2
J00737] 6-bromo-l-methylindolinc
100738] To a suspension of NaH (60%, 59 mg, 1 .46 mmol) in DMF (5 mL) at 0 °C was added a solution of 6-bromoindoline (222 mg, 1.13 mmol) in DMF (3 mL). After 15 minutes, Mel (320 mg, 2.0 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The product was purified by Si02 flash chromatography
(hexanes:ethyl acetate = 90: 10) to afford 144 mg of 6-bromo- l -methylindoline (61 % yield). MS (EI) for CqH ioBrN: 212.1 (MH+) 214.1 (M+2H), t = 1 .936 min
Step 3
[00739] l-methyl-6-(4,4,5,5-tetramcthyI-l ,3,2-dioxaborolan-2-yl)indoIine
|00740] A 25 mL pressure vessel was purged with nitrogen and charged with 6-bromo- l - methylindoline ( 144 mg, 0.682 mmol), bispinacolato(diboron) (220 mg, 0.867 mmol), potassium acetate (134mg, 1.364 mmol) in DMSO (5 mL). Pd(dppf)Cl2 CH2Cl2 (28 mg, 0.034 mmol, 5 mol%) was added, and nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was heated to 80 °C for 12 hours, cooled to rt. and filtered through a pad of Celite and Si02. A ter partitioning between water and ethyl acetate, the reaction mixture was extracted with EtOAc (2 X 50 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The product was purified by Si02 flash chromatography (hexanes:ethyl acetate = 80:20) to afford 169 mg of l -methyl-6-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)indoline (96% yield). MS (EI) for C|5I½BN02: 260.2 (ΜΙ-Γ), I = 1 .997 min
General Scheme 16
Scheme 16: Synthesis of compounds of formula SS
Figure imgf000270_0001
[00741] A compound of formula SS, wherein X is halogen, can be synthesized according to Scheme 16. A compound of formula oo is cyclized to produce a compound of formula pp using, for example, 2-bromomalonate in basic conditions. Hydrolysis of the ester functionality provides qq. and then subsequent decarboxylation provides the benzofuran of formula IT. The compound of formula rr can then be converted to the corresponding compound of formula SS as described above.
Example 7d: Synthesis of 2-(7-fluorobcnzofuran-5-yl)-4,4,5,5-tctramethyl-l ,3,2-
Figure imgf000270_0002
Step 1
|00742) Synthesis of Ethyl 5-bromo-7-fluorobenzofuran-2-carboxylate [00743] To a solution of 5-biOmo-3-iluoro-2-hydroxybenzaldehyde (550 mg, 2.51 mmol) in 2-butanone (15 mL) were added diethyl 2-bromomalonate (720 mg. 3.01 mmol) and potassium carbonate (381 mg, 2.76 mmol). The reaction mixture was heated to 80 °C for 5 hours and then cooled down to room temperature. After partitioning between water and ethyl acetate, the reaction mixture was extracted with EtOAc ( 2 X 50 mL). The combined organic layers were dried over Na^SOa, filtered, and concentrated under reduced pressure. The product was purified by Si02 Hash chromatography (hexanes:ethyl acetate = 80:20) to afford 220 mg of ethyl 5-bromo-7-fluorobenzo furan-2-carboxylate (31 % yield). 1 H NM'R (400 MHz. CDC13):6 7.62 (br s, 1 H), 7.48 (m, 1 H), 7.35 (m, 1 H), 4.45 (q, 2H), 1.44 (t, 3H).
Step 2
[00744| 5-bronio-7-fluorobenzof'uran-2-carboxyHc acid
|00745] To a solution of ethyl 5-biOmo-7-fluorobenzofuran-2-carboxylate (221 mg. 0.77 mmol) in ethanol (10 mL) was added 5 N NaOH (800
Figure imgf000271_0001
and healed to 90 °C.for 30 minutes. The reaction mixture was cooled to room temperature and brought to pH 3-4 with I HCl (4 mL). The reaction was partitioned between ethyl acetate and water and extracted with EtOAc ( 2 X 50 mL). The combined organic layers were dried over Na^SOa, filtered, and concentrated under reduced pressure to afford 159 mg of 5-bromo-7-fluorobenzofuran-2- carboxylic acid (80% yield). MS (El) for C9H4BrF03: 257.1 (M-H)
Step 3
|00746] 5-bromo-7-fluorobenzofuran
[00747] To a sealed tube containing 5-bromo-7-fluorobenzofuran-2-carboxylic acid (470 mg. 1 .81 mmol) in quinoline (4 mL) was added copper (II) oxide (CuO, 139 mg, 1.75 mmol). The reaction mixture was heated to 1 70 °C for 3 hours. After cooling down to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The reaction was extracted with EtOAc (2 X 50 mL) and the combined organic layers were dried ove filtered, and concentrated under reduced pressure. The crude product was purified by Si02 flash chromatography (hcxanes:ethyl acetate = 80:20) to afford 220 mg of 5- bromo-7-fluorobenzofuran (57% yield). Ή NMR (400 MHz, CDC13):5 7.66 (d, 1 H), 7.52 (d, 1 H), 7.20 (dd, 1 H): 6.77 (br t, 1 H).
Step 4
[00748] 2-(7-fluorobenzofui an-5-yI)-4,4,5,5-tetramcthyI-l,3,2-dioxaborolane [00749] A 25 mL pressure vessel was purged with nitrogen and charged with -bromo-7- fhtorobenzofuran (220 mg, 0.935 mmol). bispinacolato(diboron) (285 mg, 1 .121 mmol). and potassium acetate ( 1 84 mg, 1 .87 mmol) in D SO (5 mL). Pd(dppf)Cl2'CH2CI2 (33 mg, 0.039 mmol, 5 mol%) was added, and nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was heated to 80 °C for 12 hours, cooled to rt, and filtered through a pad of Celite and Si02. After partitioning between water and ethyl acetate, the reaction mixture was extracted with EtOAc (2 X 50 mL). The combined organic layers were dried over Na2SOa, filtered, and concentrated under reduced pressure. The product was puri fied by SiO? Hash chromatography (hexanes:ethyl acetate = 80:20) to afford 200 mg of 2- (7-fluoi benzofuran-5-yl)-4,4,5,5-tetramethyl- l ,3,2-dioxaborolane (76% yield). Ή N R (400 MHz, CDC13): δ 7.86 (s: 1 H), 7.65 (d, 1 H), 7.46 (d: 1 H), 6.80 (t, 1 H), 1.35 (s, 12H). MS (El) for C 14H 16BFO3 : 263.2 ( H*)
Example 7e: 2-(7-fluoro-3-mcthylbcnzofuran-5-yI)-4,4,5,5-tetramethyl-l,3,2- dio
Figure imgf000272_0001
Step 1
[00750] 5-bromo-3-fluoro-2-(triisopropylsilyIoxy)benzaldehyde [0075.1 ] To a solution of 5-bromo-3-fiuoro-2-hydroxybenzaldehyde (5.20g: 0.023 mol) in Ti-IF (100 niL) was added imidazole (2.34 g, 0.0345 mol). The resulting homogenous mixture was cooled to 0 °C, and triisopropyl silyl chloride (5.76 g. 0.030 mol) was added slowly over 5 minutes. The reaction mixture was stirred at room temperature for 2 hours. After partitioning between water and ethyl acetate, the reaction mixture was extracted with EtOAc (2 X 150 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure. The product was purified by Si02 flash
chromatography (hexanes:ethyl acetate = 90: 10 to 80:20) to afford 7.36 g (85% yield) of 5- bromo-3-fluoro-2-(triisopropylsilyloxy)benzaldehyde. Ή NMR (400 MHz, CDC13):5 10.41 (s, 1 H), 7.70 (s, 1 H), 7.42 (dd, 1 H), 1.33 (m, 3H), 1 .10 (d, 18H).
Step 2
[00752] l-(5-bromo-3-fluoro-2-(triisopropyIsHyIoxy)phenyl)ethanol
|0()753] To a -78 °C solution of 5-bromo-3-fluoro-2-(triisopropylsilyloxy)benzaldehyde (8.75 g, 0.023 mol) in THF (100 mL) was added MeMgBr (3.0M in diethylether, 10 mL) dropwise over a period of 15 minutes. The reaction was warmed up to room temperature over a period of 3 hours, cooled to 0 °C, and quenched slowly with H20 (25 mL). After partitioning between water and ethyl acetate, the reaction mixture was extracted with EtOAc (2 X 1 0 mL). The combined organic layers were dried over Na SO<t, filtered, and concentrated under reduced pressure. The product was purified by SiO? flash
chromatography (hexanes:ethyl acetate = 90: 10) to afford 8.40 (94% yield) of l-(5-bromo-3- fli!oro-2-(triisopropylsilyloxy)phenyl)ethanol. Ή NMR (400 MHz, CDC13):5 7.36 (s, 1 H), 7.12 (dd, 1 H), 5.23 (m, 1 H), 1.45 (d, 31T), 1.32- 1 .24 (m, 3 H), 1.08 (d, 1 8H).
Step 3
[00754] l-(5-bromo-3-fluoro-2-(triisopropylsilyloxy)phcnyI)cthanonc
[00755] To a 0 °C solution of 1 -(5-biOmo-3-fluoro-2-(triisopi pylsilyloxy)phenyl)ethanol (9.79 g, 0.025 mol) in CH2C12 (100 mL) was added Dess-Martin reagent ( 13.8 g, 0.032 mol) in 2 portions. The reaction mixture was stirred at room temperature for 12 hours and juenched with sodium thiosulfate Na2S2O7 ( 1 00 mL). The reaction was partitioned between ethyl acetate and
Figure imgf000273_0001
and extracted with EtOAc (2 X 250 mL). The combined organic layers were dried over Na2S0 ! filtered, and concentrated under reduced pressure. The product was purified by Si02 flash chromatography (hexanes:ethyl acetate = 80:20) to afford 8.872 g (91 % yield) of 1 -(5-bi mo-3-nuoi -2-(triisopropylsilyloxy)phenyl)ethanone. Ί-Ι NMR (400 MHz, CDC13):8 7.39 (m, 1 H), 7.30 (dd, 1 H), 2.50 (s, 3H), 1.39 (m, 3H), 1 .08 (d, 18H)
Slep 4:
|00756] l-(5-bromo-3-fluoro-2-hydrox phcn l)ethanonc
100757 J To a 0 °C solution of l -(5-bromo-3-iluoiO-2-(tnisopropy)silyloxy)phenyl)ethanone (8.87 g, 0.023 mol in THF (100 mL) was added TBAF (1.0 M in THF, 34 mL) over 15 minutes. The reaction was warmed up to room temperature over a period of 2 hours. The reaction was partitioned between ethyl acetate and saturated NH4CI and extracted with EtOAc (2 X 250 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure. The product was purified by Si02 flash
chromatography (hexanes:ethyl acetate = 90: 10 to 70:30) to afford 5.50 g of l -(5-bromo-3- fiuoro-2-hydroxyphenyI)ethanone (quant.). Ή NMR (400 MHz, CDC13):5 12.21 (s, 1H), 7.68 - 7.58 (m, 1 H), 7.44 (ddd, 1 H), 2.74 - 2.51 (in. 3H).
Step 5
[00758] tert-butyl 2-(2-acctyl-4-bromo-6-fluorophenoxy)acetate
[00759] To a solution of l -(5-bromo-3-fluoro-2-hydroxyphenyl)ethanone (4.50 g. 0.019 mol) in DMF (40 mL) were added K2C03 (7.87 g, 0.057 mol), tert-butyl 2-bromoacetate (4.48 g, 0.023 mol), and sodium iodide (285 mg, 1.9 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was then partitioned between ethyl acetate and brine and extracted with EtOAc ( 2 X 250 mL). The combined organic layers were dried over Na2SO.|, filtered, and concentrated under reduced pressure. The product was purified by Si02 flash chromatography (hexanes:ethyl acetate = 95:5 to 80:20) to afford 4.54 g of tert-butyl 2- (2-acetyl-4-bromo-6-fluorophenoxy)acetate (70% yield). Ή NMR (400 MHz. CDC13): δ 7.63 - 7.53 (m, 1 H), 7.43 - 7.34 (m, 1 H), 4.70 (s, 3H), 2.71 (s, 4H), 1 .41 (s, 9H).
Step 6:
[00760J 2-(2-acetyI-4-bromo-6-fluoropheno.\y)acetic acid
[007611 To a solution of tert-butyl 2-(2-acetyl-4-bromo-6-fiuoiOphenoxy)acetate (4.54 g, 0.013 mol) in dichloromethane (50 mL) was added TFA (9.97 mL, 0.13 1 mol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with aqueous I N HC1 (50 mL) and extracted with EtOAc (2 X 250 mL). The combined organic layers were dried over filtered, concentrated under reduced pressure and used directly in the next step.
Step 7
[00762] 5-biOmo-7-fluoro-3-mcthylbcnzofuran
[00763] To a solution of 2-(2-acetyl-4-bromo-6-fluoi phenoxy)acetic acid (3.91 g, 0.013 mol) in a 1 : 1 mixture of acetic anhydride and acetic acid (20 mL) was added NaOAc (2.21 g, 0.026 mol). The reaction mixture was heated to 1 10 °C for 12 hours. After cooling down to room temperature, the reaction was quenched with H20 (100 mL) and extracted with EtOAc (2 X 250 mL). The combined organic layers were dried over Na2S0 , filtered, and concentrated under reduced pressure. The product was purified by Si02 flash
chromatography (hexanes:ethyl acetate = 95:5) to afford 2.56 g of 5-bromo-7-fluoro-3- methylbenzofuran (86% yield). Ή NMR (400 Hzs CDCI3): δ 7.44 (L 2H), 7.18 (dd, 1 H), 2.21 (s, 3H).
Step 8
[00764] 2-(7-nuoro-3-methylbenzofuran-5-yI)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane
[00765] A 100 mL pressure vessel was purged with nitrogen and charged with 5-bromo-7- lluoro-3-methylbenzofuran (3.04 2.. 0.0137 mol). bispinacolato(diboron) (4.38 g, 0.0172 mol), potassium acetate (2.68 g, 0.0274 mol) in DMSO (40 mL). Pd(dppf)Cl2 «CH2Cl2 (279 nig. 0.34 mmol. 2.5 mol%) was added, and nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was heated to 80 °C for 12 hours, cooled to rt. and filtered through a pad of Celite and Si02. After partitioning between water and ethyl acetate, the reaction mixture was extracted with EtOAc (2 X 250 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure. The product was purified by Si02 Hash chromatography (hexanes:ethyl acetate = 95:5) to afford 3.76 g of 2-(7-fiuoi -3-methylbenzofuran-5-yl)-4!4.5.5-tetramethyl- l ,3,2-dioxaborolane (quant, yield). Ή NMR (400 MHz, CDCI3): δ 7.78 (s, 1 H), 7.44 (dd, 2H), 2.26 (s, 3H), 1.37 (s, 12H). Example 7f: Synthesis of Preparation of 4,4,5,5-tctramethyl-2-(3- mcthylbenzo[b]thiophcn-5-yI)-l ,3,2-dioxaboroIane.
Figure imgf000276_0001
reflux
[00766J To a solution of 1 g (5.5 mmol) of 5-chloro-3-methylbenzo[b]thiophene in 1 mL neat triethylamine, is added 1 .2 mL (8.25 mmol) of 4,4,5,5-tetramethyl- l ,3,2-dioxaborolane, 360 mg (0.88 mmol) of dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, and 57 mg (0.22 mmol) of bis (acetonitrile)dichloropalladium (11). The solution is refluxed under nitrogen for 1 8h, cooled, diluted with EtOAc and filtered through Celite. The orgainic solution is washed twice with I N HCl and brine, dried over MgS04, concentrated under reduced pressure to afford 1.6 g of 4,4.5, 5-tetramethyl-2-(3-methylbenzo[b]thiophen-5-yl)- 1 ,3,2-dioxaborolane. Ή NMR (400 Hz, cdcl3) 6 8.19 (s, 1H), 7.88 - 7.83 (m, 1 H), 7.79 - 7.74 (m, 1 H), 7.04 (d, J = 1 .1 Hz, 1 H), 2.48 (s, 3H), 1.38 (s, 12H).
Example 7g: Synthesis of 2-(3-chlorobenzofuran-5-yl)-4,4,5,5-tetramethyl-l ,3,2- dioxaborolane.
-^ Pd(drpp^f)Cr
Figure imgf000276_0002
Step 1
[00767] Preparation of 5-bromo-3-chIorobenzofuran: Chlorine gas is bubbled through a cooled solution of 1 .0 g (5.08 mmol) of 5-bromobenzofuran in 12 mL of glacial acetic acid for 0.5 h. The reaction mixture is concentrated in situ to give 1.38 g of crude dichloro material which is used directly in the next reaction. This material was treated with 45 mL of a 0.1 KOH/EtOH solution fro 18h. The reaction is neutralized with 6N HCl and concentrated in situ, dissolved in EtOAc. Extraction with EtOAc again, combining organic layers and final was with brine, drying over MgS04 and concentration in situ afforded 859 mg of crude material. This was further puri fied on Si02 eluting with hexane to afford 352 mg (34%) of the pure product: Ή NMR (400 MHz, CD3CN) δ 8.23 - 8.07 (m, 1H), 7.94 - 7.83 (m, 1H , 7.69 (d,J= 1.7 Hz, 1H), 7.61 (ddd,.7= 8.0, 2.2, 1.0 Hz, 1H), 7.55 (d,./= 1.3 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1 H), 7.45 (t, ./ = 7.8 Hz, 1 H), 7.37 (d, J = 7.7 Hz, 1 H), 6.69 (s, 1 H), 6.56 - 6.43 (m, 1H), 6.28 (d,J = 7.1 Hz, 1H), 5.18 (s, 1H), 2.43 (s,.2H), 2.25 (d, J= 1.0 Hz, 2H), 1.97 - 1.96 (m, H), 1.58 (d:J= 6.9 Hz, 2H); MS (El) for C25H23N5O: 357.2 (MH+).
Step 2:
[00768] 2-(3-chIorobcnzofuran-5-yl)-4,4,5,5-tctramcthyl-l,3,2-dioxaborolane: To a solution of 352 mg (1.53 mmol) of 5-bromo-3-chlorobenzofuran in 1.5 mL of DME is added 465 mg (1.8 mmol) of 4,414'!4',5,5,5, ;5,-octamethyl-2,2'-bi(l,3,2-dioxaboi lane), 291 mg (2.3 mmol) of KOAc, and 31 mg
|00769] [1,1 '-bis(diphenyphosphino)ferrocene]dichloropalladium(II). The reaction is heated to lOOoC for 3h, cooled, diluted with water, extracted twice with EtOAc, dried over a2S04 and concentrated under reduced pressure to afford 568 mg of the crude product which was used in the next reaction without further purification. Ή NMR (400 MHz, cdcl3) δ 8.12 (s, 1H), 7.82 (d, .7=8.4 Hz, 1H), 7.64 (t, .7 =2.4 Hz, 1H), 7.48 (ddd,J=8.4, 1.3, 0.6 Hz, 1H), 1.38 (d,J= 1.3 Hz, 12H).
General Scheme 17
Scheme 17: Synthesis of compounds of formula TT
Figure imgf000277_0001
100770] A compound of formula TT, wherein R29, R30, R3i and R32 are non-reactive substituents such as hydrogen, alkyl and alkoxy, can be synthesized according to Scheme 17. A compound of formula tt is produced by coupling a boronate of formula ss with 4,6- dichloro-2-methylpyrimidine as described above. Subsequent alkylation, as described above, with a compound of formula uu, wherein Lg is a Leaving Group, provides a compound of formula vv. Coupling of a compound of formula vv with a compound of formula ww. as described above, provides a compound of formula TT.
Example 8: Synthesis of 6-[4-chloro-3-(mcthy!amino)phcnyl]-2-mcthyl-N-[(lR)-l , 2,3,4- tetrahydronaphthalcn-l-yl|pyrimiclin-4-aminc.
Figure imgf000278_0001
Step 1
[00771 ] 2-chIoro-5-(6-chloro-2-methyIpyrimidin-4-yl)aniline
[00772] A pressure vessel was charged with 4,6-dichloro-2-methylpyrimidine ( 1 .0 g, 6.13 mmol, 1.0 eq), 3-amino-4-chlorophenylboronic acid (1 .27 g. 6.13 mmol, 1.0 eq), 1 ,2-DME (20.0 mL), EtOH (5.0 mL), H20 (5.0 mL), and 2C<¾ ( 1.27 g, 9.20 mmol, 1.5 eq). The reaction was purged with nitrogen before adding Pd(PPh3)4 (350 mg, 0.300 mmol, 0.05 eq), sealed, and heated to 85°C for 18 h. The reaction was then cooled to rt and presadsorbed onto silica gel. The product was purified by Si02 flash chromatography (90: 10 to 80:20 hexanes/ethyl acetate) to afford 2-chloro-5-(6-chloro-2-methylpyrimidin-4-yl)aniline as a yellow solid (566 mg, 37% yield). Ή N R (400 MHz, CDCI3): 7.54 (d, 1 H), 7.49 (s, 1 H), 7.36 (d, 1 H), 7.32 (dd, 1 H), 4.23 (br s, 2H), 2.76 (s, 3H); MS (El) for C, , H9C12N3: 254.0 (MH+).
Step 2
[00773] 2-chloro-5-(6-chlor()-2-methylpynmidiri-4-yl)-N-methylaniIine
[00774] A round-bottom flask was charged with 2-chloro-5-(6-chloro-2-methylpyrimidin-4- yl)aniline (97 mg, 0.383 mmol, 1 .0 eq) and D F (1 .2 mL). The reaction was cooled to 0 °C before adding NaH: 60% in mineral oil (3 1 mg, 0.767 mmol, 2.0 eq). The reaction was then warmed to rt for 1 h before adding Mel (48 ML, 0.767 mmol, 2.0 eq). After 30 min, the reaction was partitioned between water and EtOAc, and the aqueous layer was extracted 3X with EtOAc. The organic layers were combined, dried over Na2SO.j, and concentrated under vacuum to give the crude product. The product was purified by Si02 flash chromatography ( 100:0 to 90: 10 hexanes/ethyl acetate) to afford 2-chloro-5-(6-chloro-2-methylpyrimidin-4- yl)-N-methylaniline as a yellow oil (25 mg, 25% yield). MS (EI) for C2H 1 1CI2N3: 268.0 (ΜΙ-Γ).
Step 3
[00775] 6-[4-chIoro-3-(mcthylamino)phenyl)-2-methy!-N-[(l R)-l,2,3,4- tctrahydronaphthaIcn-l-yl]pyrimidin-4-aminc Compound 132
(00776] A pressure vessel was charged with 2-chloro-5-(6-chloro-2-methylpyrimidin-4-yl)- N-methylaniline (35 mg, 0.131 mmol, 1 .0 eq), (R)- 1 , 2,3, 4-tetrahydronaphthalen- l -amine (38 0.262 mmol, 2.0 eq), DMA ( 1 .0 mL), and DIEA (57 V , 0.328 mmol, 2.5 eq). The reaction was sealed and heated to 120°C for 18 h. The reaction was then cooled to rt and partitioned between water and EtOAc. The aqueous layer was extracted 3X with EtOAc, and the organic layers were combined, dried over Na2S04, and concentrated under vacuum to give the crude product as a brown oil. Purification by preparative HLPC (reverse-phase, acetonitrile/water with 25 mM ammonium acetate), followed by concentration under reduced pressure and lyophilization afforded 6-[4-chloro-3-(methyIamino)phenyl]-2-methyl-N-[(l R)- l ,2,3,4-tetrahydronaphthalen- l -yl]pyrimidin-4-amine (Compound 132, 7 mg. 14%) as a white solid. Ή Is! MR (400 MHz, d6-DMSO): 7.62 (d, I H), 7.32 (d, I H), 7.21 (m, 2H), 7.15 (m, 3H), 6.77 (s, I H), 5.65 (d, 1 H), 5.40 (br s, I H), 2.81 (d, 3 IT), 2.77 (m, 2H), 2.44 (s, 3H), .1.96 (m, 2H), 1 .91 (m, I H), 1.80 (m, 2H); MS (EI) for C22I½C1N4: 379.2 (MH+).
[00777] The following compounds were made in a manner analogous to Example 8:
[00778] Compound 135 [(2-chloro-5-{2-mcthyl-6-[(l R)-l ,2,3,4-tctrahydronaphthalen-l- ylamino]pyrimidin-4-yl}phcnyl)amino]acctonitri]e Ή NMR (400 MHz, d6-DMSO): 7.76 (d, I H), 7.45 (d, I H), 7.34 (m, I H), 7.22 (d, I H), 7.13 (m, 3H), 6.78 (s, I H), 6.28 (t, I H), 5.42 (br s, 1 H), 4.41 (d, 2H), 2.77 (m, 2H), 2.45 (s, 3H), 1.97 (m, 2H), 1.91 (m, I H), 1 .80 (m, 2H); MS (El) for C23H22C1N5: 404.2(MH+).
[00779] Compound 137 6-[4-chloro-3-(dimethylamino)phcnyl[-2-methyl-N-|(lR)- l,2,3,4-tctrahydronaphthaIen-l-yl|pyrimidin-4-aminc Ή NMR (400 MHz, d6-DMSO): 7.73 (s, I H), 7.67 (d, 1 H), 7.54 (m, 1 H), 7.47 (d, I H), 7.20 (t, 1 H), 7.13 (m, 2H), 6.80 (s, I H), 5.39 (brs, 1H),2.78 (m, 8H), 2.45 (s, 3H), 1.96 (m, 2H), 1.89 (m, IH), 1.80 (m, 2H); MS (EI) for C23H25CIN4: 393.2 (MIT).
[00780] Compound 1392-methyl-6-[4-mcthyl-3-(methylamino)phcnyI]- -[(lR)-l,2,3,4- tetrahydronaphthalen-l-yl|pyrimidin-4-aniinc Ή NMR (400 MHz, dfi-DMSO): 7.54 (d, IH), 7.21 (d, IH), 7.12 (m, 3H), 7.04 (m, 2H), 6.75 (s, IH), 5.40 (br s, IH), 5.15 (q, IH), 2.78 (d, 3H), 2.76 (m, 2H), 2.43 (s, 3H), 2.10 (s, 3H), 1.97 (m, 2H), 1.91 (m, IH), 1.79 (m, 2H); MS (El) for C23H26 4: 359.2 (MH+).
[00781] Compound 141 [(2-mcthyl-5-{2-mcthyl-6-[(lR)-l,2,3,4-tctrahydronaphthalen- l-ylamino]pyrimidin-4-yl}phenyl)amino|acetonitrile Ή NMR (400 MHz, d6-DMSO): 7.66 (m, IH), 7.28 (m, IH), 7.21 (d, 2H), 7.13 (m, 3H), 6.75 (s, IH), 5.79 (t, IH), 5.41 (brs, IH), 4.32 (d, 2H), 2.77 (m, 2H), 2.44 (s, 3H), 2.15 (s, 3H), 1.96 (m, 2H), 1.87 (tn, IH), 1.80 (m, 2H); MS (El) for C24H25 5: 384.2 (MH+).
[00782] Compound 158 N~2-(2-chloro-5-{2-mcrhyI-6-[(lR)-l,2,3,4- tctrahydronaphthalen-l-ylamino]pyrimidin-4-yl}phcnyl)-N-methylglycinamidc Ή NMR
(400 MHz, d6-DMSO): 8.00 (d, 1 H), 7.71 (d, IH), 7.38 (d, IH), 7.14 (m, 5H), 6.69 (s, IH), 5.78 (m, IH), 5.40 (brs, IH), 3.81 (d,2H),2.77 (m, 2H), 2.64 (d,3H),2.43 (s, 3H), 1.94 (m, 2H), 1.86 (m, IH), 1.78 (m, 2H); MS (EI) for C24H26CI 5O: 436.2 (MH÷).
[00783] Compound 2992-methyl-6-[4-methyl-3-(prop-2-yn-l-yloxy)phcnyl]-N-[(lR)- l,2,3,4-tetrahydronaphthalcn-l-yl|pyrimidin-4-amine: Ή NMR (400 MHz, d3-MeOD): 7.57 (s, 1), 7.34 (d, 1), 7.28 (t, 2), 7.26 (m, 3), 6.67 (br s, 1), 5.53 (br s, 1), 4.85 (d, 2), 4.64 (brs, l),2.94(t, 1), 2.85 (m, 2), 2.53 (s, 3), 2.26 (s, 3), 2.07 (m, 2), 1.92 (m, 4); MS (EI) for C25 H2j N3 O: 384.27 (MH+).
[00784] Compound 3986-[4-chIoro-3-(prop-2-yn-l-ylamino)phcnyl]-2-mcthyi-N-[(lR)- l,2,3,4-tctrahydronaphthaIen-l-yl[pyrimidin-4-amine Ή NMR (400 MHz, d6-DMSO): 7.72 (brd, IH), 7.38 (m, 2H), 7.27 (m, IH), 7.21 (m, IH), 7.13 (m, 3H), 6.76 (s, IH), 6.01 (t, IH), 5.42 (br s, IH), 4.04 (d, 2H), 2.76 (m, 2H), 2.44 (s, 3H), 1.96 (m, 2H), 1.80 (m, 2H): MS (EI) for C24H23CIN4: 403.2 (MH+).
[00785] Compound 4222-methyl-6-[4-methyI-3-(prop-2-yn-l-yIamino)phcnyl|-N-[(lR)- l,2,3,4-tctrahydronaphthaIcn-l-yl|pyrimidin-4-aminc Ή NMR (400 MHz, d6-DMSO): 7.62 (br s, IH), 7.23 (m, 3H), 7.13 (m, 3H), 7.07 (d, IH), 6.73 (m, 3H), 5.50 (t, IH), 5.41 (br s, IH), 3.96 (m, 2H), 2.78 (m, 2H), 2.43 (s, 3H), 2.12 (s, 3H), 1.96 (m, 2H), 1.79 (m, 2H): MS (EI) for C24H25N5: 383.2 ( H ).
[00786] Compound 425 |(5-{6-[(4R)-3,4-dihydro-2H-chromen-4-ylamino]-2- mcthyIpyrimidin-4-yI}-2-mcthylphcnyl)amino|acctonitrilc Ή NMR (400 MHz, dfi- D SO): 7.79 (brs, 1H), 7.29 (m, IH), 7.22 (m, 2H), 7.16 (m, 2H), 6.87 (t, IH), 6.80 (m, 1H), 6.77 (m, 1H), 5.80 (t, 1H): 5.38 (br s, IH), 4.34 (d, 2H), 4.25 (m, 2H), 2.46 (s, 3H), 2.15 (s, 3H), 2.14 (m, 1 H), 2.02 (m, 11-I); MS (El) for C23H23N5O: 387.3 (ΜΙ-Γ).
100787] Compound 429 |(2-fluoro-5-{2-mcthyl-6-[(l R)-l,2,3,4-tetrahydronaphthaIen-l- ylamino]pyrimidin-4-yl}phcnyl)amino]acctonitrilc Ή NMR (400 MHz, d6-DMSO): 7.69 (m, 1H), 7.32 (m, IH), 7.20 (m, 2H), 7.13 (m, 3H), 6.73 (m, 1H), 6.35 (t, IH), 5.41 (br s, 1H), 4.37 (d, IH), 3.16 (d, 2H), 2.78 (m, 4H), 2.44 (s, 3H), 1.96 (in. IH), 1.79 (m, IH); MS (EI) for C23H22FN5: 388.2 (Ml-l").
J00788] Compound 514 |(2-mcthyl-5-{2-mcthyl-6-[(lR)-l,2,3,4-tctrahydronaphthalen- l-ylamino|pyrimidm-4-yI}phenyl)oxy|acctonitrUc: Ή NMR (400 MHz, d3-MeOD): 7.30 (d, 1), 7.20 (m, 2), 7.14 (m, 3), 6.64 (s, 1), 5.63 (t, 1), 2.85 (m, 2), 2.68 (s, 3), 2.25 (s, 3), 2.16 (m, 1), 1.94 (m, 3). MS (El) for C20H|7BrR,S: 427.0 (MH+).
Example 9: Synthesis of 2-methy]-N-{(lS)-l-|3-(methyloxy)phenyl]cthyl}-N'-[(lR)- l, -tetrahydr<)naphthalcn-l-yl]pyrimidine-4,6-diamine Compound 165.
Figure imgf000281_0001
micowave
[00789] A microwave vessel was charged with (R)-6-chloro-2-methyl-N-(l,2,3,4- tetrahydronaphthalen-l-yl)pyrimidin-4-amine (73mg, 0.27 mmol) and (S)-l-(3- methoxyphenyl)ethanamine (500uL, 3.37 mmol) and microvvaved for 30 min at 120 "C. The reaction was cooled to RT. Purification by preparative HPLC (reverse-phase,
acelonitrile/water with 25 mM ammonium acetate), followed by concentration under reduced pressure and lyophilization afforded 2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-N'- [(lR)-l,2,3!4 etrahydronaphthalen-l-yl]pyrimidine-4,6-diamine (61 mg, 59% yield). Ή NMR (400 MHz, CDC13): δ 7.23 (t, 1H)S 7.12 (m, 4H), 6.86 (m, 2H), 6.75 (d, IH), 5.38 (d, IH), 4.97 (s, IH), 4.48 (t, 1 H), 3.77 (s, 3H), 2.75 (m, 2H), 2.34 (s, 3H), 1.96 (m, IH), 1.82 (m, 3H), 1.51 (d, 3H); MS (EI) for
Figure imgf000281_0002
389.3 (MH+).
Example 10: N-[3-(dimcthylamino)propyl]-3-({2-mcthyl-6-|3- (mcthyloxy)phenyl]pynmidin-4-yl}amino)-3-|3-(methyloxy)phcnyl|propanamide Compound 123.
Figure imgf000282_0001
Figure imgf000282_0002
Step 1 :
[00790] 3-(3-rncthoxyphcnyl)-3-(6-(3-rnethoxyphcnyl)-2-mcthylpyrirnidin-4- ylamino)propanoic acid.
[00791 ] To a solution of ethyl 3-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl }amino)-3-[3-(methyloxy)pheny!]piOpanoate (544 mg, 1.29 mmol) in 10 mL THF/H20 (1/1 ) vvas added LiOH (2N, 2.6 mL). The resulting reaction.mixture was heated to 70 °C for 12 hours, cooled to room temperature and acidified with IN HC1. The reaction mixture was extracted with ethyl acetate (2 x 50 mL) and the combined organic layers were washed with brine, dried over NaoSO,), filtered, and concentrated under reduced pressure. The product was purified by Si02 flash chromatography (hexanes:ethyl acetate = 20:80 to ethyl acetate) to afford 3-(3-methoxyphenyl)-3-(6-(3-methoxyphenyl)-2-methylpyrimidin-4- ylamino)propanoic acid (350 mg, 68% yield). Ή N R (400 MHz, d6-DMSO): 7.45 (m, 3H), 7.25 (l, 1 H), 7.10 (m, 3 H), 6.81 (m, 2H), 5.63 (br s, 1 H), 3.82 (s, 3H), 3.73 (s, 3H), 2.78 (m, 2H); 2.45 (s, 3H). MS (EI) for C22H23 3O4: 394.2 (Ml-f)
Step 2:
[00792| N-[3-(dimethyIamino)propyI|-3-({2-methyI-6-[3-(methylox) phenyI]pyrirnit!in- 4-yl}amino)-3-[3-(methyloxy)phcnyl]propanamidc Compound 123.
[00793J To a solution of 3-(3-methoxyphenyl)-3-(6-(3-methoxyphenyl)-2-methylpyrimidin- 4-ylamino)propanoic acid ( 1 mg, 0.1 56 mmol) in DMF (4 mL) were added N,N- dimethylpropane-l ,3-diamine ( 19 mg, 0.186 mmol), EDCI (45 mg, 0.233 mmol), HOBt (7 mg, 0.046 mmol) and diisopropylethylamine (80 mg, 0.620 mmol). The reaction mixture was stirred at room temperature for 12 hours, quenched with water and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2 x 25 mL), washed with saturated aqueous NaHC03 (25 mL), NH4CI (25 mL), and 10% LiCl (25mL). The organic layers were combined, dried over Na2S04, and concentrated under reduced pressure. Purification by preparative HPLC (reverse-phase, acetonitrile/water with 25 mM ammonium acetate), followed by concentration under reduced pressure and lyophilization afforded N-[3- (dimethylamino)propyl]-3-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4-yl}amino)-3-[3- (methyloxy)phenylJpi panamide (53.5 mg, 72% yield). Ή NMR (400 MHz, CDCI3): 7.30- 7.27 (m, 4H), 7.26 (m, 1 H), 7.05 (m, 2H), 6.97 (dd, 1 H), 6.77 (dd, 1 H), 5.5 (br s, 1 H), 3.86 (s, 3H), 3.80 (s, 3H), 3.54 (m, 1 H), 3.31 (m, 1 H), 3.00-2.92 (m, 3H), 2.72 (s, 3H), 2.71 (m, 1 H), 2.48 (s, 3H), 1.99 (m, 2H). MS (El) for C27H35N5O3: 478.3 (MH+).
|00794| The following compounds were made following the procedure for making
Compound 123:
[00795] ethyl N-{3-({2-mcthyl-6-[3-(methyloxy)phenylIpyrimidin-4-yl}amino)-3-|3- (inethyloxy)phcnyl]propanoyI}-beta-alaninate Compound 129. Ή NMR (400 MHz. CDCb): 7.31 (m, 2H), 7.26 (m; 1 H), 7.16 (m, 2H), 6.83 (m, 3H), 6.72 (m, 1 H), 6.44 (br s, 1 H), 5.68 (br s, 1 H), 4.07 (q, 21T), 3.76 (m, 1 H), 3.75 (s, 3H), 3.67 (s, 3H), 3.52-3.43 (m, 2H), 3.12 (m, 1 H), 2.70 (m, 1 H), 2.66 (s, 3H)S 2.47 (m, 2H), 1.23 (t, 3H). MS (EI) for C27H32N4O5: 493.2 (MH÷)
Example 11 : Synthesis of 3-({2-mcthyl-6-[3-(niethyIoxy)phenyl]pyrtmidin-4-yl}amino)- 3-| -(methyloxy)phenyl]propan-l-ol Compound 124.
Figure imgf000283_0001
100796] To a 0 °C solution of ethyl 3-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)-3-[3-(methyloxy)phenyl]propanoate ( 100 mg, 0.237 mmol) in THF (5 mL) was added L1AI H4 (0.5 mL, 1 .0 M in THF). The reaction was allowed to warm up to room temperature and stirred for an hour. The excess L1AIH4 was quenched carefully with water at 0 °C.Na2S04 was added and the reaction mixture was stirred for 10 minutes. The solids were filtered off and the resulting solution was partitioned between water and ethyl acetate. The reaction was extracted with ethyl acetate (2x 50 mL) and combined organic layers were dried ove a2S04, filtered, and concentrated under reduced pressure. Purification by preparat ive HPLC (reverse-phase, 0.1 % TFA in acetonitrile/0.05% TFA in water)), followed by concentration under reduced pressure and lyophilization afforded 3-({2-methyl-6-[3- (methyloxy)phenyl]pyrimidin-4-yl}amino)-3-[3-(methyloxy)phenyl]propan- l -ol (13.7 mg.
15.2% yield).
Example 12: Synthesis of 2-methyl-6-(3-mcthyl-l-bcnzofuran-5-yl)-N-I(lS)-l-(3-
Figure imgf000284_0001
[00797] A pressure vessel was charged with (S)-N-(l -(3-bromophenyl)ethyl)-2-methyl-6-(3- methylbenzofuran-5-yl)pyrimidin-4-amine (55 mg. 0.130 mmol), pyrimidin-5-ylboronic acid (25 mg, 0.156 mmol), Pd(dpp 2Cl2 · CH2C12 (5.3 mg, 0.0065 mmol, 5 mol%) and 2M sodium carbonate ( a2C03, 130 pL) in 3 mL of 1 ,2-dimethoxyethane (DME). The reaction mixture was purged with nitrogen for 10 minutes and heated to 90 °C for 12 hours. The reaction was then cooled to room temperature and filtered through a pad of Si02, washed with 25 mL of a solution of ethyl acetate/methanol = 98/2, and concentrated under reduced pressure.
Purification by preparative HPLC (reverse-phase, acetonitrile/methanol with 25 mM ammonium acetate), followed by concentration under reduced pressure and lyophilization afforded 2-methyl-6-(3-methyl- l -benzofuran-5-yl)-N-[(l S)- l -(3-pyrimidin-5- ylphenyl)ethyl]pyrimidin-4-amine ( 16.9 mg, 31% yield). Ή NM (400 MHz, d6-DMSO):8 9.18 (s, 1 H), 9.14 (s, 2H), 8.16 (s, 1 H), 7.90 (br d: 1 H), 7.79 (br s, 2H), 7.67-7.65 (m, 1 H), 7.56-7.50 (m, 2H), 7.50-7.46 (m, 1 H), 6.84 (br s, 1 H), 5.40 (br s, 1 H), 2.38 (s, 3H), 2.25 (s, 3H), 1.88 (s, 3H, acetate peak), 1.51 (d, 3H). MS (EI) for C26H23N50: 422.1 (MH+).
|00798| The following compounds were made in a manner analogous to Example 12.
100799] Compound 305 6-(l ,3-benzothiazol-6-yl)-2-methyl-N-{l-[3-(5-mcthyI-l,2,4- o.\adiazol-3-yl)phenyl]ethyI}pyrimidin-4-amine MS (El) for C23H2oN6OS: 429.02 (MH+).
[00800] Compound 321 5-{3-[(lS)-l-{[2-methyl-6-(3-methyI-l-bcnzofuran-5- yl)pyrimidin-4-yl]amino}ethyl]phcnyl}pyrimidin-2-amine Ή NMR (400 MHz. d6- DMSO):6 1 1.99 (s, 1 H), 8.59 (s, 2H), 8.16 (s, 1 H), 7.91 -7.84 (m, 2H), 7.65 (m, 1 H), 7.49 (m, 1 H), 7.42-7.35 (m, 2H), 6.89 (bi s, 1 H), 6.81 (s, 2H), 5.41 (br s. 1 H), 2.45 (s, 3H), 2.24 (s, 3H), 1.91 (s, 3H, acetate peak), 1.53 (d, 3H). MS (EI) for C2()H24N60: 437.2 (MH+).
[00801] Compound 322 N-{(l S)-l -|3-(6-aminopyridiii-3-yl)phcnyl|ethyl}-2-methyl-6-(3- niethyl-l -bcnzofuran-5-yl)pyrimidin-4-amine Ή NMR (400 MHz, d6-DMSO):8 8.25 (d, 1H): 8.17 (s, 1H), 7.88 (dd, 1H), 7.81-7.76 (m, 2H), 7.69 (dd, 1H), 7.59 (m, 1H), 7.40 (m, 1H), 7.37-7.33 (m, 2H), 6.85 (br s, 1 H), 6.51 (d, 1H), 6.07 (s, 2H), 5.35 (br s, 1H), 2.40 (s, 3H), 2.24 (s, 3H), 1.51 (d, 3H). MS (EI) for C27H25N5O: 436.1 (MH+).
100802) Compound 323 Ethyl (4-{3-|(lS)-l-{|2-methyI-6-(3-mcthyl-l-benzofuran-5- yl)pyrimidin-4-yl]amino}cthyl]phcnyl}-lH-pyrazol-l-yl)acctate Ή NMR (400 MHz, d6- DMSO):58.18 (brs, 1H), 8.16 (s, 1H): 7.93 (s, H I).7.91 (m, 1H), 7.82-7.74 (m, 2H), 7.60 (m, 1H), 7.43 (m, 1H), 7.32-7.25 (m, 2H), 6.87(brs, IH), 5.35 (brs, IH), 5.09 (s, 2H), 4.15 (q, 2H), 2.40 (s, 3H), 2.24 (s, 3H), 1.50 (d, 3H), 1.20 (t, 3H). MS (EI) for C29H29N5O3: 496.2 (MH+).
100803) Compound 328 (4-{3-[(lS)-l-{|2-methyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-yI]amino}ethyl]phcnyl}-1 H-pyrazol-l-yl)accHc acid Ή NMR (400 MHz, d6-D SO):58.18 (br s, IH), 8.14 (s, IH), 7.95-7.88 (m, 2H), 7.81-7.73 (m, 2H), 7.66 (m, IH), 7.52-7.44 (m, 1 H), 7.36 (t, IH), 7.28 (m, IH), 7.00-6.93 (m, IH), 5.22 (br s, IH), 4.99 (s, 2H), 2.60 (s, 3H), 2.27 (s: 3H), 1.58 (d, 3H). MS (EI) for C27H25NJO3: 468.2 (MH+).
100804) Compound 3296-(l,3-bcnzothiazol-6-yl)-2-methyl-N-[(lS)-l-(3-pyrimidin-5- ylphenyI)ethyI]pyrimidin-4-amine Ή NMR (400 MHz, d6-DMSO):89.47 (s, 1 H), 9.20 (s, 1 H), 9.16 (s, 2H), 8.80 (s, 1 H), 8.14 (br s, 2H), 7.92 (br s, 1 H), 7.67 (dd, 1 H), 7.56-7.50 (m, 2H), 6.92 (s, IH), 5.41 (br s, IH), 2.41 (s, 3H), 1.88 (s, 3H, acetate peak), 1.55 (d, 3H). MS (EI) for C24H20 6S: 425.1( H+).
100805) Compound 3325-|3-(l-{[6-(l,3-bcnzothiazoI-6-yl)-2-methylpyrimidin-4- yI|amino}ethyI)phenyl]pyrimidin-2-amine Ή NMR (400 MHz, d6-DMSO):59.46 (s, IH), 8.79 (s, IH), 8.50 (s, 2H), 8.13 (brs, 2H), 7.91 (brs,lH), 7.47 (m, IH), 7.40-7.32 (m, 2H), 6.91 (brs, IH), 6.80 (s, 2H), 5.40 (brs, IH), 2.41 (s, 3H), 1.52 (d, 3H). MS (EI) for
C24H21N7S: 440.1 (ΜΙ-Γ).
100806] Compound 334 Ethyl (4-{3-[(lS)-l-{|6-(l,3-benzothiazol-6-yl)-2- methylpyrimidin-4-yl]amino}cthyl|phcnyl}-lH-pyrazol-l-yI)acctatc Ή NMR (400 MHz, d6-DMSO):59.47 (s, IH), 8.80 (s, lH),8.16(s, IH), 8.15-8.06 (m, 2H), 7.93 (s, IH), 7.89- 7.84 (m, IH), 7.43 (m IH), 7.32 (t, IH), 7.28 (m, IH), 6.90 (br s, IH), 5.36 (br s, IH), 5.09 (s, 2H), 4.16 (q, 2H), 2.41 (s, 3H), 1.51 (d, 3H), 1.21 (t, 3H). MS (EI) for C27H26N602S: 499.1 (ΜΙ- ).
(00807) Compound 339 N-{l-[3-(6-aminopyridin-3-yl)phenyl]cthyl}-6-(l,3- bcnzothiazoI-6-yl)-2-methylpyrimidin-4-aminc Ή NMR (400 MHz, d6-DMSO):59.47 (s, 1 H), 8.80 (s, 1 H), 8.24 (br d, 1 H), 8.16-8.07 (m, 2H), 7.90 (br s, 1 H), 7.69 (dd, 1 H), 7.42- 7.31 (m,3H), 6.90 (s, 1H),6.52 (d, 1H), 6.07 (s, 2H), 5.38 (br s, 1 H), 2.41 (s, 3H), 1.51 (d, 3H). MS (EI) for C25I½N6S: 439.1 (MH+).
[00808] Compound 3466-(l,3-benzothiazol-6-yl)-2-methyI-N-{l-[3-(2-methyl-l,3- thiazoI-4-yl)phenyl]cthyI}pyrimidin-4-aminc Ή NMR (400 MHz, d6-DMSO):69.47 (s, 1H), 8.78 (s, 1H), 8.13-8.05 (m, 3H), 7.91 (s, 1H), 7.77 (m, 1H), 7.39 (m, 2H), 6.90 (brs, 1H), 5.39 (br s, 1H), 2.72 (s, 3H), 2.42 (s, 3H), 1.52 (d, 3H). MS (EI) for C24H21N5S2: 444.0 (MH+).
[00809] Compound 3492-mcthyl-6-(3-methyl-l-bcnzofuran-5-yl)-N-{(lR)-l-[3-(l- methyI-lH-pyrazoI-4-yl)phenyl)cthyl}pynmidin-4-aminc Ή NMR (400 MHz, d(l- DMSO):58.16(s, 1H), 8.11 (s, 1H), 7.93 (dd, 1 H), 7.85 (s, 1H), 7.81 (s, 1H), 7.75 (brs, 1H), 7.59 (m, 1 H), 7.39 (dd. lH)f 7.31 (t, 1H), 7.25 (m, 1H): 6.85 (brs, 1H), 5.33 (br s, 1H),3.86 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H), 1.50 (ds 3H). MS (EI) for C26H25N5O: 424.2 (MH+).
[00810] Compound 3632-nicthyl-6-(4-mcthyI-3,4-dihydro-2H-l,4-benzoxazin-6-yl)-N- {l-[3-(l-mcthyl-lH-pyrazol-4-yl)phenyl]cthyl}pyrimidin-4-amine MS (EI) for C26H2SN60: 441.2 (Μ1-Γ).
[00811] Compound 368 {4-[3-(l-{[6-(l,3-bcnzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}cthyl)phenyl]-lH-pyrazoI-l-yl}acctic acid MS (EI) for C25H22N6O2S: 471.2 (MH÷).
100812] Compound 3696-(3-cthyl-l-bcnzofuran-5-yI)-2-nicthyl-N-{l-[3-(l-methyl-lH- pyrazol-4-yl)phcnyI]cthyl}pyrimidin-4-aniinc MS (EI) for C27H27N50: 38.1 (MH*).
[00813] Compound 3796-(l,3-benzothiazol-6-yl)-2-methyI-N-(l-{3-[6- (mcthyloxy)pyridin-3-yl]phcnyl}ethyl)pyrimidin-4-aminc MS (EI) for C26H23N5OS: 454.1 (ΜΙ-Γ).
[00814] Compound 3876-(l,3-bcnzothiazol-6-yl)-2-methyl-N-{(lR)-l-[3-(l-mcthyl-lH- pyrazol-4-yI)phenyl]ethyl}pyrimidin-4-amine MS (EI) for C24H22N6S: 427.1 (MH+).
[00815] Compound 400 N-{(lS)-l-[3-(l-cthyl-lH-pyrazol-4-yl)phenyl|ethyl}-2-mcthyl- 6-(3-mcthyl-l-benzofuran-5-yl)pyrimidin-4-aminc Ή NMR (400 MHz, d6-DMSO): 8.17 (s, 2H), 7.94 (dd, 1H), 7.86 (s, 1H), 7.82 (s, 1H), 7.76 (m, 1H), 7.68 (m, 1 H), 7.60 (m, l H), 7.42 (d,lH), 7.31 (t, 1H), 7.26 (m, 1H), 6.86 (m, 1 H), 5.33 (brs, lH),4.14(q, 2H),2.41 (s, 3H), 2.24 (s, 3H), 1.49 (d, 3H), 1.40 (t, 3H); MS (EI) for C27H27N5O: 438.2 (MH+).
[00816] Compound 4032-mcthyl-6-(3-mcHiyl-l-bcnzofuran-5-yl)-N-{(lS)-l-[3-(l- methyl-l H-pyrazol-5-yl)phcnyI]ethyl}pyrimidin-4-amine Ή NMR (400 MHz, d6-DMSO): 8.17 (s, lH), 7.90 (s, 1H), 7.83 (m, 1H), 7.72 (m, 1H), 7.61 (m, 1H), 7.48 (m, 3H), 7.43 (m, I H), 6.95 (s, 1 H), 6.40 (s, I H), 5.47 (br s, 1 H), 5.24 (br s, 1 H), 3.84 (s, 3H), 2.49 (s, 3H), 2.26 (s, 3H), 1.55 (d, 3H); MS (EI) for C26H25N5O: 424.2 (MH*).
100817] Compound 4102-mcthyl-6-(3-methyl-l-bcnzofuran-5-yl)-N-{(lS)-l-[3-(lH- pyrazoI-4-yl)phenyljcthyl}pyrimidin-4-aminc Ή NMR (400 MHz, dfi-DMSO): 8.26 (s, IH), 8.17 (m, 2H), 7.92 (m, 2H), 7.82 (m, IH), 7.72 (m, IH), 7.60 (m, IH), 7.45 (d, IH), 7.31 (t, IH), 7.24 (m, IH), 7.09 (m, IH), 6.86 (m, IH), 5.34 (br s, IH), 2.41 (s, 3H), 2.24 (s, 3H), 1.52 (d, 3H); MS (EI) for C25H23N5O: 410.2 (MH+).
[00818] Compound 4122-nicthyl-6-(3-mcthyl-l-benzofuran-5-yI)-N-{(lS)-l-[3-(l- niethyl-lH-pyrrol-2-yl)phcnyl]cthyl}pyi-imidin-4-amine Ή NMR (400 MHz, d6-DMSO): 8.19 (s, IH), 7.93 (d, IH), 7.82 (m, 2H), 7.59 (d, IH), 7.50 (m, IH), 7.36 (m, 2H), 7.28 (m, lH),6.83(m,2H), 6.l4(m, IH), 6.05 (m, IH), 5.35 (br s, IH), 3.61 (s, 3H), 2.40 (s, 3H), 2.25 (s, 3H), 1.52 (d, 3H); MS (EI) for C27H26N4O: 423.2 (MH+).
[00819] Compound 4156-(l,3-bcnzothiazoI-6-yI)-2-mcthyI-N-[l-(3-pyridin-3- ylphenyl)ethyl]pyrimidin-4-amine Ή NMR (400 MHz, d6-DMSO): 9.47 (s, IH), 8.91 (d, IH), 8.80 (s, IH), 8.58 (dd, IH), 8.15 (m, 2H), 8.08 (m, 2H), 7.60 (m, 2H), 7.48 (m, 3H), 6.93 (s, IH), 5.44 (br s, IH), 2.43 (s.3H), 1.54 (d, 3H): MS (EI) for C25H21N5S: 424.2 (MH+). 100820] Compound 4166-(l,3-bcnzothiazol-6-yl)-2-mcthyI-N-{l-[3-(l-methyl-lH- pyrazol-4-yl)phenyl|cthyl}pyrimidin-4-amine Ή NMR (400 MHz, d6-DMSO): 9.47 (s, IH), 8.79 (s, IH), 8.12 (m, 2H), 7.85 (m, 2H), 7.81 (s, IH), 7.56 (s, IH), 7.40 (d, IH), 7.31 (t, IH), 7.26 (m, IH), 6.90 (s, IH), 5.34 (br s, IH), 3.86 (s, 3H), 2.42 (s, 3H), 1.52 (d, 3H); MS (EI) for C24H22 6S: 427.2 (MH+).
100821] Compound 4196-(l,3-benzothiazol-6-yl)-2-methyI-N-{(lS)-l-[3-(l-methyl-lH- pyrazol-5-yI)phenyI|cthyI}pyrimidin-4-aminc Ή NMR (400 MHz, d6-DMSO): 9.47 (s, IH), 8.80 (s, IH), 8.15 (m, 2H), 7.94 (m, IH), 7.55 (m, 2H), 7.46 (m, 2H), 7.39 (m, IH), 6.90 (s, IH), 6.38 (s, IH), 5.43 (br s, IH), 3.82 (s, 3H), 2.41 (s, 3H), 1.52 (d, 3H); MS (EI) for C24H22N6S: 427.2 (ΜΙ-Γ).
[00822] Compound 4216-(l,3-bcnzothiazoI-6-yl)-N-{(lS)-l-|3-(l-cthyl-lH-pyrazol-4- yI)phcnyl]cthyl}-2-mcthylpyrimidin-4-amine Ή NMR (400 MHz, d6-DMSO): 9.47 (s, IH), 8.79 (s, IH), 8.17 (m, IH), 8.12 (m, 2H), 7.86 (m, 2H), 7.67 (m, IH), 7.41 (d, I H), 7.31 (t, IH), 7.24 (m, IH), 6.90 (s, IH), 5.35 (br s, IH), 4.16 (q, 2H), 2.42 (s, 3H), 1.50 (d, 3H), 1.40 (t, 3H); MS (EI) for C25H24N6S: 441.2 (MH*).
[00823] Compound 4232-methyl-6-(3-mcthyl-l-bcnzofuran-5-yl)-N-{(lS)-l-[3-(lH- pyrazol-5-yI)phcnyl|cthyI}pyrimidin-4-aminc Ί-Ι NMR (400 MHz, d6-DMSO): 8.16 (s, IH), 7.91 (d, 2H), 7.81 (m, 3H), 7.62 (m, 2H), 7.36 (m, 2H), 6.86 (m, IH), 6.69 (s, IH), 5.37 (br s, 1H), 4.97 (m, 1H), 2.40 (m, 3H), 2.23 (m, 3H), 1.50 (d, 3H); MS (El) for C25H23N5O: 410.2 (MH+).
100824] Compound 4276-(l,3-benzot iazol-6-yI)-2-mcthyl-N-{(lS)-l-[3-(lH-pyrazoI-4- yi)phenyl]cthyl}pyrimidin-4-aminc Ή NMR(400 MHz, d6-DMSO): 9.47 (s, 1H), 8.79 (s, 1 H).8.10 (m, 4H), 7.87 (m, 1 H), 7.70 (m.1 H), 7.45 (d, 1 H), 7.31 (t, 1 H), 7.25 (m, 1 H), 6.91 (s, IH), 5.37 (brs, lH),4.96(m, IH), 2.42 (s, 3H), 1.51 (d, 3H); MS (EI) for C23H2oN6S: 413.2 (MH+).
100825] Compound 4336-(l,3-benzothiazol-6-yl)-2-mcthyl-N-{(]S)-l-[3-(l-nicthyl-lH- pyri-ol-2-yl)phcnyl]ethyl}pyrimidin-4-aminc Ή NMR (400 MHZ, d6-DMSO): 9.48 (s, IH), 8.80 (s, IH), 8.15 (m, 2H), 7.93 (m, IH), 7.50 (m, IH), 7.37 (m, 2H), 7.29 (s, IH), 6.90 (s, lH)f 6.83 (s, IH), 6.14 (m, IH), 6.05 (m, IH), 5.35 (brs, IH), 3.61 (s, 3H), 2.42 (s, 3H), 1.52 (d, 3H); MS (EI) for C25H23N5S: 426.2 (MH+).
[00826] Compound 436 N-|(lS)-l-biphcnyI-3-ylethyl]-2-mcthyI-6-(3-methyI-l- benzofuran-5-yl)pyrimidin-4-aminc MS (EI) for C2SH25 3O: 420.2 (MH+).
[00827] Compound 4406-(l,3-benzothiazol-6-yl)-N-[(lS)-l-biphenyl-3-ylethyl]-2- mcthyIpyrimidin-4-aminc MS (EI) for QaH^S: 423.2 (ΜΙΓ).
100828] Compound 4516-(l,3-bcnzothiazol-6-yl)-2-mcthyl-N-{l-[3-(lH-pyrrol-2- yl)phcnyI]ethyI}pyrimidin-4-amine MS (EI) for C24H21N3S: 412.1 (MH+).
[00829] Compound 4596-(l,3-bcnzothiazol-6-yI)-N-[l-(3'-nuorobiphenyl-3-yl)ethyl]-2- nicthylpynmidin-4-aminc MS (EI) for C26H21FN4S: 441.1 (ΜΙ- ).
[00830] Compound 4732-mcthyl-6-(3-mcthyl-I-bcnzofuran-5-yl)- -{(lS)-l-[3-(l- mcthyI-lH-pyrazoI-4-yl)phcnyI]ethyl}pyrimidin-4-aniine Ή NMR (400 Hz, d6-DMSO):
8.17 (s, IH), 8.11 (s, 1H),7.93 (dd, I H), 7.85 (s, 1H),7.82 (s, IH), 7.76 (m, 1H),7.67 (m,
1 H), 7.60 (m, 1 H), 7.40 (d, 1 H), 7.30 (t, 1 H), 7.25 (m, 1 H), 6.86 (m, IH), 5.34 (br s, 1 H),
3.86 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 1.49 (d, 3H); MS (EI) for C26H25N5O: 424.2 (MH+).
[00831] Compound 4746-(l,3-bcnzothiazol-6-yl)-2-mcthyl-N-{(lS)-l-[3-(l-methyl-lH- pyrazoI-4-yI)phenyl]ethyI}pyrimidin-4-amine Ή NMR (400 MHz, dg-DMSO): 9.47 (s,
IH), 8.79 (s, IH), 8.12 (m, 2H), 7.85 (m, 2H), 7.81 (s, IH), 7.57 (s, IH), 7.42 (d, IH), 7.31 (t,
I H), 7.25 (m, IH), 6.90 (s, IH), 5.34 (brs, 1 H), 3.87 (s,3H),2.42 (s, 3H), 1.50 (d,3H); MS
(EI) for C24H22N6S: 427.2 (MH+).
[00832] Compound 5026-(l,3-benzothiazol-6-yI)-2-mcthyl-N-{(lS)-l-[3-(lH-pyrazol-5- yl)phenyl]ethyl}pyrimidin-4-aminc: Ή NMR (400 MHz, d6-DMSO): 12.43 (s, IH), 9.44 (s, IH), 8.72 (br s, IH), 8.12 (m, 2H), 7.85 (br s, 2H), 7.61 (br s, IH), 7.45 (m, 2H), 6.92 (br s, I H), 6.65 (d, I H), 5.35 (m, 1 H), 2.38 (s, 3H), 1.45 (d, 3H); MS (EI) for C23H20N6S: 413.1
[00833] Compound 518 N-| l -(3-furan-3-ylphcnyl)cthyl]-2-methyl-6-(3-mcthyl-l- benzofuran-5-yl)pyrimidin-4-amine Ή NMR (400 MHz, dj-MeOH): 8.05 (br s, I H), 7.93 (br s, I H), 7.72 (br d, 3H), 7.66 (s, 1 H), 7.58 (l, I H), 7.48 (br d, 1 H), 7.32-7.40 (m, 2H), 6.84(d, 2H), 5.79 (m, I H), 2.62 (s,.3H), 2.37 (s, 3H), 1.65 (d, 3H); MS (EI) for C26H23 3O2: 410.1 (ΜΙ- ).
[00834] Compound 520 2-methyl-6-(3-mcthyI-l-benzofuran-5-yl)-N-{l-[3-(3- thienyl)phenyl]cthyl}pyrimidin-4-aminc: MS (El) for C-26H23N3OS: 426.1 (MH+)
[00835] Compound 525 6-(l ,3-bcnzothiazol-6-yl)-N-{l-[3-(3,5-dimcthylisoxazoI-4- yl)phenyl]cthyl}-2-mcthylpyrimidin-4-aminc: MS (EI) for C25H23N5OS: 442.1 (MH+).
[00836] Compound 528 6-(l,3-bcnzothiazoI-6-yl)-N-| l-(3-furan-3-ylphenyl)ethyl]-2- methylpyrimidin-4-amine: MS (EI) for C2.1H20N4OS: 413.1 (MH+).
[00837] Compound 530 6-(l ,3-bcnzothiazol-6-yl)-2-methyl-N-{l-[3-(3- thicnyl)phcnyl]ethyl}pyrimidin-4-amine: MS (El) for C2 H20N4S2: 429.0 (MH+).
[00838] Compound 549 5-|3-(l-{[6-(l ,3-bcnzotliiazol-6-yl)-2-mcthylpyrimidin-4- yl]amino}ethyl)phenyI]pyridinc-3-carboxamidc MS (EI) for C26H22Nf,OS: 467.1 (ΜΙ- ).
[00839] Compound 551 6-(l ,3-bcnzothiazol-6-yl)-2-mcthyl-N-(l-{3-[5- (trifIuoromethyl)pyridin-3-yIJphcnyI}cthyI)pyrimidin-4-amine MS (ΕΓ) for C26H20N5F3S: 492.1 (ΜΗ ').
[00840] Compound 572 5-{3-[(l S)-l-{[2-mcthyI-6-(l-methyI-lH-indol-6-yl)pyrimidin-4- yIlamino}ethyl]phcnyl}pyrimidin-2-aminc I H NMR (400 MHz, dmso) δ 8.61 (d, 2H), 8.21 (d, 1 H), 8.06 (s, 1 H), 7.93 - 7.54 (m, 4H), 7.51 - 7.33 (m, 4H), 6.92 - 6.75 (m, 3H), 6.45 (d, I H), 3.89 - 3.78 (m, 3H), 2.44 (d, 3H), 1 .60 - 1 .44 (m, 3H); MS (EI) for C26H25N7: 436.2 (MH+).
|008411 Compound 596 Ethyl 5-[3-(l -{[6-(l ,3-bcnzothiazol-6-yl)-2-mcthylpyrimidin- 4yl]amino}cthyl)phenyI|pyridinc^3-carboxyIate MS (EI) for C28H25N5O2S: 496.1 (MH+). 100842] Compound 599 5-{3-[(l S)-l -{[6-(l ,3-bcnzothiazoI-6-yl)-2-mcthylpyrimjdin- 4yl]amino}ethyI]phenyl}pyrimidin-2-amine Ή NMR (400 MHz, dmso-d6): δ 9.47 (s, I H), 9.14 (s, 2H), 8.79 (s, I H), 8.14 (s, 2H), 7.92 (s, 2H), 7.69 (d, I H), 7.57 - 7.44 (m, I H), 6.91 (s, I H), 5.50 - 5.34 (m, 1 H), 2.41 (s, 3H), 1 .54 (d, 3H). MS (EI) for C24H21N7S: 440.1 (MH+). 100843] Compound 600 6-(l ,3-bcnzothiazol-6-yI)-N-{(lS)-l-[3-(5-fluoropyridin-3- yI)phcnyI]ethyI}-2-mcthylpyrimidin-4-aminc Ή NMR (400 MHz, dmso-d6): δ 9.54 - 9.42 (m, I H), 8.82 (dd, 2H), 8.60 (d, 1 H), 8.20 - 8.03 (m, 3H), 7.93 (s, 2H), 7.66 (dd, I H), 7.57 - 7.41 (m, 1 H), 6.93 (s, 1 H), 5.43 (s, 1 H), 2.42 (s, 3H), 1 .55 (d, 3H). MS (EI) for C25H20FN5S: 442.1 (Μ1-Γ).
[00844] Compound 601 6-(l ,3-ben othiazol-6-yI)-2-methyl- -{(l S)-l-[3-(6- methylpyridin-3yl)phcnyI)cthyl}pyriniidin-4-amine MS (El) for C26H30N5S: 438.1 (MH+).
[00845] Compound 603 6-(l,3-benzothiazol-6-yl)-2-mcthyl-N-{(lS)-l-[3-(5- mct ylpyridin-3-yl)phenyl]ethyl}pyrimidin-4-amine Ή NMR (400 MHz, dmso-de): δ 9.49 (s, 1 H), 8.78 (s, IH), 8.71 (s, 1 H), 8.43 (s, 1 H), 8.16 (s, 2H), 7.86 (m, 2H), 7.59 (d, 1H), 7.51 - 7.43 (m, 2H), 6.93 (s, 1 H), 5.45 (s, 1 H), 2.45 (s, 3H), 2.38 (s, 3H), 1 .55 (d, 3H). MS (EI) for C26H23N5S : 438.1 ( H+).
[00846] Compound 604 6-(l,3-bcnzothiazoI-6-yl)-N-{(lS)-l-(3-(6-fIuoro-5- mcthylpyridin-3-yI)phenyl]cthyl}-2-mcthylpyrimidin-4-aminc MS (EI) for C26H22FN5S: 456.1 (MH÷).
[00847] Compound 605 6-(l ,3-bcnzothiazol-6-yl)-N-{(l S)-l-[3-(6-nuoropyridin-3- yl)phenyl]ethyl}-2-mcthylpyrimidin-4-aminc MS (EI) for C25H20FN5S: 442.0 (MH+). 100848] Compound 606 N-{(lS)-l-|3-(5-nuoropyridin-3-yl)phenyI]cthyl}-2-nicthyl-6-(3- methyI-l-benzofuran-5-yl)pyrimidin-4-amine Ή NMR (400 MHz, dmso-ds): δ 8.83 (t, I H), 8.59 (d, 1 H), 8.18 (d, I H), 8.12 - 8.06 (m, 1 H), 7.94 (d, I H), 7.82 (s, 2H), 7.65 (dt, I H), 7.49 (m, 2H), 6.87 (s, I H), 5.41 (s, I H), 2.41 (s, 3H), 2.24 (s, 3H), 1.54 (d, 3H). MS (EI) for C27H23FN4O: 439.1 (MH+).
[00849] Compound 608 N-{(lS)-l-[3-(2-chloropyrimidin-5-yl)phcnyl]ethyl}-2-methyl-6- (3-methyl-l-benzofuran-5-yl)pyrimidin-4-amine Ή NMR (400 MHz, dmso-d^): δ 9.16— 9.07 (m, 2H), 8.16 (d, 1 H), 7.92 (d, 2H), 7.80 (d, 1 H), 7.72 - 7.67 (m, 1 H), 7.63 - 7.45 (m, 3H), 6.85 (s, I H), 5.40 (s, I H), 2.38 (s, 3H), 2.22 (s, 3H), 1 .51 (d, 3H). MS (EI) for C26H22CI 5O: 456.1 (MH+).
[00850] Compound 609 6-(l ,3-benzothiazol-6-yI)-N-{(l S)-l-|3-(2-chIoropyrimidin-5- yI)phenyl]cthyI}-2-mcthylpyrimidin-4-aminc MS (EI) for C2,|H i9Cl 6S: 459.0 (MH÷).
[00851 ] Compound 610 N-{(lS)-l -[3-(6-nuoropyi idin-3-yI)phenyl]cthyl}-2-meihyl-6-(3- methyl-l-benzofuran-5-yl)pyrimidin-4-aminc Ή NMR (400 MHz, dmso-df,): δ 8.57 (d. IH), 8.35 - 8.25 (m, 1 H), 8.1 8 (d, 1 H), 7.92 (t, 1 H), 7.82 (d, 2H), 7.65 - 7.54 (m, 2H), 7.54 - 7.43 (m, 2H), 7.37 - 7.24 (m, I H), 6.80 (d, I H), 5.41 (s, I H), 2.51 (dt, 3H), 2.24 (s, 3H), 1.54 (d, 3H). MS (EI) for C27H23FN4O: 439.1 (MH+).
[00852] Compound 620 N-{(lS)-l-|3-(5-aminopyridin-3-yl)phcnyl|ethyl}-2-mcthyl-6-(3- methyI-l-benzofuran-5-yl)pyriniidin-4-aminc Ή NMR (400 MHz, dmso-d6): δ 8.17 (s, I H), 8.03 (d, I H), 7.92 (dt, 2H), 7.82 (s, I H), 7.71 (s, I H), 7.59 (d, I H), 7.42 (d, 2H), 7.14 (t, !H), 6.87 (s, IH), 5.43 (s, 2H), 5.32 -5.12 (m, 1H), 2.41 (s, 3Ή), 2.24 (s, 3H), 1.52 (d,3H). MS (El) for C27H25N5O: 436.2 (MH+).
100853] Compound 623 N-{(lS)-l-]3-(5-chloropyridin-3-yl)phcnyl]cthyI}-2-methyl-6-(3- methyl-l-bcnzofuran-5-yl)pyrimidin-4-aminc Ή NMR (400 MHz, dmso-d6): δ 8.91 (d, 1 H), 8.64 (t, 1 H), 8.28 (dd, 1 H), 8.17 (t, 1 H), 7.88 (s, 3H), 7.69 (d, 2H), 7.50 (dt, IH), 6.93 (d, IH), 5.49 (s, IH), 2.51 (s, 3H), 2.25 (s, 3H), 1.57 (d, 3H). MS (EI) for C27H23CIN4O: 455.1 (MH+).
[00854] Compound 6246-(l,3-bcnzothia/.o!-6-yl)-N-{(lS)-l-[3-(5-chloropyridin-3- yl)phcnyl]cthyl}-2-mcthylpyrimidin-4-aminc MS (El) for C25H20CIN5S: 458.1 (MH+). 100855] Compound 637 (5-{3-|(lS)-l-{|6-(l,3-benzothiazol-6-yI)-2-mcthyIpyrimidin-4- yl]amino}ethyl|phenyl}pyridin-2-yI)methanol Ή NMR (400 MHz, dmso-d6): δ 9.47 (s, IH), 8.79 (d, 2H), 8.25 - 8.07 (m, 3H), 7.94 (s, 1 H), 7.56 (d, 2H), 7.54 - 7.39 (m, 2H), 6.92 (s, 1H): 5.48 (t, IH), 5.43 - 5.24 (m, IH), 4.61 (d, 2H), 2.37 (d, 3H), 1.54 (d, 3H). MS (EI) forC26H2;,N5OS: 454.1 (ΜΗ').
100856] Compound 6382-mcthyl-6-(3-mcthyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(4- mcthyl-3,4-dihydro-2H-pyrido]3,2-b]]l,4]oxazin-7-yl)phenyl]cthyl}pyrimidin-4-amine
Ή NMR (400 MHz, dmso-d6): δ 8.19 (d, IH), 8.03 (d, 1 H), 7.93 (dd, 1 H), 7.89 - 7.73 (m, 2H), 7.59 (d, IH), 7.50 - 7.41 (m, IH), 7.33 (dd, 2H), 7.30 - 7.23 (m, IH), 6.79 (d, IH), 5.39 (s, IH), 4.24 (dd, 2H), 3.54 - 3.40 (m, 2H), 3.06 (s, 3H), 2.41 (s, 3H), 2.23 (d, 3H), 1.51 (d, 3H). MS (EI) for C30H29N5O2: 492.0 (MH*).
[00857] Compound 639 (5-{3-[(lS)-l-{[6-(l,3-bcnzothiazol-6-yl)-2-mcthylpyrimidin-4- yl]amino}ethyl|phenyl}pyridin-3-yl)merhanoI Ή NMR (400 MHz, dmso-d6): δ 9.45 (d, 1H): 8.88-8.71 (m, 2H), 8.53 (d, IH), 8.17 (d, 2H), 8.00 (l, 1H): 7.89 (d, IH), 7.64 - 7.55 (m, I H), 7.52-7.39 (m, 2H), 6.91 (s, IH), 5.39 (br s, 1H),4.62 (s, 2H), 2.42 (s, 3H), 1.91 (s, 2H: OAc), 1.55 (d, 3H). MS (El) for C26H23 5OS: 454.1 (MH+).
[00858] Compound 640 N-{(lS)-l-|3-(5-amino-6-chloropyridin-3-yI)phenyl]ethyl}-2- mcthyl-6-(3-mcthyl-l-bcnzofuran-5-yl)pyrimidiii-4-aminc Ή NMR (400 MHz, dmso-d6): δ 8.17 (s, 1 H), 7.98 - 7.75 (m, 3H), 7.74 - 7.54 (m, 1 H), 7.44 (d, 2H), 7.37 (d, 1 H), 6.86 (s, 1 H), 5.69 (s, 2H), 5.38 (s, IH), 2.58 - 2.49 (m, 3H), 2.23 (s, 3H), 1.52 (d, 3H). MS (EI) for C27H24CINSO: 470.1 (MH+).
100859] Compound 6426-(3,4-difluorophcnyl)-2-mcthyI-N-{l-[3-(l-mcthyI-lH-pyrazol- 4-yl)phcnyl]ethyl}pyrimidin-4-amineMS (EI) for C23H21F2N5: 464.1 (M-H).
|00860| Compound 643 (5-{3-[(lS)-l-{[2-methyl-6-(3-mcthyl-t-benzofuran-5- yl)pyrimidin-4-yl]amino}ethyl]phcnyl}pyridin-3-yI)mcthanol Ή NMR (400 MHz, dmso- d6): ) δ 8.78 (d, 1 H), 8.52 (s, 1 H), 8.1 8 (s, 1 H), 7.99 (s, 1 H), 7.93 (d, 1 H), 7.82 (m, 3H), 7.59 (s, 2H), 7.47 (d, I H), 6.96 - 6.70 (m, I H), 5.41 (t: I H), 4.61 (d, 2H), 2.41 (s, 3H), 2.23 (s, 3H), 1 .53 (d, 3H). MS (EI) for
Figure imgf000292_0001
451 .2 (MH+).
[00861 ] Compound 646 6-(4-chloro-3,5-dinuorophcnyI)-2-met yl-N-{l -[3-(l -methyl- lH-pyrazol-4-yl)pheny!]cthyI}pyrimidin-4-amine MS (EI) for C23H20CIF2N5: 440.1 (ΜΙ- ).
[008621 Compound 647 2-mcthyl-N-{l-[3-(1.-mcthyU H-pyrazol-4-yl)phcnyl|cthyl}-6- (3,4,5-trinuorophenyl)pyrimidin-4-aminc MS (EI) for C23H20F3N5: 424.1 (Μ1- ).
[00863) Compound 649 5-{3-[(l S)-l-{[6-(3,4-dinuorophenyl)-2-methyIpyrimidin-4- yl]amino}cthy]]p enyI}pyrimidin-2-aminc MS (EI) for C23H2pF2Nfi: 419.2 (MH+).
[008641 Compound 650 5-{3-[(lS)-l-{[6-(4-chloro-3,5-difluorophenyl)-2- mct ylpyrimidin-4-yI|amino}ethyljphenyl}pyrimidin-2-amine Ή NMR (400 MHz, dmso- d6): δ 8.57 (s, 2H), 8.12 - 7.62 (m, 3H), 7.47 (d, I H), 7.38 (s, 2H), 6.88 (s, I H), 6.81 (s, 2H), 5.31 (s5 I H), 2.40 (s; 3H), 1.49 (t, 3H). MS (EI) for C23H 19CIF2N6: 453.9 (MH÷).
[00865) Compound 651 l-(5-{3-[(l S)-l-{[2-methyI-6-(3-mcthyl-l-ben/.ofuran-5- yl)pyrimidin-4-yl]amino}ethyI|phcnyl}pyridin-3-yl)ethanone Ή NMR (400 MHz, dmso- d6): 5 9.13 (dd, 2H), 8.50 (t, 1 H), 8.1 8 (s, 1 H), 8.05 - 7.75 (m, 3H), 7.69 (d, 1 H), 7.65 - 7.44 (m, 3H), 6.87 (s, 1 H), 5.5 1 - 5.28 (m, I H), 2.71 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H), 1.54 (d, 3H). MS (EI) for C29H26N O2: 463.2 (MI ).
[00866] Compound 655 ethyl 5-{3-[(lS)-l-{[2-mcthyl-6-(3-methyl-l-bcnzofuran-5- yl)pyrimidin-4-yI|amino}ethyl|phcnyl}pyridinc-3-carboxylate Ή NMR (400 MHz, dmso- d6): δ 9.16 (d, I H), 9.09 (d, I H), 8.49 (t, I H), 8.17 (s, 2H), 8.04 - 7.74 (m, 2H), 7.75 - 7.58 (m, 2H), 7.61 - 7.39 (m, 2H), 6.89 (s, I H), 5.44 (s, I H), 4.50 - 4.22 (m, 2H), 2.44 (s, 3H), 2.24 (s, 3H), 1.54 (t, 3H), 1.42 - 1 .29 (m, 3H). MS (EI) for C30H28N4O3: 493.2 (MH+).
[00867] Compound 658 l-(5-{3-[(l S)-l-{[2-mcthyl-6-(3-niethyl-l -benzofuran-5- yI)pyrimidin-4-yl|amino}ethyl|phcnyl}pyridin-3-yl)cthanoI Ή NMR (400 MHz, dmso- d6): 5 8.75 (t, IH), 8.54 (d, I H), 8.18 (s, I H), 8.00 (d, I H), 7.96 - 7.76 (m, 3.H), 7.59 (d, 2H), 7.46 (dd, 2H), 6.87 (s, 1 H), 5.38 (t, 1 H), 4.96 - 4.81 (m, I H), 2.41 (s, 3H), 2.23 (s, 3H), 1.54 (d, 3H), 1.47 - 1.37 (m, 3H). MS (EI) for 02<;Η2χ 4θ2: 465.2 (MH+).
[00868] Compound 659 2-(5-{3-[(lS)-l-{[2-mcthy!-6-(3-mcthyl-l -benzofuran-5- yl)pyrimidin-4-yl[amino}ethy!| phcnyl}pyridin-3-yl)propan-2-ol Ή NMR (400 MHz, dmso-de): 5 8.72 (d, I H), 8.68 (d, I H), 8.18 (s, I H), 8.07 (t, I H), 7.93 (d, I H), 7.82 (s, 2H), 7.58 (d, 2H), 7.53 - 7.38 (m, 2H), 6.95 - 6.80 (m, 1 H), 5.39 (s, 1 H), 5.30 (s, 1 H), 2.41 (s, 3H), 2.23 (s, 3H), 1 -54 (d, 3I-I), 1 .51 (s, 6H). MS (EI) for C30H30N4O2: 479.2 (MH+). [00869] Compound 663 2-mcthyl-6-(3-methyl-l-bcnzofuran-5-yl)-N-[(lS)-l-(3-pyridin- 3-yIphenyl)ethyIJpyrimidin-4-aminc Ή NMR (400 MHz. d6-DMSO): 8.91 (d, 1 H), 8.58 (dd, 1 H), 8.18 (m, 1 H), 8.07 (m, 1 H), 7.93 (d, 1 H), 7.82 (m, 2H), 7.58 (m, 2H), 7.48 (m, 3H), 6.87 (br s, 1 H), 5.30 (m, 1 H), 5.05 (ms 1 H), 2.41 (s, 3H), 2.24 (s: 3H), 1.53 (d, 3H); MS (EI) for C27H24N4O: 421.2 (MH+).
[00870] Compound 664 6-(l ,3-bcnzothiazol-6-yl)-N-{l -]3-(2-nuoropyridin-3- yl)phenyl]ethyI}-2-mcthylpyrimidin-4-aminc MS (El) for C2SH20FN5S: 442.2 (MH+).
[00871 ] Compound 665 6-(l ,3-benzothiazo!-6-yI)-2-mcthyI-N-{l-[3-(2-methylpyridin-4- yl)phenyl]ethyI}pynmidin-4-aminc MS (El) for C26H23N5S: 438.2 (ΜΙ- ).
[00872] Compound 669 2-mcthyI-6-(3-methyl-l-bcnzofuran-5-yl)-N-{(l S)-l-[3-(6- methylpyridin-3-yI)phcnyl]cthyl}pyrimidin-4-amine Ή NMR (400 MHz, d6-DMSO): 8.76 (d, 11-1), 8.18 (s, 1 H), 7.95 (m, 2H), 7.82 (m, 2H), 7.56 (m, 2H), 7.46 (m, 2H), 7.34 (d, 1 H), 6.87 (br s, 11-1), 5.40 (m, 1 H), 5.05 (m, 1 H), 2.49 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 1 .52 (d, 3H); MS (EI) for C2gH26N40: 435.2 (ΜΙ-Γ).
[00873] Compound 671 2-mcthyI-6-(3-inethyI-l-benzofuran-5-yl)-N-{(lS)-l-[3-(5- methylpyridin-3-yl)phenyl]cthyl}pyrimidin-4-amine Ή NMR (400 MHz, d6-DMSO): 8.68 (s, 1 H), 8.40 (s, 1 H), 8.16 (s, 1 H), 7.90 (m, 2H), 7.79 (m, 2H), 7.55 (m, 2H), 7.45 (m, 2H), 6.84 (br s, 1 H), 5.37 (m, 1 H), 5.05 (m, 1 H), 2.39 (s, 3H), 2.35 (s, 3H), 2.20 (s, 3H), 1 .51 (d, 3H); MS (EI) for C28H26N.iO: 435.2 (ΜΗ ').
[00874] 'Compound 672 N-{(l S)-l-[3-(6-nuoro-5-methylpyridin-3-yl)plicnyl]cthyl}-2- methyl-6-(3-methyl-l -benzofuran-5-yl)pyrimidin-4-aminc Ή NMR (400 MHz. d6- DMSO): 8.35 (s, 1 H), 8.15 (m, 2H), 7.92 (d, 1 H), 7.82 (m, 2H), 7.58 (m, 2H), 7.47 (m, 2H), 6.86 (m, 1 H), 5.39 (m, 1 H), 5.03 (m, 1 H), 2.41 (s, 3H), 2.32 (s, 3H), 2.23 (s, 3H), 1 .54 (d, 3H); MS (EI) for C28H2jFN40: 453.2 (MM 1).
[00875] Compound 673 6-(l ,3-benzothiazoI-6-yl)-N-{(l S)-l-[3-(2-fluoropyridin-4- yl)phenyl]cthyl}-2-methylpyrimidin-4-aminc MS (EI) for C25H2oF 5S: 442.1 (MI-f ).
[00876] Compound 675 N-{( l S)-l -[3-(6-chloropyridin-3-yl)phcnyl]ethyl}-2-methyl-6-(3- mcthyl-l-bcnzofuran-5-yl)pyrimidin-4-aminc Ή NMR (400 MHz, d6-DMSO): 8.79 - 8.71 (m, 1 H), 8.17 (dd, 2H), 7.93 (d, 1 H), 7.82 (s, 2H), 7.65 - 7.56 (m, 3H), 7.55 - 7.42 (m, 2H), 6.86 (s, 1 H), 5.40 (s, 1 H), 5.21 - 4.85 (m, 1 H), 2.41 (s, 3H), 2.23 (s, 3H), 1.53 (d, 3H); MS (EI) for C27H23C1N40: 455.1 (Μ - ).
[00877] Compound 679 6-(l ,3-benzothiazoI-6-yl)-N-{(l S)-l-[3-(6-chIoropyridin-3- yl)phcnyl]ethyl}-2-mcthylpyrimidin-4-amine MS (EI) for C25H20C1N5S: 458.1 (MH+). [00878] Compound 680 6-(l -benzofuran-5-yl)-2-mcthyI-N-{l-[3-(l-methyl-lH-pyrazol- 4-yl)phenyl|ethyl}pyrimidin-4-aminc MS (El) for C-25H23N5O: 410.2 (MH+).
[00879] Compound 690 6-(l ,3-benzothiazoI-6-yI)-N-{(l S)-l-[3-(6-chIoro-5- methylpyridin-3-yl)phcnyI|cthyI}-2-mcthyIpyrimidin-4-aniinc MS (El) for C26H22CI 5S: 472.1 (MH+).
[00880] Compound 691 N-{(l S)-l-|3-(6-chloro-5-methylpyridin-3-yl)phenyl]ethyl}-2- niethyI-6-(3-methyl-l-bcnzofuran-5-yI)pyrimidin-4-amine Ή NMR (400 MHz, de- DMSO): 8.58 (dd, 11-1), 8.17 (m, 2H), 8.14 (dd, I H), 7.93 (d, I H), 7.85 - 7.80 (m, 2H), 7.63 - 7.57 (m, 2H): 7.53 - 7.45 (m, I H), 6.84 (d, I H), 5.39 (s, I H), 5.21 - 4.97 (m, I H), 3.35 (s, 3H), 2.41 (s, 3H), 2.23 (s, 3H), 1 .50 (d, 3H); MS (E ) for C28H25CIN4O: 468.9 (MH+).
[00881 ] Compound 694 6-(4-chloro-3-nuorophcnyI)-2-mcthyl-N-{l-[3-(l-methyl-lH- pyrazol-4-yl)phenyI]ethyl}pyrimidin-4-aminc MS (EI) for C23H21CIFN5: 422.0 (MH+).
[00882] Compound 695 6-(3-fluorophenyl)-2-methyI-N-{(l S)-l -[3-(l-methyl-lH- pyrazoI-4-yl)phenyl]ethyl}pyrimidin-4-aminc MS (EI) for C23H22FN5: 388.0 (MH+).
[00883] Compound 696 5-{3-[(l S)-l-{[6-(4-chlorophenyl)-2-mcthy]pyrimidin-4- yl]amino}ethyl]phcny }pyrimidin-2-aminc Ή NMR (400 MHz, d6-DMSO): 8.57 (s, 2H), 7.98 (d, 2H), 7.87 (s, I H), 7.69 (s, I H), 7.52 (d, 2H), 7.47 (d, I H), 7.38 (t, 2H), 6.81 (s, 3H),
5.37 (s, I H), 5, 10 - 4.88 (m, I H), 2.39 (s, 3H), 1.50 (d, 3H); MS (EI) for C23H2|CI 6: 416.9 (MH+).
100884] Compound 697 5-{3-[(l S)-l-{[6-(4-chloro-3-nuorophcnyl)-2-mcthyIpyriniidin- 4-yl]amino}cthyl]phenyl}pyrimidin-2-aminc Ή NMR (400 MHz, d6-DMSO): 8.58 (s, 2H),
7.93 (s, 2H), 7.82 (s, I H), 7.69 (s, I H), 7.47 (d, I H), 7.39 (t, 2H), 6.85 (s, I H), 6.82 (s, 2H),
5.38 (s, I H), 5.00 (s, I H), 2.39 (s, 3H), 1.51 (d, 3H); MS (El) for C-23H20CIFN6: 434.9 (MH+). |00885| Compound 698 N-{(lS)-l-|3-(5-aminopyndin-3-yl)phenyl]ethyl}-6-(4-chIoro-3- fluorpphenyl)-2-mcthylpyrimidin-4-aminc Ή NMR (400 MHz, d6-DMSO): 8.02 (d, I H),
7.94 (t, 3H), 7.82 (s, I H), 7.74 - 7.62 (m. 2H), 7.43 (s, 311), 7.13 (t, I H), 6.84 (s, I H), 5.43 (s, 2H), 5.12 - 4.94 (m, IH), 2.39 (s, 3H), 1 .51 (d, 3H); MS (EI) for C24H2|C1FN5: 434.2 (ΜΙ-Γ)·
[00886] Compound 703 6-(4-chloro-3-nuorophcnyI)-2-methyl-N-{(lS)-l-[3-(l-methyl- lH-pyrazol-4-yl)phcnyl]cthyl}pyrimidin-4-aniinc Ή NMR (400 MHz, d6-DMSO): 8.10 (s, I H), 7.93 (s, I H), 7.84 (s, 2H), 7.69 (s, I H), 7.64 - 7.57 (m, I H), 7.40 (d, I H), 7.30 (t, I H), 7.24 (s, l H), 6.83 (s, I H), 5.33 (s, I H), 5.04 - 4.75 (m, I H), 3.86 (s, 3H), 2.39 (s, 3H), 1.49 (d, 3H); MS (EI) for C23H21CIFN5: 421 .9 (MH+).
[008871 Compound 704 6-(3-nuorop cnyI)-2-mcthyl-N-{(l R)-l-[3-(l -methyl-l H- pyrazoI-4-yl)phenyl]ethyl}pyrimidin-4-amine MS (El) for C23H22FN5: 388.0 (MH+). [00888] Compound 707 N-{(lS)-l-[3-(4-chloropyridin-3-yI)p enyl]cthyl}-2-mcthyl-6-(3- methyl-l-benzofuran-5-yl)pynmidin-4-amine Ή NMR (400 MHz, d6-DMSO): 8.59 (s, IH), 8.54 (d, IH), 8.18 (d, IH), 7.92 (dd, IH), 7.82 (s, 2H), 7.67 (d, IH), 7.59 (d, 2H), 7.53 (s, IH), 7.48 (t, IH), 7.37 (d, IH), 6.85 (s, IH), 5.50- 5.25 (m, IH), 2.40 (s, 3H), 2.25 (s, 3H), 1.52 (d, 3H); MS (El) lor C27H23CIN4O: 454.9 (MH+).
[00889] Compound 7086-(4-chloro-3-fluorophcnyl)-N-{(lS)-l-[3-(l-ethyl-lH-pyrazoI- 4-yl)phcnylJethyI}-2-mcthylpyrimidin-4-aminc Ή NMR (400 MHz, d6-DMSO): 8.16 (s, IH), 7.94 (s, IH), 7.85 (d, 2H), 7.69 (s, 2H), 7.41 (d, IH), 7.30 (t, IH), 7.21 (d, IH), 6.84 (s, IH), 5.34 (s, lH),5.14-4.79 (m, IH), 4.27 -4.05 (m, 2H), 2.40 (d, 3H), 1.50 (d, 3H), 1.41 (l: 3H); MS (EI) for C-24H23CIFN5: 435.9 (ΜΙ-Γ).
[00890] Compound 7095-{3-[(lS)-l-{|2-methyl-6-(3-mcthyl-l-benzofuran-5- yl)pyrimidin-4-yI]amino}cthyl]phcnyl}pyridinc-3-carboxamide Ή NMR (400 MHz, df,- DMSO):9.04 (d, IH), 9.01 (d, IH), 8.49 (s, IH), 8.28 (s, IH), 8.17 (s, IH), 7.93 (d, IH), 7.90 -7.84 (m, 11-0,7.81 (s, IH), 7.71 (s, IH), 7.67 (d, IH), 7.59 (d, IH), 7.55 - 7.46 (m, 2H), 6.92 - 6.79 (m, 1 H), 5.52 - 5.23 (m, IH), 5.17 - 4.89 (m, 1 H), 2.41 (s, 3H), 2.23 (s, 3H), 1.54 (d, 3H); MS (EI) for C28H2SN5O2: 464.1 (MH÷).
[00891] Compound 735 N-{(lS)-l-I3-(5-aminopyridin-3-yl)phcnyI]cthyI}-6-(l,3- benzothiazol-6-yl)-2-mcthylpyrimidin-4-amine Ή NMR (400 MHz, dmso-d6): δ 9.47 (s, IH), 8.79 (d, IH), 8.13 (d, 2H), 8.03 (d, 1 H), 7.93 (d, IH), 7.68 (s, IH), 7.42 (d, 3H), 7.13 (t, IH), 6.90 (s, IH), 5.43 (s, 2H), 2.42 (s, 3H), 1.53 (d, 3H). MS (EI) for C-25H22N6S: 439.2 (MH+).
[00892] Compound 7365-{3-[(lS)-l-{[2-methyI-6-(3-mcthyl-l-benzoiuran-5- yI)pyrimidin-4-yI|amino}ethylJphcnyI}pyrimidin-2-oI Ή NMR (400 MHz, dmso-de): δ 8.62 (s, 2H), 8.17 (s, IH), 7.93 (d, IH), 7.79 (d, 2H), 7.61 (s, IH), 7.48 (d, IH), 7.38 (d, 2H), 6.85 (s, IH), 5.46-5.22 (m, IH), 2.40 (s, 3H), 2.24 (s, 3H), 1.50 (d, 3H). MS (EI) for
C26H23N5O2: 438.1 (MH+).
[00893] Compound 7136-(l,3-bcnzothiazoI-6-yl)-2-methyl-N-(l-{3-[5- (mcthyloxy)pyridin-3-yl|phcnyl}ethyl)pyrimidin-4-aminc MS (El) for C2 H23N5OS: 454.1 (MH÷)
[00894] Compound 7146-(l,3-bcnzothiazol-6-yl)-N-{l-|3-(2-nuoropyrimidin-5- yI)phenyl]ethyI}-2-methylpyrimidin-4-amine MS (EI) for C24HigFN6S: 443.1 (MH+)
[00895] Compound 7155-[3-(l-{|6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyI)phcnyl]pyrimidine-2-carbonitriIc MS (EI) for C25H19N7S: 450.1 (MH+) 100896] Compound 716 6-(l ,3-bcnzothiazol-6-yI)-N-{l-|3-(6-iluoro-2-mcthylpyridin-3- yl)phenyl]ethyl}-2-methylpyrimidin-4-amine MS (EI) for C26H22F 5S: 456.1 (MH*) 100897] Compound 717 5-[3-(l -{[6-(l,3-bcnzothiazol-6-yI)-2-mcthylpyrimidin-4- yl]amino}ethyl)phenyl]pyridinc-3-carbonitrile MS (EI) for C26H20 6S: 449.1 (MH+) 100898] Compound 718 6-(l ,3-ben/.otUiazol-6-yl)-N-{l-]3-(4-chloropyridin-3- yl)phenyl]ethyl}-2-methylpyrimidin-4-aminc MS (EI) for C25H20CIN5S: 458.1 (MH+) 100899] Compound 719 6-(l ,3-bcnzothiazol-6-yl)-N-{l-[3-(2,6-dimcthylpyridin-3- yl)phenyI]cthyl}-2-methylpyrimidin-4-aminc MS (EI) for C27H25N5S: 452.1 .1 (MH*) 100900] Compound 720 4-[3-(l-{|6-(l ,3-bcnzothiazol-6-yI)-2-methylpyrimidin-4- yl|amino}ethyl)phcnyI] pyriniidin-2-aminc MS (EI) for C2.1H21 N7S : 440.1 .1 (MH+) |00901| Compound 725 6-(3-amino-4-chlorophenyl)-2-mcthyl-N-{l-[3-(l -mcthyl-l H- pyrazoI-4-yl)phcnyl]cthyl}pyrimidin-4-amine MS (EI) for C23H23C1N6: 419.1 (MH+) 100902] Compound 726 6-(4-chloro-3-mcthylphcnyl)-2-mcthyl-N-{l -]3-(l-methyl-lH- pyrazol-4-yI)phenyl]ethyl}pyrimidin-4-amine Ή NMR (400 MHz, d6-DMSO): 8.16 (br s, 2H), 7.82 (br d, 2H), 7.62 (m, 3H), 7.48 (bi s, l H), 7.32 (t, I H), 7.21 (br d, I H), 6.92 (br s, I H), 5.23 (m, I H), 3.92 (s, 3H), 3.61 (s, 3H): 3.42 (s, 3H), 1.60 (d, 3H); MS (EI) for
C24l½ClN5: 4.18.2 (MH+).
[00903] Compound 727 2-fluoro-4-|2-mcthyl-6-({l>[3-(l-mcthyl-lH-pyrazol-4- yl)phcnyl]ethyI}amino)pyrimidin-4-yl]bcnzamidc MS (EI) for C24H23F 60: 431 .1 (MH÷) [00904] Compound 728 6-(l ,3-bcnzothiazoI-5-yl)-2-methyl-N-{l-[3-(l -methyl-l H- pyrazol-4-yl)phcnyl]ethyI}pyrimidin-4-aminc MS (EI) for CwHaNeS: 427.1 (ΜΙ- )
[00905] Compound 731 5-{3-|(l S)-l -{[2-mcthyl-6-(3-methyI-l-bcnzofuran-5- yl)pyrimidin-4-yl]amino}cihyl|phcnyl}pyridinc-3-carbonitrile
100906] Ή NMR (400 MHz, dj-MeOH): 9,15 (br s, I H), 8.47 (ni, I H), 8.42 (d, I H), 8.31 (br s, I H), 7.82 (br s, IH), 7.78 (t, I H), 7.70 (m, 3H), 7.57 (br s, 2H), 6.91 (s, I H), 5.64 (br m, I H), 2.64 (s, 3H), 2.35 (s, 3H), 1.74 (d, 3H); MS (EI) for C28H23 5O: 446.2 (MH+).
100907] Compound 668 2-mcthyl-6-(3-mcthyl-l-bcnzofuran-5-yl)-N-{l -|5-(l-methyl- l H-pyrazol-4-yl)pyridin-3-yl|cthyI}pyrimidin-4-aminc 2-methyl-6-(3-methyl-l - benzofuran-5-yl)-N-{ l -[5-( l -methyl- l H-pyrazol-4-yl)pyridin-3-yl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6a. Ή NMR (400 MHz, d6-DMSO): 8.67 (d, I H), 8.45 (s, I H), 8.22 (s, I H), 8.17 (d, I H), 7.99 (m, 1 H), 7.93 (m, 2H), 7.80 (m, 2H), 7.58 (d, I H), 6.85 (s, I H), 5.29 (m, IH), 3.86 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H), 1.53 (d, 3H); MS (EI) for ε25Η2.|Ν60: 425.2 (MH+). 100908] Compound 6865-|5-(l-{[2-mcthyl-6-(3-methyl-l-bcnzofuran-5-yl)pyrimidin-4- yl]amino}cthyl)pyridin-3-yl]pyrimidin-2-aminc 5-[5-(l-{[2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-yl]amino}ethyl)pyridin-3-yl]pyrimidin-2-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6a. Ή NMR (400 MHz, d6-D SO): 8.73 (s, IH), 8.64 (s, 2H), 8.60 (s, IH), 8.20 (s, 1 H), 8.17 - 8.05 (m, lH),7.92(s, 1H),7.83 (s, 1H),7.61 (d, IH), 6.93 (5,21- ,6.89(3, IH), 6.71 (s, 1 H), 5.46 - 5.26 (m, IH), 2.42 (s,3H),2.25 (s, 3H), 1.56 (d, 3H); MS (El) for C25H23N7O: 438.1 (MI ).
100909] Compound 6935'-(l-{|2-methyl-6-(3-mcthyI-l-bcnzofuran-5-yl)pyrimidin-4- yllaminoJethy -S^'-bipyridin-S-amine 5'-(l-{[2-methyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-yl]amino}ethyl)-3,3'-bipyridin-5-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6a. Ή NMR (400 MHz, d6-DMSO): 8.68 (d, 2H), 8.20 (s, 1 H), 8.06 (d, 2H), 7.98 (d, IH), 7.94 (d, IH), 7.88 (d, IH), 7.82 (d, IH), 7.60 (d, IH), 7.17 (t, IH), 6.88 (s, IH), 5.50 (s, 2H), 5.43 - 5.20 (m, 1 H), 2.41 (s, 3H), 2.25 (d, 311), 1.56 (d, 3H); MS (EI) for C26H24N60: 437.0 (MH+).
[00910] Compound 6995-[5-(l-{[6-(4-chloro-3-fluorophenyl)-2-mcthylpyrimidin-4- yl]amino}ethyl)pyridin-3-yl]pyrimidin-2-aminc 5-[5-(l-{[6-(4-chloro-3-fluorophenyl)-2- methylpyrimidin-4-yl]amino}ethyl)pyridin-3-yl]pyrimidin-2-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6a. Ή NMR (400 MHz. d6-DMSO): 8.72 (d, IH), 8.63 (s, 2H), 8.58 (s, 1 H), 8.08 (s, IH), 7.96 (s, 2H), 7.88 - 7.77 (m, IH), 7.70 (t, IH), 6.93 (s, 2H), 6.86 (s, IH), 5.38 (s, IH), 2.39 (s, 3H), 1.55 (d, 3H); MS (EI) for C22H19CIFN7: 435.9 (ΜΙ-Γ).
[00911] Compound 7006-(4-chloro-3-fluorophenyl)-2-methyl-N-{l-[5-(l-methyl-lH- pyrazol-4-yl)pyridin-3-yl|ethyl}pyrimidin-4-amine 6-(4-chloi -3-nuorophenyl)-2-methyl- N-{l-[5-(l-methyl-lH-pyrazol-4-yl)pyridin-3-yl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6a. Ή NMR (400 MHz, dft-DMSO): 8.68 (d, IH), 8.45 (s, IH), 8.23 (s, IH), 7.95 (d, 4H),7.87-7.77 (m, IH), 7.70 (t, IH), 6.86 (s, IH), 5.39 - 5.21 (m, IH), 3.88 (s, 3H), 2.39 (s, 3H), 1.53 (d, 3H); MS (El) for C221½C1FN6: 422.9 (MH+).
[00912] Compound 7016-(4-cliloro-3-fluorophcnyl)-N-{l-[5-(l-ethyl-lH-pyrazol-4- yI)pyridin-3-yl]ethyl}-2-mcthylpyrimidin-4-amine 6-(4-chloro-3-fluorophenyl)-N-{ 1 -[5- (1 -ethyl- l H-pyrazol-4-y0pyridin-3-yl]ethyl}-2-melhylpyrimidin-4-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6a. Ή NMR (400 MHz, d6-DMSO): 8.76 (d, I H), 8.52 (s, I H), 8.35 (s, I H), 8.01 (s, 4H), 7.90 (s, 1 H), 7.76 (t, 1 H), 6.92 (s, 1 H), 5.40 (s, 1 H), 4.23 (q, 2H), 2.46 (s, 3H), 1 .60 (d, 3H), 1 .47 (t, 3H); MS (El) for C23i½ClFN6: 436.9 (MH+).
[00913] Compound 546 5-[2-fluoro-5-(l -{[2-methyl-6-(3-mcthyl-l-bcnzoturan-5- ) )pyrimidin-4-yl|amino}ethyl)phcnyl[pyrimidin-2-amine 5-[2-fluoro-5-(l -{[2-methyl-6- (3 iiethyl-l -benzofuran-5-yl)pyrimidi was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6e. I H NMR (400 MHz, dmso) δ 8;43 (d, 2H), 8.17 (d, I H), 7.92 (d, I H), 7.78 (d, 2H), 7.68 - 7.35 (m, 7H), 7.24 (dd, 1 H), 6.86 (m, 3H), 5.54 - 5.02 (m, I H), 2.39 (s, 3H), 2.22 (s, 3H), 1.48 (d, 3H); MS (El) for C26H23F 60: 455.2 (MH+).
[00914] Compound 547 N-{(1 R)-l -[4-fluoro-3-(l-mcthyl-l H-pyrazol-4-yl)phenyl]ethyl}- 2-methyl-6-(3-mcthyl-l -benzofuran-5-yl)py rimidin-4-aminc N-{( 1 R)- 1 -[4-fluoro-3-( 1 - methyl- 1 H-pyrazol-4-yl)phenyl]ethyl}-2-methyl-6-(3-methyl- l -benzofuran-5-yl)pyrimidin-4- amine was synthesized in a manner analogous to Example 12. while the amine was synthesized in a manner analogous to Example 6e. MS (EI) for C20H74F O: 442.2 (Μ1-Γ).
[00915] Compound 548 N-{(l S)-l-[4-fluoro-3-(l-methyl-lH-pyrazoI-4-yl)phenyllcthyl}- 2-mcthyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4-aminc N-{(l S)- l -[4-fluoro-3-(l - methy 1- 1 H-pyrazol-4-yl)pheny I jethy 1 } -2-methy l-6-(3-melhy 1- 1 -benzofuran-5-y l)pyrimidin-4- amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6e. 'H NMR (400 MHz, dmso) δ 8.18 (s, I H), 8.1 1 (s, I H), 7.99 - 7.87 (m, 2H), 7.79 (d, 2H), 7.59 (d, I H), 7.28 (s, I H), 7.20 (dd, I H), 6.85 (s, I H), 5.46 - 5.13 (m, I H), 3.89 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 1.49 (d, 3H); MS (EI) for C26H24FN5O: 442.2 (MM 1).
[00916] Compound 565 5-|3-fIuoro-5-(l-{[2-mcthyl-6-(3-methyl-l-bcnzofuran-5- yl)pyrimidin-4-yl]amino}ethyl)pheny ]pyrimidin-2-amine 5-[3-iTuoro-5-(l -{[2-methyl-6- (3-methyl-l -benzofuran-5-yI)pyrimidin-4-yl]amino}ethyl)phenyI]pyrimidin-2-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6e. Ή NMR (400 MHz. dmso) δ 8.60 (s, 2H), 8.18 (d, I H), 7.89 (t, 2H), 7.80 (s, 1 H), 7.70 - 7.43 (m, 4H), 7.35 (d, 1 H), 7.19 (d, 1 H), 6.87 (s, 3H), 5.36 (s, I H), 2.39 (s, 3H), 2.30 - 2.13 (m, 3H), 1.88 (s, 2H), 1.48 (d, 3H); MS (EI) for
C26H23FN6O: 454.9 (Μ1- ).
100917] Compound 566 N-{l -|3-nuoro-5-(l-mcthyl-l H-pyrazol-4-yl)phenyl]ethyI}-2- mcthyl-6-(3-mcthyI-l-benzofuran-5-yl)pynmidin-4-aminc N-{ l -[3-fluoro-5-(l -methyl- l H-pyrazol-4-yl)phenyl]ethyl }-2^nethy]-6-(3-methyl-l -benzofuran-5-yl)pyrimidin-4-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6e. 1 H NMR (400 MHz, dmso) 5 8.16 (s, 2H), 8.00 - 7.85 (m, 2H), 7.80 (s, 2H), 7.70 - 7.40 (m 2H), 7.25 (d, 1 H), 7.03 (d, 1H), 6.85 (s, IH), 5.30 (s, 1 H), 3.83 (s, 3H), 2.38 (s, 3H), 2.24 (d, 3H), 1 .88 (s, I H), 1.47 (d, 3H); MS (EI) for C26H24FN5O: 442.0 (MH÷).
100918] Compound 568 N-{l-[3-(5-amino-6-chloropyridin-3-yl)-5-tluorophenyl]ethyl}- 2-mcthyl-6-(3-mcthyl-l-bcnzofuran-5-yl)pyrimidin-4-aminc N-{ l-[3-(5-amino-6- chloropyridin-3-yl)-5-nuorophenyl]ethyl}-2-methyl-6-(3-methyl-l -benzofuran-5- yl)pyrimidin-4-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6e. MS (EI) for C27H23N5CIFO: 488.2 (MH+).
[009191 Compound 570 5-|2-methyl-5-(l-{[2-mcthyI-6-(3-methyl-l-bcnzofuran-5- yl)pyrimidin-4-ylJamino}cthyI)phenylJpyrimidin-2-aminc 5-[2-methyI-5-(l -{ [2-methyl-6- (3-methyl-l-benzofuran-5-yl)pyrimidin-4-yl]amino}ethyl)phenyl]pyrimidin-2-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6e. Ή NMR (400 MHz, dmso) δ 8.25 (s, I H), 8.23 - 8.17 (m, I H), 7.92 (d, I H), 7.82 (s, 1 H), 7.79 - 7.66 (m, I H), 7.59 (d, I H), 7.30 (s, I H), 7.24 (d, I H), 6.74 (s, 2H), 2.40 (s, 2H), 2.23 (d, 4H), 1.48 (d, 2H).MS (EI) for C27H26N6S: 451 .2 (MH+).
[00920] Compound 571 2-mcthyl-6-(3-nicthyl-l-bcnzofuran-5-yl)-N-{l-[4-mcthyl-3-(l- methyl-lH-pyrazol-4-yl)phenyl]cthyl}pyrimidin-4-arnine 2-methyl-6-(3-methyl-l - benzofuran-5-yl)-N-{ l -[4-methyl-3-( l -methyl-l M-pyrazol-4-yI)phenyl]ethyl}pyrimidin-4- amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6e. Ή NMR (400 MHz, dmso) δ 8.17 (s, I H), 7.92 (d, 2H), 7.81 (d, I H), 7.73 (s, I H), 7.65 (s, I H), 7.63 - 7.55 (m, I H), 7.45 (s, I H), 7.27 - 7.13 (m, 2H), 5.31 (s, I H), 3.88 (s, 3H), 3.81 (s, I H), 3.67 (s, I H), 2.40 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H), 1.47 (d, 3H);.MS (El) for C27H27N5O: 438.2 (MH+).
[00921 ] Compound 559 -KlSJ-l -iS'-fluoro-S^'-bip ridin-S- eth ll^-meth l-G-iS- methyl-l-benzofuran-5-yI)pyriiuidin-4-amine N-[(l S)- l -(5'-fluoro-3.3'-bipyridin-5- yl)ethyl]-2-methyl-6-(3-methyl-l -benzofuran-5-yl)pyrimidin-4-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6j. Ή NMR (400 MHz, dmso) δ 8.89 (d, 2H), 8.73 (s, 1 H), 8.65 (d, 1 H), 8.40 - 8.12 (m, 3H), 7.95 (d, IH), 7.84 (dd, 4.6 Hz, 2H), 7.66 - 7.45 (m, 2H), 6.90 (s, I H), 5.39 (s, I H), 2.41 (s, 3H), 2.25 (s, 3H), 1.91 (s, I H), 1.58 (d, 3 H); MS (EI) for C26H22N6OS: 467.1 (MH+). [009221 Compound 560 N-KlSJ-l-ie'-nuoro-S^'-bipyridin-S-y cthyll^-meth l-G-iS- methyI-l-bcnzofuran-5-yl)pyrimidin-4-amine N-[(lS)-l-(6'-fluoiO-3,3'-bipyridin-5- yl)ethyl]-2^iietliy-6-(3-methyl-l-benzofuraii-5-yl)pyrimidin-4-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6j. Ή NMR (400 MHz, dmso) δ 8.82 (d, IH), 8.68 (d, 2H), 8.38 (td, 1H), 8.20 (s, 2H),7.95 (d, IH), 7.90 -7.79 (m,2H),7.61 (d, lH),7.36(dd, IH), 6.89 (s, 11- ,5.39(5, IH), 2.41 (s, 3H), 2.25 (s, 3H), 1.90 (d, IH), 1.57 (d, 3H); MS (EI) for C26H22N5OF: 440.0 (MH+).
[00923] Compound 561 N-{(lS)-l-[5-(l-ethyl-lH-pyrazol-4-yl)pyridin-3-yl|ethyl}-2- methyl-6-(3-methyl-l-bciizofuran-5-yl)pyrimidin-4-amineN- {(IS)- l-[5-(l -ethyl- 1 H- pyiazol-4-yl)pyridin-3-yl]ethyl}-2-methyl-6-(3-methyl!-benzofuran-5-yl)pyrimidin-4-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6j. Ή NMR (400 MHz. dmso) δ 8.70 (d, IH), 8.47 (s, IH), 8.30 (s, IH), 8.19 (d, IH), 8.11 -7.89 (m, 3H), 7.83 (d, 2H), 7.61 (d, IH), 6.87 (s, IH), 5.58 -4.99 (m, IH), 4.16 (q, 2H), 2.41 (s, 3H), 2.25 (s, 3H), 1.98 - 1.84 (m, IH), 1.54 (d, 3H),
1.40 (t, 3H); MS (EI) for C26H2ftNftO: 439.0 (MH+).
[00924] Compound 5626-chIoro-5'-[(lS)-l-{|2-methyI-6-(3-methyl-l-bcnzofuran-5- yl)pyrimidin-4-yl]amino}cthyI[-3,3'-bipyridin-5-amine 6-chloro-5'-[(lS)-l-{[2-methyl-6- (3-methyl-l-benzofuran-5-yl)pynmidin-4-yl]amino}ethyl]-3,3'-bipyridin-5-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6j. Ή NMR (400 Hz, dmso) δ 8.69 (d, 2H), 8.20 (d, IH), 8.09 (s, IH), 7.94 (t, 2H), 7.92 - 7.85 (m, IH), 7.82 (d, IH), 7.61 (d, IH), 7.41 (t, IH), 6.88 (s, IH), 5.76 (s, 2H), 5.38 (s, IH), 2.41 (s, 3H), 2.25 (s, 3H), 1.56 (d, 3H); MS (EI) for C26H23N60C1: 470.9 (MH÷).
1009251 Compound 5635-{5-[(lS)-l-{I2-methyl-6-(3-methyl-l-bcnzofuran-5- yl)pyninidin-4-yI]annno}cthyl}pyi idin-3-yl}pyrimidin-2-aminc 5-{5-[(lS)-l-{[2-methyl- 6-(3-melhyl!-benzofuran-5-yl)pyrimidin-4-yl]amino}ethyl]pyridin-3-yl}pyrimidin-2-ami was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6j. Ή NMR (400 MHz, dmso) δ 8.72 (d, IH), 8.62 (d, 3H), 8.20 (s, IH), 8.11 (s, IH), 7.95 (d, IH), 7.83 (d, 2H), 7.60 (d, IH), 6.90 (d, 3H), 5.37 (s, IH),
2.41 (s, 3H), 2.25 (s, 3H), 1.90 (s, 2H), 1.55 (d, 3H); MS (EI) for C2sH2jN70: 438.2 (ΜΙ- ).
[00926) Compound 5732-methyl-6-(3-mcthyl-l-bcnzofuran-5-yl)-N-{(lS)-l-[5-(l- mcthyl-lH-pyrazoI-5-yl)pyridin-3-yl]cthyI}pyrimidin-4-aminc 2-methyl-6-(3-methyl-l - benzofuran-5-yl)-N-{(l S)-l-[5-(l -methyl- 1 H-pyrazol-5-yl)pyridin-3-yl]ethyl}pyrimidin-4- amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6j. Ή NMR (400 MHz, dmso) δ 8.71 (s. IH), 8.62 (d; IH), 8.21 (s, IH), 8.08 - 7.86 (m: 3H)S 7.82 (s, IH), 7.61 (d, IH), 7.52 (d, IH), 6.89 (s, IH), 6.52 (d, IH), 5.67 -4.92 (m, IH), 3.85 (s, 3H), 2.40 (d, 3H), 2.25 (d, 4H), 1.86 (s, 2H), 1.56 (d, 3H); MS (El) for C25H24N()0: 425.0 (ΜΙ- ).
|00927] Compound 5742-mcthyI-6-(3-mcthyl-l-bcnzofuran-5-yI)-N-{(lS)-l-[5-(lH- pyrazol-4-yl)pyridin-3-yl]cthyl}pyrimidin-4-aminc 2-methyl-6-(3-methyl-l-benzofuran-5- yl)-N-{(lS)-l-[5-(lI-i-pyiazol-4-yl)pyridin-3-yl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6j. Ή NMR (400 MHz, dmso) δ 8.74 (d, IH), 8.47 (s, IH), 8.31 (s, IH), 8.20 (d, IH), 8.03 (d, 21-1), 7.94 (d, IH), 7.86-7.77 (m, 2H), 7.71 -7.43 (m, 2H), 6.88 (s, IH), 5.31 (s, IH), 2.41 (s, 3H), 2.25 (d, 3H), 1.54 (d, 3H); MS (El) for CMH^O: 411.2 (Ml- ). 100928] Compound 6882-mcthyl-6-(3-methyl-l-bcnzofuran-5-yl)-N-{(lR)-l-[5-(l- Hicthyl-lH-pyrazol-4-yl)pyridin-3-yl|ethyl}pyrimidin-4-aminc 2-methyl-6-(3-methyl-l- benzor'uran-5-yl)-N-{(lR)- l-[5-(l -methyl- 1 H-pyrazol-4-yl)pyridin-3-yl]ethyl}pyrimidin-4- amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6j. MS (EI) for C25H2 N O: 425.1(MH+). 100929] Compound 7322-methyl-6-(3-mcthyl-l-ben7.ofuran-S-yl)-N-[(lS)-l-(6,-methyl- 3,3'-bipyridin-5-yl)ethyI|pyrimidin-4-aminc 2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N- [(lS)-l-(6'-methyl-3,3'-bipyridin-5-yl)ethyl]pyrimidin-4-amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6j. Ή NMR (400 MHz, dmso) δ 8.81 (dd, 2H), 8.69 (s, 1 H), 8.20 (s, 2H), 8.04 (dd, IH), 8.00 - 7.75 (m, 3H), 7.61 (d, IH), 7.48 - 7.29 (m, IH), 6.89 (s, IH), 5.39 (s, IH), 2.53 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H), 1.57 (d, 3H); MS (EI) for C27H25N5O: 436.2 (MH÷).
[00930] Compound 7332-mcthyI-6-(3-mcthyl-l-benzofuran-5-yl)-N-{(lS)-l-[5-(l- mcthyl-lH-pyrazol-4-yl)pyridin-3-yl|cthyI}pyrimidin-4-amine 2-melhyl-6-(3-methyI-l- benzofuran-5-yl)-N-{( lS)-l-[5-(l -methyl- 1 H-pyrazol-4-yl)pyridiii-3-yl]ethyl}pyrimidin-4- amine was synthesized in a manner analogous to Example 12 while the amine was synthesized in a manner analogous to Example 6j. Ή NMR (400 MHz, dc-DMSO): 8.69 (d, IH), 8.47 (s, IH), 8.24 (s, ΓΜ), 8.20 (d, IH), 8.01 (s, IH), 7.94 (d, 2H), 7.82 (t, 2H), 7.61 (d, IH), 6.87 (s, IH), 5.43 - 5.14 (m, IH), 3.88 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H), 1.54 (d, 3H); MS (EI) for C2sH24N60: 425.0 (MH+).
100931] Compound 6025-{3-l(lS)-l-{|6-(3-cthyl-l-benzofuran-5-yl)-2- methylpyrimidin-4 yl]amino}cthyl]phcnyl}pyrimidin-2-amine 5-{3- (lS)-l-{[6-(3-ethyl- l-benzofuran-5-yl)-2-methylpyrimidin-4-yljamino}cthyl]phenyl}pyrimidin-2-aniine was synthesized in a manner analogous to Example 12 and the boronic ester was synthesized in a manner analogous lo Example 7a. 1 I I NMR (400 MHz, dmso-d6): δ 8.59 (s, 2H), 8.16 (s, ! H), 7.94 - 7.79 (m, 2H), 7.67 (d, 1 H), 7.48 (dd, 1 H), 7.39 (t, 2H), 6.81 (s, 2H), 5.40 (s, 1H), 2.69 (br s, 2H), 2.43 (s, 3H), 1.52 (d, 3H), 1.27 (br t, 3H). MS (EI) for C27H26 60: 451 .1 (MH+).
[00932] Compound 607 6-(7-nuoro-l-benzofuran-5-yl)-2-methyl-N-{l -[3-(l-methyl-l H- pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine 6-(7-fliioro-l -benzofuran-5-yl)-2-methyl-N- { l -[3-(l -methyl-l H-pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 12 and the boronic ester was synthesized in a manner analogous to Example 7d. MS (EI) for C25H22FN5O: 428.1 (MH+).
[009331 Compound 613 5-{3-|(l S)-l-{[6-(7-fluoro-l-bcnzofuran-5-yl)-2- mcthylpyrimidin-4-yl]amino}cth I]phenyl}pyrimidin-2-amine 5-{3-[(l S)-l -{[6-(7-fluoro- l -benzofiiran-5-yl)-2-methylpyrimidin-4-yl]amino}ethyl]phenyl}pyrimidin-2-amine was synthesized in a manner analogous to Example 12 and the boronic ester was synthesized in a manner analogous to Example 7d. Ή NMR (400 MHz, dmso-d6): δ 8.59 (s, 2H), 8.21 - 8.10 (m, ΓΗ), 7.82 (s, 2H), 7.47 (s, I I I), 7.38 (d, 2H), 7.16 (s, 1 H)S 6.83 (d, 3H), 5.38 (s, l H), 2.40 (s, 3H), 1 .52 (d, 3H). MS (EI) for C2>l-hiFN60: 441 .2 (MH+).
[00934J Compound 636 6-(7-nuoro-3-mct yl-l-benzofuran-5-yl)-2-mcthyl-N-{l-[3-(l- methyl-l H-pyrazoI-4-yl)phenyl]cthyl}pyrimidin-4-amine 6-(7-fluoro-3-methyl-l - bcnzofuran-5-yl)-2-methyl-N- { 1 -[3-( 1 -methyl- 1 H-pyrazol-4-yl)phenyl]ethyl }pyrimidin-4- amine was synthesized in a manner analogous to Example 12 and the boronic ester was synthesized in a manner analogous lo Example 7c. Ή NMR (400 MHz. dmso-dc): δ 8.1 1 (s, 1 H), 8.02 (d, 1 H), 7.94 (s, 1 H), 7.84 (t, 3H), 7.41 (d, 1 H), 7.29 (dd, 2H), 6.89 (s, 1 H), 5.46 - 5.15 (m, 1 H), 3.86 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H), 1.50 (d, 3H). MS (EI) for C26H24FN5O: 442.2 (ΜΙ- ).
[00935] Compound 641 6-(7-fluoro-3-mcthyl-l-benzofuran-5-yl)-2-mcthyl-N-{(lS)-l-[3- (1 -methyl-1 H-pyrazol-4-yl)phcnyl]cthyl}pyrimidin-4-amine 6-(7-fluoro-3-methyl- l - benzofuran-5-yl)-2-methyl-N-{( ] S)-l -|3-(1 -methyl-1 H-pyrazol-4-yl)phenyl]ethyl}pyrimidin- 4-amine was synthesized in a manner analogous to Example 12 and the boronic ester was synthesized in a manner analogous to Example 7e. Ή NMR (400 MHz, dmso-d< : 5 8.1 1 (s, 1 H), 8.02 (t, 1 H), 7.94 (s, 1 H), 7.84 (d, 3H), 7.41 (d, 1 H), 7.29 (dd, 21-1), 6.89 (s, 1 H), 5.44 - 5.21 (m, 1 H), 3.86 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H), 1.50 (d, 3H). MS (EI) for C26H24FN5O: 442.2 (MH+). [00936] Compound 644 N-{(l S)-l-]3-(5-aminopyridin-3-yl)phcnyl]cthyl}-6-(7-fluoro-3- methyl-l -benzofuran-5-yI)-2-mcthyIpyrimidin-4-amine N-{(l S)-l -[3-(5-aminopyridin-3- yl)phenyl]ethyl}-6-(7-lluoro-3-methyl-l -benzofuran-5-yl)-2-methylpyrinndin-4-amine was synthesized in a manner analogous to Example 12 and the boronic ester was synthesized in a manner analogous to Example 7c. Ή NMR (400 MHz, dmso-d6): δ 8.03 (s, 2H), 7.93 (d, 2H), 7.83 (s, I H), 7.75 - 7.66 (m, I H), 7.44 (s, 3H), 7.15 (s, 1 H), 6.89 (s, I H), 5.44 (s, 2H), 2.41 (s, 3H), 2.26 (s, 3H), 1 .52 (d, 3H). MS (EI) for C27H24F 50: 454.2 (MH+).
[00937] Compound 645 6-(7-fluoro-3-mcthyI-l-benzofuran-S-yl)-N-{(lS)-l-[3-(5- fluoropyndin-3-yl)phcnyl[cthyl}-2-methylpynmidin-4-amine 6-(7-fluoro-3-methyl-l - benzofuran-5-yl)-N-{(l S)- l -[3-(5-fluoropyridih-3-yl)ph
amine was synthesized in a manner analogous to Example 12 and the boronic ester was synthesized in a manner analogous to Example 7c. Ή NMR (400 MHz, dmso-de): δ 8.83 (s, I H), 8.59 (d, I H), 8.17 - 8.02 (m, 2H), 7.93 (s, 3H), 7.66 (d, I H), 7.49 (q, 2H), 6.90 (s, I H), 5.51 - 5.23 (m, I H), 2.41 (s, 3H), 2.25 (s, 3H), 1 .54 (d, 3H). MS (El) for C27H22F2N4O: 457.2 (MH+).
[00938] Compound 648 N-{(lS)-l-|3-(5-aniino-6-chIoropyrid!n-3-yl)phenyl]cthyl}-6-(7- fluoro-3-methyl-l-benzofuran-5-yl)-2-methylpyrimUlin-4-aminc N-{(l S)- l-[3-(5-amino- 6-chloropyridin-3-yl)phenyl]ethyl}-6-(7-fluoro-3-methyl- l-benzoi:Liran-5-yl)-2- methylpyrimidin-4-amine was synthesized in a manner analogous to Example 12 and the boronic ester was synthesized in a manner analogous to Example 7c. Ή NMR (400 MHz, dmso-de): δ 8.01 (d, I H), 7.96 (s, I H), 7.88 (d, I H), 7.80 (d, IH), 7.69 (s, I H), 7.44 (d, 3H), 7.36 (t, I H), 6.87 (d, I H), 5.71 (d, 2H), 5.42 (br s, 1 H), 2.44 (s, 3H), 2.19 (d, 3H), 1 .54 (d, 3H). MS (EI) for C27H2_ClFNsO: 488.1 (MH+).
[00939] Compound 652 6-(7-nuoro-3-methyl-l-benzofuran-5-yl)-2-mcthyl-N-{l -[5-(lH- pyrazol-4-yI)pyridin-3-yl]ethyl}pyrimidin-4-amine 6-(7-fluoro-3-melhyl- l -benzofuran-5- yl)-2-methyl-N-{ 1 -[5-( 1 H-pyrazol-4-yl)pyridin-3-yl]ethyl}pyrimidin-4-amine was synthesized in a manner analogous to Example 12, the boronic ester was synthesized in a manner analogous to Example 7e, and the amine was synthesized in a manner analogous to Example 6a. Ή NMR (400 MHz, dmso-d6): δ 8.73 (t, 1 H), 8.47 (s, I H), 8.05 (m, 4H), 7.94 (d, I H), 7.84 (t, I H), 6.90 (d, I H), 5.47 - 5.17 (m, 1 H), 2.41 (s, 3H), 2.26 (s, 3H), 1 .55 (d, 3H). MS (EI) for C24H2| FN60: 429.2 (MH+).
[00940] Compound 653 N-{ l-I5-(l-ethyl-l H-pyrazoI-4-yl)pyridin-3-yI|ethyl}-6-(7- fluoro-3-mcthyl-l -bcnzofuran-5-yl)-2-methylpyrimidin-4-aminc N-{ l -[5-(l -ethyl-l H- pyrazol-4-yl)pyridin-3-yl]ethyl}-6-(7-nuoro-3-methyl-l -benzofuran-5-yl)-2- methylpyrimidin-4-amine was synthesized in a manner analogous to Example 12, the boronic ester was synthesized in a manner analogous to Example 7e, and the amine was synthesized in a manner analogous to Example 6a. Ή NMR (400 MHz, dmso-de): δ 8.68 (d, 1 H): 8.47 (s, I H), 8.28 (d, 1 1 1), 8.05 (s, 2H), 7.95 (d, J 2H), 7.80 (dd, I H), 6.89 (d, I H), 5.19 (br s, I H), 4.24 - 4.10 (m, 2H)S 2.41 (s, 3H), 2.26 (s, 3H)S 1 .54 (d, 3H), 1 .40 (t, 3H). MS (EI) for C26H2sF 60: 457.2 (MH+).
(00941 ] Compound 654 6-(7-fluoro-3-mcthyl-l-bcnzofuran-5-yl)-N-{(lS)-l-[3-(6- fluoropyridin-3-yI)phcnyl]cthyI}-2-mcthyIpyrimidin-4-aminc 6-(7-fIuoro-3-methyl- l - benzofuran-5-yl)-N-{(l S)- l -[3-(6-tluoiOpyridin-3-yl)phen> ]ethyl}-2-methylpyrimidin-4- amine was synthesized in a manner analogous to Example 12 and the boronic ester was synthesized in a manner analogous to Example 7e. Ή NMR (400 MHz, dmso-de): δ 8.55 (t, I H), 8.28 (tt, 11-0, 8.03 (s, 1 H), 7.96 - 7.74 (m, 3H), 7.58 (d, I H), 7.53 - 7.42 (m, 2H), 7.30 (dt, I H), 6.86 (d, I H), 5.34 (d, 1 H), 2.41 (s, 3H), 2.25 (s, 3H), 1.51 (d, 3H). MS (EI) for C27H22F2N4O: 457.2 (MH+).
[00942] Compound 660 6-(7-nuoro-3-methyI-l-benzofuran-5-yl)-2-methyl-N-{l-[5-(l- methyl-l H-pyrazoI-4-yl)pyridin-3-yl]cthyl}pyrimidin-4-amine 6-(7-fluoro-3-methyl- l - benzofuran-5-yl)-2-methyl-N- { l -[5-(l -methyl- 1 H-pyrazol-4-yl)pyridin-3-yl]ethyl}pyrimidin- 4-amine was synthesized in a manner analogous to Example 12, the boronic ester was synthesized in a manner analogous to Example 7c, and the amine was synthesized in a manner analogous to Example 6a. Ή NMR (400 MHz, dmso-d6): δ 8.69 (s, I H), 8.48 (s, I H), 8.24 (s, I H), 8.05 (s, 2H), 7.98 - 7.93 (m, 2H), 7.88 (d, I H), 6.89 (d, I H), 5.45 - 5.19 (m, 1 H), 3.88 (s, 3H), 2.41 (s, 3H), 2.27 (d, 3H), 1.51 (t, 3H). MS (EI) for C25H23FN6O: 443.2 (MH+).
[00943] Compound 661 5-[5-(l-{[6-(7-nuoro-3-methyl-l-bcnzofui an-5-yl)-2- methyIpyrimidin-4-yI]amino}ethyl)pyridin-3-yI]pyrimidin-2-aminc 5-[5-( l -{ [6-(7-fluoro- 3-methyl- l -benzofuran-5-yl)-2-methylpyrimidin-4-yl]annno}ethyl)pyridin-3-yl]pyrimidi amine was synthesized in a manner analogous to Example 12, the boronic ester was synthesized in a manner analogous to Example 7c, and the amine was synthesized in a manner analogous to Example 6a. Ή NMR (400 MHz, dmso-d6): δ 8.73 (s, I H), 8.64 (s, 2H), 8.60 (s, l l-I), 8.06 (s, 2H), 7.94 (d, I H), 7.88 (s, 2H), 6.92 (d, 2H), 5.37 (s, I H), 2.41 (s, 3H), 2.27 (d, 3H), 1.55 (d, 3H). MS (EI) for C2JH22FN7O: 456.0 (ΜΙ-Γ).
[00944] Compound 662 5-{3-|(l S)-l-{[6-(7-lluoro-3-methyl-l -bcnzofuran-5-yl)-2- methylpyrimidin-4-yl]amino}cthyl]phenyI}pyrimidin-2-amine 5-{3-[( l S)- l -{[6-(7-fluoro- 3-methyl- l -benzofuran-5-yl)-2-methylpyrimidin-4-yl]amino}ethyl]phenyl}pyrimidin-2- amine was synthesized in a manner analogous to Example 12, the boronic ester was synthesized in a manner analogous to Example 7c. Ή NMR (400 MHz, dmso-d6): δ 8.58 (s, 2H)..8.03 (s, 1H), 7.94 (s, 1H), 7.83 (s, 2H): 7.54 - 7.43 (m, 1H), 7.38 (d, 2H), 6.89 (s, 1H ,
6.81 (s, 2H), 5.47 - 5.19 (m, 1H), 2.41 (s, 3H), 2.26 (s, 3H), 1.52 (d, 3H). MS (EI) for C¾H23FN60: 455.2 (MH+).
100945] Compound 5806-(l-bcnzothicn-5-y!)-2-mcthyl-N-{l-[3-(l-mcthyl-lH-pyrazol- 4-yl)phcnyl]ethyl}pyrimidin-4-aminc 6-(l-benzothien-5-yl)-2-methyl-N-{l-[3-(l-methyl- lH-pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine was synthesised analogous to Example 12 while the boron ester was synthesized analogous to Scheme 7Γ. Ή NMR (400 MHz. CD3CN) δ 8.44 (s, 1H), 7.98 (d,./= 8.5 Hz, 1H), 7.92 (d,./ = 8.0 Hz, 1H), 7.82 (s, 1H), 7.76 (d,J = 0.8 Hz, 1H), 7.65 -7.58 (m, 2H), 7.44 (d,./=5.3 Hz, 1H), 7.41 -7.37 (m, 1H), 7.32 (t,.7= 7.6 Hz, lH), 7.29-7.24 (m, 1H), 6.72 (s; 1H), 6.21 (d,./= 7.4 Hz, 1 H), 5.10 (s, 1 H), 3.87 (s, 3H), 2.43 (s, 3H), 1.56 (d, ./= 6.9 Hz, 4H); MS (EI) for C25K23N5S: 426.05 (MH+)
[00946] Compound 5912-methyl-6-(3-methyl-l-benzothien-5-yl)-N-{(lS)-l-[3-(l- methyI-lH-pyrazoI-4-yl)phcnyI|cthyI}pyrimidin-4-amine 2-methyl-6-(3-methyl-l- benzothien-5-yl)-N-{(l S)-l-[3-(l -methyl- lH-pyrazol-4-y)phenyl]ethyl}pyrimidin-4-amine was synthesised analogous to Example 12 while the boron ester was synthesized analogous to Scheme 7f. Ή NMR (400 MHz, CD3OD) δ 8.14 (s, 1 H), 7.94 (s, 1H), 7.93 - 7.86 (m, 1 H),
7.82 (s, 1 H), 7.75 (d, .7 = 7.5 Hz, 1 H), 7.62 (s, 1 H), 7.54 - 7.50 (m, 1 H), 7.43 (d, J =1.5 Hz, 11-1), 7.33 (t, ./= 7.6 Hz, 1 H), 7.30 - 7.23 (m, 2H), 6.69 (s, 1H), 3.9.1 (s, 3H), 2.50 (s, 3H), 1.57 (dd,./= 19.2, 6.9 Hz, 3H); MS (El) forC26H25 $S: 440.11 (MH+)
[00947] Compound 592 N-{(lS)-l-[3-(5-aniinopyridin-3-yl)phcnyI|cthyl}-2-metliyl-6-(3- methyl-l-benzothien-5-yl)pyrimidin-4-amine N-{(lS)-l-[3-(5-aminopyridin-3- yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l-benzolhien-5-yl)pyrimidin-4-amine was synthesised analogous to Example 12 while the boron ester was synthesized analogous to Scheme 7f. Ή NMR (400 MHz, CD3OD) δ 8.16 (s, lH), 8.02 (t, .7= 6.9 Hz, 1 H), 7.93 (d, J = 2.4 Hz, 11-1), 7.85 (t,J= 26.1 Hz, 1H), 7.71 (d, 7 = 26.2 Hz, IH), 7.67 (s, 1H), 7.45 (s, 3H), 7.30 (d, J = 1.9 Hz, 1 H), 7.23 (s, 1 H), 6.70 (s, 1 H), 4.90 (s, 1 OH), 2.55 - 2.46 (m, 3H), 2.43 (s, 3H), 1.61 (d, ./ = 6.8 Hz, 3H); MS (EI) for C27H2jNsS: 452.04 (MH+).
[00948] Compound 593 N-{(lS)-l-[3-(6-fluoropyridin-3-yl)phenyl]ethyl}-2-methyl-6-(3- methyl-l-bcnzothicn-5-yl)pyrimidin-4-aminc N-{(lS)-l-[3-(6-fluoropyndin-3- yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l-benzothien-5-yl)pyrimidin-4-amine was synthesised analogous to Example 12 while the boron ester was synthesized analogous to Scheme 7f. Ή NMR (400 MHz, CD3OD) 58.41 (s, 1H), 8.17 (d,J= 10.7 Hz, 2H), 8.04 (dd, ./= 17.9, 8.5 Hz, 1H), 7.67 (d, J = 6.9 Hz, 2H), 7.61 - 7.46 (m, 3H), 7.36 (s, l H), 7.14 (dd, ./ = 8.4,2.3 Hz, 1H), 6.90 (s, 1H), 6.77 (s, 1 H), 5.61 (q, .7=6.8 Hz, 1H), 2.66 (s, 3H), 2.51 (s, 3H), 1.70 (dd, J= 12.0, 7.0 Hz, 3H); MS (El) for C27H23FN4S: 455.03 (ΜΙ-Γ).
[00949] Compound 594 N-{(lS)-l-[3-(5-nuoropyridin-3-yl)phcnyl]cthyl}-2-methyl-6-(3- mcthyl-l-bcnzothicn-5-yl)pyrimidin-4-aminc N-{(1 S)-l -[3-(5-fluoropyridin-3- yl)phenyljethyl}-2-methyl-6-(3-niethyl-l-benzothien-5-yl)pyrirnidin-4-amine was synthesised analogous to Example 12 while the boron ester was synthesized analogous to Scheme 7f. 'HNMR (400 MHZ, CD3OD)68.71 (s, 1H), 8.49 (s, 1 H), 8.21 (d,J= 1.8Hz, 1H),8.11 (d,_/=8.5Hz, 1H), 7.95 (d, J = 9.7 Hz, 1H), 7.77 (s, 1H), 7.70 (dd,J=8.4, 1.8 Hz, 1H), 7.67 - 7.60 (m, 1H), 7.58 - 7.52 (m, 2H), 7.41 (t,J= 5.3 Hz, 1H), 6.88 (d,J= 23.6 Hz, lH),5.73 -5.47 (m, 1H), 2.66 (s, 3K), 2.53 (s, 3H), 1.71 (t, .7=8.1 Hz, 3H); MS (EI) for C27H23FN4S: 455.04 (ΜΙ- ).
100950] Compound 5955-{3-[(lS)-l-{|6-(3-chloro-l-bcnzofuran-5-yl)-2- methyIpyrimidin-4-yl]amino}cthyl]phenyl} pyrimidin-2-aminc 5-{3-[(lS)-l-{[6-(3- chloro-l-benzot:uran-5-yl)-2-methYlpyrimidin-4-yl]amino}ethyl]phenyl} pyrimidin-2-amine was synthesised analogous to Example 12 while the boron ester was synthesized analogous to Scheme 7f. Ή NMR (400 MHz, CD3CN) δ 8.52 (s, 2H): 8.16 (d, ./= 29.0 Hz, 1H), 7.95 (d, ./ = 8.5 Hz, 1H), 7.81 (s, 1H), 7.59 (s, 1H), 7.55 (d, ./= 8.7 Hz, 1H), 7.52 (d,J= 0.6 Hz, 1H), 7.40 (s, 3H), 6.64 (s, 1H), 6.14 (d,./= 7.2 Hz, 1H), 5.48 (s, 2H), 5.17 (s, 1H), 2.45 (s, 3H), 1.96 (s, 9H), 1.57 (d, ./= 6.9 Hz, 3H); MS (El) for C27H23FN4S: 457.08 (MH+).
Example 13: Synthesis of 2-methyl-6-(2-phenylcthyl)-N-|(l R)-l, 2,3,4- tctra
Figure imgf000306_0001
Slep 1 :
[00951 ] 2-methyl-6-|(E)-2-phenylethenyl]-N-[(lR)-l ,2,3,4-tctrahy(]ronaphthalen-l- yl]pyrimidin-4-aminc
100952] To a solution of (R)-6-chloro-2-methyl-N-(l ,2,3,4-letrahydronaphthalen- l - yl)pyrimidin-4-amine (0.24 g, 0.88 mmol) in toluene (5 ml) were added
tetrakis(triphenylphosphine)palladium(0) (20 mg. 0.02 mmol), styrylboronic acid (0.33 g , 2.20 mmol). sodium carbonate (2.0 N, 1 .36 ml. 3.10 mmol) and ethanol (2 ml). The solution was degassed with nitrogen for 3-5 min. The reaction was then heated to 85-90 °C overnight. The reaction was cooled to room temperature and diluted with ethyl acetate (300 ml). The crude solution was passed through a pad of silica geJ under vacuum. The filtrate was washed with saturated aqueous sodium bicarbonate (50 ml) and saturated aqueous sodium chloride (50 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford impure product. Column puri fication on silica (7:3 hexanes/ ethyl acetate) afforded 2-methyl-6-[(E)-2-phenylethenyl]-N-[( l R)-l ,2,3,4-tetrahydi naphthalen-l - yl]pyrimidin-4-amine (0.16 g, 54%) which was used as intermediate in the next step. MS (EI) for C23H23N3: 342.2 (ΜΙ-Γ).
Step 2:
[00953] 2-methyl-6-(2-phenyIethyl)-N-[(l R)-l,2,3,4-tetrahydronap thalen-l - yl|pyrimidin-4-amine.
[00954] To a solution of 2-methyl-6-[(E)-2-phenylethenyl]-N-[(l R)- l ,2,3!4- tetrahydronaphthalen- l -yl]pyrimidin-4-amine (58 mg, 0.1 7 mmol) in methanol (15 ml) were added ammonium formate (0.1 1 g, 1 .70 mmol) and palladium (10% on activated carbon, 22 mg). The reaction was heated al 85 °C for 4 hr. The reaction was cooled to room temperature, filtered through a pad of Celite and washed with ethyl acetate (4 x 50 ml). The organic layer was washed with water (50 ml), saturated sodium bicarbonate (50 ml), saturated sodium chloride (50 ml), dried over magnesium sulfate, and concentrated at reduced pressure to afford the crude product. The crude product in methanol (10 ml) was further treated with 4.0 N hydrochloric acid in dioxane solution (10 ml). The product was concentrated , unsaturated with diethyl ether (20 ml), filtered, and dried to afford 2-methyl-6-(2-phenylcthyl)-N-[(l R)- l ^J^-tetrahydronaphthalen- l -y^pyrimidin^-amine (34 mg. 58%) as hydrogen chloride salt. Ή NMR (400 MHz, d6-DMSO): 9.62 (d, 1 H), 7.32 (d, 4H), 7.05-7.22 (m, 5H), 6.45 (s, l H), 5.45 (m, lH), 2.92 (br s, 2H), 2.75 (m, 2H), 2.58 (s, 3H), 2.46 (br t, 2H), 1.74-1.95 (m, 4H); MS (EI) for C23H25N3: 344.2 (MH+). Example 14: Synthesis ol' 2-methyl-6-{[3-(methyloxy)phcnyl]oxy}-N-|(lR)-l,2,3,4- tetrahydronaphthaIen-l -yI]pyrimidin-4-amine (Compound 532).
Figure imgf000308_0001
[00955] To a solution oi' (R)-6-chloro-2-mefhyl-N-(1.2,3.4-tetrahydronaphthalen- l - yl)pyrimidin-4-amine (0.24 g. 0.88 mmol) in N.N-dimethylibrmamide (1 ml) were added cesium carbonate (0.25 g. 0.76 mmol) and 3-methoxyphenol (54 nig, 0.19 mmol). The reaction was then heated to 100 °C for 6 hr. The reaction was cooled to room temperature and diluted with ethyl acetate (200 ml). The organic layer was washed with water (40 ml), saturated aqueous sodium bicarbonate (50 ml), saturated aqueous sodium chloride (50 ml), dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford impure product. Column purification on silica (7:3 to 2:8 hexanes/ ethyl acetate) afforded an oily product which was treated with 1 equivalent of 1 .0 N aqueous hydrochloric acid followed by an overnight lypholization afforded 2-methyl-6-{ [3-(methyloxy)phenyl]oxy}-N-[( l R)- l ,2,3,4-tetrahydronaphthalen- l -yl]pyrimidin-4-amine (16 mg, 40%) as hydrogen chloride salt. Ή N R (400 MHz, d6-DMSO): 8.66 (br s, 1 H), 7.42 (t, 1 H), 7.10-7.25 (m, 5H), 6.81 - 6.95 (m, 3H), 4.40 (s, 1 H), 3.75 (s, 3H), 3.19(s, 3H), 2.75 (m, 2H), 1 .45-1.97 (m, 4H); MS (EI) for C22H23N3O2: 362.2 (MIT1).
Example 15: Synthesis of 2-methyl-6-(3-mcthyl-l-benzofuran-5-yl)-N-[(lS)-l-{3-[2-(4- rncthylpipera in-l-yl)pyrimidin-5-yl]phenyl}cthyl|pyriniidin-4-arnine (Compound 552).
Figure imgf000308_0002
[00956] A round bottom flask was charged with N-(l -(3-(2-chloropyrimidin-5- yl)phenyl)ethyl)-2-melhyl-6-(3-methylbenzofuran-5-yl)pyrimidin-4-arnine (50 mg, 0.1 1 mmol, 1.0 eq), N-Methyl piperizine ( 109ul, 1 .09 mmol, 10 eq) and DMF (0.5mL). The reaction mixture was heated to 80°C overnightand cooled to RT. Water and EtOAc were added to the mixture. The organic layer was partitioned, dried over Na2S04 and concentrated to give 2-methyl-6-(3-niethyl- l -benzofiiran-5-yl)-N-[(l S)-l -{3-[2-(4-methylpiperazin-l - yl)pyrimidin-5-yI]phenyl }ethyl]pyrimidin-4-amine as a crude oil, which was purified via reversed phase HPLC eluting with a gradient of 25mM NI-LtOAc/ACN. The appropriate fractions are pooled and lyophilized to give 33 mg (58% yield) of 2-methyl-6-(3-methyl-l - benzofuran-5-yl)-N-[( 1 S)- 1 - {3-[2-(4-methylpiperazin- 1 -yl)pyrimidin-5- yl]phenyl}elhyl]pyrimidin-4-amine. Ή NMR (400 MHz, dmso) δ 7.84 (dd: 7.9 Hz, 2H), 7.64 (s, 2H), 7.53 (d, 2H), 7.45 (s, 1 H), 7.29 (ddd, 4H), 4.12 (s, 1 H), 3.17 (s, 3H), 2.96 (d, 3H), 2.30 (s, 3H), 2.23 - 2.02 (m, 3H), 1.90 - 1 .57 (m, 4H), 1 .45 (s, 2H), 1 .13 (t, 1 H); MS (El) for C 19H33N7O: 520.2 (MH+).
[00957] Other compounds made according to example 15:
100958] Compound 550 6-(l ,3-benzothiazol-6-yl)-2-methy]-N-[(lS)-l-{3-[2-(4- mcthylpipcrazin-l-yl)pyrimidin-5-yl]phcnyI}cthyl]pyrimidin-4-aniine 1 H NMR (400 MHz. dmso) δ 9.47 (s, 1 H), 8.78 (m, 3H), 8.14 (s, 2H), 7.93 (s, 1 H), 7.74 (s, 1 H), 7.52 (d, 1 H), 7.42 (d, 2H), 6.92 (s, 1 H), 5.41 (s, 1 H), 3.40 (br s, burned 4H), 3.07 (d, 4H), 2.63 (s, 3H), 2.41 (s, 3H), 1.91 (s, 2H-OAc), 1.53 (d, 3H); MS (EI) for C29H30N8OS: 523.2 (MH+). 100959] Compound 553 3-|(5-{3-](l S)-l-{[2-mcthyl-6-(3-mcthyl-l-benzofuran-5- yl)pyrimidin-4-yl]amino}ethyl]phcnyl}pyrimidin-2-yl)amino]propan-l-ol Ή NMR (400 MHz, dmso) δ 8.59 (s, 2H), 8.15 (s, lH), 7.91 (d, 1 H), 7.79 (s, 3H), 7.57 (d, 1 H), 7.45 (d, 1 H), 7.36 (d, 2H), 7.30 (t, 1 H), 6.84 (s, 1 H), 5.36 (s, 1 H), 2.38 (s, 3H), 2.22 (s, 3H), 1 .88 (d, 1 H), 1 .76 - 1 .59 (m, 2H), 1 .49 (d, 3H); MS (EI) for C-29H30N6O2: 495.2 (MH+).
100960] Compound 554 Methyl N-(5-{3-](l S)-l-{[2-methyI-6-(3-methy!-l-bcnzofuran-5- yl)pyrimidin-4-yl]amino}ethyI|phcnyl}pyrimidin-2-yl)glyciiiate 'H NMR (400 MHz. dmso) δ 8.66 (s, 2H), 8.18 (d, 1 H), 7.93 (d, 1 H), 7.75 (dd, 4H), 7.59 (d, 1 H), 7.54 - 7.45 (m, 1 H), 7.40 (d, 2H), 6.86 (s, 1 H), 5.38 (s, 1 H), 4.06 (d, 2H), 3.64 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H), 1 .89 (s, 1 H), 1.51 (d, 3H); MS (EI) for C29l¾ 603: 509.1 (ΜΙ- ).
100961 ] Compound 555 2-nicthyI-6-(3-methyl-l-bcnzofuran-5-yl)-N-[(lS)-l-{3-[6-(4- metliylpiperazin-l-yl)pyridin-3-yl]phenyl}ethyl]pyrimidin-4-amine Ή NMR (400 MHz, dmso) δ 8.45 (d, 1 H), 8.18 (s, 1 H), 7.93 (d, 1 H), 7.88 - 7.79 (m, 3H), 7.59 (d, 1 H), 7.47 (d, 1 H), 7.38 (t, 2H), 6.90 (t, 2H), 5.38 (s, 1 H), 3.57 - 3.49 (m, 5H), 2.44 - 2.37 (m, 7H), 2.23 (d, 6I-I), 1.91 (s, 2H), 1.52 (d, 3H); MS (EI) for C32H34N60: 519.2 (ΜΙ-Γ).
100962] Compound 556 2)2-dimethyl-3-|(5-{3-](I S)-l-{|2-mcthyI-6-(3-methyI-l - benzofuran-5-yI)pyrimidin-4-yl]amino}cthyl|phenyI}pyrimidin-2-yl)amino]propan-l-ol Ή NMR (400 MHz, dmso) δ 8.62 (s, 2H), 8.18 (s, 1 H), 7.93 (d, 1 H), 7.82 (s, 2H), 7.60 (s, IH), 7.52 - 7.46 (m, IH), 7.38 (d, 2H), 7.27 (t, IH), 4.74 (s, 1H), 3.24 (d, 2H), 3.16 (d, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 1.51 (d, 3H); MS (El) for C3|H34 602: 523.2 (MH+).
100963] Compound 557 N-(5-{3-I(lS)-l-{|2-mcthyl-6-(3-mcthyl-l-benzofuran-5- yI)pyrimidin-4-yl]amino}ethyl|phcnyI}pyrimidin-2-yl)glycinc MS (EI) for C28H26N6O3: 495.2 (ΜΙ-Γ).
[00964] Compound 5583-|(5-{3-[(1S)-l-{[2-mcthyl-6-(3-mcthyI-l-benzofuran-5- yl)pyrimidin-4-yl]amino}cthyl]phcnyI}pyrimidin-2-yI)amino|propanc-l,2-diol Ή NMR
(400 MHz, dmso) δ 8.58 (s, 2H), 8.13 (s, IH), 7.89 (d, IH), 7.75 (s, 2H), 7.59 (t, 2H), 7.47- 7.30 (m, 3H), 7.03 (t, 1 H), 6.83 (s, 1 H), 5.33 (s, IH), 3.36 (t, 2H), 2.37 (s, 3H), 2.20 (s, 3H), 1.86 (s, 2H), 1.48 (d, 3H); MS (EI) for C29H30N6O3: 510.9 (MH+).
[00965] Compound 575 (2S)-3-[(5-{3-[(lS)-l-{|2-mcthyl-6-(3-mcthyl-l-bcnzofuran-5- yl)pyrimidin-4-yl]amino}cthyl|phcnyl}pyrimidin-2-yl)amino]propane-l,2-diol Ή NMR
(400 MHz, dmso) δ 8.62 (s, 2H), 8.18 (s, IH), 7.93 (d, IH), 7.81 (s, 3H), 7.60 (s, IH), 7.48 (d, 11-1), 7.39 (d, 2H), 7.12 (t, 111), 6.86 (s, 1 H).4.71 (d, 2H), 3.76 - 3.60 (m, IH), 2.41 (s, 3H), 2.24 (s, 3H), 1.88 (s, IH), 1.51 (d, 3H); MS (EI) for C29H30N6O3: 510.9 (MH+).
[00966] compound 581 N'-{5-]3-(l-{|6-(l,3-bcnzothiazoI-6-yl)-2-mcthylpyrimidin-4- yl]amino}ethyl)phenyl]pyrimidin-2-yl}-N,N-dimcthylcthanc-l,2-diamine Ή NMR (400 MHz, CDjCN) 59.16 (d, J= 1.1 Hz, 1 H), 8.67 (s, 1 H), 8.56 (s, 211), 8.16-8.03 (m, 2H), 7.65 (s, IH), 7.51 -7.36 (m, 3H), 6.75 (s, IH), 6.46-6.23 (m, 2H), 5.15 (s, IH), 3.56 (q, J= 5.9 Hz, 2H), 2.71 (t,./= 6.1 Hz, 2H), 2.43 (s, 3H), 2.37 (d,J= 6.7 Hz, 6H), 2.01 - 1.89 (m, 6H), 1.58 (d, .7 = 6.9 Hz, 3H); MS (EI) for CzgfyoNgS: 511.52 (MH ).
100967] Compound 584 N-{(lS)-l-[3-(2-{4-]2-(dimcthylamino)ethyl]piperazin-l- yl}pyrimidin-5-yl)phenyI]cthyl}-2-mcthyl-6-(3-mcthyl-l-bcnzofuran-5-yl)pyrimidin-4- amine Ή NMR (400 MHz, CD3CN) δ 8.50 (d, .7 = 20.3 Hz, 2H), 8.06 (s, IH), 7.82 (d, J = 8.6 Hz, IH), 7.58 (s, IH), 7.47 (s, 1H)S 7.41 (d,./= 8.7 Hz, IH), 7.35 (dd, ./= 4.5, 2.7 Hz, IH), 7.32 (dd, .7 = 4.8, 1.8 Hz, 2H), 6.61 (s, IH), 6.12 (d, .7= 7.6 Hz, IH), 5.19-4.95 (m, IH), 3.78 - 3.61 (m, 3H), 2.45 - 2.34 (m, 6H), 2.34 (s, 4H), 2.17 (d, J = 8.2 Hz, 4H), 1.49 (d,
Figure imgf000310_0001
577.29 (MH+).
[009681 Compound 5852-[4-(5-{3-[(lS)-l-{[2-mcthyl-6-(3-mcthyl-l-bcnzofuran-5- yl)pyrimidin-4-yl]amino}ethyl|phcnyl}pyrimidin-2-yl)piperazin-l-yI]ethanol Ή NMR (400 MHz, CD3CN) 88.52 (d, J= 2.8 Hz, 2H), 8.05 (s, IH), 7.81 (d, J =8.6 Hz, IH), 7.58 (s, lH),7.46(s, 1H),7.39 (d,J=8.7 Hz, 1 H), 7.37 - 7.33 (m, IH), 7.33 - 7.28 (m, 2H), 6.60 (s, IH), 6.15 (s, IH), 5.06 (s, IH), 3.77-3.68 (m, 4H), 3.49 (t, J= 5.7 Hz, 2H), 2.48 - 2.38 (m, 71-1), 2.32 (d, J = 4.8 Hz, 4H), 2.15 (s, 4H), 1.86 (s, 1 H), 1.48 (d, ./ = 6.9 Hz, 3H); MS (EI) for C32H35N7O2: 550.16 (ΜΙ-Γ).
[00969] Compound 5862-mcthyI-6-(3-met yl-l-benzofuran-5-yl)-N-{(lS)-l-|3-(2-{4- [(l-mcthyl-lH-imidazol-2-yl)methyl]pipcrazin-l-yl}pyrimidin-5- yl)phcnyl]cthyl}pyrimidin-4-amine Ή NMR (400 MHz, CD3CN) δ 8.57 - 8.48 (m, 211),
8.06 (s, H ), 7.82 (dd,J=8.6, 1.4 Hz, 1H), 7.58 (s, 1H),7.49 (dd, ./= 12.4, 8.3 Hz, 2H), 7.39 (t,./= 8.4 Hz, 1H), 7.33 (td,J= 5.6, 3.0 Hz, 3H), 7.02 (s, 1H), 6.85 (s, 1H), 6.62 (s, 1H), 6.19 (d, .7=7.5 Hz, 1H),5.09 (s, 1H),4.00 (t, .7 = 6.2 Hz, 2H), 3.83 - 3.41 (m, 4H), 2.60 (t, .7=6.2 Hz, 2H), 2.41 (dd,./= 13.1, 8.1 Hz, 6H), 2.34 (d,J=6.0 Hz, 4H), 2.16 (s, 3H), 1.89 (d,J = 2.1 Hz, 1H), 1.49 (d, J= 6.9 Hz, 3H); MS (El) for C35H37N9O: 600.21 (MH+).
[00970] compound 5872-({2-[4-(5-{3-[(lS)-l-{|2-mcthyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-yl]amino}cthyl|phcnyl}pyrimidin-2-yl)pipcrazin-l-yl|ethyl}oxy)ethanol
[00971] 1H NMR (400 MHz, CD3CN) δ 8.62 (t, J = 1.7 Hz, 2H), 8.16 (s, 1H), 7.91 (d, J =
8.7 Hz, 1H), 7.68 (s, IH), 7.57 (s, IH),- 7.54- 7.38 (m, 4H), 6.71 (s, 1H), 6.28 (d, J = 7.5 Hz, 1H), 5.18 - 5.13 (m, IH), 3.86-3.76 (m, 4H), 3.51 (td, J = 5.7, 1.7 Hz, 2H), 3.36-3.27 (m, 3H), 2.54 (ddd, J = 11.0, 7.3, 3.1 Hz, 6H), 2.44 (d, J = 1.4 Hz, 3H), 2.26 (s, 3H), 1.98 (t, j = 1.7 Hz, IH), 1.59 (d, J = 6.8 Hz, 3H); MS (EI) for C33H37N7O2: 564.11 (MH+).
{00972] compound 5882-({2-[4-(5-{3-[(lS)-l-{[2-methyI-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-yl]amino}ethyl]phcnyl}pyrimidin-2-yl)piperazin-l-yl]cthyl}oxy)ethanol MS (El) for C34H39N7O3: 594.14 (ΜΙ- ).
[009731 Compound 5892-methyl-6-(3-mcthyl-l-bcnzofuran-5-yl)-N-[(lS)-l-(3-{2-[4-(2- morpholin-4-ylcthyl)piperazin-l-yI]pyrimidin-5-yI}phcnyl)cthyl]pyrimidin-4-amine Ή
NMR (400 MHz, CD3CN) δ 8.82 - 8.56 (m, 2H), 8.23 (s, IH), 7.99 (dd, .7= 8.7, 1.6 Hz, IH), 7.75 (s, 1H),7.64 (d,.7=0.9Hz, IH), 7.67-7.33 (m, 5H), 6.78 (s, IH), 6.33 (d, .7= 7.6 Hz, IH), 5.24 (s, 1 H), 3.91 - 3.82 (m, 4H), 3.72 - 3.65 (m, 4H), 2.61 - 2.54 (m, 8H), 2.53 - 2.47 (m, 7H), 2.34 (d, .7= 10.3 Hz, 3H), 1.66 (d, .1= 6.9 Hz, 3H); MS (EI) for C36H42N802: 619.16 (ΜΙ-Γ).
[009741 Compound 5976-(l,3-benzothiazoI-6-yI)-N-(l-{3-|6-(dimethyIamino)pyridin-3- yl]phcnyl}cthyl)-2-methylpyriniidin-4-aminc MS (EI) for C27H26N6S: 467.1 (MH+).
100975] Compound 6115-{3-[(lS)-l-{[6-(l,3-benzothiazoI-6-yl)-2-niethylpyrimidin-4- yI]amino}cthyl]phenyl}-N-mcthylpyrimidin-2-amine MS (EI) for C25H23N7S: 454.1 ( H+).
100976] Compound 612 -mcthyI-5-{3-[(lS)-l-{[2-methyl-6-(3-mcthyl-l-benzofuran-5- yl)pyrimidin-4-yl]amino}cthyl]phcnyl}pyrimidin-2-aminc Ή NMR (400 MHz, dmso-do): 58.63 (s, 2H), 8.18 (d, 1H), 7.94 (d, 1H), 7.80 (t, 2H), 7.59 (d, 1H), 7.53 - 7.46 (m, 1H), 7.44 -7.33(m, IH), 7.33 -7.20 (m, IH), 6.86 (s, 1 H).5.37 (s, IH), 2.84 (d,3H),2.41 (s, 3H), 2.24 (s, 3H), 1.53 (t, 3H). MS (EI) for C27H26 60: 451.2 (MH+).
1009771 Compound 6145-{3-[(lS)-l-{[6-(l,3-bcn othiazol-6-yl)-2-methylpyrimidin-4- yl|amino}cthyl]phenyl}-N, -dimcthyIpyrimidin-2-amine MS (EI) for C26H25 7S: 468.2 ( H÷)
[009781 Compound 615 N,N-dimcthyl-5-{3-[(lS)-l-{[2-methyl-6-(3-incthyl-l- bcnzofuran-5-yl)pyrimidin-4-yllamino}cthyl]phenyI}pyrimidin-2-amine Ή NMR (400 MHz. dmso-de): δ 8.71 - 8.62 (m, 21-1), 8.16 (d, 1H), 7.92 (d, IH), 7.80 (d, 1H), 7.57 (d, 1H), 7.51 -7.45 (m, 1 H), 7.38 (t, 2H), 6.85 (s, 1 H), 5.46 - 5.32 (m, 1 H), 3.19-3.11 (m, 6H), 2.38 (s, 3H), 2.22 (s, 3H), 1.50 (d, 3H). MS (El) for C28H28 f>0: 465.2 (MH+)
[00979] Compound 616 N-ethyl-5-{3-[(lS)-l-{[2-methyl-6-(3-niethyl-l-benzofuran-5- yl)pyrimidin-4-yllamino}ethyl| phenyl} pyrimidin-2-aniine MS (EI) for C28H28N60: 465.2 (MH+)
[00980] Compound 6175-{3-[(lS)-l-{[6-(l,3-bcnzothiazol-6-yI)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}-N-ethylpyrimidin-2-aminc S (EI) for C26H25N7S: 468.1 (MH*) 100981] Compound 6182-mcthyl-6-(3-methyI-l-benzofuran-5-yl)-N-{(lS)-l-[3-(2- morpholin-4-ylpyrimidin-5-y )phenyI]cthyl}pyrimidin-4-aminc Ή NMR (400 MHz, dmso-d6): δ 8.76 - 8.67 (m, 2H), 8.16 (t, IH), 7.92 (d, IH), 7.79 (m, 2H), 7.57 (d, IH), 7.51 - 7.47 (m, IH), 7.38 (t, 2H), 6.85 (s, IH), 5.37 (s, 1 H), 3.79 - 3.71 (m, 4H), 3.66 (ddd, 4H), 2.38 (s, 3H), 2.22 (s, 3H), 1.50 (d, 3H). MS (EI) for C3oH3oN602: 507.2 (MH*)
[00982] Compound 6192-mcthyI-6-(3-mcthyl-l-bcnzofuran-5-yl)-N-{(lS)-l-[3-(2- piperazin-l-ylpyrimidin-5-yl)phenyl]ethyI}pyrimidin-4-amine Ή NMR (400 MHz, dmso- de): δ 8.84 (s,2H),8.19(t, IH), 7.97 (s, 1 H), 7.88 - 7.77 (m, 2H), 7.74 (dd, IH), 7.60 (d, IH), 7.51 - 7.40 (m, 2H), 7.13 (d, IH), 5.59-5.48 (m, IH), 4.02 (m, 2H), 3.69 (m, 2H), 3.43 (m, 2H), 3.17 (m, 2H), 2.64 (s, 3H), 2.28 (s, 3H), 1.60 (d, 3H). MS (EI) for C30H31N7O HC1: 506.2 (MH÷)
100983] Compound 6212-|(5-{3-[(lS)-l-{|2-methyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-yl]amino}ethyl]phcnyl}pyrimidin-2-yl)amino]cthanol Ή NMR (400 MHz, dmso-d6): δ 8.63 (s, 2H), 8.17 (d, IH), 7.95 -7.62 (m, 3H), 7.51 (d, 1 H), 7.48 - 7.35 (m, 2H), 7.26 (t, IH), 6.96 (s, IH), 5.45 (s, IH), 3.58 - 3.49 (m, 2H), 3.39 (dd, 2H), 2.38 (s, 3H, overlapped), 2.26 (s, 3H), 1.56 (d, 3H). MS (EI) for C2sI-l28N602: 481.1 (ΜΙ-Γ) 100984] Compound 622 N,N-diethy]-5-{3-](lS)-l-{|2-methyl-6-(3-methyl-l-bcnzofuran- 5-yi)pyrimidin-4-yl]amino}cthyl|phcnyl}pyrimidin-2-aminc MS (Ef) for C30H3 N6O: 493.2 (Μ1-Γ)
100985] Compound 6255-{3-|(lS)-l-{[6-(l,3-bcnzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}cthyl]phenyl}-N,N-diethylpyrimidin-2-aminc MS (EI) for C28H29N7S: 496.2 (MH÷)
[00986] Compound 6266-(l,3-bcnzothiazol-6-yl)-N-](lS)-l-{3-]2-(4-ethylpipcrazin-l- yI)pyrimidin-5-yl|phcnyl}cthyl]-2-mcthylpyrimidin-4-amine Ή NMR (400 MHz, dmso- dfl): δ 9.47 (s, IH), 8.79 (s, 2H, overlapped), 8.14 (s, 2H), 7.94 (s, 1H), 7.75 (s, 1H), 7.49 (d, 1H), 7.43 (d, 2H), 6.92 (s, IH), 5.41 (s, IH), 4.07 - 3.41 (m, 6H, overlapped), 3.25-2.84 (m, 4H), 2.41 (s, 3H), 1.53 (d, 3H), 1.20 (d, 3H). MS (EI) for C3ol¾2N8S: 537.2 (ΜΙ-Γ)
[00987] Compound 627 l-(5-{3-|(lS)-l-{[6-(l,3-bcnzotbiazol-6-yl)-2-mcthyIpynmidin- 4-yl]amino}ethyl|phcnyI}pyrimidin-2-yl)pipcridin-4-oI MS (EI) for C29H29N7OS: 524.2 (ΜΙ- )
[00988] Compound 628 N-[(lS)-l-{3-[2-(4-cthyIpiperazin-l-yI)pyrimidin-5- yl|phenyI}cthyI]-2-methyl-6-(3-meth l-l-bcnzofuran-5-yl)pyrimidin-4-amine Ή NMR
(400 MHz, dmso-de): δ 8.71 (s, 2H), 8.19 (d, IH).7.94 (d, IH), 7.82 (s, 2H), 7.59 (d, IH), 7.54 -7.47 (m, IH), 7.40 (d, 2H), 6.87 (s, IH), 5.39 (s, IH), 3.82 - 3.63 (m,4H),2.51 (dt, 2H), 2.43 - 2.30 (m,4H, overlapped), 2.24 (s, 3H), 1.52 (d, 3H), 1.08-0.91 (m, 3H). MS (EI) for C32H35N7O: 534.2 (MH+)
100989] Compound 629 l-(5-{3-[(lS)-l-{I2-methy]-6-(3-mcthyl-l-benzofuran-5- yl)pyrimidin-4-yl]amino}ethyl]phcnyl}pyrimidin-2-yl)piperidin-4-ol'H'NMR (400 MHz, dmso-d6): δ 8.69 (s, 2H), 8.18 (d, IH), 7.94 (d, IH), 7.82 (s, 2H), 7.59 (d, IH), 7.55 - 7.46 (m, IH), 7.41 (t, 2H),6.87(s, lH),5.39(s, lH),4.77(d, 1 H), 4.31 (dt, 2H , 3.82- 3.61 (m, 1 H), 3.34 - 3.23 (m, 2H), 2.25 (s, 3H), 1.78 (dt, 21-1), 1.52 (d, 3H), 1.40 - 1.22 (m, 2H). MS (EI) for C31H32 6O2: 521.2 (MH+)
100990] Compound 630 l-(5-{3-[(lS)-l-{[2-methyI-6-(3-mcthyl-l-benzofuran-5- yl)pyrimidin-4-yl]aniino}cthyI|phenyl}pyrimidin-2-yl)pyriOlidin-3-ol Ή NMR (400 MHz, dmso-d6): δ 8.69 (s, 2H),8.19(d, 1 H), 7.94 (d, IH), 7.82 (s, 2H), 7.60 (d, IH), 7.54- 7.45 (m, IH), 7.41 (t, 2H), 6.88 (s, IH), 5.39 (s, IH), 5.01 (d, IH), 4.41 (d, IH), 3.67-3.46 (m, 4H), 2.41 (s, 3H), 2.25 (s, 3H), 2.05 - 1.98 (m, 1 H), 1.96- 1.86 (m, 1 H), 1.53 (d, 3H). MS (EI) for C3oH3oN602: 507.2 (MH+) 100991 1 Compound 631 N-(l -mcthylcthyl)-5-{3-[(l S)-l -{[2-mcthyl-6-(3-mcthyl-l- benzofuran-5-yl)pyriniidin-4-yl)aniino}ethyl|p cnyl}pyrimidin-2-aminc MS (EI) for
Figure imgf000314_0001
100992] Compound 632 [ l-(5-{3-[(l S)-l -{|2-niethyl-6-(3-methyl-l-bcnzofuran-5- yl)pyrimidin-4-yl]amino}cthyl]phenyI}pyriniidin-2-yl)pipcridin-4-yl]mcthanol Ή NMR
(400 MHz, dmso-df,): δ 8.68 (s, 2H), 8.1 8 (d, 1 M), 7.94 (d, 1H), 7.82 (s, 2H), 7.59 (d, 1 H), 7.51 - 7.45 (m, 1 H), 7.40 (t. 2H), 6.87 (s, 1 H), 5.44 - 5.28 (m, 1 H), 4.69 (t, 2H), 4.58 - 4.40 (m, 1 H), 3.32 - 3.22 (m, 2H), 2.97 - 2.84 (m, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 1 .71 (dd, 3H), 1 .50 (d, 3H), 1.18 - 0.95 (m, 1 H). MS (EI) for C32H34N6O2: 535.2 (MH+)
100993] Compound 633 N-|( l S)-l -{3-|2-(4-nuoropipcridin-l-yl)pynmidin-5- yl]phenyI}ethyI]-2-niethyl-6-(3-mcthyl-l-bcnzofuran-5-yl)pyrimidin-4-aminc Ή NMR (400 MHz, dmso.de): δ 8.72 (d, 21-1), 8.18 (d, 1 H), 7.94 (d, 1 H), 7.82 (d, 3H), 7.59 (d, 1 H), 7.53 - 7.47 (m, 1 H), 7.41 (d, 2H), 6.87 (s, 1 H), 5.38 (br s, 1 H), 5.07 - 4.81 (m, 1 H), 4.05 - 3.88 (m, 2H), 3.85 - 3.65 (m, 2H), 2.41 (s, 3H), 2.25 (s, 3H),.2.03 - 1.84 (m, 2H), 1 .79 - 1.63 (m, 2H), 1.52 (d, 3H). MS (EI) for C3| H3|FN60: 523.2 (MH+)
100994] Compound 634 N-(furan-2-ylmethyl)-5-{3-|(lS)-l-{l2-mct yl-6-(3-methyI-l- benzofuran-5-yl)pyrimidin-4-yl]amino}cthyI]phcnyl}pyrimidin-2-aminc Ή NMR (400 MHz, dmso-dfi): δ 8.66 (s, 2H), 8.18 (s, 1 H), 7.94 (d, 1 H), 7.82 (t, 3H), 7.64 - 7.54 (m, 1 H), 7.53 - 7.47 (m, 1 H), 7.37 (t, 2H), 6.87 (s, 1 H). 6.38 (dd, 1 H), 6.23 (t, 1 H), 5.38 (br s, 1 H), 4.53 (d, 2H), 2.41 (s, 3H), 2.24 (s, 3H): 1.52 (d, 3H). MS (EI) for C3|H28 602: 517.2 (MH+) 100995] Compound 635 N-(furan-3-yImethyl)-5-{3-[(lS)-l-{[2-mcthyl-6-(3-methyI-l - benzofuran-5-yl)pyrimidin-4-yl]amino}ethyl]phcnyl}pyrimidin-2-amine Ή NMR (400 MHz, dmso-de): δ 8.65 (s, 2H), 8.17 (s, 1H), 7.93 (d, 1 H), 7.82 (s, 2H), 7.70 (t, 1 H), 7.63 - 7.55 (m, 2H), 7.52 - 7.47 (m, 1 H), 7.39 (d, 2H), 6.87 (s, 1 H), 6.48 (dd, 1H), 5.45 - 5.30 (m, 1 H), 4.37 (d, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 1.52 (d, 3H). MS (EI) for C3|H28N602: 517.2 (ΜΙ- )
100996] Compound 666 N-[(l S)-l-{3-|6-(dimcthylamino)pyridin-3-yl]phenyl}cthyl]-2- methyl-6-(3-methyl-l -bcnzofuran-5-yI)pyrimidin-4-aminc MS (EI) for C29H29N5O: 464.2 (MH+).
[00997] Compound 667 6-(l ,3-bcnzothiazol-6-yl)-2-metIiyl-N-{l -[3-(6-piperazin-l- y!pyridin-3-yl)phcnyl]ethyl}pyrimidin-4-aminc MS (EI) for C29H29N7S: 508.2 (MH+).
[00998] Compound 670 2-mcthyl-6-(3-metliyl-l-bcnzofuran-5-yI)-N-{(l S)-l -[3-(6- piperazin-l-ylpyridin-3-yl)phcnyl]cthyl}pyrimidin-4-aminc Ή NMR (400 MHz, d6- DMSO): 9.36 (m, 211), 8.49 (m, 1 H), 8. 17 (s, 1 H), 7.97 (m, 2H), 7.81 (m, 2H), 7.72 (m, 1 H), 7.58 (m, 1H), 7.44 (m, IH), 7.12 (m, 2H), 5.54 (m, 1H), 5.31 (m, 1H), 3.83 (m, 4H), 3.20 (m, 4H), 2.64 (s, 3H), 2.28 (s, 3H).1.60 (ds 3H); MS (EI) for C3|H32 0: 505.3 (MH+).
100999] Compound 6762-mcthyI-N-[(lS)-l-{3-I6-(mcthylamino)pyridin-3- yl]phenyI}cthyl]-6-(3-methyl-l-bcnzofuran-5-yI)pyrimidin-4-aminc MS (EI) for C28H27N5O: 450.2 (MH+).
1001000] Compound 6772-methyl-6-(3-methyl-l-bcnzofuran-5-yI)-N-{(lS)-l-[3-(6- morpholin-4-ylpyridin-3-yl)phenyl]ethyI}pyrimidin-4-amine MS (EI) for C31H31 5O2: 506.2 (MH+).
[001001] Compound 6782-[(5-{3-[(lS)-l-{[2-mcthyl-6-(3-methyl-l-bcnzofuran-5- yl)pyrimidin-4-yI]amino}cthyl|phcnyl}pyridin-2-yl)amino]ethanoI MS (EI) for C29H29N5O2: 480.2 ( Ι-Γ).
[001002] Compound 683 N-[(l S)-l-{3-|6-(cthyIamino)pyridin-3-yl]phcnyl}cthy l|-2- methyI-6-(3-mcthyI-l-benzofuran-5-yl)pyrimidin-4-amine MS (EI) for C29H29N5O: 464.2 (MH+).
[001003] Compound 684 N-[(lS)-l-{3-[6-(4-cthylpiperazin-l-yI)pyridin-3- yl]phcnyl}ethyl]-2-mcthyl-6-(3-mcthyl-l-bcnzofuran-5-yl)pyrimidin-4-amine Ή NMR
(400 MHz, d6-DMSO): 8.45 (d, 1H), 8.18 (s. IH), 7.96-7.91 (m, 2H), 7.86 (s, IH), 7.84- 7.80 (m, 2H), 7.63 - 7.56 (m, 1 H), 7.49 - 7.44 (ms 1 H), 7.38 (s, 2H), 6.92 (d, IH), 5.37 (m, IH), 3.52 (m, 5H), 2.47 - 2.43 (m, 4H), 2.40 (m, 2H), 2.24 (s, 3H), 1.52 (d, 3H), 1.23 (s, 3H), 1.04 (t, 3H); MS (EI) for C33H3<i 60: 533.2 (MH+).
[001004] Compound 6856-(l,3-bcnzothiazol-6-yl)-N-[(lS)-l-{3-[6-(4-cthylpiperazin-l- yl)pyridin-3-yl]phcnyl}cthyl]-2-methylpyriniidin-4-aminc MS (EI) for C31H33N7S: 536.2 (MH+).
[001005] Compound 6876-(l,3-bcnzothiazoI-6-yl)-2-mcthyl-N-{(lS)-l-[3-(6-morpholin- 4-yIpyridin-3-yl)phcnyI]cthyl}pyrimidin-4-aminc MS (EI) for C29H2sN6OS: 509.2 (M.H+).
[001006]Compound 689 l-(5-{3-[(lS)-l-{]2-mcthj -6-(3-mcthyl-l-benzofuran-5- yI)pyrimidin-4-yl]amino}cthyl]phcnyl}pyndin-2-yl)pipcridin-4-ol Ή NMR (400 MHz, d6-DMSO): 8.43 (d, IH), 8.18 (d, 1 H), 7.93 (d, IH), 7.85 -7.76 (m, 3H), 7.73 - 7.64 (m, IH), 7.59 (d, IH), 7.46 (dd, IH), 7.38 (I, 2H), 6.92 (d, IH), 6.86 (s, IH), 5.38 (s, IH), 4.71 (d, 1H),4.05 (dt,2H), 3.76 -3.61 (m, IH), 3.12 (m, 2H), 2.41 (s,3H),2.21 (d, 3H), 1.84- 1.73 (m, 2H , 1. 1 (d, 3H), 1.42 - 1.29 (m, 2H); MS (EI) for C32H33N5O2: 520.2 (ΜΗ').
[001007] Compound 7026-(4-chloro-3-fluorophenyl)-2-methyI-N-{(lS)-l-[3-(6- piperazin-l-ylpyridin-3-yl)phcnyl|cthyl}pyrimidin-4-aminc Ή NMR (400 MHz. d6- D SO): 8.43 (d, IH), 7.93 (s, 2H), 7.82 (dd, 2H), 7.69 (s, 2H), 7.46 (d, 1 H), 7.37 ( 2H), 6.89 (d, 1H), 6.85 (s, lH),5.37(s, 1 H), 5.10 - 4.90 (m, lH), 3.54 - 3.39 (m, 4H), 2.82 - 2.72 (m, 4H), 2.39 (s, 3H), 1.51 (d, 311); MS (El) for C28H28C1FN6: 502.9 (MH÷).
[0010081 Compound 7053-[(5-{3-((IS)-l-{[6-(4-chloro-3-fluorophenyl)-2- methyIpyrimidin-4-yl]amino}cthyl|phcnyl}pyrimidin-2-yl)amino|propane- 1,2-diol Ή
NMR (400 MHz. d6-DMSO): 8.61 (s, 2H), 7.93 (s, 2H), 7.82 (s, 1H), 7.69 (s, 2H), 7.48 (d, 1H), 7.39 (t, 2H), 7.13 (t, 1 H), 6.84 (s, 1 H), 5.38 (s, 1 H), 5.04 - 4.75 (m, 1 H), 4.76- 4.36 (m, 1I-I), 3.74 - 3.61 (m, 1H), 3.45 (dd, 2H), 3.27 - 3.19 (m, 2H), 2.39 (s, 3H), 1.51 (d, 3H); MS (EI) for C26H26ClF f,02: 508.9 (MH+).
1001009] Compound 706 l-(5-{3-|(lS)-l-{|6-(4-chloro-3-fluorophenyl)-2- nicthylpyrimidin-4-yl]amino}cthyl|phenyl}pyrimidin-2-yl)pipcridin-4-ol Ή NMR (400 MHz, d6-DMSO): 8.67 (s, 2H), 7.92 (s, 2H), 7.85 - 7.75 (m, 1H), 7.69 (s, 2H), 7.48 (s, 1H), 7.39 (d,2H), 6.85 (s, lH),5.38(s, 1 H), 5.18 - 4.87 (m, 1H), 4.76 (d, 1H), 4.31 (dd, 2H), 3.76 (d, 1H)S 3.29 (s, 1H), 2.39 (s, 3H), 1.79 (d, 2H), 1.51 (d, 3H), 1.42 - 1.25 (m, 2H); MS (El) for C28H28C1FN60: 518.9 (MH+).
1001010] Compound 7216-(l,3-benzothiazoI-6-yl)-2-mcthyI-N-{(lS)-l-[3-(2-piperidin-l- ylpyrimidin-5-yI)phcnyl]cthyl}pyrimidin-4-aminc MS (EI) for C29H29N7S: 508.2 (MH+)
[001011]Compound 722 '-(5-{3-l(lS)-l-{[6-(l,3-bcnzothiazol-6-yl)-2-niethylpyrimidin- 4-yl]amino}cthyl]phcnyl}pyrimidin-2-yI)-N,N-dimcthylpropanc-l,3-diamine Ή NMR
(400 MHz, d -MeOH): 9.36 (s, 1H), 8.62 (brs, 2H), 8.58 (brs, lH), 8.18 (d, 1H), 7.96 (brd, 1H),7.62 (brs, 1H),7.42 (brs,3H): 6.82 (brs, 1 H), 5.21 (br m, 1H), 3.54 (t, 2H),3.20 (m, 2H), 2.85 (s, 6H), 2.45 (s, 3H), 2.02 (m, 2H), 1.62 (d, 3H); MS (EI) for C29H32 SS: 525.2 (MH+).
1001012] Compound 723 N-[(lS)-l-{3-[2-(4-acctylpipcrazin-l-y])pyrimidin-5- yl]phcnj }cthy!]-2-methyI-6-(3-mctbyl-l-benzofuran-5-yl)pyrimidin-4-amine
1001013] Ή NMR (400 MHz, d4-MeOH): 9.57 (s, 2H), 7.98 (br s, 1H), 7.70 (br d, 1H), 7.60 (br s, 1H), 7.53 (br s, lH), 7.24 (br d, 1H), 7.38 (br s, 3H), 6.65 (br s, 1H), 5.21 (br m, 1H), 3.85 (m, 2H), 3.80 (m, 2H), 3.64 (m, 2H), 3.58 (m, 2H), 2.48 (s, 3H), 2.21 (s, 3H), 2.14 (s, 314), 1.61 (d.3H); MS (EI) for C32H33 7O2: 548.2 (ΜΙ- ).
|001014]Compound 7245-{3-|(lS)-l-{]2-metliyl-6-(3-methyl-l-benzofuran-5- yl)pynmidin-4-yl]amino}cthyl]phenyl}-N-(tctrahydrofuran-2-yImcthyI)pyrimidin-2- aminc Ή NMR (400 MHz, d -MeOH): 8.53 (s, 2H), 7.95 (br s, 1H), 7.71 (d, 1H), 7.62 (br s, 1H), 7.52 (brs, 1H), 7.46 (d, 1H), 7.39 (br s, 3H), 6.62 (br s, 1H),5.31 (br m, lH),4.12(m, 1H), 3.82 (m, 1H), 3.73 (m, H), 3.51 (m, 2H), 2.48 (s, 3H), 2.21 (s, 3H), 1.85-2.10 (m, 3H), 1.64 (m, 1H), 1.58 (d, 3H); MS (EI) for C31H32N6O2: 521.2 (MH*). [001015] Compound 567 l-(5-{5-|(lS)-l-{[2-mcthyl-6-(3-mcthyl-l-bcnzofuran-5- yl)pyrimidin-4-yl]amino}ethyl|pyridin-3-yl}pyrimidin-2-yl)piperidin-4-oI Ή NMR (400 MHz. dmso) δ 8.71 (s, 3H), 8.58 (s 1H), 8.17 (s, 1H), 8.13 - 8.05 (m, 1H), 7.91 (s, 1H), 7.80 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, lH), 6.86 (s, 1H), 6.79 - 6.59 (m, 1H), 4.28 (d, J = 13.3 Hz, 2H), 2.38 (s, 3H), 2.22 (s, 3H), 1.88 - 1.68 (m, 3H), 1.53 (d, J = 6.6 Hz, 3H) 1.31 (d, J = 9.2 Hz, 2H); MS (El) for C30H31N7O2: 522.3 (MH+).
[001016) Compound 6563-[(5-{3-|(lS)-l-{[6-(7-fluoro-3-mcthyl-l-bcnzofuran-5-yl)-2- methylpyrimidin-4-yl|amino}cthyI|phenyl}pyrimidin-2-yl)amino]propane-l,2-dioI Ή
NMR (400 MHz, dmso-dfl): δ 8.63 (s, 2H), 8.04 (s, 1H), 7.93 (s, 1H), 7.83 (s, 2H), 7.48 (d, 1H), 7.39 (d, 1H), 7.12 (t, 1H), 6.89 (s, 1H), 5.38 (s, 1H), 4.82 (d, 1H), 4.60 (t, 1H), 3.73 - 3.59 (m, 1 H), 3.34 - 3.23 (m, 3H), 2.41 (s, 3H), 2.26 (s, 3H), 1.52 (d, 3H). MS (EI) for C29H29FN6O3: 529.2 (MH")
[001017] Compound 657 l-(5-{3-[(lS)-l-{[6-(7-nuoro-3-nicthyI-l-benzofuran-5-yI)-2- mcthylpyrimidin-4-yl|amino}ethyl]phenyl}pyrimidin-2-yI)piperidin-4-ol Ή NMR (400 MHz, dmso-de): δ 8.67 (d, 2H), 8.02 (s, 1H), 7.86 (ds 3H), 7.47 (d, 1H), 7.38 (s, 2H), 6.83 (d, 1H).5.47 - 5.25 (m, 1H), 4.83-4.65 (m, 1H), 4.26 (dd, 2H), 3.73 (dd, 1H), 2.55 - 2.46 (m, 3H), 2.24 (s, 3H), 1.75 (t, 2H), 1.50 (d, 3H), 1.32 (dt, 2H). MS (El) for C.3iH3,FN602: 539.2 (MH÷)
[001018] Compound 729 N-[(lS)-l-{3-|2-(4-acetyIpipcrazin-l-yl)pyrimidin-5- yl]phenyl}cthyl]-2-methyl-6-(3-methyl-l-benzothicn-5-yl)pyrimidin-4-aminc Ή NMR (400 MHz. d6-DMSO): 8.80 (s, 1H), 8.72 (s, 1H), 8.27 (br d, H I), 7.82 (br s, 1H), 7.76 (br s, 1H), 7.62 (brd, 2H), 7.48 (m, 2H), 7.02 (brs, 1H), 5.28 (brm, 1H), 4.80 (brs, 1H), 3.86 (m, 2H), 3.78 (m, 2H), 3.52 (m, 4H), 2.61 (s, 3H), 2.45 (s, 3H), 2.02 (s, 3H), 1.61 (d, 3H); MS (EI) for C32H33N7OS: 564.2 (ΜΙ-Γ).
[001019] Compound 730 N-{(lS)-l-[3-(2-{4-[2-(dimcthyIamino)cthyIlpiperazin-l- yl}pynmidin-5-yl)phcnyI|ethyl}-2-mcthyl-6-(3-methy!-l-bcnzothien-5-yI)pyrimidin-4- aminc Ή NMR (400 MHz, d6-DMSO): 9.41 (br s, 1H), 8.82 (br s, 2H), 8.32 (br s, 1H), 8.25 (d, 1H), 7.81 (brd, 1H), 7.62 (brs, 2H), 7.48 (d, 2H), 7.12 (brs, 1H)S 4.81 (brm, 1H), 3.62 (m, 4H), 3.26 (m, 4H), 2.85 (s, 6H), 2.62 (s, 3H), 2.51 (s, 3H), 1.65 (d, 3H), 1.22 (m, 4H); MS (EI) for C34H40N8S: 593.3 (ΜΙ- ).
[001020[Compound 7345-{3-[(lS)-l-{|2-methyl-6-(3-methyl-l-benzothien-5- yI)pyrimidin-4-yl]amino}cthyI]plienyl}pyrimidin-2-aminc MS (EI) for1 H NMR (400 MHz, dmso) δ 8.58 (s, 2H), 8.31 (br s, 1 H).7.99 (m, 2H), 7.82 (br m, 2H), 7.43 (m, 4H), 6.81 (br s, 2H), 2.43 (m, 6H), 1.52 (d, 3H); MS (EI) for C26H24N6S: 453.0 (MH+). Biological Examples
[0010211 Suitable in vitro examples for measuring iPFK-2 activity and the inhibition thereof by compounds are known in the art. Compounds of formula 1 have been tested using one of more of the assays described in Biological Examples 1 and 2.
Biological Example 1
iPFK-2 Luciferasc-Coupled Chemiluminescence Assay Protocol
[001022] iPFK-2 activity was measured as the percent of ATP consumed following the kinase reaction using luciferase-luciferin-coupled chemiluminescence. The kinase reaction consists of active enzyme phosphorylating the 2-position of the substrate (friictose-6-phosphate) to form the product (fructose-2.6-bisphosphale). All reactions were conducted in 384-well white, medium binding microtiter plates (Greiner). Kinase reactions were initiated by combining test compounds (at varying concentrations), ATP. substrate (fructose-6- phosphate), and kinase in a 20 μL· volume. The standard assay concentrations for enzyme, ATP, and substrate are 50 nM, 5 μΜ, and 20 . respectively. The assay buffer is composed of 20 niM Tris-HCL (pH 7.5), 10 mM gCl2. 5 mM KPi (pH 7.5), 0.1 mM EDTA (pH 8.0), 0.02% NP-40, and 1 mM DTT. The reaction mixture was incubated at ambient temperature for 3 h. Following the kinase reaction, a 1 0 μί aliquot of luciferase-luciferin mix (Promega Kinase-Glo) was added and the chemiluminescence signal measured using an EnVision plate reader (Perkin Elmer). Total ATP consumption was limited to 40-60%. IC50 values were calculated by nonlinear regression analysis using the four-parameter equation [Y = min + (max - min) / ( 1 + (X/IC5o)N)] where Y is the observed signal, X is the inhibitor
concentration, min is the background signal in the absence of enzyme (0% enzyme activity), max is the signal in the absence of inhibitor (100% enzyme activity), IC50 is the inhibitor concentration at 50% enzyme inhibition and N represents the empirical Hill slope as a measure of cooperativily. Typically N should approximate unity. Curve fitting was performed using commercial software (idbs ActivityBase XE).
Biological Example 2
iPFK-2/PPI-PFK UV-VIS Assay Protocol
[001023] iPFK-2 activity was measured using UV-Visible spectrometry to monitor the change in absorption as the reaction progresses via a number of coupling steps. First iPFK-2 phosphorylates fructose-6-phosphate to form fructose-2,6-bisphosphate, which activates the pyrophosphate-dependent phosphofructokinase (PPi-PFK) that depends on the concentration of fructose-2,6-bisphosphate. The activated PPI-PFK. then produces fructose- 1 ,6- bisphosphate from fructose-6-phosphate. Once coupled with aldolase, triosephosphate isomerase, and glycerophosphate dehydrogenase, the amount of fructose- 1 ,6-bisphosphate formed is correlated directly with the loss of NADH whose concentration can be determined by UV-Vis absorbance at 340 nm. Therefore the NADH absorbance is proportional to the concentration of fructose-2.6-bisphosphate, the product of iPF -2. All reactions were conducted in 384-well v-bottom plates. Kinase reactions were initiated by combining test compounds (at varying concentrations), ATP, substrate (fructose-6-phosphate), and kinase in a 30 μί volume. The standard assay concentrations are prepared as detailed in Table 2.
Table 2. Kinase Reagent Preparation
Figure imgf000319_0001
[001024] The assay buffer is comprised of 20 mM Tris-HCL (pH 7.5), 5 mM KPi (pH 7.5), 0.1 mM EDTA (pH 8.0), 0.02% NP-40, and 1 mM DTT. The reaction mixture is incubated for ten minutes before addition of the ATP/substrate, then at ambient temperature for one hour. 0.1 M NaOH is then added to the plate and heated at 90°C for ten minutes.
[001025J After cooling, 3 μL· of the reaction mixture is diluted in 178 μί of the coupling buffer in a 384-well clear flat bottom plate. The coupling buffer is comprised of 20 mM Tris- HC1 (pH 7.5), 10 mM MgCb, and 1 mM DTT. Then, 20 μΐ, of coupling enzyme mix is added to this plate and incubated, with shaking, at room temperature for fifteen minutes. The coupling enzyme mix is prepared as detailed in Table 3
Table 3. Coupling Enzyme Mix Preparation
Stock Reagent Dilution Final
Concentration (3X) Concentration
20 mM NADH (N6785) 0.45 mM 0.15 mM
[add 7\ 0 μΙ buffer to 10 mg
Sigma vial)
10 mg/niL Aldolase (A2714) 0.15 mg/mL 0.05 mg/mL
[rabbit muscle]
3 mg/mL TOPI (T6258) 0.003 mg/mL 0.001 mg mL
[triosephosphate isomerase]
3 mg/mL G3PF (G6880) 0.03 mg/mL 0.01 mg/mL [glycerophosphate
dehydrogenase-rabbit muscle]
100 mM F6P (F3627) 3 mM 1 mM
[fructose-6-phosphate]
1 mg/mL PPi-PF (F2258) 0.03 mg/mL 0.01 mg/mL
[phosphofructokinase]
[001026] After the coupling enzyme mix, 20 ί of pyrophosphate (7.5 mM , Sigma P-8135) is added to the plate and incubated, with shaking, at room temperature for fifteen minutes. Ί hen, 30 μΐ.. of 0.25 M EDTA solution is added to the plate. The absorbances at 340 nm were then read on an EnVision plate reader (Perkin Elmer) and recorded. lCso values were calculated by nonlinear regression analysis using the four-parameter equation [Y min + (max - min) / (1 + (X/1CJO)N)] where Y is the observed signal, X is the inhibitor
concentration, min is the background signal in the absence of enzyme (0% enzyme activity), max is the signal in the absence of inhibitor ( 100% enzyme activity), IC50 is the inhibitor concentration at 50% enzyme inhibition and N represents the empirical Hill slope as a measure of cooperativity. Typically N should approximate unity. Curve fitting was performed using commercial software (idbs ActivityBase XE).
(001027] Table 4 summarizes the observed activities of compounds of formula 1 in Assays 1 and 2. In the table. "+++" means an activity of (IC50 value) greater than 0 and less than 500 nM. and " ++ " means an activity of 500 and less than 1000 nM, and means an activity greater than 1000 nM.
Table 4.
IPFK2 IPFK2 IPFK2
Tabic IPFK2 Tabic IPFK2 Tabic IPFK2
PPI- PPI- PPI- Comp (IC50) Comp (IC50) Comp (1C50)
PFK PFK PFK
20 +++ +++ 36 +++ 52 ++
21 +++ +++ 37 +++ 53 ++
22 +++ +++ 38 +++ 54 +
23 +++ +++ 39 ++ 55 + ++
24 +++ +++ 40 +++ 56 +
25 +++ 41 ++ 57 +
26 +++ 42 ++ 58 +
27 +++ 43 ++ 59 +
28 +++ 44 ++ 60 +
29 +++ 45 ++ 61 +
30 +++ +++ 46 ++ 62 +
31 +++ 47 ++ 63 +
32 +++ 48 ++ 64 +
jj +++ +++ 49 ++ 65 +
34 +++ 50 ++ 66 +
35 +++ 51 ++ 67 + IPFK2 I FK2 IPFK2
Tabic IPF 2 Table IPFK2 Tabic IPFK2
PPI- PPI- PPl- Comp (IC50) Comp (IC50) Comp (IC50)
PFK PFK PFK
68 + 114 + 160 +
69 + 115 + 161 +
70 + 116 + 162 +
71 + 117 + 163 +++ +++
72 + 118 + 164 +++ +++
73 + 119 + 165 +
74 + 120 + 166 + +
75 + 121 + 167 +
76 + 122 + 168 +++
77 + 123 + 169 +++
78 + 124 + 170 +++
79 + 125 + 171 +++
80 +++ +++ 126 + 172 +++
81 + 127 + 173 +++
82 + 128 + 174 +++
83 + 129 + 175 +++
84 +++ +++ 130 + 176 ++
85 +++ +++ 131 +++ +++ 177 ++
86 +++ +++ 132 +++ +++ 178 ++
87 +++ +++ 133 +++ +++ 179 +
88 +++ 134 +++ +++ 180 +
89 +++ 135 +++ 181 +
90 +++ 136 +++ +++ 182 + +
91 +++ +++ 137 +++ 183 +
92 +++ 138 +++ +++ 184 +
93 +++ 139 +++ +++ 185 +
94 +++ 140 +++ 186 +
95 +++ 141 +++ +++ 187 +
96 +++ 142 +++ 188 +
97 +++ 143 +++ 189 +
98 +++ 144 +++ 190 +
99 +++ 145 +++ 191 +++ +++
100 ++ ++ 146 +++ 192 +++
101 ++ 147 +++ 193 +++
102 ++ 148 +++ 194 +++
103 ++ 149 ++ 195 +++
104 + 150 ++ 196 +++
105 + 151 ++ 197 +++
106 + 152 ++ 198 +++
107 + 153 + 1.99 +++
108 + 154 + 200 ++
109 + 155 + 201 ++
110 + 156 + + 202 +
111 + 157 + 203 +
112 + 158 + 204 +
113 + 159 + 205 + IPFK2 IPFK2 IPFK2
Table IPFK2 Table IPF 2 Tabic IPFK2
PPI- PPI- PPI- Comp (IC50) Comp (IC50) Comp (IC50)
PF PFK PFK
206 + 252 ++ + 298 +++ +++
207 + 253 +++ 299 +++ +++
208 + 254 +++ 300 +++ +++
209 + 255 +++ 301 +++ +++
210 +++ +++ 256 +++ 302 ++ +++
21 1 +++ +++ 257 ++ 303 +++ +++
212 +++ +++ 258 ++ 304 ++ +++
213 +++ +++ 259 ++ 305 + +++
214 +++ +++ 260 + 306 + ++
215 ++ +++ 261 + 307 ++ ++
216 +++ +++ 262 +++ +++ 308 + ++
21 7 +++ +++ 263 +++ +++ 309 + ++
218 ++ +++ 264 +++ +++ 3 10 ++ ++
219 +++ +++ 265 ++.+ +++ 3 1 1 + ++
220 ++ +++ 266 ++ +++ 3 12 + +
221 +++ +++ 267 ++ +++ 313 + +
222 ++ +++ 268 +++ +++ 3 14 + +
223 + +++ 269 ++ +++ 315 +
224 ++ +++ 270 ++ ++ 316 +
225 ++ +++ 271 ++ ++ 31 7 +
226 + ++ 272 + + 3 1 8 +++
227 +++ ++ 273 + 3 19 +++
228 +++ ++ 274 + 320 +++ +++
229 +++ ++ 275 + 321 +++ +++
230 ++ ++ 276 +++ 322 +++ +++
231 +++ ++ 277 +++ 323 +++ +++
232 +++ ++ 278 ++ 324 +++ +++
233 +++ ++ 279 ++ 325 +++ +++
234 ++ ++ 280 ++ 326 +++ +++
235 ++ ++ 281 + 327 +++ +++
236 ++ ++ 282 + 328 +++ +++
237 + ++ 283 + 329 +++ +++
238 + ++ 284 + 330 +++ +++
239 + ++ 285 + 331 +++ +++
240 +++ ++ 286 + ->_>/ +++ +++
241 +++ + 287 + 333 +++ +++
242 ++ + 288 + 334 +++ +++
243 ++ + 289 + 335 +++ +++
244 + + 290 +++ +++ 336 +++ +++
245 + + 291 +++ +++ 337 ++ +++
246 + + 292 +++ +++ 338 +++ +++
247 ++ + 293 +++ +++ 339 +++ +++
248 + 294 +++ +++ 340 +++ +++
249 + + 295 +++ +++ 341 ++ +++
250 + + 296 +++ +++ 342 ++ +++
25 1 + 297 +++ +++ 343 ' + +++ IPFK2 IPFK2 IPFK2
Tabic 1PFK2 Table IPFK2 Table IPF 2
PPI- PPI- PPI-
Comp (IC50) Comp (1C50) Comp (IC50)
PFK PF PFK
344 +++ +++ 390 +++
436 +++
345 +++ +++ 391 + ++
346 +++ +++ 392 + 437 +++ +++
347 +++ +++ 393 + 438 ++ +++
348 + +++ 394 + 439 +++ +++
349 ++ +++ 395 + 440 + +++
350 +++ +++ 396 +++ +++ 441 +++ +++
351 ++ +++ 397 +++ +++ 442 ++ +++
352 +++ +++ 398 +++ +++ 443 ++ +++
353 +++ +++ 399 +++ +++ 444 +++ +++
354 +++ +++ 400 +++ +++ 445 ++ +++
355 + +++ 401 +++ +++ 446 +++ +++
356 ++ ++ 402 +++ +++ 447 + +++
357 ++ +++ 403 +++ +++ 448 +++ +++
358 ++ +++ 404 +++ +++ 449 +++ ++
++
359 +++ +++ 405 +++ +++ 450 +++
360 +++ ++ 406 +++ +++ 451 + ++
361 +++ ++ 407 +++ +++ 452 + ++
++
362 ++ ++ 408 +++ +++ 453 +++
363 ++ +++ 409 +++ +++ 454 +++ ++
364 +++ ++ 410 +++ +++ 455 ++ ++
365 + ++ 41 1 +++ +++ 456 ++ ++
366 +++ ++ 412 +++ +++ 457 + ++
367 + ++ 413 +++ +++ 458 ++ ++
368 +++ ++ 414 +++ +++ 459 + +
369 + +++ 415 +++ +++ 460 +++ +
370 +++ ++ 416 +++ +++ 461 ++ +
371 ++ ++ 417 +++ +++ 462 +++ +
372 + + 418 +++ +++ 463 + +
373 + + 419 +++ +++ 464 + +
374 + + 420 +++ +++ 465 +
375 + + 421 +++ +++ 466 +
376 +++ + 422 +++ +++ 467 +
+
377 + + 423 +++ 468 +
378 + + 424 +++ +++ 469 +++
+++
379 + ++ 425 +++ +++ 470
380 +++ + 426 +++ +++ 471 +++
381 + + 427 +++ +++ 472 +
382 + + 428 +++ +++ 473 +++ +++
383 + + 429 +++ +++ 474 +++ +++
384 ++ + 430 + +++
475 +++ +++
385 + + 431 +++ +++
476 +++ +
386 + + 432 ++ +++ 477 +++ +++
387 + 433 + +++ 478 +++ ++
388 + 434 +++ +++ 479 +
389 +++ 435 ++ +++ 480 +++ +++ IPFK2 IPFK2 IPFK2
Table IPFK2 Table IPFK2 Table IPFK2
PPI- PPI- PI- Comp (IC50) Comp (IC50) Comp (IC50)
PFK PFK PF
481 +++ +++ 527 + + 573 +++
482 ++ +++ 528 + + 574 +++
483. + ++ 529 + + 575 +++
484 ++ + 530 + + 576 + +
485 ++ + 531 + 577 + +++
486 + ++ 532 + 578 +++ +++
487 + 533 +++ 579 +++ +++
488 + 534 ++ 580 +++ +++
489 + 535 +++ +++ 581 +++ +++
490 + 536 +++ +++ 582 +++ +++
491 +++ 537 +++ +++ 583 ++ +
492 ++ 538 +++ +++ 584 +++
493 ++ 539 +++ +++ 585 +++
494 + 540 ++ + 586 +++
495 + 541 +++ +++ 587 +++
496 + 542 +++ +++ 588 +++
497 + 543 ++ +++ 589 +++
498 + 544 + ++ 590 +++ +++
499 + 545 + ++ 591 +++
500 + 546 +++ +++ 592 +++
501 +++ +++ 547 + ++ 593 +++ +++
502 ++ +++ 548 +++ +++ 594 +++ +++
503 +++ +++ 549 +++ +++ 595 +++
504 ++ +++ 550 +++ +++ 596 + ++
505 +++ +++ 551 +++ 597 ++ ++
506 +++ ++ 552 +++ 598 + ++
507 ++ ++ 553 +++ 599 +++ +++
508 ++ 554 +++ 600 +++ +++
509 + ++ 555 +++ 601 +++ +++
510 ++ + 556 +++ +++ 602 +++ +++
51 1 + + 557 +++ 603 +++ +++
512 + + 558 +++ 604 +++ +++
513 ++ 559 +++ 605 +++ +++
514 +++ +++ 560 +++ 606 +++ +++
51 5 +++ +++ 561 +++ 607 +++ +++
516 +++ +++ 562 +++ 608 +++ +++
517 +++ +++ 563 +++ 609 +++ +++
518 ++ +++ 564 +++ 610 +++ +++
519 + +++ 565 +++ 61 1 +++ +++
520 + +++ 566 +++ 612 +++ +++
521 ++ +++ 567 +++ 613 +++ +++
522 +++ +++ 568 +++ 614 +++ +++
523 ++ +++ 569 +++ 615 +++ +++
524 + +++ 570 +++ 616 +++ +++
525 + ++ 571 +++ 61 7 +++ +++
526 +++ ++ 572 +++ 61 8 +++ +++ IPFK2 IPFK2 IPFK2
Tabic IPFK2 Tabic I F 2 Tabic IPF 2
PPI- PPI- PPI- Comp (IC50) Comp (IC50) Comp (IC50)
PF PFK PFK
619 +++ +++ 665 ++ ++ 71 1 ++ +++
620 +++ +++ 666 +++ +++ 712 ++ +
621 +++ +++ 667 +++ +++ 713 +++ +++
622 +++ +++ 668 +++ +++ 714 +++ +++
623 +++ +++ 669 +++ +++ 715 +++ +++
624 +++ 670 +++ +++ 716 ++ +++
625 ++ 671 +++ +++ 71 7 +++ +++
626 +++ 672 +++ +++ 71 8 +++ +++
627 +++ 673 +++ +++ 719 +++
628 +++ 674 +++ +++ 720 +
629 +++ 675 +++ +++ 721 ++
630 +++ 676 +++ +++ 722 +++
63 1 +++ 677 +++ +++ 723 +++
632 +++ 678 +++ +++ 724 +++ +++
633 +++ 679 +++ 725 +++
634 +++ +++ 680 +++ +++ 726 +++
635 +++ 681 + 727 +++
636 +++ 682 +++ +++ 728 +++
637 +++ 683 +++ 729 +++
638 +++ 684 +++ 730 +++
639 +++ 685 +++ 73 1 +++
640 +++ +++ 686 +++ 732 +++
641 +++ 687 +++ 733 +++ +++
642 ++ 688 +++ 734 +++ +++
643 +++ 689 +++ 735 +++ +++
644 +++ 690 +++ 736 +++
645 +++ 691 +++
646 +++ 692 +++
647 ++ 693 +++
648 +++ 694 +++ +++
649 +++ 695 +++ +++
650 +++ 696 +++
651 +++ 697 +++
652 +++ 697 +++
653 +++ 699 +++
654 +++ 700 +++
655 +++ 701 +++
656 +++ 702 +++
657 +++ 703 +++
658 +++ ' 704 +
659 +++ 705 +++
660 +++ 706 +++
661 ' +++ 707 +++
662 +++ 708 +++
663 +++ +++ 709 +++
664 + ++ 710 ++ +++ |001028] It should be noted that, as used in this specification and the appended claims, singular articles such as "a," "an," and "the," may refer to a single object or to a plurality of objects unless the context clearly indicates otherwise. Thus, for example, reference to a composition containing "a compound" may include a single compound or two or more compounds. It is to be understood that the above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those of skill in the art upon reading the above description. Therefore, the scope of the invention should be determined with references to the appended claims and includes the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references, including patents, patent applications and publications, are herein incorporated by reference in their entirety and for all purposes.

Claims

What is claimed is:
1 . A compound of fo
Figure imgf000327_0001
or a pharmaceutically acceptable salt thereof, wherein:
W is a branched or straight C 1.12 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Qi)2-, -C(Q2)2-, -CHQi-, -CI-IQ2-, -CO-. -CS-, -CONRA-. -CONRANRA-, -C02-, -OCO-, -NRA-, -NRAC02-, -0-, -NRACONR'\ -OCONRA- , -NRANRA-, -NRACO-: -S-, -SO-, -S02-: -S02NRA-, -NRAS02-, or -NRAS02NRA;
each RA is independently hydrogen. C|.g aliphatic; cycloaliphatic,
heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1 -3 of Qi or Q2;
X i , X2, and X3 are each independently absent or are a cycloaliphatic,
heterocycloaliphatic, aryl, or heteroaryl. each or which are optionally and independently substituted with 1 -3 of Qi , or Q2, and wherein at least one of X|, X2. and X3 is present;
Y is absent or is a branched or straight C M ? aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q i)2-, -C(Q2)2-, -CHQt-, -CHQ2-. -CO- , -CS-, -CONRB-, -C(=NRB)NRl\ -C(=N ORB) Rb-: -NRUC(=NRU)NRU-, -CONRBNRB-, - CO2-, -OCO-, -NR -. -NRBC02-, -0-, -NR"CONRB-, -OCONR"-, -N RBN RB-, -NRBCO-, -S-, -SO-, -S02-( -S02NRB-, -NR S02-, or -NRuS02NR ;
each RB is independently hydrogen, Ci-g aliphatic, cycloaliphatic.
heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1 -3 of Qi or Q2;
Z is independently hydrogen, C .n aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl. optionally substituted with 1 -3 of Qj or Q2; or
L is absent or is NH, N(C |.s aliphatic), or is a branched or straight C aliphatic chain wherein up to two carbon units of L are optionally and independently replaced by -C(Qi)2-, -C(Q2)2-, -CO-, -CS-, -CON Rc-, -C0NRcNRc-, -C02-, -0C0-, -NRC-, -NRcC02-, -0-, -NRcC0NRc-, -OCONRc-, -NRCNRC-, -NRcCO-, -S-, -SO-, -S02-, -S02NRc-, -NRcS02-, or -NRcS02NRc;
each Rc is independently hydrogen, C|.g aliphatic, cycloaliphatic,
heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1 -3 of Qi or Q2;
Ring A is a monocyclic, bicyclic, or tricyclic cycloaliphatic, heterocycloaliphatic, aryl. or heteroaryl. any of which may be optionally substituted with 1 -3 of halo. -OH, oxo, -CF3, -OCF3, cyano, or a C| .n branched or straight aliphatic, wherein 1 -3 methylene groups of the aliphatic are optionally and independently replaced with -C(O)-, -0-, -NH-, -C(0)NH-. or -C(0)0-, and wherein the aliphatic is optionally further substituted with 1 -3 of halo, cyano. OH or Ci-3 aliphatic;
each Q, is independently halo, oxo, -CN, -N02, -N=0, -NHOQ2) =NQ2, =NOQ2, -OQ2, -SOQ2, -S02Q2) -SON(Q2)2: -S02 (Q2)2, -N(Q2)2, -C(0)OQ2, -C(0)-Q2, -C(0)N(Q2)2, -C(=NQ2)NQ2-, -NQ2C(=NQ2)NQ2-, -C(0)N(Q2)(OQ2), -N(Q2)C(0)-Q2, -N(Q2)C(0)N(Q2)2, -N(Q2)C(0)0-Q2, -N(Q2)S02-Q2 -N(Q2)SO-Q2or aliphatic optionally including 1 -3 substituents independently selected from Q2 or Q3.
each Q2 is independently hydrogen, aliphatic, alkoxy, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heleroaryl ring, each optionally including 1 -3 substituents independently selected from Q3;
each Q3 is halo, oxo, CN, N( NH2, CF3 OCF3, OH, -COOH, or C C alkyl optionally substituted with 1 -3 of halo, oxo, -CN, -N02, -CF , -OCF3: -OH, -SH, -S(0)3H, - NH2, or -COOH;
provided that the compound of formula I is not
Figure imgf000328_0001
2. The compound of claim 1 , wherein L is absent or is NH.
3. The compound of claims 1 -2, wherein W is absent.
4. The compound of claims 1 -2, wherein W is a branched or straight CM2 aliphatic chain.
5. The compound of claims 4, wherein W is -CH(CH3)-.
6. The compound of claims 1 -5. wherein X| is a fused bicyclic cycloaliphatic, hcterocycloaliphatic, aryl, or heteroaryl and X2 and X3 are absent.
7. The compound of claim 6, wherein X| is naphthalenyl, chromanyl, isochromanyl, thiocromanyl, isothiocromanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
tetrahydronaphthyl, indanyl, or indenyl.
8. The compound of claims 1 -5, wherein X | is an optionally substituted monocyclic cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl.
9. The compound of claim 8. wherein | is an optionally substituted cyclohexyl, oxazolyl, phenyl, pyridyl, pyrimidinyl, piperidinyl, or pyrrolidinyl.
10. The compound of claim 8, wherein X| is optionally substituted phenyl, pyridyl, or pyrimidinyl.
1 1 . The compound of claims 8- 1 0, wherein X2 and X3 are absent.
12. The compound of claims 8- 10, wherein X3 is absent.
13. The compound of claim 12, wherein X2 is heterocycloaliphatic, aryl, or heteroaryl.
14. The compound of claim 1 2, wherein X2 is pyridyl, pyrimidinyl, tetrazolvl, triazolyl, imidazolyl, or pyrazolyl.
15. The compound of claim 12. wherein X2 is heterocycloaliphatic, aryl or heteroaryl and X is heterocycloaliphatic or heteroaryl.
16. The compound of claims 8- 10, wherein X2 is pyridyl, pyrimidinyl, tetrazolyl, triazolyl, imidazolyl, or pyrazolyl and X3 is piperizinyl, piperidinyl, or morpholinyl.
17. The compound of claims 1 - 16 wherein;
Y is absent or is a branched or straight d .i2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Q |)2-, -C(Q2)2-, -CHQ , -CHQ2-, -CO- , -CS-, -CONR15-, -CONIl'W-, -CO2-, -OCO-. -NRB-, -NRBC02-, -0-, -NRl5C0NRB-, -0C0NRB-, -NRBCO-: -S-, -SO-, -S02-, -S02NR -, or -NRBS02NRB; and
Z is hydrogen, C|_s aliphatic, cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, optionally substituted with 1 -3 of Qj or Q2.
18. The compound of claim 17, wherein Y is present and is a branched or straight C|.|2 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Qi)2-, -C(Q2)2-, -CI-IQ 1 -, -CHQ2-, -CO-, -CS-, -C0NR -, -CONR NRB-, -C02-, -OCO-, - NR"-, -NRBC02-, -0-, -NRBCONRB-, -OCONRB-, -N RBCO-, -S-, -SO-, -S02-, or -S02NRB-.
19. The compound of claims 1 -18, which is a compound of formula 1A, IB, or IC.
Figure imgf000330_0001
20. The compound of claims 1- 19, which is a compound of formula IA-1 , IB- 1 , or IC-1.
Figure imgf000330_0002
Figure imgf000331_0001
21 . The compound of claims 19-20, wherein i in any formula 1A or IA- 1 is chosen from chromanyl, isochromanyl. thiocromanyl, isothiocromanyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, tetrahydronaphthyl, indanyl, indenyl, each of which is optionally and independently substituted with 1 -3 of halo, nitro. cyano, hydroxy, amino, Ci.6 alkyl, C | .6 alkoxy, C| .f, alkyl, C \ .(, alkylcarbonyl, Cj.6 alkoxycarbonyl, Cj-e alkylaminocarbonyl, C| .6 alkylcarbonylamino. or C i-6 alkylcarbonyloxy.
22. The compound of claims 19-20. wherein i in formula IA or IA- 1 is optionally substituted phenyl or pyridyl.
23. The compound of claim 22. which is a compound of formula IA-2 or IB-2
Figure imgf000331_0002
wherein:
A] , and A3 are N, and A2, is CH or C-halo; or A2 is N and A | and A3 are CH or C- halo; and
R2 is H, alkyl, alkoxy, haloalkoxy, or halo.
24. The compound of claims 1 -23, wherein R2 is H or halo.
25. The compound of claim 1 which is a compound of formula IE- 1
Figure imgf000332_0001
Figure imgf000333_0001
Figure imgf000334_0001
IE-2
wherein ring D is phenyl or pyridyl optionally substituted with R7 which is H, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -OH, CN, N02; and Rin E is a ar l or heteroaryl
Figure imgf000334_0002
, halo, -OH, CN, N02, and NH; and Rl0 is selected from H,-CH0HCH3, -CHOH(CH3)2 CO e, C02Et, NHMe, NHEt, NMe2, NEt2, NHCHMe2 CH2OH, -CH2C02Ets CH2C02H, CONH2, -NHCH2CH2CH2OH, -NHC^CC^H.-NHCFhCC^Me, -NHCH2CH20H, -
Figure imgf000334_0003
Figure imgf000335_0001
27. The compound of claims 1 -26 wherein Ring A is an optionally substituted monocyclic or bicyclic aryl or heteroaryl.
28. The compound of claims 1 -26 wherein Ring A is an optionally substituted phenyl.
29. The compound of claims 1 -26 wherein Ring A is
Figure imgf000335_0002
, wherein at least one of A, B, and C are N, NH, N(alkyl), S, SO, SO:, or O and the others of A, B, and C are CH, CH. or C(alkyl); and R5 is H or alkyl. In a further embodiment, one of A and C is N. S, or O. In a further embodiment, one of A and C is N and the other of A and C is S or O.
30. The compound of claims 1 -26 wherein Ring A is selectexd from the group consisting of phenyl substituted one, two, or three groups selected from halo, alkyl, haloalkyl. alkoxy, haloalkoxy, hydro yalkyl. alkoxyalkyl, amino, alkylamino. dialkylamino, -CONH2, - CON H e, -NH-CHz-CN, -CN, -C02alkyl, NH-CH2-CONHMe, CH2CONH-CH2CH2OH,
1 .3- benzodioxol-5-yl, 2,2-difluoro- 1 .3-benzodioxol-5-yl, benzo[c Jthiazol-5-yI, 1 ,3- benzothiazol-6-yl, 1 -alkyl- 1 H-indol-6-yl. 1 -| 2-(methyloxy)ethyl]- 1 H-indol-6-yl, 1 H-indol-4- y! , 1 -methyl- l H-indol-4-yl , 1 H-indol-5-yl . 1 H-indol-6-yl, l -methyl-2,3-dihydro- I H-indol-
6- yl. 1 H-indol-7-yl. 1 ,3-benzodioxol-5-yl. 1 -benzofuran-5-yl , 3-methyl- l -benzofuran-5-yl,
7- lluoro-3-methyl- l -benzofuran-5-yl, l -benzoihien-5-yl, l ,3-benzoxazol-6-yl, 2,3-dihydro-
1 .4- benzodioxin-6-yl, 1 H-benzimidazol-6-yl. 1 -methyl- 1 H-benzimidazol-6-yl, 1 H-indazol-5- yl, 1-alkyl-l H-indazoI-6-yl, 4-acetyl-3,4-dihydro-2H-l,4-benzoxazin-6-yl, 1,2,3.4- tetialiydronaphthalen-l-yl .6-naphthalen-2-yl. and 1 -methyl- 1 H-pyrrolo[3,2-b]pyridin-6-yl.
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
32. The compound of claim 1 , which is a compound of formula II
Figure imgf000338_0002
I I
wherein:
Het is a heteroaryl ring which is optionally substituted with 1 -3 of Q3; and two instances of R3 on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to fonn a 5-6 membered cycloaliphatic or heteroaliphatic, saturated or unsaturated ring, which is optionally substituted with 1 -3 o Q2.
33. The compound of claim 3 1 . wherein two instances of R3 on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a benzo-fused furanyl or thiophenyl ring, which is optionally substituted with 1 -3 of Q2.
34. The compound of claim 1 which is a compound of formula HI
Figure imgf000339_0001
III
wherein:
W is absent or is a branched or straight C 1.12 aliphatic chain wherein up to two carbon units are optionally and independently replaced by -C(Qi)2-; -C(Q2)2-: -CHQi-, -CHQ2-, -CO- , -CS-, -CONRA-, -CO RANRA-, -C02-, -OCO-, -NRA-, -NRAC02-, -0-, -NRACONRA-, -OCONRA-, -NRANR' -NRACO-, -S-, -SO-, -S02-, -S02NRA-, -NRAS02-, or
-NRAS02NRA;
R is X1-X2-X3-Y-Z. wherein X|. X2. X3, Y, and Z are as previously defined;
at least one of A, B, and C are N, NH, N(alkyl), S, SO, S02, or 0 and the others of ABC are CH, CH, C(alkyl); and
R5 is 1-1, halo, hydroxy, alkoxy, haloalkoxy, hydroxy-alkylene, or alkyl.
35. The compound of claim 34, wherein one of A and C is N, S, or O.
36. The compound of claim 35. wherein one of A and C is N and the other of A and C is
S.
37. The compound of claim 36, which is a compound of formula IIIA, III-B, or IU-C.
Figure imgf000339_0002
Figure imgf000340_0001
38. The compound of claim 1 which is a compound of formula V
Figure imgf000340_0002
V
wherein Ring A is as previously defined in claim 3 1 for a compound of formula 1 and R is cycloaliphatic, heterocycloaliphatic. aryl, or heteroaryl, each or which are optionally and independently substituted with 1 -3 of Q i , Q2, or Q2.
39. The compound of claim 38, wherein R(, is selected from the group consisting of 2,3- dihydro- 1 H-inden- 1 -yl , 1 ,2,3.4-tetrahydronaphthalen- 1 -yl. naphthalen- 1 -y 1, 6-nitro-3.4- dihydro-2H-chiOmen-4-yl), 3,4-dihydro-2H-chromen-6-yl, 3,4-dihydro-2H-cl romen-4-yl, 3,4-dihydro-2H- l -benzothiopyran-4-yl, furanyl, wherein each of the groups may be optionally substituted with one, two, or three groups selected from halo, nito, -NH-CO-Me, alkyl. and alkoxy.
40. In another embodiment, the compound of formula V is a compound of formula VA.
Figure imgf000340_0003
VA
wherein Ring A is as previously defined in claim 31 , Xv is CH2, NH, or 0, and R|2 is one or two groups independently selected from alkyl. -NHCOMe, -NHCOEt.
41 . A compound of claim which is:
(S)-5-(3-( l -(6-(7-fluoro-3-methylbenzofuran-5-yl)-2-methylpyrimidin-4- ylamino)ethyl)phenyl)pyrimidin-2-amine; (S)-2-methyl-N-( 1 -(5-( 1 -methyl- 1 H-pyrazol-4-yl)pyridin-3-yl)ethyl)-6-(3- inethylbenzofuran-5-yl)pyrimidin-4-amine;
(S)-N-(l-(3-(5-aminopyndin-3-yl)phenyl)ethyl)-6-(4-chloro-3-fluoi phenyl)-2- methy]pyrimidin-4-amine;
(S)-5-(3-(l-(2-methyl-6-(3-methylbenzofuran-5-yl)pyrimidin-4- ylamino)ethyl)phenyl)pyrimidin-2-amine;
N-(l-(5-(l -ethyl- lH-pyrazol-4-yl)pyridin-3-yl)ethyl)-6-(7-fluoro-3- methylbenzofuraii-5-yl)-2-methylpynmidin-4-amine;
5- (3-nuoiO-5-(l-(2-methyl-6-(3-methylbenzofuran-5-yl)pyrimidin-4- ylamino)ethyl)phenyl)pyrimidin-2-amine;
(S)-5-(3-(l-(2-methyl-6-(3-methylbenzo[b]thiophen-5-yl)pynmidin-4- ylamino)ethyl)phenyl)pyrimidin-2-amine;
(S)-N-(l-(3-(5-aminopyridin-3-yl)phenyl)ethyl)-2-metliyl-6-(3- methylbenzo[b]lhiophen-5-yl)pyrimidin-4-amine;
N-(2.3-dihydro- 1 H-inden- 1 -yl)-6-(3-ll orophenyl)-2-methylpyrimidin-4-amine;
6- (Benzo[d]lhiazol-5-yl)-2-methyI-N-(2-methyibutyl)pyrimidin-4-amine;
(S)-6-(Benzo[d]thiazol-5-yl)-N-(l-cyclohexylethyl)-2-methylpyrimidin-4-amine; 2-methyl-6-[3-(methyloxy)phenyl]-N-[( 1 )- 1.2,3 ,4-tetrahydronaphthalen-l - yl]pyrimidin-4-amine;
2-methyl-6-[3-(methyloxy)phenyl]-N-{(lR-)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
2-metlwl-6-[3-(methyloxy)phenyl]-N-{(lS)-l-[3-(melhyloxy)phenyl]ethyl}pyrimid 4-amine;
2-methyl-6-[3-(methyloxy)phenyl]- -{(lS)-l-[4-(methyloxy)phenyl]ethyl}pyrimid 4-amine;
(R)-6-(Benzo[d]thiazol-5-yl)-2-methyl-N-(l,2,3,4-telrahydronaphthalen-l- yl)pyrimidin-4-amine;
,N-diethyl-2-{[3-( 1 -{ [2-methy -6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}a etamide;
2-methyl-6-(l-methyl-lH-indol-6-yl)-N-[(lF )-L233,4-tetrahydiOnaphlhalen-l- yrjpyrimidin-4-amine;
. N-[(4R)-3!4-dihydiO-2H-chromen-4-yl]-2-methyl-6-(l -methyl-1 H-indol-6- yl)pyrimidin-4-amine; KN-dimethyl-2- { [3-( 1 -{ [2-methyl-6-(l -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
6-(l -ethyl- 1 H-indol-6-yl)-2-methyl-N-[( 1 R)- 1 ,2,3,4-tetrahydronaphthalen- 1 - yl]pyrimidin-4-amine;
3- (l -{ [2-methyl-6-( 1 -methyl- 1 H-indoI-6-yl)pyrimidm-4- yl]amino}elhyl)benzenesulfonamide;
N-ethyl-2- { [3-( 1 -{ [2-methy!-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
N-(cyanomethyl)-3-( 1 -{ [2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyI)benzenesulfonamide;
2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)-N-( 1 -{3-[(2-morpholin-4-yl-2- oxoethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
4- { [3-( 1 - { [2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}butanoic acid;
6-( 1 ,3-benzodioxol-5-yl)-2-methyl-N-[( 1 R)- 1 ,2,3,4-tetrahydronaphthalen- 1 - yl]pyrimidin-4-amine;
2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)-N-{( 1 S)- 1 -[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
2- methyl-6-(l -methyl- lH-indol-6-yl)-N-[( IS)- l-phenylethyl]pyrimidin-4-amine; 6-(lH-indol-6-yI)-2-methyl-N-[(l I^-l^J^-tclrahydronaphthalen-l-yllpyrimidin^- amine;
6-[2-chloro-3-(methyloxy)phenyl]-2-melhyl-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
6-(l,3-benzodioxol-5-yl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin- 4-amine;
3- (l-{[2-methyl-6-(l -methyl- lH-indol-6-yl)pyvimidin-4-yl]amino}ethyl)phenol;
6-( 1 H-indol-5-yl)-2-methyl-N-[( 1 R)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl]pyrimidin-4- amine;
6-(lH-indol-5-yl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
ethyl N-({[3-(l-{[2-methy]-6-(l -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetyl)glycinate;
N-[(lS)-l-(4-tluorophenyl)ethyl]-2-methyl-6-(l-methyl-n-J-indol-6-yl)pyrimidin-4- amine; 2-methyl-6-(l-methyl-lH-indol-6-yl)-N-[(lS)-l-(4-methyIphenyl)ethyl]pyrimidin-4- amine;
ethyl 4- { [3-( 1 - { [2-methy l-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}butanoate;
6-(3-fluorophenyl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
6-[2-chloro-3-(methyloxy)phenyl]-2-methyl-N-[(lR)-l,2,3.4-tetrahydronaphthaleri-l- yl]pyrimidin-4-amine;
2-({3-[l-({6-[2-chloro-3-(methyloxy)phenyl]-2-melhylpyriniidin-4- yl}amino)ethyl]phenyl}oxy)-N-methylacetamide;
2- {|3-(l-{[6-(l,3-benzodioxol-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}- -methylacetamide;
N-(cyanomethyl)-3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]benzenesulfonamide;
({3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pynmidin-4- yl}amino)ethyl]phenyl}oxy)acetOnitrile;
3- [l-({6-[2-chloiO-3-(melhyloxy)phenyl]-2-methylpynmidin-4- yl}amino)ethyl]benzenesulfonamide;
6-[2-n oro-3-(methyloxy)phenyl]-2-melliyl-N-{(lS)-l-[3- (mclhyloxy)phenyl]ethyI}pyrimidin-4-amine;
6-[2-chloro-3-(methyloxy)phenyl]-N-(2.3-dihydro- 1 H-inden- 1 -yl)-2- methylpyrimidin-4-amine;
N-methyl-2-({3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl }amino)ethyl]phenyl }oxy)acetamide;
N-[l-(3-bromophenyl)ethyl]-6-[2-chloro-3-(methyloxy)phenyl]-2-methylpyrimidin-4- amine;
2-methyl-6-{l-[2-(methyloxy)ethyl]-lH-indol-6-yl}- -[(lR)-l ,2,3,4- telrahydiOnaphthalen-l-yl]pyrimidin-4-amine;
6-[2-nuoro-3-(methyloxy)phenyl]-2-methyl-N-[(lR)-l,2,3,4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
methyl ({3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenyl}oxy)acetate;
methyl N-{3-[l -({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl }amino)ethyl]pheny 1 } glycinate; -[( ] S)- 1 -(4-chlorophenyl)ethyl]-2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- amine;
3-[l-({2-methyl-6-|3-(methyloxy)phenyl]pyrimiclin-4- yl}amino)ethyl]benzenesulfbnamide;
6-(l-ethyl-lH-indol-6-yl)-2-melhyl-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyriniidin-4-amine;
6-[2-chloi -5-(methyloxy)phenyI]-2-methyl-N-[(lR)-l:2.3.4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
methyl N-({3-[ 1 -({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyrjphenyl}sulfonyl)glycinate;
2- methyl-6-(l-melhyl-lH-indol-5-yl)-N-{(lS)-l-[3- (methyloxy)phenyl]ethyI}pyrimidin-4-amine;
3- [l-({2-methyl-6-[3-(methyloxy)phenyl]pyriniidin-4-yl}amino)ethyl]phenol;
1 ,1 -dimethylethyl (cyanomethyl)({3-[l -({2-methyl-6-[3-
(methyloxy)phenyl]pyrimiclin-4-yl}amino)ethyl]phenyl}sulfonyl)carbamate;
2-methyl-6-[3-(methyloxy)phenyl]-N- {(1 S)- 1 -[3- (trifluoromethyl)phenyl]ethyl}pyrimidin-4-ainine;
2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-6-{3- [(lnfluoiOmelhyl)oxy]phenyl}pyrimidin-4-amine;
2-methyl-6-{3-[(methyloxy)methyl]phenyl}-N-[(lR)-l;2,3!4-tetrahydronaphthaleri-l- yl]pyrimidin-4-amine;
2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyr}-6-[3,4,5- tris(methyloxy)phenyl]pyiimidin-4-amine;
methyl N-{[(l,l-dimethylethyl)oxy]carbonyl}-N-({3-[l-({2-methyl-6-[3- (methyloxy)phenyl]pyrimidin-4-yl}amino)ethyl]phenyl}sulfonyl)glycinate;
6-[2-chloro-5-(methyloxy)phenyl]-2-methyl-N-{( 1 S)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-[3-(methyloxy)phenyl]-N-(5,6J,8-tetrahydi naphthalen-l-yl)pyrimidin- 4-amine;
6-(lH-indol-6-yl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
2-niethyl-6-[3-(methy oxy)phenyl]-N-naphthalen-l-ylpyrimidin-4-amine;
2-methyl-6-[3-(methyloxy)phenyl]-N-[(lS)-l,2,3,4-letrahydi naphthalen-l- yl]pyrimidin-4-amine; 2-methyl-N-[(l )-l,213,4-letra ydronaphthalen-l-yl]-6-{3- [(trifluoromethyl)oxy]phenyl}pyrimidin-4-amine;
N-{3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenyl} glycine;
N-({3-[l-({2-met yl-6-[3-(metliyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenyl}sulfonyl)glycine;
methyl -{3-[({2-melhyl-6-[3-(metliyloxy)phenyl]pyrimidin-4- yl}amino)methyl]phenyl}glycinate;
N nethyl-2-{[3-(l-{[2-melhy -6-(l-metliyl-lH-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
2-methyl-6-|3-(methyloxy)phenyl]-N-{l-[3-(me iyloxy)phenyl]propyl}pyrimidin-4- amine;
6-(1.3-benzothiazol-6-yl)-2-methyl-N-(6-nitro-3,4-dihydro-2H-chromen-4- yl)pyrimidin-4-amine;
N-(4-{[6-(l ,3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]amino}-3,4-dihydiO-2H- chramen-6-yl)acetamide;
2-methyl-6-(3-methyl- 1 -benzoi uran-5-yl)-N-[( 1 R)- 1.2.3,4-teirahydronaphthalen- 1 - yljpynmidin-4-amiue;
6-(l-benzoriiran-5-yl)-2-methyl-N-[(lR)-l,2.3.4-tetrahydi naphthalen-l- yl]pyriinidin-4-amine:
6-(l-benzothien-5-yl)-2-melhyl-N-[(lR)-1.2,3,4-tetrahydiOnaphlhalen-l- yl]pyrimidin-4-amine;
6-(l,3-beirzothiazol-6-yl)-2-mcthyl-N-[(lR)-l,2,3,4-telrahydronaphthalen-l- yl]pyrimidin-4-amine;
2-methyl-6-(4-methyl-3J4-dihydro-2H-l!4-benzoxazin-6-yl)-N-[(lR)-l,2,3,4- tetrahydronaphthalen- 1 -yl]pyrimidin-4-amine;
2-methy -6-(3-methyl-l-benzoiuran-5-yl)-N-{(lS)-l-[3- (melhyloxy)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(l-methyl-2,3-dihydi -lH-indol-6-yl)-N-[(lll)-l, 2,3,4- tetrahydronaphthalen- 1 -y 1 ]pyrimidin-4-amine;
6-(1.3-benzoxazol-6-yI)-2-methyl-N-[(l R)-l .2.3,4-tetrahydronaphthalen-l - yjpyrimidin-4-amine;
6-(l-benzoiuran-5-yl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine; 6-(2.3-diliydro-l,4-benzodio.\in-6-yl)-2-methyl-N-[(l )- 1,2,3,4- tetrahydronaphthalen-l-yl]pyrimidin-4-amine;
2-methyl-6-( 1 -methyl- 1 H-benzimidazol-6-yl)-N-[(lR)- 1.2,3, 4-tetrahydronaphthalen- 1 -yl]pyrimidin-4-amine;
6-(l-beirzothien-5-yl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyljethyl}pyrimidin-4- amine:
6-(3-amino-4-methylphenyl)-2-methyl-N-[(lR)-l,2,3,4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-6-(4-methylphenyl)pyrimidin-4- amine:
6-(4-chloi phenyl)-2-methyl-N-{ ( 1 S)- 1 -[3-(melhy loxy)phenyl]ethyl } pyrimidin-4- amine;
6-(l,3-benzothiazol-6-yr)-2-metliyl-N-(2-methylbutyl)pyriiTiidin-4-amine;
2-methyl-6-( 1 -methyl- 1 H-indazol-6-yl)-N-[(l R)- 1 ,2,3,4-tetrahydronaphthalen- 1 - yl]pyrimidin-4-amine;
6-(3-chloi phenyl)-2-methyl-N-{(lS)-l-[3-(melhyloxy)phenyl]ethyl}pyrimidin-4- amine;
6-(1.3-benzothiazol-6-yl)-2-methyl-N-[(lS)-l,2.3.4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
6-(3,4-dihydro-2 H- 1 :4-benzoxazin-6-yl)-2-methy l-N-[( 1 R)- 1.2,3,4- tetrahydiOnaphthalen-l-yl]pynmidin-4-amine;
2-methyl-6-(l-methyl-lH-indol-4-yl)-N-[(rR)-l,2,3,4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
6-(2-nuorophenyl)-2-n thyl-N-{(lS)-l-|3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
6-(lH-indol-4-yl)-2-methyl-N-[(] R)-l,2!3,4-tetrahydronaphthalen-l-yjpyrimidin-4- amine;
6-(2,3-dihydro-l H-indol-6-yl)-2-methy!-N-[(l R)- 1 ,2,3,4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine:
6-(2,2-difluoro-l :3-benzodioxol-5-yl)-2-methyl-N-[(l R)-l ,2,3,4- tetrahydronaphthalen- 1 -yl]pyrimiciin-4-amine;
6-(4-fliiorophenyl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine; 2Miiethyl-N-{(lS)-l-[3-(ii thyloxy)phenyljethyl}-6-(2-methylphenyl)pyrimidin-4- amine;
6-(lH-indazol-5-yl)-2-methyl-N-[(l R)- 1.2,3 ,4-tetrahydronaphthalen-l-yljpyrimidin- 4-amine:
6-( 1 -ethyl- 1 H-indazol-6-y l)-2-methyl-N-[( 1 R)- 1,2,3 ,4-tetrahydronaphthalen- 1 - yl]pyrimidin-4-amine;
6-(l!3-benzoxazol-6-yl)-2 ethyl-N-{(lS)-l-[3-(methyIoxy)phenyl]ethyl}pyrimidin- 4-amine;
4- { [6-( L3-benzothiazol-6-yl)-2-methylpyi"imidin-4-yl]amino } -4-[3- (methyloxy)phenyl]butanenitrile;
6-(l H-indol-7-yl)-2-methyl-N-[( 1 R)-l ^
amine;
6-(l H-indazol-6-yl)-2-methyl-N-[(l R)-l ,2 ,4-tetrahydronaphthalen- 1 -yl]pyrimidin- 4-amine;
6-(lH-benzimidazol-6-yl)-2-methyl-N-[(lR)-l,2.3.4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
6-( 3-benzolhiazol-6-yl)-2-methyl-N-{(lR)-l-[3- (methyloxy)phenyl]ethyl}pynmidin-4-amine;
6-( I H-indol-4-yl)-2-methyl-N-{( l S)- 1 -[3-(methyloxy)phenyl]ethyl} pyrimidin-4- amine;
6-(lH-indol-7-yl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
6-(2-chloropheiiyl)-2-methyl- -{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrirnidin-4- amine;
2- melhyl-6-(l -methyl- 1 H-benzimidazo!-6-yl)-N-{(l S)- 1 -[3- (methyloxy)phenyljethyl}pyrimidin-4-amine;
N-[3-(dimethylamino)propyl]-3-({2-methyl-6-[3-(methyloxy)pheny]pynmidin-4- yl}amino)-3-[3-(methyloxy)phenyl]propanamide;
3- ({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4-yl}amino)-3-[3- (methy loxy )pheny l] propan- 1 -o l ;
6-(4-acetyl-3!4-dihydro-2H-lJ4-benzoxazin-6-y!)-2-methyl-N-[(lR)-l, 2,3,4- tetrahydronaphlhalen- 1 -y l]pyrimidin-4-amine;
ethyl 3-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4-yl}amino)-3-[3- (methyloxy)phenyl]propanoate; 6-[3-(dimethylamino)phenyl]-2-methyl-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyiimidin-4-amine;
6-( 1 I-I-indazol-5-yl)-2-methyl-N-{( 1 S)- 1 -[3-(melhyloxy)phenyl]ethyl }pyrimidin-4- amine;
ethyl N-{3-({2-methyl-6-[3-(methyloxy)pheny |pyrimidin-4-yl}arnino)-3-[3- (methyloxy)phenyl]piOpanoyl}-beta-alaninate;
6-[4-(dimethylamino)phcnyl]-2-methyl-N-{ ( 1 S)- 1 -[3- (metliyloxy)phenyl]ethyl}pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
6-[4-chloro-3-(methylainino)phenyl]-2-methyl-N-[(]R)-l,2,3,4-tetrahydronaphthalen- 1 -yI]pyrimidin-4-amine;
6-(4-chloi -3-methylphenyl)-2-mcthyl-N-[(l )-l,2,3.4-tetrahydronaphthalen-l- yl |pyrimidin-4-amine;
2-fluoro-4-{2-rnet" yl-6-[(lR)-l,2.3,4-tetrahydronaphthaIen-l-ylamino]pyrimidin-4- yl}benzamide;
[(2-chloro-5-{2-methyl-6-[(lR)-l,2,3.4-tetrahydronaphthalen-l-ylamino]pyrimidin-4- yl}phenyl)amino]acetonitrile;
2-methyl-6-(4-methylpheny])-N (lR)-l,2J3,4-ietrahydronaphthalen-l-yl]pyrimidin- 4-amine;
6-[4-chloi -3-(dimethylamino)plienyl]-2-metliyl-N-[(lR)-l, 2,3,4- tetrahydronaphthalen-l-yl]pyrimidin-4-amine;
6-(4-chlorophenyl)-2-methyl-N-[(l R)-l .2,3,4-tetrahydronaphthalen-l -ylJpyrimidin-4- amine;
2-methyl-6-[4-methyl-3-(methylamino)phenyl]-N-[(lR)-l, 2,3,4- tetrahydronaplithalen-l-yl]pyrimidin-4-amine;
6-(3,4-dichlorophenyl)-2-mefhyl-N-[(lR)-l,2,3,4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
[(2-methyl-5-{2-methyl-6-[(l )-l,2,3,4-tetrahyclronaphthalen-l-ylamino]pyrimidin- 4-yl}phenyl)amino]acetonitrile;
6-(4-chloro-3-fluoi plienyl)-2-methyl-N-[(l R)- 1.2.3, 4-tetrahydronaphthalen- 1- yljpyrimidin-4-amine;
2-chloro-5-{2-methyl-6-[(lR)-l,2,3,4-tetrahydronaphthalen-l-ylamino]pyrimidin-4- yl}benzonitrile; 2-methyl-N-[(lR)-l,2,3,4-tetrahydronapluhalcn-l-yl]-6-[4- (trifluoromethyl)phenyl]pyrimidin-4-amine;
6-(3-fluorophenyl)-2-methyl-N-[(]R)-l,2,3.4-tetiahydronaphthalen-l-yl]pyrimidin-4- amine;
6-[3-(dimethylamino)plienyl]-2-methyl-N-|'( 1 R)- 1 ,2,3,4-tetrahydronaphthalen- 1 - yl]pyrimidin-4-amine;
2- methyl-6-(2-nielhylphenyI)-N-[(lR)-l,2,3,4-tetrahydronaphthalen-l-yl]pyriniidin- 4-amine;
3- {2-methyl-6-[( 1 R)- 1 ,2,3,4-tetrahydronaphthalen- 1 -ylamino]pyrimidin-4- yl}benzonitrile;
6-(3-chlorophenyl)-2-methyl-N-[(lR)-l,2J.4-tetrahydronaphthalen-l-yl|pyrimidin-4- amine;
2-methyl-6-[4-(methylamino)phenyl]-N-[(] R)-1.2,3,4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
6-(4-nuoi phenyl)-2-methyl-N-[(lR)-l,2,3,4-tetrahydronaphthalen-l-yl]pyrimidin-4- amine;
methyl 2-chloro-5-{2-methyl-6-[(lR)-K2,3,4-letrahydiOnaphthalen-l- ylamino]pyrimidin-4-yl}benzoate:
6-(4-aminophenyl)-2-methyl-N-[(lR)-l,2,3,4-telrahydronaphthalen-l-yl]pyrimidin-4- amine;
6-(2-fluorophenyl)-2-methyl-N-[(l R)-l,2,3,4-tetrahydronaphthalen-l-yl]pyrimidin-4- amine;
6-(2-chlorophenyl)-2-methyl-N-[(lR)-l ,2,3,4-tetrahydronaphthalen- l-yl]pyrimidin-4- amine;
4- {2-methyl-6-[(lR)-l,2!3,4-tetrahydronaphthalen-l-ylamino]pyrimidin-4- yl}benzonitrile;
6-(3-aminophenyl)-2-methyl-N-[(lR)-1.2.3,4-tetrahydronaphthalen-l-yl]pyrimidin-4- amine;
N~2— (2-chloro-5-{2-methyl-6-[(lR)-l,2,3,4-tetrahydronaphthalen-l- ylamino]pyrimidin-4-yl}phenyl)-N-methyIglycinamide;
6-[4-(dimethylamino)phenyl]-2-methyl-N-[(lR)-l,2,3,4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine:
2-chloro-N-methyl-5-{2-methyl-6-[(l R)- 1.2.3.4-tetrahydronaphthalen- 1 - ylamino]pyrimidin-4-yl}benzamide; 2- melhyl-N-[(l R)-l ,2,3,4-ielrahydronaphlhalen-l -yl]-6-{4- [(trifIuoromethyl)oxy]plienyl}pyrimidin-4-amine;
3- {2-methyl-6-[(l R)-l ,2.3.4-letrahydronaphthalen-l -ylamino]pyrimidin-4- yl}benzamide;
6-(3-amino-4-chlorophenyl)-2-methyl- -[( 1 R)- 1 ,2.3,4-tetrahydronaphthalen- 1 - yl]pyrimidin-4-amine;
4- {2-methyl-6-[(lR)-1.2,3.4-tetrahydronaphthalen-l-ylamino]pyrimidin-4- yl}benzamide;
2-methyl-N-{(lS)-l-[3-(metliyloxy)phenyl]ethyl}-N'-[(lR)-l,2;3!4- tetrahydronap t alen- 1 -yl ]pyrimidine-4,6-diamine;
6-(l,3-benzothiazol-6-yl)-N-[(4R)-3.4-dihydro-2H-chromen-4-yl]-2-methylpyrimidin- 4-amine;
6-(1.3-bcnzothiazoI-6-yl)- -[(4S)-3,4-dihydro-2H
4-amine;
6-(1.3-benzothiazol-6-yl)-N-(3,4-dihydro-2H-chiOmen-4-yl)-2-methylpyrimidin-4- amine;
6-(l ,3-benzothiazol-6-yl)-N-(3.4-dihydro-2H- 1 -bcnzothiopyran-4-yl)-2- melhy I pyrim i d i n-4-ami ne :
6-(l.3-benzothiazol-6-yl)-N-(3,4-dihydro-l H-2-benzothiopyran-4-yl)-2- methylpyrimidin-4-amine;
N-(5-{[6-(l,3-benzothiazol-6-yl)-2-methy]pynmidin-4-yl]amino}-5,6,7,8- tetrahydronaphthalen-2-yl)acetamide;
6-furan-3-yl-2-methyl-N-[(lR)-l,2,3,4-tetraliydronaphthalen-l-yl]pyrimidin-4-amine;
2-methyl-N-{(lS)-l-[3-(methyloxy)p enyl]ethyl}-6-phenylpyrimidin-4-amine;
6-(3-ethylphenyl)-2-methyl-N-{(lS)-l-[3-(niethyloxy)phenyl]et'hyl}pyrimidin-4- amine;
N~l~-[6-(],3-benzothiazol-6-yl)-2-methylpynmidin-4-yl]-l,2.3,4- tetrahydronaphthalene- 1.6-diamine;
2-methyl-6-(3-methylphenyl)-N-[(l R)-l,2,3,4-tetrahydronaphlhalen-l-y]]pyrimidin- 4-amine;
2-methyl-N-{(l S)-l-[3-(methyloxy)phenyl]ethyl}-6-(3-methylphenyl)pyrimidin-4- amine;
6-(l.3-benzothiazol-6-yl)-2-methyl-N-[6-Cmet'hyloxy)-l.2s3.4-tetrahydronaphthalen- l -yl Jpyrimidin-4-amine; '6-(l,3-benzothiazol-6-yl)-2-methyl-N-[5-(methylo.\y)-l52,3,4-tetrahydronaphthalen- 1 -yl]pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(6-methyl-354-dihydro-2H-chromen-4- yl)pyrimidin-4-amine;
6-(3-elhylphenyl)-2-methyl-N-[(1R)-lJ2,3,4^etrahydronaplnhalen-l-yl]pyrimidin-4- amine;
2-metliyl-6-(2-methylpyridin-4-yl)-N-[(l R)- 1 ,2,3,4-tetrahydronaphthalen- 1 - yl]pyrimidin-4-amine;
6-(l,3-benzotliiazol-6-yl)-2-methyl-N-[7-(nielhyloxy)-l,2,3,4-tetrahydronaphthalen- l -yl]pyrimidin-4-amine;
2-methyl-6-pyridin-4-yl-N-[(lR)-l,2:3,4 etrahydiOnaphthaIen-l-yl]pyrimidin-4- amine;
2-methyl-N-{(]S)-l-[3-(methyloxy)phenyl]ethyl}-6-(2-methylpyridin-4-yl)pyrinn 4-amine;
2-methyl-6-(l H-pyrazol-4-yl)-N-[(l R)-l,2,3,4-tetrahydronaphthalen-l-yl]pynmidin- 4-amine;
2-methyl-6-pyridin -yl-N-[(lR)- 1,2,3,4 ^
amine;
2-methyl-N-[(] R)-l,2,3.4-tetrahydronaphthalen-l-yl]-4,5'-bipyrimidin-6-amine;
2 iielhyl-N-{(lS)-l-[3-(methy!oxy)p enyl]ethyl}-6-pyridin-3-ylpyrimidin-4-aiTii
2-methy l-N-{( l S)- 1 -[3-(methyloxy)phenyl]ethyl } -6-pyridin-4-ylpyrimidin-4-amine:
6-(2,3^ihydro-l-benzoi iran-5-yI)-2Mnethyl-N-[(lR)-l,2,3,4-tetraliydronaphthalen-l- yl]pyrimidin-4-amine;
2-methyl-6-[(E)-2-phenylethenyl]-N-[(lR)-l,2,3:4-tetrahydiOnaphthalen-l- yl]pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-(6-iluoiO-3.4-dihydro-2H-chroinen-4-yl)-2- methylpyi'imidin-4-amine;
(4-{2-methyl-6-[(l R)- 1.2.3.4-tetrahydiOiiaphlhalen-l -ylamino]pyrimidin-4- yl}phenyl)methanol;
2-methyl-6-phenyl-N-[(lR)-l,2,3!4-tetrahydiOnaphthalen-l-yl]pynmidin-4-amine; 4-{2-methyl-6-[(lR)-l;2.3,4 etrahydiOnaplnlialen-l-ylamino]pyrimidin-4-yl}phen 6-(l,3-benzothiazol-6-yl)-2-melhyl-N-(2-mel yl-l,2,3,4-telrahydronaphlhalen-l- yl)pyrimidin-4-amine; 6-( 1 -benzofuran-2-yl)-2-meihyl-N-[( 1 R)- 1 ,2,3,4-letrahydronaphthalen- 1 - yl]pyrimidin-4-amine;
6-[3:4-bis(methyloxy)phenyl]-2-niethyl-N-[(lR)-l;2.3.4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
2- methyI-6-naphthalen-2-yl-N-[(lR)-l .2,3,4-tetrahydronaphthalen-l-yl]pyrimidin-4- amine;
3- {2-methyl-6-[(l R)-1.2.3.4-tetrahydiOnaplithalen-l-ylamino]pyrimidin-4-yl}phenol; N-[l-(3-bromophenyl)elhyl]-2-met yl-6-[3-(metliyloxy)phenyl]pynmidin-4-arnine; 3-{2-methyl-6-[(l R)-1.2.3.4-tetrahydronaphthalen-l-ylamino]pyrimidin-4- yl}benzaldehyde;
6-[2-nuoro-5-(metliyloxy)plienyl]-2 ^ethyI-N (l )-l:2,3.4-tetraliydronaphthalen-l- yl]pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-N-(5,7-dimethyl- 1.2,3.4-tetrahydronaphthalen- 1 -yl)-2- methylpyrimidin-4-amine;
1- (3-{2-methyl-6-[(l R)-1.2.3,4-tetrahydronap lhalen-I-ylaminojpyrimidin-4- yl}phenyl)ethanone;
(3-{2-methyl-6-[(l R)-l,23.4 etraliydronaphthalei l-ylamino]pyrimidin-4- yl}phenyl)methanol;
6-[3-(ethyloxy)phenyl]-2-methyl-N-[(lR)-l,2,3,4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
2- methy]-6-(4-methyl-3 ,4-di hydro-2H- 1 ,4-benzoxazi n-7-yl)-N-[( 1 R)- 1 ,2,3 ,4- tetrahydronaphthalen-l-yl]pyrimidin-4-amine;
N-[ 1 -(3-{ [(1 ,3-dimethyl-l H-pyrazol-5-yl)methyl]oxy}phenyl)ethyl]-2-methyl-6-(l - methyl- 1 H-indol-6-yl)pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-N-[( 1 S)- 1 -(3-{ [( 1 ,3-dimethyl- 1 H-pyrazol-5- yl)methyl]oxy}phenyl)ethyl]-2-methylpyiimidin-4-amine;
2-nuoro-5-(l-{[2-methyl-6-(3-methyl-l-benzoi ira]i-5-yl)pyrimidin-4- yl]amino}ethyl)phenoI;
N-{l-[4-nuoro-3-(l-methyl-lH-pyrazol-4-yl)phenyl]ethyI}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
6-[2-chloiO-3-(methyloxy)phenyl]-N-[ -(3-{[(1.3-dimelhyl-lH-pyrazol-5- yl)methyl]oxy}phenyl)ethyl]-2-melhylpyrimidin-4-amine;
2-methyl-6-[4-methyl-3-(methyloxy)phenyl]-N-{( 1 S)- 1 -| 3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine; 3-[(]S)-l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidii 4-yl]amino}ethyl]phenol;
N-[l-(3-{[(l,3-dimet1iyl-lH-pyrazol-5-yl)methyl]oxy}phenyl)ethyl]-2-methyl-6-[4- metliyl-3-(methyloxy)phenyIjpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(!-{3-[(lH-pyrazol-3- yImelhyl)oxy] phenyl } ethyl)pyrimidin-4-amine;
3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyiimidin-4-yl]amino}ediyl)-N- (cyanomethyl)benzenesulfonairiide;
6-(1.3-benzothiazol-6-yl)-N-(l-{3-[(isoxazol-3-ylmethyl)oxy]phenyl}ethyl)-2- methylpyrimidin-4-amine;
3-(l-{[6-(l,3-benzothiazol-6-yr)-2-methylpyrimidin-4-yl]amino}ethyl)-N-but-2-yn ylbenzenesulfonamide;
2-methyl-6-[4-methyl-3-(methyloxy)phenyl]-N-[!-(3-{[(l -methyl- lH-pyrazol-3- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
6-(13-benzothiazol-6-yl)-N-[l-(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)methyl]oxy}-4- fluoi phenyl)ethyl]-2-methylpyrimidin-4-amine;
2- ({3-[l-({2-methyl-6-[4-methyl-3-(methyloxy)phenyrjpynmidin-4- yl}amino)ethyl]phenyl}oxy)acetamide;
3- (l-{[6-(l,3-benzodiiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)-N-prop-2-yn- 1 -ylbenzenesulfonamide;
6-(l,3-benzothiazol-6-yr)-N-{l-[4-fluoro-3-(l-methyl-lH-pyrazol-4-yl)phenyl]ethyl}- 2-methylpyrimidin-4-amine;
{[3-(l-{[6-(l,3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetonitrile;
N-( 1 - { -[(2-azepan- 1 -yl-2-oxoetliyl)oxy]phenyl}elhyl)-6-( 1 ,3-benzothiazol-6-yl)-2- methylpyrimidin-4-amme;
2- { [3-( 1 -{ [6-( 1 ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- vl]amino}elhyl)phenyl]oxy}-N-(l-methylethyl)acetamide;
6-(2,3-dihydro- 1 -benzo(uran-5-yl)-2-methyl-N-{( 1 S)- 1 -[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-y l)-2-methyl-N-[ 1 -(3- { [2-(2-methy laziridin- 1 -y 0-2- oxoethyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
2-{[3-(l-{[6-(l;3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N.N-dimethylacetamide; 3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)benzenesulfonamide;
6-( 1 ;3-benzothiazol-6-yl)-2-methyl-N-[l -(3-{[(5-methylisoxazol-3- yl)methyl]oxy}phenyl)etliyl]pyrimidin-4-amine;
{[3-(l -{[2-methyl-6-(l -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acelonitrile;
6-(l .3-benzothiazol-6-yl)-2-methyl-N-{ 1 -|3-(prop-2-yn- 1 - ylpxy)phenyl]etliyl}pynmidin-4-amine;
N-{l-[2-fluo!O-3-(methyloxy)phenyl]ethyl}-2-methyl-6-(3-methyl-l-benzo uran-5- yl)pyrimidin-4-amine;
2- chloro-5-(l-{[2-methyI-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yljamino}ethyl)plienol;
3- [l-({2-methyl-6-[4-methyl-3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenol;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(2-oxo-2-piperidin-l- ylethyl)oxy]phenyl}ethyI)pyrimidin-4-amine;
N-( 1 - {3-[(2-azetidin- 1 -yl-2-oxoethyl)oxy]phenyl } ethyl)-6-(l ,3-benzothiazol-6-yl)-2- methylpyrimidin-4-amine:
2- { [3-( 1 - { 16-( 1 ,3-benzotliiazoI-6-yi)-2-met!iylpyriiTiidin-4- yl]amino}ethyl)phenyl]oxy}-N-(2-hydroxypropyl)acetamide;
3- (l-{[6-(1.3-benzothiazol-6-yl)-2-melhylpyrimidin-4-yl]amino}ediyl)-N-(2- hydi xyethyl)benzenesul fonamide;
6-(l,3-benzothiazol-6-yl)-N-[l-(5-{[(l,3-dimethyl-lI-I-pyrazol-5-yl)methyl]oxy}-2- nuorophenyl)ethyl]-2-methylpyiimidin-4-ainine;
3-( l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)-N-[2- (methyloxy)ethyl]benzenesulfonamide;
3-[(l R)-l-{[6-(l,3-benzoUiiazol-6-yl)-2-me iylpyrimidin-4-yl]amino}ethyl]phenol;
6-( 1 ,3-benzolliiazol-6-yl)-2-methy]-N-(l-{3-[(2-morpholin-4-yl-2- oxoethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
3-(l-{[6-(l,3-benzolhiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)-4- fluorophenol;
3-[l-({6-[2-fluoiO-3-(methyloxy)plienyl]-2-methylpyrimidin-4- yl}amino)ethyl]phenol; N,N-diethyl-2-({3-[l-({6-[2-iliioro-3-(methyloxy)phenyl]-2-methylpyrimidin yl}amino)ethyl]phenyl}oxy)acetamide;
6-( 1 ,3-benzothiazol-6-yl )- -[( 1 R).1 -(3- { [( 1.3-dimethyl- 1 H-pyrazol-5- yl)methyl]oxy}phenyl)ethyI]-2-methylpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(2-oxo-2-pyrrolidin-l- ylethyl)oxy]phenyl}ethy])pyriniidin-4-amine;
2-methyl-6-(l-inetliyl-lH-indol-6-yl)-N-[l-(3-{[2-oxo-2-(4-pyridin-2-ylpiper yl)ethyl]oxy}phenyl)etliyl]pyrimidin-4-amine;
methyl 1 -({ [3-( 1 - { [2-melhyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetyl)piperidine-4-carboxylate;
2-{[3-(l-{[6-(l J3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yrjamino}ethyl)phenyl]oxy}-N-methylacetamide;
2- {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}- -ethylacetamide;
3- (l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4-yjamino}ethyl)phenol { [3-(l - { [2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetic acid;
4- {[3-(l-([6-(1.3-benzothiazol-6-yl)-2-methylpyi'imidin-4- yl]amino}ethyl)phenyl]oxy}butanoic acid;
ethyl 4-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}butanoate:
1,1-dimethylethyl (3S)-3-({[6-(l .3-benzothiazol-6-yl)-2-methylpyrimidin-4- y]amino}methyl)piperidine-l-carboxylate:
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N.N-diethylacetamide:
6-(4-chlo! phenyI)-2-melhyI-N-{l-[3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3-fluorophenyl)-2-methyl-N-{ l-[3-(l -methyl- lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-[3-(methyloxy)phenyl]-N- { 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(l H-indol-5-yl)-2-methyl-N-{ l-[3-(l -methyl- 111-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine; 2-methyl-6-(3-methylp enyl)-N-{ 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6 l,3-benzothiazol-6-yl)-N-[(2-chloro-6-nuorophenyl)methyl]-2-methylpyrimidin-4- amine;
2-methyl-N-{1 3-(l-methyl-lH-pyrazol-4-yl)phenyl]ethyl}-6-phenylpyrimidin-4- amine;
2-methyl-6-[4-(methyloxy)phenyl]-N-{ l-[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(2.4-dichlorophenyl)-2-methyl-N-{l-[3-(l -methyl- lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(2-methylphenyl)-N-{ 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3-chloiO-4-iluorophenyl)-2-methyl-N-{ 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl } pyrimidin-4-amine;
N-{2-[3-({[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}methyl)piperidin-l-yl]-2-oxoelhyl}-N-methylbenzamide;
2-methyl-N-{l-[3-(l -methyl- lH-pyrazol-4-yl)phenyl]ethyl}-6-naphthalen-2- ylpyrimidin-4-amine;
6-(1.3-benzothiazol-6-yl)-2-methyl-N-[(2R)-2-phenylpropyl]pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-melhyl-N-(2-pyridin-3-ylethyl)pyrimidin-4-amine;
6-(l!3-benzothiazol-6-yl)-N-(2-ethylhexyl)-2-methylpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-pyridin-3-ylethyl)pyrimidin-4-amine;
6-(1.3-benzothiazol-6-yl)-N-(2,3-dihydi -lH-inden-2-yl)-2-methylpyrimidin-4- amine;
6-(1.3-benzothiazol-6-yl)-N-(1.4-dimethylpenty )-2-methylpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-[2-(l H-imidazol-4-yl)ethyl]-2-methylpyrimidin-4-amine; 6-(l,3-benzothiazol-6-yl)-2-methyl- -[(2S)-2-phenylpropyl]pyrimidin-4-amine;
5- {f6-(1 -benzothiazol-6-yl)-2-methylpyrimidiiv4-yl]amino}-2,2-dimethylpentan-l- ol;
6- (l,3-benzothiazol-6-yl)-2-melhyl-N-{[3-(lH-pyrrol-l-yl)phenyl]methyl}pyrimidin- 4-amine;
1,1-dimethylethyl 3-({[6-( 1.3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yl]amino}methyl)piperidine-l-carboxylate;
6-(l J-benzothiazol-6-yl)-2-methyl-N-(2-pyridin-4-ylethyl)pyrimidin-4-amine; 6-(1.3-benzotlnazol-6-yl)-2-methyl-N-[(3-phenylisoxazol-5-yl)methyl]pynmidin-4- amine;
N'-[6-(1.3-benzotlnazol-6-yl)-2-methylpyrimidin-4-yl]-N-methyl-N-phenylpiOpane- 1,3-diamine;
2-methyl-6-(3-methyl-l
Figure imgf000357_0001
l-[3-(l H-tetrazol-1- yl)phenyl]etliyl}pyrimidin-4-amine;
2-methyl-6-(3-methyi- 1 -benzofuran-5-yl)-N-{ 1 -[3-(4H- 1 ,2,4-triazol-4- yl)plienyl]elhyl}pyrimidin-4-amine;
2-melhyl-6-(3-methyl-l-benzofuran-5-yI)-N-[l-(3 iitrophenyl)ethyl]pyrimidin-4- amine;
2-methyl-6-[4-methyl-3-(met yloxy)phenyl]-N-[(lR)-l ,2,3.4-tetrahydronaphthalen-l- yljpynmidin-4-amine;
6-( 1.3-benzothiazol-6-yl)-2-methyl-N- { 1 - [3-( 1 H - 1 ,2,3-triazol- 1 - yl)phenyl]ethyl}pyrimidin-4-amine;
N-[3-(l -{ 12-methyl-6-(3 -methyl- 1 -benzofxiran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyl]prop-2-enamide;
2-mcthyl-6-( 1 -methyl- 1 H-indol-6-yl)-N-{ 1 -[3-(l -mclh l-1 H-pyrazol-4- y!)phenyl]ethyl}pyrimidin-4-amine;
N-[l-(3-aminophenyl)ethyl]-2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- amine;
6-(l :3-benzothiazol-6-yl)-2-methyl- -{ 1 -[3-(5-methyl-l H-tetrazol- 1 - yl)phenyl]ethyl}pyrimidin-4-amine;
2- methyl-6-[4-methyl-3-(prop-2-yn-l-yloxy)phenyl]-N-[(lR)-l ,2,3,4- tetrahydronaphthalen- 1 -y l]pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-{l-[3-(ll-l-letrazol-l- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(l ,3-benzothiazol-6-yl)-2-methyl-N- { 1 -[3-(4H- 1 ,2..4-triazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
3- (l-{[6-(l,3-benzolhiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)benzonitrile; 2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}- ,N-diethylpropanamide:
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl|amino}ethyl)phenyl]oxy}-2-methylpropanamide; 6-(l,3-benzothiazol-6-yl)-2-methyl-N-{]-[3-(5-methyl-L2,4-oxadiazol-3- yl)phenyl]ethyl}pyrimidin-4-amine;
2- {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyiimidin-4- yl]amino}ethyl)phenyl]oxy}propanamide;
3- (l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyI)benzenecarboximidamide;
N-[3-(l-{[6-(] 3-benzot iazol-6-yl)-2-met ylpyiimidin-4-yl]amino}ethyl)phenyl]- 1 H-pyrazole-5-carboxamide;
N-[3-(l-{[6-(l ,3-benzothiazol-6-yl)-2-methylpynmidin-4-yl]amino}ethyl)phenyl]-l- methyl- 1 H-pyrazole-3-carboxamide;
2- methyl-5-{2 i thyl-6-[(lR)-l,2J,4-teiraliydronaphthalen-l-ylamino]pyrinn*din-4- yl}phenol;
N-[3-(l-{[6-(1.3-benzot iazol-6-yl)-2-melhylpyrimidin-4- yl]amino}ethyl)phenyl]dicarbonimidic diamide;
N-[3-(l-{[6-(l,3-benzothiazol-6-yI)-2-methylpyrimidin-4- yl]amino}elhyl)phenyl]lOrmainide;
1- [3-(l-{[6-(l,3-benzolhiazol-6-y!)-2-niethylpyrimidin-4- yl]amino}ethyl)phenyl]urea;
N-[3-(l-{[6-(13-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)pheny]]-l- methy -lH-imidazole-4-SLilfonamide:
6-(l,3-benzothiazol-6-yl)-2-methyl-N-{l-[3-(2H-tetrazol-5- yl)phenyl]ethyl}pyrimidin-4-amine;
1 ,1-dimethylethyl (2-{[3-(l-{[6-(l!3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}elhyl)phenyl]amino}-2-oxoelhyl)methyIcarbamate;
3- (l-{[6-(l,3-benzodiiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)-N'- hydroxybenzenecarboximidamide;
N-[6-(l,3-benzothiazol-6-yl)-2-methylpy
amine;
N-[6-(l,3-benzothiazol-6-yl)-2-met ylpynmidin-4-yl]-l -methyl- 1,2,3,4- tetrahydroq inolin-4-amine;
2- methy]-6-(3-methyl-]-benzof ran-5-yl)-N-[(lS)-l-(3-pyrimidin-5- ylphenyl)ethyl]pyrimidin-4-amine;
5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine; N-{(lS)-l-[3-(6-aminopyriclin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
ethyl (4-{3-[(lS)-l-{[2-methyl-6-(3Hiiethyl-l-benzoluran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}-l H-pyrazol-l-yl)acetate;
2-methyl-l-{[3-(l-{[2-methyl-6-(3-methyl-l-benzo uran-5-yl)pynmidin-4- yl]amino}ethyl)phenyl]oxy}propan-2-ol;
1- {[3-(l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}propan-2-one;
6-(3-ethyl-l-benzoturan-5-yl)-2-melhyl-N-[(lR)- 1.2.3 ,4-tetrahydrohaphthalen-l- yl]pyrimidin-4-amine;
6-(l-benzothien-5-yl)-N-|(4R)-3,4-dihydro-2H-chromen-4-yl]-2-methylpyrimidin-4- amine;
(4-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pynmidin-4- yl]amino}ethyl]phenyl}-lH-pyrazol-l-yl)acetic acid;
6-(1.3-benzothiazol-6-yl)-2-methyl-N-[(lS)-l-(3-pyrimidin-5- ylphenyl)ethyl]pyrimidin-4-amiiie:
2- methyl-6-(l-methyl-lH-indol-2-yl)- -[(lR)-l,2.3.4-telrahydronaphthalen-l- yl]pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-[l-(3-{[(5-methyl-l,2,4-oxadiazol-3- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
5- [3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]pyrimidin-2-amine;
2-methyl-6-( 1 -methyl- 1 H-pyrrolo[3,2-b]pyridin-6-yl)-N-[(l R)- 1,2, 3,4- tetrahydronaphthalen-l-yl]pyrimidin-4-amine;
ethyl (4-{3-[( 1 S)- 1 -{ [6-( 1 ;3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyI}-l H-pyrazol-l-yl)acetate;
6- (7-fluoro-l-benzofuran-5-yl)-2-methyl- -{(lS)-l-[3- (methyloxy)phenyl]ethyl } pyrimidin-4-amine;
6-(4-ethyl-3,4-dihydiO-2H-l,4-benzoxazin-6-yl)-2-melhyl-N-[(lR)-l, 2,3,4- tetrahydroniiphthalen-l-yl]pyrimidin-4-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-[l -(3-methylphenyl)elhyi]pyrimidin-4- amine;
6-(l,3-benzothiazol-6-yl)-N-| l-(3-{[(l-ethylpiperidin-3-yl)methyjoxy}phenyl)ethyl]- 2-methylpyrimidin-4-amine; N-{l-[3-(6-aminopyridin-3-yl)p enyl]ethyl}-6-(l,3-benzothiazol-6-yl)-2- methylpyrimidin-4-amine;
6-(l!3-benzothiazol-6-yl)-2-melhyl-N-[l-(3-{[( l-methylpiperidin-3- yl)metliyl]oxy}phenyl)ethyl]pyrimidin-4-aminc;
N-[ l -(3- { [( 1 ,3-dimethyi- 1 H-pyrazol-5-yl)methyl]oxy }phenyl)ethyl]-2-methyl-6-( l - methyl- 1 H-indol-2-yl)pyrimidin-4-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-[( l S)- 1 -(4- methylphenyl)ethyl]pyrimidin-4-amine;
N-[ 1 -(3-{ [(1 ,3-dimethyl- 1 H-pyrazol-5-yl)methyl]oxy}phenyl)ethyl]-6-(3-ethyl- 1 - benzol'uran-5-yl)-2-methylpyrimidin-4-amine;
6-(1.3-benzothiazol-6-yl)-2-methyI-N-(l-{3-[(piperidin-3- y methyl)oxy]phenyl}ethyl)pyrimidin-4-amiiie;
1- {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}propan-2-one:
6-(l ,3-benzothiazo]-6-yl)-2-methyl-N-{ 1 -[3-(2-methyl-l ,3-thiazol-4- yl)phcnyl]ethyl}pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-[l-(5-{[(K3-dimethyl-ll-l-pyrazo]-5- yl)methyl]oxy}pyridtn-3-yl)ethyl]-2-methylpyrimidin-4-amine;
6-(3-ethyl-l-benzofuran-5-yl)-2-methyl-Tsl-{(lS)-l-[3- (methyloxy)pheny1]ethyl}pyrimidin-4-amine;
2- methyl-6-(3-methyl- 1 -benzofuran-5-y l)- - { ( 1 R)- 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-{[3-({[6-(l,3-benzothiazol-6-yl)-2-melhylpyrimidin-4-yl]amino}methyl)-4- ' fluorophenyl]oxy}-N.N-diethylacetatnide;
2- methyl-6-(3-methyl-l-benzoliiran-5-yl)-N-{[3- (methyloxy)phenyl]methyl}pyrimidin-4-amine;
l-{[3-(l-{[6-(l!3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}propan-2-ol;
l-{[3-(l-{[6-(l;3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-2-methylpiOpan-2-ol;
N-[l-(2-nuorophenyl)ethyl]-2-methyl-6-(3-methyl-l-benzoixiran-5-yl)pyrimidin-4- amine;
3- (l-{[6-(3-ethyl-l-benzoturaiv5-yl)-2-methylpynmidin-4-yl]amino}ethyl)pheno^ 2-methyl-6-(l-methyl-lH-indol-2-yl)-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyi'imidin-4-amine;
6-(l,3-benzolhiazol-6-yl)- -[l-(2-cliloropyndin-4-yl)ethyj-2-methylpyrimidin-4- amine;
e-ilJ-benzothiazol-e-y ^-metliyl-N-fl- S-ICiS-methyl-l^^-oxadiazol-S- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
N-[l-(3-{[(l-acetylpiperidin-3-yl)methyl]oxy}phenyl)ethyl]-6-(l,3-benzothiazol-6- yl)-2-methylpyrimidin-4-amine;
2-{[3-(l-{[2-methyl-6-(l-melhyl-lH-indol-2-yl)pynmidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
methyl {f(2-chloro-5-{2-methyl-6-[(lR)-L2..3,4-tetrahydronaphthalen-l- ylamino]pyrimidin-4-yl}phenyl)methyl]oxy} acetate;
6-(1.3-bcnzothiazol-6-yI)-2-metliyl-N-(l-{3-[(piperidin-4- ylmethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
2-methyl-6-(4-methyl-3.4-dihydi -2H-l,4-benzoxazin-6-yl)-N-{l-[3-(l -methyl- 1H- pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine;
N-[l-(3-{[2-(4-acetylpiperazin-l-yl)ethyl]oxy}phenyl)ethyl]-6-(l,3-benzothiazol-6- yl)-2-methylpyrimidin-4-amine;
6-(1..3-benzothiazol-6-yl)-N-{[2-bromo-5-(melhyloxy)phenyl]methyI}-2- methylpyrimidin-4-amine;
2-{[3-({[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]amino}methyl)-4- fluoiOphenyl]oxy}-N,N-dimethylacetamide;
6-(l-beiizothien-2-yl)-2-methyl-N-[(l )-l,23,4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
{4-[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4-ylJamino}ethyl)phenyl]- 1 H-pyrazol-l-yl}acetic acid;
6-(3-ethy 1- 1 -benzofuran-5-yl)-2-methyl-N- { 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2- {[3-(l-{ 6-(])3-benzothiazol-6-yl)-2-methylpyrimidin-4- yrjamiiio}ethyl)plienyl]oxy}-N-[2-(metliyloxy)ethyl]acetamide;
3- ({[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]amino}methyl)-4- fluorophenol;
6-(lH-indol-2-yl)-2-methyl-N-[(l R)-1.2.3;4-tetrahydronaphthalen-l-y ]pyrimidin-4- amine; 2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}- 1 -cyclopropylethanone;
2-{[3-(l-{[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-phenylacetamide;
6-(l-benzofuran-2-yl)-2-nielliyl-N-{(lS)-l-[3-(mcthyloxy)phenyl]ethyl}pyrimidin-4- amine;
6-(l)3-benzothiazol-6-yl)-N-({2-lluoro-5-[(2-morpholin-4-yl-2- oxoethyl)oxy]phenyl}methyl)-2-methylpyrimidin-4-amine;
1 , 1 -dimethylethyl 3-({[3-( 1 -{ [6-(l ,3-benzothiazol-6-yl)-2-niethylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}melhyl)piperidine-l-carboxylate;
1 , 1 -dimethylethyl 4-({[3-(l -{[6-( 1 ,3-benzothiazoI-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}meVhyl)piperidinc-l-carboxylate;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[6-(methyloxy)pyridin-3- yl]phenyl}ethyl)pyrimidin-4-amine;
N!N-diethyl-2-{[3-(l-{[2-methyl-6-(4-methyI-3:4-dihydro-2H-l!4-benzoxazin-6- yl)pyrimidin-4-yl]amino}ethyl)phenyl]oxy}acetamide;
2-methyl- - {( 1 S)- 1 -[3-(melhyloxy)phenyl]ethyl } -6-( 1 -methyl- 1 H-pyrrolo[3,2- b]pyridin-6-yl)pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-[(5-bromo-2-fluorophenyI)methyl]-2-methylpyrimidin-4- amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-[l-(2-melhylphenyl)ethyl]pyrimidin-4- amine;
6-(l,3-benzothiazol-6-yl)-N-{[2-nuoi -5-(methyloxy)phenyl]methyl}-2- metliylpyrimidin-4-amine:
6-(l,3-benzothiazol-6-yl)-N-[(5-{[(L3-dimethyl-lH-pyrazol-5-yl)methyl]oxy}-2- nuoiOphenyl)melhyl]-2-methylpyrimidin-4-amine:
methyl {[3-({[6-(1.3-benzolhiazol-6-yl)-2-methylpyrimidin-4-yl]amino}methyl)-4- nuorophenyl]oxy}acetate;
6-( 1 ,3-benzothiazol-6-yl)-2-melhyl-N-{(lR)-l -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
- (lS)-3-{[3-(l-{[6-(l;3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino } ethyl)pheny l]oxy } - 1 -phenylpropan- 1 -ol ;
(2-chloro-5-{2-methyl-6 '(lR)-L2:3;4-tetrahydronaphthalen-l-ylamino]pyrimidin-4- y 1 } pheny l)methanol ; 6-(3-chloro-4-methylphenyl)-2-methyl-N-[( I )- 1 ,2,3,4-tetrahydronaphthalen- 1 - yl]pyrimidin-4-amine;
N-(2-hydroxyet yl)-2-(5-{2-methyl-6-[(lR)-l:2,3,4-tetrahydronaphthalen-l- yIamino]pyrimidin-4-yl}-1-benzofuran-3-yl)acetamide;
2-(6-{2-methyl-6-[(l R)-l,2.3;4-tetrahyd] naphtlialen-l-ylamino]pyrimidin-4-yl}-2.3- dihydro-4H- 1 ,4-benzoxazin-4-yl)ethanol;
2-(6-{2-methyl-6-[(l R)-l,2.3.4-tetrahydronaphthalen-l-ylamino]pyrimidin-4-yl}-2,3- dihydro- 1 H-indol- 1 -yl)ethanol;
ethyl (5-{2-methyl-6-[(l R)-l,2.3,4-tetrahydronaphthalen-l-ylamino]pyrimidin-4-yl}- l-benzofuran-3-yl)acetate;
methyl (6-{2-methyl-6-[(lR)-l,2.3.4-tetrahydronapht'halen-l-ylamino]pyrimidin-4- y I } -2.3-dihydro- 1 H-indol- 1 -yl)acetate;
N-[(4R)-3.4-dihydro-2i-l-chromen-4-yl]-2-methyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-amine;
NJN-diethyl-2-{[3-(]-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pynmidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
6-[4-chloro-3-(prop-2-yn-l-ylamino)phenyl]-2-methyl-N-[(lR)- 1,2,3,4- tctrahydronaphthalen- 1 -ylJpyrimidin-4-amii'ie;
N-[l-(3-{[2 lH-imidazol-l-yl)ethyl]oxy}phenyl)ethyl]-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
N-{(lS)-l-[3-(l-ethyl-lH-pyrazol-4-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
6-(4-chloro-3-methylphenyl)-N-[(4R)-3,4-dihydro-2H-chromen-4-yl]-2- methylpyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-(l-{3-[(piperidin-3- ylmethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-y l)-N-{ (1 S)- 1 -[3-( 1 -methyl- 1 H-pyrazol-5- yl)phenyl]ethyl}pyrimidin-4-amine;
2-{ [3-( 1 -{ [2-methyl-6-(3-methyl- 1 -benzofiiran-5-yl)pyrimidin-4- yl amino}ethyI)phenyl]oxy}ethanol;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-[(lS)-l-{3-[(2-morpholin-4-yl-2- oxoethyl)oxy]phenyl}ethylJpyrimidin-4-amine;
N-[l-(3-{[3-(dimethylamino)propyl]oxy}phenyl)ethyl]-2-methyl-6-(3-methyl-l- benzo uran-5-yl)pyrimidin-4-amine; 2- methyl-6-(3-methyl-l -benzof'iiran-5-yl')-N-[l -(3 -{ [(1 -meth l- 1 H-pyrazol-3- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
3- (l-{[2-methyl-6-(3-methyl-l-benzoi\u¾ 5-yl)pyrimidin-4-yl]amino}ethyl)phenol; N-[( 1 S)- 1 -(3-bromophenyl)ethyl]-2-methyl-6-(3-methy 1- 1 -benzofuran-5- yl)pyrimidin-4-amine;
2- methyl-6-(3-methyl- 1 -benzofiiran-5-y 1)-N- { ( 1 S 1 -[3-( 1 H-pyrazol-4- yl)phenyl|ethyl}pyrimidin-4-amine;
3- [( 1 S)- 1 -{ [2-methyl-6-(3-methyl-l -benzofuran-5-yl)pyrimidin-4- yl]ammo}ethyl]phenol; ·
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N- {( 1 S)- 1 -[3-( 1 -methyl- lH-pyrrol-2- yl)phenyl]ethyl}pyrimidin-4-amine;
N-[(4R)-3:4-dihydro-2H hromen-4-yl]-2-methyl-6 4-methyl-3,4-dihydiO-2H-l,4- benzoxazin-6-yl)pyrimidin-4-amine:
2-metliyl-6-(3-methyl-l-benzol iran-5-yl)-N (lS)-l-phenylethyl]pyrimidin-4-amine;
6-(1.3-benzothiazoI-6-yl)-2-methyl-N-[l-(3-pyridin-3-ylphenyl)ethyl]pyrimidin-4- amine:
6-(l ,3-benzothiazol-6-yl)-2-methyl-N-{ 1 -[3-( 1 -methyl- 1 H-pyrazo!-4- yl)phenyl]ethyl}pyrimidin-4-amine;
N-[(lS)-l-(4-fliioi phenyl)ethyl]-2-methyl-6-(3-methyl-l-benzofia-an-5-yl)pyrimidm^ 4-amine;
6-( 1 -benzofuran-5-yl)-N-[ 1 -(3- { [( 1 ,3-dimethyl- 1 H-pyrazol-5- yl)methyl]oxy}phenyl)elhyl]-2-methylpyrimidin-4-amine;
6-(l ;3-benzothiazol-6-yl)-2-methyl-N-{(l S)-l -[3-(l -methyl- 1 H-pyrazol-5- yI)phenyl]ethyl}pyrimidin-4-amine;
N-[l-(3-fluorophenyl)ethyl]-2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- amine;
6-(l,3-benzothiazol-6-yl)-N-{(lS)-l-[3-(l-ethyl-lH-pyrazol-4-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
2-methyl-6-[4-methyl-3-(pi p-2-yn-l-ylamino)phenyrj-N-[(l )- 1,2,3,4- tetrahydronaphthalen- 1 -yl]pyrimidin-4-amine;
2-methyl-6-(3-methyl- 1 -benzol'uran-5-yl)-N- {( 1 S)- 1 -[3-( 1 H-pyrazol-5- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofiiran-5-yl)-N-[(lR)-l-{3-[(2-morpholin-4-yl-2- oxoethyl)oxy]phenyl}ethyl]pyrimidin-4-amine; [(5-{6-[(4R)-3,4-dihydro-2H-chromen-4-ylamino]-2-methylpyrimidin-4-yl}-2- melhylphenyl)amino]acetonitrile;
3- [(lR)-l-{[2-metliy]-6-(3-methyl-l-benzofuran-5-yI)pyri!'nidin-4- yl]amino}ethyl]phenol;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-{(lS)-l-[3-(lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-f l-(3- {[(rnelhylsulibnyl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
[(2 1uoro-5-{2-methyl-6-[(rR)-1.2 ,4-letiahydronaphthalen-l-ylamino]pyrirnidin-4- yl}phenyl)aminojacetonilrile;
2-methyl-6-(3-methyl-l-benzofuian-5-yl)-N-{(lR)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
2- (methyloxy)-4- { 2-methy l-6-[( 1 R)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 - ylamino]pyrimidin-4-yl}benzamide;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(2-morpholin-4- ylethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-2-methyl-N- {( 1 S)- 1 -[3-( 1 -methyl- 1 H-pyrral-2- yl)phenyl]ethyl}pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-2-methyl-N-| 1 -(3-{ [2-(2-methyl- 1 H-imidazol- 1 - yl)ethyl]oxy}phenyl)ethyl |pyrimidin-4-amine;
6-(l-benzoiiiran-5-yl)-2-methyl-N-[l-(3-{[(l-methyl-lH-pyrazol-3- yl)methyl|oxy}phenyl)elhyl]pyrimidin-4-amine;
N-[(]S)-l-biphenyl-3-ylethyl]-2-methyl-6-(3-methyl-l-benzo uran-5-yl)pyrimidin-4- amine;
4- {[3-(l-{[6-(l,3-beiizothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy} butan- 1 -ol:
6-(l,3-benzothiazol-6-yl)-2-methyl-N-| l-(3-morpholin-4-ylphenyl)ethyl]pyrimidin-4- amine;
3- {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy} propane- 1,2-diol;
6-(l J-benzothiazol-6-y -N-|(lS)-l-biphenyl-3-ylclhyl]-2-niethylpyrimidin-4-amine; 2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}ethanol; 1 -{[3-(l -{[6-( 1 ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyI]oxy}-3-fluoi propan-2-ol:
6-(1,3-Βεηζο11ιϊαζο1-6^1)-Ν-[1-(3- ΓθπιορΗοηγ1)ε^1]-2-ηΐ6ΐ1ιγ1ρ>'ππιΐάΐη-4-αηιίηε;
3- {[3-(l-{[6-(l,3-bcnzothiazol-6-yl)-2-metliylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}piOpan- 1 -ol;
4- {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}- ,N-dimethylbutanamide;
6-(l,3-benzothiazol-6-yl)-N-| l-(3-{[3-(diethylamino)propyl]oxy}phenyl)ethyl]-2- methylpyrimidin-4-amine;
6-( 1 ,3-benzothiazo! -6-y l)-2-methyl-N-[ 1 -(3- { [2-( 1 H-pyrrol- 1 - yl)ethyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
6-(]:3-benzothiazol-6-yl)-2-metby!-N-(l-{3-[(3-morpholin-4- ylpropyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
2- { [3-( 1 -{ [6-( 1.3-benzothiazoI-6-y )-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-(2-hydroxyethyl)acetamide;
2-{[3-(l-{[6-(l ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- y]amino}ethyI)phenyl]oxy}- -cyclopropylacetamide;
6-(l ,3-benzothiazol-6-yl)-2-methyl-N-{ 1 -[3-( 1 H-pyrrol-2-yl)phenyl]ethyl } pyrimidin- 4-amine;
6-( 1 benzothiazol-6-yl)-2-methyl-N-[ 1 -(3- { [2-( 1 H-pyrazol- 1 - yl)ethyl]oxy}pheny)ethyl]p)Timidin-4-amine;
N,N-diethyl-2-[(3-{ l-[(2-methyl-6-naphthalen-2-ylpyrimidin-4- yl)amino]ethyl}phenyl)oxy]acetamide;
6-(1.3-benzothiazol-6-yl)-2-melhyl- -(l-{3-[(3-pyrrolidin-l- ylpropyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-N-[ 1 -(3-{ [3-(dimethylamino)pi pyl]oxy}phenyl)ethyl]-2- methylpyrimidin-4-amine;
6-(lJ3-benzothiazol-6-yl)-2-methyl-N-{ l-[2-Cmethyloxy)pyridin-4- yl]ethyl}pyrimidin-4-amine;
1,1-dimethylethyl 3-({[3-(l-{f2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- y]amino}ethyl)phenyjoxy}methyl)piperidine-l-carboxylate;
2-{ [3-(l -{ [6-( 1 ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-cyclohexylacetamide; 6-(l,3-benzotln\zol-6-yl)-N-[l-(3'-nuoiObiphenyl-3-yl)ethyl]-2-met ylp)Timidin-4- amine;
2-methyl-6-quinolin-6-yl-N-[(lR)-l,2,3,4 etrahydronaphthalen-l-yl]pyrimidin-4- amine:
6-(l,3-benzothiazol-6-yl)-N-[(2-lluoropheiiyl)methyl]-2-niethylpyrinn^in-4-amine; 2-methyl-6-quinoxalin-6-yl-N-[(l )-1.2,3,4-tetrahydronaphthalen-l-yl]pyrimidin-4- amine;
methyl {[3-(l-{[6-(l,3-benzothiazoI-6-yI)-2-methylpynmidin-4- yl]amino}ethyl)phenyl]oxy} acetate;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-[l-(3-{[2- (methylsuHOnyl)ethyl]oxy}plienyl)ethyl]pyrimidin-4-amine;
6-(3-amino-4-methylphenyl)-2-methyl-N-{(lS)-]-[3- (methyloxy)phenyl]ethyl } pyrimidin-4-amine;
2-methyl-N-{(l S)-l-[3-(methyloxy)phenyl]ethyl}-6-quinolin-6-ylpyrimidin-4-arnine
{[3-(l-{[6-(l,3-benzolhiazol-6-yl)-2-met'hylpyrimidin-4- yl]amino}ethyl)pheny]]oxy}acetic acid;
6-(l,3-benzothiazol-6-y[)-2-metbyl-N-(piperidin-3-ylmethyl)pyrimidin-4-amine;
6-(3-amino-4-chIorophenyl)-N-|(4R)-3.4-dihydro-2H-chromen-4-yl]-2- methylpyrimidiri-4-amine;
6-(1 -benzothiazol-6-yl)-N-[(2-chlorophenyl)methyI]-2-methylpyrimidin-4-amine;
6-(l,3-benzotliiazol-6-yl)-N-[(2-chloro-6-fluoro-3-methylphenyl)methyl]-2- methylpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-{[2-chIoro-6-niioro-3-(methyloxy)phenyl]methyl}-2- methylpyrimidin-4-amine;
2-mcthyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(l-methyl-lH-pyrazol-4- yl)plienyl]ethyl}pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-2-methyl-N-{( 1 S)- 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
N!N-dimethyl-2-({3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl] phenyl } oxy)acelamide;
N-[l-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)ethyl]-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
N,N-dimethyl-2-({3-[(lR)-l-{[2Hiiethyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}oxy)acetamide; 6-(l,3-benzotln'azol-6-yl)-N-[l-(3-{[2-(dimelhylamino)ethyl]oxy}phenyl)ethyl]-2- methylpyrimidin-4-amine;
6-(1.3-benzothiazol-6-yl)-2-methyl-N-{[l-(lH-pyrrol-2-yIcarbonyl)piperidin-3- yl]methyl}pyrimidin-4-amine;
6-(2,5-dimethylphenyI)-2-methyl-N- { 1 -|3-( 1 -methyl- 1 l-I-pyrazol-4- yl)phenyl]ethy!}pyrimidin-4-amine;
6-(3,4-dichloiOpheny])-2-methyl- -{ l-[3-(l -methyl- 1 H-pyrazol-4- yl)phenyr]ethyl}pyrimidin-4-amine;
6-(4-ethylphenyl)-2-methyl-N-{l-[3-(l-methyl-lH-pyrazol-4- yl)phenyl]elhyl}pyrimidin-4-amine;
6-(4-iluoro-3-methylphenyl)-2-methyl-N-{ 1 -[3-(l -methyl- lH-pyiazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-2-methyl-N-( { 1 -[( 1 -methy lcyclopropyl)carbony l]piperidin- 3-yl}methyl)pyrimidin-4-amine;
6-(13-benzothiazol-6-yl)-N-{[l-(cyclopentylcarbonyl)pipendin-3-yl]methyl}-2- methylpyrimidin-4-amine;
2-methyl-6-[4-( 1 -methylethyl)phenyl]- -{ 1 -[3-(l -methyl-1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
e-fl^-benzothiazol-e-yrj-N-ffl-^yclobutylcarbony piperidin-S-ylJmethyl}^- riiethylpyrimidin-4-amine;
6-[2-fluoiO-4-(methyloxy)phenyl]-2-metliyl-N-{ l -[3-( l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(l.3-benzolhiazol-6-yl)-N-{[l-(cyclohexylcarbonyl)piperidin-3-yl]methyl}-2- m ethylpyri m i d i n-4-am i ne ;
6-[3-(dimethylamino)phenyl]-2-methyl-N-{ l -[3-(l -methyl-l H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-methylbutyl)pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(3-methylbutyl)pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-(2-cyclohex-l-en-l-ylethyl)-2-methylpyrimidin-4-amine;
4-(2-{[6-(l;3-benzothiazol-6-yl)-2-melhylpyiimidin-4-yl]amino}ethyl)phenol;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-pentylpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-methylpiOpyl)pyrimidin-4-amine;
6-( l ,3-benzothiazol-6-yl)-2-methyI-N-( l -methylhexyl)pyrimidin-4-amine; 6-(lJ3 ienzothiazol-6-yl)-2-met yl-N-[(lS)-l,2,2-trimethylpi pyl]pyrimidin-4- amine;
6-(l!3-benzothiazol-6-yl)-2 netliyl- -(2-pyndin-2-ylethyl)pyrirnidin-4-amine; 6-( l ,3-benzothiazol-6-yl)-2-methyl-N-[ l -methyl-2-(methyloxy)elhyl]pyrimidin-4- amine;
6-(L3-benzothiazol-6-yl)- -[(l S)-l-(3-biOmophenyl)ethyl]-2-melhylpyrimidin-4- amine;
6-(K3-benzothiazol-6-yl)-2-methyl-N-{(lS)-l-[3-(lH-pyrazol-5- yl)phenyl]ethyl}pyrimidin-4-amine;
(2E)-3-{3-[(l S)-l -{[6-(l ,3-benzotIiiazol-6-y )-2-mediylpyrimidin-4- yl]amino}ethyl]phenyl}-N-ethylpiOp-2-enaniide;
2-{ 13-( 1 - { [6-( 1 ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-[2-(dimethylamino)ethyl]acetamide;
2-{ [3-( 1 -{ [6-( 1 ,3-benzothiazol-6-yl)-2-methyIpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-piOpylacetamide;
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyjoxy}-N-ethyl-N-methylacetamide:
6-(l!3-benzotliiazol-6-yl)-2-methyl-N-[l-(3-nitrophenyl)ethyl]pyrimidin-4-amine;
(2E)-3-{3-[(lS)-l-{[6-(L3-benzothiazol-6-yl)-2-methyIpyrimidin-4- yI]amino}ethyl]phenyI }-N-( 1 , 1 -dimethylethyl)prop-2-enamide;
N-[l-(3-aminophenyl)ethyl]-6-(1.3-benzothiazol-6-yl)-2-mediylpyrimidin-4-amine;
2-({[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy} methyl)- 1.3-oxazole-4-carboxylic acid;
methyl 2-({[3-(l-{[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl|oxy} methyl)- l,3-oxazole-4-carboxylate;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-[(lS)-l-phenylethyl]pyrimidin-4-amine;
6-(lJ3-benzolhiazol-6-yl)-N-(2!2-dimethy-3,4-dihydiO-2H-chromen-4-yl)-2- methyIpyrimidin-4-amine;
[(2-methyl-5- (2-methyl-6-| ( 1 R)- 1 ,2,3,4-tetrahydronaphthalen- 1 -ylamino]pyrimidin- 4-yl}phenyl)oxy]acetonitrile;
2-methyl-6-(2-phenylethyl)-N-[(l R)-l,2,3.4-tetrahydiOnaphthalen-l-yl]pyrimidin-4- amine;
2-melhyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lS)-l-[4- (methyloxy)phenyl]ethyl}pyrimidin-4-amine; 6-(]I3-benzothiazol-6-yl)-N-[l-(3-{[(l,3-dimethyl-lH-pyrazol-5- yl)methyl]oxy}phenyl)ethyl]-2-methylpyrimidin-4-amine;
N-[l-(3-fiiran-3-ylphenyl)ethy]]-2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrirnidin- 4-amine;
6-(l,3-benzothiazoI-6-yl)-2-methyl-N-(l-{3- [(phenylmetliyl)oxy]phenyl}ethyl)pyrimidin-4-amine:
2-methyl-6-(3-met yl-l-benzofuran-5-yl)-N-{l-[3-(3-diienyl)phenyl]ethyl}pyrimidin- 4-amine;
6-(l,3-benzothiazol-6-yl)-2-metliyl-N-(l-{3-[(pyridin-3- ylmethyl)oxy]phenyl}ethyI)pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-metliyl- -[l-(3-{[(3-methylisoxazol-5- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-aminc;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-[l-(3-{[(2-methyl-l,3-thiazol-4- yl)met yl]oxy}phenyl)ethyl]pyrimidin-4-amine;
6-(l J3-benzothiazol-6-yl)-2-methyl- -{ ]-[3-(propyloxy)phenyl]ethyl}pyrimidin-4- amine;
6-(lJ3-benzothiazol-6-yl)-N-{l-f3-(3,5-dimethylisoxazol-4-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
6-{2-methyi-6-[(l )-l,2.3,4-tetrahydronaphthalen-l-ylarnino]pyrirnidin-4-yl}-4H- · chromen-4-one;
6-(l!3-benzothiazol-6-yl)-2-methyl-N-[l-(3-{[(4- methylp enyl)methyl]oxy}phenyl)ethyl]pynmidin-4-amine;
6-(l3-benzothiazol-6-yl)-N-[l-(3-furan-3-ylphenyl)ethyl]-2-methylpyrimidin-4- amine;
6-( l :3-benzothiazol-6-yl)-2-methyl-N-f l -(3-{ [(3- { [(4-methylphenyl)oxy]methyl }- l.2.4-oxadiazol-5-yl)methyl]oxy}phenyl)elhyrjpyrimidin-4-amine;
6-(l3-benzothiazol-6-yl)-2-methyl-N-{l-[3-(3-thienyl)phenyl]ethyl}pyrimidiri-4- amine;
6-(2:l :3-benzoxadiazol-5-yl)-2-methyl-N-[(l R)-l ,2,3,4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
2-melhyl-6-{[3-(methyloxy)phenyl]oxy}-N-[(l RH^^^-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
N-(5-{[6-(l13-benzothiazo]-6-yl)-2-methylpyrimidin-4-yl]amino}-5,6,7,8- tetrahydronaphthalen-2-yl)propanamide; 2-methyl-6-(l-melhyl-lH-indol-5-yl)-N-[(lR)-l,213,4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
6-() -benzothiazol-6-yl)-N-fl-(3-{[2-(lH-imidazol-l-yl)ethyl]oxy}phenyl)ethyl]-2- niethylpyrimidin-4-amine;
2-{[3-(l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyljoxy}acetamide;
N-[l-(3-{[(l,3-dimethyl H-pyrazol-5-yl)rnethyl]oxy}phenyl)ethyl]-2-methyl-6-(3- methyl-l-benzofuran-5-yl)pynmidin-4-amine;
2-{[3-(l-{[6-(1.3-beiizolhiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
2-methyl-6-(3-mefhyl-l-benzofuran-5-yl)-N-(I-{3-[(2-morpholin-4-yl-2- oxoethyl)oxy]phenyl}ethyl)pyrimidin-4-aniine;
2-methyl-6-quinolin-3-yl-N-[(l R)-l,2,3,4-tetrahydronaphthalen-l-yl]pyrimidin-4- amine;
N,N-dimethyl-2-{[3-(l-{l^-methyl-6-(3-methy]-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
6-(L3-benzothiazol-6-yl)-2-methyl-N-[l-(3-{[(l-methyl-lH-pyrazol-3- yl)methyl]oxy}phenyl)efhyl]pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-(l-{3-[(2-fluoroelhyl)oxy]phenyl}ethyl)-2- methylpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(2,2>2- trifluoroethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
N-[l-(3-bromo-4-fl oiOphenyI)elhyl]-2-methyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-amine;
5-[2-fluoiO-5-(l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)plienyl]pyrimidiii-2-amine;
N-{(1 R)-l -[4-fluoro-3-(l -methyl- 1 H-pyrazol-4-yl)phenyl]ethyl}-2-methyl-6-(3- methyl-l-benzofuran-5-yl)pyrimidin-4-amine;
N-{(lS)-l-[4-iluoro-3-(]-methyl-lH-pyrazol-4-yl)phenyl]ethyl}-2-methyl-6-(3- methyl-l-benzofuran-5-yl)pyrimidin-4-amine;
5- [3-( 1 - { 16-( 1 ,3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]pyridine-3-carboxaniide;
6- (l,3-benzothiazol-6-yl)-2-metliyl-N-[(lS)-l-{3-[2-(4-methylpiperazin-l- yl)pyrimidin-5-yl]phenyl}ethyl]pyrimidin-4-amine; 6-(l,3-benzothiazol-6-yr)-2-methyl-N-(l-{3-[5-(trifluoiOmethyl)pyridin-3- yl]phenyl}ethyl)pynmidin-4-amine;
2- methy]-6-(3-methyl-l-benzofuran-5-yl)-N-[(lS)-l-{3-[2-(4-methylpiperazin-l- yl)pyrimidin-5-ylJphenyl}ethyl|pyrimidin-4-amine;
3- [(5-{3-[(lS)-l-{[2-methyl-6-(3-melhyl-l-benzoiuran-5-yl)pyniTiidin-4- yl]amino}ethyl]phenyl } pyrimidin-2-yl)amino]propan- 1 -ol
methyl N-(5-{3-[(l S)-l-{[2Hiielhyl-6-(3-methyl-l-benzo(uran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)glycinate;
2- methyl-6-(3-methyl-l-benzofuran-5-yl)-N-[(lS)-l-{3-[6-(4-methylpiperazin-l- yl)pyndin-3-yl]phcnyl}etliyl]pyrimidin-4-amine
2,2-dimethyl-3-[(5- { 3-[( 1 S)- 1 -{ [2-melhyl-6-(3-methyl- 1 -benzol:'Liran-5-y])pyrimidin- 4-yl]amino}ethyl]phenyl}pyriniidin-2-yl)aniino]piOpan-l-ol;
-(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzoiuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)glycine; '
3- [(5-{3-[(lS)-l-{[2-melhyl-6-(3-met yl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)amino]propane-1.2-diol;
N-[( 1 S)- 1 -(5'-fluoi -3!3'-bipyridin-5-yl)ethyl]-2-methyl-6-(3-methyl- 1 -benzofuran-5- yl)pyrimidin-4-amine;
N-[(l S)- 1 -(6, ]uoro !3'-bipyndin-5-yl)ethyl]-2-methyl-6-(3-methyl-l -benzofuran-5- yl)pyrimidin-4-amine;
N- {( 1 S)- 1 -[5-( 1 -ethyl- 1 H-pyrazol-4-yl)pyridin-3-yl]ethyl } -2-methyl-6-(3-methyl- 1 - benzofuran-5-yl)pyrimidin-4-amine;
.6-chloro-5'-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]-3,3'-bipyridin-5-amine;
5-{5-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuian-5-yl)pyrimidin-4- yl]amino}ethyl]pyridin-3-yl}pyrimidin-2-amine;
N 1-(3-bromo-5-nuorophenyl)ethyl]-2-metliyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-arnine;
5-[3-lluoro-5-( l - { [2-melhyl-6-(3-methyl- 1 -benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyl]pyrimidin-2-amine;
N-{l-[3-fluoro-5-(l-methyl-lH-pyrazol-4-yl)phenyl]ethyl}-2-niethyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
l-(5-{5-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- >4]amino}ethyl]pyridin -yl}pyrimidin-2-yl)pipendin-4-ol; N-{l-[3-(5-amino-6-chloropyridin-3-yl)-5-nuorophenyl]ethyl}-2-methyl-6-(3-methyl- l-benzofuran-5-yl)pyrimidin-4-amine;
N-[l-(3-bromo-4-melliylphenyl)ethyl]-2-methyl-6-(3-methyl-l-benzoii.iran-5- yl)pyrimidin-4-amine;
5-[2-methyl-5-(l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyiimidin-4- yl]amino}ethyl)phenyl]pyrimidin-2-amine;
2-methyl-6-(3-methyl-l -benzofuran-5-yl)-N-{ 1 -[4-methyl-3-(l -methyl- 1 H-pyrazol-4- yr)phenyl]ethyl}pyrimidin-4-amine;
5- { 3-[( 1 S)- 1 - { [2-methy l-6-( 1 -melhyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
2-methyl-6-(3-methyl- 1 -benzofuian-5-yl)-N- {( 1 S 1 -[5-(l -methyl- 1 H-pyrazol-5- yl)pyridin-3-yl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l -benzo†uran-5-yl)-N-{( 1 S)- 1 -[5-( 1 H-pyrazol-4-yl)pyridin-3- yljethyl}pyrimidin-4-amine;
(2S)-3-[(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]an no}elhyl]phenyl}pyrimidin-2-yl)amino]propane-l,2-diol;
2-methyl-N-{ 1 -[3-( 1 -methyl- 1 H-pyrazol-4-yl)phenyl]ethyI } -6-[4- (trifliioromethyl)phenyl]pyrimidin-4-aniine;
6- (2,3-dihydro-l,4-benzodioxin-6-yl)-2-niethyl-N-{l-[3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-{( 1 S)- 1 -[3-( 1 H-pyrazol- 1 - yl)phenyl]elhyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzoliran-5-yl)-N-{(lS)-l-[3-(2H-lJ2,3-triazol-2- yl)phenyl]etliy I } pynmidin-4-amine;
6-(l-benzothien-5-yl)-2-methyl-N-{l-[3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
N'-{5-[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyr|pyrimidin-2-yl}-NJN-dimethylethane-1.2-diamine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-{ ( 1 S)- 1 -[3-( 1 H-tetrazol- 1 - yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methy 1- 1 -benzof'uran-5-yl)-N- {( 1 )-l -[3-( 1 H-tetrazol- 1 - yl)pheny l]ethyl } pyri m id i n-4-am i ne ;
N-{(lS)-l-[3-(2-{4-[2-(dimethylamino)ethyl]piperazin-l-yl}pyrimidin-5- yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4-amine; 2-[4 5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzoftiran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperazin-l-yl]ethanoI;
2-methyl-6-(3-methy!-l -benzofuran-5-yl)-N-{(l S)-l -[3-(2-{4-[(l -methyl- 1 H- imidazol-2-yl)methyl]piperazin-l-yl}pyrimidm^
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lS)-I-[3-(2-{4-[2- (methyloxy)ethyl]piperazin-l-yl}pyrimidin-5-yl)phenyl]ethyl}pyrimidin-4-amine;
2-({2-[4-(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperazin-l-yl]ethyl}oxy)et anoH
2-meth l-6-(3-meth ]-l-benzof^ιran-5- l)- -[(lS)-l-(3-{2-[4-(2-Ino holin-4- ylethyl)piperazin-l-yl]pyrimidin-5-yl}phenyl)ethyl]pyrimidin-4-amine;
N-[(lS)-l-(3-bromophcnyl)ethyl]-2-methyl-6-(3-methyl-l-benzothien-5-yl)pyrimidin- 4-amine;
2-methyl-6-(3-methyl-l-benzotliien-5-yl)-N-{(lS)-l-[3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
N-{(lS)-l-[3-(5-aminopyridin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzothien-5-yl)pyrimidin-4-amine;
N-{(lS)-l-[3-(6-fluoropyridin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzolhien-5-yl)pyrimidin-4-amine;
N-{(lS)-l-[3-(5-fluoropyridin-3-yl)phenyl]ethy]}-2-methyl-6-(3-methyl-]- benzothien-5-yl)pyrimidin-4-amine;
5- {3-[(lS)-l-{[6-(3-chloiO-l-benzofuran-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
ethyl 5-[3-(1 -{[6-(l ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]pyridinc-3-carboxylat'e;
6- (l,3-benzothiazol-6-yl)-N-(l-{3-[6-(dimethylamiiio)pyridin-3-yl]phenyl}ethyl)-2- methylpyrimidin-4-amine;
N-[(lS)-l-(3-bromophenyl)ethyl]-6-(3-ethyl-l-benzofuran-5-yl)-2-methylpyrimidin- 4-amine;
5- {3-[(lS)-l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
6- (l,3-benzothiazol-6-yl)-N-{(lS)-l-|3-(5-fluoropyridin-3-yl)phenyl]ethyl}-2- methylpyrimicIin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-{(lS)-l-[3-(6-methy]pyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine; 5- {3-[(lS)-l-{[6-(3-ethyl-l-benzoliran-5-yl)-2-melhylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
6- (l,3-benzothiazol-6-yl)-2-met yl-N-{(lS)-l-[3-(5-methylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-{(lS)-l-[3-(6-fluoro-5-methylpyridin-3- yl)phenyl]ethyl}-2-methylpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-{(lS)-l-[3-(6-fluoropyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
-{(lS)-l-[3-(5-fluorapyridin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
6-(7-fluoro-l-benzoluran-5-yl)-2-methyl-N-{ l-[3-(1 -methyl- lH-pyrazol-4- yl)phenyl]ethyI}pyrimidin-4-amine;
N-{(lS)-l-[3-(2-chloropyrimidin-5-yl)pheny!]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-{(lS)-l-[3-(2-chloropyrimidin-5-yl)phenyl]elhyl}-2- methylpyrimidin-4-amine;
N-{(lS)-l-[3-(6-fluoropyridin-3-yl)phenyl]elhyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
5-{3-[(lS)-l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}-N-methylpyrimidin-2-amine;
N-methyl-5-{3-[(lS)-l-{[2-methyl-6-(3-metliyl-l-benzoruran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-aniine;
5- { 3-[( 1 S)- 1 - { [6-(7-fluoro- 1 -benzoiuran-5-y l)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-aniine;
5-{3-[(lS)-l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- ylJamino}ethyl]phenyl}-N,N-dimethylpyninidin-2-amine;
N,N-dimethyl-5- {3-|(l S)-l -{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
N-ethyl-5-{3-[(lS)-l-{[2-melhyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
5- { 3-[( 1 S)- 1 - { [6-( 1 ,3-benzolhiazol-6-y l)-2-methy lpyrimidin-4- yl]amino}ethyl]phenyl}-N-ethylpyrimidin-2-amine;
2-methyl-6-(3-methyl-l-benzofiiran-5-yl)-N-{(lS)-l-[3-(2-morpholin-4-ylpyrimidin- 5-yl)phenyl]ethyl}pynmidin-4-amine: 2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-{( 1 S)- 1 -[3-(2-piperazin- 1 -ylpyrimidin-5- yl)phenyljethyl}pyrimidin-4-amine;
N-{(lS)-l-[3-(5-aminopyndiiv3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzouran-5-yl)pyrimidin-4-amine;
2-[(5-{3-[(lS)-]-{[2-melhyl-6-(3-niethyl-l-benzofiiran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)amino]ethanol;
N,N-diethyl-5-{3-[(lS)-l-{[2-methyl-6-(3 iiethyl-l-benzofuran-5-yl)pyrimi yl]amino}ethyI]phenyl}pynmidin-2-amine;
N-{(lS)-l-[3-(5-chloropyridin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzo(uran-5-yl)pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-{(lS)-l-[3-(5-chioropyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine:
5- {3-[(lS)-l-{[6-(l!3-benzothiazol-6-> )-2-methyIpyrimidin-4- yl]amino}ethyl]phenyl}-N,N-diethylpyrimidin-2-amine;
6- (1.3-benzolhiazol-6-yl)-N-[(lS)-]-{3 2-(4-ethylpiperazin-l-yl)pyrimidin-5- yl]phenyl}ethyl]-2-methylpyrimidin-4-amine;
l-(5-{3-[(lS)-l-{|6-(],3-benzot iazol-6-yl)-2-melhylpyrimidin-4- yl]amino}ethyl]phenyl}pyrirnidin-2-yl)pipendin-4-oI;
N-[(lS)-l-{3-[2-(4-ethylpiperazin-l-yl)pyrimidin-5-yl]phenyl}ethyl]-2-methyl-6- methyl-l-benzofiiran-5-yl)pyrimidin-4-amine;
l-(5-{3-[(lS)-l-{[2 nethyl-6-(3-methyl-l-benzofuran-5-yl)pynmidin-4- yl]amino}ethyl]plienyl}pyrimidin-2-yl)pipei"idin-4-ol;
l-(5-{3-[(IS)-l-{ 2-methyl-6-(3-methyl-l-benzoiuran-5-yl)pynmidin-4- yI]amino}ethyl]phenyI}pyniTiidin-2-Yl)pyrrolidin-3-ol;
N-(l -methylethyl)-5-{3-[( 1 S)- 1 -{[2-melhyl-6-(3-methyl- 1 -benzofiiran-5- yl)pyrimidin-4-yl]amino}ethyl]phenyl}pyriinidin-2-aniine:
[l-(5-{3-[(lS)-l-{[2-methyl-6-(3 iielhyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperidin-4-yl]methanol;
N-[(lS)-l-{3-[2-(4 1uoropiperidin-l-yl)pyrimidin-5-yl]phenyl}ethyl]-2-methyl-6-(3- methyl-l-benzofuran-5-yl)pyrimidin-4-amine;
N furan-2-y!methyl)-5-{3-[(lS)-l-{[2 iiethyl-6-(3 ^ethyl-l-benzofuran-5- yl)pyrirnidin-4-yl]amino}ethyl]phenyl}pynmidin-2-amine;
N-(furan-3-ylmethyl)-5-i3-[(lS)-l-{[2-methyl-6-(3^iiethyl-l-benzofuran-5- yl)pyrimidin-4-yl]amino}ethyl]phenyl}pyrimidin-2-ainine; 6-(7-fluoro-3-methyl-l-benzofuran-5-yl)-2-methyl-N-{l-[3-( I -methyl- lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine:
(5-{3-[(lS)-l-{[6-(l!3-benzothiazol-6-yr)-2-methylpyrimidin-4- yl]amino}ethyl]p enyl}pyridin-2-yl)met anol;
2-methyl-6-(3-metliyl-l-benzoinan-5-yl)-N-{(lS)-l-[3-(4-methyl-3,4-dihydro-2H- pyrido[3.2-b][l,4]oxazin-7-yl)phenyl]elliyl}pyrimidin-4-ainine;
(5- {3-[( 1 S)- 1 - { [6-( 1 ,3-benzolhiazol-6-yl)-2-methy lpyrimidin-4- yl]amino}ethyl]phenyl}pyridin-3-yl)methanol;
N-{(lS)-l-[3-(5-amino-6-chloropyridin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yI)pyrimidin-4-amine;
6-(7-fluoro-3-met yl- 1 -benzofuran-5-yl)-2-methyl-N-{( 1 S)- 1 -[3-( 1 -methyl- 1 H- pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3!4-difluorophenyl)-2-methyl- -{l-[3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pynmidin-4- yIjamino}ethyl]phenyl}pyridin-3-yl)methanol;
N-{(lS)-l-[3-(5-aminopyndin-3-yl)phenyl]etliyl}-6-(7-fluoro-3-methyl-l- benzofuran-5-yl)-2-metliylpyrimidin-4-amine;
6-(7-lluoiO-3-methyl-l-benzofuran-5-yl)- -{(lS)-l-[3-(5-iluoiOpyridin-3- y)phenyl]ethyl}-2-methy]pyrimidin-4-amine;
6-(4-chloro-3,5-difluoiOphenyl)-2-methyl-N-{l-[3-(l -methyl- lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-N-{l-[3-(l-methyl-lH-pyrazol-4-yl)phenyl]ethyl}-6-(3,4,5- ti'iiluorophenyl)pyrimidin-4-amine;
N-{(lS)-l-[3-(5-amino-6-chloropyridin-3-yl)phenyl]ethyl}-6-(7-fluoiO-3-methyl-l- benzofuran-5-yl)-2-methylpyrimidin-4-amine;
5-{3-[(lS)-l-{[6-(3,4-dif]uorophenyl)-2-melhylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
5- {3-[(lS)-l-{[6-(4-chloro-3?5-ditluoiOphenyl)-2-methylpyrimidin-4- y 1] amino } ethy l]phenyl } py ri m idin-2-amine;
l-(5-{3-[(lS)-l-{[2-methyl-6-(3-methy]-l-bcnzofuran-5-yl)pyrimidin-4- ylJamino}ethyl]phenyl}pyridin-3-yI)ethanone;
6- (7-fluoro-3-methyl-l-benzofuran-5-yl)-2-methyl-N-{ l-[5-(lH-pyrazol-4-yl)pyridin- 3-yl]ethyl}pyiimidin-4-amine; N-{l-[5-(l-ethyl-lH-pyrazol-4-yl)pyridin-3-yl]ethyl}-6-(7-nuoro-3-methyI-l- benzofuran-5-yl)-2-met y]pyrimidin-4-amine:
6-(7-fluoro-3-melhyl-l -benzofuran-5-yl)-N-{ ( 1 S)- 1 -[3-(6-†luoropyridin-3- yl)phenyl]ethyi}-2-methylpyi-imidin-4-ainine;
ethyl 5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridine-3-carboxylate;
3-[(5-{3-[(lS)-l-{[6-(7-nuoro-3-methyl-l-benzofuran-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)amino]propane-l,2-diol;
1 -(5-{3-[( 1 S)- 1 - { [6-(7-fluoiO-3-methyl- 1 -benzofuran-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperidin-4-ol;
1- (5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridiii-3-yl)elhanol;
2- (5-{3-[(lS)-l-{[2-methyl-6-(3-met yl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridin-3-yl)propan-2-ol;
6-(7-fluoro-3-methyl- 1 -benzofuran-5-yl)-2-methyl-N-{ 1 -[5-( 1 -methyl- 1 H-pyrazol-4- yl)pyridin-3-yl]ethyl}pyrimidin-4-amine;
5-[5-(l-{[6-(7-nuoro -iiiethyl-l-benzofuran-5-yl)-2-methylpyrimidin-4- yl (amino }ethyl)pyridin-3-yl]pynmidin-2-amine;
5- {3 (lS)-l-{[6-(7-fluoiO-3-metliyl-l-benzofuran-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-[( 1 S)- 1 -(3-pyridin-3- ylphenyl)ethyl]pyrimidin-4-amine;
6- (l,3-benzothiazol-6-yl)-N-{ l-[3-(2-nuoropyridin-3-yl)phenyI]ethyl}-2- methylpyrimidin-4-amine;
6-(l .3-benzothiazol-6-yl)-2-methyl-N-{ 1 -[3-(2-methylpyridin-4- yl)phenyl]ethyl } pyrimidin-4-amine;
N-[( 1 S)- 1 -{3-[6-(dimelhylamino)pyridin-3-y l]phenyl } elhyl]-2-methyl-6-(3-methyl- 1 - benzof\iran-5-yl)pyrimidin-4-amine;
6-(l,3-benzothiazol-6-y )-2-methyl-N-{ l-[3-(6-piperazin-l-ylpyridin-3- yl)phenyl]ethyI}pyrimidin-4-amine;
2-methyl-6-(3-niethyl-l-benzoluran-5-yl)-N-{l -[5-(l -methyl- 1 H-pyrazol-4- yl)pyridin-3-yl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofiiran-5-yl)-N-{(lS)-l-[3-(6-methylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine: 2-methyl-6-(3-niethyl-l-benzoiiiran-5-yl)-N-{(lS)-l-[3-(6-piperazin-l-ylpyridi yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-melhyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(5-methylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
N-{(lS)-l-[3-(6-nuoro-5-methylpyridin-3-yl)phenyI]ethyl}-2-niethyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
6-(1 -benzothiazol-6-yl)-N-{(lS)-l-[3-(2-fluoropyridin-4-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
5- [4-(l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yljamino}ethyl)pyridin-2-yjpyrimidin-2-amine;
N-{(lS)-l-[3-(6-chloropyridin-3-yl)phenyl]ethy }-2-methyl-6-(3-methyl-l- benzofuian-5-yl)pyrimidin-4-amine;
2-methyl-N-[(l S)-l-{3-[6-(methylamino)pyridin-3-yl]phenyl}ethy]]-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
2 nethyl-6-(3^iietliyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(6-morpholin-4-ylpyndin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
2-[(5-{3-[(]S)-l-{[2-methyl-6-(3-methy]-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridin-2-yl)amino]ethanol;
6- (l:3-benzothiazol-6-yl)-N-{(lS)-l-[3-(6-chloi pyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
6-(l -benzofuran-5-yl)-2-methyl-N-{ 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2Mnethyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lR)-l-[2-(l-methyl-lH-pyrazol-4- yl)pyridiri-4-yl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N- {( 1 S)- 1 -[2-( 1 -methyl- 1 H-pyrazol-4- yl)pyridin-4-yl]ethyl}pyrimidin-4-amine;
N-[( 1 S)-l -{3-[6-(ethylamino)pyridin-3-yl]phenyl}ethyl]-2-methyl-6-(3-methyl-l - benzofuran-5-yl)pynmidin-4-aminc;
N-[(lS)-l-{3-[6-(4-ethylpiperazin-l-yl)pyridin-3-yl]phenyl}ethyl]-2-methyl-6-(3- methyl-l-benzofuran-5-yl)pyrimidin-4-amine;
6-(1 -benzothiazol-6-yl)-N-[(lS)-l-{3-[6-(4-ethyIpiperazin-l-yl)pyridin-3- yl]phenyl}ethyl]-2-methylpyrimidin-4-amine;
5-[5-( 1 -{ [2-methyl-6-(3-melhyl- 1 -benzo uran-5-yl)pyrimidin-4- yl]amino}ethyl)pyridin-3-yljpyriniidin-2-amine: 6-(l ,3-benzothiazol-6-yl)-2-methyl-N-{( 1 S)-l -[3-(6-morpholin-4-ylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lR)-l-[5-(l-methyl-lH-pyrazol-4- yl)pyridin-3-yl]ethyl}pyrimidin-4-amine;
l-(5-{3-[(lS)-l-{[2-methyl-6-(3-mctIiyl-l-benzofuran-5-yl)pyriniidin-4- yl]amino}ethyl]phenyl}pyridin-2-yl)piperidin-4-ol;
6-(l,3-benzothiazol-6-yl)- -{(lS)-]-[3-(6-chloro-5-methylpyridin-3- yl)phenyl]ethyl}-2-methylpyrimidin-4-amine;
N-{(lS)-l-[3-(6-chloi -5-methylpyridin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
N-[ 1 -(5-bromopyridin-3-yl)ethyl]-2-methyl-6-(3-metliyl- 1 -benzofuran-5- yl)pyrimidin-4-amine;
5,-(l-{[2-methyl-6-(3-metliyl-l-benzofuran-5-yl)pyrimidin-4-yl]ann'no}ethyl)-3 bipyridin-5-amine;
6-(4-chloro-3-fluorophenyl)-2-methyl-N-{ 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3-†1uorophenyI)-2-methyl-N- {(1 S)- 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
5-{3-[(lS)-l-{[6-(4-chlorophenyl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
5-{3-[(lS)-l-{[6-(4-chloro-3-l:liiorophenyl)-2-methylpynmidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
N-{(lS)-l-[3-(5-aminopyridin-3-yl)pl nyl]ethyl}-6-(4-chloiO-3-fluorophenyl)-2- methylpyrimidin-4-amine;
5- [5-(l-{[6-(4-chIoiO-3-fluoroplienyl)-2-methylpyrimidin-4-yl]amino}ethyl)pyridin- 3-yl]pyrimidin-2-amine;
6- (4-chloiO-3-fluorophenyl)-2-niethyl-N-{l-[5-(l -methyl- lH-pyrazol-4-yl)pyridin-3- yl]ethyl}pyrimidin-4-amine;
6-(4-chloro-3-fliiorophenyl)-N-{l-[5-(l -ethyl- lH-pyrazol-4-yl)pyridin-3-yl]ethyl}-2- methylpyrimidin-4-amine;
6-(4-chloro-3-nuoiOphenyl)-2-methyl-N-{( 1 S)- 1 -[3-(6-piperazin-l -ylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(4-chloro-3-fluorophenyl)-2-methyl-N-{(l S)- 1 -[3-( 1 -methyl-1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine; 6-(3-fluorophenyl)-2-methyl-N-{(l )-l-[3-(l-meihyl-lH-pyrazol-4- yI)phenyl]ethyl}pyrimidin-4-amine;
3-[(5-{3-[(lS)-l-{[6-(4-chloro-3-nuorophenyl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)amino]pi pane-l,2-diol;
1 -(5- {3-[(l S)- 1 -{ [6-(4-chloro-3-fluorophenyl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperidin-4-ol;
N-{(lS)-l-[3-(4-chloiOpyridin-3-yl)p enyl]etliyl}-2-methyl-6-(3-niethyl-l- benzofi.iran-5-yl)pyrimidin-4-amine;
6-(4-chloro-3-nuorophenyl)-N-{(lS)-l-[3-(l-ethyl-lH-pyrazol-4-y!)phenyl]ethy]}-2- met ylpyrimidin-4-amine;
5- {3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyI}pyridine-3-carboxaniide;
3- [2-methyl-6-({ 1 -[3-(l -methyl-1 H-pyrazol-4-yl)phenyl]ethyl}amino)pyrimidin-4- yl]phenol;
6- (2,3-dihydro- 1 -benzofuraii-5-yl)-2-methyl-N-{ 1 -[3-( 1 -methyl-1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-[2-fliioiO-3-(methyloxy)phenyj-2-methyl-N-{ l-[3-(l -methyl-1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yI)-2-methyl-N-( 1 -{3-[5-(methyloxy)pyridin-3- yl]phenyl}ethyl)pyrimidin-4-amine;
6-(1.3-benzothiazol-6-yl)-N-{l-[3-(2-(luoi pynmidin-5-yl)phenyl]ethyl}-2- melhylpyi'imidin-4-amine;
5- [3-(l-{[6-(l ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]pyrimidine-2-carbonitrile;
6- (1.3-benzothiazol-6-yl)-N-{l-[3-(6-lluoiO-2-methylpyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
5- [3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]pyridine-3-carbonitrile;
6- (l,3-benzothiazol-6-yl)-N-{l-[3-(4-chlorapyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
6-(l!3-benzothiazol-6-yl)-N-{l-[3-(2 )-dimethylpyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
4- [3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpynmidin-4- yl]amino}ethyl)phenyl]pyrimidin-2-amine; 6-( 1 ,3-benzothiazol-6-yl)-2-methyl-N-{( 1 S)- 1 -[3-(2-piperidin- 1 -ylpyrimidin-5- yl)phenyl]ethyl}pyrimidin-4-amine;
N'-(5-{3-[(lS)-l-{[6-(1..3-benzothiazol-6-yl)-2-methylpyrimidin-4- yI]amino}ethyl]phenyl}pyrimidin-2-yl)-N,N-diiTietliylpropane-l,3-diamine;
-[(lS)-l-{3-[2-(4-acetylpiperazin-l-yl)pynmidin-5-yl]phenyl}ethyl]-2-methyl-6-(3- methyl- 1 -benzofuraii-5-yl)pyrimidin-4-amine;
5- {3-[(lS)-l-{[2-melhyl-6-(3-melhyl-l-benzoluran-5-yl)pyrimidin-4- yl]amino}ethyl]pheny]}-N-(tetraliycli furan-2-yImethyl)pyrimidin-2-ainine;
6- (3-amino-4-chlorophenyl)-2-methyl-N-{ 1 -|3-(1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(4-chloro-3-methylphenyl)-2-methyl-N- { 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-fluoro-4-[2-methyl-6-({ 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}amino)pyrimidin-4-yl]benzamide;
6-(l,3-benzothiazol-5-yl)-2-methyl-N-{l-[3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
N-[(lS)-l-{3-[2-(4-acetylpiperazin-l-yl)pyrimidin-5-yl]phenyl}ethyl]-2-methyl-6-(3- meth l-l-benzothien-5-yl)pyrimidin-4-amine;
N-{(lS)-l-[3-(2-{4-[2-(dimethylamino)ethyl]piperazin-l-yl}pyrimidin-5- yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l-benzothien-5-yl)pyrimidin-4-amine;
5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridine-3-carbonitrile;
2-methyl-6-(3-methyl- 1
Figure imgf000382_0001
S)- 1 -(6'-methyl-3,3'-bipyridin-5- yl)ethyl]pyrimidin-4-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N- {( 1 S)-l -[5-(l -methyl- 1 H-pyrazol-4- yl)pyndin-3-yl]ethyl}pyrimidin-4-amiiie
5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzothien-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
N-{(lS)-l-[3-(5-aminopyridin-3-yl)phenyl]ethyl}-6-(l ,3-benzothiazol-6-yl)-2- methylpyrimidin-4-amine; and
5-{3-[( 1 S)- 1 - { [2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-ol;
(S)-5-(3-(l-(6-(7-fluoro-3-methylbenzof ran-5-yl)-2-methylpyrimidin-4- ylamino)ethyl)phenyl)pyrimidin-2-amine; (S)-2-methyl-N-(l-(5-(1 -methyl- 1 H-pyrazol-4-y l)pyridin-3-yl)ethyl)-6-(3- methyIbenzofuran-5-yl)pyrimidin-4-amine;
(S)-N-(]-(3-(5-aminopyriclin-3 yl)phenyl)ethyl)-6-(4-chloro-3-fluoI phenyl)-2- methylpyrimidin-4-amine;
(S)-5-(3-(l-(2-methyl-6-(3-methylbenzot'uran-5-yl)pynmidin-4- ylamino)ethyl)phenyl)pyrimidin-2-amine;
N-(l-(5-(l-ethyl-lH-pyrazol-4-yl)pyridin-3-yl)ethyl)-6-(7-fluoro-3- melhylbenzol\iran-5-yl)-2-metliylpyrimidin-4-amine;
5-(3-fluoiO-5-(l-(2-metliyl-6-(3-melhyIbenzofuran-5-yl)pyrimidin-4- ylamino)ethyl)phenyl)pyrimidin-2-amine;
(S)-5-(3-(l-(2-meth\ -6-(3-methylbenzo[b]thiophen-5-yl)pyrimidin-4- ylamino)ethyl)phenyl)pyrimidin-2-amine; or
(S)-N-(l-(3-(5-aminopyridin-3-yl)phenyl)ethyl)-2-methyl-6-(3- methylbenzo[b]thiophen-5-yl)pyrimidin-4-amine.
42. A compound of claims 1-35 which is:
(5 6-(Benzo[^thiazol-5-yl)-N-(l-cyclohexylethyl)-2-mediylpyrimidin-4-aniine;
2-methyl-6-[3-(methylo>y)phenyl]-N-{(lR)-l-[3- (methyloxy)phenyl]elhyl}pyrimidin-4-amine;
2-methyI-6-[3-(methyloxy)phenyl]-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pynmid 4-amine;
2- methyl-6-[3-(methyloxy)phenyl]-N-{(lS)-l-[4-(methyloxy)phenyl]ethyl}pyrimid 4-amine;
N,N-diethyl-2-{[3-(l-{ 2-methyl-6-(l-methyl-lH-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
N,N-dimethyl-2-{[3-(l-{[2-methyl-6-(l-melhyl-lH-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetamide:
3- (l-{[2-methyl-6-(l-methyl-l H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)benzenesulfonamide;
N-ethyl-2-{[3-(l-{[2-methyl-6-(l-methyl-rH-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acctamide;
N-(cyanomethyl)-3-( ]-{[2-methyl-6-(l -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)benzenesulfonamide; 2-methyl-6-(l -methyl- lH-indol-6-yl)-N-(l-{3-[(2-morpholin-4-yl-2- oxoethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
4-{ [3-(l -{ [2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}butanoic acid;
2-methyl-6-(l-methyl-lH-indol-6-yl)- -{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyi"imidin-4-amine;
2- methyl-6-(l-methyl-lH-indol-6-yl)-N-[(lS)-l-pheiiylethyl]pyriniidin-4-amine; 6-[2-chlo!O-3-(methyloxy)phenyl]-2-methyl-N-{(lS)-l-[3-
(melhyloxy)phenyl]ethyl}pyrimidin-4-amine;
6-(l,3-benzodioxol-5-yl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin- 4-amine;
3- (l-{[2-methyl-6-(l-methyl-lH-indol-6-yl)pyrimidiii-4-yl]amino}ethyl)phenol; 6-(lH-indol-5-yl)-2-melhyl-N-{(lS)-l-|3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
ethyl N-({[3-(l-{[2-methyl-6-(l-methyl-lH-indol-6-yl)pyrimidin-4- yrjamino}ethyl)phenyrjoxy}acetyl)glycinate;;
N-[(lS)-l-(4-nuorophenyl)ethyl]-2-methyl-6-(l-methyl-lH-indol-6-yl)pyrimidin-4- amine;
2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)-N-[( 1 S)- 1 -(4-methylphenyl)ethyl]pyrimidin-4- amine;
ethyl 4-{[3-(l-{[2-methyl-6-(l-methyl-lH-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}butanoate;
6-(3-fluorophenyl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
2-({3-[l-({6-[2-chloi -3-(methyloxy)phenyl]-2-methylpynmidin-4- yl}amino)ethyl]phenyl}oxy)- -methylacelamide;
2- {[3-(l-{[6-(l,3-benzodioxol-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-methylacetamide;
N-(cyanomethyl)-3-| 1 -({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]benzenesulfonamide;
({3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenyl}oxy)acetonitrile;
3- [l-({6-[2-chloiO-3-(melhyloxy)phenyl]-2-methylpyrimidin-4- yl}amino)ethyl]benzenesulfOnamide;
). 6-[2-fluoro-3-(methyloxy)phenyl]-2-methyl-N-{(lS)-l-[3- (melhyloxy)phenyl]ethyl}pyrimidin-4-amine;
N-methyl-2-({3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl } amino)ethy I] phenyl } oxy)acetamide;
N-[l-(3-biOmophenyl)ethyl]-6-[2-chloro-3-(methyloxy)phenyl]-2-methylpyrimidin-4- amine;
methyl ({3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl } amino)ethyl]pheny 1 } oxy)acetate;
methyl N-{3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyjphenyl}glycinate;;
N-[( 1 S)- 1 -(4-chlorophenyl)ethyl]-2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- amine;
3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]benzenesuliOnamide;
6-(l -elhyl-1 H-inclol-6-yl)-2-methyl-N-{(l S)- 1 -[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
methyl N-({3-[ 1 -({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenyl}sulfonyl)glycinate;;
2- methyl-6-( 1 -methyl- 1 H-indol-5-yl)-N-{( 1 S)- 1 -| 3- (melhyloxy)phenyl]ethyl}pyrimidin-4-amine;
3- [l-({2-methyl-6-[3-(metl\vloxy)phenyl]pyrimidin-4-yl}amino)ethyl]phenol;
1,1-dimethylethyl (cyanomethyl)({3-[l-({2-methyl-6-[3-
(methyloxy)phenyl]pyrimidin-4-yl}amino)ethyl]phenyl}sulfonyl)carbamate;
2-melhyl-6-[3-(methyloxy)phenyl]-N-{( 1 S)-l -[3- (trifluoromethyl)phenyl]ethyl}pyrimidin-4-amine;
2-melhyl-N-{(lS)-l-[3-(methyloxy)phenyl]elhyl}-6-{3- [(triiluoromethyl)oxy]phenyl}pyrimidin-4-amine;
2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]elhyl}-6-[3,4:5- tris(methyloxy)phenyl]pyrimidin-4-amine;
methyl N-{[(l,l-dimethylethyl)oxy]carbonyl}-N-({3-[l-({2-methyl-6-[3- (methyloxy)phenyl]pyrimidin-4-yl}amino)elhyl]phenyl}sulfonyl)glycinate;:
6-[2-chloro-5-(methyloxy)phenyl]-2-melhyl-N-{(lS)-l-[3- (mclhyloxy)phenyl]elhyl}pynmidin-4-amine: 6-(lH-ind l-6-yl)-2-met yl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
N-{3-[l-({2-melhyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenyl} glycine
N-({3-[l-({2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenyl}sulfonyl)glycine:
N-metliyl-2-{ [3-( 1 -{ [2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
6-(l-benzoiuran-5-yl)-2-metliyl- -{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrirnidin-4- amine;
6-(l-benzothien-5-yl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-6-(4-methylphenyl)pyrimi amine;
6-(4-chloi phenyl)-2-methyl-N- {( 1 S)-l -[3-(methyloxy)phenyl]ethyl} pyrimidin-4- amine;
6-(3-chlorophenyl)-2-methy -N- {( 1 S)- 1 -[3-(methyloxy)phenyl]ethyl } pyrimidin-4- amine;
6-(2-fluorophenyl)-2-methyl-N-{(lS)-l-[3-(metliyloxy)phenyl]ethyl}pyrimidin-4- amine;
6-(4-fluoiOphenyl)-2-methyl-N-{(lS)-l-[3-(melhyloxy)phenyl]ethyl}pyrimidin-4- amine;
2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]elhyl}-6-(2-methylphenyl)pyrimidin-4- amine;
6-(l!3-benzoxazol-6-yl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin- 4-amine;
6-(l ,3-benzothiazol-6-yl)-2-methyl-N-{(l R)- 1 -[3- (methyloxy)phenylJethyl}pyrimidin-4-amine;
6-(l H-indol-4-yl)-2-methyl-N- {( 1 S)- 1 -[3-(methyloxy)phenyl]ethyl }pyrimidin-4- amine;
6-( 1 H-indol-7-yl)-2-methyl- -{ (1 S)- 1 -[3-(methyloxy)phenyl]ethy } pyrimidin-4- amine; 6-(2-c lorop enyl)-2-rnethyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
2-methy l-6-( 1 -methyl- 1 H-benzimidazol-6-yl)-N- { ( 1 S)- 1 -[3- (methyloxy)phenyl]etliyl}pyrimidin-4-amine;
6-[3-(dimethylamino)phenyl]-2-methyi-N-{(lS)-l-[3- (methy loxy)pheny l]ethyl } pyrimidin-4-amine;
6-(lH-indazol-5-yi)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- aminc;
6-[4-(dimethylamino)phenyl]-2-methyl-N-{(l S)-1 -[3- (methyloxy)phenyl]ethyl}pyiimidin-4-amine;
6-(l!3-benzothiazoI-6-yl)-2-metliyl-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-N-{(lS)-l-[3-(methy]oxy)phenyl]ethyl}-6-phenylpyrimidin-4-amine;
6-(3-elhylphenyl)-2-methyl-N-{(lS)-l-[3-(methy]oxy)phenyl]ethyl}pyrimidin-4- amine;
2-methy I-N-{( IS)- l-[3-(methyloxy)phenyl]ethyl}-6-(3-methylphenyl)pyrimidin-4- amine:
2-methyl-6-pyridin-4-yl-N-[(lR)-l,2.3,4-tetrahydronaphthalen-l-yl]pyrimidin-4- amine;
2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-6-pyridin-3-ylpyrimidin-4-amine;
2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}-6-pyridin-4-ylpyrimidin-4-amine;
N-[l-(3-bromophenyl)ethyl]-2-methyl-6-[3-(methyloxy)phenyl]pyrimidin-4-amine;
N-[l -(3- { [(1 ,3-dimethyl- 1 H-pyrazol-5-yl)methyl]oxy}phenyl)ethyl]-2-methyl-6-( 1 - methyl-lH-indol-6-yl)pyrimidin-4-amine;
6-(L3-benzothiazol-6-yl)- -[( 1 S)- 1 -(3-{ [( 1 ,3-dimethyl- 1 H-pyrazol-5- yl)methyl]oxy}phenyl)elhyl]-2-methylpyrimidin-4-amine;
2-fluoro-5-(l-{[2-methyl-6-(3-methy-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)phenol
N-{l-[4-fluoro-3-(l-methyl-lH-pyrazol-4-yl)phenyjethyl}-2-methyl-6-(3-methyl-l- benzoiiran-5-yl)pyrimidin-4-amine;
6-[2-chloro-3-(methyloxy)phenyl]-N-[l-(3-{[(1.3-dimethyl-lH-pyrazol-5- yl)methyl]oxy}phenyl)ethyrj-2-methylpyrimidin-4-amine;
2-methyl-6-[4-methyl-3-(methyloxy)phenylJ-N-{(lS)-l-[3- (methyIoxy)phenyl]ethy 1 } pynmidin-4-amine; 3-[(lS)-l-{[6-(l.3-benzothiazol-6-yl)-2-niethylpynmidin-4-yl]amino}et yl]phenol
N-[l-(3-{[(l)3-dimethyl-ll-l-pyiazol-5-yl)methyl]oxy}pheny])ethyl]-2-methyl-6-[4- methyl-3-(methyloxy)phenyl]pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-melhyl-N-(l-{3-[(lH-pyrazol-3- ylmetliyl)oxy]phenyl}ethyl)pyrimidiii-4-amine;
3-(l-{[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)-N- (cyanomethyl)benzeiiesulfonamide;
6-(l -benzothiazol-6-yl)-N-(l-{3-[(isoxazol-3-ylmethyI)oxy]phenyl}ethyl)-2- methylpyrimidin-4-amine;
3-(l-{[6-(l.3-benzotliiazol-6-yl)-2 nethylpynmidin-4-yl]amino}ethyl)-N-but-2-yn-l- ylbenzenesulfonamide;
2-methyl-6-[4-methyl-3-(methyloxy)phenyl]-N-[l -(3- {[(l -methyl- lH-pyrazol-3- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
6-(l !3-benzothiazol-6-yl)-N-[ l -(3-{ [( l ,3-dimethyl- 1 H-pyrazol-5-yl)methyl]oxy } -4- ttuorophenyl)elhyl]-2-melhylpyrimidin-4-amine;
2- ({3-[l-({2-methyl-6-[4-methyl-3-(methyloxy)phenyl]pyrimidin-4- yl}amino)ethyl]phenyl}oxy)acetamide;
3- (l-{[6-(1.3-benzolhiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)-N-prop-2-yn- 1 -ylbenzenesulfonaniide;
6-(1.3-benzothiazol-6-yl)-N-{ l-[4-nuoiO-3-(l-methyl-lH-pyrazol-4-yl)phenyl]ethyl}- 2-methylpyrimidin-4-amine;
{[3-(l-{[6-(l ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetonitrile
N-(l-{3-[(2-azepan-l-yl-2-oxoethyl)oxy]plienyl}ethyl)-6-(1.3-benzothiazol-6-yl)-2- methylpyrimidin-4-amine;
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-melhylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-(l-methylethyl)acetamide;
6-(2,3-dihydro-l-benzo< jran-5-yl)-2-melhyl-N-{(lS)-l-[3- (methyloxy)plienyl]ethyl}pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-[l-(3-{[2-(2-methylaziridin-l-yl)-2- oxoetliyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
2-{[3-(]-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N.N-dimethylacetamide; 3-(l-{[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)benzenesulfonamide;
6-(K3-benzothiaz.ol-6-y])-2-methyl-N-[l-(3-{[(5-methylisoxazol-3- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
{ [3-( 1 -{ [2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acelonitrile;
6-( 1 ,3-benzothiazol-6-yl)-2-methyl-N-{ 1 -| 3-(prop-2-yn- 1 - y loxy)phenyl ]elhy 1 } pyri m idi n-4-am i ne:
-{ l-[2-f1uoro-3-(methyIoxy)phenyl]ethyl}-2-methyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-amine;
2- cliloiO-5-(l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yI)pyrimidin-4- yl]amino}ethyl)phenol;
3- [l-({2-rnethyl-6-[4-methyl-3-(methyloxy)phenyl]pyrimidin-4- yl }amino)ethy l]phenol
6-(l,3-benzothiazol-6-yl)-2-methy]-N-(l-{3-[(2-oxo-2-piperidin-l- ylethyl)oxy]phenyl}elhyl)pyrimidin-4-amine;
N-( 1 - {3-[(2-azetidin- 1 -yl-2-oxoelhyl)oxy]phenyl }ethyl)-6-( 1.3-benzothiazol-6-yl)-2- methylpyrimidin-4-amine;
2- {[3-(l-{[6-(l;3-benzothiazol-6-yl)-2-methylpyrimidin-4- y ]amino}ethyl)phenyl|oxy}-N-(2-liydroxypiOpyl)acetamide;
3- (l-{[6-(l,3-benzothiazol-6-yl)-2-methylpynmidin-4-yl]amino}ethyl)-N-(2- hydroxyethyl)benzenesullOnamide;
6-(L3-benzothiazol-6-yl)-N-[l-(5-{[(l)3-dimethyl-lH-pyrazol-5-yl)methyl]oxy}-2- fluorophenyl)ethyl]-2-methylpyrimidin-4-amine;
3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyiimidin-4-yl]amino}ethyl)-N-[2- (methyloxy)elhyl]benzenesulfonamide;
3-[(lR)-l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4-yrjamino}ethyl]phenol
6-(l,3-benzothiazol-6-\i)-2-methyl-N-(l-{3-[(2-morpholin-4-yl-2- oxoethyl)oxy]phenyl}ethyl)pyi'imidin-4-amine;
3-(]-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethy )-4- fluoiophenol
3-[l-({6-[2-fluoro-3-(niethyloxy)phenyl]-2-methylpyriniidin-4-yl}amino)ethyl]phenol N,N-diethyi-2-({3-[ l-({6-[2-fluoro-3-(methyloxy)phenyl]-2-methylpyrimidin-4- yl}amino)ethyl]phenyl}oxy)acetamide; 6-(l,3-benzothiazol-6-yl)-N- (lR)-l-(3-{[(l,3-limelliyl-lH-pyrazol-5- yl)inethyl]oxy}phenyl)ethyl]-2-methylpyrimidin-4-amine;
6-(l!3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(2-oxo-2-pyiTolidin-l- ylethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)-N-[ 1 -(3-{ [2-oxo-2-(4-pyridin-2-ylpiperazin- 1 - yl)elhyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
methyl 1 -( { [3-( 1 -{ [2-methy l-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phcnyl]oxy}acelyl)pipei'idine-4-carboxylate;
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyljoxy}-N-methylacetamide;
2- {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidiiv4- yl]amino}ethyl)phenyl]oxy}-N-ethylacetamide;
3- (l-{[6-(l !3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)phenol { [3-( 1 -{ [2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetic acid;
4- {[3-(l-{[6-(l,3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}butanoic acid;
ethyl 4- { [3 -( 1 - { [6-( 1.3-be zothiazol-6-yl)-2-methy lpyrimidin-4- yl]amino}ethyl)phenyljoxy}butanoate;
1,1-dimethylethyl (3S)-3-({[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}methyl)piperidine-l-carboxylate;
2-{[3-(l-{[6-(l;3-beiizolhiazol-6-yl)-2-methylpyriniidin-4- yl]amino}ethyl)phenyl]oxy}-N.N-diethylacelamide;
6-(4-chloropheny l)-2-methyl-N- { 1 -[3-( 1 -methyl- 1 l-I-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3-fluoiOphenyl)-2-methyl-N-{ 1 -[3-(l -methyl-1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-[3-(methyloxy)phenyl]-N-{l-[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-aniine;
6-( 1 H-ind6l-5-yl)-2-melhyl-N-{ 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)plienyl]ethyl}pyi'imidin-4-amine;
2-methyl-6-(3-methylphenyl)-N-{ 1 -[3-(l -methyl-1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine; 6-(l,3-benzothiazol-6-yl)-N-[(2-chloro-6-nuorophenyl)methyl]-2-melhylpyrimidin-4- amine;
2-met yl-N-{l-[3-(l -methyl- lH-pyrazol-4-yl)phenyl]ethyl}-6-phenylpyrimidin-4- amine;
2-methyl-6-[4-(methyloxy)phenyl]-N-{ 1 -[3-( 1 -methyl-1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(2,4-dichlorophenyl)-2-methyl-N-{l-[3-(l -methyl-1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(2-methylphenyl)-N- { 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3-chloiO-4-fluorophenyl)-2-methyl-N-{l-[3-(l-melhyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
N-i^- -CI^-Cl^-benzothiazol-e-y ^-methylpyrimidin^- yl]amino}methyl)piperidin-l-yl)-2-oxoethyl}-N-methylbenzamide;
2-methyl-N-{ l-[3-(l -methyl-1 H-pyrazol-4-yl)phenyl]ethyl}-6-naphthalen-2- ylpyrimidin-4-amine;
6-(l ,3-benzothiazol-6-yl)-2-melhyl-N-( I -pyridin-3-ylelhyl)pyrimidin-4-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-y l)-N-{ 1 -[3-( 1 H-tetrazol- 1 - yl)phenyl]elhy 1 } pyrimidin-4-amine;
2-methyl-6-(3-methyI- 1 -benzofuian-5-yl)-N-{ 1 - 3-(4H- 1 ,2,4-triazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofiiran-5-yl)-N-[l-(3-niti phenyl)ethyl]pyriniidin-4- amine;
6-(l -benzothiazol-6-yl)-2-methyl-N-{l-[3-(lH-l,2;3-triazol-l- yl)plienyl]ethyl}pyrimidin-4-amine;
N-[3-(l-{|2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyl]piOp-2-enamide;
2-methyl-6-( 1 -methyl- 1 H-indol-6-yl)-N- { 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl } pyrimidin-4-amine;
N-[l-(3-aminophenyl)ethyl]-2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- amine;
6-(l :3-benzothiazoI-6-yl)-2-methyl-N-{ 1 -[3-(5-methyl- 1 H-tetrazol- 1 - yl)phenyl]ethyl}pynmidin-4-amine; 6-( 1 ,3-benzothiazol-6-yl)-2-melhyl-N-{ 1 -[3-(l H-tetrazol-1 - yl)phenyl]elhyl}pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-2-met yl-N-{ 1 -[3-(4H- 1 ,2,4-'triazoI-4- yl)phenyljethyl}pyrimidin-4-amine;
3-(l-{[6-(1.3-benzothiazol-6-yl)-2 nethylpyrimidin-4-yl]amino}ethyl)benzonitrile
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N,N-diethylpropanamide;
2-{[3-(l-{[6-(l :3-benzothiazol-6-yl)-2-methylpyrimidin-4- yI]amiiio}ethyl)phenyl]oxy}-2-methylpropanamide;
e-Cl^-benzothiazol^-y ^-melhyl-N-O- -CS-methyl-l^^-oxadiazol^- yl)phenyl]ethyl}pyrimidin-4-amine;
2- {[3-(l-{[6-(l ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)pheiiyl]oxy}piOpanamide;
3- (]-{[6-(l,3-bcnzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)benzenecarboximidamidc;
N-[3-(l-{[6-(]!3-benzothiazol-6-yl)-2Hiiethylpyrimidin-4-yl]amino}ethyl)phenyl]- 1 H-pyrazole-5-carboxamide;
N-[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpy
methyl- 1 H-pyrazole-3-carboxamide;
N-[3-(l-{[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]dicarbonimidic diamide;
N-[3-(l-{[6-(l .3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]formamide;
l-[3-(l-{[6-(l,3-beiizothiazol-6-yl)-2'-methylpyrimidin-4- yl]amino}ethyl)phenyl]urea;
N-[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)phe methyl- lH-imidazole-4-sulibnamide;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-{l-[3-(2H-tetrazol-5- yl)phenyr|ethyl}pyrimidin-4-amine;
1,1-dimethylethyl (2-{[3-(l-{[6-(K3-benzothiazol-6-yl)-2-methylpynmidin-4- yl]amino}ethyl)phenyl]amino}-2-oxoethyl)methylcarbamate;
3-(l-{[6-(1.3-benzot"hiazol-6-yl)-2-methylpyrimidin-4-yl]amino}ethyl)-N'- hydroxybenzenecarboximidamide; 2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-[(lS)-l-(3-pyrimidin-5- ylphenyl)ethyl]pyrimidin-4-amine;
5- {3-[(lS)-l-{[2-melhyl-6-(3-methyl-l-bcnzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
N-{( 1 S)- 1 -[3-(6-aminopyiidin-3-yl)phenyl]ethyl } -2-inethyl-6-(3-methyl- 1 - benzofuran-5-yl)pyrimidin-4-amine:
ethyl (4-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyjphenyl}-lH-pyrazol-l-yl)aceta(e;
2-methyl- 1 - { [3-( 1 - { [2-methyl-6-(3-methyl- 1 -benzof uran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}propan-2-ol;
1 -{[3-( 1 -{[2-methyI-6-(3-methyI- 1 -benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)pheny ]oxy}pi"opaii-2-one:
6- (3-ethyl-l-benzol nan-5-yl)-2 iiethyl-N-[(lR)-l,2,3,4-tetrahydronaphthalen-l- yl]pyrimidin-4-amine;
(4-{3-[( 1 S)- 1 -{ [2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}-lH-pyrazol-l-yl)acetic acid;
6-(l ,3-benzothiazol-6-yl)-2-methyl-N-|'( 1 S)-l -(3-pyrimidin-5- ylphenyl)ethyl]pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuiai>5-yl)-N-[l-(3-{[(5-methyl-l,2.4-oxadiazol-3- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
5- [3-( 1 -{ [6-( 1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- y ]amino}ethyl)phenyl]pyrimidin-2-amine;
ethyl (4-{3-[(lS)-l-{[6-(l,3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyjphenyl}-lH-pyrazol-l-yl)acetate;
6- (7-ΠΙΙΟΙΌ- 1 -benzofuran-5-yl)-2-methyl-N-{(l S)-l -[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-[l-(3-methylphenyl)ethyl]pyrimidin-4- amine;
6-(1.3-benzothiazol-6-yl)-N-[l-(3-{[(l-ethylpiperidin-3-yl)methyl]oxy}phenyl)ethyI]- 2-methylpyrimidin-4-amine;
N-{l-[3-(6-aminopyridin-3-yl)phenyl]elhyl}-6-(l,3-benzothiazol-6-Yl)-2- methylpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl- -[l-(3-{[(l-methylpiperidin-3- y )methyl]oxy}phenyl)ethyl]pyrimidin-4-amine; N-[l-(3-{[(l,3-dimethyl-H-l-pyrazol-5-yl)methyl]oxy}phenyl)etliyl]-2-methyl-6-(l- methyl- 1 H-indol-2-yl)pyrimidiii-4-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-[( l S)- 1 -(4- methylplienyl)ethyl]pyrimidin-4-amine;
N-[l-(3-{[(l,3-dimethyl-lH-pyrazol-5-yl)methyl]oxy}phenyl)ethyl]-6-(3-ethyl-l- benzofuran-5-yl)-2-methylpynmidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(piperidin-3- y methyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
1- {[3-(l-{[6-(l,3-benzotliiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}propan-2-oiie;
6-( 1 ,3-benzothiazol-6-y])-2-methyl-N-{ 1 -[3-(2-methyl- 1 ,3-thiazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-N-[ 1 -(5-{ f( 1 ,3-dimethyl- 1 H-pyrazol-5- yl)rnethyl]oxy}pyridin-3-yl)ethyl]-2-methylpynmidin-4-amine;
6-(3-ethyl-l-benzoiiiaii-5-yl)-2-methyl-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
2- methyl-6-(3-methyl-l-benzot\iran-5-yl)-N-{(lR)-l-[3-(l-methy -lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
l-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- ylJamino}ethyl)phenyl]oxy}propan-2-ol;
1- {[3-(l-{[6-(l,3-benzothiazoI-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-2-methylpiOpan-2-ol;
N-[l-(2-fluorophenyl)ethyl]-2-nietliyl-6-(3-methyl-l-benzoi'uran-5-yl)pyrimidiiv4- amine;
3- (l-{[6-(3-ethyl-l-benzofuran-5-yl)-2-methylpyrimidin-4-yl]amino}ethyl)pte
2- methyl-6-(l-methyl-lH-indol-2-yl)-N-{(lS)-l-[3- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
6-(l -benzothiazol-6-yl)-N-[l-(2-chloropyridin-4-yl)ethyl]-2-methylpyriniidin-4- amine;
6-( 1 ,3-benzothiazol-6-y l)-2-methyl-N-[ 1 -(3-{ [(5-methyl- 1 ,2,4-oxadiazol-3- yl)metliyl]oxy}phenyl)ethyl]pyi'imidin-4-amine;
N-[l-(3-{[(l-acetylpiperidin-3-yl)methyl]oxy}phenyl)elhyI]-6-(l,3-benzothiazol-6- yl)-2-methylpyrimidin-4-amine; 2-{[3-(l-{[2-methyl-6-(l-methyl-lH-indol-2-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetamide;
6-(L3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(piperidin-4- ylniethyl)oxy]phenyl}ethyl)pyrimidin-4-amine:
2-methyl-6-(4-melhyl-3,4-dihydiO-2H-l,4-benzoxazin-6-yl)-N-{l-[3-(l -methyl- 1H- pyrazol-4-yl)phenyl]ethyl } pyri midin-4-amine;
N-[ 1 -(3- { [2-(4-acetylpiperazin- 1 -yl)ethyl]oxy } phenyl)ethyl]-6-( 1.3-benzothiazol-6- yl)-2-methylpyrimidin-4-amine;
{4-[3-(l-{[6-(13-beiizothiazol-6-yl)-2-methylpynmidin-4-yl]amino}ethyl)phenyl]- lH-pyrazol-l-yl} acetic acid;
6-(3-elhyl-l-benzoruraii-5-yr)-2-methyl-N-{l-[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amiiie;
2-{[3-(l-{[6-(l,3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyljoxy}-N-[2-(methyloxy)ethyl]acetamide;
2-{ [3-( 1 - { [6-( 1 ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-l-cyclopiOpylethanone;
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yjamino}ethyl)phenyl]oxy}-N-phenylacetamide;
6-(l-benzofiiran-2-yl)-2-methyl-N-{(lS)-l-[3-(methyloxy)phenyl]ethyl}pyrimidin-4- amine;
1,1 -dimethylethyl 3-({[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}melhyl)piperidine-l-carboxylate;
1.1 -dimethylethyl 4-({ [3-(l -{ [6-(l ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}melhyl)piperidine-l-carboxylate;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[6-(methyloxy)pyridin-3- yl]phenyl}ethyl)pyrimidin-4-amine;
N;N-diethyl-2- { [3-( 1 - { [2-methyl-6-(4-methyl-3 ,4-dihydro-2H- 1 ,4-benzoxazin-6- yl)pyrimidin-4-yl]amino}ethyl)phenyl]oxy}acetamide;
2-methyl-N-{(lS)-l- 3-(melhyloxy)phenyl]ethyl}-6-(l-methy]-lH-pyn lo[3..2- b]pyridin-6-yl)pyrimidin-4-amine;
2-methyl-6-(3-methyl-l -benzoiiiian-5-yl)-N-[l-(2-methylphenyl)ethyl]pyrimidin-4- amine;
6-(l ,3-benzothiazol-6-yl)-2-methyl-N-{(l R)-l -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine; (lS)-3-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-melhylpynmidin-4- yl]amino}ethyl)phenyl]oxy}-l-phenylpropan-l-ol;
N,N liethyl-2-{[3-(l-{[2-methyl-6-(3 iiethyl-l-benzoiuran-5-yl)pyrirnidin-4- yl]amino}elhyl)phenyl]oxy}acetamide;
N-[l-(3-{[2-(lH-imidazol-l-yI)ethyl]oxy}pheny!)ethyl]-2-niethy]-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
N-{(lS)-l-[3-(]-ethyl-lH^yrazol-4-yl)phenyl]etliyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-(l-{3-[(pipendin-3- yImethyI)oxyjphenyl}ethyl)pyrimidin-4-amine;
2Miiethyl-6-(3 nethyl-l-bciizotuOn-5-yl)-N-{(lS)-l-[3-(l-methyl-lH-pyrazol-5- yl)phenyl]ethyl}pyrimidin-4-amine;
2-{ [3-(l -{ [2-melhyl-6-(3-methyl- 1 -benzofiiran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}ethanol;
2-methyl-6-(3 nelhyl-l-benzoiiran-5-yl)-N-[(lS)-l-{3-[(2-morpholin-4-yl-2- oxoethyl)oxy]phenyl}ethyl]pyrimidin-4-amine;
N-[l -(3-{[3-(dimethylamino)propyl]oxy}pheny])ethyl]-2-methyl-6-(3-metliyl-l- benzofuran-5-yl)pyrimidin-4-amine;
2- methyi-6-(3-methy I- 1 -benzofuran-5-yl)-N-[ 1 -(3 - { [( I -methyl- 1 H-pyrazol-3- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
3- (l-{[2-methyl-6-(3-methyl-]-benzofuran-5-yl)pyrimidin-4-yl]amino}ethyl)phenol -[(lS)-l-(3-biOmophenyl)ethyl]-2-methyl-6-(3-methyl-l-benzoluran-5- yl)pyrimidin-4-aniine;
2- methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-{( 1 S)- 1 -[3-( 1 H-pyrazol-4- yl)phenyl]etIiyl}pyrimidin-4-amine;
3- [(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pynmidin-4- yl]amino}ethyl]phenol
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-{ ( 1 S)-l -[3-(l -methyl- 1 H-pyrrol-2- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-[(lS)-l-phenylethyl]pyrimidin-4-aniine; 6-(l,3-benzothiazol-6-yl)-2-methyl- -[l-(3-pyridin-3-ylphenyl)ethyl]pynmidin-4- amine;
6-(1.3-benzothiazol-6-yl)-2-methyl-N-{ l-[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine; N-[(lS)-l-(4-fluoraphenyl)ethyl]-2-rnethyl-6-(3-melhyl-l-benzofuran-5-yl)pyrimidin- 4-amine;
6-(l -benzofuran-5-yl)-N-[l -(3-{[( 1 ,3-dimethyl-l H-pyrazol-5- yl)methyl]oxy}phenyl)el yl]-2-melhylpyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-2-methyl-N-{( 1 S)- 1 -[3-( 1 -methyl- 1 H-pyrazol-5- yl)phenyl]ethyl}pyrimidin-4-amine;
-[]-(3-nuorophenyl)ethyl]-2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- amine;
6-(L3-benzothiazol-6-yl)-N-{(lS)-l-[3-(l -ethyl-1 H-pyrazol-4-yl)phenyl]ethyl}-2- methyIpyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(lH-pyrazol-5- yl)phenyl]ethyl}pyrimidin-4-amine;
2- methyl-6-(3-meihyl-l-benzofuran-5-y -N-[(lR)-l-{3-[(2-morpholin-4-yl-2- oxoethyl)oxy]phenyl}ethyl]pyrimidin-4-amine; '
3- [(lR)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenol
6-(l,3-benzotliiazol-6-yl)-2-methyl- -{(lS)-l-[3-(lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(L3-benzothiazol-6-yl)-2-methyl-N-[l-(3- {[(methylsulfonyl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
[(2-iluoi -5-{2-methyl-6-[(lR)-l,2.3 etra^^
yl}phenyl)amino]acetonitrile;
2-methyl-6-(3-methyl-l-benzofiiran-5-yl)-N-{(lR)-l-[3- (methyloxy)phenyl]etliyl}pyiimidin-4-amine;
2-(metliyloxy)-4-{2-methyl-6-[(lR)-l!2,3,4-tetrahydronaphthalen-l- ylamino]pyrimidin-4-yl}benzamide;
6-(L3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(2-morpholin-4- ylethyl)oxy]plienyl}etliyl)pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-{(lS)-l-[3-(l-methyl-lH-pyrrol-2- yl)phenyl]ethyl}pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-2-methyl-N-[ 1 -(3-{ [2-(2-methyl- 1 H-imidazoI- 1 - yl)ethyl]oxy}phenyl)ethyrjpyrimidin-4-amine;
6-(l-benzofiiran-5-yl)-2-methyl-N-|'l-(3-{[(l-methyl-lH-pyrazol-3- yl)methyl]oxy}phenyl)ethyl]pyiimidin-4-amine; N-[(lS)-l-biphenyl-3-ylethyl]-2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- amine;
4-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-met ylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}butan-i-ol;
6-(l,3-benzothia2ol-6-yl)-2-methyl-N-[l-(3-morpholin-4-ylphenyl)ethyl]pyrirnidin-4- amine;
3-{[3-(]-{[6-(l,3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yl|amino}ethyl)phenyl]oxy} propane- 1,2-diol;
6-(l .3-benzolhiazol-6-yl)-N-[(lS)-l-biphenyl-3-yle iyl]-2-methylpyrimidin-4-amine;
2- { 3-(l-{[6-(l,3-benzothiazol-6-yI)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}ethaiiol;
1- {[3-(l-{[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-3-lluoropropan-2-ol;
6-(1.3-benzothiazol-6-yl)-N-[l-(3-bi niophenyI)ethyl]-2-methyIpyrimidin-4-ami
3- { [3-( 1 - { [6-( 1 ,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}elhyl)phenyl]oxy}propan-l-ok
4- {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}elhyl)phenyl]oxy}-N.N-dimethylbutanainide:
6-(l,3-benzothiazol-6-yl)-N-[l-(3-{[3-(dielhylamino)propyl]oxy}phenyl)ethyl]-2- methylpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-[l-(3-{[2-(1H-pyrrol-l- yl)ethyl]oxy}phenyl)ethyl]pynmidin-4-amine;
6-(1.3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[(3-morpholin-4- ylpropyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
2- {[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-(2-liydroxyethyl)acetamide;
• 2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-cyclopropylacetamide;
6-(l,3-benzothiazol-6-yl)-2-niethyl-N-{l-[3-(lH-pyrrol-2-yl)phenyl]ethyl}pyrimidin^ 4-amine;
e-Cl^-benzothiazol^-y ^-methyl- -tl-iS-i^-ClH-pyrazol-l- yl)ethyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
N,N-diethyl-2-[(3-{l-[(2-metliyl-6-naphthalen-2-ylpyrimidin-4- yl)amino]ethyl}phenyr)oxy]acetamide; 6-(1.3-benzothiazol-6-yl)-2-met yl-N-(l-{3-[(3-pyrrolidin-l- ylpropyl)oxy]phenyl}elhyl)pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-[l-(3-{[3-(dimethylamino)propyl]oxy}phenyl)ethyl]-2- methylpyrimidin-4-amine;
6-(l .,3-benzothiazol-6-yl)-2-methyl-N-{ l-[2-(met yloxy)pyridin-4- yl]ethyl}pyrimidin-4-amine;
1,1-dimethyIethyl 3-({[3-(l-{[2-methyl-6-(3-melhyl-l-benzoi'uran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyl]oxy}methyl)piperidine-l-carboxylate;
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-melhyIpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-cyclohexylacetamide;
6-(l,3-benzothiazol-6-yl)-N-[l-(3'-iliiorobiphenyl-3-yl)ethyl]-2-methylpyrimidin-4- amine;
methyl {[3-(l-{[6-(l,3-bcnzolhiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetate;
6-(L3-benzothiazol-6-yi)-2-methyl-N-[l-(3-{[2- (methylsullbnyl)cthyl]oxy}phenyl)ethyI]pyrimidin-4-amine;
6-(3-amino-4-methylphenyl)-2-methyl-N-{(l S)- 1 -[3- (methyloxy)phenyl jethyl } pyrimidin-4-amine;
2-methyI-N-{(lS)-l-[3-(methyloxy)phen> Jethyl}-6-quinolin-6-ylpyrimidin-4-amine:
{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}acetic acid;
2-methyl-6-(3 -methyl- 1 -benzofuran-5-yl)-N- {( 1 S)- 1 -[3-( 1 -methyl - 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-{(lS)-l-[3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyI}pyrimidin-4-amine;
N,N-dimethyl-2-({3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}oxy)acetamide;
N-[l-(3-{[2-(dimethylamino)elhyl]oxy}phenyl)ethyl]-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
N,N-dimelhyl-2-({3-[(l R)-l-{[2-melhyl-6-(3-methyl-l-benzol iran-5-yI)pyrimidin-4- yl]amino}ethyl]phenyl}oxy)acelamide;
6-(1 -benzothiazol-6-yl)-N-[l-(3-{[2-(dimelhylamino)elhyl]oxy}phenyl)ethyl]-2- methyIpyrimidin-4-amine; 6-(2,5-dimethylphenyl)-2-methyl-N-{l-[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3:4-dichlorophenyl)-2-methyl-N-{l-[3-(l-melhyl-lH-pyrazol-4- yl)phenyl]eihyl}pyrtmidin-4-amine;
6-(4-ethylphenyl)-2-methyI-N-{l-|3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(4-fluoiO-3-methylphenyl)-2-methyl-N-{ 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl } pyrimidin-4-amine;
2-methyl-6-[4-(1-methylethyl)phenyl]-N-{l-[3-(l -methyl- lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-[2-fluoiO-4-(methyloxy)phen>iJ-2-melhyl-N- {l-[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-[3-(dimethylamino)phenyl]-2-methyl-N-{l -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl } pyriniidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-[(lS)-l-(3-bromophenyl)ethyl]-2-methylpyrimidin-4- amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-{(lS)-l-[3-(lH-pyrazol-5- yl)phenyl]elhyr}pyrimidin-4-amine:
(2E)-3-{3-[(lS)-l-{[6-(l:3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}-N-elhylprop-2-enamide;
2-{[3-(l-{[6-(1.3-benzothiazol-6-y )-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}- -[2-(dimethylamino)ethyl]acetamide;
2- { [3-( 1 - { [6-( 1 ,3 -benzothiazol-6-y l)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-propylaceiamide;
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]oxy}-N-ethyl-N-methylacetamide;
6-(1.3-beirzothiazol-6-yl)-2-methyl-N-[l-(3-nitiOphenyl)ethyl]pyrimidin-4-amine;
(2E)-3-{3-[(lS)-l-{[6-(l,3-benzothiazol-6-yl)-2-methy]pyrimidin-4- yl]amino}ethyI]pheny 1 } -N-( 1 , 1 -dimethylethyl)prop-2-enamide;
N-[l-(3-aminophenyl)ethyl]-6-(1.3-benzothiazol-6-yl)-2-methylpyrimidiiv4-amine;
2-({[3-(l-{[6-(l,3-benzothiazol-6-y )-2-methylpynmidin-4- yl]amino}ethyl)phenyl]oxy} methyl)- l,3-oxazole-4-carboxylic acid;
methyl 2-({[3-(l-{[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidih-4- yl]amino}ethyl)phenyl]oxy} methyl)- l,3-oxazole-4-carboxylate; 6-(1.3-benzolhiazol-6-yl)-2-methyl-N-[(lS)-l-phenylethyl]pynmidin-4-amine;.
2-methyl-6-(3-methyl-l-benzofiiran-5-yl)-N-{(lS)-l-[4- (methyloxy)phenyl]ethyl}pyrimidin-4-amine;
6-( 1 ,3-benzothiazol-6-yl)-N-[ 1 -(3-{ [( 1 ,3-dimethyI- 1 H-pyrazol-5- yl)methyl]oxy}phenyl)ethyl]-2-methylpyrimidin-4-amine;
N-[l-(3-iiran-3-yIphenyl)ethyl]-2-methyl-6-(3-niethyl-l-benzofuran-5-yl)pyrimidin- 4-amine:
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-{3- [(phenylmethyl)oxy|phenyl}ethyl)pyrimidin-4-amine;
2 nethyi-6-(3 nethyl-l-benzofiiran-5-yI)-N-{]-[3-(3-thienyl)phenyl]ethyl}pyrimidin- 4-amine;
6-(l,3-benzothiazol-6-yi)-2-methyl-N-(l-{3-[(pyndin-3- ylmethyl)oxy]phenyl}ethyl)pyrimidin-4-amine;
6-(1.3-benzothiazol-6-yl)-2-methyl-N- l-(3-{[(3-methylisoxazol-5- yl)methyl]oxy}plienyl)ethyl]pyrtmidin-4-amine;
6-( 1 ,3-benzothiazol-6-yI)-2-methyl-N-[l -(3- { [(2-methyl- 1 ,3-thiazol-4- yl)methyl]oxy}phenyl)ethyjpyrimidin-4-amine;
6-(1.3-benzothiazol-6-yI)-2-methyl-N-{ l-[3-(propyloxy)phenyl]ethy }pyrimidin-4- amine;
6-(l,3-benzothiazol-6-yl)- -{l-[3-(3,5-dimelhylisoxazoI-4-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
6-{2-melhyl-6-[(l ^-l^ ^-tetrahydi naphlhalen-l-ylarninoJpyrimidin^-ylJ^H- chromen-4-one;
6-( 1 ,3-benzothiazol-6-yl)-2-methyl-N-[ 1 -(3- { [(4- methylphenyl)melhyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-[l-(3-furan-3-ylphenyl)ethyl]-2-methylpyrimidin-4- amine;
6-(l:3-benzothiazol-6-yi)-2-melhyl-N-[l-(3-{[(3-{[(4-methyIphenyl)oxy]methyl}- 1.2,4-oxadiazol-5-yl)methyl]oxy}phenyl)cthyl]pynmidin-4-amine;
6-(13-benzotlnazol-6-yl)-2-methyl-N-{l-[3-(3-thienyI)phenyl]ethyl}pyrimidin-4- amine;
6-(L3-benzotlnazol-6-yl)-N-fl-(3-{[2-(lI-l-iniidazol-l-yl)ethyrjoxy}phenyI)ethyl]-2- methylpyrimidin-4-amine; 2-{[3-(l-{[2-methyl-6-(3-methyl-l-benzoluran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyl]o.\y}acetamide;
N-[l-(3-{[(1.3-dimelhyl-]l-l-pyrazol-5-yl)methyl]oxy}phenyl)ethyl]-2-methyl-6-(3- met!iyl-l-benzofuran-5-yl)pyrimidin-4-amine;
2-{[3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenylJoxy}acetamide;
2-melhyl-6-(3-melhyl-l-benzo(' ran-5-yl)-N-(l-{3-[(2-moi holin-4-yl-2- oxoethyi)oxy]phenyl}ethyl)pyrimidin-4-amine;
N.N-dimethyl-2-{[3-(l-{[2-metliyl-6-(3 nethyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}elhy])phenyl]oxy}acetamide;
6-( 1 ,3-benzothiazol-6-yl)-2-methyI-N-[ 1 -(3-{[(l -methyl- 1 H-pyrazol-3- yl)methyl]oxy}phenyl)ethyl]pyrimidin-4-amine;
6-(l>3-benzothiazol-6-yl)-N-(l-{3-[(2-fluoroethyl)oxy]phenyl}ethyl)-2- methylpyrimidin-4-amine;
6-(l ,3-benzothiazol-6-yl)-2-methyl- -(l -{3-[(2:2,2- tri{luoroethyI)oxy]phenyl}ethyl)pyrimidin-4-amine;
N-[l-(3-bromo-4-fluoiOphenyl)ethyl]-2-methyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-amine;
5-[2-iluoro-5-(l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyI]pyrimidin-2-amine;
N-{(lR)-l-[4-iluoro-3-(l-methyl-lH-pyrazol-4-yl)phenyl]ethyl}-2-methyl-6-(3- methyl-l-benzofuran-5-yl)pyrimidin-4-amine;
N-{(lS)-l-[4-l:luoro-3-(l-melhyI-lH-pyrazol-4-yl)phenyl]ethyl}-2-methyl-6-(3- metliyl-l-benzoruran-5-yl)pyrimidin-4-ainine;
5- [3-(l-{[6-(l,3-benzothiazol-6-yI)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]pyridine-3-carboxamide;
6- (l,3-benzothiazol-6-yl)-2-methyl-N-[(lS)-l-{3-[2-(4-methylpiperazin-l- yl)pyrimidin-5-yl]phenyl}ethyl]pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[5-(trifluoiOmediyl)pyridin-3- yl]phenyl}ethyl)pyriniidin-4-amine;
2- methyl-6-(3-methyl- 1 -benzoiuran-5-yl)-N-[( 1 S)- 1 - {3-[2-(4-methylpiperazin- 1 - yl)pyrimidin-5-yl]phenyI}ethyl]pyrimidin-4-amine;
3- [(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzo{'uran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)amino]propan-l-ol; methyl N-(5-{3-[(lS)-l-{[2-methyl-6-(3Miiethyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]pheny!}pyrimidin-2-yl)g]ycinate;
2- methyl-6-(3-methyl-l-benzoiuran-5-yl)-N-[(lS)-l-{3-[6-(4-methylpiperazin-l- yl)pyridin-3-yr|phenyl}ethyl]pyrimidin-4-amine;
2.2-dimethyl-3-[(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzoftiran-5-yl)pyrim 4-yl]amino}ethyl]phenyl}pyrimidin-2-yl)amino]pi pan-l-ol;
N-(5-{3-[(l S)-l -{[2-methyl-6-(3-methyl-l -benzofuran-5-yl)pyrimidin-4- yl]amino}ethy!]phenyl}pyrimiclin-2-yl)glycine;
3- [(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzoftiran-5-yi)pyrimidin-4- yl]annno}ethyl]phenyl}pyrimidin-2-yl)amino]piOpane-1.2-diol;
N-[(lS)-l-(5'-fluoro :3'-bipyndin-5-yl)ethyl]-2-methyl-6 3-methyl-l-benzofuran-5- yl)pyrimidin-4-amine;
N-tflS^l-iG'-fluoro-S '-bipyridin-S-y ethyll^-meUiyl-e-iS-methyl-l-benzoiuran-S- yl)pyrimidin-4-amine;
N-{(lS)-l-[5-(l -ethyl- lH-pyrazol-4-yl)pyridin-3-yl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-aniine;
6-chIoro-5'-[( 1 S)- 1 -{ [2-methy l-6-(3-methyl- 1-benzo furan-5-yl)pyrimidin-4- yl]amino}ethylj-3,3'-bipyridin-5-amine;
5- { 5-[( 1 S)- 1 - { [2-methy l-6-(3-methy 1- 1 -benzo furan-5-y l)pyrimidin-4- yl]amino}ethyI]pyridin-3-yl}pyrimidin-2-amine;
N-[]-(3-biOmo-5-fluoiOphenyl)ethyrj-2-methyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-amine;
5-[3-fluoiO-5-( 1 -{ [2-methyl-6-(3-methyl- 1 -benzo furan-5-yl)pyrimidin-4- yI]amino}ethyl)phenyl]pyrimidin-2-amine;
-{l-[3-iluoro-5-(l -methyl- lH-pyrazol-4-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
1 -(5-{ 5-[( 1 S)- 1 - { [2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]pyHdin-3-yl}pyrimidin-2-yl)pipendin-4-ol
N-{l-[3-(5-amino-6-chloropyridin-3-yl)-5-nuorophenyl]etl'iyl}-2-methyl-6-(3-methyl- l-benzoiuran-5-yl)pyrimidin-4-amine;
N-[l-(3-bromo-4-methylphenyl)ethyl]-2-melhyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-amine;
5-[2-methyl-5-( 1 -{ [2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl)phenyl]pyrimidin-2-amine; 2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-{'l -[4-methyl-3-(l -methyl- 1 H-pyrazol yl)phenyl]ethyl}pyrimidin-4-amine;
5- {3-[(lS)-l-{[2-methyl-6-(l-methyl-ll-l-indol-6-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyi'imidin-2-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-{(l S)- 1 -[5-(l -methyl- lH-pyrazol-5- yl)pyridin-3-yl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lS)-l-[5-(lH-pyrazol-4-yl)pyridin- yI]elhyl}pyrimidin-4-amine;
(2S)-3-[(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)amino]propane-1.2-diol
2-melhyl-N-{ 1 -[3-( 1 -methyl-1 H-pyrazol-4-yl)phenyl]ethyl}-6-[4- (trifluo!'ometliyl)phenyl]pyrimidin-4-amine;
6- (2,3-dihydiO-l,4-benzodioxin-6-yl)-2-methyl-N-{ l-[3-(l -methyl-1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-{( 1 S)- 1 -[3-( 1 H-pyrazol- 1 - yl)phenyl]ethyl}pyi-imidin-4-amine;
2-nu'thyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(2H-l,2,3-triazol-2- yl)phenyl]ethyl}pyrimidin-4-amine;
6-( 1 -benzothien-5-yl)-2-methyl-N-{ 1 -| 3-( 1 -methyl-1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
N'-{5-[3-(l-{[6-(lJ3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]pyrimidin-2-yl}-lS,,N-dimethylethane-l ,2-diamine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(lH-tetrazol-l- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{(lR)-l-[3-(lH-tetrazol-l- yl)phenyl]ethyl}pyrimidin-4-amine;
N-{(lS)-l-[3-(2-{4-[2-(dimethylamino)ethyl]piperazin-l-yl}pyrimidin-5- yl)phenyl]ethyI}-2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4-amine;
2-[4-(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]a:nino}ethyl]phenyl}pyrimidin-2-yr)piperazin-l-yl]ethanol
2-methyl-6-(3-methyl- 1 -benzof uran-5-yl)-N-{( 1 S)- 1 -[3-(2-{4-[( 1 -methyl- 1 H- imidazol-2-yl)methyl]piperazin-l-yl}pyrimidin-5-yl)phenyl]ethyl}pyiimidin-4-ami
2-melhyl-6-(3-methyl-l-benzofiiran-5-yl)-N-{ClS)-l-[3-(2-{4-[2- (niethyloxy)ethyl]piperazin-l-yl}pyrimidin-5-yl)phenyl]ethyl}pyrimidin-4-amine; 2-({2-[4-(5-{3-[(lS)-l-{[2-methyl-6-(3 nethyI-l-benzoairan-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperazin-l-yl]ethyl}oxy)ethanol
2-niethyl-6-(3 nethyl-l-benzoiuran-5-yl)-N-[(lS)-l-(3-{2-[4-(2-morpholin-4- ylethyl)piperazin-l-y!]pyrimidii>5-yl}phenyl)ethyl]pynmidin-4-amine;
N-|(lS)-l-(3-bromopheiiyl)ethyl]-2-methyl-6-(3-mediyl-l-benzothien-5-yl)pyrimidin- 4-amine;
2-methy l-6-(3-methyl- 1 -benzothien-5-yl)-N-{( 1 S)- 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyI}pyrimidin-4-amine;
N-{(lS)-l-[3-(5-aminopyridin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzolhien-5-yl)pyrimidin-4-amine;
N-{(lS)-l-[3-(6-fluoropyridin-3-y!)phenyrjetliyl}-2-methyl-6-(3-methyl-l- benzothien-5-yl)pyrimidin-4-amine;
N-{(lS)-l-[3-(5-fluoropyridin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzothien-5-yl)pyrimidin-4-amine;
5- {3-[(l S)-l-{[6-(3-chloro-l-benzofuran-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
ethyl 5-[3-( 1 - { [6-( 1 ,3 -benzothiazol-6-yl)-2-methy lpyrimidin-4- yl]amino}ethyl)phenyl]pyridme-3-carboxylate;
6- (1.3-benzothiazol-6-yl)-N-(l-{3-[6-(dimethylamino)pyridin-3-yl]phenyl}ethyl)-2- methylpyrimidin-4-amine;
N-[ ( 1 S)- 1 -(3-bromophenyl)ethyl]-6-(3-ethyl- 1 -benzofuran-5-yl)-2-methylpyrimidin- 4-amine;
5- {3-[(lS)-l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
6- (lJ3-benzothiaz;ol-6-yr)-N-{(lS)-l-[3-(5-nuoropyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-aniine:
6-(l;3-benzothiazol-6-yl)-2-methyl-N-{(lS)-l-[3-(6-methylpyridin-3- yl)phenyI]ethyl}pyrimidin-4-amine:
5- {3-[(lS)-l-{[6-(3-ethyl-l-benzofuran-5-yl)-2-methylpyrimidin-4- y.l]amiiio}ethyl]phenyl}pyrimidin-2-amine;
6- (l,3-benzothiazol-6-yl)-2-methyl-N-{(lS)-l-|3-(5-methylpyndin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(l33-benzothiazoI-6-yl)-N-{(lS)-l-[3-(6-nuoi -5-methylpyridin-3- yl)phenyl]ethyl}-2-methylpyrimidin-4-aminc; 6-(l,3-benzothiazol-6-yl)-N-{(lS)-l-[3-(6-fluoropyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amiiie;
N-{(lS)-l-[3-(5-fluoiOpyridin-3-yl)phenyl]elhyl}-2-methyl-6-(3-melhyl-l- benzofuran-5-yl)pyrimidin-4-amine;
6-(7-fluoro-l -benzofuran-5-yl)-2-methyl-N-{ 1 -[3-(l -methyl-l H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
N-{(lS)-l-[3-(2-chloropyrimidin-5-yl)p enyl]etliyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-{(lS)-l-[3-(2-chloropyrimidin-5-yl)phenj'l]ethyl}-2- methylpyrimidin-4-amine;
N-{(.lS)-l-[3-(6-lluoropyridin-3-yl)plienyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
5-{3-[(lS)-l-{[6-(l:3-beiizothiazol-6-yl)-2-metlwlpyrimidin-4- yl]amino}ethyl]p enyl}-N-methylpyrimidin-2-amine;
N-methyl-5-{3-[(lS)-l-{[2-metliyl-6-(3-melhyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2 -amine:
5- {3-[( 1 S)- 1 - { [6-(7-fliioro- 1 -benzofuran-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
5-{3-[(lS)-l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- y ]amino}ethyl]phenyl}-N,N-dimethylpyrimidin-2-amine;
N,N-dimethyl-5-{3-[(lS)-l-{[2-melhyl-6-(3-melhyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyI}pyrimidin-2-amine;
N-ethyl-5-{3-|(lS)-l-{|2-meUiyI-6-(3-metliyl-l-benzotiiran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pynmidin-2-amine;
5- {3-[( 1 S)- 1 - { [6-( 1 ,3-benzothiazol-6-yl)-2-methy lpyrimidin-4- yl]amino}ethyl]phenyl}-N-ethylpyrimidin-2-amine;
2-methyl-6-(3-methyl-l-benzoruran-5-yr)-N-{(] S)-l-[3-(2-morpholin-4-ylpyrimidin- 5-yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzoiiiran-5-yl)-N-{(lS)-l-[3-(2-piperazin-l-ylpyrimidin-5- yl)phenyl]ethyl}pyrimidin-4-amine;
N-{(lS)-l-[3-(5-aminopyridin-3-yl)phenyl]etliyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
2-[(5-{3-[(lS)-l-{[2-methyl-6-(3-metliyl-l-benzol iran-5-yI)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)amino]eilianol N,N-diethyl-5-{3-[(lS)-l-{[2-metliyl-6-(3-met yl-l-benzo-furan-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
N-{(lS)-l-[3-(5-chloropyridin-3-yl)phenyl]ethyl}-2-melhyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
6-(l:3-benzothiazol-6-yl)-N-{(lS)-l-[3-(5-chloropyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
5- {3-[(lS)-l-{[6-(L3-benzolhiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}-N.N-diethylpyrimidin-2-amine;
6- (l,3-benzothiazol-6-yl)-N-[(lS)-1-{3-[2-(4-ethyipiperazin-l-yl)pynmidin-5- yl]phenyl}ethyl]-2-methylpyrimidin-4-amine;
l-(5-{3-[(lS)-l-{[6-(L3-beiizothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperidin-4-ol
N-[( 1 S)- 1 -{3-[2-(4-ethylpiperazin- 1 -yl)pyrimidin-5-yl]phenyl }ethyl]-2-methyl-6-(3- methyl-l-benzofuran-5-yl)pyrimidin-4-amine;
l-(5-{3-[(lS)-l-{[2Hiunhyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperidin-4-ol;
1- (5-{3-[(l S)-l-{[2-methyl-6-(3-niethyl-l-benzofuran-5-yl)pyiirnidin-4- yl]amino}ethyl]phenyl}pynmidin-2-yl)pyn'olidin-3-ol;
N-(l-methylethyI)-5-{3-[(lS)-l-{[2-mel yl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-yl]amino}ethyl]phenyl}pyrimidin-2-amine;
[l-(5-{3-[(lS)-l-{[2-methyl-6-(3-methyI-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperidin-4-yl]methanol;
N-[(lS)-l-{3-[2-(4-fluoropiperidin-l-yl)pynmidin-5-yl]phenyl}ethy]]-2-rnethyl-6-(3- methyl-l-benzofuran-5-yl)pyrimidin-4-amine;
N-(fiiran-2-ylmelhyl)-5-{3-|(lS)-l-{ 2-methyI-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-yl]amino}ethyl]phenyl}pyrimidin-2-amiiie;
N iuran-3-ylmetliyl)-5-{3-[(lS)-l-{ 2-melhyl-6-(3-methyl-l-benzofuran-5- yl)pynmidin-4-yl]amino}ethyjphenyl}pynmidin-2-amine;
6-(7-nuoro-3-methyl- 1 -benzofuran-5-y l)-2-methy l-N-{ 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
(5-{3-[(1S)-l-{[6-(L3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyridin-2-yl)melhanol
2- methyl-6-(3-methyl-l-beirofuran-5-yl)-N-{(lS)-l-[3-(4-methyl-3,4-dihydro-2H- pyrido[3,2-b] [ 1 ,4]oxazin-7-yl)phenyl]ethyI } pyrimidin-4-aniine; (5-{3-[(lS)-l-{[6-(L3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyridin-3-yl)methanol
N-{(lS)-l-[3-(5-amino-6-chloropyridin-3-yl)plienyl]ethyl}-2-methy]-6-(3-methy]-l- benzofuran-5-yl)pyrimidin-4-amine:
6-(7-fluoro-3-methyl- 1 -benzofuran-5-yl)-2-methyl-N-{( 1 S)- 1 -[3-( 1 -methyl- 1 H- pyrazol-4-yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3,4-difluorophenyl)-2-methyl-N-{ 1 -[3-( 1 -methyl-1 H-pyiazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
(5-{ 3-[( 1 S)- 1 -{ [2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridin-3-yl)melhanol;
N-{ ( 1 S)- 1 -[3-(5-aminopyridin-3-yl)phenyl]ethyl } -6-(7-i:liioiO-3-methyl- 1 - benzofuran-5-yl)-2-melhylpyrimidin-4-amine;
6-(7-fluoro-3-niethyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(5-fluoiOpyridin-3- yl)phenyl]elhyl}-2-methylpyrimidin-4-amine;
6-(4-chloro-3,5-difluorophenyl)-2-methyl-N- { 1 -f 3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine:
2-melhyl-N-{ 1 -[3-(l -methyl-1 H-pyrazol-4-yl)phenyl]ethyl}-6-(3,4!5- trifluoropheiiyl)pyrimidin-4-amine;
N-{(lS)-l-[3-(5-amino-6-chloropyridin-3-yl)phenyl]ethyl}-6-(7-fluoro-3-methyl-l- benzofuran-5-yl)-2-methylpyrimidin-4-amine;
5-{3-[(lS)-l-{[6-(3,4-dinuorophenyl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
5- {3-[(lS)-l-{[6-(4-chloro-3,5-dinuorophenyl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
1 -(5-{ 3-[( 1 S)- 1 - {[2-methyl-6.-(3-methyl- 1 -benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridin-3-yl)ethanone;
6- (7-nuoro-3-methyl-l-benzofuran-5-yl)-2-methyl-N-{l-[5-(lH-pyrazol-4-yl)pyridin- 3-yl]ethyl}pyrimidin-4-amine;
N-{ l-[5-(l -ethyl- lH-pyrazol-4-yl)pyridin-3-yl]ethyl}-6-(7-fluoro-3-methyl-l- benzofuran-5-yl)-2-methylpyrimidin-4-amine;
6-(7-fluoro-3-methyl-l -benzofuran-5-yl)-N-{(lS)-l-[3-(6-fluoropyridin-3- yl)phenyl]ethyl}-2-methylpyrimidin-4-amine;
ethyl 5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzoi:'uran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridine-3-carboxylate; 3-[(5-{3-[(lS)-l-{[6-(7-fluoro-3-niel yl -benzofuran-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)amino]propane-1.2-diol
l-(5-{3-[(lS)-l-{[6-(7-fluoro-3-methyl-l-benzo uran-5-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)piperidin-4-ol;
1- (5-{3-[(lS)-l-{[2-methyl-6-(3-melhyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridin-3-yl)ethanol;
2- (5-{3-[(lS)-l-{[2-melhyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridin-3-yl)propan-2-ol:
6-(7-fluoro-3-methyl- 1 -benzofuran-5-yl)-2-melhy 1-N- {1 -[5-( 1 -melhyl- 1 H-pyrazol-4- yl)pyridin-3-yl]ethyl } pyrimidin-4-amine;
5-[5-Cl-{[6-(7-fluoro-3-methyl-l-benzofuran-5-yI)-2-methyIpyrimidin-4- yl]amino}ethyl)pyridin-3-y]]pyrimidin-2-amine;
5- {3-[(lS)-l-{[6-(7-fluoro-3-methyi-l-benzofuran-5-yr)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-aminc;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-[(l S)-l-(3-pyridin-3- ylphenyl)ethyl]pyrimidin-4-amine;
6- (1 -benzothiazol-6-yl)-N-{l-[3-(2-fluoi pyridin-3-y])phenyl]ethyl}-2- methylpyrimidin-4-amine:
6-( 1 ,3-benzothiazol-6-yl)-2-methyl-N-{ 1 -[3-(2-methylpyridin-4- yl)phenyl]ethyl}pyrimidin-4-amine;
-[(lS)-l-{3-[6-(dimethylamino)pyridin-3-yl]phenyl}eth>4]-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
6-(l ,3-benzothiazol-6-yl)-2-methyl-N-{ 1 -[3-(6-piperazin-l -ylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofuran-5-yl)-N-{l-[5-(l -methyl- lH-pyrazol-4- yl)pyridin-3-yl]ethyl}py midin-4-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N- {( 1 S)- 1 -[ 3-(6-methylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-melhyl- 1 -benzofuran-5-yl)-N-{( 1 S)- 1 -[3-(6-piperazin-l -ylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-melhyl-l-benzofuran-5-yl)-N-{(lS)-l-[3-(5-methylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
N-{(lS)-l-[3-(6-nuoro-5-methylpyridin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine: 6-(l,3-benzothiazol-6-yi)-N-{(lS)-]-[3-(2- luoropyridin-4-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
5- [4-(]-{[2-methyl-6-(3-melhyl-l-benzofuran-5-yl)pyriniidin-4- yl]amino}ethyl)pyridin-2-yl]pynmidin-2-amine;
N-{( 1 S)- 1 -[3-(6-chloropyridin-3-yl)phenyl]ethyl }-2-methyl-6-(3-methyl- 1 - benzofuran-5-yl)pyrimidin-4-amine;
2-methyl-N-[(lS)-l-{3-[6-(methylamino)pyridin-3-yl]phenyl}ethyl]-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzofiu-an-5-yl)-N-{(lS)-l-[3-(6-morphoIin-4-ylpyridin-3- yl)phenyl]etliyl}pyrimidin-4-amine;
2-[(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridin-2-yl)amino]ethanol
6- (l,3-benzothiazo]-6-yl)-N-{(lS)-l-[3-(6-chloropyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
6-(l-beizof iran-5-yl)-2-rnethyl-N-{l-[3-(l-methyl-lH-pyrazoI-4- yl)phenyl]ethy 1 } pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzoluraiv5-yl)-N-{(lR)-l-[2-(1-methyl-lH-pyrazol-4- yl)pyridin-4-yl]ethy]}pyrimidin-4-amine;
2-methyl-6-(3-methyl-l -benzofuran-5-yl)-N-{(l S)-l-[2-(l -methyl- 1 H-pyrazol-4- yl)pyridin-4-yl]ethyl}pyrimidin-4-amine;
N-[( 1 S)- 1 - { 3-[6-(ethy lamino)pyridin-3-y l]phenyl } ethyl]-2-methyl-6-(3 -methyl- 1 - benzofuran-5-yl)pyrimidin-4-amine;
-[(lS)-l-{3-[6-(4-ethylpiperazin-l-yi)pyridiiv3-yl]phenyl}ethyl]-2-methyl-6-(3- methyl-l-benzofuran-5-yl)pyrimidin-4-amine:
6-(l,3-benzothiazol-6-yl)-N-[(lS)-l-{3-[6-(4-ethylpiperazin-l-yl)pyridin-3- yl]phenyl}ethyl]-2-methylpyrimidin-4-amine;
5- [5-(l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yrj mino}ethyl)pyndin-3-yjpyrimidin-2-amine;
6- (l :3-benzothiazol-6-yl)-2-methyl-N-{( 1 S)- 1 -[3-(6-morpholin-4-ylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-amine;
2-methyl-6-(3-methyl- 1 -benzofuran-5-yl)-N-{ ( 1 R)- 1 -[5-( 1 -methyl- 1 H-pyrazol-4- yl)pyridin-3-yl]ethyl}pyrimidin-4-amine;
l-(5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-beiizofuran-5-yl)pyvimidin-4- yl]amino}ethylJphenyl}pyridin-2-yl)piperidin-4-ol 6-(K3-benzothiazol-6-yl)-N-{(lS)-l-[3-(6-chloiO-5-methylpyridin-3- yl)phenyl]ethyl}-2-methylpyrimidin-4-amine;
N-{(lS)-l-[3-(6-chloro-5-n thylpyridin-3-yl)phenyl]ethyl}-2-methyl-6-(3-methyl-l- benzofiiran-5-yl)pynmidin-4-amtne;
N-[l-(5-bromopyridin-3-yl)ethyl]-2-melhyl-6-(3-methyl-l-benzofuran-5- yl)pyrimidin-4-amine;
5'-(l-{[2-melhyl-6-(3Miiethyl-l-benzoiurai 5-yl)pyrimidin-4-yrjamino}ethyl)-3,3'- bipyridin-5-amine;
6-(4-chloiO-3-nuorophenyl)-2-methyl-N-{l-[3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3-iluorophenyl)-2-methyl-N-{( 1 S)- 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
5-{3-[(lS)-l-{[6-(4-chlorophenyl)-2-methylpyrimidin-4- yl]amino}ethy!]phenyl}pyrimidin-2-amine;
5-{3-[(lS)-l-{[6-(4-chloro-3-fluoiOphenyl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-amine;
N-{(lS)-l-[3-(5-aminopyridin-3-yl)phenyl]ethyl}-6-(4-chloro-3-tluorophenyl)-2- methylpyrimidin-4-amine;
5- [5-(l-{[6-(4-chloro-3-fluorophenyl)-2-mclhylpyrimidin-4-yl]amino}ethyl)pyridin- 3-yl]pyrimidin-2-amine;
6- (4-chloro-3-nuorophenyl)-2-methyl-N-{l-[5-(l-methyl-lH-pyrazol-4-yl)pyridin-3- yl]ethyl}pyrimidin-4-amine;
6-(4-chloro-3-fluorophenyl)-N-{ 1 -[ 5-( 1 -ethyl- 1 H-pyrazol-4-yl)pyridin-3-yl]ethyl } -2- methylpyrimidin-4-amine;
6-(4-chloro-3-lluorophenyl)-2-methyl-N-{( 1 S)- 1 -[3-(6-piperazin- 1 -ylpyridin-3- yl)phenyl]ethyl}pyrimidin-4-arnine;
6-(4-chloiO-3-duorophenyl)-2-methyl-N- {(1 S)- 1 -[3-( 1 -methyl- 1 H-pyiazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(3-nuorophenyl)-2-methyl- - {( 1 R)- 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
3-f(5-{3-[(lS)-l-{[6-(4-chloi -3-lliiorophenyl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)amino]propane-1.2-diol
l-(5-{3-[(lS)-l-{[6-(4-chloro-3-lluorophenyl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pynmidin-2-yl)pipendin-4-ol -{(lS)-l-[3-(4-chlorojDyridin-3-yl)phenyl]ethyl}-2-niethyl-6-(3-methyl-l- benzofuran-5-yl)pyrimidin-4-amine;
6-(4-chloro-3-fluorophenyl)-N-{(lS)-l-[3-(l-ethy!-lH-pyrazol-4-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
5- {3-[(lS)-l-{[2-methyl-6-(3 nelliyl-l-benzofiiran-5-yl)pynrnidin-4- yl]amino}ethyl]phenyl}pyridine-3-carboxamide;
3- [2-methyl-6-( {l-[3-(l -methyl- 1 H-pyrazol-4-yl)pheiiyr]ethyl}amino)pyrimidin-4- yl]phenol
6- (2.3-dihydro-l-benzoiuran-5-yl)-2-methyl- -{ 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-[2-fluoro-3-(methyloxy)phenyl]-2-methyl-N-{ 1 -[3-( 1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-2-methyl-N-(l-{3-[5-(methyloxy)pyridin-3- yl]phenyl}ethyl)pyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-{ l-[3-(2-fluoropyi'imidin-5-yl)phenyI]ethyl}-2- methylpyrimidin-4-amine;
5- [3-(l-{[6-(1.3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]pyrimidine-2-carbonitrile;
6- (l,3-benzothiazol-6-yl)-N-{l-[3-(6-nuoro-2-methylpyndin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
5- [3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpynmidin-4- yl]amino}ethyl)phenyl]pyridine-3-carbonitiile;
6- (l,3-benzothiazol-6-yl)-N-{l-[3-(4-chloropyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
6-(l,3-benzothiazol-6-yl)-N-{l-[3-(2.6-dimethylpyridin-3-yl)phenyl]ethyl}-2- methylpyrimidin-4-amine;
4- [3-(l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl)phenyl]pyrimidin-2-amine:
6-(l ,3-benzothiazol-6-yl)-2-methyl- -{(l S)- 1 -[3-(2-piperidin-l -ylpyrimidin-5- yl)phenyl]ethyl}pyrimidin-4-amine;
N'-(5-{3-[(lS)-l-{[6-(l,3-benzothiazol-6-yl)-2-methylpyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-yl)-N,N-dimethylpropane-l,3-diamine;
N-[(lS)-l-{3-[2-(4-acetylpiperazin-l-yl)pynniidin-5-yl]phenyl}ethyl]-2-methyl-6-(3- methyl-l-benzofuran-5-yl)pyrimidin-4-amine; 5- { 3-[( 1 S)- 1 - {[2-methyl-6-(3-metliyl- 1 -benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}-N-(telrahydrofuran-2-ylmethyl)pyrimidin-2-aminc;
6- (3-amino-4-chlorophenyl)-2-methyl-N-{ 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pynmidin-4-amine;
6-(4-chloio-3-methyIphenyl)-2-methyl-N-{l -[3 -(1 -methyl- 1 H-pyrazol-4- yl)phenyl]ethyl}pyrimidin-4-amine;
2-i]uoro-4-[2-methyl-6-({l-[3-(l-methyl-lH-pyrazol-4- yl)phenyl]ethyl}amino)pyrimidin-4-yl]beiizamide;
6-(l ,3-benzothiazol-5-yl)-2-methyl-N-{ 1 -[3-(l -methyl- 1 H-pyrazol-4- yl)phenyl jethyl } pyrimidin-4-amine;
N-[(lS)-l-{3-[2-(4-acetylpiperazin-l-yl)pyrimidin-5-yl]phenyl}ethyl]-2-methyl-6-(3- methyl-l-benzothien-5-yl)pyrimidin-4-amine;
N-{(lS)-l-[3-(2-{4-[2-(dimethylamino)ethyl]piperazin-l-yl}pyrimidin-5- yl)phenyl jethyl }-2-methyl-6-(3-methyl-l-benzothien-5-yl)pyrimidin-4-amine;
5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzofuran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyridine-3-carbonitrile;
2-methyl-6-(3 -methyl- l-benzofuran-5-yl)-N-[(lS)-l-(6'-methyl-3, 3 '-bipyridin-5- yl)ethyl]pyrimidin-4-amine;
2-methyl-6-(3-methyl-l-benzoi*uran-5-yl)-N-{(]S)-l-[5-(l-melhyl-lH-pyrazol-4- yl)pyridin-3-yl]ethyl}pyrimidin-4-amine;
5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzothien-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pynmidin-2-amine;
N-{(lS)-l-[3-(5-aminopyridin-3-yl)phenyl]ethyl}-6-(l:3-benzothiazol-6-yl)-2- methylpyrimidin-4-amine;
5-{3-[(lS)-l-{[2-methyl-6-(3-methyl-l-benzoluran-5-yl)pyrimidin-4- yl]amino}ethyl]phenyl}pyrimidin-2-ol;
(S)-5-(3-(l-(6-(7-fliioiO-3-methylbeiizofuran-5-yl)-2-methylpyrimidin-4- \ amino)ethyl)phenyl)pyrimidin-2-amine;
(S)-2-methyl-N-(l -(5-(l -methyl- 1 H-pyrazol-4-yl)pyridin-3-yl)ethyl)-6-(3- methylbenzofuran-5-yl)pyrimidin-4-amine;
(S)-N-(l-(3-(5-aminopyridin-3-yl)phenyl)ethyl)-6-(4-chloiO-3-fluoiOphenyl)-2- methy I py ri m i d in-4-am i ne ;
(S)-5-(3-(l-(2-methyl-6-(3-methylbenzofuran-5-yl)pyrimidin-4- ylamino)ethyl)phenyl)pynmidin-2-amine; N-( l -(5-( 1 -ethyl- 1 H-pyrazol-4-yl)pyridin-3-yl)elhyl)-6-(7-fluoiO-3- methylbenzofuran-5-yl)-2-methylpyrimidin-4-amine:
5-(3-fluoro-5-(l -(2-niethyl-6-(3-methylbenz iuran-5-yl)pyrimidin-4- ylamino)ethyl)phenyl)pyrimidin-2-amine;
(S)-5-(3-(l -(2-metliyl-6-(3-methylbenzo[b]thiophen-5-yl)pyrimidin-4- ylamino)ethyl)phenyl)pyrimidin-2-amine; or
(S)-N-( l -(3-(5-aminopyridin-3-yl)phenyl)ethyI)-2-methyl-6-(3- methylbenzo[b]thiophen-5-yl)pyrimidin-4-amine.
43. A pharmaceutical composition comprising a compound of claims 1 -42 and a pharmaceutically acceptable carrier, excipient. or diluent.
44. A method of treating a disease or disorder mediated by 1PFK-2, comprising administering to a subject in need of such treatment a compound of claims 1 -42 or a composition of claim 37.
45. The method of claim 44, wherein the disease is cancer.
46. The method of claims 45, wherein the cancer is adipose cancers, anogenital cancer, bladder cancer, blood cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, connective tissue cancer, glioblastoma, glioma, kidney cancer, leukemia, lung cancer, lymphoid cancer, ovarian cancer, pancreatic cancer, prostate cancer, prostate cancer, retinal cancer, skin cancer, stomach cancer, or uterine cancer.
PCT/US2012/035794 2011-04-29 2012-04-30 Inhibitors of inducible form of 6-phosphofructose-2-kinase WO2012149528A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP12725560.2A EP2702043A1 (en) 2011-04-29 2012-04-30 Inhibitors of inducible form of 6-phosphofructose-2-kinase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161481035P 2011-04-29 2011-04-29
US61/481,035 2011-04-29

Publications (1)

Publication Number Publication Date
WO2012149528A1 true WO2012149528A1 (en) 2012-11-01

Family

ID=46208154

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/035794 WO2012149528A1 (en) 2011-04-29 2012-04-30 Inhibitors of inducible form of 6-phosphofructose-2-kinase

Country Status (2)

Country Link
EP (1) EP2702043A1 (en)
WO (1) WO2012149528A1 (en)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140274702A1 (en) * 2013-03-15 2014-09-18 Dow Agrosciences, Llc 4-amino-6-(heterocyclic)picolinates and 6-amino-2-(heterocyclic)pyrimidine-4-carboxylates and their use as herbicides
US20150018422A1 (en) * 2012-02-13 2015-01-15 Takeda Pharmaceutical Company Limited Aromatic ring compound
US9149038B2 (en) 2013-03-15 2015-10-06 Dow Agrosciences Llc 4-amino-6-(heterocyclic)picolinates and 6-amino-2-(heterocyclic)pyrimidine-4-carboxylates and their use as herbicides
US9278985B2 (en) 2013-03-15 2016-03-08 Dow Agrosciences Llc 4-amino-6-(heterocyclic)picolinates and 6-amino-2-(heterocyclic)pyrimidine-4-carboxylates and their use as herbicides
CN106188038A (en) * 2015-06-01 2016-12-07 中国科学院上海药物研究所 One class has the compound of kinase inhibiting activity, preparation method and purposes
US9521847B2 (en) 2014-09-15 2016-12-20 Dow Agrosciences Llc Synergistic weed control from applications of pyridine carboxylic acid herbicides and synthetic auxin herbicides and/or auxin transport inhibitors
US9526244B2 (en) 2014-09-15 2016-12-27 Dow Agrosciences Llc Safened herbicidal compositions comprising pyridine carboxylic acids
US9763445B2 (en) 2014-09-15 2017-09-19 Dow Agrosciences Llc Safened herbicidal compositions comprising a pyridine carboxylic acid herbicide
WO2018210992A1 (en) 2017-05-18 2018-11-22 Idorsia Pharmaceuticals Ltd Pyrimidine derivatives
WO2018210994A1 (en) 2017-05-18 2018-11-22 Idorsia Pharmaceuticals Ltd Phenyl derivatives as pge2 receptor modulators
US10448638B2 (en) 2014-09-15 2019-10-22 Dow Agrosciences Llc Synergistic weed control from applications of pyridine carboxylic acid herbicides and ALS inhibitors
US10450300B2 (en) * 2015-10-08 2019-10-22 Suzhou Yunxuan Yiyao Keji Youxian Gongsi Wnt signaling pathway inhibitors and therapeutic applications thereof
US10455836B2 (en) 2014-09-15 2019-10-29 Dow Agrosciences Llc Synergistic weed control from applications of pyridine carboxylic acid herbicides and photosystem II inhibitors
JP2020525420A (en) * 2017-06-13 2020-08-27 ベイジン アダマドル バイオテクノロジー リミテッド ライアビリティ カンパニー Aminopyrimidine compounds, their preparation and their use
US11241431B2 (en) 2015-11-20 2022-02-08 Idorsia Pharmaceuticals Ltd N-substituted indole derivatives as PGE2 receptor modulators
US11325899B2 (en) 2017-05-18 2022-05-10 Idorsia Pharmaceuticals Ltd Benzofurane and benzothiophene derivatives as PGE2 receptor modulators
US11839613B2 (en) 2017-05-18 2023-12-12 Idorsia Pharmaceuticals Ltd Pyrimidine derivatives as PGE2 receptor modulators

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041164A2 (en) * 2002-10-30 2004-05-21 Merck & Co., Inc. Kinase inhibitors
WO2004085388A2 (en) * 2003-03-24 2004-10-07 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US20040204386A1 (en) * 2002-10-17 2004-10-14 Cell Therapeutics, Inc. Pyrimidines and uses thereof
WO2008113255A1 (en) * 2007-03-16 2008-09-25 The Institute Of Radiation Medicine, Academy Of Military Medical Sciences, Pla Benzamide derivatives with anti-proliferative activity, pharmaceutical preparations thereof
WO2008128984A1 (en) * 2007-04-20 2008-10-30 Probiodrug Ag Aminopyrimidine derivatives as glutaminyl cyclase inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040204386A1 (en) * 2002-10-17 2004-10-14 Cell Therapeutics, Inc. Pyrimidines and uses thereof
WO2004041164A2 (en) * 2002-10-30 2004-05-21 Merck & Co., Inc. Kinase inhibitors
WO2004085388A2 (en) * 2003-03-24 2004-10-07 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
WO2008113255A1 (en) * 2007-03-16 2008-09-25 The Institute Of Radiation Medicine, Academy Of Military Medical Sciences, Pla Benzamide derivatives with anti-proliferative activity, pharmaceutical preparations thereof
WO2008128984A1 (en) * 2007-04-20 2008-10-30 Probiodrug Ag Aminopyrimidine derivatives as glutaminyl cyclase inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 25 September 2008 (2008-09-25), XP002680762, retrieved from STN Database accession no. 2008:1155828 *
LOMBARDO, L. J. ET AL.: "Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 47, no. 27, 7 December 2004 (2004-12-07), pages 6658 - 6661, XP002402759, ISSN: 0022-2623, DOI: 10.1021/JM049486A *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150018422A1 (en) * 2012-02-13 2015-01-15 Takeda Pharmaceutical Company Limited Aromatic ring compound
US9382188B2 (en) * 2012-02-13 2016-07-05 Takeda Pharmaceutical Company Limited Aromatic ring compound
US9611282B2 (en) 2013-03-15 2017-04-04 Dow Agrosciences Llc 4-amino-6-(heterocyclic)picolinates and 6-amino-2-(heterocyclic)pyrimidine-4-carboxylates and their use as herbicides
US9006250B2 (en) * 2013-03-15 2015-04-14 Dow Agrosciences Llc 4-amino-6-(heterocyclic)picolinates and 6-amino-2-(heterocyclic)pyrimidine-4-carboxylates and their use as herbicides
US9149038B2 (en) 2013-03-15 2015-10-06 Dow Agrosciences Llc 4-amino-6-(heterocyclic)picolinates and 6-amino-2-(heterocyclic)pyrimidine-4-carboxylates and their use as herbicides
US9278985B2 (en) 2013-03-15 2016-03-08 Dow Agrosciences Llc 4-amino-6-(heterocyclic)picolinates and 6-amino-2-(heterocyclic)pyrimidine-4-carboxylates and their use as herbicides
US20140274702A1 (en) * 2013-03-15 2014-09-18 Dow Agrosciences, Llc 4-amino-6-(heterocyclic)picolinates and 6-amino-2-(heterocyclic)pyrimidine-4-carboxylates and their use as herbicides
US9637505B2 (en) 2013-03-15 2017-05-02 Dow Agrosciences Llc 4-amino-6-(heterocyclic)picolinates and 6-amino-2-(heterocyclic)pyrimidine-4-carboxylates and their use as herbicides
US10455836B2 (en) 2014-09-15 2019-10-29 Dow Agrosciences Llc Synergistic weed control from applications of pyridine carboxylic acid herbicides and photosystem II inhibitors
US9521847B2 (en) 2014-09-15 2016-12-20 Dow Agrosciences Llc Synergistic weed control from applications of pyridine carboxylic acid herbicides and synthetic auxin herbicides and/or auxin transport inhibitors
US9763445B2 (en) 2014-09-15 2017-09-19 Dow Agrosciences Llc Safened herbicidal compositions comprising a pyridine carboxylic acid herbicide
US9526244B2 (en) 2014-09-15 2016-12-27 Dow Agrosciences Llc Safened herbicidal compositions comprising pyridine carboxylic acids
US10231451B2 (en) 2014-09-15 2019-03-19 Dow Agrosciences Llc Synergistic weed control from applications of pyridine carboxylic acid herbicides and synthetic auxin herbicides and/or auxin transport inhibitors
US10448638B2 (en) 2014-09-15 2019-10-22 Dow Agrosciences Llc Synergistic weed control from applications of pyridine carboxylic acid herbicides and ALS inhibitors
CN106188038A (en) * 2015-06-01 2016-12-07 中国科学院上海药物研究所 One class has the compound of kinase inhibiting activity, preparation method and purposes
WO2016192630A1 (en) * 2015-06-01 2016-12-08 中国科学院上海药物研究所 Compound having kinase inhibiting activity, method of preparing same, and use of same
US10450300B2 (en) * 2015-10-08 2019-10-22 Suzhou Yunxuan Yiyao Keji Youxian Gongsi Wnt signaling pathway inhibitors and therapeutic applications thereof
US11241431B2 (en) 2015-11-20 2022-02-08 Idorsia Pharmaceuticals Ltd N-substituted indole derivatives as PGE2 receptor modulators
WO2018210992A1 (en) 2017-05-18 2018-11-22 Idorsia Pharmaceuticals Ltd Pyrimidine derivatives
WO2018210994A1 (en) 2017-05-18 2018-11-22 Idorsia Pharmaceuticals Ltd Phenyl derivatives as pge2 receptor modulators
US11325899B2 (en) 2017-05-18 2022-05-10 Idorsia Pharmaceuticals Ltd Benzofurane and benzothiophene derivatives as PGE2 receptor modulators
US11446298B2 (en) 2017-05-18 2022-09-20 Idorsia Pharmaceuticals Ltd Pyrimidine derivatives
US11712438B2 (en) 2017-05-18 2023-08-01 Idorsia Pharmaceuticals Ltd Phenyl derivatives as PGE2 receptor modulators
US11839613B2 (en) 2017-05-18 2023-12-12 Idorsia Pharmaceuticals Ltd Pyrimidine derivatives as PGE2 receptor modulators
JP2020525420A (en) * 2017-06-13 2020-08-27 ベイジン アダマドル バイオテクノロジー リミテッド ライアビリティ カンパニー Aminopyrimidine compounds, their preparation and their use
JP7028900B2 (en) 2017-06-13 2022-03-02 ベイジン アダマドル バイオテクノロジー リミテッド ライアビリティ カンパニー Aminopyrimidine compounds, their preparation methods, and their use

Also Published As

Publication number Publication date
EP2702043A1 (en) 2014-03-05

Similar Documents

Publication Publication Date Title
WO2012149528A1 (en) Inhibitors of inducible form of 6-phosphofructose-2-kinase
US10174029B2 (en) Pyrimidine-2,4-diamine derivatives for treatment of cancer
JP6635949B2 (en) MTH1 inhibitors for the treatment of inflammatory and autoimmune diseases
US9980952B2 (en) Modulators of methyl modifying enzymes, compositions and uses thereof
EP2858983B1 (en) Tnf-alpha modulating benzimidazoles
TW523511B (en) Pharmaceutical composition comprising substituted imidazole compounds and process for preparing compounds
EP1442024B1 (en) AMINOBENZAMIDE DERIVATIVES AS GLYCOGEN SYNTHASE KINASE 3$g(b) INHIBITORS
EP1831198B1 (en) Pyridine carboxamide derivatives for use as anticancer agents
AU2007204208A1 (en) Morpholino pyrimidine derivatives and their use in therapy
JP2005511608A (en) Aminopyrimidines and -pyridines
JP2005530748A (en) Histone deacetylase inhibitor
EP1615898A1 (en) 2-aminopyrimidine derivatives and their medical use
TW201016676A (en) Heterocyclic derivatives and methods of use thereof
TW201139415A (en) Heterocyclic aspartyl protease inhibitors
CA2463822A1 (en) Heteroaryl amines as glycogen synthase kinase 3beta inhibitors (gsk3 inhibitors)
AU2002363177A1 (en) Aminobenzamide derivatives as glycogen synthase kinase 3Beta inhibitors
MX2011000738A (en) 3,4-diarylpyrazoles as protein kinase inhibitors.
CZ20023199A3 (en) Adenosine receptor modulators
TW200306838A (en) Chemical compounds
US10358435B2 (en) Triazolyl pyrimidinone compounds as PDE2 inhibitors
CA2782885A1 (en) Tyrosine kinase inhibitors
EA030404B1 (en) Flap modulators
WO2014106800A2 (en) Substituted 2-amino pyrimidine derivatives as kinase inhibitors
WO2005023782A1 (en) Substituted fused pyrimidine-4(3h)-one compound
WO2003057689A1 (en) Aminopyrimidine compounds, processes for their preparation and pharmaceutical compositions containing them

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12725560

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2012725560

Country of ref document: EP